CA2253948C - Carboline derivatives - Google Patents
Carboline derivatives Download PDFInfo
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- CA2253948C CA2253948C CA002253948A CA2253948A CA2253948C CA 2253948 C CA2253948 C CA 2253948C CA 002253948 A CA002253948 A CA 002253948A CA 2253948 A CA2253948 A CA 2253948A CA 2253948 C CA2253948 C CA 2253948C
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- carbolin
- beta
- tetrahydro
- propene
- methylenedioxyphenyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Abstract
Carboline derivatives of formula (I), are potent and selective inhibitors of cyclic guanosine 3',5'-monophosphate specific phosphodiesterase (cGMP specific PDE) and have utility in a variety of therapeutic areas where such inhibition is thought to be beneficial, including the treatment of cardiovascular disorders.
Description
CARBOLINE DERIUATIUES.
This invention relates to a series of carboline derivatives, to processes for their preparation, pharmaceutical compositions containing them, and their use as therapeutic agents. In particular, the invention relates to carboline derivatives which are potent and selective inhibitors of cyclic guanosine 3',5'-monophosphate specific phosphodiesterase (cGMP specific PDE) having utility in a variety of therapeutic areas where such inhibition is thought to be beneficial, including the treatment of cardiovascular disorders.
Thus, according to a first aspect, the present invention provides compounds of formula (I) Ro R' w ~ (I) O (R2)~
Ra (R3)m wherein R° represents -hydrogen or -halogen;
R' is selected from the group consisting of:
-hydrogen, -NO2, -trifluoromethyl, -trifluoromethoxy, -halogen, -cyano, a 5- or 6- membered heterocyclic group containing at least one heteroatom - 25 selected from oxygen, nitrogen and sulphur (optionally substituted by - C(=0)ORa or C,~alkyl), -- ~ -C,_salkyl optionally substituted by -ORa, -C,_3alkoxy.
-C(=~)Ra~
-O-C(=0)Ra, -C(=0)ORa, -C,.~alkylene C(=0)ORa, -O-C,.~alkylene -C(=0)ORa, -C,~,alkylene-0-C,.~alkylene-C(=0)ORe, -C(=0)NRaSOzR', -C(=0)C,.~alkylene Het, wherein Het represents 5- or 6-membered heterocyclic group as defined above, -C,~,alkylene NRaRb, -Cz.salkenyleneNRaRb, -C(=0)NRaR°, -C(=0)NRaR', -C(=0)NRaC,.~alkylene ORb -C(=0)NRaC,.aalkylene Het, wherein Het represents a 5- or 6-membered heterocyclic group as defined above, -ORa -OCz.~alkylene NRaRb, -OC,~alkylene-CH(ORa)CHz NReRb, -O-C,.~alkylene Het, wherein Het represents a 5- or 6- membered heterocyclic group as defined above, -O-Cz.~alkylene-ORa, -O-Cz~alkylene-NRa-C(=0)-ORb, -NRaRb, -NRaC,.~alkyleneNRaRb, -NReC(=0)Rb, -NRaC(=0)NReR°, -N(SOzC,.~alkyl)z, -NRa(SOzC,.~alkyl), -S02NReRb, and -OSOztrifluoromethyl;
Rz is selected from the group consisting of:
-hydrogen, -halogen, -ORa, -C,_s alkyl, -NOz, and -NR'Rb, or R' and R2, together form a 3- or 4- membered alkylene or alkenyiene chain, optionally containing at least one heteratom ;
R3 is selected from the group consisting of:
-hydrogen, -halogen, -N 02, -trifluoromethoxy, -C,.salkyl, and -C(=0)ORa;
R4 is hydrogen, or R3 and R4 together form a 3- or 4- membered alkylene or alkenylene chain, optionally containing at least one heteratom;
Ra and Rb, which may be the same or different, are independently selected from hydrogen and C,.salkyl;
R' represents phenyl or C4~cycloalkyl, which phenyl or C4~cycloalkyl can be optianaliy substituted by one or more halogen atoms, one or more -C(=0)ORa or one or more -ORa;
n is an integer selected from 1, 2 and 3;
m is an integer selected from 1 and 2;
and pharmaceutically acceptable salts and solvates {e.g. hydrates) thereof.
The terms alkyl or alkylene as used herein respectively contain the appropriate indicated number of carbon atoms and appropriately include straight chained and branched alkyl or alkyiene groups, typically methyl, methyiene, ethyl and ethylene groups, and straight chained and branched propyl, propylene, butyl and butylene groups. The term CZ_salkenylene as used herein contains 2 to 6 carbon atoms and appropriately includes straight chained and branched alkenylene groups, in particular ethenylene or the like.
The terms Ca.s cycloalkyl denotes cyclic groups containing 4 to 6 carbon atoms, namely cyclobutane, cyclopentane and cyclohexane.
The term halogen as used herein includes fluorine, chlorine, bromine and iodine.
The term 5- or 6-membered heterocyclic group as used herein includes 5- or 6- membered heterocycloalkyl and heteroaryl groups, e.g. tetrahydrofuranyl, piperidyl, piperazinyl pyrrolidinyl, morpholinyl, pyridyl, imidazolyl, furyl, and tetrazolyl.
Appropriately, R° represents hydrogen. Alternatively R° may represent halogen, in particular fluorine.
R' may represent any of the substituents as hereinbefore described, or more particularly may represent any of -ORa, -0-C2.~alkyleneNRaRb, -O-C,_ 4alkyleneHet and -O-C2~alkylene-ORa. In particular, R' represents -O-C2_ 4alkylene NRaRb, wherein suitably C2.~alkylene may represent ethylene and aptly, Ra and Rb may independently represent methyl.
Particularly suitably RZ represents hydrogen. Alternatively, in the case where R' and R2 together form a 3- or 4- membered alkylene or alkenylene chain optionally containing at least one heteratom as hereinbefore described, suitably R' and Rz together form a methylenedioxy chain, an ethyieneoxy chain, an ethylenedioxy chain, an ethenyleneoxy chain, a propylene chain, a butylene chain or -NRaethylene-O-. Aptly, R' and RZ together form methylenedioxy, propylene or -N(CH3)-(CH2)2-O-.
Suitably R3 and R', together form a 3- or 4- membered alkylene or alkenylene chain, optionally containing at least one heteratom as hereinbefore described.
Particularly suitably R3 and R4 together form a methylenedioxy chain, an ethyleneoxy chain, an ethylenedioxy chain, an ethenyleneoxy chain, a propylene chain, a butylene chain or -NRaethylene-O-. Aptly R3 and R°
together form a methylenedioxy chain, an ethyleneoxy chain, an ethylenedioxy chain, an ethenyleneoxy chain or a propylene chain. !n particular, R3 and R°
together form methylenedioxy or ethyleneoxy, most particularly ethyleneoxy.
A particular subgroup of compounds according to the present invention can be represented by formula (la) O
v N RS (la) t R6 H
wherein RS is selected from the group consisting of -OH, -OCZ~alkylene NRaRb and O-C,_ 4alkylene Het, wherein Het is as hereinbefore described and I c R6 represents wherein C represents a 5- or 6-membered nng which may be saturated or partially or fully unsaturated and comprises carbon atoms and optionally one or two heteroatoms selected from oxygen, sulphur and nitrogen, optionally substituted by C,.~alkyl;
This invention relates to a series of carboline derivatives, to processes for their preparation, pharmaceutical compositions containing them, and their use as therapeutic agents. In particular, the invention relates to carboline derivatives which are potent and selective inhibitors of cyclic guanosine 3',5'-monophosphate specific phosphodiesterase (cGMP specific PDE) having utility in a variety of therapeutic areas where such inhibition is thought to be beneficial, including the treatment of cardiovascular disorders.
Thus, according to a first aspect, the present invention provides compounds of formula (I) Ro R' w ~ (I) O (R2)~
Ra (R3)m wherein R° represents -hydrogen or -halogen;
R' is selected from the group consisting of:
-hydrogen, -NO2, -trifluoromethyl, -trifluoromethoxy, -halogen, -cyano, a 5- or 6- membered heterocyclic group containing at least one heteroatom - 25 selected from oxygen, nitrogen and sulphur (optionally substituted by - C(=0)ORa or C,~alkyl), -- ~ -C,_salkyl optionally substituted by -ORa, -C,_3alkoxy.
-C(=~)Ra~
-O-C(=0)Ra, -C(=0)ORa, -C,.~alkylene C(=0)ORa, -O-C,.~alkylene -C(=0)ORa, -C,~,alkylene-0-C,.~alkylene-C(=0)ORe, -C(=0)NRaSOzR', -C(=0)C,.~alkylene Het, wherein Het represents 5- or 6-membered heterocyclic group as defined above, -C,~,alkylene NRaRb, -Cz.salkenyleneNRaRb, -C(=0)NRaR°, -C(=0)NRaR', -C(=0)NRaC,.~alkylene ORb -C(=0)NRaC,.aalkylene Het, wherein Het represents a 5- or 6-membered heterocyclic group as defined above, -ORa -OCz.~alkylene NRaRb, -OC,~alkylene-CH(ORa)CHz NReRb, -O-C,.~alkylene Het, wherein Het represents a 5- or 6- membered heterocyclic group as defined above, -O-Cz.~alkylene-ORa, -O-Cz~alkylene-NRa-C(=0)-ORb, -NRaRb, -NRaC,.~alkyleneNRaRb, -NReC(=0)Rb, -NRaC(=0)NReR°, -N(SOzC,.~alkyl)z, -NRa(SOzC,.~alkyl), -S02NReRb, and -OSOztrifluoromethyl;
Rz is selected from the group consisting of:
-hydrogen, -halogen, -ORa, -C,_s alkyl, -NOz, and -NR'Rb, or R' and R2, together form a 3- or 4- membered alkylene or alkenyiene chain, optionally containing at least one heteratom ;
R3 is selected from the group consisting of:
-hydrogen, -halogen, -N 02, -trifluoromethoxy, -C,.salkyl, and -C(=0)ORa;
R4 is hydrogen, or R3 and R4 together form a 3- or 4- membered alkylene or alkenylene chain, optionally containing at least one heteratom;
Ra and Rb, which may be the same or different, are independently selected from hydrogen and C,.salkyl;
R' represents phenyl or C4~cycloalkyl, which phenyl or C4~cycloalkyl can be optianaliy substituted by one or more halogen atoms, one or more -C(=0)ORa or one or more -ORa;
n is an integer selected from 1, 2 and 3;
m is an integer selected from 1 and 2;
and pharmaceutically acceptable salts and solvates {e.g. hydrates) thereof.
The terms alkyl or alkylene as used herein respectively contain the appropriate indicated number of carbon atoms and appropriately include straight chained and branched alkyl or alkyiene groups, typically methyl, methyiene, ethyl and ethylene groups, and straight chained and branched propyl, propylene, butyl and butylene groups. The term CZ_salkenylene as used herein contains 2 to 6 carbon atoms and appropriately includes straight chained and branched alkenylene groups, in particular ethenylene or the like.
The terms Ca.s cycloalkyl denotes cyclic groups containing 4 to 6 carbon atoms, namely cyclobutane, cyclopentane and cyclohexane.
The term halogen as used herein includes fluorine, chlorine, bromine and iodine.
The term 5- or 6-membered heterocyclic group as used herein includes 5- or 6- membered heterocycloalkyl and heteroaryl groups, e.g. tetrahydrofuranyl, piperidyl, piperazinyl pyrrolidinyl, morpholinyl, pyridyl, imidazolyl, furyl, and tetrazolyl.
Appropriately, R° represents hydrogen. Alternatively R° may represent halogen, in particular fluorine.
R' may represent any of the substituents as hereinbefore described, or more particularly may represent any of -ORa, -0-C2.~alkyleneNRaRb, -O-C,_ 4alkyleneHet and -O-C2~alkylene-ORa. In particular, R' represents -O-C2_ 4alkylene NRaRb, wherein suitably C2.~alkylene may represent ethylene and aptly, Ra and Rb may independently represent methyl.
Particularly suitably RZ represents hydrogen. Alternatively, in the case where R' and R2 together form a 3- or 4- membered alkylene or alkenylene chain optionally containing at least one heteratom as hereinbefore described, suitably R' and Rz together form a methylenedioxy chain, an ethyieneoxy chain, an ethylenedioxy chain, an ethenyleneoxy chain, a propylene chain, a butylene chain or -NRaethylene-O-. Aptly, R' and RZ together form methylenedioxy, propylene or -N(CH3)-(CH2)2-O-.
Suitably R3 and R', together form a 3- or 4- membered alkylene or alkenylene chain, optionally containing at least one heteratom as hereinbefore described.
Particularly suitably R3 and R4 together form a methylenedioxy chain, an ethyleneoxy chain, an ethylenedioxy chain, an ethenyleneoxy chain, a propylene chain, a butylene chain or -NRaethylene-O-. Aptly R3 and R°
together form a methylenedioxy chain, an ethyleneoxy chain, an ethylenedioxy chain, an ethenyleneoxy chain or a propylene chain. !n particular, R3 and R°
together form methylenedioxy or ethyleneoxy, most particularly ethyleneoxy.
A particular subgroup of compounds according to the present invention can be represented by formula (la) O
v N RS (la) t R6 H
wherein RS is selected from the group consisting of -OH, -OCZ~alkylene NRaRb and O-C,_ 4alkylene Het, wherein Het is as hereinbefore described and I c R6 represents wherein C represents a 5- or 6-membered nng which may be saturated or partially or fully unsaturated and comprises carbon atoms and optionally one or two heteroatoms selected from oxygen, sulphur and nitrogen, optionally substituted by C,.~alkyl;
5 and pharmaceutically acceptable salts and solvates (e.g. hydrates thereof).
Typically, RS represents -OCZ.~alkylene NRaRb, in particular OCHZCH2N(CH3)2. Alternatively, R5 may represent -O-C,~alkylene Het, where Het may suitable be piperidyl, pyrrolidinyl (optionally substituted by C,~alkyl, e.g. methyl) or morpholinyi.
Particularly aptly R6 represents I > or i i I > , especially I
o ~ o The compounds of formula (I) may contain one or more asymmetric centres and thus can exist as enantiomers or diastereoisomers. It is to be understood that the invention includes both mixtures and separate individual isomers of the compounds of formula (I).
The pharmaceutically acceptable salts of the compounds of formula (I) which contain a basic centre are acid addition salts formed with pharmaceutically acceptable acids. Examples include the hydrochloride, hydrobromide, sulphate or bisulphate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, gluconate, methanesulphonate, benzenesulphonate and p-toiuenesulphonate salts. Compounds of the formula (I) can also provide pharmaceutically acceptable metal salts, in particular alkali metal salts, with bases. Examples include the sodium and potassium salts.
Particular individual compounds of the invention include:
(E)-1-( 1-Phenyl-1, 3,4, 9-tetrahydro-(i-carbol in-2-yl)-3-phenylpropene-1-one (E)-1-(1-Phenyl-1,3,4,9-tetrahydro-~-carbolin-2-yl)-3-(4-nitrophenyl)propene-1-one (E)-1-( 1-Phenyl-1, 3,4, 9-tetrahydro-(i-carbolin-2-yl)-3-(4-trifluoromethylphenyl )-propene-1-one (E)-1-( 1-Phenyl-1,3,4,9-tetrahydro-[3-carbolin-2-yl)-3-(4-methoxy-phenyl)propene-1-one (E)-1-[1-(4-Methoxyphenyi)-1,3,4,9-tetrahydro-~-carbolin-2-yl)-3-(4-trifluoromethylphenyl)propene-1-one (E)-N-[4-[3-Oxo-3-( 1-phenyl-1,3,4,9-tetrahydro-~i-carbolin-2-yl)propenyl)phenyl)-acetamide (E)-1-(1-(4-Methoxyphenyl)-1, 3,4,9-tetrahydro-~i-carbolin-2-yl}-3-phenylpropene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl )-1, 3,4, 9-tetrahydro-(i-carbolin-2-yl)-3-phenyl-propene-1-one (E)-1-(1-Phenyl-1,3.4, 9-tetrahydro-(3-carbolin-2-yl )-3-(4-formylphenyl)propene-1-one (E)-N-[4-(3-Oxo-3-(1-(4-nitrophenyl)-1,3,4,9-tetrahydro-p-carbolin-2-yi)propenyl)-phenyl)acetamide (E)-1-(1-(4-Nitrophenyl)-1, 3,4, 9-tetrahydro-(i-carbolin-2-yl)-3-phenyipropene-1-one (E)-1-[1-(4-Trifluoromethoxyphenyl)-1, 3,4, 9-tetrahydro-p-carbolin-2-yl)-3-phenyl-propene-1-one (E)-1-[1-(4-Methylphenyl )-1, 3,4, 9-tetrahydro-(3-carbolin-2-yl)-3-phenylpropene-1-one (E)-N-(4-(3-Oxo-3-( 1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-(3-carbolin-2-yl)-propenyl]phenyl)acetamide (E)-4-[3-Oxo-3-(1-phenyl-1,3,4,9-tetrahydro-(3-carbolin-2-yl)-propenyl]benzoic acid, methyl ester (E)-1-[1-(2-Chiorophenyl)-1, 3,4,9-tetrahydro-(3-carbolin-2-ylj-3-phenyfpropene-1-one (E)-1-( 1-Phenyl-1,3,4,9-tetrahydro-p-carbolin-2-yl)-3-(3,4-methylenedioxyphenyl)-propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1, 3,4, 9-tetrahydro-(i-carbolin-2-yl)-3-(4-bromophenyl)propene-1-one (E)-1-[1-(4-Chlorophenyl )-1, 3,4,9-tetrahydro-j3-carbolin-2-yl)-3-phenylpropene-1-one WO 97!43287 PCT/EP97/02277 (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4, 9-tetrahydro-[3-carbolin-2-yl]-3-(4-ethoxyphenyl)propene-1-one (E)-4-[3-Oxo-3-( 1-(3,4-methylenedioxyphenyl }-1, 3,4, 9-tetrahydro-[i-carbol in-2-yl)propenyl]acetic acid, phenyl ester (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-~i-carbofin-2-yl]-3-(4-hydroxyphenyl)propene-1-one (E)-1-[1-(3,4-Methyienedioxyphenyl)-1,3,4,9-tetrahydro-(3-carbolin-2-yl]-3-(4-formylphenyl)propene-1-one (E)-1-[4-[3-Oxo-3-( 1-(3,4-methylenedioxyphenyl}-1, 3,4, 9-tetrahydro-[3-carbol in-2-yl)-propenyl]phenyl]-3-phenylurea (E)-1-[1-(3,4-Methylenedioxyphenyl)-1, 3,4,9-tetrahydro-[i-carbolin-2-yl]-3-(4-aminophenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxy-phenyl)-1, 3,4,9-tetrahydro-[i-carbolin-2-yl]-3-(4-nitro-phenyl)-propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-p-carboiin-2-yl]-3-[(4-bis(methylsulfonyl)aminophenyl]propene-1-one (E}-4-[3-Oxo-3-[1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-[3-carbolin-2-yl]-propenyl]benzoic acid, methyl ester (E)-N-[4-[3-Oxo-3-[1-(3,4-methylenedioxyphenyl )-1,3,4, 9-tetrahydro-[i-carbol in-2-yl]progenyl]phenyl]methanesulfonamide (E)-4-[3-Oxo-3-[1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-[3-carbolin-2-ylJpropenyl]benzamide]
(E)-4-[3-Oxo-3-[1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-p-carbolin-2-yl]-progeny!]benzoic acid (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-~-carbolin-2-yl]-3-(4-cyanophenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-[3-carbolin-2-yl]-3-(4-trifluoromethylphenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1, 3,4, 9-tetrahydro-[3-carbolin-2-yl]-3-(3,4-_30 methylenedioxyphenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1, 3,4, 9-tetrahydro-[3-carboiin-2-yl]-3-(4-chlorophenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1, 3,4,9-tetrahydro-~-carbolin-2-ylJ-3-(4-trifluoromethoxyphenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4, 9-tetrahydro-j3-carbolin-2-y!]-3-(4-methylphenyl)propene-1-one (E)-[4-[3-Oxo-3-( 1-(3,4-methyienedioxyphenyl)-1, 3,4, 9-tetrahydro-~-carbol in-2-yl)propenyl]phenyl]urea (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-~-carbolin-2-yl]-3-(4-hydroxymethylphenyl)propene-1-one (E)-N-Benzyl-4-[3-oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-ji-carbolin-2-yt)propenyl]benzamide (E)-1-[1-(3,4-Methyienedioxyphenyl)-1,3,4,9-tetrahydro-~i-carbolin-2-yl]-3-(2,4-dichlorophenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1, 3,4,9-tetrahydro-~-carbolin-2-yl]-3-(3-methoxy-4-hydroxyphenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1, 3,4,9-tetrahydro-~i-carbolin-2-yl]-3-(3-hydroxy-4-methoxyphenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-ji-carbolin-2-yl]-3-(4-fluorophenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-p-carbolin-2-yl]-3-indan-5-yl-1-propene-1-one (E)-N-[4-[3-Oxo-3-(1-(3,4-methyienedioxyphenyl )-1, 3,4, 9-tetrahydro-ji-carbolin-2-yl)propenyl]benzoyl]benzenesulfonamide (E)-1-[1-(3,4-Methyienedioxyphenyl)-1,3,4,9-tetrahydro-(3-carbolin-2-yl]-3-(3,4-dichforophenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-~-carbolin-2-yl]-3-(3,4-dimethoxyphenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-ji-carbolin-2-yl]-3-(3,4-dihydroxyphenyl)propene-1-one (E )-N-Methyl-N-[4-(3-oxo-3-( 1-(3,4-methylened ioxyphenyl)-1, 3,4, 9-tetrahydro-~-carbolin-2-yl)propenylJphenyl]acetamide (E)-2,2-Dimethyl-N-[4-[3-Oxo-3-( 1-(3,4-methylenedioxyphenyl)-1, 3,4, 9-tetrahydro-ji-carbolin-2-yl)propenyl]phenyl]propionamide (E)-1-[1-(3,4-Methylenedioxyphenyl )-1,3,4,9-tetrahydro-(3-carbolin-2-yl]-3-(3, 5-dimethoxyphenyl)propene-1-one (E)-(N)-{4-[3-[1-(3,4-Methyienedioxyphenyl)-6-fluoro-1,3,4,9-tetrahydro-(3-carbolin-2-yl]-3-oxopropenyl]phenyl}-acetamide WO 97!43287 PCT/EP97/02277 (E)-1-[1-(3,4-Methylenedioxyphenyl}-1, 3,4,9-tetrahydro-(i-carbolin-2-yl]-3-(3,4, 5-trimethoxyphenyl)propene-1-one (E)-N-[4-[3-Oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-p-carbolin-2-yl)propenyl]phenyl)isobutyramide (E)-1-[1-(3,4-Methylenedioxyphenyl)-6-fluoro-1, 3,4, 9-tetrahydro-(i-carbolin-2-yl]-3-phenylpropene-1-one (E)-N-(2-Methoxyethyl)-4-(3-oxo-3-{ 1-(3,4-methylenedioxyphenyl)-1,3,4, 9-tetrahydro-~-carbofin-2-yl)propenyl]benzamide (E)-1-[1-(3,4-Methylenedioxyphenyl}-1,3,4,9-tetrahydro-[i-carbolin-2-yl]-3-(3-hydroxyphenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1, 3,4, 9-tetrahydro-[i-carbolin-2-yl]-3-(3-methoxyphenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-[i-carboiin-2-yl]-3-(3-nitrophenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-[3-carbolin-2-yl]-3-[4-(2-dimethyiaminoethoxy)phenyl]propene-1-one (E)-N-(2-Morpholin-4-ytethyl)-4-(3-oxo-3-{1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-~-carbolin-2-yl)propenyf]benzamide (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-(i-carbolin-2-yl]-3-[4-(1 H-tetrazol-5-yl)phenyl]propene-1-one (E )-1-[1-(3,4-Methylenedioxyphenyl)-1, 3,4, 9-tetrahydro-[3-carbolin-2-yl]-3-(3-aminophenyl)propene-1-one (E)-N-Cyclohexyl-4-[3-oxo-3-( 1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-[i-carbolin-2-yl)propenyl]benzamide (E)-N-(Tetrahydrofuran-2-ylmethyl)-4-[3-oxo-3-(1-(3,4-methylenedioxyphenyl)-1, 3,4, 9-tetrahydro-[3-carboi in-2-yl)propenyl]benzamide (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-(3-carbolin-2-yl]-3-(3-cyanophenyl)propene-1-one (E)-N-(4-Piperidine-4-carboxylic acid, ethyl ester)-4-[3-oxo-3-(1-(3,4-~0 methyienedioxyphenyl)-1,3,4,9-tetrahydro-(3-carbolin-2-yl)propenyl]benzamide (E)-N-(4-Piperidine-4-carboxylic acid)-4-(3-oxo-3-( 1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-~-carbolin-2-yi)propenyl]benzamide (E)-3-[3-Oxo-3-[1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-~-carbolin-2-yl]-propenyl]benzoic acid (E)-1-[1-(3,4-Methylenedioxyphenyl)-1, 3,4, 9-tetrahydro-~-carbolin-2-yl]-3-(3-(4-methylpiperazine-1-carbonyl)phenyl)propene-1-one (E)-N-(2-Piperazin-1-ylethyl)-3-[3-oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-[i-carbolin-2-yl)propenyl]benzamide 5 (E)-4-[3-Oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-(3-carbolin-yl)-propenyl]acetic acid ethyl ester {E)-1-[1-{3,4-Methylenedioxyphenyl)-1, 3,4, 9-tetrahydro-~3-carbolin-2-yl]-3-(3-tetrazolophenyl)propene-1-one (E)-2-[3-Oxo-3-[1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-(i-carbolin-2-10 yl]-propenyl]benzoicacid, methyl ester {E)-3-[3-Oxo-3-[1-(3,4-methylenedioxyphenyl)-1, 3,4, 9-tetrahydro-[3-carbolin-yl]-propenyl]benzoic acid, methyl ester (E)-1-{4-[3-Oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-{i-carbolin-2-yl)-propenyl]phenyl)piperidine-4-carboxylic acid, ethyl ester (E)-N-{1-Ethylpyrrolidin-2-yl-methyl)-3-[3-oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-(3-carbolin-2-yl)propenylJbenzamide (E)-1-[1-(3,4-Methylenedioxyphenyl)-1, 3,4, 9-tetrahydro-(3-carbol in-2-yl]-3-(3-(2-dimethylaminoethoxy)phenyl)propene-1-one ( E)-1-[ 1-(3,4-Methylenedioxyphenyl )-1, 3,4, 9-tetrahydro-[i-carboiin-2-yIJ-3-(3, 5-diterbutyl-4-hydroxyphenyl)propene-1-one (E)-3-[3-Oxo-3-[1-(4-methoxycarbonylphenyl)-1, 3,4, 9-tetrahydro-[i-carbolin-2-yl]propenylJbenzoic acid, methyl ester (E)-2-[3-Oxo-3-[1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-[i-carbolin-2-yIJ-propenylJbenzoic acid (E)-(4-[3-Oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-[i-carbolin-2-yl)propenyl]phenoxy)acetic acid, ethyl ester (E)-(4-[3-Oxo-3-( 1-(3,4-methylenedioxyphenyl)-1,3,4, 9-tetrahydro-~-carbolin-yl)-propenyl]phenyl)acetic acid (E)-{4-[3-Oxo-3-( 1-(3, 4-methylenedioxyphenyl)-1, 3,4, 9-tetrahydro-~-carbol in-2-yl)propenylJphenoxy)acetic acid (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-~3-carbolin-2-yl]-3-(3-nitro-4-chlorophenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-(i-carbolin-2-ylJ-3-(5-nitro-2-chlorophenyl)propene-1-one (E)-3-Chtoro-4-[3-oxo-3-[1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-(3-carboiin-2-yl]propenyl]benzoic acid, methyl ester (E)-(4-[3-Oxo-3-( 1-(3,4-methylenedioxyphenyl)-1,3,4, 9-tetrahydro-~-carboiin-yl)propenyl]benzyloxy)acetic acid (E)-1-[1-(3,4-Methylenedioxyphenyl)-1, 3,4,9-tetrahydro-~i-carbolin-2-yl]-3-(5-amino-2-chlorophenyl)propene-1-one (E)-3-Chloro-4-[3-oxo-3-[1-{3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-ø-carbolin-2-yl]propenyl]benzoic acid (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-p-carbolin-2-yl]-3-(3, dibromo-4-hydroxyphenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1, 3,4, 9-tetrahydro-[i-carbolin-2-yl]-3-(4-(2-dimethylaminopropoxy)phenyl)propene-1-one (E)-2-Chloro-5-[3-oxo-3-[1-(3,4-methylenedioxyphenyl)-1,3,4, 9-tetrahydro-[3-carbolin-2-yl]propenyl]benzoic acid, methyl ester (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-[3-carbolin-2-yl]-3-(4-(2-diisopropylaminoethoxy)phenyl)propene-1-one {E)-2-Chloro-5-[3-oxo-3-[1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-~-carbolin-2-yl]propenyl]benzoic acid (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4, 9-tetrahydro-[i-carbolin-2-yl]-3-(3-hydroxy-4-nitrophenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-p-carbolin-2-yl]-3-(3,5-dimethyl-4-hydroxyphenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-[i-carbofin-2-yl]-3-(3-(2-dimethylaminoethoxy)-4-nitrophenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-[i-carbolin-2-yl]-3-(3-(2-dimethylaminoethoxy)-4-aminophenyl)propene-1-one (E)-1-[1-{3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-[i-carbolin-2-yl]-3-(3-nitro-4-hydroxy-5-methoxyphenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1, 3,4,9-tetrahydro-~-carbolin-2-yl]-3-(3-.30 chlorophenyl)propene-1-one (E)-1-[1-(4-Methoxy-phenyl)-1,3,4,9-tetrahydro-[i-carbolin-2-yl]-3-(2-chloro-5-nitrophenyl)propene-1-one {E)-1-[1-{3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-~-carbolin-2-yl]-3-(2,6-dichlorophenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-ji-carbolin-2-yl]-3-(4-methylaminomethylphenyl)propene-1-one (E)-1-[1-(3,4-Methyienedioxyphenyl)-1,3,4, 9-tetrahydro-j3-carbolin-2-yl]-3-(3-methylphenyl)-propene-1-one (E)-N-Methyl-(4-[3-oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-[3-carbolin-2-yl)propenyl]benzenesulfonamide (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4, 9-tetrahydro-[i-carbolin-2-yl]-3-(3-hydroxy-4-acetylphenyl)propene-1-one (E)-1-[1-(2, 3-Dihydrobenzofuran-5-yl )-1, 3,4, 9-tetrahydro-[3-carboiin-2-yl]-3-(2-chloro-5-nitrophenyl)propene-1-one (E}-1-[1-(3,4-Methyienedioxyphenyl)-1, 3,4, 9-tetrahydro-[i-carbol in-2-yl]-3-(2-hydroxyphenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4, 9-tetrahydro-ji-carbolin-2-yl)-3-(3-nitro-2-piperidin-1-ylphenyl)propene-1-one (E)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-ji-carbolin-2-yl]-3-phenylpropene-1-one (E)-1-[1-(4-Isopropylphenyl)-1,3,4, 9-tetrahydro-(i-carboiin-2-yl]-3-(3-nitrophenyl)propene-1-one (E)-1-[1-(2, 3-Dihydrobenzofuran-5-yl }-1, 3,4, 9-tetrahydro-j3-carbol in-2-yl]-3-(3-nitrophenyl)propene-1-one (E)-(R)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-[i-carbolin-2-yl]-3-phenylpropene-1-one (E)-(S)-1-(1-(3,4-Methylenedioxyphenyl}-1, 3,4,9-tetrahydro-~-carbofin-2-yl]-3-phenylpropene-1-one (E)-1-[1-(4-Methoxyphenyl)-1,3,4,9-tetrahydro-p-carbolin-2-yl]-3(3-nitrophenyl)propene-1-one (E)-1-j1-(4-Methylphenyl)-1,3,4,9-tetrahydro-ji-carboiin-2-yl]-3-(2-chloro-5-nitrophenyl)propene-1-one (E)-N-(Tetrahydrofuran-2-ylmethyl)-3-[3-oxo-3-( 1-(3,4-methylenedioxy)-1,3,4, tetrahydro-j3-carbolin-2-yl)propenyl]benzamide (E)-1-[1-(Indan-5-yl}-1,3,4,9-tetrahydro-~-carbolin-2-yl]-3-phenylpropene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-ji-carbolin-2-yl]-3-(3-acetylphenyl)propene-1-one (E)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-(3-carbolin-2-yl)]-3-(4-(2-dimethylaminoethoxy)phenyl)propene-1-one (E)-4-[3-Oxo-3-[1-(4-methoxyphenyl)-1,3,4, 9-tetrahydro-ø-carbolin-2-yl]propenyl]-benzoic acid, methyl ester (E)-1-[ 1-(3,4-Methylenedioxyphenyl)-1, 3,4, 9-tetrahydro-ø-carbolin-2-yl]-3-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-ø-carbolin-2-yl]-3-(2-hydroxy-5-nitrophenyl)propene-1-one (E)-4-[3-Oxo-3-[1-(2, 3-dihydrobenzofuran-5-yl)-1, 3,4, 9-tetrahydro-~-carbolin-2-yl]propenyl]benzoic acid, methyl ester (E)-4-[3-Oxo-3-(1-(4-methoxyphenyl)-1, 3,4, 9-tetrahydro-ø-carbolin-2-yl]propenyl]benzoic acid (E)-4-[3-Oxo-3-[1-{2,3-dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-ø-carbolin-2-y1]propenyl]benzoic acid ( E)-1-[1-(Benzofuran-5-yl )-1, 3,4, 9-tetrahydro-ø-carbol in-2-yl]-3-phenyipropene-1-one (E)-3-[3-Oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-ø-carbolin-2-yl)-propenyl]phenyl)trifluoromethanesulfonic acid, phenyl ester (E)-1-[1-(3,4-Methylenedioxyphenyl)-1, 3,4,9-tetrahydro-ø-carboiin-2-yIJ-3-(4-(2-hydroxyethoxy)phenyl]propene-1-one (E)-1-[1-(Benzofuran-5-yl-1,3,4,9-tetrahydro-ø-carbolin-2-yl)]-3-(4-(2-dimethylaminoethoxy)phenyl)propene-1-one (E)-1-[1 (3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-ø-carbolin-2-yl]-3-{2-dimethylaminophenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl )-1, 3,4, 9-tetrahydro-ø-carbolin-2-yl]-3-(2-piperidin-1-ylphenyl)propene-1-one (E)-4-[3-Oxo-3-(1-(benzofuran-5-yl-1,3,4,9-tetrahydro-ø-carbolin-2-yl]-propenyl]-benzoic acid, methyl ester (E)-4-[3-( 1-Benzofuran-5-yl-1, 3,4, 9-tetrahydro-ø-carbolin-2-yl )-3-oxo-propenyl]-benzoic acid (E)-4-[3-Oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-[i-carbolin-2-._30 yl)propenyl]phenyl)trifluoromethanesulfonic acid, phenyl ester (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-ø-carbolin-2-yl]-3-(2-(2-dimethylaminoethoxy)phenyl)propene-1-one (E)-1-[1-(3-F luoro-4-methoxyphenyl )-1, 3,4, 9-tetrahydro-ø-carbol in-2-yl]-3-phenylpropene-1-one (E)-(R)-1-[1-(2, 3-Dihydrobenzofuran-5-yl)-1, 3,4, 9-tetrahydro-~-carbol i n-2-yl )]-3-(4-(2-dimethylaminoethoxy)phenyl)propene-1-one (E)-1-(2,3-Dihydrobenzo(1,4]dioxin-6-yl)-1,3,4,9-tetrahydro-~-carbolin-2-yl]-3-phenylpropene-1-one (E)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-[i-carbolin-2-yl)]-3-{4-(2-pyrrolidin-1-ylethoxy)phenyl)propene-1-one (E)-1-[ 1-(3,4-Methylenedioxyphenyl )-1, 3,4,9-tetrahydro-p-carbolin-2-yl]-3-(4-pyrrolidin-1-yiphenyl]propane-1-one (E)-(R)-1-[1-(2, 3-Dihydrobenzofuran-5-yl)-1, 3, 4, 9-tetrahydro-[3-carbolin-2-yl]-3-(3-nitrophenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-[i-carbolin-2-yl]-3-[4-imidazol-1-ylphenyl]propene-1-one (E)-4-[3-(1-(2,3-Dihydrobenzo[1,4]dioxin-6-y!)-1,3,4, 9-tetrahydro-[i-carbolin-yl]-3-oxopropenyl]benzoic acid, methyl ester (E)-1-[1-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-1,3,4,9-tetrahydro-(3-carbolin-2-yl]-3-(3-nitrophenyl)propene-1-one (E)-1-[1-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-1, 3,4,9-tetrahydro-[3-carbolin-2-yl)]-3-(4-(2-dimethylaminoethoxy)phenyl)propene-1-one (E)-1-[1-(3-Fluoro-4-methoxyphenyl)-1, 3,4,9-tetrahydro-[3-carbolin-2-yl)]-3-(4-(2-dimethylaminoethoxy)phenyl)propene-1-one (E)-4-[3-(1-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-1,3,4,9-tetrahydro-~-carbofin-2-yl]-3-oxopropenyl]benzoic acid (E)-(R)-1-(1-(2, 3-Dihydrobenzofuran-5-yl)-1, 3,4, 9-tetrahydro-[3-carbolin-2-yl]-3-phenylpropene-1-one (E)-(S)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-[3-carbolin-2-yl)]-3-(4-(2-dimethylaminoethoxy)phenyl}propane-1-one (E)-1-[1-(2, 3-Dihydrobenzofuran-5-yl )-1, 3,4, 9-tetrahydro-/3-carbolin-2-yl]-3-(4-aminophenyl)propene-1-one ( E)-(S )-1-[ 1-(2, 3-Dihydrobenzofuran-5-yl )-1, 3, 4, 9-tetrahydro-[3-carboi in-2-yl]-3-phenylpropene-1-one (E)-(S)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4, 9-tetrahydro-p-carbolin-2-yl]-(3-nitrophenyl)propene-1-one (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-p-carbolin-2-yl)]-(4-(1-(S}-methyfpyrrolidin-2-yl-methoxy)phenyl)propene-1-one (E)-(R)-1-[1-(2, 3-D ihydrobenzofuran-5-yl )-1, 3,4, 9-tetrahydro-[i-carbolin-2-yl]-3-(3-hydroxyphenyl)propene-1-one ( E)-(R)-1-[1-(2, 3-D ihydrobenzofuran-5-yl}-1, 3,4, 9-tetrahydro-~i-carbolin-2-yl )]-3-(4-(2-dimethylamino-1-methylethoxy)phenyl)propene-1-one (E)-1-( 1-Phenyl-1,3,4,9-tetrahydro-[i-carbolin-2-yl)-3-(4-(4-methylpyperazin-yl)-phenyl)propene-1-one (E)-(R)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-~-carbolin-2-yl)]-3-(4-(1-(S)-methylpyrrolidin-2-yl-methoxy)phenyl)propene-1-one (E)-(R)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4, 9-tetrahydro-~-carbolin-2-yl)]-10 (4-(2-dimethylamino-1-methylethoxy)phenyl)propene-1-one (E)-(R)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-~-carbolin-2-yl)]-3-(4-(2-dimethylaminopropoxy)phenyl)propene-1-one (E}-4-[3-Oxo-3-[1-(3,4-fluorophenyl)-1, 3,4, 9-tetrahydro-[i-carbolin-2-yl]-propenyl]benzoic acid, methyl ester 15 (E)-(R)-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-[i-carbolin-2-yl)]-3-(4-(2-diethylaminoethoxy)phenyl)propene-1-one (E)-(R) 1-[1-(2, 3-Dihydrobenzofuran-5-yl}-1, 3,4, 9-tetrahydro-~-carbol in-2-yl )]-3-(4-(2-dimethylaminopropoxy)phenyl)propene-1-one (E}-4-[3-Oxo-3-[1-(3,4-difluorophenyl)-1,3,4,9-tetrahydro-[i-carbolin-2-yl]propenyl]-benzoic acid (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-[i-carbolin-2-yl]-(4-aminophenyl)propene-1-one (E)-(R)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-[i-carbolin-2-yl]-3-(4-aminophenyl)propene-1-one (E)-(R)-1-[1-(3,4-Methyienedioxyphenyl)-1,3,4,9-tetrahydro-(3-carbolin-2-yl)]-(4-(2-pyrrolidin-1-ylethoxy)phenyl)propene-1-one (E}-(R)-1-[1-(3,4-Methyienedioxyphenyl)-1,3,4, 9-tetrahydro-p-carbolin-2-yl)]-(4-(2-diethylaminoethoxy)phenylpropene-1-one (E)-1-[1-(3-Fluoro-4-methoxyphenyl)-1,3,4,9-tetrahydro-~-carbolin-2-yl)]-3-(3-nitrophenyl)propene-1-one (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-y1)-1,3,4, 9-tetrahydro-[3-carbolin-2-yl]-3-(4-trifluoromethyiphenyl)propene-1-one (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-~-carbolin-2-yl]-(3-trifluoromethylphenyl)propene-1-one (E)-(R)-1-[1-(2, 3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-{i-carbolin-2-yl]-3-(4-(2-morpholin-4-ylethoxy)phenyl)propene-1-one (E)-(R)-1-[1-(2, 3-Dihydrobenzofuran-5-yl)-1, 3,4, 9-tetrahydro-~i-carbolin-2-yl]-3-(4-(2-(ethylmethylamino)ethoxy)phenyl)propene-1-one {E)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-[i-carbolin-2-yl]-3-(4-(3-(dimethylamino)propenyl)phenyl)propene-1-one (E)-(R)-1-[1-(2, 3-Dihydrobenzofuran-5-yl)-1, 3,4, 9-tetrahydro-(3-carbo I in-2-yl]-3-(4-(3-dimethyiamino-2-hydroxypropoxy)phenyl)propene-1-one ( E)-(R)-1-( 1-(2, 3-Dihydrobenzofuran-5-yl)-1, 3, 4, 9-tetrahydro-(3-carboi in-2-yl)-3-(4-formyiphenyl)propene-1-one (E)-(R)-1-[1-{2,3-Dihydrobenzofuran-5-yl}-1,3,4,9-tetrahydro-j3-carbolin-2-ylJ-(4-propylaminomethyl)phenyl)propene-1-one (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-~3-carbolin-2-yl]-[4-(2-dimethylaminoethyiamino)phenylpropene-1-one (E}-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-ji-carbolin-2-yl]-(4-(2-aminoethoxy)phenyl)propene-1-one (E)-(R)-1-[1-(2, 3-Dihydrobenzofuran-5-yl)-1, 3,4, 9-tetrahydro-{i-carbol in-2-yl]-3-(4-hydroxyphenyl)propene-1-one (E)-(R)-1-[1-(2, 3-Dihydrobenzofuran-5-yl)-1, 3,4, 9-tetrahydro-[3-carbolin-2-yl]-3-(4-(4-methylpiperazin-1-yl)phenylpropene-1-one (E)-(R)-1-[1-(2, 3-Dihydrobenzofuran-5-yl)-1,3,4, 9-tetrahydro-~-carbolin-2-yIJ-3-(4-methyiaminomethyl)phenyl)propene-1-one (E)-(R)-1-j1-{2, 3-Dihydrobenzofuran-5-yl)-1, 3,4, 9-tetrahydro-[3-carbol in-2-yl]-3-(4-isopropylaminomethyl)phenyl)propene-1-one (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-~i-carbolin-2-yl]-(4-dimethylaminomethyl)phenyl)propene-1-one (E}-(R)-1-[ 1-(2, 3-Dihydrobenzofuran-5-yl}-1, 3,4, 9-tetrahydro-[i-carbol in-2-yl]-3-[4-(3-dimethylaminopropoxy)phenylJpropene-1-one (E)-(R}-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-~-carbolin-2-yl)-(4-(2-piperidin-1-ylethoxy)phenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-[i-carbolin-2-yl)-3-(4-(2-piperidin-1-ylethoxy)phenylJpropene-1-one (E}-(R)-[2-(4-{3-[1-(2, 3-Dihydrobenzofuran-5-yl)-1,3,4, 9-tetrahydro-[3-carbolin-2-yl]-3-oxopropenyl)phenoxy)ethyl]methylcarbamic acid, tertbutyl ester ( E)-(R)-1-[ 1-(2, 3-D ihydrobenzofuran-5-yl )-1, 3, 4, 9-tetrahydro-(3-carbolin-2-yl]-3-[4-(2-methylaminoethoxy)phenyl]propene-1-one and pharmaceutically acceptable salts and solvates (e.g. hydrates) thereof.
A specific compound of the invention is:
(E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-~3-carbolin-2-yl)]-3-(4-(2-dimethylaminoethoxy)phenyi)propene-1-one and pharmaceutically acceptable salts and solvates (e.g. hydrates) thereof.
It has been shown that compounds of the present invention are potent and selective inhibitors of cGMP specific PDE. Thus, compounds of formula (!) ace of interest for use in therapy, specifically for the treatment of a variety of conditions where inhibition of cGMP specific PDE is thought to be beneficial.
As a consequence of the selective PDE 5 inhibition exhibited by compounds of the present invention, cGMP levels are elevated, which in turn can give rise to beneficial anti-platelet, anti-neutrophil, anti-vasospastic, vasodilatory, natriuretic~ and diuretic activities as well as potentiation of the effects of endothelium-derived relaxing factor (EDRF), nitrovasodilators, atrial natnuretic factor (ANF), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP) and endothelium-dependent relaxing agents such as bradykinin, acetylcholine and 5-HT~. The compounds of formula (I) therefore have utility in the treatment of a number of disorders, including stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, congestive heart failure, renal failure, atherosclerosis, conditions of reduced blood vessel patency (e.g.
post-percutaneous transluminal coronary angioplasty), peripheral vascular disease, vascular disorders such as Raynaud's disease, inflammatory diseases, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, erectile dysfunction and diseases characterised by disorders of gut motility (e.g.
irritable bowel syndrome).
It will be appreciated that references herein to treatment extend to prophyfaxis as well as treatment of established conditions.
_30 It will also be appreciated that a compound of formula (I), or a physiologically acceptable salt or solvate thereof can be administered as the raw compound, or as a pharmaceutical composition containing either entity.
There is thus provided as a further aspect of the invention a compound of formula (I) for use in the treatment of stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, congestive heart failure, renal failure, atherosclerosis, conditions of reduced blood vessel patency, (e.g. post-PTCA}, peripheral vascular disease, vascular disorders such as Raynaud's disease, inflammatory diseases, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, erectile dysfunction or diseases characterised by disorders of gut motility (e.g. IBS).
According to another aspect of the invention, there is provided the use of a compound of formula (I) for the manufacture of a medicament for the treatment of stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, congestive heart failure, renal failure, atherosclerosis, conditions of reduced blood vessel patency, (e.g.
post-PTCA), peripheral vascular disease, vascular disorders such as Raynaud's disease, inflammatory diseases, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, erectile dysfunction or diseases characterised by disorders of gut motility (e.g. IBS).
In a further aspect, the invention provides a method of treating stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, congestive heart failure, renal failure, atheroscierosis, conditions of reduced blood vessel patency, (e.g.
post-PTCA), peripheral vascular disease, vascular disorders such as Raynaud's disease, inflammatory diseases, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, erectile dysfunction or diseases characterised by disorders of gut motility {e.g. IBS) in a human or non-human animal body which comprises administering to said body a therapeutically effective amount of a compound with formula (I).
Compounds of the invention may be administered by any suitable route, for example by oral, buccal, sub-lingual, rectal, vaginal, nasal, topical or parenteral (including intravenous, intramuscular, subcutaneous and intracoronary) administration. Oral administration is generally preferred.
For administration to man in the curative or prophylactic treatment of the disorders identified above, oral dosages of a compound of formula (1) will generally be in the range of from 0.5-800mg daily for an average adult patient . (70kg). Thus for a typical adult patient, individual tablets or capsules contain from 0.2-400mg of active compound, in a suitable pharmaceutically acceptable -vehicle or carrier, for administration in single or multiple doses, once or several times per day. Dosages for intravenous, buccal or sublingual administration will typically be within the range of from 0.1-400 mg per single dose as required.
In practice the physician will determine the actual dosing regimen which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case but there can be individual instances in which higher or lower dosage ranges may be merited, and such are within the scope of this invention.
For human use, a compound of the formula (I) can be administered alone, but wilt generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, the compound may be administered orally, buccally or sublingually, in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavouring or colouring agents. Such liquid preparations may be prepared with pharmaceutically acceptable additives such as suspending agents (e.g.
methylcellulose, a semi-synthetic glyceride such as witepsol or mixtures of glycerides such as a mixture of apricot kernel oil and PEG-6 esters or mixtures of PEG-8 and capryliclcapric glycerides). A compound may also be injected parenterally, for example intravenously, intramuscularly, subcutaneously or intracoronarily. For parenteral administration, the compound is best used in the form of a sterile aqueous solution which may contain other substances, for example salts, or monosaccharides such as mannitol or glucose, to make the solution isotonic with blood.
Thus, the invention provides in a further aspect a pharmaceutical composition comprising a compound of the formula (I) together with a pharmaceutically acceptable diluent or carrier therefor.
There is further provided by the present invention a process of preparing a pharmaceutical composition comprising a compound of formula (I), which process comprises mixing a compound of formula (I) together with a pharmaceutically acceptable diluent or carrier therefor.
A compound of formula (I) may also be used in combination with other therapeutic agents which may be useful in the treatment of the above-mentioned disease states. The invention thus provides, in another aspect, a combination of a compound of formula (I) together with another therapeutically active agent.
The combination referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical compositions -comprising a combination as defined above together with a pharmaceutically acceptable diluent or carrier comprise a further aspect of the invention.
5 The individual components of such a combination may also be administered either sequentially or simultaneously in separate pharmaceutical formulations.
Appropriate doses of known therapeutic agents for use in combination with a compound of formula (I) will be readily appreciated by those skilled in the art.
Compounds of formula (I) may be prepared by any suitable method known in 10 the art or by the following processes which form part of the present invention. In the methods below R°, R1,R2~ R3, and R4 are are as defined in formula (I) above unless otherwise indicated.
There is a further provided by the present invention a process (A) of preparing a compound of formula (I), which process comprises reacting 15 compounds of formula (II) and (lll) ~R~m x °~~ / I (III) 20 ~R2)"
where X represents a hydroxyl or halogen group.
Suitably the reaction is carried out in the presence of 1,3 dicyclohexylcarbodiimide (DCC) or 1-(3-dimethylaminopropyl)-3 ethylcarbodiimide (EDCI) and 1-hydroxybenzotriazole (HOBT) in a suitable organic solvent, such as dimethylformamide (DMF) or dichloromethane (DCM) for several hours, e.g. 8 hours to 2 days.
Compounds of formula (I) may be prepared as individual enantiomers from the appropriate enantiomer of formula (II) or as a racemic mixture from the appropriate racemic compound of formula (II). Individual enantiomers of the compounds of the invention may be prepared from racemates by resolution using methods known in the art for the separation of racemic mixtures into their constituent enantiomers, for example using HPLC on a chiral column such as Hypersil naphtyl urea or using separation of salts of diastereoisomers.
A compound of formula (II) may be prepared by Pictet-Spengler cyclization between a tryptamine derivative of formula (IV) and an aldehyde of formula (V) / I I CH2CH.,NH~
H
H O
(V) I
(R3)m Re The reaction may conveniently be effected in a suitable solvent such as a halogenated hydrocarbon (e.g. dichloromethane) or an aromatic hydrocarbon (e.g. toluene) in the presence of an acid such as trifluoroacetic acid (TFA).
The reaction may conveniently be carried out at a temperature of from 20 °C
to refiux to provide a compound of formula (Il) in one step. The reaction may also be carried out in a solvent such as an aromatic hydrocarbon (e.g. toluene) under reflux optionally using a Dean-stark apparatus to trap the water produced.
The reaction provides racemic compounds of formula (II). Enantiomers may be obtained from a resolution with N-acetyl leucine using fractional crystallization in EtOAc:MeOH as solvent. (R) and (S) enantiomers may be isolated as salts depending upon whether N-acetyl-(D) and (L)-leucine was used as the starting material.
Compounds of formulae (IV) and (V) are commercially available compounds or prepared by standard synthetic techniques as hereinafter described in the Examples.
A compound of formula (I!I) can be prepared from a corresponding aldehyde of formula (VI) R' H
(VI) O (R2)~
suitably by employing a Wittig reaction followed by basic hydrolysis.
Alternatively a compound of formula (III) may be prepared from a compound of formula (VI) by a Knoevenhagel reaction employing malonic acid.
Compounds of formula {VI) can be prepared from known corresponding alcohol, nitrite, or halide derivatives, using techniques well known in the art of synthetic organic chemistry.
According to a further general process (B) compounds of formula (I) can be converted to alternative compounds of formula (I), employing suitable interconversion techniques such as hereinafter described in the Examples.
Compounds of this invention may be isolated in association with solvent molecules by crystallization from or evaporation of an appropriate solvent.
The pharmaceutically acceptable acid addition salts of the compounds of formula (I) which contain a basic centre may be prepared in a conventional manner. For example, a solution of the free base may be treated with a suitable acid, either neat or in a suitable solution, and the resulting salt isolated either by filtration or by evaporation under vacuum of the reaction solvent.
Pharmaceutically acceptable base addition salts may be obtained in an analogous manner by treating a solution of a compound of formula (I) with a suitable base. Both types of salt may be formed or interconverted using ion-exchange resin techniques.
Thus, according to a further aspect of the invention, we provide a process for preparing a compound of formula (I) or a salt or solvate (e.g. hydrate) thereof which comprises process (A) or (B) as hereinbefore described followed by i) salt formation; or ii) solvate (e.g. hydrate) formation.
WO 97/43287 PCTlEP97/02277 The following additional abbreviations are hereinafter used in the accompanying examples: rt {room temperature), DMSO (dimethylsuiphoxide), NBS (N-bromosuccinimide), THF (tetrahydrofuran), TFA (trifluoroacetic acid), PTSA { p-toluene sulphonic acid), AIBN (2,2'-azobis isobutyronitrile), and TBDMSCI (tert-butyfdimethylsilyl chloride).
Intermediate 1 1-Phenyl-2.3,4,9-tetrahydro-1 H-Q-carboline A solution of tryptamine (15 g, 94.0 mmol) and benzaldehyde (10.9 g, 1.1 equiv.) in DCM (800 mL) was treated with TFA (15 mL, 2 equiv.). The resulting mixture was stirred at rt for one day and then neutralized to pH 7 with a saturated aqueous solution of sodium carbonate. After filtration and concentration to dryness the residue was recrystallized from 2-propanol to give the title compound (11.0 g, 47%) as white crystals.
MP: 175-177 °C.
Intermediate 2 1-(4-Methoxyphenyl)-2.3,4.9-tetrahydro-1 H-Q-carboline This product was prepared using the same procedure as for Intermediate 1 with tryptamine (15 g, 94.9 mrnol), 4-methoxybenzaldehyde (12.9 g, 1.1 equiv.) and TFA (14.6 mL, 2 equiv.) to give the title compound (20.9 g, 80%) as a brownish powder.
MP: 131 °C.
Intermediate 3 1-(4-Nitrophenyl)-2.3.4.9-tetrahydro-1 H-Q-carboline This product was prepared using the same procedure as for Intermediate 1 with tryptamine (2.0 g, 12.5 mmol), 4-nitrobenzaldehyde (1.88 g, 1 equiv.) and TFA
(1.9 mL, 2 equiv.) to give the title compound (3.1 g, 86%) as a yellow powder.
MP: 190 °C.
intermediate 4 1~4-Trifluoromethoxyphenyll-2L3.4,9-tetrahydro-1 H-(~-carboline This product was prepared using the same procedure as for Intermediate 1 with tryptamine (2.0 g, 12.5 mmol), 4-trifluoromethoxybenzaldehyde (2.4 g, 1 equiv.
) and TFA (1.9 mL, 2 equiv.) to give the title compound (1.6 g, 38%) as a white powder.
MP: 68-69 °C.
Intermediate 5 1-(4-Chlorophenyl)-2.3.4.9-tetrahydro-1 H-fi-carboline This product was prepared using the same procedure as for Intermediate 1 with tryptamine {5.0 g, 30 mmol), 4-chlorobenzaldehyde (4.6 g, 1 equiv.) and TFA
(4.6 mL, 2 equiv.) to give the title compound (4.16 g, 49%) as a white powder.
MP: 161 °C.
Intermediate 6 1-(4-Methylphenyl)-2.3.4.9-tetrahydro-1 H-Q-carboline This product was prepared using the same procedure as for Intermediate 1 with tryptamine (1.0 g, 6.2 mmol), 4-methylbenzaidehyde (0.74 g, 1 equiv.) and TFA
(1 mL, 2 equiv.) to give the title compound (1.6 g, 100%) as a white powder.
MP: 207-209 °C.
intermediate 7 1-(3,4-Methylenedioxyphenyl)-2 3 4 9-tetrahydro-1 H-!3-carboline This product was prepared using the same procedure as for Intermediate 1 with tryptamine (20.0 g, 120 mmol), 3,4-methylenedioxybenzaldehyde (20.6 g, 1.1 equiv.) and TFA (18 mL, 2 equiv.) to give the title compound (22 g, 60%) as white crystals after recrystallization from ethanol.
MP: 178 °C.
Intermediate 8 4-(2,3,4.9-Tetrahydro-1H-Q-carbolin-1-yl)benzoic acid methyl ester This product was prepared using the same procedure as for Intermediate 1 with tryptamine (2.8 g, 17.4 mmol), 4-formylbenzoic acid, methyl ester (2.87 g, 1.1 equiv. ) and TFA (2.7 mL, 2 equiv. ) to give the title compound (0.5 g, 9%) as white crystals after recrystallization from isopropanol: H20.
MP: 179 °C.
Intermediate 9 '1-Indan-5-yl-2.3,4.9-tetrahydro-1 H-Q-carboline This product was prepared using the same procedure as for Intermediate 1 with 5 tryptamine (1.28 g, 8.0 mmol), indan-5-carboxaldehyde (1.3 g, 1.1 equiv.) and TFA (1.2 mL, 2 equiv.) to give the title compound (0.36 g, 14%).
~ H NMR (CDC13) b 7.6 (s, 1 H), 7.4 (m, 1 H), 6.9-7.2 (m, 6H), 5.1 (s, 1 H), 3.3-3.4 (m, 1 H), 2.9-3.1 (m, 1 H), 2.7-2.9 (m, 6H), 1.9-2.2 (q, 2H).
10 Intermediate 10 1-(2.3-Dihydrobenzofuran-5-yl)-2.3.4.9-tetrahydro-1 H-a-carboline This product was prepared using a two-step procedure. A solution of tryptamine (32.4 g, 0.2 mol) and 2,3-dihydrobenzofuran-5-carboxaldehyde (30.0 g, 1 equiv.) in toluene (1 L) was heated under reflux for 4 hours. After removal of 15 mL of water and evaporation of toluene the residue was dissolved in DCM (1 L) in the presence of TFA (31 mL, 2 equiv.). The resulting mixture was stirred at rt for 16 hours. Then 1 L of a saturated aqueous solution of NaHC03 was added.
After extraction with DCM and drying over MgS04, the organic solution was evaporated in vacuo. Recrystaflization from DCM:iPrZO (2:30) gave the title 20 compound as white crytals in a 80% yield.
'H NMR (CDC13) 8 7.6 (s, 1 H), 7.5-7.6 (m, 1 H), 7-7.3 (m, 5H), 6.7-6.75 (d, 1 H), 5.1 (s, 1 H), 4.5-4.6 (t, 2H), 3.3-3.45 (m, 1 H), 3.05-3.2 (t, 3H), 2.7-3 (m, 2H).
Intermediate 11 25 1-(4-isopropylphenyl)-2,3.4.9-tetrahydro-1 H-Q-carboline This product was prepared using the same procedure as for Intermediate 1 with tryptamine (5.0 g, 31.2 mmol), 4-isopropylbenzaldehyde (5.08 g, 1.1 equiv.) and TFA (4.8 mL, 2 equiv.) to give the title compound (5.9 g, 67%) as white crystals after recrystallization from iPrZO.
MP: 146 °C.
Intermediate 12 1-(2.3-Benzofuran-5-yl)-2.3.4.9-tetrahydro-1 H-(3-carboline This product was prepared using the same procedure as for Intermediate 1 with tryptamine (2.27 g, 14.1 mmoi), 2,3-benzofuran-S-carboxaldehyde (2.1 g, 1 equiv., prepared according to the procedure of Dorn, C.P et al EP 481671A1) and TFA (2.2 mL, 2 equiv.) to give the title compound (3.0 g, 74%) as white crystals after recrystallization from cyclohexane.
MP: 134-136 °C.
Intermediate 13 1-(2,3-Dihydrobenzof1.41dioxin-6-yl)-2 3 4 9-tetrahydro-1 H-~-carbolin_e This product was prepared using the same procedure as for Intermediate 1 with tryptamine (4.92 g, 30.7 mmol), 2,3-dihydrobenzo[1,4Jdioxin-6-carboxaldehyde (5.05 g, 1.0 equiv.) and TFA (5.0 mL, 2 equiv.) to give the title compound (7.05 g, 75%) as white crystals after recrystallization from iPr20.
MP: 144 °C.
Intermediate 14 1 ~3-Fluoro-4-methoxyphenyl)-2 3 4 9-tetrahydro-1 H-8-carboline This product was prepared using the same procedure as for Intermediate 1 with tryptamine (4.80 g, 30.0 mmol), 3-fluoro-4-methoxybenzaldehyde (4.86 g, 1.05 equiv. ) and TFA (4.6 mL, 2 equiv. ) to give the title compound (5.2 g, 59% ) as white crystals.
MP: 68 °C.
Intermediate 15 1-(3,4-Difluorophenyl)-2.3 4 9-tetrahydro-1 H-Q-carboline This product was prepared using the same procedure as for Intermediate 1 with tryptamine (5.4 g, 33.5 mmol), 3,4-difluorobenzaldehyde (5.0 g, 1.05 equiv.) and TFA (5.2 mL, 2 equiv.) to give the title compound (7.8 g, 82%) as white crystals.
MP: 151 °C.
Intermediate 16 1-(3.4-Methylenedioxyphenyl)-6-fiuoro-2 3 4 9-tetrahydro-1 H ~ carboline This product was prepared using the same procedure as for Intermediate 1 with 5-fluorotryptamine (1.59 g, 8.9 mmol), 3,4-methylenedioxybenzaldehyde (1.47 g, 1.1 equiv.) and TFA (1.4 mL , 2 equiv.) to give the title compound (2.34 g, 85%) as white crystals.
MP: 172 °C.
Analysis for C,aH,sFN20z:
Calculated: C,69.67; H,4.87; N,6.12.
Found: C,69.47; H,4.85; N,6.23%
Intermediate 17 1-(2-Chlorophenyl)-2.3.4.9-tetrahydro-1 H-Q-carboline This product was prepared using the same procedure as for Intermediate 1 with tryptamine (1.0 g, 6.2 mmol), 2-chlorobenzaldehyde (0.7 mL, 1.0 equiv.) and TFA (1.0 mL, 2 equiv.) to give the title compound (1.2 g, 69%).
H NMR (CDC13) b 7.6 (s, 1 H), 7.45 (d, 1 H), 7.40 (d, 1 H), 6.9-7.2 (m, 6H), 5.6 (s, 1 H), 3.2-3.0 (m, 2H), 2.9-2.7 (m, 2H), 2.4 (s, 1 H).
Intermediate 18 (S)-1-(3,4-Methylenedioxyphenyl)-2.3.4,9-tetrahydro-1 H-Q-carboline (S)-1-(3,4-Methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-p-carboline was obtained from the resolution of the corresponding racemic amine with N-acetyl-(L)-Leucine (Sigma) in MeOH followed by a recrystallization from MeOH.
Treatment of the suspension of the recrystallized material in DCM with a saturated aqueous solution of NaHC03 gave the enantiomerically pure (S)-1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1 H-(3-carboline as beige crystals in a 55% yield.
MP: 173 °C.
Analysis for C,8H,6NZ0z. 0.35H20:
Calculated: C,72.39; H,5.64; N,9.38.
Found: C,72.35; H.5.44; N,9.1 %.
ja]p'9~6- -35 (c = 0.53, MeOH).
Intermediate 19 ~1-(3.4-Methylenedioxyphenyl)-2.3.4,9-tetrahydro-1 H-t3-carboline - 30 Following the same protocol as for Intermediate 18 (R)-1-(3,4-methyienedioxyphenyl)-2,3,4,9-tetrahydro-1 H-(3-carboline was obtained from the resolution of the corresponding racemic amine with N-acetyl-(D)-Leucine (Sigma) in MeOH followed by a recrystallization from MeOH. Treatment of the suspension of the recrystallized material in DCM with a saturated aqueous solution of NaHC03 gave the enantiomerically pure (R)-1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1 H-~-carboline as white crystals in a 59% yield.
MP: 92-94 °C.
Analalysis for C,sH,6NZOz:
Calculated: C,73.95; H,5.52; N,9.58.
Found: C,73.72; H,5.52; N,9.52%.
[a]p2''= 34 (c = 0.50, MeOH).
Intermediate 20 (R)-1-(2,3-Dihydrobenzofuran-5-yl)-2 3 4 9-tetrahydro-1 H-Q-carboline Following the same protocol as for Intermediate 18 (R)-1-(2,3-dihydrobenzofuran-5-yl)-2,3,4,9-tetrahydro-1 H-(3-carboline was obtained from the resolution of the corresponding racemic amine with N-acetyl-(D)-Leucine (Sigma) in MeOH:EtOAc followed by a recrystallization from MeOH. Treatment of the suspension of the recrystallized material in DCM with a saturated aqueous solution of NaHC03 gave the enantiomerically pure (R)-1-(2,3-dihydrobenzofuran-5-yl)-2,3,4,9-tetrahydro-1 H-p-carboline as white crystals in a 55% yield.
MP: 98-99 °C.
Analysis for C,9H,eNzO. 0.15H20:
Calculated: C,77.87; H,6.29; N,9.56.
Found: C,77.83; H,6.33; N,9.44%
[a]pz' = 42 (c = 0.50, MeOH).
Intermediate 21 (S)-1-(4-(2.3-Dihydrobenzo(b)furan)-2 3 4 9-tetrahydro-1 H-t3-carboiine Following the same protocol as for Intermediate 18 (S)-1-(2,3-dihydrobenzofuran-5-yl)-2,3,4,9-tetrahydro-1 H-~-carboline was obtained from the resolution of the corresponding racemic amine with N-acetyl-(L)-Leucine (Sigma) in MeOHIEtOAc followed by a recrystallization from MeOH. Treatment of the suspension of the recrystallized material in DCM with a saturated aqueous solution of NaHC03 gave the enantiomerically pure (S)-1-(2,3-dihydrobenzofuran-5-yl)-2,3,4,9-tetrahydro-1 H-/3-carboline as a pale yellow powder in a 45% yield.
MP: 175 °C.
Anaialysis for C,9H,eNzO. 1.OHzO:
Calculated: C,74.0; H,6.54; N,9.08.
Found: C,74.01; H,5.88; N,8.92%.
[a]p'9'= -49 (c = 0.50, MeOH).
Intermediate 22 (E)-3-(4-Ureidovhenyl)acrylic acid A stirred solution of (E)-3-{4-aminophenyl)acrylic acid (1.0 g, 5.0 mmol) and potassium isocyanate (2.0 g, 5 equiv.) in a mixture of water and acetic acid (50 mL) was heated at 100 °C for 12 hours. After cooling, a white solid precipitated out. Filtration, washing of the filter cake with a mixture of water and MeOH, and drying it in vacuo gave the title compound (0.82 g, 80%) as a white solid.
MP > 350 °C.
Intermediate 23 (E)-3-(4-Acetylmethylaminophenyl)acrylic acid A stirred solution of N-(4-formylphenyl)-N-methylacetamide {1.0 g, 5.64 mmol), malonic acid (1.06 g, 1.8 equiv.) and piperidine (0.1 g, catalytic amount) in pyridine (3.5 mL) was heated at 60 °C for 12 hours. Pouring the resulting mixture into HCI (1N) gave a precipitate. Filtration gave the title compound (1.2 g, 98%) as a white solid.
MP: 213-215 °C.
Analysis for C,zH,3N03. 0.2Hz0:
Calculated: C,64.68; H,6.06; N,6.29;
Found: C,64.43; H,6.18; N,6.36%.
N-(4-Formyiphenyl)-N-methylacetamide (1.0 g, 46%) was obtained as an oil from N-{4-formylphenyl)acetamide (2.0 g, 12.2 mmol) in THF in the presence of iodomethane (1.2 mL, 1.5 equiv.) and NaH (0.73 g, 1.5 equiv., 60% in mineral oil).
'H NMR (CDC13, 250 MHz) b 2.0 (s, 3H), 3.4 {s, 3H), 7.4 (d, 2H), 8.0 (d, 2H).
Intermediate 24 (E)-3-(4-(2-Methoxyethylcarbamoyl)phenyllacrylic acid The same method was employed as in the preparation of Intermediate 23 but starting from 4-formyl-N-{2-methoxyethyl)benzamide to give the title compound -as a white powder in a 57% yield.
MP: 205 °C.
5 4-Formyl-N-(2-methoxyethyl)benzamide (158 mg, 48%) was obtained by oxidation of 4-hydroxymethyl-N-(2-methoxyethyl)benzamide (330 mg, 1.6 mmol) in DCM in the presence of Mn02 (3.0 g, 22 equiv.).
'H NMR {CDC13, 250 MHz) b 9.9 (s, 1 H), 7.8 (s, 4H), 6.8 (s, 1 H), 3.4-3.6 (m, 4H), 3.2 (s, 3H).
10 4-Hydroxymethyl-N-(2-methoxyethyl)benzamide (330 mg, 14%) was obtained as an oil (Rf= 0.7, DCM:MeOH (9:1 )) by coupling 4-(hydroxymethyl)benzoic acid (1.0 g, 6.5 mmol) with 2-methoxyethylamine (0.6 mL, 6.5 mmol) in the presence of Et3N (0.95 mL, 1.0 equiv.), EDCI (1.2 g, 1.0 equiv.) and HOBT (0.88 g, 1.0 equiv. ).
Intermediate 25 (E)-(4-(2-Dimethylaminoethoxy)phenyllacrylic acid The same method was employed as in the preparation of Intermediate 23 but starting from 4-(2-dimethylaminoethoxy)benzaldehyde to give the title compound as a white powder in a 100% yield.
MP: 243 °C.
4-(2-Dimethyfaminoethoxy)benzaldehyde (20.6 g, 65%) was obtained by alklylation of 4-hydroxybenzaldehyde (20 g, 164 mmol) in DMF with dimethylaminoethyl chloride (144 g, 8 equiv.) and KzC03 (24.9 g, 1.1 equiv.) for 16 hours at 80 °C.
'H NMR (CDC13, 250 MHz) 8 9.85 (s, 1 H), 7.9-7.8 (d, 2H), 7-6.9 (d, 2H), 4.2 (t, 2H), 2.7 (t, 2H), 2.3 (s, 6H).
Intermediate 26 (E)-3-f4-(2-Morphoiin-4-yl-ethylcarbamoyl)phenyllacrvlic acid The same method was employed as in the preparation of Intermediate 23 but starting from 4-formyl-N-(2-morpholin-4-yl-ethyl)benzamide to give the title compound as a gummy solid.
4-Formyl-N-(2-morpholin-4-yl-ethyl)benzamide (0.14 g, 55%) was obtained by oxidation of 4-hydroxymethyl-N-{2-morpholin-4-yl-ethyl)benzamide (0.24 g, 0.9 mmol) and Mn02 (1.73 g, 20 mmol).
'H NMR (CDC13, 250 MHz) b 10 (s, 1 H), 7.9 (s, 4H), 6.8 (s, 1 H), 3.5 (t, 5H), 2.6 (t, 2H), 2.3 (m, 5H).
4-Hydroxymethyl-N-(2-morpholin-4-yl-ethyl)benzamide (240 mg, 14%) was obtained as a colourless oil (Rf= 0.6, DCM:MeOH (9:1 )) by coupling 4 (hydroxymethyl)benzoic acid (1.0 g, 6.5 mmol) with 2-morpholinethylamine (0.85 g (1.0 equiv.) in the presence of Et3N (0.95 mL, 1.0 equiv.), EDCI (1.2 g, 1.0 equiv.) and HOST (0.88 g, 1.0 equiv.).
Intermediate 27 SE)-3-(4-Cyclohexvlcarbamoylphenyl)acrylic acid The same method was employed as in the preparation of Intermediate 23 but starting from N-cyclohexyl-4-formylbenzamide to give the title compound as a white powder in a 54% yield.
MP: 214 °C.
N-Cyclohexyl-4-formylbenzamide (0.6 g, 60%) was obtained by oxidation of N-cyciohexyl-4-(hydroxymethyl)benzamide (1.0 g, 4.29 mol) with MnOz (0.2 g, 22 equiv. ), as a white powder.
MP: 163 °C.
'H NMR {CDC13, 250 MHz) 8 10 (s, 1 H), 7.95 (s, 4H), 6.6 (s, 1 H), 4.1 {m, 1 H), 3.9-3.7 (m, 3H), 3.4-3.3 (m, 1H), 2.1-1.9 (m, 2H); 1.8-1.7 (m, 2H).
N-Cyclohexyl-4-{hydroxymethyl)benzamide(1.0 g, 66%) was obtained as white crystals by coupling 4-(hydroxymethyl)benzoic acid with cyclohexylamine (0.75 mL, 1 equiv. ) in the presence of Et3N (0.95 mL, 1.0 equiv. ), EDC I ( 1.2 g, 1.0 equiv.} and HOBT (0.88 g, 1.0 equiv.).
MP: 185 °C.
'H NMR (CDC13, 250 MHz} b 7.8-7.7 (d, 2H), 7.5-7.4 (d, 2H), 6.8 (s, 1 H), 4.8 (s, 2H), 4.2 (m, 1 H), 4.0-3.75 (m, 2H), 3.4-3.3 (m, 1 H), 2.7 (m, 1 H), 2-1.9 (m, 2H), 1.6 (m, 1 H), 1.1 (m, 1 H).
Intermediate 28 (E)-3-~4-f(Tetrahydrofuran-2-ylmethyl)carbamoyllphenyl)acrylic acid WO 97/43287 _ The same method was employed as in the preparation of Intermediate 23 but starting from 4-formyl-N-(tetrahydrofuran-2-ylmethyl)benzamide to give the title --compound as a white powder in a 49% yield.
MP: 215 °C.
4-Formyl-N-(tetrahydrofuran-2-ylmethyl)benzamide (0.36 g, 50%) (Rf= 0.3, DCM:MeOH) was obtained as an oil by oxidation of 4-hydroxymethyl-N-(tetrahydrofuran-2-ylmethyl)benzamide (0.72 g, 3.0 mmol) with Mn02 (0.36 g, 22 equiv. ).
4-Hydroxymethyi-N-(tetrahydrofuran-2-ylmethyl)benzamide (0.72 g, 46%) was obtained as a colourless oil (Rf= 0.6, DCM:MeOH (9:1 )) by coupling 4 (hydroxymethyl)benzoic acid (1.0 g, 6.5 mmol) with tetrahydrofuran-2-yl methylamine (0.67 mL, 1.0 equiv.) in the presence of EtsN (0.95 mL, 1.0 equiv.), EDCI (1;2 g, 1.0 equiv.) and HOBT (0.88 g, 1.0 equiv.).
Intermediate 29 (E)-1-(4-(2-Carboxyvinyl)benzoyllpiperidine-4-carboxylic acid ethyl ester The same method was employed as in the preparation of intermediate 23 but starting from 1-(4-formylbenzoyl)piperidine-4-carboxylic acid, ethyl ester to give the title compound as a white powder in a 46% yield.
MP: 165 °C.
1-(4-Formylbenzoyl)piperidine-4-carboxylic acid, ethyl ester (960 mg, 49%) (Rf=
0.6, DCM:MeOH(95:5)) was obtained as an oil by oxidation of 1-(4-hydroxymethylbenzoyl)piperidine-4-carboxylic acid, ethyl ester (2.0 g, 6.8 mmol) with MnOz (13.1 g, 22 equiv.).
'H NMR (CDC13, 250 MHz) b 10.0 (s, 1 H), 7.9 (d, 2H), 7.5 {d, 2H), 4.5 (d, 1 H), 4.1 (q, 2H), 3.6 (d, 1 H), 3.1 (br s, 2H), 2.5 (m, 1 H), 2.1-1.6 {m, 4H), 1.2 (t, 3H).
1-(4-Hydroxymethylbenzoyl)piperidine-4-carboxylic acid, ethyl ester (1.9 g, 100%) was obtained as a colorless oil (Rf= 0.1, DCM:MeOH (95:5)) by coupling 4-(hydroxymethyl)benzoic acid (1.0 g, 6.5 mmol) with 4-piperidine-4-carboxylic acid, ethyl ester (1 mL, 6.5 mmol ) in the presence of Et3N (0.95 mL, 1.0 equiv.), EDCI (1.2 g, 1.0 equiv.) and HOST (0.88 g, 1.0 equiv.).
. 'H NMR (CDC13, 250 MHz) b 7.2 (s, 4H), 4.5 (s, 2H), 4.3 {br s, 1H), 4.1 (q, 2H), 3.6 (br s, 1H),3 (t, 2H), 2.5 {m, 1H), 2.1-1.6 (m, 4H), 1.2 (t, 3H).
Intermediate 30 (E)-3-(4-Ethoxycarbonylmethylphenyl)acrylic acid The same method was employed as in the preparation of intermediate 23 but starting from (4-formylphenyl)acetic acid, ethyl ester gave the title compound as a yellow gum in a 52% yield.
'H NMR (CDC13, 250 MHz) 8 7.8-7.6 (m, 3H), 7.4-7.3 {d, 2H), 6.9-6.8 (d, 1 H), 4.1-3.9 {q, 2H), 3.55 (s, 2H), 1.2 (t, 3H).
4-(4-Formylphenyl)acetic acid, ethyl ester was prepared according to the procedure of Biagi,G.; Livi,O.; Verugi,E. Farmaco-Ed. Sc. 1988, 43, 597-611.
Intermediate 31 -1-(4-(2-Carboxyvinyl)phenyllpiperidine-4-carboxylic acid, ethyl ester The same method was employed as in the preparation of Intermediate 23 but starting from 1-(4-formylphenyl)piperidine-4-carboxylic acid, ethyl ester to give the title compound as a yellow powder in a 86% yield.
MP: 212 °C.
Analysis for C,~HZ,N04. 0.15H20:
Calculated: C,66.71; H,7.01; N,4.58;
Found: C,66.77; H,7.01; N,4.79%.
1-(4-Formylphenyl)piperidine-4-carboxylic acid, ethyl ester was prepared according to the procedure of Duckworth, D.M. HindIey,R.; Richard,M. EP
68669A1.
Intermediate 32 (E)-4-(2-Carboxyvinyl)-3-chlorobenzoic acid, methyl ester The same method was employed as in the preparation of Intermediate 23 but starting from 3-chloro-4-formylbenzoic acid, methyl ester to give the title compound as a white powder in a 58% yield.
MP: 221 °C.
3-Chloro-4-formylbenzoic acid, methyl ester (4.0 g, 81 %) was prepared by reaction of 4-bromomethyl-3-chlorobenzoic acid, methyl ester (6.0 g, 26 mmol) with silver p-toluenesulfonate (15.0 g, 2.0 equiv.) in 100 mL of DMSO in the presence of Et3N (100 mL, 7 equiv.) at rt for 1 hour. Quenching the resulting mixture with 100 mL of water, extraction with 2 x 100 mL of EtOAc, washing with 50 mL of water, drying over Na2S04 and flash chromatography with WO 97!43287 PCT/EP97/02277 cyclohexane:EtOAc (95:5) as eluting solvent, gave the title compound (2.3 g, 42%) as an oil. ..
'H NMR (CDC13, 250 MHz) b.10.5 (s, 1 H), 8.1 (s, 1 H), 7.8-7.7 (d, 1 H), 7.4-7.3 (d, 1 H), 3.8 (s, 3H).
4-Bromomethyl-3-chlorobenzoic acid, methyl ester (6.0 g, 87%) was obtained as an orange oil by refiuxing for 12 hours 4-methyl-3-chlorobenzoic acid, methyl ester (5.7 g, 31 mmol) with NBS (6.4 g, 1.2 equiv.) in the presence of a catalytic amount of AIBN in CC14.
'H NMR (CDC13, 250 MHz) 8 8.0 (s, 1 H), 7.9-7.8 (d, 1 H), 7.45-7.35 {d, 1 H), 4.5 (s, 1 H), 3.9 (s, 3H).
4-Methyl-3-chlorobenzoic acid, methyl ester (5.7 g, 53%) was obtained as an orange oil by refluxing overnight 4-methyl-3-chlorobenzoic acid (9.9 g, 58 mmol) in MeOH in the presence of PTSA.
'H NMR (CDC13, 250 MHz) 8 8.0 (d, 1 H), 7.85 (dd, 1 H), 7.3 (d, 1 H), 4.0 (s, 3H), 2.5 (s, 3H).
Intermediate 33 (E)-5-(2-Carboxyvinyl)-2-chlorobenzoic acid methyl ester The same method was employed as in the preparation of intermediate 32 but starting from 2-chloro-5-formylbenzoic acid, methyl ester to give the title compound as a yellow powder in a 76% yield.
MP: 194 °C.
2-Chloro-5-formylbenzoic acid, methyl ester (0.6 g, 25%) was obtained a gum by reaction of 5-bromomethyl-2-chlorobenzoic acid, methyl ester (3.1 g,11.7 mmol) with silver p-toluenesulfonate (6.4 g, 1.75 equiv.) in DMSO in the presence of Et3N (1.2 mL, 7 equiv.) at rt for 1 hour.
'H NMR (CDC13, 250 MHz) b 10 (s, 1 H), 8.4 (d, 1 H), 7.9 (dd, 1 H), 7.7-7.6 (d, 1 H), 4.0 (s, 3H).
5-Bromomethyl-2-chiorobenzoic acid, methyl ester (3.1 g, 11.7 mmol) was obtained as a gum in a 45% yield by refluxing for 12 hours 5-methyl-2 chlorobenzoic acid, methyl ester (4.78 g, 25.9 mmol) with NBS (5.56, 1.2 equiv.) . in the presence of a catalytic amount of AIBN in CC14.
'H NMR (CDC13, 250 MHz) 8 7.9 (s, 1 H), 7.4 (br s, 2H) 4.5 (s, 2H), 3.9 (s, 3H).
5-Methyl-2-chlorobenzoic acid, methyl ester (4.78 g, 90%) was obtained as a - brown oil, by refluxing overnight 3-methyl-4-chlorobenzoic acid (5.0 g, 29 mmol) in MeOH in the presence of a catalytic amount of PTSA.
'H NMR (CDC13, 250 MHz) 8 7.6 (s, 1 H), 7.25-7.2 (d, 1 H) , 7.15-7.1 (d, 1 H), 3.8 5 (s, 3H), 2.2 (s, 3H).
Intermediate 34 (E)-(3-Hydroxy-4-nitrophenyl)acrylic acid The same method was employed as in the preparation of Intermediate 23 but 10 starting from 3-hydroxy-4-nitrobenzaldehyde to give the title compound as a white powder in a 88% yield.
MP: 237 °C.
Intermediate 35 15 (E)-(3,5-Dimethyl-4-hydroxyphenyl)acryiic acid The same method was employed as in the preparation of Intermediate 23 but starting from 3,5-dimethyl-4-hydroxybenzaldehyde gave the title compound as a white powder in a 94% yield.
MP: 190 °C.
intermediate 36 (E)-(3-Nitro-4-hydroxy-5-methoxphenyl)acrylic acid The same method was employed as in the preparation of Intermediate 23 but starting from 3-vitro-4-hydroxy-5-methoxybenzaldehyde to give the title compound as a white powder in a 75% yield.
MP: 248 °C.
Intermediate 37 (E)-3-(3-Nitro-2-piperidin-1-yl-phenyl)acrylic acid The same method was employed as in the preparation of Intermediate 23 but starting from 2-chloro-3-nitrobenzaldehyde to give the title compound as a . yellow powder in a 100% yield.
'H NMR (CDC13, 250 MHz) 8 10.3 (br s, 1 H), 8.1 (d,1 H), 7.65 (dd, 1 H), 7.55 (dd, 1 H), 7.05 (t, 41 H). 6.3 (d, 1 H), 2.9 (m, 2H), 1.6 (m, 6H).
2-Chloro-3-nitrobenzaldehyde (150 mg, 20%) was prepared by reaction of 1-bromomethyl-2-chloro-3-nitrobenzene (1.0 g, 3.9 mmol) with silver p-toluenesulfonate (1.94 g, 1.75 equiv.) in DMSO in the presence of Et3N (4 mL, equiv.) at rt for 1 hour.
'H NMR (CDC13, 250 MHz) 8.10.5 (s, 1 H), 8.1 (dd, 1 H), 8.0 (dd, 1 H), 7.5 (t, 1 H).
1-Bromomethyl-2-chloro-3-nitrobenzene (13.3 g, 68%} was obtained as a yellow oil by refluxing for 2 hours a mixture of 2-chloro-3-nitrotoluene (10 g, 58 mmol) with NBS (10.3 g, 1 equiv.) in the presence of a catalytic amount of AIBN in CC14.
'H NMR (CDC13, 250 MHz) b 7.75 (dd, 1 H), 7.65 (dd, 1 H), 7.45 (m, 1 H), 4.6 (s, 2H).
Intermediate 38 E)-3-(4-Methyl-3,4-dihydro-2H-benzo(1 4loxazin-6-yl)acrvlic acid The same method was employed as in the preparation of Intermediate 23 but starting from 4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-carboxaldehyde (prepared according to the procedure of Kotha,S.; Bindra,V.; Kuki,A.
Heterocyles 1994, 38, 5-8) to give the title compound as a yellow powder in a 61 % yield MP: 190 °C.
Analysis for C,ZH,3N05:
Calculated: C,65.74; H,5.98; N,6.39;
Found: C,65.85; H,6.04; N,6.33%.
Intermediate 39 (E)-3-(2-Hydroxy-5-nitrophenyl)acrylic acid The same method was employed as in the preparation of Intermediate 23 but starting from 2-hydroxy-5-vitro benzaldehyde to give the title compound as a yellow powder in a 11 % yield.
MP:265-267.°C
Intermediate 40 IE)-3-(3-(Trifiuoromethanesulfonyloxy)phenyllacrylic acid The same method was employed as in the preparation of Intermediate 23 but starting from trifluoromethanesulfonic acid, 3-formylphenyl ester (prepared according to the procedure of Kingsbury,W.D.; Pendrak,l.; Leber,J.D_;
Boehm,J.C.; Mallet,B.; Sarau,H.M.; Foley, J.J.; Schmidt, D.B.; Daines,R.A. J.
Med. Chem. 1993, 36, 3308-3320) to give the title compound as pink crystals in a 36% yield.
MP: 107 °C.
Intermediate 41 (E)-3-(4-(Trifluoromethanesulfonyloxy)phenyllacrylic acid The same method was employed as in the preparation of Intermediate 23 but starting from trifluoromethanesulfonic acid, 4-formylphenyl ester (prepared according to the procedure of Creary,X.; Benage,B.; Hilton,K. J. Org. Chem.
1983, 48(77), 2887-2891 ) to give the title compound as white crystals in a 61 yield.
MP: 194 °C.
Intermediate 42 (E)-3-f4-(2-Pyrrolidin-1-ylethoxy)phenyllacrylic acid The same method was employed as in the preparation of Intermediate 23 but starting from 4-(2-pyrrolidin-1-ylethoxy)benzaldehyde (prepared according to the procedure of Sakaguchi,J.; Nishino, H.; Ogawa,N.; Iwanaga,Y.; Yasuda,S.;
Kato,H.; Ito,Y. Chem. Pharm. Bull. 1992, 40, 202-211 ) to give the title compound as a yellow solid in a 60% yield.
MP: 183 °C.
Intermediate 43 (E)-3-(4-Pyrrolidin-1-yiphenyl)acrylic acid The same method was employed as in the preparation of intermediate 23 but starting from (4-pyrrolidin-1-ylphenyl)benzaldehyde (prepared according to the procedure of Duckworth, D.M. HindIey,R.; Richard,M. EP 68669A1) to give the title compound as a yellow solid in a 65% yield.
MP: 265 °C.
Intermediate 44 -3-(4-ImidaZOl-1-ylphenyl)acrylic acid The same method was employed as in the preparation of Intermediate 23 but starting from 4-imidazol-1-ylbenzaldehyde (prepared according to the procedure -of Sircar,l.; DueII,B.; BristoI,J.A.; Weishaar,R.E.; Evans,D.B. J. Med. Chem.
1987, 30, 1023-1029) to give the title compound as pink crystals in a 5S%
yield.
MP: 326-327 °C.
Intermediate 45 ~E)-(S)-3-(4-(1-Methylpyrrolidin-2-ylmethoxy)phenyllacrylic acid The same method was employed as in the preparation of Intermediate 23 but starting from (S)-4-(1-methylpyrrofidin-2-ylmethoxy)benzaldehyde to give the title compound as a beige powder in a 66% yield.
MP: 251 °C.
[aJp2' _ -9 (c = 0.35, pyridine).
(S}-4-{1-Methyfpyrrolidin-2-ylmethoxy)benzaldehyde (0.96 g, 44%) was obtained as an orange oil by refluxing for 12 hours at 80°C, 4-hydroxybenzaldehyde (1.22 g, 10 mmol) with (S)-2-chloromethy!-1-methylpyrrolidine, hydrochloride (2.55 g, 1.5 equiv. ) in DMF in the presence of K2C03 (3.82 g, 2.8 equiv).
'H NMR (CDC13, 250 MHz) 8 9.9 (s, 1 H), 7.85 (d, 2H), 7.0 (d, 2H), 4.1 (dd, 1 H), 4.0 (dd,1 H), 3.1 {d tr, 1 H), 2.7 (m, 1 H), 2.5 (s, 3H), 2.3 (m, 1 H), 2 (m, 1 H), 1.8 (m, 3H).
(S)-2-Chloromethyl-1-methylpyrrolidine, hydrochloride was prepared according to the procedure of D'Ambra,T.E.; Bacon,E.R.; Edward, R.; BeII,M.R., Carabateas,P.M.; Eissenstat,M.A.; Kumar,V.; Mallamo,J.P,.; Ward,S.J. EP
444451 A2.
Intermediate 46 ~E)-3-(4-(2-Dimethylamino-1-methylethoxy)phenyllacrylic acid The same method was employed as in the preparation of Intermediate 23 but starting from 4-(2-dimethylamino-1-methylethoxy)benzaldehyde to give the title compound as a white powder in a 86% yield.
MP: 235 °C.
Analysis for C,aH,9N03.HC1:
Calculated: C,58.84; H,7.05; N,4.9;
Found C,S8.49; H,7.08; N.5.05%.
4-(2-Dimethylamino-1-methylethoxy)benzaldehyde (2.1 g, 18%) was obtained as an orange oil by refluxing for 12 hours, 4-hydroxybenzaldehyde (7 g, 57 mmoi), K2C03 (8.7 g, 1.1 equiv.) and 2-chloropropyldimethylamine, hydrochloride (13.6 g, 1.5 equiv. ) in DMF.
'H NMR (CDC13, 250 MHz) b 9.7 (s, 1 H), 7.65 (d. 2H), 6.85 (d, 2H), 4.5 (m, 1 H), 2.5 (m, 1 H), 2.3 (m, 1 H), 2.1 (m, 6H), 1.2 (d, 3H).
Intermediate 47 (E)-3-(4-(4-Methylpiperazin-1-yl)phenyljacrylic acid The same method was employed as in the preparation of intermediate 23 but starting from 4-(4-methylpiperazin-1-yl)benzaldehyde (prepared according to the procedure of Sakai,K.; Suzuki,M.; Nunami,K.; Yoneda,N.; Onoda,Y. Iwasawa,Y.
Chem. Pharm. Bull. 1980, 28, 2384-2393) to give the title compound as a white powder in a 65% yield.
MP: 223-226 °C.
Intermediate 48 (E)-3-i4-(2-Dimethylaminopropoxy)phenyllacrylic acid The same method was employed as in the preparation of Intermediate 23 but starting from 4-(2-dimethylaminopropoxy)benzaldehyde (prepared according to the procedure of Mizzoni,R.H. US 3483209) to give the title compound as a beige powder in a 100% yield.
MP: 231 °C.
Intermediate 49 (E)-3-(4-(2-Morpholin-4-ylethoxy)phenyllacrylic acid The same method was employed as in the preparation of Intermediate 23 but starting from 4-(2-morpholin-4-ylethoxy)benzaldehyde (prepared according to the procedure of Naruto,S.; Mizuta,H.; Sawayama,T.; Yoshida,T.; Uno,H.;
Kawashima,K.; Sohji,Y.; Kadokawa,T.; Nishimura,H. J. Med. Chem. 1982, 25, 1240-1245) to give the title compound as a white powder in a 96% yield.
MP: 228 °C.
Intermediate 50 (E)-3-~4-f2-(Ethylmethylamino)ethoxylphenyl~acrylic acid The same method was employed as in the preparation of Intermediate 23 but starting from 4-[2-(ethyimethylamino)ethoxy]benzaldehyde to give the title _ compound as a beige powder in a 73% yield.
MP: 206 °C.
5 Analysis for C,4H,9NOs.HCI:
Calculated: C,58.84; H,7.05; N,4.9;
Found C,59.08; H,7.07; N,5.02%.
4-[2-(Ethylmethylamino)ethoxy]benzaldehyde(5.0 g, 59%) was obtained as a brown oil by refluxing for 12 hours 4-hydroxybenzaldehyde (5 g, 41 mmol), 10 K2C03 (6.2 g, 1.1 equiv.) and (2-chloroethyl)ethylmethylamine, hydrochloride (9.7 g , 1.5 equiv. ) in DMF.
'H NMR (CDC13, 250 MHz) b 9.7 (s, 1 H), 7.7 (d, 2H), 6.9 (d, 2H), 4.1 (t, 2H), 2.6 (t, 2H), 2. (s, 6H).
15 Intermediate 51 ~E)-3-(4-(3-Dimethylaminopropenyl)phenyllacrylic acid This product was prepared by refluxing for .,four hours, (E)-3-[4-(3-dimethylaminopropenyl)phenyl]acrylic acid, methyl ester with NaOH (0.16 g, 2 equiv.) in 10 mL of MeOH. After evaporation of the solvent in vacuo, treatment 20 with 5 mL of HCI (1 N) gave the title compound (0.4 g, 85%) as a gummy orange solid.
'H NMR (CDC13, 250 MHz) 8 7.6 (d, 2H), 7.4 (d, 1 H), 7.2 (d, 2H), 6.6 (d, 1 H), 6.4 (d, 1 H), 5.8 (m, 1 H), 3.7 (d, 2H), 2.6 (s, 6H).
(E)-3-[4-(3-Dimethylaminopropenyl)pheny!]acrylic acid, methyl ester was 25 prepared by the following way: (2-dimethylaminoethyl)triphenylphosphonium bromide (7.2 g, 17.4 mmol) in 30 mL of DMF was treated with KHMDS (27 mL, 1.01 equiv., 0.5 M in toluene) at -78 °C for one hour. At -40 °C, 3-(4-formylphenyl)acrylic acid, methyl ester (2.54 g, 13.3 mmol, prepared according to the procedure of Syper,L.; Miochowski,J. Synthesis, 1984, 9, 747-752) was 30 added dropwise. The resulting mixture was stirred for 12 hours at rt and quenched with water. Extraction with EtOAc, drying over MgS04 and evaporation in vacuo gave a residue that was purified via flash chromatography with DCM:MeOH (90:10) as eluting solvent The title compound (1.1 g, 34%) was obtained as an orange oil.
'H NMR {CDC13, 250 MHz) b 7.6 (d, 1H), 7.4 (d, 2H), 7.2 (d, 2H), 6.5 (d, 1H), 6.4 (d, 1 H), 5.8 (m, 1 H), 3.2 (dd, 2H), 2.1 (s, 6H).
Intermediate 52 (E)-3-f4-(2-(Tertbutyldimethylsilanyloxyl-3-dimethylaminopropenyl)phenyllacrylic acid This product was prepared by refluxing for four hours (E}-3-[4-(2-(tertbutyldimethylsilanyloxy)-3-dirnethylaminopropanyl]phenylJacrylic acid, methyl ester (0.8 g, 2.03 mmol) and NaOH (1 N) (4 mL, 2 equiv. ) in 10 mL of MeOH. Evaporation of the solvent in vacuo and treatment with 5 mL of HCI (1 N) gave the title compound (0.4 g, 60%) as a beige solid solid.
MP: 207 °C.
(E)-3-[4-(2-(Tertbutyldimethyisilanyloxy)-3-dimethylaminopropoxy)phenyl]acrylic acid, methyl ester (0.8 g, 40%) was obtained as a yellow oil by reaction for 4 hours of (E)-3-[4-{3-dimethylamino-2-hydroxypropoxy)phenyl]acrylic acid, methyl ester (1.35 g, 5.13 mmol) with TBDMSCI (0.93 g, 6.2 mmol) in 50 mL of DMF in the presence of imidazole (0.84 g, 2.4 equiv.). After evaporation in vacuo, the residue was taken up in DCM, washed with water, dried over MgS04, evaporated in vacuo and purified via flash chromatography using DCM:MeOH
as eluting solvent.
'H NMR (CDC13, 250 MHz) S 7.5 (d, 1 H), 7.3 (d, 2H), 6.8 (d, 2H), 6.2 (d, 1 H}, 4.0 (m, 2H), 3.8 (m, 1 H), 3.7 (s, 3H), 2.4-2.2 (m, 2H), 2.1 {s, 6H), 0.7 (s, 9H), 0.0 (d, 6H).
(E)-3-(4-(3-Dimethylamino-2-hydroxypropoxy)phenyl]acrylic acid, methyl ester (1.5 g, 60%) was obtained as an oil by reaction of 4-(3-dimethylamino-2 hydroxypropoxy)benzaldehyde (2.0 g, 8.96 mmol) in 80 mL of toluene with triphenylphosphoranylidene methyl acetate (3.6 g, 1.2 equiv.) at 100 °C
for one day. After concentration in vacuo, the residue was taken up in DCM, washed with water, dried over Na2S04, evaporated in vacuo and purified via flash chromatography using DCM:MeOH (95:5) as eluting solvent.
'H NMR (CDCi3, 250 MHz) b 7.6 (d, 1 H}, 7.5 (d, 2H), 7.3 (d, 2H), 6.3 (d, 1 H), 4.2 (m, 1 H), 4.1 (m, 1 H), 3.8 (m, 3H), 3.3 (s, 1 H), 2.8 (dd, 1 H), 2.6 (dd, 1 H), 2.4 (s, 6H).
4-(3-Dimethylamino-2-hydroxypropoxy)benzaldehyde (8.2 g, 61 %) was obtained as an a yellow oil, by reaction of 4-oxiranylmethoxybenzaldehyde (6 g, 33.6 mmol, prepared according to the procedure of Baldwin,J.J.; Hirchmann,R.;
Lumma,W.C.; Ponticello,G.S.; Sweet,C.S.; Scriabine,A. J. Med. Chem. 1977, 20, 1024-1029) in 100 mL of MeOH with dimethylamine (34 mL, 2 equiv. ). The resulting mixture was stirred at reflux for 2 days. Evaporation in vacuo gave a residue that was taken up in DCM, washed with brine and dried over MgS04 and evaporated in vacuo.
'H NMR (CDC13, 250 MHz) 8 9.7 (s, 1H), 7.6 {d, 2H), 7.0 (d, 2H), 4. (m, 3H), 3.6 (s, 1 H), 2.5 (dd, 1 H), 2.3 (dd, 1 H), 2.25 (s, 6H).
Intermediate 53 (E)-3-(4-(2-(Dimethylaminoethylamino)phenyl)acrylic acid The same method was employed as in the preparation of Intermediate 23 but starting from 4-[2-(dimethylaminoethyl)amino]benzaldehyde (prepared according to the procedure of Klaus,M.; Mohr,P.; Weiss,E. EP 331983 A2) to give the title compound as an oil in a 100% yield.
'H NMR (CDC13, 250 MHz) 8 7.5 (d, 1 H), 7.2 (d, 2H), 6.5 (d, 2H), 6.1 (d, 1 H
j, 4.6 (s, 1 H), 3.0 (m, 2H), 2.5 (t, 2H), 2.2 (s, 6H).
Intermediate 54 (E)-3-~4-(2-(1.3-Dioxo-1 3-dihydroisoindol-2-yl)ethoxylphenyl)acryiic acid The same method was employed as in the preparation of intermediate 23 but starting from 4-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethoxy]benzaldehyde (prepared from the procedure of HindIey,R.M.; Haigh,D.; Cottam,G.P. WO
9207839 A1 ) to give the title compound as an oil in a 99% yield.
'H NMR (CDC13, 250 MHz) 8 12.3 (s, 1 H), 7.9 (m, 4H), 7.6 (d, 2H), 7.5 (d, 1 H), 7.0 (d, 2H), 6.4 (d, 1 H), 4.4 (t, 2H), 4.0 (t, 2H).
Intermediate 55 (E)-3-(4-(2-(Piperidin-1-ylethoxy)phenyllacrylic acid The same method was employed as in the preparation of Intermediate 23 but starting from 4-(2-piperidin-1-yl-ethoxy)benzaldehyde (which was prepared . according to the procedure of Naruto,S.; Mizuta,H.; Sawayama,T.; Yoshida,T.;
Uno,H.; Kawashima,K.; Sohji,Y.; Kadokawa,T.; Nishimura,H. J. Med. Chem.
1982, 25, 1240-1245), to give the title compound as a white powder in a 60%
yield.
MP: 231 °C.
Intermediate 56 (E)-3-~4-(2-(Tertbutoxvcarbonyimethvlamino)ethoxvlahenvllacrylic acid (E)-3-[4-(2-Methylaminoethoxy)phenyl]acrylic acid (0.8 g, 3.6 mmol) in dioxane (100 mL) was treated with NaOH (2N) (22 mL, 12 equiv.). After one hour of stirring at 70 °C, ditertbutyldicarbonate (1.6 g, 2 equiv.) was added slowly. The reaction was judged to be complete after 3 hours of stirring at 70 °C.
After filtration of the white precipitate, the filtrate was acidified to pH=1 with HCI (1 N).
A new white solid precipitated out . Filtration and drying in vacuo gave the title compound (0.6 g, 50%) as white crystals.
' H NMR (CDC13, 250 MHz) 8 7.8 (d, 1 H), 7.65 (d, 2H), 7.0 (d, 2H), 6.4 (d, 1 H), 4.25 (t, 2H), 3.7 (t, 2H), 3.1 (s, 3H), 1.5 (s, 9H).
(E)-3-[4-(2-Methylaminoethoxy)phenyl]acrylic acid (1.1 g, 41%) was obtained as a white solid by hydrolysis of (E)-3-[4-(2-methylaminoethoxy)phenyl]acrylic acid, methyl ester (3.0 g, 12.0 mmol) with NaOH (6.0 g, 12 equiv.) in MeOHITHF at 40 °C.
MP: 245 °C.
(E)-3-(4-(2-Methylaminoethoxy)phenyl]acrylic acid, methyl ester (3.0 g, 70%) was obtained as a yellow oil by reaction of trimethylphosphonoacetate (4.2 g, 23.0 mmol) and n-butyl lithium (9.0 mL, 18.0 mmol, 2.0 M in cyclohexane) at -°C, followed by the addition of 4-(2-methylaminoethoxy)benzaidehyde (3.2 g, 18.0 mmol) at - 40 °C. The resulting mixture was stirred at rt for 16 hours, quenched with water, extracted with EtOAc, dried over MgS04 and concentrated in vacuo.
'H NMR (CDC1~, 250 MHz) b 7.65 (d, 1 H), 7.45 (d, 2H), 6.9 (d, 2H), 6.25 (d, 1 H), 4.10 (t, 2H), 3.75 (s, 3H), 2.95 (t, 2H), 2.5 (s, 3H).
4-(2-Methylaminoethoxy)benzaldehyde (3.2 g, 51 °~) was obtained as a yellow oil by reaction of 4-(2-methylaminoethoxy)benzonitrile (7.0 g, 40.0 mmol) with diisobutylaiuminum hydride (40 mL, 1.5 equiv., 1.5 M in toluene) in toluene (400 mL) at - 78°C. After 4 hours of stirring at - 78 °C the resulting mixture was treated with a mixture of waterIMeOH (4 mL). At rt an additional 20 r~L of water was added. The resulting suspension was filtered on a bed of celite~The celite was washed with Et20 (3 x 200 mL). The filtrate was concentrated in vacuo and purified via flash chromatography of silica gel using MeOH:DCM (1:9) as eluting solvent.
'H NMR (CDC13, 250 MHz) b 9.8 {s, 1 H), 7.8 (d, 2H), 7.0 (d, 2H), 4.1 (t, 2H), 2.9 (t, 2H), 2.5 (s, 3H).
4-(2-Methylaminoethoxy)benzonitrile (0.6 g, 15%) was obtained as a yellow oil by reaction of 4-(2-chloroethoxy)benzonitrile (2.0 g, 11.0 mmol, prepared according to the procedure of Mizuno,K.; Kimura,Y.; Otsuji,Y. Synthesis, 1979, 9, 688) with methylamine (4.3 mL, 5 equiv., 40% in water) at 70 °C for 16 hours.
The resulting mixture was extracted with DCM, dried over MgS04, concentrated in vacuo and purified via flash chromatography of silica gel using MeOH:DCM
(2:8) as eluting solvent, to give the title compound.
'H NMR (CDC13, 250 MHz) 8 7.6 (d, 2H), 7.0 (d, 2H), 4.1 (t, 2H), 3.0 (t, 2H), 2.5 (s, 3H).
Example 1 ~E)-1-(1-Phenyl-1.3 4 9-tetrahydro-Q-carboiin-2-yl)-3-phenylpropene 1 one To a solution of intermediate 1 (0.2 g, 0.81 mmol) and NaHC03 {0.08 g, 1.2 equiv.) in 10 mL of DCM was added (E)-cinnamoyl chloride (0.2 g, 1.5 equiv.).
After 4 hours of stirring at rt the reaction was judged to be completed by tlc monitoring (Si02, DCM:MeOH 98:2) and was quenched with 5 mL of a saturated aqueous solution of NaHC03. The reaction mixture was extracted with DCM, washed with brine (5 mL), dried over MgS04 and concentrated in vacuo. Flash chromatography on a 2 x 20 cmz column using DCM:MeOH (98:2) as eluting solvent and removal of the solvent in vacuo gave after recrystallization from propanol, the title compound (0.1 g, 33%) as white crystals.
MP: 130-132 °C.
Analysis for CZ6Hz2N20:
Calculated: C,82.51; H,5.86; N,7.40;
Found: C,82.24; H,5.93; N,7.36%.
Example 2 (El-1-(1-Phenyl-1.3 4.9-tetrahydro-~-carbolin-2-yl)-3-(4-nitrophenyl)propene 1 one The same method as employed as in the preparation of Example 1 but starting from (E)-4-nitrocinnamoyl chloride gave after recrystallization from iPr20:2-propanol (3:1 ), the title compound as a yellow powder in a 47% yield.
MP: 230-231 °C.
5 Analysis for CzsHZ,N303:
Calculated: C,73.74; H,5.00; N,9.92;
Found: C,73.89; H,5.12; N,9.86%.
Example 3 10 (E)-1-(1-Phenyl-1,3,4,9-tetrahydro-a-carbolin-2-yi)-3-(4-trifluoromethylphenyl)-propene-1-one The same method as employed in the preparation of Example 1 but starting from (E)-4-trifluoromethylcinnamoyl chloride gave after recrystallization from pentane, the title compound as a white powder in a 41 % yield.
15 MP: 211 °C.
Analysis for CZ,H2,F3N20. 0.4Hz0:
Calculated: C,71.48; H,4.84; N,6.17;
Found: C,71.84; H,4.81; N,6.19%.
20 Example 4 ~E )-1-( 1-Phenyl-1, 3,4.9-tetrahydro-~-carbol in-2-yl )-3-(4-methoxy-phenyl)propene-1-one The same method as employed in the preparation of Example 1 but starting from (E)-4-methoxycinnamoyl chloride gave after recrystallization from 2-propanol, 25 the title compound as white crystals in a 61 % yield.
MP: 160-163 °C.
Analysis for C2~Hz4N202. 0.5(2-propanol):
Calculated: C,78.06; H,6.44; N,6.39;
Found: C,78.04; H,6.02; N,5.97%.
Example 5 (E)-1-(1-(4-Methoxyphenyl)-1.3.4,9-tetrahydro-Q-carboiin-2-yl~-3-(4-trifluoromethyiphenyl )propene-1-one The same method as employed in the preparation of Example 1 but starting from intermediate 2 and (E)-4-trifluoromethylcinnamoyl chloride gave after recrystallization from pentane, the title compound as a white powder in a 61 yield.
MP: 130-135 °C.
Analysis for CZ8H2sNzOzF3. 0.3H20:
Calculated: C,69.79; H,4.94; N,5.81;
Found: C,69.9; H,4.84; N,5.73%.
Example 6 (E)-N-(4-f3-Oxo-3-(1-phenyl-1 3.4.9-tetrahydro-(3-carbolin-2-yl)propenyllphenyll-acetamide To a solution of Intermediate 1 (0.2 g, 0.81 mmol) in 40 mL of DCM were added Et3N (0.13 mL, 1.1 equiv. ), DCC (0.18 g, 1.1 equiv. ), HOBT (0.12 g, 1.1 equiv. ) and (E)-3-(4-acetylaminophenyl)acrylic acid (0.18 g, 1.1 equiv.). After 24 hours of stirring at rt the reaction was judged to be completed by tlc monitoring (SiOz, DCM:MeOH 95:5) and was quenched with 150 mL of water. A white solid precipitated out and was filtered off. The filtrate was extracted with DCM, washed with brine (5 mL), dried over MgS04 and concentrated in vacuo. Flash chromatography on a 2.5 x 25 cm2 column of silica gel using DCM:MeOH (98:2) as eluting solvent and removal of the solvent in vacuo gave the title compound (0.18 g, 51 %) as yellow crystals after recrystailization from 2-propanol:pentane.
MP: 177-180 °C.
Analysis for CzeH2sN3OzØ7H20:
Calculated: C,75.05; H,5.94; N,9.38;
Found: C,75.01; H,5.81; N,9.22%.
Example 7 ~E)-1-f 1-(4-Methoxyphenyl)-1,3.4,9-tetrahydro-Q-carbolin-2-yl)-3-phenylpropene-1-one The same method as employed in the preparation of Example 1 but starting from Intermediate 2 gave the title compound as white crystals in a 56% yield.
MP: 127 °C.
Analysis for Cz~H24N20z. 0.5Hz0:
Calculated: C,77.67; H,6.04; N,6.71;
Found: C,77.91; H,6.0; N,6.73%.
Example 8 - (E)-1-[1-(3.4-Methylenedioxyphenyl)-1.3.4.9-tetrahydro-ti-carbolin-2-yll-3-phenyl-propene-1-one The same method as employed in the preparation of Example 1 but starting from Intermediate 7 gave after recrystallization from 2-propanol:iPr20 (2:8), the title compound as white crystals in a 38% yield.
MP: 236-238 °C.
Analysis for Cz,H24NZOz. 0.5H20:
Calculated: C,76.76; H,5.25; N,6.63;
Found: C,76.87; H,5.35; N,6.54%.
Example 9 (El-1-( 1-Phenyl-1.3.4,9-tetrahydro-Q-carbolin-2-yl)-3-(4-formylphenyl)propene-one The same method as employed in the preparation of Example 6 but starting from (E)-4-formylcinnamic acid gave after recrystallization from acetone:MeOH
(10:3), the title compound as yellow crystals in a 60% yield.
MP: 146 °C.
Analysis for Cz,H22N202. 0.4H20:
Calculated: C,78.39; H,5.55; N,6.77;
Found: C,78.33; H,5.54; N,6.67%.
Example 10 (E)-N-[4-[3-Oxo-3-(1-(4-nitrophenyl)-1 3 4 9-tetrahydro-Q-carbolin-2-_ yl)propenyll-phenyllacetamide The same method as employed in the preparation of Example 6 but starting from Intermediate 3 gave after recrystallization from 2-propanol, the title compound as white crystals in a 51 % yield.
MP: 185 °C.
Analysis for CzaH2aNa04. 0.6H20:
Calculated: C,68.45; H,5.17; N,11.4;
Found: C,68.37; H,5.06; N,11.26%.
Example 11 (E)-1-(1-(4-Nitrophenyl)-1.3.4.9-tetrahydro-Q-carbolin-2-yl~-3-phenylpropene-1-one The same method as employed in the preparation of Example 1 but starting from Intermediate 3 gave after recrystallization from 2-propanol, the title compound as a yellow powder in a 15% yield.
MP: 205-206 °C.
Analysis for CzsH2,N3O3. 0.2H20:
Calculated: C,73.12; H,5.05; N,9.84;
Found: C,72.95; H,5.15; N,9.81 %.
Example 12 E)-1-(1-(4-Trifluoromethoxyphenyl)-1,3.4 9-tetrahydro-Q-carbofin-2-yll-3-phenyl-propene-1-one The same method as employed in the preparation of Example 1 but starting from Intermediate 4 gave after recrystallization from pentane, the title compound as white crystals in a 44% yield.
MP: 119 °C.
Analysis for CZ,HZ,NZOZF3:
Calculated: C,70.12; H,4.58; N,6.06;
Found: C,70.02; H,4.58; N,6.02%.
Example 13 1 E)-1-( 1-(4-Methylphenyl )-1, 3.4.9-tetrahydro-Q-carbo I i n-2-yll-3-phenylpropene-1-one The same method as employed in the preparation of Example 1 but starting from Intermediate 6 gave after recrystallization from pentane, the title compound as white crystals in a 50% yield.
MP: 125-127 °C.
Analysis for C2,H2aN20. 0.6Hz0:
Calculated: C,80.41; H,6.3; N,6.95;
Found: C,80.49 ; H,6.2 ; N,7.25%.
Example 14 ~E)-N-(4-(3-Oxo-3-(1-(3.4-methylenedioxyphenyl)-1.3 4 9-tetrahydro-(3-_carbolin-2-yl)-propenyllphenyllacetamide The same method as employed in the preparation of Example 6 but starting from Intermediate 7 and {E)-3-(4-acetylaminophenyl)acrylic acid gave after recrystallization from 2-propanol:pentane, the title compound as white crystals in a 85% yield.
MP: 185 °C.
Analysis for Cz9H25N3Oa. 0.4H20:
Calculated: C,71.56; H,5.34; N,8.63;
Found: C,71.59; H,5.32; 8.66%.
Example 15 LE)-4-(3-Oxo-3-(1-phenyl-1 3,4.9-tetrahydro-Q-carbolin-2-yl)-propenyflbenzoic acid. methyl ester To a solution of Example 9 (0.2 g, 0.49 mmol) in 20 mL of MeOH was added activated MnOz {0.59 g, 14 equiv. ), sodium cyanide (0.05 g, 2 equiv. ) and acetic acid (0.05 g, 1.7 equiv.). The resulting mixture was stirred for 5 hours. Tlc monitoring showed a new compound (Si02,DCM:MeOH (95:5), Rf= 0.82). The mixture was filtered through a short column of cefite using 150 mL of a mixture of MeOH:EtOAc:CHCl3 (1:25:25). After evaporation in vacuo the residue was purified via flash chromatography on a 2 x 20 cmz column using DCM as eluting solvent. Evaporation and recrystallization from EtOH gave the title compound (0.15 g, 70%) as yellow crystals.
MP: 222 °C.
Analysis for C28H24NzOs. 0.03H20:
Calculated: C,76.1; H,5.61; N,6.34;
Found: C,76.05; H,5.68; N,6.15%.
Example 16 (E)-1-(1-(2-Chlorophenyl)-1,3.4.9-tetrahydro-(3-carbolin-2-yll-3-phenylpropene-one The same method as employed in the preparation of Example 1 but starting from Intermediate 17 gave after recrystaliization from EtOH, the title compound as white crystals in a 27% yield.
MP: 220-221 °C.
Analysis for CZ6Hz~N20C1:
Calculated: C,75.63; H,5.13; N,6.78;
Found: C,75.4; H,5.21; N,6.79%.
Example 17 E)-1-(1-Phenyl-1,3,4.9-tetrahydro-a-carbolin-2-yl)-3-(3 4-5 methylenedioxyphenyl)-propene-1-one The same method as employed in the preparation of Example 1 but starting from (E)-(3,4-methylenedioxy)cinnamoyl chloride gave after recrystallization from EtOH, the title compound as a white powder in a 65% yield.
MP: 221 °C.
10 Analysis for Cz,HzzNz03. 0.3Hz0:
Calculated: C,75.79; H,5.32; N,6.55;
Found: C,75.76; H,5.37; N,6.53%.
Example 18 15 (E)-1-(1-(3.4-Methylenedioxyphenyl)-1,3.4.9-tetrahydro-(3-carbolin-2-yll-3-(4-bromophenyl)propene-1-one The same method as employed in the preparation of Example 1 but starting from Intermediate 7 and (E)-4-bromocinnamoyl chloride gave after recrystallization from EtOH, the title compound as a white powder in a 10% yield.
20 MP: 188-190 °C.
Analysis for CZ~H2,NzO3Br. 0.3H20:
Calculated: C,63.99; H,4.3; N,5.53;
Found: C,63.53; H,4.23; N,5.38%.
25 Example 19 (E)-1-(1-(4-Chlorophenyl)-1 3.4 9-tetrahydro-(3-carbolin-2-yl)-3-phenylpropene-one The same method as employed in the preparation of Example 1 but starting from Intermediate 5 gave after recrystallization from EtOH, the title compound as 30 white crystals in a 72% yield.
MP: 213-214 °C.
Analysis for CzsHz,N20C1:
Calculated: C,75.63; H,5.13; N,6.78;
Found: C,75.55; H,5.16; N,6.63%
Example 20 ( E )-1-f 1-(3.4-Methylenedioxyphenyl )-1, 3.4.9-tetrahydro-~-carbol i n-2-yll-3-(4-ethoxyphenyl)propene-1-one To a solution of Intermediate 7 (0.2 g,0.68 mmol) in 40 mL of DCM were added Et3N (0.1 mL, 1.1 equiv.), EDCI (0.14 g, 1.1 equiv.), HOBT (0.12 g, 1.1 equiv.) and (E)-4-ethoxycinnamic acid (0.14 g, 1.1 equiv.). After 48 hours of stirring at rt the reaction was judged to be completed by t1c monitoring (Si02, DCM:MeOH
(95:5)) and was quenched with 50 mL of water. The reaction mixture was extracted with DCM, washed with brine (5 mL), dried over MgS04 and concentrated in vacuo. Flash chromatography on a 2.5 x 25 cmz column of silica gel using DCM:MeOH (98:2) as eluting solvent and removal of the solvent in vacuo gave the title compound (0.21 g, 67%) as white crystals after recrystallization from EtOH.
MP: 199-200 °C.
Analysis for Cz9H26Nz04. 0.3Hz0:
Calculated: C,73.8; H,5.68; N,5.94;
Found: C,73.72; H,5.68; N,5.97%.
Example 21 (E)-4-f3-Oxo-3-(1-(3.4-methylenedioxyphenyl)-1.3.4.9-tetrahydro-(i-carbolin-2-yl)propenyllacetic acid, phenyl ester The same method as employed in the preparation of Example 20 but starting from (E)-4-acetoxycinnamic acid gave after recrystallization from MeOH, the title compound as white crystals in a 54% yield.
MP: 216 °C.
Analysis for CzsHz4NzOs:
Calculated: C,72.49; H,5.03; N,5.83;
Found: C,72.3; H,5.11; N,5.84%.
Example 22 (E)-1-f 1-(3,4-Methylenedioxyphenyl)-1.3.4.9-tetrahydro-Q-carbolin-2-yll-3-(4-hydroxyphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-4-hydroxycinnamic acid gave after recrystaltization from EtOH:pentane the title compound as white crystals in a 57% yield.
MP: 175 °C.
Analysis for Cz~HzZN2O4 Ø3H20:
Calculated: C,73.06; H,5.13; N,6.31;
Found: C,73.14; H,5.36; N,6.44%.
Example 23 (E)-1-! 1-(3.4-Methylenedioxyphenyl)-1.3.4.9-tetrahydro-Q-carbol in-2-yll-3-(4-formylphenyl )propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-4-formylcinnamic acid gave after recrystallization from MeOH the title compound as white crystals in a 100% yield.
MP: 208 °C.
Analysis for C28HzzN204. 0.3H20:
Calculated: C,73.77; H,5.00; N,6.15;
Found: C,73.77; H,4.96; N,6.05%.
Example 24 ( E)-1-!4-!3-Oxo-3-( 1-(3.4-methylenedioxyphenyl )-1, 3.4, 9-tetrahydro-(3-carboi in-2-yl)-propenyllphenyll-3-phenylurea The same method as employed in the preparation of Example 20 but starting from (E)-3-[4-(3-(phenylureido)phenyl]acrylic acid (which was prepared in situ by reaction of phenylisocyanate (1 equiv.), (E)-4-aminocinnamic acid (1 equiv.) and Et3N (1 equiv.)), gave after recrystallization from EtOH the title compound as white crystals in a 61 % yield.
MP: 192 °C.
Analysis for C~HzeN4Oa. 0.22(EtOH:H20):
Calculated: C,72.48; H,5.26; N,9.82;
Found: C,72.87; H,5.17; N,9.42%.
Example 25 (E)-1-!1-(3,4-Methyienedioxyphenyl)-1.3.4.9-tetrahydro-Q-carbolin-2-yll-3-(4-aminophenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-4-aminocinnamic acid gave after recrystallization from EtOH:DCM:2 propanol (10:2:2) the title compound as white crystals in a 63% yield.
WO 97/43287 PCT/EP97/02277 _ MP: 262-265 °C.
Analysis for Cz7H23N3O3. 0.3Hz0:
Calculated: C,73.22; H,5.37; N,9.49;
Found: C,72.9; H,5.47; 9.32%.
Example 26 ~E~-1-(1-(3 4-Methylenedioxyphenyl)-1,3.4.9-tetrahydro-Q-carbolin-2-yll-3-(4-nitrophenyl)-propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-4-nitrocinnamic acid gave after recrystallization from EtOH, the title compound as yellow crystals in a 69% yield.
MP: 158° C.
Analysis for CZ~Hz,N30s:
Calculated: C,69.37; H,4.53; N,8.99;
Found: C,69.57; H,4.61; N,8.92%.
Example 27 (El-1-(1-(3 4-Methylenedioxyphenyl)-1,3.4,9-tetrahydro-Q-carbolin-2-yll-3-((4-bis(methylsulfonyl)aminophenyllpropene-1-one This product was prepared by refluxing for two hours a solution of Example 25 (0.2 g, 0.6 mmol), mesyl chloride (0.1 mL, 5 equiv.), Et3N {0.4 mL, 5 equiv.) in 20 mL of THF. The disappearance of the starting material and the formation of a new compound were confirmed by tlc (Si02, DCM:MeOH (95:5), Rf= 0.84). After evaporation of THF the residue was dissolved in DCM (15 mL) and washed with HZO (10 mL). The organic solution was dried over MgSOa and concentrated in vacuo to give a residue which was purified via flash chromatography on a 2.5 x 25 cm2 column using DCM:MeOH (98:2) as eluting solvent. Recrystallization from EtOH gave the title compound (0.09 g, 25%) as a white powder.
MP: 276 °C.
Analysis for C29H27N3O7Sz. 0.3Hz0:
Calculated: C,58.14; H,4.64; N,7.01;
Found: C,57.76; H,4.69; N,6.81%.
Example 28 LE)-4-f 3-Oxo-3-f 1-(3.4-methylenedioxyphenyl)-1.3 4 9-tetrahydro-a-carbolin-2-yll-propenyllbenzoic acid. methyl ester The same method as employed in the preparation of Example 20 but starting from (E)-4-(2-carboxyvinyl)benzoic acid, methyl ester acid (prepared according to the procedure of Taylor,E.C.; Young, W.B.; Chaudhari,R.; PateI,H.
Heterocycles 1993, 36, 1897-1908), gave after recrystallization from MeOH:H20 (99:1 ), the title compound as yellow crystals in a 84% yield.
MP: 211 °C.
Analysis for CZ9Hz4Nz05. 0.3H20:
Calculated: C,71.68; H,5.1; N,5.76;
Found: C,71.76; H,5.02; N,5.68%.
Example 29 (E)-N-f4-f3-Oxo-3-f1-(3.4-methylenedioxyphenyl)-1 3 4 9-tetrahydro-f3-carbolin-2-yllpropenyllphenyilmethanesulfonamide The same method as employed in the preparation of Example 27 but using 1 equiv. of mesyl chloride gave after recrystallization from EtOH the title compound as an off-white powder in a 10% yield.
MP: 203 °C.
Analysis for C2gHz5N3O5S. 0.2H20:
Calculated: C,64.78; H,4.93; N,8.09;
Found: C,64.66; H,5.15; N,7.73%.
Example 30 (E)-4-f3-Oxo-3-f1-(3,4-methytenedioxyphenyl)-1 3 4 9-tetrahydro-(3-carboiin-2-Yllpropenyllbenzamide into a solution of Example 28 (0.2 g, 0.4 mmol) in 50 mL of MeOH was bubbled ammonia and the resulting mixture was stirred at 35°C for two days. The mixture was concentrated in vacuo to give a residue which was washed with 2x30 mL of water. Extraction, drying over MgS04 and concentration in vacuo gave a residue that was purified via radial chromatography using DCM:MeOH (90:10) as eluting solvent and via preparative chromatography (20x20- cm plate, 0.5 mm , SiO~) using the same eluant. The title compound (0.025 g, 13%) was isolated as white crystals after recrystallization from MeOH:H20.
MP: 183 °C.
Analysis for CZ8H23N3O4:
Calculated: C,70.07; H,5.17; N,8.76;
Found: C,69.97; H,5.16; N,8.84%.
5 Example 31 ~E )-4-I3-Oxo-3-f 1-f 3.4-methylenedioxyphenyl )-1, 3,4.9-tetrahydro-(3-carbolin-2-yll-propen~lbenzoic acid This product was prepared by refluxing for four hours a stirred solution of Example 28 (0.5 g, 1.04 mmol) and NaOH (1N) (5.2 mL, 5 equiv.) in 50 mL of 10 MeOH. After evaporation of the solvent in vacuo, the residue was treated with 10 mL of HCI (1 N). A solid precipitated out and was filtered off.
Recrystallization from MeOH gave the title compound (0.35 g, 72%) as white crystals.
MP: 254-256 °C.
Analysis for CzeHZZN20s. 0.2H20:
15 Calculated: C,72.09; H,4.75; N,6.01;
Found: C,71.60; H,4.84; N,5.88%.
Example 32 (E)-1-(1-(3.4-Methylenedioxyphenyl)-1,3.4,9-tetrahydro-Q-carbolin-2-yll-3-(4-20 cyanophenvl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-4-cyanocinnamic acid gave after recrystallization from EtOH the title compound as white crystals in a 69% yield.
MP: 167 °C.
25 Analysis for CzeHz,N303. 0.1 H20:
Calculated: C,74.85; H,4.76; N,9.35;
Found: : C,74.72; H,4.81; N,9.27%.
Example 33 30 (E)-1-f1-(3.4-Methylenedioxyphenyl)-1,3.4.9-tetrahydro-(i-carbolin-2-yll-3-(4-trifluoromethyfphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-4-trifluoromethylcinnamic acid gave after recrystallization from EtOH
the title compound as white crystals in a 73% yield.
35 MP: 233 °C.
Analysis for CzaHz,F3Nz03. 0.2H20:
Calculated: C,68.07; H,4.37; N,5.67;
Found: C,68.04; H,4.32; N,5.65%.
Example 34 ( E )-1-f 1-(3,4-Methylened ioxyphenyl )-1, 3.4. 9-tetrahydro-Q-carbo f in-2-yl l-3-(3.4-methylenedioxyphenyl )propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3,4-methylenedioxycinnamic acid gave after recrystallization from EtOH
the title compound as yellow crystals in a 73% yield.
MP: 233 °C.
Analysis for CzaHzzNzOs:
Calculated: C,72.09; H,4.75; N,6.01;
Found: C,71.79; H,4.76; N,5.93%.
Example 35 (E)-1-(1-(3,4-Methylenedioxyphenyl)-1.3.4.9-tetrahydro-a-carbolin-2-yll-3-(4-chlorophenyl )propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-4-chlorocinnamic acid gave after recrystallization from EtOH the title compound as white crystals in a 55% yield.
MP: 203 °C.
Analysis for Cz~H2,N203C1:
Calculated: C,70.97; H,4.63; N,6.13;
Found: C,71.04; H,4.76; N,6.04%.
Example 36 ( ~ 1-( 1-(3, 4-Methylenedi oxyphenyl)-1, 3,4.9-tetrahydro-Q-carbol in-2-yll-3-(4-trifluoromethoxyphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-4-trifluoromethoxycinnamic acid (prepared according to the procedure of Yagupol'skii, 1_.M., Troitskaya, V.I. Zhurnal Obshchei Khimii 1960, 30, 3104) gave after recrystallization from EtOH the title compound as yellow crystals in a 35% yield.
MP:203-205°C.
Analysis for C2sHz,F3Nz04:
Calculated: C,66.4; H,4.18; N,5.53;
Found: C,66.23; H,4.26; N,5.54.
Example 37 LE)-1-f 1-(3.4-Methylenedioxyphenyl)-1,3.4,9-tetrahydro-Q-carbolin-2-yll-3-(4-methylphenyl )propene-1-one The same method as employed in the preparation of Example 20 but starting from (E}-4-methylcinnamic acid gave after recrystallization from EtOH:DCM
(99:1 ) the title compound as white crystals in a 67% yield.
MP: 240 °C.
Analysis for CZ$H24NzOs. 0.7Hz0:
Calculated: C,74.88; H,5.7; N,6.24;
Found: C,74.83; H,5.45; N,6.35.%.
Example 38 (E)-f4-f3-Oxo-3-(1-(3 4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-t3-carboiin-2-yl)propenyllphenyllurea The same method as employed in the preparation of Example 20 but starting from Intermediate 22 gave after recrystallization from EtOH the title compound as white crystals in a 49% yield.
MP: 208 °C.
Analysis for CZSHz4N4O4. 0.5HzO:
Calculated: C,68.7; H,5.15; N,11.44;
Found: C,68.51; H,5.14; N,11.35%.
Example 39 (E)-1-(1-(3.4-Methylenedioxyphenyl)-1.3,4.9-tetrahydro-(3-carbolin-2-yll-3-(4-hydroxymethylphenyl )propene-1-one This product was prepared by stirring a solution of Example 23 (0.3 g, 0.66 rnmol) in 40 mL of MeOH with NaBH4 (0.1 g, 4 equiv.) at rt for two hours.
Evaporation of the solvent gave a residue which was dissolved in DCM (100 mL) and washed twice with water (50 mL). Extraction with DCM, drying over MgS04 and evaporation in vacuo gave the title compound (0.2 g, 67%) as white crystals after recrystallization from EtOH.
MP: 206 °C.
Analysis for C28Hz4NzO4. 0.3EtOH:
Calculated: C,73.66; H,5.58; N,6.01;
Found: C,73.69; H,5.5; N,6.06%.
Example 40 ~E)-N-Benzyl-4-(3-oxo-3-(1-(3 4-methylenedioxyphenvll-1 3 4 9-tetrahvdro Q
carbolin-2-yl)propenyllbenzamide This product was prepared by stirring a solution of Example 31 (0.2 g, 0.43 mmol) in 50 mL of THF with benzylamine (0.5 mL, 9 equiv.), Et3N (1 mL) and diphenylphosphoryl azide (0.5 mL). After two days the reaction mixture was concentrated in vacuo. The residue was taken up in 100 mL of DCM and washed with 3 x 50 mL of water. Drying over Na2S04 and evaporation of the solvent gave a residue which was purified via flash chromatography with cyclohexane and EtzO. Evaporation in vacuo and recrystallization from EtOH
gave the title compound (0.03 g, 13%) as white crystals.
MP: 203 °C.
Analysis for C35H29N3O4:
Calculated: C,75.66; H,5.26; N,7.56;
Found: C,75.5; H,5.22; N,7.55%.
Example 41 (E)-1-(1-(3,4-Methylenedioxyphenyl)-1 3 4 9-tetrahydro-Q-carbolin-2-yll-3 (2 4 dichlorophenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-2,4-dichlorocinnamic acid gave after recrystallization from EtOH:H20 the title compound as a white powder in a 66% yield.
MP: 194 °C.
Analysis for Cz,H2oNz03C12:
Calculated: C,66.00; H,4.10; N,5.70;
Found: C,65.85; H,4.13; N,5.78%.
Example 42 (E)-1-(1-(3.4-Methylenedioxyphenyl)-1 3 4 9-tetrahydro-Q-carbolin-2-yll 3 (3 methoxy-4-hydroxyphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3-methoxy-4-hydroxycinnamic acid gave after recrystallization from EtOH:H20 (10:1 ) the title compound as an oft-white powder in a 62% yield.
MP: 155 °C.
Analysis for CzsH2aN20s:
Calculated: C,71.78; H,5.16; N,5.98;
Found: C,71.44; H,5.16; N,5.76%.
Example 43 ~,E)-1-f1-(3.4-Methylenedioxyphenyl)-1.3.4.9-tetrahydro-Q-carbolin-2-yll-3-(3-hydroxy-4-methoxyphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3-hydroxy-4-methoxycinnamic acid gave after recrystallization from EtOH:HZO the title compound as an off-white powder in a 47% yield.
MP: 213 °C.
Analysis for CZSHzaNzOs. 0.3H20:
Calculated: C,70.96; H,5.23; N,5.91;
Found: C,71.09; H,5.60; N,5.66%.
Example 44 (E)-1-f 1-(3,4-Methylenedioxyphenyl)-1,3,4.9-tetrahydro-Q-carbolin-2-yl1-3-(4-fluorophenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-4-fluorocinnamic acid gave after recrystallization from EtOH the title compound as white crystals in a 74% yield.
MP: 138-139 °C.
Analysis for C2,Hz,F3N20s:
Calculated: C,73.62; H,4.81; N,6.36;
Found: C,73.78; H,4.81; N,5.97%.
Example 45 (E)-1-( 1-(3.4-Methylenedioxyphenyl )-1.3.4, 9-tetrahydro-(3-carbolin-2-yll-3-indan-5-yl-1-propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3-indane-5-ylacrylic acid gave, after precipitation, the title compound as a yellow powder in a 22% yield.
MP: 115 °C.
5 Analysis for C2pH26N2O3. 0.6Hz0:
Calculated: C,76.12; H,5.79; N,5.92;
Found: C,76.13; H,5.79; N,5.72%.
Example 46 10 ~E)-N-(4-f3-Oxo-3-(1-(3.4-methylenedioxyphenyl)-1 3 4 9-tetrahydro-(3 carbolin 2-yl)propenyllbenzoyllbenzenesulfonamide The same method as employed in the preparation of Example 20 but starting from Example 31 and benzenesulfonamide gave after recrystallization from EtOH:H20 the title compound as white crytals in a 20% yield.
15 MP: 134 °C.
Analysis for C2oHzsNz03. 0.6H20:
Calculated: C,56.13; H,6.67; N,10.91;
Found: C,55.97; H,6.75; N,10.82%.
20 Example 47 (E)-1-f1-(3.4-Methylenedioxyphenyl)-1 3 4 9-tetrahydro-f3-carbolin 2 yll 3 (3 dichlorophenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3,4-dichlorocinnamic acid gave after recrystallization from EtOH:H20 25 (99:1 ) the title compound as a white powder in a 45% yield.
MP: 212 °C.
Analysis for CZ,HZOCIzN203:
Calculated: : C,66.00; H,4.10; N,5.70;
Found: C,65.68; H,4.12; N, 5.68%.
Example 48 (E)-1-f1-(3.4-Methylenedioxyphenyl)-1 3 4 9-tetrahydro-Q-carbolin 2 yll 3 (3 4 dimethoxypheny!)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3,4-dimethoxycinnamic acid gave after recrystallization from EtOH:DCM the title compound as a white powder in a 61 % yield.
MP: 233 °C.
Analysis for CZgHZSN20s. 0.5 H20:
Calculated: C,70.86; H,5.54; N,5.70;
Found. C,70.66; H,5.44; N,5.70%.
Example 49 ~E)-1-f1-(3 4-Methylenedioxyphenyl)-1.3 4 9-tetrahydro-f3-carbolin-2-yll-3-(3,4-dihydroxyphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3,4-dihydroxycinnamic acid gave after recrystallization from EtOH:DMF
the title compound as a white powder in a 41 % yield.
MP: 163-165 °C.
Analysis for Cz,H22N20s. 0.3DMF:
Calculated: C,70.34; H,5.10; N,6.76;
Found: C,70.38; H,5.13; N,6.66%.
Example 50 (E)-N-Methyl-N-~4-(3-oxo-3-( 1-(3 4-methylenedioxyphenyl )-1, 3,4.9-tetrahydro-_ca_rb_olin-2-yl )propenyllphenyllacetamide The same method as employed in the preparation of Example 20 but starting from Intermediate 23 gave after recrystallization from EtOH:H20 (10:0.6) the title compound as an off-white powder in a 86% yield EtOH:HzO.
MP: 165 °C.
Analysis for C3oHz,N304Ø4Hz0:
Calculated: C,71.96; H,5.6; N,8.39;
Found: C,71.8; H,5.57; N,8.28%.
Example 51 (El-2 2-Dimethyl-N-(4-(3-Oxo-3-(1-(3.4-methylenedioxyphenyl)-1.3,4.9-tetrahydro-(3-carbolin-2-yl)propenyllphenyllpropionamide This product was prepared by condensation of Example 25 (0.2 g; 0.46 mmol) with 2,2-dimethylpropionyl chloride (0.09 mL, 1.5 equiv.) and NaOH (1N) (0.7 mL, 1.5 equiv.) in a mixture of EtOAc:DCM (6:1). When starting material had disappeared, 40 mL of a mixture of DCM:H20 (2:1 ) was added. Extraction with DCM, washing with a saturated aqueous solution of NH4C1 and brine, drying over MgS04 and evaporation of the solvent in vacuo gave the title compound (0.2 g, 83%) after recrystallization from EtOH:H20 (1:1 ).
MP: 172-174 °C.
Analysis for C32H3,N3O4. 0.1 H20:
Calculated: C,71.23; H,6.16; N,7.79;
Found: C,70.99; H,6.02 ; N.7.84%.
Example 52 ~E)-1-(1-(3,4-Methylenedioxyphenyl)-1.3,4.9-tetrahydro-a-carbolin-2-yll-3-(3.5-dimethoxyphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3,5-dimethoxycinnamic acid gave after recrystallization from EtOH the title compound as a white powder in a 61 % yield.
MP: 178 °C.
Analysis for C29H2sNz05:
Calculated: C,72.19; H,5.43; N,5.81;
Found: C,72.3; H,5.48; N,5.63%.
Example 53 ~E)-(N)-(4-f 3-(1-(3,4-Methylenedioxyphenyl)-6-fluoro-1, 3.4,9-tetrahydro-~3-carbolin-2-yll-3-oxopropenyflphenyl~-acetamide The same method as employed in the preparation of Example 20 but starting from intermediate 16 and and (E)-3-(4-acetylaminophenyl)acrylic acid gave after recrystallization from MeOH the title compound as a white crystals in a 72%
yield.
MP:179-181 °C.
Analysis for CZSHzaN3OaFØ4H20:
Calculated: C,69.01; H,4.95; N,8.33;
Found: C,68.97; H,4.91; N.8.34%.
Example 54 E)-1-f1-(3,4-Methylenedioxyphenyl)-1 3 4 9-tetrahydro-l3-carbolin-2-yll-3-(3.4.5-trimethoxyphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3,4,5-trimethoxycinnamic acid gave after recrystallization from MeOH
the title compound as a white powder in a 49% yield.
MP: 211 °C.
Analysis for CsoHzsNzOs:
Calculated: C,70.3 ; H,5.51; N,5.47;
Found: C,70.49; H,5.59; N,5.34.%.
Example 55 ~E) N-f4-f3-Oxo-3-(1-(3 4-methylenedioxyphenyl)-1 3 4 9-tetrahydro-Q-carbolin-2-yl )propenyllphenyllisobutyramide The same method as employed in the preparation of Example 51 but starting from isobutyryl chloride gave after recrystallization from EtOH the title compound as a white powder in a 85% yield.
MP: 171 °C.
Analysis for C3,HZSN3Oa. 0.4(HzO:MeOH):
Calculated: C,72.61; H,6.02; N,7.99;
Found: C,72.33; H,5.77; N,8.33%.
Example 56 (El-1-f 1-(3 4-Methylenedioxyphenyl)-6-fluoro-1 3 4.9-tetrahydro-Q-carbolin-2-yll-3-phenylpropene-1-one The same method as employed in the preparation of Example 1 but starting from Intermediate 16 gave after recrystallization from EtOH the title compound as white crystals in a 71 % yield.
MP: 227-228 °C.
Analysis for CZ~Hz,N203F:
Calculated: C,73.63; H,4.81; N,6.36;
Found: C,73.72; H,4.77; N,6.43%.
Example 57 (E)-N-(2-Methoxyethyl)-4-(3-oxo-3-( 1-(3.4-methylenedioxyphenyl)-1.3.4,9-tetrahydro-(3-carbolin-2-yl)propenyllbenzamide The same method as employed in the preparation of Example 20 but starting from Intermediate 24 gave after recrystallization from EtOH the title compound as white crystals in a 43% yield.
MP: 170 °C.
Analysis for CZ,H2,Nz03F. 1.3H20:
Calculated: C,68.07; H,5.82; N,7.68;
Found: C,67.98; H,5.8; N,7.7%.
Example 58 (E)-1-f1-(3,4-Methylenedioxyphenyl)-1,3.4,9-tetrahydro-Q-carbolin-2-yll-3-(3-hydroxyphenyl )propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3-hydroxycinnamic acid gave after recrystallization from EtOH:H20 the title compound as white crystals in a 54% yield.
MP: 248 °C.
Analysis for C2~HZZN204:
Calculated: C,73.96; H,5.06; N,6.39;
Found: C,74.04; H,5.1; N,6.37%.
Example 59 (E)-1-f 1-(3.4-Methylenedioxyphenyl)-1,3.4.9-tetrahydro-a-carbolin-2-yll-3-(3-methoxyphenyl )propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3-methoxycinnamic acid gave after recrystallization from EtOH the title compound as white crystals in a 49% yield.
MP: 218 °C.
Analysis for C28HzaN20a:
Calculated: C,74.32; H,5.35; N,6.19;
Found: C,74.37; H,5.61; N,6.32%.
Example 60 (E)-1-(1-(3.4-Methylenedioxyphenyl)-1.3.4.9-tetrahydro-(3-carbolin-2-yl)-3-(3-nitrophenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3-nitrocinnamic acid gave after recrystallization from EtOH:H20 (20:1 ) the title compound as white crystals in a 91 % yield.
MP: 156-158 °C.
5 Analysis for C2sHzaNz04:
Calculated: C,69.37; H,4.54; N,8.99;
Found: C,69.12; H,4.77; N,8.81 %.
Example 61 10 (E) 1 f 1 (3 4 Methylenedioxyphenyl)-1 3 4 9-tetrahydro-Q-carbolin-2-yll-3-f4-(2-dimethylaminoethoxy)phenyllpropene-1-one The same method as employed in the preparation of Example 20 but starting from intermediate 25 gave after recrystallization from EtOH:H20 the title compound as white crystals in a 45% yield.
15 MP: 157 °C.
Analysis for C3~H3,N3O4:
Calculated: C,73.07; H,6.13; N,8.25;
Found: C,72.7 ; H,6.17; N,8.12%.
20 Example 62 _(E) N (2 Morpholin-4-ylethyl)-4-f3-oxo-3-(1-(3 4-methylenedioxyphenvl)-1.3,4,9-t_etrahydro-(3-carbolin-2-y!)propenyllbenzamide The same method as employed in the preparation of Example 20 but starting from Intermediate 26 gave after recrystallization from EtOH:H~O the title 25 compound as white crystals in a 13% yield.
MP: 145 °C.
Analysis for C~H~,N40s. 0.7Hz0:
Calculated: C,69.07; H,6.03; N9.48;
Found: C,69.08; H, 6.03; N,9.45%.
Example 63 (E) 1 [1 (3 4-Methylenedioxyphenyl)-1 3 4 9-tetrahydro-(3-carbolin-2-yll-3-(4-(1 H-tetrazol-5-yl)phenyllpropene-1-one To a solution of Example 32 (0.25 g, 0.56 mmol) in 10 mL of toluene were added successively trimethylsilylazide (0.30 mL, 4 equiv.} and dibutyltinoxide (0.06 g, 0.4 equiv.). The resulting mixture was stirred at reflux for two days. Tfc monitoring showed formation of a new compound (DCM:MeOH (80:20), Rf=0.35).The reaction mixture was concentrated in vacuo. The resulting yellow gum was dissolved in MeOH and concentrated in vacuo. The residue was partitioned between EtOAc (25 mL) and an aqueous saturated solution of NaHCOs (25 mL).The organic phase was extracted with an additional portion of an aqueous saturated solution of NaHC03 (25 mL). The combined aqueous extracts were acidified to pH= 2 with HCI (1 N) and then extracted with EtOAc (2x25 mL). The combined organic extracts were dried over MgS04, filtered and concentrated to give a yellow powder that was purified via flash chromatography (Si02, DCM:MeOH (90:10)). Recrystallization from 2-propanol:iPr20 (1:1 ) gave the title compound (0.19 g, 70 %} as white crystals.
MP: 232-233 °C.
Analysis for C28HZZNsOs. 0.4H20:
Calculated: C,67.02; H,4.92; N,16.28;
Found: C,66.83; H,4.53; N,15.96%.
Example 64 (E)-1-f 1-(3,4-Methylenedioxyphenyl)-1 3 4 9-tetrahydro-(i-carbolin-2-yll-3-(3 aminophenyl)propene-1-one A solution of Example 60 (1.36 g, 2.9 mmol), SnCIz.H20 (2.8 g, 5 equiv.) in EtOH
was refluxed overnight. After evaporation of the solvent, the residue was taken up in 50 mL of NaOH (1N). The aqueous phase was extracted with 2 x 100 mL
of DCM and 2 x 50 mL of EtOAc. The combined organic layers were dried over NaZS04 and concentrated in vacuo. Flash chromatography (SiOZ, DCM:MeOH
(95:5) and recrystallization from EtOH:DCM gave the title compound (0.27 g, 21 %) as a pale yellow powder.
MP: 139-141 °C.
Analysis for CZ,H23N30s:
Calculated: C,74.13; H,5.30; N,9.60;
Found: C,73.93; H,5.35; N,9.43%.
Example 65 -(E)-N-Cyclohexy!-4-f3-oxo-3-(1-(3.4-methylenedioxyphenyl)-1 3 4 9-tetrahydro ~3-carbolin-2-yl)propenyl~benzamide The same method as employed in the preparation of Example 20 but starting from Intermediate 27 gave after recrystallization from EtOH: H20 the title compound as white crystals in a 6% yield.
MP: 214 °C.
Analysis for CzsH2,N303. 0.1 HzO:
Calculated: C,72.19; H,6.24; N,7.43;
Found: C,72.28; H,6.19; N,6.93%.
Example 66 (E)-N-(Tetrahydrofuran-2-ylmethyl)-4-(3-oxo-3-(1-(3,4-methylenedioxyphenyl)-1 3 4 9-tetrahydro-13-carbolin-2-yl)propenyllbenzamide The same method as employed in the preparation of Example 20 but starting from Intermediate 28 gave after recrystallization from EtOH:HzO (8:2) the title compound as white crystals in a 61 % yield.
MP: 168 °C.
Analysis for C3zH29N3Os. 0.8H20:
Calculated: C,69.88; H,5.61; N,7.64;
Found: C,69.74; H,5.78; N,7.22%.
Example 67 (El-1-(1-(3 4-Methylenedioxyphenyl)-1,3,4.9-tetrahvdro-(3-carbolin-2-yll-3-(3-cyanophenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-cyanocinnamic acid gave after recrystalfization from EtOH:HzO (8:2) the title compound as white crystals in a 46% yield.
MP: 228-230 °C.
Analysis for C2aH2,NsOs. 0.8H20:
Calculated: C,72.81; H,4.93; N,9.10;
Found: C,72.74; H,4.69; N,8.99%.
Example 68 (E)-N-(4-Piperidine-4-carboxylic acid. ethyl ester)-4-(3-oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3.4.9-tetrahydro-t3-carbolin-2-yf)propenyllbenzamide The same method as employed in the preparation of Example 20 but starting from Intermediate 29 gave after recrystallization from iPr20 the title compound as white crystals in a 28% yield.
MP: 144-145 °C.
Analysis for C3gH35N3~6~ 0.7H20:
Calculated: C, 69.93; H,5.93; N,6.8;
Found: C,69.84; H,5.83; N,6.81 %.
Example 69 (E)-N-(4-Piperidine-4-carboxylic acid)-4-(3-oxo-3-(1-(3 4-methylenedioxyphenyl)-1.3.4.9-tetrahydro-(i-carbolin-2-yl)propenyllbenzamide This product was prepared by refluxing a solution of Example 68 (0.21 g, 0.36 mmol) with NaOH (1 N) (0.72 mL, 2 equiv.) in 20 mL of MeOH for 12 hours. After cooling the mixture was poured into Hz0 (100 mL) and acidified with HCI (1 N).
Extraction with 2 x 50 mL of DCM, drying over NaZS04 and concentration in vacuo gave a residue which was recrystallized from MeOH:H20 to give the title compound (0.05 g, 24%) as white crystals.
MP: 204-205 °C.
Analysis for C~H3,N30s. 0.4H20:
Calculated: C,68.56; H,5.58; N,7.05;
Found: C,68.58; H,5.12; N,7.06%.
Example 70 (E)-3-f3-Oxo-3-f1-(3,4-methylenedioxyphenyl)-1 3 4 9-tetrahydro-(3-carboiin-2-yll-propenyllbenzoic acid The same method as employed in the preparation of Example 20 but starting from (E)-3-(2-carboxyvinyl)benzoic acid gave after recrystallization from MeOH, the title compound as a white powder in a 21 % yield.
MP: 156-158 °C.
Analysis for CZeH22N2Os. 0.8HZ0:
Calculated: C,69.93; H,4.95; N,5.83;
Found: C,69.94; H,4.62; N,5.65%.
Example 71 WO 97!43287 PCT/EP97/02277 (E)-1-f1-(3 4-Methylenedioxyphenyl)-1.3.4.9-tetrahydro-a-carbolin-2-yll-3-(3-(4-methylpiperazine-1-carbonyf )phenyl )propene-1-one The same method as employed in the preparation of Example 20 but starting from Example 70 and 4-methylpiperazine gave after recrystallization from MeOH:HzO, the title compound as a white powder in a 30% yield.
MP: 151 °C.
Analysis for C33H3zN4O4. HzO:
Calculated: C,69.95; H,6.05; N,9.89;
Found: C,69.63; H,5.93; N,9.99%.
Example 72 (E)-N-(2-Piperazin-1-ylethyl)-3-[3-oxo-3-( 1-(3.4-methylenedioxyphenyl )-1.3,4, 9-tetrahydro-Q-carbolin-2-yl)propenyllbenzamide The same method as employed in the preparation of Example 20 but starting from Example 70 and 1-(2-aminoethyl)piperazine gave after recrystallization from iPrzO, the title compound as a white powder in a 23% yield.
MP: 138-140 °C.
Analysis for C34H35NSO4. 3.1 HzO:
Calculated: C,64.46; H,6.55; N,11.05;
Found: C,64.46; H,6.25; N,11.00%.
Example 73 ~E )-4-f 3-Oxo-3-( 1-(3 4-methylenedioxyphenyl )-1, 3, 4, 9-tetrahydro-Q-carbof in-2-yl)-propenyllacetic acid ethyl ester The same method as employed in the preparation of Example 20 but starting from Intermediate 30 gave after recrystallization from DCM:pentane, the title compound as a white powder in a 17% yield.
MP: 92-95 °C.
Analysis for C3, HzeNzOs. 0.9Hz0:
Calculated: C,70.95; H,5.72; N,5.34;
Found: C,71.32; H,6.0; N,4.93%.
Example 74 (E)-1-f 1-(3 4-Methylenedioxyphenyl)-1.3,4.9-tetrahydro-t3-carbolin-2-yll-3-(3-tetrazolophenyl)propene-1-one WO 97/43287 _ The same method as employed in the preparation of Example 63 but starting from Example 67 gave after recrystallization from MeOH:HzO, the title .
compound as a white powder in a 5% yield MP: 260-264 °C.
5 Analysis for CZSHzzNs03. 2.2H20:
Calculated: C,63.43; H,5.02; N,15.85;
Found: C,63.31; H,4.37; N,15.47%.
Example 75 10 (E)-2-(3-Oxo-3-(1-(3,4-methylenedioxyphenyl)-1 3 4 9-tetrahydro-(3-carbolin-yll-propenYllbenzoicacid, methyl ester The same method as employed in the preparation of Example 20 but starting from (E)-2-(2-carboxyvinyl)benzoic acid, methyl ester (prepared according to the procedure of Alabaster, R.J.; Cottrell, I.F.; Hands, D.; Humphrey, G.R.;
15 Kennedy, D.J.; Wright, S.H.B. Synthesis 1989, 8, 598-603), gave after recrystallization from MeOH, the title compound as white crystals in a 46%
yield.
MP: 203-204 °C.
Analysis for CZ,HZ,N30s:
Calculated: C,72.49; H,5.03; N,5.83;
20 Found: C,72.59; H,5.1; N,5.67%.
Example 76 (E1-3-(3-Oxo-3-(1-(3.4-methylenedioxyphenyl)-1 3 4 9-tetrahydro-Q-carbolin-2-yll-propenyllbenzoic acid. methyl ester 25 The same method as employed in the preparation of Example 20 but starting from (E)-3-(2-carboxyvinyl)benzoicacid, methyl ester (prepared according to the procedure of Baker,S.R.; Jamieson,W.B; Todd,A. EP 134111 A1), gave after recrystallization from MeOH, the title compound as yellow crystals in a 61 yield.
30 MP: 165-167 °C.
Analysis for CZSH2aNzOs:
Calculated: C,72.49; H,5.03; N,5.83.;
Found: C,72.53; H,5.02; N,5.93%.
35 Example 77 (E)-1-(4-f3-Oxo-3-(1-(3.4-methylenedioxyphenyl)-1,3.4.9-tetrahydro-~-carbolin-2-yl)-propenyllphenyl)piperidine-4-carboxylic acid, ethyl ester The same method as employed in the preparation of Example 20 but starting from Intermediate 31 gave after recrystallization from MeOH, the title compound as yellow crystals in a 45% yield.
MP: 175 °C.
Analyses for C3sHssNsOs.
Calculated: C,72.77; H,6.11; N,7.27;
Found: C,72.99; H,6.16; N,7.03%.
Example 78 (E)-N-(1-Ethylpyrrolidin-2-yl-methyl)-3-f3-oxo-3-(1-(3,4-methylenedioxyphenyl)-1.3.4.9-tetrahydro-Q-carbolin-2-yl)propenyllbenzamide The same method as employed in the preparation of Example 20 but starting from Example 70 and 2-pyrrolidin-1-ylethyiamine gave after recrystallization from iPr20, the title compound as a white powder in a 53% yield.
MP: 128-130 °C.
Analysis for C35H36N404~
Calculated: C,72.9; H,6.29; N,9.72;
Found: C,72.9; H,6.42; N,10.01%.
Example 79 (E)-1-f 1-(3.4-Methylenedioxyphenyl)-1.3.4,9-tetrahydro-~-carbolin-2-yll-3-(3-(2-dimethylaminoethoxy)phenyl)propene-1-one To a solution of Example 58 (0.25 g, 0.57 mmol) in 50 mL of DMF was added KzCOs {0.24 g, 3 equiv.) and an excess of dimethylaminodiethyl chloride (about 15 equiv.). The resulting mixture was heated at 60 °C for four hours until disappearance of the starting material (tlc monitoring, DCM:MeOH (90:10). A
new compound was formed (Rf= 0.20). After evaporation of DMF, the residue was taken up in 150 mL of DCM, washed with 2x50 mL of water, dried over NazSOa and recrystallized from EtOH:HzO.to give the title compound (0.06 g, . 22%) as yellow crystals.
MP: 76-78 °C.
Analysis for C3,H3,N3O4. 0.6Hz0:
Calculated: C,71.55; H,6.24; N,8.07;
WO 97/43287 , Found: C,71.34; H,6.45; N,7.8%.
Example 80 (E)-1-(1-(3,4-Methyienedioxyphenyl)-1,3,4.9-tetrahydro-Q-carbolin-2-yll-3-(3.5-diterbutyl-4-hydroxypheny~propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3,5-ditertbutyl-4-hydroxycinnamic acid gave after recrystallization from cyclohexane, the title compound as yellow crystals in a 45% yield.
MP: 137 °C.
Example 81 (E)-3-f3-Oxo-3-(1-(4-methoxycarbonylphenyl)-1.3 4.9-tetrahydro-Q-carbolin-2-yllpropenyllbenzoic acid. methyl ester The same method as employed in the preparation of Example 20 but starting from Intermediate 8 and (E)-3-{2-carboxy-vinyl)benzoic acid, methyl ester (prepared according to the procedure of Baker,S.R.; Jamieson,W.B; Todd,A. EP
134111 A1 ), gave after recrystallization from 2-propanol, the title compound as white crystals in a 70% yield.
MP: 182 °C.
Analysis for CsoHzsN20s:
Calculated: C,72.86; H,5.3; N,5.66;
Found: C,72.49 ; H,5.31 ; N,5.68%.
Example 82 (E)-2-f3-Oxo-3-f1-(3,4-methylenedioxyphenyl)-1.3 4 9-tetrahydro-Q-carbolin-2-yll-propenyllbenzoic acid The same method as employed in the preparation of Example 31 but starting from Example 75 gave after recrystallization from MeOH the title compound as off-white crystals in a 78% yield.
MP: 174 °C.
Analysis for CzeHZ2N205:
Calculated: C,72.09; H,4.75; N,6.01;
Found: C,72.53; H,4.72; N,5.76%.
Example 83 (E) (4 f3 Oxo-3-(1-(3 4-methylenedioxyphenyl)-1 3.4.9-tetrahydro-~-carbolin-2-1 mr~penyllphenoxy)acetic acid. ethyl ester The same method as employed in the preparation of Example 79 but starting from Example 22 and bromoacetic acid, ethyl ester, gave after recrystallization from EtOH:2-propanol the title compound as yellow crystals in a 28% yield.
MP: 99-98 °C.
Analysis for Cs,H2sNzOs. 2.4Hz0:
Calculated: C,65.57; H,5.82; N,4.93;
Found: C,65.34; H,5.4; N,5.09%.
Example 84 (El (4 (3 Oxo-3-(1-(3 4-methylenedioxyphenyl)-1 3 4 9-tetrahydro-(3-carbolin-2-yl)-propenyllphenyl)acetic acid The same method as employed in the preparation of Example 31 but starting from a solution of Example 73 in EtOH gave after recrystallization from iPrz0:2-propanol the title compound as white crystals in a 51 % yield.
MP: 231 °C.
Analysis for CzgH24N2O5~ 0.25iPrOH:
Calculated: C, 72.11; H, 5.29; N,5.64;
Found: C, 71.9; H, 5.15; N, 5.74%.
Example 85 (E)-(4-(3-Oxo-3-(1-(3 4-methylenedioxyphenyl)-1 3 4.9-tetrahydro-(3-carbolin-2-yl)propenyllphenoxy)acetic acid The same method as employed in the preparation of Example 31 but starting from Example 83 gave after recrystallization from iPr20:2-propanol the title compound as yellow crystals in a 45% yield.
MP: 158-160 °C.
Analysis for CzsHzaN20s . 0.9HzO:
Calculated: C,67.93; H,5.07; N,5.46;
Found: C,68.0; H,4.86; N,5.21 %.
Example 86 (E)-1-f1-(3 4-Methylenedioxyphenyl)-1.3 4.9-tetrahydro-~-carbolin-2-yll-3-(3-nitro-4-chlorophenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3-vitro-4-chlorocinnamic acid gave after recrystallization from EtOH
the title compound as yellow crystals in a 56% yield.
MP: 240 °C.
Analysis for CZ,HZON30sCl:
Calculated: C,64.61; H,4.02; N,8.37;
Found: C,64.5; H,3.97; N,8.28%.
Example 87 (E)-1-f1-(3,4-Methylenedioxyphenyl)-1 3 4 9-tetrahydro-Q-carbolin-2-yll-3-(5 vitro-2-chlorophenyl )propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-5-vitro-2-chiorocinnamic acid gave after recrystallization from EtOH:H20 the title compound as yellow crystals in a 44% yield.
MP: 146 °C.
Analysis for C2,HzoN3OsCl. 0.1 H20:
Calculated: C,64.38; H,4.04; N,8.34;
Found: C,64.12; H,3.81; N,8.35%.
Example 88 (E)-3-Chioro-4-f3-oxo-3-f1-(3 4-methylenedioxyphenyl)-1 3 4 9-tetrahydro-a carbolin-2-ylipropenyllbenzoic acid. methyl ester The same method as employed in the preparation of Example 20 but starting from intermediate 32 gave after recrystallization from EtOH the title compound as a white powder in a 57% yield.
MP: 166 °C.
Analysis for CzsH23N205C1. 0.15EtOH:
Calculated: C,67.43; H,4.62; N,5.37;
Found: C,67.09; H,4.56; N,5.51 %.
Example 89 . (E)-(4-f3-Oxo-3-(1-(3.4-methylenedioxyphenyl)-1 3 4 9-tetrahydro-(~-carbolin y~propenyllbenzyloxy)acetic acid The same method as employed in the preparation of Example 79 but starting from a solution of (E)-(4-(3-oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-~3-carbolin-2-yl)propenyl]benzyloxy)acetic acid, ethyl ester in EtOH
gave after recrystallization from MeOH:HzO the title compound as an off-white solid in a 40% yield.
MP: 162-163 °C.
5 Analysis for C3oHzsN20s. 0.1 H20:
Calculated: C,68.17; H,5.13; N,5.49;
Found: C,68.16; H,5.46; N,5.51 %.
(E)-(4-[3-Oxo-3-(1-(3,4-methyienedioxyphenyl}-1,3,4,9-tetrahydro-[3-carbolin-2-10 yl)propenyl]benzyloxy)acetic acid, ethyl ester:
To a solution of Example 39 (0.7 g, 1.5 mmol) in 50 mL of DMF was added KzC03 (0.25 g, 1.2 equiv.) and ethylbromoacetate (0.2 mL, 1.1 equiv.). The resulting mixture was heated at 60 °C for 16 hours until disappearance of the starting material (tlc monitoring, DCM:MeOH (95:5)) A new compound was 15 formed (Rf= 0.8). After evaporation of DMF, the residue was taken up in 150 mL
of DCM, washed with 2x50 mL of water, dried over Na2S04 and purified via radial chromatography with DCM to give the title compound (0.85 g, 11 %) as a white powder.
1 H NMR (CDC13) b 7.8-6.65 (m, 14H), 5.9 (s, 2H), 4.7 (s, 2H), 4.6-4.3 (q, 2H), 20 4.2-4.0 (m, 4H), 3.6-3.5 (m, 1 H), 3.2-2.9 (m, 2H), 1.3-1.2 (t, 3H).
Example 90 (El-1-(1-(3,4-Methylenedioxyphenyl)-1.3,4,9-tetrahydro-(3-carbolin-2-yl1-3-(5-amino-2-chforophenyl)propene-1-one 25 The same method as employed in the preparation of Example 64 but starting from Example 87 gave after recrystallization from EtOH:DCM, the title compound as a white powder in a 17% yield.
MP: 251-252 °C.
Analysis for Cz~HZ~CIN303. 0.4Hz0:
30 Calculated: C,67.68; H,4.8; N,8.77;
Found: C,67.71; H.4.73; N,8.65%.
Example 91 (E)-3-Chloro-4-(3-oxo-3-(1-(3.4-methylenedioxyphenyl)-1.3.4.9-tetrahydro-(i-35 carbolin-2-yllpropenyllbenzoic acid The same method as employed in the preparation of Example 31 but starting from Example 88 gave after recrystallization from 2-propanol the title compound as a yellow powder in a 40% yield.
MP: 169 °C.
Analysis for C28H2, NZOS. HzO:
Calculated: C,64.8; H,4.47; N,5.40;
Found: C,64.47; H,4.13; N,5.60%.
Example 92 (E)-1-(1-(3.4-Methylenedioxyphenyl)-1.3 4.9-tetrahydro-a-carbolin-2-yll-3-(3 5-dibromo-4-hydroxyphenyt)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3,5-dibromo-4-hydroxy cinnamic acid gave after recrystallization from EtOH: H20 the title compound as white crystals in a 13% yield.
MP: 148-150 °C.
Analysis for C2,HzoNZOaBr2. 1.6EtOH:
Calculated: C,54.14; H,4.45; N,4.18;
Found: C,54.1; H,4.15; N,3.77%.
Example 93 (E)-1-(1-(3,4-Methylenedioxyphenyl)-1.3 4.9-tetrahydro-(3-carbolin-2-yl1-3-(4-(2-dimethylaminopropoxy)phenyl)propene-1-one The same method as employed in the preparation of Example 79 but starting from Example 22 and dimethylaminopropyl chloride gave after recrystallization from cyclohexane:DCM:pentane the title compound as white crystals in a 16%
yield.
MP: 106 °C.
Analysis for C32H33N3O4. 0.3Hz0:
Calculated: C,72.65; H,6.40; N,7.94;
Found: C,72.74 ; H,6.56; N,7.63%.
Example 94 (E)-2-Chloro-5-(3-oxo-3-(1-(3.4-methylenedioxyphenyl)-1 3 4 9-tetrahydro-a-carbolin-2-ytlpropenyllbenzoic acid. methy~ ester The same method as employed in the preparation of Example 20 but starting from Intermediate 33 gave after recrystallization from MeOH:DCM the title compound as a white powder in a 59% yield.
MP: 228 °C.
Analysis for CzsH23CIN20s. 1.05Hz0:
Calculated: C,65.24; H,4.74; N,5.25;
Found: C,64.91; H,4.27; N,5.13%.
Example 95 (E)-1-f1-(3 4-Methylenedioxyphenyl)-1.3,4.9-tetrahydro-a-carbolin-2-yll-3-(4-(2-diisopropylaminoethoxy)phenyl)propene-1-one The same method as employed in the preparation of Example 79 but starting from Example 22 and diisopropylaminodiethyl chloride gave after recrystallization from MeOH:H20 the title compound as pale yellow crystals in a 12% yield.
MP: 92-93 °C.
Analysis for C35H39N3O4:
Calculated: C,74.31; H,6.95; N,7.43;
Found: C,74.34; H,7.16; N,7.10%.
Example 96 ( E)-2-Chloro-5-(3-oxo-3-f 1-(3.4-methylened ioxyphenyl )-1, 3, 4.9-tetrahydro-[i-carbolin-2-yllpropenyl)benzoic acid The same method as employed in the preparation of Example 31 but starting from Example 94 gave after recrystalfization from MeOH the title compound as white crystals in a 78% yield.
MP: 178 °C.
Analysis for C2gH2~N2O5. 0.7Me0H:
Calculated: C,65.86; H,4.58; N,5.35;
Found: C, 65.73 ; H, 4.44 ; N, 5.51 %.
Example 97 (E)-1- 1-(3 4-Methylenedioxyphenyl)-1.3,4.9-tetrahydro-Q-carbolin-2-yll-3-(3-hydroxy-4-nitrophenyl)propene-1-one WO 97/43287 _ The same method as employed in the preparation of Example 20 but starting from Intermediate 34 gave after recrystallization from EtOH the title compound as yellow crystals in a 77% yield.
MP: 172 °C.
Example 98 (E)-1-(1-(3,4-Methylenedioxyphenyl)-1 3 4 9-tetrahydro-Q-carbolin-2-yll-3 (3 5 dimethyl-4-hydroxyphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 35 gave after recrystallization from MeOH:H20 the title compound as a white powder in a 71 % yield.
MP: 151-152 °C.
Analysis for Cz9H26Nz04. 0.4H20:
Calculated: C,73.52; H,5.7; N,5.91;
Found: C,73.56; H,5.59; N 6.29%.
Example 99 (E)-1-11-(3.4-Methylenedioxyphenyl)-1.3 4 9-tetrahydro-(3-carbolin-2-yll-3-(3 (2 dimethylaminoethoxy)-4-nitrophenyl)propene-1-on_e The same method as employed in the preparation of Example 79 but starting from Example 97 and dimethylaminodiethyl chloride gave after recrystallization from MeOH the title compound as a pale yellow powder in a 18% yield.
MP: 189 °C.
Analysis for Cs,H3oN40s. 1.5H20:
Calculated: C,64.02; H,5.72; N,9.63;
Found: C,64.18; H,5.41; N,9.21%.
Example 100 (E)-1-(1-(3.4-Methylenedioxyphenyl)-1 3 4 9-tetrahydro-Q-carbolin-2-yll 3 (3 (2 dimethyiaminoethoxy)-4-aminophenyl)propene-1-one The same method as employed in the preparation of Example 64 but starting from Example 99 gave after recrystallization from iPrzO the title compound as a pale yellow powder in a 17% yield.
MP: 143 °C.
Analysis for C3,H3zN4O4. 0.5H20:
Calculated: C,69.78 ;H,6.23; N,10.5;
Found: C,69.87; H,5.98; N,10.42%.
Example 101 (E)-1-f1-(34-Methylenedioxyphenyl)-1.3.4.9-tetrahydro-t3-carbolin-2-yll-3-(3-nitro-4-hydroxy-5-methoxyphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from intermediate 36 gave after recrystallization from EtOH:DCM the title compound as pale yellow crystals in a 45% yield.
MP: 172 °C.
Analysis for CzeH23N3O,. 0.8H20:
Calculated: C,63.7; H,4.7; N,7.96;
Found: C,63.71; H,4.31; N,7.98%.
Example 102 (E)-1-f1-(3 4-Methylenedioxyphenyl)-1.3.4 9-tetrahydro-(i-carbolin-2-yll-3-(3-chloro-phenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3-chlorocinnamic acid, gave after recrystallization from EtOH the title compound as white crystals in a 48% yield.
MP: 212-213 °C.
Analysis for Cz~H2,CINzO:
Calculated: C,70.97; H,4.63; N,6.13 Found: C,70.65; H,4.63; N,6.16%.
Example 103 (E)-1-(1-(4-Methoxy-phenyl)-1 3 4,9-tetrahydro-t3-carbolin-2-yll-3-(2-chloro-5-nitrophenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 2 and (E)-2-chloro-5-nitrocinnamic acid gave after recrystallization from 2-propanoi the title compound as a yellow powder white in a 18% yield.
MP: 136-138 °C.
Analysis for CZ~HZZCIN304. 0.2Hz0:
Calculated: C,65.98; H,4.59; N,8.55;
Found: C,65.91; H,4.4; N,8.42%.
Example 104 (E)-1-(1-(3.4-Methylenedioxyphenyl)-1,3.4,9-tetrahydro-(3-carbolin-2-yll-3-(2 5 dichlorophenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-2,6-dichlorocinnamic acid gave after recrystallization from cyclohexane the title compound as a white powder in a 41 % yield.
MP: 118-120 °C.
10 Analysis for CZ,HzoCIzN203. 0.2HZ0:
Calculated: C,65.52; H,4.15; N,5.66;
Found: C,65.74; H,4.62; N,5.29%.
Example 105 15 (E)-1-f1-(3.4-Methylenedioxyphenyl)-1349-tetrahydro-(3-carboiin-2-yll-3-(4-methylaminomethylphenyl)propene-1-one A solution of (E)-1-[1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-[3-carbolin-2-yl)-3-(4-methyiiminomethylphenyl)propene-1-one (0.46 g, 1.1 mmol), NaBH3CN (0.14 g, 2.3 mmol) and acetic acid (0.11 mL) in 20 mL of MeOH was 20 stirred at rt for one hour. The reaction mixture was quenched with 50 mL of an aqueous saturated solution of NaHC03. Extraction with 2x30 mL of DCM, washing with brine, drying over NazS04 and concentration in vacuo gave a residue that was purified via flash chromatography of silica gel using DCM:MeOH (97:3) as eluting solvent. Recrystallization from DCM:cyclohexane 25 gave the title compound (0.05 g, 10%) as a white powder.
MP: 201 °C.
Analysis for Cz9HZ,CI2N303. 0.5Hz0:
Calculated: C,73.4; H,5.95; N,8.85;
Found: C,73.66; H,5.82; N,8.57%.
30 A stirred solution of Example 23 (0.5 g, 1.0 mmol) in MeOH was refluxed with methylamine (1.6 mL, 1.5 equiv., 33% in EtOH) for one hour. Evaporation in . vacuo gave (E)-1-[1-(3,4-methylenedioxyphenyl}-1,3,4,9-tetrahydro-~-carbolin-2-yl]-3-(4-methyliminomethylphenyl)propene-1-one (0.46 g, 90%).
'H NMR (CDC13, 250 MHz) 8 8.2 (d, 1 H), 8.1 (s, 1 H), 7.8-7.65 (m, 3H), 7.55-7.5 (m, 3H), 7.4-7.1 (m, 3H), 7.0-6.85 (m, 2H), 6.8-6.6 (dd, 2H), 5.9 (s, 2H), 4.2-(br d, 1 H), 3.5 (s+m, 4H), 3.05-2.85 (m, 2H).
Example 106 ~E)-1-f1-(3 4-Methylenedioxyphenyi)-1.3.4,9-tetrahydro-(i-carbolin-2-yll-3-(3-_methylphenyl)-propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3-methylcinnamic acid gave after recrystallization from MeOH the title compound as a white powder in a 67% yield.
MP: 196 °C.
Analysis for CZaHzaN203:
Calculated: C,77.04; H,5.54; N,6.62;
Found: C,76.76; H,5.56; N,6.33%.
Example 107 (E)-N-Methyl-(4-(3-oxo-3-(1-(3.4-methylenedioxyphenyl)-1.3.4.9-tetrahydro-Q-carbolin-2-yl)propenyllbenzenesulfonamide The same method as employed in the preparation of Example 20 but starting from (E)-4-(N-methylsulfonamide)cinnamic acid gave after recrystallization from EtOH:H20 the title compound as white crystals in a 79% yield.
MP: 162 °C.
Analysis for C28HZSN30s. 0.4EtOH:
Calculated: C,64.78; H,5.17; N,7.87;
Found: C,64.46; H,4.82; N,7.76%.
Example 108 ~E)-1-f1-(3 4-Methylenedioxyphenyl)-1,3,4.9-tetrahydro-p-carbolin-2-yll-3-(3-hydroxy-4-acetylphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3-hydroxy-4-acetylcinnamic acid gave after recrystaliization from EtOH
the title compound as yellow crystals in a 87% yield.
MP: 217-218 °C.
Analysis for CZSHzaNz05:
Calculated: C,72.49; H,5.03; N,5.83:
Found: C,72.24; H,5.25; N,5.53%.
Example 109 (E)-1-f 1-(2.3-Dihydrobenzofuran-5-yl)-1.3.4.9-tetrahydro-f3-carbolin-2-yll-3-(2-chloro-5-nitrophenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 10 and (E)-2-chloro-5-nitrocinnamic acid gave after recrystallization from EtOH:H20 (95:5) the title compound as yellow crystals in a 62% yield.
MP: 154 °C.
Analysis for CZ~H22CIN3O4. 0.5(HzO:MeOH):
Calculated: C,66.08; H,4.55; N,8.36;
Found: C,66.3; H,4.52; N,7.94%.
Example 110 ~E)-1-f 1-(3.4-Methylenedioxyphenyl)-1.3,4.9-tetrahydro-Q-carbolin-2-yll-3-(2-h~droxyphenyi)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-2-hydroxy cinnamic acid gave after recrystallization from EtOH:HzO, the title compound as white crystals in a 47% yield;
MP: 154 °C.
Analysis for CZ,H2zN204. 0.6H20:
Calculated: C,72.18; H,5.2; N,6.24;
Found: C,72.19; H,4.93; N,6.13%.
Example 111 (E)-1-f 1-(3,4-Methylenedioxyphenyl )-1.3.4, 9-tetrahydro-(3-carbol in-2-yll-3-(3-nitro-2-piperidin-1-ylphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 37 gave after recrystallization from MeOH the title compound as yellow crystals in a 31 % yield.
MP: 162-163 °C.
Analysis for C32H3oN4O$. 0.2H20:
Calculated: C,65.52; H,5.84; N,9.55;
Found: C,65.9; H,5.49; N,9.59%.
Example 112 (E?-1-f1-(2 3-Dihydrobenzofuran-5-yll-1,3.4.9-tetrahydro-~-carbolin-2-yll-3-phenylpropene-1-one The same method as employed in the preparation of Example 1 but starting from Intermediate 10 gave after recrystallization from EtOH the title compound as white crystals in a 52% yield.
MP: 190 °C.
Analysis for Cz8Hz4N202:
Calculated: C,79.98; H,5.75; N,6.66;
Found: C,79.94; H.5.86; N,6.62%.
Example 113 ~E)-1-f 1-(4-Isopropyiphenyl)-1.3,4.9-tetrahydro-~-carbolin-2-yll-3-(3-nitrophenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from intermediate 11 and (E)-3-nitrocinnamic acid gave after recrystallization from EtOH the title compound as yellow crystals in a 54% yield.
MP: 195 °C.
Analysis for CzsH2,N303:
Calculated: C,74.82; H,5.85; N,9.03;
Found: C,74.43; H.5.84; N,9.17%.
Example 114 (E)-1-(1-(2 3-Dihydrobenzofuran-5-yl)-1.3,4,9-tetrahydro-~-carbolin-2-yl]-3-(3-nitrophenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 10 and (E)-3-nitrocinnamic acid gave after recrystallization from EtOH the title compound as white crystals in a 35% yield.
MP: 174-176 °C.
Analysis for CzgH2~N3O4. 0.1 HzO:
Calculated: C,71.97; H,5.0; N,8.99;
Found: C,71.78; H.4.89; N,8.83%.
Example 115 E)-(R)-1-(1-(3,4-Methylenedioxyphenyl)-1.3.4.9-tetrahydro-!3-carbolin-2-yll-3-~henylpropene-1-one The same method as employed in the preparation of Example 1 but starting from Intermediate 19 gave after recrystallization from EtOH the title compound as white crystals in a 60% yield.
MP: 232-233 °C.
Analysis for Cz,HzZN203. 0.2H20:
Calculated: C,76.11; H,5.3; N,6.57;
Found: C,76.2; H,5.27; N,6.77%
[a]pz' _ -336 (c = 0.50, MeOH).
Example 116 (E)-(S)-1-(1-(3.4-Methylenedioxyphenyl)-1.3.4.9-tetrahydro-(i-carbolin-2-yll-3-phenylpropene-1-one The same method as employed in the preparation of Example 1 but starting from Intermediate 18 gave after recrystallization from iPrOH the title compound as white crystals in a 32% yield.
MP: 235-236 °C.
Analysis for Cz7H22NzO3. 0.1 H20:
Calculated: C,76.43; H,5.27; N,6.6;
Found: C,76.26; H,5.21; N,6.61 %.
(a]p2' = 378 (c = 0.5, MeOH).
Example 117 (E)-1-(1-(4-Methoxyphenyl)-1.3.4 9-tetrahydro-(i-carbolin-2-yll-3(3-nitrophenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 2 and (E)-3-nitrocinnamic acid gave after recrystallization from EtOH the title compound as yellow crystals in a 63% yield.
MP: 227 °C.
Analysis for Cz,H23N3O4. 0.1 EtOH:
Calculated: C,71.32; H,5.19; N,9.17;
Found: C,70.96; H,5.14; N,9.23%.
Example 118 ~I~-1-j,1-~4-Met nhen~!~~-1.3.4_9-tetra,~dro-Q-carbolin-2-yu-~-t2-rhloro-5-nitrqBhen~J)~oene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 6 and (E}-2-chloro-5-nitrocinnamic acid gave after 5 recrystallization from EtOH the title compound as a yellow powder in a 57%
yield.
MP: 211-213 °C.
Analysis for Cz,H23CINa03:
Calculated: : C,68.72; H,4.7; N,8.9;
10 Found: C,68.42; H,4.73; N,8.91 %.
Example119 E -N- Tetrah drof ran-2- Im h I -3- o- - 1- 4-m h tetrahydro-f3-carbolin-2-ylloropeny~benzamide 15 The same method as employed in the preparation of Example 20 but starting from Example 70 and tetrahydrofurfurylamine gave after recrystallization from EtOH the title compound as a white powder in a 30% yield.
MP: 172-173 °C.
Analysis for Cg3H3~ N3O5. 0.4H20:
20 Calculated: C,71.18; H,5.76; N,7.55;
Found: C,71.1; H,5.88; N,7.45%.
Example 120 E -1- 1- n -5-25 The same method as employed in the preparation of Example 1 but starting from intermediate 9 and tetrahydrofurfurylamine gave after recrystallization from EtOH the title compound as white crystals in a 51 % yield.
MP: 223 °C.
Analysis far CZ9HzBN20. 0.4H20:
30 Calculated: C,81.81; H,6.34; N,6.58;
Found: C,81.87; H,6.34; N,6.5%.
Example 121 35 ~ ~I~henvlyaropene-1-one 8s The same method as employed in the preparation of Example 20 but starting from 3-acetylcinnamic acid (prepared according to the procedure of Cleland,G.H. J. Org. Chem. 19fi9, 34, 744-747) gave after recrystallization from EtOH the title compound as a yellow powder in a 42% yield.
MP: 191 °C.
Analysis for CzsH24CIN20a:
Calculated: C,74.98; H,5.21; N,6.03;
Found: C,74.85; H,5.28; N,6.1 %.
Example 122 (E )-1-( 1-(2.3-Dihydrobenzofuran-5-yl )-1.3.4, 9-tetrahydro-(3-carbol i n-2-y( )1-3-(4--dimethylaminoethoxylphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 10 and Intermediate 25 gave after recrystallization from CH3CN the title compound as white crystals in a 37% yield.
MP: 146 °C.
Analysis for C3zH3sN3Os. 1.5H20:
Calculated: C,71.89; H,6.79; N,7.86;
Found: C,72.04; H,7.09; N,7.93%.
Example 123 ~E)-4-f 3-Oxo-3-(1-(4-methoxypheny!)-1,3,4, 9-tetrahydro-~-carbolin-2-yllpropenyllbenzoic acid, methyl ester The same method as employed in the preparation of Example 20 but starting from Intermediate 2 and (E)-4-(2-carboxyvinyl)benzoic acid, methyl ester gave after recrystallization from EtOH the title compound as yellow crystals in a 73%
yield.
MP: 189 °C.
Analysis for CZSH2sNz04. 0.1 EtOH:
Calculated: C,74.44; H,5.69; N,5.95;
Found: C,74.1; H, 5.65; N,6.01 %.
Example 124 (E)-1-(1-(3, 4-Methylenedioxyphenyl )-1.3.4, 9-tetrahydro-Q-carbol in-2-yl)-3-(4-methyl-3.4-dihydro-2H-benzof 1,4loxazin-6-yl)propene-1-one WO 97!43287 PCT/EP97/02277 The same method as employed in the preparation of Example 20 but starting from Intermediate 38 gave after recrystallization from EtOH the title compound as yellow crystals in a 69% yield.
MP: 231-232 °C.
Analysis for C2sHz6NzO4. 0.1 EtOH:
Calculated: C,73.01; H,5.51; N, 8.51;
Found: C,72.54; H,5.58; N,8.44%.
Example 125 (E)-1-(1-(3 4-Methylenedioxyphenyl)-1.3.4.9-tetrahydro-Q-carbalin-2-yll-3-(2-hydroxy-5-nitrophenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 39 gave after recrystallization from EtOH the title compound as yellow crystals in a 30% yield.
MP: 205 °C.
Analysis for Cz,HZ,N30s. 0.6EtOH:
Calculated: C,65.78; H,5.14; N,7.94;
Found: C,65.52; H,4.98; N,8.04%.
Example 126 (E)-~-f 3-Oxo-3-f 1-(2.3-dihydrobenzofuran-5-yl )-1. 3,4.9-tetrahydro-8-carbol in-2-yllpropenyllbenzoic acid, methyl ester The same method as employed in the preparation of Example 20 but starting from Intermediate 10 and (E)-4-(2-carboxyvinyl)benzoic acid, methyl ester gave after recrystallization from EtOH the title compound as white needles in a 88%
yield.
MP: 186 °C.
Analysis for CsoHzsNz04. 0.2H20:
Calculated: C,74.73; H,5.52; N,5.81;
Found: C,75.45; H, 5.38; N,6.07%.
Example 127 ( E)-4-f3-Oxo-3-( 1-(4-methoxyphenyl )-1.3.4.9-tetrahydro-!3-carbolin-2-yllpropenyllbenzoic acid The same method as employed in the preparation of Example 31 but starting from Example 123 gave after recrystallization from MeOH: H20 the title compound as a grey powder in a 43% yield.
MP: 147-149 °C.
Analysis for CZ8H24N2O4:
Calculated: C,74.32; H,5.35; N,6.19;
Found: C,74.3; H,5.37; N,6.07%.
Example 128 (E)-4-(3-Oxo-3-(1-(2,3-dihydrobenzofuran-5-yl)-1 3.4 9-tetrahydro->3-carbolin-yllpropenyllbenzoic acid The same method as employed in the preparation of Example 31 but starting from Example 126 gave after recrystallization from MeOH the title compound as white crystals in a 53% yield.
MP: 222-224 °C.
Analysis for C29Hz4Nz04:
Calculated: C,74.98; H,5.21; N,6.03;
Found: C,75.21; H,5.3; N,6.21 %.
Example 129 (E)-1-f 1-(Benzofuran-5-yi)-1.3.4.9-tetrahydro-Q-carbolin-2-yll-3-phenylpropene-1-one The same method as employed in the preparation of Example 1 but starting from Intermediate 12 gave after recrystallization from EtOH the title compound as white crystals in a 35% yield.
MP: 241-242 °C.
Analysis for CZ8H22N20z:
Calculated: C,80.36; H,5.3; N,6.69;
Found: C,80.44; H,5.3; N,6.89%.
Example 130 (E)-3-f3-Oxo-3-(1-(3,4-methylenedioxyphenyl)-1 3 4 9-tetrahydro-Q-carbolin-2-~~-propenyllphenyl)trifluoromethanesuffonic acid phenyl ester The same method as employed in the preparation of Example 20 but starting from Intermediate 40 gave after recrystallization from EtOH the title compound as white crystals in a 38% yield.
MP: 169 °C.
Analysis for CzsHz,FsNzOsS. 0.2HzO:
Calculated: C,58.58; H,3.76; N,4.88;
Found: C,58.84; H,3.71; N,4.3%.
Example 131 (E)-1-[1-(3 4-Methylenedioxyphenyl)-1,3,4.9-tetrahydro-Q-carbolin-2-yll-3-[4-(2-hydroxyethoxylphenyllpropene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-4-(2-hydroxyethoxy)phenyf (prepared according to the procedure of Oku,T.; Kayakiri,H.; Satoh,S.; Abe,Y.; Sawada,Y.; Inoue,T.; Tanaka,H.; EP
622361 ) gave after recrystallization from EtOH the title compound as white crystals in a 57% yield.
MP: 136 °C.
Analysis for CzsHzsNzOs. 1.2EtOH:
Calculated: C,58.58; H,3.76; N,4.88;
Found: C,58.84; H,3.71; N,4.3%.
Example 132 ~E)-1-[1-(Benzofuran-5-yl-1 3 4 9-tetrahydro-Q-carbolin-2-yl)1-3-(4-(2-_dimethylaminoethoxy)phenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 12 and Intermediate 25 gave after recrystallization from CH3CN the title compound as white crystals in a 23% yield.
MP: 159 °C.
Analysis for C32H3~N3O3. 0.1 HzO:
Calculated: C,75.75; H,6.2; N,8.28;
Found: C,75.58; H,5.97; N,8.35%.
Example 133 (E)-1-[1-(3 4-Methylenedioxyphenyl)-1.3.4.9-tetrahydro-f~-carbolin-2-yll-3-(2-dimethylaminophenyl)propene-1-one WO 97!43287 PCT/EP97/02277 The same method as employed in the preparation of Example 20 but starting from (E)-2-dimethylaminocinnamic acid (prepared according to the procedure of Suschitzky,H.; Hollywood,F. Synthesis 1982, 662-665) gave after recrystallization from MeOH:H20 the title compound as a yellow powder in a 5 51 % yield.
MP: 172 °C.
Analysis for C29H2,N3O3:
Calculated: C,74.82; H,5.85; N,9.03;
Found: C,74.75; H,5.85; N,8.9%.
Example 134 (E)-1-(1-(3,4-Methylenedioxyphenyl)-1,3.4.9-tetrahydro-Q-carbolin-2-yl1-3-f2 piperidin-1-ylphenyi)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-2-piperidin-1-ylcinnamic acid (prepared according to the procedure of Suschitzky,H.; Hollywood,F. Synthesis 1982, 662-665) gave after recrystallization from MeOH:HzO the title compound as a yellow powder in a 37% yield.
MP: 129 °C.
Analysis for Cs2H3,N3O3:
Calculated: C,76.02; H,6.18; N,8.31;
Found: C,75.66; H,6.18; N,8.29%.
Example 135 (E)-4-(3-Oxo-3-(1-(benzofuran-5-yl-1.3.4.9-tetrahydro-~-carbolin-2-y11-propenyll-benzoic acid. methyl ester The same method as employed in the preparation of Example 20 but starting from Intermediate 12 and (E)-4-(2-carboxyvinyl)benzoic acid methyl ester gave after recrystallization from EtOH the title compound as yellow crystals in a 76%
yield.
MP: 221 °C.
Analysis for C3oHz4Nz04:
Calculated: C,75.62; H,5.08; N,5.88;
Found: C,75.75; H,5.31; N,5.86%.
Example 136 (E)-4 f3 (1-Benzofuran-5-yl-1 3 4 9-tetrahydro-Q-carbolin-2-yll-3-oxo-propenvl~-benzoic acid The same' method as employed in the preparation of Example 31 but starting from Example 135 gave after recrystallization from CH3CN the title compound as yellow crystals in a 66% yield.
MP: 283 °C.
Analysis for C2sHz2NzOa. 0.6H20:
Calculated: C,73.59; H,4.94; N,5.92;
Found: C,73.48; H.4.78; N,5.93%.
Example 137 ,~E)-4 f3 Oxo-3-(1-(3 4-methylenedioxyphenyl)-1 3 4 9-tetrahydro-(i-carbolin-2-yl)propenyllphenylltrifluoromethanesulfonic acid. phenyl ester The same method as employed in the preparation of Example 20 but starting from Intermediate 41 gave after recrystallization from EtOH the title compound as white crystals in a 51 % yield.
MP: 254 °C.
Analysis for CZBH2, F3NzOsS:
Calculated: C,58.95; H,3.71; N,4.91;
Found: C,58.79; H.3.8; N,4.77%.
Example 138 (E)-1-f1-(3 4-Methvlenedioxyphenyl)-1 3 4 9-tetrahydro-l3-carbolin-2-yll-3-(2-(2-'dimethylaminoethoxy)phenyl)propene-1-one The same method as employed in the preparation of Example 79 but starting from Example 110 and dimethylaminodiethyl chloride gave after recrystallization from CH3CN:pentane the title compound as yellow crystals in a 70% yield.
MP: 131 °C.
Analysis for C3,H~,N30a. 1.3Hz0:
Calculated: C,68.95; H,6.35; N,7.88;
Found: C,69.77; H.6.28; N,7.84%.
Example 139 (El-1-f 1-(3-Fluoro-4-methoxyphenyl)-1.3.4.9-tetrahydro-a-carbolin-2-yll-3-~henylpropene-1-one The same method as employed in the preparation of Example 1 but starting from Intermediate 14 gave after recrystallization from DCM:cyclohexane the title compound as white crystals in a 66% yield.
MP: 122 °C.
Analysis for Cz,Hz3FN20z. 0.4CH2C12:
Calculated: C,71.47; H,5.21; N,6.08;
Found: C,71.46; H,5.27; N,6.12%.
Example 140 (E)-(R)-1-f 1-(2.3-Dihydrobenzofuran-5-yl)-1.3.4, 9-tetrahydro-a-carbolin-2-yl )1-3-(4-(2-dimethyiaminoethoxy)phenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and Intermediate 25 gave after recrystallization from CH3CN the title compound as white crystals in a 85% yield.
MP: 187-189 °C.
Analysis for C3zH33N3O3:
Calculated: C,75.71; H,6.55; N,8.20;
Found: C,75.60; H,6.76; N,8.10%.
[aJp2' _ -310 (c = 0.40, CHC13).
Example 141 (E)-1-(2,3-Dihydrobenzof 1.4ldioxin-6-yl)-1,3,4,9-tetrahydro-Q-carbolin-2-yl1-phenylpropene-1-one The same method as employed in the preparation of Example 1 but starting from Intermediate 13 gave after recrystailization from EtOH the title compound as white crystals in a 39% yield.
MP: 216 °C.
Analysis for CzeH24N2O3. 0.6Hz0:
Calculated: C,75.18; H,5.68; N,6.26;
. Found: C,75.17; H,5.41; N,6.4%.
Example 142 (E) 1 f1-(2 3-Dihydrobenzofuran-5-yl)-1 3 4.9-tetrahydro-l3-carbolin-2-yl)1-3-(4-~2-pyrrolidin-1-ylethoxylphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 10 and Intermediate 42 gave after recrystallization from 2-propanol:iPrzO the title compound as white crystals in a 26% yield.
MP: 152 °C.
Analysis for C~H35N3O3. 0.5Hz0:
Calculated: C,75.25; H,6.69; N,7.74;
Found: C,75.31; H,6.6; N,7.69%.
Example 143 (E)-1-f1-(3 4-Methylenedioxyphenyl)-1.3 4.9-tetrahydro-8-carbolin-2-yll-3-f4-pyrrolidin-1-ylphenyllpropene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 43 gave after recrystallization from EtOH:HzO the title compound as white crystals in a 73% yield.
MP: 154 °C.
Analysis for C3,Hz9N3O3. 0.6H20:
Calculated: C,74.11; H,6.06; N,8.36;
Found: C,74.22; H,5.97; N,7.97%.
Example 144 (E)-(R)-1-f1-(2 3-Dihydrobenzofuran-5-yl)-1,3,4.9-tetrahydro-Q-carbolin-2-yll-(3-nitrophenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and (E)-3-nitrocinnamic acid gave after recrystallization from EtOH the title compound as yellow crystals in a 51 % yield.
MP: 155 °C.
Analysis for CzeHZ3N3Oa:
Calculated: C,72.25; H,4.98; N,9.03;
Found: C,72.2; H,5.0; N,9.01 %.
[a]p'9 = -347 (c = 0.33, MeOH).
Example 145 (E)-1-f 1-(3.4-Methylenedioxyphenyl)-1.3,4.9-tetrahydro-Q-carbolin-2-yll-3-f4-imidazol-1-ylphenyllpropene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 44 gave after recrystallization from EtOH the title compound as white crystals in a 69% yield.
MP: 204 °C.
Analysis for C30H24N4O3. 0.6Hz0:
Calculated: C,72.68; H,5.04; N,11.3;
Found: C,72.67; H,4.85; N,11.34%.
Example 146 (E~-4-f3-f 1-(2,3-Dihydrobenzof 1,4ldioxin-6-yl)-1.3,4,9-tetrahydro-Q-carbolin-yll-3-oxopropenyllbenzoic acid, methyl ester The same method as employed in the preparation of Example 20 but starting from Intermediate 13 and (E)-4-(2-carboxyvinyl)benzoic acid, methyl ester gave after recrystallization from MeOH the title compound as a white powder in a 35%
yield.
MP: 136 °C.
Analysis for C3oHzsN20s. 0.1 H20:
Calculated: C,72.6; H,5.32; N, 5.64;
Found: C,72.31; H,5.26; N,5.74%.
Example 147 (E)-1-f 1-(2,3-Dih~drobenzof 1.4ldioxin-6-yl)-1,3.4,9-tetrahydro-~-carbolin-2-yll-3-(3-nitrophenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 13 and (E)-3-nitrocinnamic acid gave after recrystallization from EtOH the title compound as a pale yellow powder in a 93% yield.
MP: 154 °C.
Analysis for CZgH23N3O5. 0.6H20:
Calculated: C,68.31; H,4.95; N,8.54;
Found: C,68.41; H,4.87; N,8.61 %.
Example 148 (E) 1 (1 (2 3 Dihydrobenzo(1 4ldioxin-6-y1)-1 3 4 9-tetrahydro-Q-carbolin-2-yl)1-_3-(4-(2-dimethylaminoethoxy)phenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 13 and Intermediate 25 gave after recrystallization from 5 CH3CN the title compound as a white powder in a 65% yield.
MP: 145 °C.
Example 149 .~E) 1 f1 (3 Fluoro-4-methoxyphenyl)-1 3 4 9-tetrahydro-(3-carbolin-2-yl)1-3-(4-(2-10 dimethylaminoethoxylphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 14 and Intermediate 25 gave after recrystallization from iPr20 the title compound as a white powder in a 60% yield.
MP: 103 °C.
15 Analysis for C31H32FN3O3. 0.4Hz0:
Calculated: C,71.49; H,6.35; N,8.07;
Found: C,71.4; H,6.51; N,8.04%.
Example 150 20 (E)-4 (3 f1-(2 3-Dihydrobenzo(1 4ldioxin-6-yl)-1.3.4.9-tetrahydro-f~-carbolin-2-yll-3-oxopropenyilbenzoic acid The same method as employed in the preparation of Example 31 but starting from Example 146 gave after recrystallization from MeOH the title compound as a white powder in a 93% yield.
25 MP: 253 °C.
Analysis for C2sH24NzOs. 0.7Hz0:
Calculated: C,70.63; H,5.19; N,5.68;
Found: C,70.78; H,5.09; N,5.72%.
30 Example 151 (E) (R) 1 f1 (2 3-Dihydrobenzofuran-5-yl)-1 3 4.9-tetrahydro-13-carbolin-2-yll-phenylpropene-1-one The same method as employed in the preparation of Example 1 but starting from Intermediate 20 gave after recrystallization from MeOH the title compound as 35 white crystals in a 100% yield.
MP: 267 °C.
Analysis for CZeHzaNzOz:
Calculated: C,79.98; H,5.75; N,6.66;
Found: C,79.86; H,5.89; N,6.72%.
[a.]pz2 = -362 (c = 0.35, CHC13).
Example 152 ~E)-(S )-1-f 1-(2.3-Dihydrobenzofuran-5-yll-1.3,4.9-tetrahydro-Q-carbol i n-2-yl )1-3-l4-(2-dimethylaminoethoxy~phenvl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 21 and Intermediate 25 gave after recrystallization from CH3CN the title compound as beige crystals in a 79% yield.
MP: 153 °C.
Analysis for C32H33N3O3. 0.5Hz0:
Calculated: C, ,74.39; H,6.63; N,8.13;
Found: C,74.36; H,6.69; N,8.44%.
[a]pz' = 314 (c = 0.40, CHC13).
Example 153 (El-1-[1-f2.3-Dihydrobenzofuran-5-yl)-1,3.4,9-tetrahydro-a-carbolin-2-yll-3-(4-aminophenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 10 and (E)-4-aminocinnamic acid gave after recrystallization from iPrOH the title compound as white crystals in a 43% yield.
MP: 183 °C.
Analysis for C3pH3~N3O2. 1.6H20:
Calculated: C,76.59; H,5.83; 9.57;
Found: C,76.62; H,5.82; N,9.59%.
Example 154 ( E )-( S )-1-f 1-(2. 3-Dihydrobenzofuran-5-yl )-1, 3,4, 9-tetrahydro-(~-carbo f in-2-yll-3-phenylPropene-1-one The same method as employed in the preparation of Example 1 but starting from Intermediate 21 gave after recrystallization from EtOH the title compound as white crystals in a 98% yield.
MP: 266 °C.
Analysis for C2sH24N20z. 0.2H20:
Calculated: C,79.30; H,5.80; N,6.61;
Found: C,79.24; H,5.92; N,6.48%.
[a]p2°= 356 (c = 0.35, CHC13).
Example 155 ~E )-( S )-1-f 1-(2. 3-D i hydrobenzof ura n-5-yl )-1. 3.4. 9-tetra hydro-Q-carbo t i n-2-y I1-3-~3-nitrophenyl )propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 21 and (E)-3-nitrocinnamic acid gave after recrystallization from 2-propanol the title compound as yellow crystals in a 77% yield.
MP: 143 °C.
Analysis for C28H23N3O4. 0.3H20:
Calculated: C,71.42; H,5.05; N,8.92;
Found: C,71.51; H,4.98; N,9.23%.
[a]p'9 = 294 (c = 0.30, CHC13).
Exameie 156 ~E)-(R)-1-f 1-(2.3-Dihydrobenzofuran-5-yl)-1,3.4.9-tetrahydro-l3-carbolin-2-yl)1-3-~4-( 1-(S)-methylpyrrotidin-2-yl-methoxylphenvl )propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and Intermediate 45 gave after recrystallization from 2-propanol the title compound as white crystals in a 73% yield.
MP: 167 °C.
Analysis for C~H35N3O3:
Calculated: C,76.52; H,6.61; N,7.87;
Found: C,76.13; H, 6.71; N,7.96%.
[ac]D2° _ -344 (c = 0.30, CHC13).
Example 157 ~E)-(R)-1-f 1-(2.3-Dihydrobenzofuran-5-yl)-1.3.4.9-tetrahydro-(3-carbolin-2-yll-3-(3-hydroxyphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and (E)-3-hydroxycinnamic acid gave after recrystallization from EtOH the title compound as white crystals in a 93% yield.
MP: 251 °C.
Analysis for C28H24N2O3. 0.8Hz0:
Calculated: C,74.58; H,5.72; N,6.21;
Found: C,74.58; H,5.65; N,6.17%.
[a]p2' _ -342 (c = 0.53, CHC13).
Example 158 (E)-(R)-1-f 1-(2.3-D ihydrobenzofuran-5-yl)-1.3.4.9-tetrahydro-fi-carbolin-2-vl )1-3-~4-(2-dimethylamino-1-methylethoxy)phenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from intermediate 20 and Intermediate 46 gave after recrystallization from CH3CN the title compound as white crystals in a 100% yield.
MP: 193 °C.
Analysis for C33H35N3~3~ 0.45H20:
Calculated: C,74.82; H,6.83; N,7.93;
Found: C,74.85; H, 6.76; N,8.21 %.
Example 159 (E)-1-( 1-Phenyl-1,3.4, 9-tetrahydro-Q-carbolin-2-yl)-3-(4-(4-methylpyperazin-yl)-phenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 1 and Intermediate 47 gave after recrystallization from EtOH
the title compound as pale yellow crystals in a 26% yield.
MP: 223-226 °C.
Analysis for C32H32N4O3. 0.4H20:
Calculated: C,72.82; H,6.26; N,10.61;
Found C,72.77; H,6.31; N,10.52%.
Example 160 (E)-( R)-1-[ 1-(3,4-Methylenedioxyphenyl )-1.3.4.9-tetrahydro-!3-carbolin-2-of )1-3-(4-( 1-( S )-methylpyrrolidin-2-yl-methoxy)phenyl )propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 19 and Intermediate 45 gave after recrystallization from iPr20 the title compound as white crystals in a 83% yield.
MP: 164 °C.
Analysis for C33H33N3O4. 0.9HZ0:
Calculated: C,71.82; H,6.36; N,7.61;
Found C,72.05; H,6.57; N,7.24%.
[a]p2' _ -285 (c = 0.40, CHC13).
Example 161 (E)-(R)-1-f1-(3 4-Methylenedioxyphenyl)-1.3,4.9-tetrahydro-l3-carbolin-2-yl)1-(4-(2-dimethyiamino-1-methylethoxy)phenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 19 and Intermediate 46 gave after recrystallization from iPrzO
the title compound as white crystals in a 56% yield.
MP: 107 °C.
Analysis for C32Hs3N3O4. 0.7Hz0:
Calculated: C,71.67; H,6.47; N,7.84;
Found: C,71.6; H, 6.53; N,7.97 %.
Example 162 (E)-(R)-1-f1-(3 4-Methylenedioxyphenyl)-1,3.4.9-tetrahydro-Q-carbolin-2-yl)1-3-(4-(2-dimethylaminooropoxy)phenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 19 and Intermediate 48 gave after recrystallization from iPr20 the title compound as white crystals in a 78% yield.
MP: 193 °C.
Analysis for C32H3~N3O4. 1.6H20:
Calculated: : C,69.57; H,6.6; N,7.61;
Found: C,69.46; H. 6.59; N,7.33%.
[a]p2' _ -266 (c = 0.40, CHC13).
Example 163 (E~-4-(3-Oxo-3-(1-(3.4-fluorophenyl)-1.3.4.9-tetrahydro-(3-carbolin-2-yll-propenyllbenzoic acid. methyl ester The same method as employed in the preparation of Example 20 but starting from Intermediate 15 and (E)-4-(2-carboxyvinyl)benzoic acid, methyl ester gave after recrystallization from EtOH:H20 the title compound as a yellow powder in a 100% yield.
MP: 200 °C.
Analysis for Cz8Hz2FzN203:
Calculated: C,71.18; H,4.69; N,5.93;
Found: C,71.21; H,4.77; N,6.03%.
Example 164 (E)-(R)-(1-(2.3-Dihydrobenzofuran-5-yl)-1 3 4 9-tetrah~dro-f3-carbofin-2-yl)1-3-(4 (2-diethylaminoethoxy)phenvl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and (E)-3-(4-(2-diethylaminoethoxy)phenyl)acryfic acid (prepared according to the procedure of Sharpe,C.J.; ShaboIt.R.S.; Brown, G.R.; Ashford,A.; Ross,J.W. J. Med. Chem. 1971, 74, 836-842), gave after recrystallization from CH3CN the title compound as white crystals in a 80%
yield.
MP: 193 °C.
Analysis for C3qH37N3O3. 0.6Hz0:
Calculated: C,74.73; H,7.05; N,7.69;
Found: C,74.53; H, 6.91; N,7.68%.
[a]p2~= -311 (c = 0.30, CHC13).
Example 165 (E)-(R)-1-f1-(2.3-Dihydrobenzofuran-5-yl)-1 34 9-tetrahydro-a-carbolin-2-yl)1-(4-(2-dimethylaminopropoxy)phenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and Intermediate 48 gave after recrystallization from CH3CN the title compound as white crystals in a 79% yield.
MP: 193 °C.
Analysis for C33H35N3O3~
Calculated: C,75.98; H,6.76; N,8.06;
Found: C,76.24; H, 6.76; N,8.21 %.
[oc]p2~ _ -293 (c = 0.40, CHCl3).
Example 166 (E)-4-f3-Oxo-3-f1-(3 4-difluorophenyll-1.3.4.9-tetrahydro-l3-carbolin-2-yllpropenyllbenzoic acid The same method as employed in the preparation of Example 31 but starting from Example 163 gave after recrystalfization from MeOH:H~O the title compound as a white powder in a 100% yield.
MP: 172 °C.
Analysis for CZ~HZOF2Nz03:
Calculated: C,68.06; H,4.65; N,5.88;
Found: C,68.15; H,4.55; N,5.99%.
Example 167 (E)-(R)-1-(1-(2 3-Dihydrobenzofuran-5-yl)-1 3.4.9-tetrahydro-Q-carbolin-2-yl1-(4-aminophenyl )propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and (E)-4-aminocinnamic acid gave after recrystallization from 2-propanol the title compound as white crystals in a 80% yield.
MP: 176 °C.
Analysis for CzsHzsNs02. 0.23H20:
Calculated: C,76.49; H,5.84; N,9.56;
Found: C,76.21; H, 5.61; N,9.96%.
[a]p2' _ -375.3 (c = 0Ø35, CHC13).
Example 168 (E)-(R)-1-f1-(3 4-Methylenedioxyphenyll-1.3,4.9-tetrahydro-f3-carbolin-2-yll-3-(4-arninophenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 19 and (E)-4-aminocinnamic acid gave after recrystallization from 2-propanol:H20 the title compound as white crystals in a 63% yield.
MP: 264 °C.
Analysis for Cz7H23N3O3 0.6H20:
Calculated: C,72.34; H,5.44; N,9.37;
Found: C,72.06; H,5.48; 9.55%.
[a]p2' _ -266 (c = 0.3, MeOH).
Example 169 ~R)-(E)-1-f1-(3,4-Methyienedioxyphenyl)-1 3 4 9-tetrahydro-a-carbolin-2-yl)1 3 ~4-(2-pyrrolidin-1-ylethoxy)phenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from intermediate 19 and Intermediate 42 gave after recrystallization from iPr20 the title compound as brown crystals in a 4% yield.
MP: 116 °C.
Analysis for C33HssNsO4. 1.7H20:
Calculated: C,69.99; H,6.48; N,7.42;
Found: C,70.02; H, 6.47; N,7.59%.
Example 170 ~E)-(Rl-1-f1-(3.4-Methylenedioxyphenyl)-1 3 4 9-tetrahydro-Q-carbolin-2-yl)1 3-(4-(2-diethylaminoethoxy)phenylpropene-1-one The same method as employed in the preparation of Example 20 but starting from 1 Intermediate 19 and (E)-3-(4-(2-diethylaminoethoxy)phenyl)acrylic acid (prepared according to the procedure of Sharpe,C.J.; Shabolt,R.S.; Brown, G.R.; Ashford,A.; Ross,J.W. J. Med. Chem. 1971, 94(9), 836-842) gave after recrystallization from iPrzO the title compound as white crystals in a 67%
yield.
MP: 94 °C.
Analysis for C33H35N3O4. 0.5Hz0:
Calculated: C,72.5; H,6.64; N,7.69;
Found: C,72.48; H,6.64; N,7.58%.
[a]p2~ _ -287 (c = 0.3, CHC13).
Example 171 (E)-1-f1-(3-Fiuoro-4-methoxyphenyl)-1 3 4 9-tetrahydro-(3-carbolin-2-yl)1-3 (3 nitropheny) )propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 14 and (E)-3-nitrocinnamic acid gave after recrystallization from DCM:2-propanol the title compound as a yellow powder in a 90% yield.
MP: 141 °C.
Analysis for C2,Hz2FN304. 0.9CHZCIz:
Calculated: C,61.16; H,4.38; N,7.67;
Found: C,61.1; H,4.39; N,7.56%.
Example 172 (E)-(R)-1-(1-(2.3-Dihydrobenzofuran-5-yl)-1.3.4.9-tetrahydro-l3-carbol in-2-yl)-3-(4-triffuoromethylphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and (E)-4-trifluoromethylcinnamic acid gave after recrystallization from 2-propanol the title compound as white crystals in a 91 yield.
MP: 141 °C.
Analysis for C2sHz3F3NzOz:
Calculated: C,71.3; H,4.75; N,5.73;
Found: C,71.37; H,4.79; N,5.86%.
(oc]pz° _ -326 (c = 0.3, CHC13).
Example 173 (E)-(R)-1-(1-(2.3-Dihydrobenzofuran-5-yl)-1,3.4.9-tetrahydro-(3-carbolin-2-yl1-(3-trifluoromethyiphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and (E)-3-trifluoromethylcinnamic acid gave after recrystallization from 2-propanol:H20 the title compound as white crystals in a 80% yield.
MP: 223 °C.
Analysis for CZSHz3FsN20z:
Calculated: C,71.3; H,4.75; N,5.73;
Found: C,71.44; H,4.73; N,5.85%.
[a]pz° _ -326 (c = 0.3, CHC13).
Example 174 (E)-(R)-1-(1-(2.3-Dihydrobenzofuran-5-yl)-1.3,4.9-tetrahydro-Q-carbolin-2-yll-(4-(2-morpholin-4-ylethoxy)phenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and Intermediate 49 gave after recrystallization from 2-propanol:HzO the title compound as white crystals in a 66% yield.
MP: 148 °C.
Analysis for C34H35N3O4:
Calculated: C,71.3; H,4.75; N,5.73;
Found: C,71.44; H,4.73; N,5.85%.
[a]p'9 = -288 (c = 0.3, CHC13).
Example 175 (E)-(R )-1-f 1-(2, 3-Dihydrobenzofuran-5-yl )-1, 3.4. 9-tetrahydro-Q-carbol in-2-yi1-3-(4-(2-(ethylmethylamino)ethoxy)phenyl )propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and Intermediate 50 gave after recrystallization from iPrZO
the title compound as a white powder in a 66% yield.
MP: 107 °C.
Analysis for C33H3sN3Os~ 0.8Hz0:
Calculated: C,73.94; H,6.88; N,7.84;
Found: C,74.09; H,7.15; N,7.48%.
[a]p2' _ -253 (c = 0.3, CHC13).
Example 176 (E)-1-f 1-(2.3-Dihydrobenzofuran-5-yl)-1.3.4.9-tetrahydro-Q-carbolin-2-yll-3-(4-(3-~dimethylamino)propenyl)phenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and Intermediate 51 gave after recrystallization from EtOH
the title compound as a white powder in a 45% yield.
MP: 216 °C.
Analysis for C33H33N3O2. 0.2H2O:
Calculated: C,78.14; H,6.88; N,7.84;
Found: C,78.03; H,6.74; N,8.21 %.
[a]p~98 = -312 (c = 0.29, CHC13).
Example 177 (E)-(R)-1-f1-(2,3-Dihydrobenzofuran-5-yl)-1.3,4.9-tetrahydro-Q-carbolin-2-yll-(4-(3-dimethylamino-2-hydroxypropoxy)phenyl)propene-1-one At 0 °C to a solution (E)-(R)-1-[1-(2,3-dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-[3-carbolin-2-yl)-3-(4-(2-(tertbutyldimethylsilanyloxy)-3-dimethylamino-2-hydroxy-propoxy)phenyl)propene-1-one (0.4 g, 0.6 mmol) in 50 mL of anhydrous THF was added tetrabutylammonium fluoride (0.6 mL, 1 equiv., 1 M
in THF). The resulting mixture was stirred at rt for one day. Quenching with water, extraction with DCM, washing with brine, drying over MgS04 and concentration in vacuo gave an oil. Recrystallization from iPrOH:HzO gave the title compound (0.2 g, 62%) as an off-white powder.
MP: 138 °C.
Analysis for C33H35N3O4. 0.5Hz0:
Calculated: C,72.5; H,6.64; N,7.69;
Found: C,72.21; H,6.75; N,7.48%.
[a]pz° _ -283 (c = 0.6, CHC13}.
(E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-(3-carbolin-2-yl]-(4-(2-(tertbutyldimethylsilanyloxy)-3-dimethylamino-2-hydroxypropoxy)phenyl)-propene-1-one was obtained in a 89% yield as a yellow oil from the same method as employed in the preparation of Example 20 but starting from Intermediate 20 and intermediate 52.
'H NMR (CDC13,250 MHz) 8 8.1 (s, 1 H), 7.5-7.3 (m, 2H), 6.9-7.2 (m, 7H), 6.8-6.5 (m, 3H), 4.5 (t, 2H), 4.2 (m, 1 H), 4.0 (m, 3H), 3.8 (m, 1 H), 3.3 (m, 1 H), 3.0 (t, 2H), 2.7-2.9 (m, 3H), 2.3-2.15 (m, 2H), 2.1 (s, 6H), 0.8 (s,9H}, 0.05 (d, 6H).
Example 178 (E)-(R)-1-(1-(2 3-Dihydrobenzofuran-5-yl)-1.3.4.9-tetrahydro-f3-carbolin-2-yl)-~,4-formylphenyl )propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and (E)-4-formylcinnamic acid gave after recrystalfization from EtOH the title compound as a white powder in a 53% yield.
MP: 175 °C.
Analysis for CzsHz4NzOs. 0.8Hz0:
Calculated: C,75.24; H,5.57; N,6.05;
Found: C,75.54; H,5.78; N,6.11 %.
[a]p2° _ -340 (c = 0.33, CHC13).
Example 179 (E)-(R)-1-f1-(2 3-Dihydrobenzofuran-5-yl)-1,3,4.9-tetrahydro-Q-carbolin-2-yll-(4-propylaminomethyl)phenyl)propene-1-one To a solution of a solution of Example 178 (0.5 g, 1.1 mmol) in 50 mL of MeOH
was added propylamine {14 rnL, 1.5 equiv.). The resulting mixture was stirred at 50 °C for 4 hours. At rt polymer-supported borohydride (1.2 g, 1.2 equiv., 2.5 mmollg) was added and the resulting mixture was stirred at 50 °C for 6 hours.
After evaporation in vacuo, the residue was washed with 2x50 mL of DCM. After filtration, the filtrate was washed with 2x50 mL of water. Drying over NazS04, evaporation in vacuo and recrystallization from MeOH gave the title compound (0.4 g, 81 %) as a pale yellow powder.
MP: 170 °C.
Analysis for C3zH33N3O2. 0.4H20:
Calculated: C,77.05; H,6.83; N,8.42;
Found: C,77.04; H,6.78; N,8.29%.
[a.]p~9 = -330 {c = 0.4, MeOH).
Example 180 (E)-(R)-1-f1-(2.3-Dihydrobenzofuran-5-yl)-1 3 4.9-tetrahydro-a-carbolin-2-yll-(4-(2-dimethylaminoethyiamino)phenylpropene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and Intermediate 53 gave after recrystallization from EtOH
the title compound as yellow crystals in a 12% yield.
MP: 160 °C.
Analysis for C32H~N40z. 0.2H20:
Calculated: C,75.33; H,6.8; N,10.98;
Found C,75.06; H,6.83; N,10.98%.
(a]p2° _ -214 (c = 0.1, MeOH).
Example 181 ~E)-(Rl-1-!1-(2.3-Dihydrobenzofuran-5-yl)-1 3 4 9-tetrahydro-(3-carbolin-2-yll-~4-(2-aminoethoxy)phenyl )propane-1-one To a solution of (E)-(R)-2-[2-(4-{3-[1-(2,3-dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-~-carbolin-2-ylJ-3-oxo-propenyl~-phenoxy)ethyl]isoindole-1,3-dione (0.85 g, 1.4 mmol) in 50 mL of MeOH:THF was added hydrazine (0.38 mL, 3 equiv., 35% in water). The resulting mixture was stirred at 45 °C for 4 hours.
Evaporation in vacuo and flash chromatography with DCM:MeOH (80:20) as eluting solvent gave the title compound (0.17 g, 26%) as yellow powder.
MP: 186 °C.
Analysis for C3oH29N3Os. 0.3CH2C1z:
Calculated: C,72.06; H,5.91; N,8.32;
Found C,72.12; H,6.08; N,8.67%.
ja,]p2° _ -285 (c = 0.29, MeOH).
(E)-(R)-2-j2-(4-{3-[1-(2, 3-Dihydrobenzofuran-5-yl )-1, 3,4, 9-tetrahydro-ji-carbolin 2-yIJ-3-oxo-propenyl)phenoxy)ethyl]isoindole-1,3-dione was obtained after recrystallization from EtOH, as a gummy solid in a 90% yield using the same method as employed in the preparation of Example 20 but starting from Intermediate 20 and Intermediate 54.
'H NMR (CDC13 250 MHz) 8 8.0-6.7 (m, 19H), 4.5 (t, 2H), 4.2-4.0 (m, 5H), 3.4 (m, 1 H), 3.0 (t, 2H), 2.9 (m, 2H).
Example 182 (E)-(R)-1-f1-(2 3-Dihydrobenzofuran-5-yl)-1,3,4.9-tetrahydro-a-carbolin-2-yll-(4-hydroxyphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and (E)-4-hydroxycinnamic acid gave after recrystallization from DMF:MeOH the title compound as a white powder in a 90% yield.
MP: 189 °C.
Analysis for C2sHzaN20s. 0.5DMF:
Calculated: C,75.51; H,5.77; N,7.12;
Found: C,75.31; H,5.84; N,6.81 %.
ja]p2° _ _310 (c = 0.32, MeOH).
Example 183 (E)-(R)-1-f1- (2 3-Dihydrobenzofuran-5-yl)-1,3.4.9-tetrahydro-(i-carbolin-2-yl1-3-(4-(4-methylpiperazin-1-yl)phenyipropene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and Intermediate 47 gave after recrystallization from DMF:EtOH the title compound as pale yellow crystals in a 48% yield.
MP: 193 °C.
Analysis for C33H34N4O2. 1.ODMF:
Calculated: C,73.07; H,6.98; N,11.83;
Found C,72.67; H,7.05; N,11.55%.
ja.]p2° _ -330 (c = 0.3, CHC13).
Example 184 (E)-(R)-1-f1-(2.3-Dihydrobenzofuran-5-yl)-1.3.4 9-tetrahydro-8-carbolin-2-yl1-(4-methylaminomethyl )phenyl )propene-1-one The same method as employed in the preparation of Example 179 but starting from methylamine gave after recrystallization from MeOH:H20 the title compound as a white powder in a 52% yield.
MP: 129 °C.
Analysis for C3oH2sNsOz.1.1 H20:
Calculated: C,74.54; H,6.51; N,8.69;
Found: C,74.68; H,6.57; N,8.59%.
[a]p2' _ -288 (c = 0.4, CHC13).
Example 185 (E)-(R)-1-f1-(2.3-Dihydrobenzofuran-5-yl)-1 3 4 9-tetrahydro-a-carbofin-2-yll-(4-isopropylaminomethyl)phenyl)propene-1-one The same method as employed in the preparation of Example 179 but starting from isopropylamine gave after recrystallization from MeOH: H20 the title compound as a white powder in a 47% yield.
MP: 158 °C.
Analysis for C32Hs3N3Oz. 0.3Hz0:
Calculated: C,77.33; H,6.81; N,8.45;
Found: C,77.42; H,6.74; N,8.26%.
[a]p2' _ -319 (c = 0.3, MeOH).
Example 186 (E)-(R)-1-f 1-(2.3-Dihydrobenzofuran-5-yl)-1.3.4.9-tetrahydro-~carboiin-2-yll-(4-dimethylaminomethyl)phenyl)propene-1-one The same method as employed in the preparation of Example 179 but using dimethylamine gave after recrystallization from iPrOH:H20 the title compound as a white powder in a 34% yield.
MP: 153-154 °C.
Analysis for Cs, Hs,NsOzØ2H20:
Calculated: C,77.38; H,6.58; N,8.73;
Found: C,77.4; H,6.49; N,8.61 %.
[a]pz' _ -336 (c = 0.3, MeOH). .
Example 187 (El-(R)-1-f1-(2 3-Dihydrobenzofuran-5-yl)-1.3.4.9-tetrahydro-~-carbolin-2-yl~-L4-(3-dimethylaminopropoxy)phenyllpropene-1-one The same method as employed in the preparation of Example 79 but starting from Example 182 and dimethylaminopropyl chloride gave after recrystalfization from CH3CN the title compound as a white powder in a 53% yield.
MP: 186 °C.
Analysis for C33H35N3O2~ 0.6H20:
Calculated: C,74.44; H,6.85; N,7.89;
Found: C,74.36; H,6.63; N,7.98%.
[a]p2° _ -326 (c = 0.3, MeOH).
Example 188 (E)-(R)-1-f1-(2 3-Dihydrobenzofuran-5-yl)-1.3.4,9-tetrahydro-p-carbolin-2-yll-(4-(2-piperidin-1-ylethoxy)phenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and intermediate 55 gave after recrystallization from CH3CN the title compound as white crystals in a 50% yield.
MP: 210 °C.
Analysis for C35H37N3O3.
Calculated: C,76.75; H,6.81; N,7.67;
Found: C,76.68; H,7.11; N,7.93%.
[a]p'8~9 = -290 (c = 0.4, CHC13).
Example 189 (E)-1-f 1-(3 4-Methylenedioxyphenyl)-1 3 4 9-tetrahydro-(3-carbolin-2-yl)-3-(4-(2-piperidin-1-ylethoxy)phenyllpropene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 55 gave after recrystallization from MeOH:H20 the title compound as a beige solid in a 32% yield.
MP: 102 °C.
Analysis for C3qH35N3O4. 0.6MeOH:
Calculated: C,73.05; H,6.63; N,7.39;
Found: C,73.24; H,6.87; N,7.02%.
Example 190 (E)-(R)-f2-(4-f3-f 1-(2.3-Dihydrobenzofuran-5-yl)-1.3,4.9-tetrahydro-(3-carbolin-2-yll-3-oxopropenyl)phenoxy)ethyllmethylcarbamic acid, tertbutyl ester The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and Intermediate 56 gave the title compound as a yellow powder in a 95% yield.
MP: 110 °C.
Analysis for C36H39N305~ 0.3H20:
Calculated: C,72.17; H,6.66; N,7.01;
Found; C,71.9; H,6.86; N,7.17%.
Example 191 (E)-(R)-1-f 1-(2.3-Dihydrobenzofuran-5-yl)-1, 3,4.9-tetrahydro-t3-carbolin-2-yll-3-j4-(2-methylaminoethoxy)phenyllpropene-1-one A solution of Example 190 (0.33 g, 0.55 mmol) in DCM (30 mL) was treated with zinc bromide (0.63 g, 5 equiv.) for 16 hours at 30 °C. A gummy solid was formed. Extraction with DCM:MeOH, washing with water, drying over NazS04 and recrystallization from iPrOH gave the title compound as white crystals in a 98% yield.
MP: 145 °C.
Analysis for C3,H3~N3O3. 0.2H20:
Calculated: C,74.89; H,6.37; N,8.45;
Found: C,74.90; H,6.70; N,8.49%.
[a]pz~= -337 (c = 0.4, MeOH).
Example 192 (E)-1-f 1-(3.4-Methylenedioxyphenyl)-1, 3,4,9-tetrahydro-(~-carbolin-2-yll-3-(4-(2-piperidin-1-ylethoxy)phenyllpropene-1-one The same method as employed in the preparation of Example 1 but starting from Intermediate 13 gave after reaystallization from MeOH:HzO the title compound as a beige solid in a 32% yield.
MP: 102 °C.
Analysis for C~,H~NsOa. 0.6MeOH:
Calculated: C,73.05; H,6.63; N,7.39;
Found: C,73.24; H,6.87; N,7.02%.
Inhibitory effect on cGMP-PDE
cGMP-PDE activity of compounds of the present invention was measured using a one-step assay adapted from Wells at al. (Wells, J. N., Baird, C. E., Wu, Y.
J.
and Hardman, J. G., Biochim. Biophys. Acta 384, 430 (1975)). The reaction medium contained 50mM Tris-HCI,pH 7.5, 5mM Mg-acetate, 250uglml 5'-Nucleotidase, 1mM EGTA and 0.15~M 8-[H~j-cGMP. The enzyme used was a human recombinant PDE 5 (ICOS, Seattle USA).
Compounds of the invention were dissolved in DMSO finally present at 2°~6 in the assay. The incubation time was 30 minutes during which the total substrate inversion did not exceed 30°~.
The ICS values for the compounds examined were determined from concentration-response curves using typically concentrations ranging from lOnM to 10~IN. Tests against other PDE enzymes using standard methodology also showed that compounds of the invention are highly selective for the cGMP
specific PDE enzyme.
cGMP level measurements Rat aortic smooth muscle cells (RSMC) prepared according to Chamley et al. in Cell Tissue Res. 177. 503 - 522 (1977) were used between the 10th and 25th SUBSTITUTE SHEET (RULE 26) passage at confluence in 24-well culture dishes. Culture media was aspirated and replaced with PBS (0.5m1) containing the compound tested at the appropriate concentration. After 30 minutes at 37°C, particulates guanylate cyclase was stimulated by addition of ANF (100nM) for 10 minutes. At tt~e end of incubation, the medium was withdrawn and two extractions were performed by addition of 65°h ethanol (0.25m1). The two ethanolic extracts were pooled and evaporated until dryness, using a Speed-vac system. cGMP was measured after acetylation by scintillation proximity immunoassay (AMERSHAM). The ECso values are expressed as the dose giving half of the stimulation at saturating concentrations Biolooical data The compounds according to the present invention were typically found to exhibit an (Cso value of less than 500 nM and an ECso value of less than 5 ErM. In vitro test data for representative compounds of the invention is given in the following table:
SUBSTITUTE SHEET (RULE 26) i aoie ~ . m wrro results Example No. IC~ rsM ECM NM
14 5 0.45 25 72 0.3 28 55 0.3 55 40 0.4 61 20 1.8 140 2 0.1 142 18 1.5 156 15 < 1 164 11 1.5 165 9 < 1 177 12 < 1 180 25 3.5 182 2 < 1 188 24 < 1 191 8 < 1 The hypotensive effects of compounds according to the invention as identified in Table 2 were studied in conscious spontaneously hypertensive rats (SHR). The compounds were admnistered orally at a dose of 5 mglkg in a mixture of 596 DMF and 95% olive oil. Blood pressure was measured from a catheter inserted in the carotid artery and recorded for 5 hours after administration. The results are expressed as Area Under the Curve (AUC from 0 to 5 hours, mmHg.hour) of the fall in blood pressure over time.
SUBSTITUTE SHEET (RULE 26) Table 2. In vivo results Example No. AUC PO (mmHg.h) s1 95 SUBSTITUTE SHEET (RULE 26) The application of which this description and claims forms part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any novel feature or combination of features described herein. They may take the form of product, composition, process or use claims and may include, by way of example and without limitation, the following claim.
Typically, RS represents -OCZ.~alkylene NRaRb, in particular OCHZCH2N(CH3)2. Alternatively, R5 may represent -O-C,~alkylene Het, where Het may suitable be piperidyl, pyrrolidinyl (optionally substituted by C,~alkyl, e.g. methyl) or morpholinyi.
Particularly aptly R6 represents I > or i i I > , especially I
o ~ o The compounds of formula (I) may contain one or more asymmetric centres and thus can exist as enantiomers or diastereoisomers. It is to be understood that the invention includes both mixtures and separate individual isomers of the compounds of formula (I).
The pharmaceutically acceptable salts of the compounds of formula (I) which contain a basic centre are acid addition salts formed with pharmaceutically acceptable acids. Examples include the hydrochloride, hydrobromide, sulphate or bisulphate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, gluconate, methanesulphonate, benzenesulphonate and p-toiuenesulphonate salts. Compounds of the formula (I) can also provide pharmaceutically acceptable metal salts, in particular alkali metal salts, with bases. Examples include the sodium and potassium salts.
Particular individual compounds of the invention include:
(E)-1-( 1-Phenyl-1, 3,4, 9-tetrahydro-(i-carbol in-2-yl)-3-phenylpropene-1-one (E)-1-(1-Phenyl-1,3,4,9-tetrahydro-~-carbolin-2-yl)-3-(4-nitrophenyl)propene-1-one (E)-1-( 1-Phenyl-1, 3,4, 9-tetrahydro-(i-carbolin-2-yl)-3-(4-trifluoromethylphenyl )-propene-1-one (E)-1-( 1-Phenyl-1,3,4,9-tetrahydro-[3-carbolin-2-yl)-3-(4-methoxy-phenyl)propene-1-one (E)-1-[1-(4-Methoxyphenyi)-1,3,4,9-tetrahydro-~-carbolin-2-yl)-3-(4-trifluoromethylphenyl)propene-1-one (E)-N-[4-[3-Oxo-3-( 1-phenyl-1,3,4,9-tetrahydro-~i-carbolin-2-yl)propenyl)phenyl)-acetamide (E)-1-(1-(4-Methoxyphenyl)-1, 3,4,9-tetrahydro-~i-carbolin-2-yl}-3-phenylpropene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl )-1, 3,4, 9-tetrahydro-(i-carbolin-2-yl)-3-phenyl-propene-1-one (E)-1-(1-Phenyl-1,3.4, 9-tetrahydro-(3-carbolin-2-yl )-3-(4-formylphenyl)propene-1-one (E)-N-[4-(3-Oxo-3-(1-(4-nitrophenyl)-1,3,4,9-tetrahydro-p-carbolin-2-yi)propenyl)-phenyl)acetamide (E)-1-(1-(4-Nitrophenyl)-1, 3,4, 9-tetrahydro-(i-carbolin-2-yl)-3-phenyipropene-1-one (E)-1-[1-(4-Trifluoromethoxyphenyl)-1, 3,4, 9-tetrahydro-p-carbolin-2-yl)-3-phenyl-propene-1-one (E)-1-[1-(4-Methylphenyl )-1, 3,4, 9-tetrahydro-(3-carbolin-2-yl)-3-phenylpropene-1-one (E)-N-(4-(3-Oxo-3-( 1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-(3-carbolin-2-yl)-propenyl]phenyl)acetamide (E)-4-[3-Oxo-3-(1-phenyl-1,3,4,9-tetrahydro-(3-carbolin-2-yl)-propenyl]benzoic acid, methyl ester (E)-1-[1-(2-Chiorophenyl)-1, 3,4,9-tetrahydro-(3-carbolin-2-ylj-3-phenyfpropene-1-one (E)-1-( 1-Phenyl-1,3,4,9-tetrahydro-p-carbolin-2-yl)-3-(3,4-methylenedioxyphenyl)-propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1, 3,4, 9-tetrahydro-(i-carbolin-2-yl)-3-(4-bromophenyl)propene-1-one (E)-1-[1-(4-Chlorophenyl )-1, 3,4,9-tetrahydro-j3-carbolin-2-yl)-3-phenylpropene-1-one WO 97!43287 PCT/EP97/02277 (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4, 9-tetrahydro-[3-carbolin-2-yl]-3-(4-ethoxyphenyl)propene-1-one (E)-4-[3-Oxo-3-( 1-(3,4-methylenedioxyphenyl }-1, 3,4, 9-tetrahydro-[i-carbol in-2-yl)propenyl]acetic acid, phenyl ester (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-~i-carbofin-2-yl]-3-(4-hydroxyphenyl)propene-1-one (E)-1-[1-(3,4-Methyienedioxyphenyl)-1,3,4,9-tetrahydro-(3-carbolin-2-yl]-3-(4-formylphenyl)propene-1-one (E)-1-[4-[3-Oxo-3-( 1-(3,4-methylenedioxyphenyl}-1, 3,4, 9-tetrahydro-[3-carbol in-2-yl)-propenyl]phenyl]-3-phenylurea (E)-1-[1-(3,4-Methylenedioxyphenyl)-1, 3,4,9-tetrahydro-[i-carbolin-2-yl]-3-(4-aminophenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxy-phenyl)-1, 3,4,9-tetrahydro-[i-carbolin-2-yl]-3-(4-nitro-phenyl)-propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-p-carboiin-2-yl]-3-[(4-bis(methylsulfonyl)aminophenyl]propene-1-one (E}-4-[3-Oxo-3-[1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-[3-carbolin-2-yl]-propenyl]benzoic acid, methyl ester (E)-N-[4-[3-Oxo-3-[1-(3,4-methylenedioxyphenyl )-1,3,4, 9-tetrahydro-[i-carbol in-2-yl]progenyl]phenyl]methanesulfonamide (E)-4-[3-Oxo-3-[1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-[3-carbolin-2-ylJpropenyl]benzamide]
(E)-4-[3-Oxo-3-[1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-p-carbolin-2-yl]-progeny!]benzoic acid (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-~-carbolin-2-yl]-3-(4-cyanophenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-[3-carbolin-2-yl]-3-(4-trifluoromethylphenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1, 3,4, 9-tetrahydro-[3-carbolin-2-yl]-3-(3,4-_30 methylenedioxyphenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1, 3,4, 9-tetrahydro-[3-carboiin-2-yl]-3-(4-chlorophenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1, 3,4,9-tetrahydro-~-carbolin-2-ylJ-3-(4-trifluoromethoxyphenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4, 9-tetrahydro-j3-carbolin-2-y!]-3-(4-methylphenyl)propene-1-one (E)-[4-[3-Oxo-3-( 1-(3,4-methyienedioxyphenyl)-1, 3,4, 9-tetrahydro-~-carbol in-2-yl)propenyl]phenyl]urea (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-~-carbolin-2-yl]-3-(4-hydroxymethylphenyl)propene-1-one (E)-N-Benzyl-4-[3-oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-ji-carbolin-2-yt)propenyl]benzamide (E)-1-[1-(3,4-Methyienedioxyphenyl)-1,3,4,9-tetrahydro-~i-carbolin-2-yl]-3-(2,4-dichlorophenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1, 3,4,9-tetrahydro-~-carbolin-2-yl]-3-(3-methoxy-4-hydroxyphenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1, 3,4,9-tetrahydro-~i-carbolin-2-yl]-3-(3-hydroxy-4-methoxyphenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-ji-carbolin-2-yl]-3-(4-fluorophenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-p-carbolin-2-yl]-3-indan-5-yl-1-propene-1-one (E)-N-[4-[3-Oxo-3-(1-(3,4-methyienedioxyphenyl )-1, 3,4, 9-tetrahydro-ji-carbolin-2-yl)propenyl]benzoyl]benzenesulfonamide (E)-1-[1-(3,4-Methyienedioxyphenyl)-1,3,4,9-tetrahydro-(3-carbolin-2-yl]-3-(3,4-dichforophenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-~-carbolin-2-yl]-3-(3,4-dimethoxyphenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-ji-carbolin-2-yl]-3-(3,4-dihydroxyphenyl)propene-1-one (E )-N-Methyl-N-[4-(3-oxo-3-( 1-(3,4-methylened ioxyphenyl)-1, 3,4, 9-tetrahydro-~-carbolin-2-yl)propenylJphenyl]acetamide (E)-2,2-Dimethyl-N-[4-[3-Oxo-3-( 1-(3,4-methylenedioxyphenyl)-1, 3,4, 9-tetrahydro-ji-carbolin-2-yl)propenyl]phenyl]propionamide (E)-1-[1-(3,4-Methylenedioxyphenyl )-1,3,4,9-tetrahydro-(3-carbolin-2-yl]-3-(3, 5-dimethoxyphenyl)propene-1-one (E)-(N)-{4-[3-[1-(3,4-Methyienedioxyphenyl)-6-fluoro-1,3,4,9-tetrahydro-(3-carbolin-2-yl]-3-oxopropenyl]phenyl}-acetamide WO 97!43287 PCT/EP97/02277 (E)-1-[1-(3,4-Methylenedioxyphenyl}-1, 3,4,9-tetrahydro-(i-carbolin-2-yl]-3-(3,4, 5-trimethoxyphenyl)propene-1-one (E)-N-[4-[3-Oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-p-carbolin-2-yl)propenyl]phenyl)isobutyramide (E)-1-[1-(3,4-Methylenedioxyphenyl)-6-fluoro-1, 3,4, 9-tetrahydro-(i-carbolin-2-yl]-3-phenylpropene-1-one (E)-N-(2-Methoxyethyl)-4-(3-oxo-3-{ 1-(3,4-methylenedioxyphenyl)-1,3,4, 9-tetrahydro-~-carbofin-2-yl)propenyl]benzamide (E)-1-[1-(3,4-Methylenedioxyphenyl}-1,3,4,9-tetrahydro-[i-carbolin-2-yl]-3-(3-hydroxyphenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1, 3,4, 9-tetrahydro-[i-carbolin-2-yl]-3-(3-methoxyphenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-[i-carboiin-2-yl]-3-(3-nitrophenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-[3-carbolin-2-yl]-3-[4-(2-dimethyiaminoethoxy)phenyl]propene-1-one (E)-N-(2-Morpholin-4-ytethyl)-4-(3-oxo-3-{1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-~-carbolin-2-yl)propenyf]benzamide (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-(i-carbolin-2-yl]-3-[4-(1 H-tetrazol-5-yl)phenyl]propene-1-one (E )-1-[1-(3,4-Methylenedioxyphenyl)-1, 3,4, 9-tetrahydro-[3-carbolin-2-yl]-3-(3-aminophenyl)propene-1-one (E)-N-Cyclohexyl-4-[3-oxo-3-( 1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-[i-carbolin-2-yl)propenyl]benzamide (E)-N-(Tetrahydrofuran-2-ylmethyl)-4-[3-oxo-3-(1-(3,4-methylenedioxyphenyl)-1, 3,4, 9-tetrahydro-[3-carboi in-2-yl)propenyl]benzamide (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-(3-carbolin-2-yl]-3-(3-cyanophenyl)propene-1-one (E)-N-(4-Piperidine-4-carboxylic acid, ethyl ester)-4-[3-oxo-3-(1-(3,4-~0 methyienedioxyphenyl)-1,3,4,9-tetrahydro-(3-carbolin-2-yl)propenyl]benzamide (E)-N-(4-Piperidine-4-carboxylic acid)-4-(3-oxo-3-( 1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-~-carbolin-2-yi)propenyl]benzamide (E)-3-[3-Oxo-3-[1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-~-carbolin-2-yl]-propenyl]benzoic acid (E)-1-[1-(3,4-Methylenedioxyphenyl)-1, 3,4, 9-tetrahydro-~-carbolin-2-yl]-3-(3-(4-methylpiperazine-1-carbonyl)phenyl)propene-1-one (E)-N-(2-Piperazin-1-ylethyl)-3-[3-oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-[i-carbolin-2-yl)propenyl]benzamide 5 (E)-4-[3-Oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-(3-carbolin-yl)-propenyl]acetic acid ethyl ester {E)-1-[1-{3,4-Methylenedioxyphenyl)-1, 3,4, 9-tetrahydro-~3-carbolin-2-yl]-3-(3-tetrazolophenyl)propene-1-one (E)-2-[3-Oxo-3-[1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-(i-carbolin-2-10 yl]-propenyl]benzoicacid, methyl ester {E)-3-[3-Oxo-3-[1-(3,4-methylenedioxyphenyl)-1, 3,4, 9-tetrahydro-[3-carbolin-yl]-propenyl]benzoic acid, methyl ester (E)-1-{4-[3-Oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-{i-carbolin-2-yl)-propenyl]phenyl)piperidine-4-carboxylic acid, ethyl ester (E)-N-{1-Ethylpyrrolidin-2-yl-methyl)-3-[3-oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-(3-carbolin-2-yl)propenylJbenzamide (E)-1-[1-(3,4-Methylenedioxyphenyl)-1, 3,4, 9-tetrahydro-(3-carbol in-2-yl]-3-(3-(2-dimethylaminoethoxy)phenyl)propene-1-one ( E)-1-[ 1-(3,4-Methylenedioxyphenyl )-1, 3,4, 9-tetrahydro-[i-carboiin-2-yIJ-3-(3, 5-diterbutyl-4-hydroxyphenyl)propene-1-one (E)-3-[3-Oxo-3-[1-(4-methoxycarbonylphenyl)-1, 3,4, 9-tetrahydro-[i-carbolin-2-yl]propenylJbenzoic acid, methyl ester (E)-2-[3-Oxo-3-[1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-[i-carbolin-2-yIJ-propenylJbenzoic acid (E)-(4-[3-Oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-[i-carbolin-2-yl)propenyl]phenoxy)acetic acid, ethyl ester (E)-(4-[3-Oxo-3-( 1-(3,4-methylenedioxyphenyl)-1,3,4, 9-tetrahydro-~-carbolin-yl)-propenyl]phenyl)acetic acid (E)-{4-[3-Oxo-3-( 1-(3, 4-methylenedioxyphenyl)-1, 3,4, 9-tetrahydro-~-carbol in-2-yl)propenylJphenoxy)acetic acid (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-~3-carbolin-2-yl]-3-(3-nitro-4-chlorophenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-(i-carbolin-2-ylJ-3-(5-nitro-2-chlorophenyl)propene-1-one (E)-3-Chtoro-4-[3-oxo-3-[1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-(3-carboiin-2-yl]propenyl]benzoic acid, methyl ester (E)-(4-[3-Oxo-3-( 1-(3,4-methylenedioxyphenyl)-1,3,4, 9-tetrahydro-~-carboiin-yl)propenyl]benzyloxy)acetic acid (E)-1-[1-(3,4-Methylenedioxyphenyl)-1, 3,4,9-tetrahydro-~i-carbolin-2-yl]-3-(5-amino-2-chlorophenyl)propene-1-one (E)-3-Chloro-4-[3-oxo-3-[1-{3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-ø-carbolin-2-yl]propenyl]benzoic acid (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-p-carbolin-2-yl]-3-(3, dibromo-4-hydroxyphenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1, 3,4, 9-tetrahydro-[i-carbolin-2-yl]-3-(4-(2-dimethylaminopropoxy)phenyl)propene-1-one (E)-2-Chloro-5-[3-oxo-3-[1-(3,4-methylenedioxyphenyl)-1,3,4, 9-tetrahydro-[3-carbolin-2-yl]propenyl]benzoic acid, methyl ester (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-[3-carbolin-2-yl]-3-(4-(2-diisopropylaminoethoxy)phenyl)propene-1-one {E)-2-Chloro-5-[3-oxo-3-[1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-~-carbolin-2-yl]propenyl]benzoic acid (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4, 9-tetrahydro-[i-carbolin-2-yl]-3-(3-hydroxy-4-nitrophenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-p-carbolin-2-yl]-3-(3,5-dimethyl-4-hydroxyphenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-[i-carbofin-2-yl]-3-(3-(2-dimethylaminoethoxy)-4-nitrophenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-[i-carbolin-2-yl]-3-(3-(2-dimethylaminoethoxy)-4-aminophenyl)propene-1-one (E)-1-[1-{3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-[i-carbolin-2-yl]-3-(3-nitro-4-hydroxy-5-methoxyphenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1, 3,4,9-tetrahydro-~-carbolin-2-yl]-3-(3-.30 chlorophenyl)propene-1-one (E)-1-[1-(4-Methoxy-phenyl)-1,3,4,9-tetrahydro-[i-carbolin-2-yl]-3-(2-chloro-5-nitrophenyl)propene-1-one {E)-1-[1-{3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-~-carbolin-2-yl]-3-(2,6-dichlorophenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-ji-carbolin-2-yl]-3-(4-methylaminomethylphenyl)propene-1-one (E)-1-[1-(3,4-Methyienedioxyphenyl)-1,3,4, 9-tetrahydro-j3-carbolin-2-yl]-3-(3-methylphenyl)-propene-1-one (E)-N-Methyl-(4-[3-oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-[3-carbolin-2-yl)propenyl]benzenesulfonamide (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4, 9-tetrahydro-[i-carbolin-2-yl]-3-(3-hydroxy-4-acetylphenyl)propene-1-one (E)-1-[1-(2, 3-Dihydrobenzofuran-5-yl )-1, 3,4, 9-tetrahydro-[3-carboiin-2-yl]-3-(2-chloro-5-nitrophenyl)propene-1-one (E}-1-[1-(3,4-Methyienedioxyphenyl)-1, 3,4, 9-tetrahydro-[i-carbol in-2-yl]-3-(2-hydroxyphenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4, 9-tetrahydro-ji-carbolin-2-yl)-3-(3-nitro-2-piperidin-1-ylphenyl)propene-1-one (E)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-ji-carbolin-2-yl]-3-phenylpropene-1-one (E)-1-[1-(4-Isopropylphenyl)-1,3,4, 9-tetrahydro-(i-carboiin-2-yl]-3-(3-nitrophenyl)propene-1-one (E)-1-[1-(2, 3-Dihydrobenzofuran-5-yl }-1, 3,4, 9-tetrahydro-j3-carbol in-2-yl]-3-(3-nitrophenyl)propene-1-one (E)-(R)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-[i-carbolin-2-yl]-3-phenylpropene-1-one (E)-(S)-1-(1-(3,4-Methylenedioxyphenyl}-1, 3,4,9-tetrahydro-~-carbofin-2-yl]-3-phenylpropene-1-one (E)-1-[1-(4-Methoxyphenyl)-1,3,4,9-tetrahydro-p-carbolin-2-yl]-3(3-nitrophenyl)propene-1-one (E)-1-j1-(4-Methylphenyl)-1,3,4,9-tetrahydro-ji-carboiin-2-yl]-3-(2-chloro-5-nitrophenyl)propene-1-one (E)-N-(Tetrahydrofuran-2-ylmethyl)-3-[3-oxo-3-( 1-(3,4-methylenedioxy)-1,3,4, tetrahydro-j3-carbolin-2-yl)propenyl]benzamide (E)-1-[1-(Indan-5-yl}-1,3,4,9-tetrahydro-~-carbolin-2-yl]-3-phenylpropene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-ji-carbolin-2-yl]-3-(3-acetylphenyl)propene-1-one (E)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-(3-carbolin-2-yl)]-3-(4-(2-dimethylaminoethoxy)phenyl)propene-1-one (E)-4-[3-Oxo-3-[1-(4-methoxyphenyl)-1,3,4, 9-tetrahydro-ø-carbolin-2-yl]propenyl]-benzoic acid, methyl ester (E)-1-[ 1-(3,4-Methylenedioxyphenyl)-1, 3,4, 9-tetrahydro-ø-carbolin-2-yl]-3-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-ø-carbolin-2-yl]-3-(2-hydroxy-5-nitrophenyl)propene-1-one (E)-4-[3-Oxo-3-[1-(2, 3-dihydrobenzofuran-5-yl)-1, 3,4, 9-tetrahydro-~-carbolin-2-yl]propenyl]benzoic acid, methyl ester (E)-4-[3-Oxo-3-(1-(4-methoxyphenyl)-1, 3,4, 9-tetrahydro-ø-carbolin-2-yl]propenyl]benzoic acid (E)-4-[3-Oxo-3-[1-{2,3-dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-ø-carbolin-2-y1]propenyl]benzoic acid ( E)-1-[1-(Benzofuran-5-yl )-1, 3,4, 9-tetrahydro-ø-carbol in-2-yl]-3-phenyipropene-1-one (E)-3-[3-Oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-ø-carbolin-2-yl)-propenyl]phenyl)trifluoromethanesulfonic acid, phenyl ester (E)-1-[1-(3,4-Methylenedioxyphenyl)-1, 3,4,9-tetrahydro-ø-carboiin-2-yIJ-3-(4-(2-hydroxyethoxy)phenyl]propene-1-one (E)-1-[1-(Benzofuran-5-yl-1,3,4,9-tetrahydro-ø-carbolin-2-yl)]-3-(4-(2-dimethylaminoethoxy)phenyl)propene-1-one (E)-1-[1 (3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-ø-carbolin-2-yl]-3-{2-dimethylaminophenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl )-1, 3,4, 9-tetrahydro-ø-carbolin-2-yl]-3-(2-piperidin-1-ylphenyl)propene-1-one (E)-4-[3-Oxo-3-(1-(benzofuran-5-yl-1,3,4,9-tetrahydro-ø-carbolin-2-yl]-propenyl]-benzoic acid, methyl ester (E)-4-[3-( 1-Benzofuran-5-yl-1, 3,4, 9-tetrahydro-ø-carbolin-2-yl )-3-oxo-propenyl]-benzoic acid (E)-4-[3-Oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-[i-carbolin-2-._30 yl)propenyl]phenyl)trifluoromethanesulfonic acid, phenyl ester (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-ø-carbolin-2-yl]-3-(2-(2-dimethylaminoethoxy)phenyl)propene-1-one (E)-1-[1-(3-F luoro-4-methoxyphenyl )-1, 3,4, 9-tetrahydro-ø-carbol in-2-yl]-3-phenylpropene-1-one (E)-(R)-1-[1-(2, 3-Dihydrobenzofuran-5-yl)-1, 3,4, 9-tetrahydro-~-carbol i n-2-yl )]-3-(4-(2-dimethylaminoethoxy)phenyl)propene-1-one (E)-1-(2,3-Dihydrobenzo(1,4]dioxin-6-yl)-1,3,4,9-tetrahydro-~-carbolin-2-yl]-3-phenylpropene-1-one (E)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-[i-carbolin-2-yl)]-3-{4-(2-pyrrolidin-1-ylethoxy)phenyl)propene-1-one (E)-1-[ 1-(3,4-Methylenedioxyphenyl )-1, 3,4,9-tetrahydro-p-carbolin-2-yl]-3-(4-pyrrolidin-1-yiphenyl]propane-1-one (E)-(R)-1-[1-(2, 3-Dihydrobenzofuran-5-yl)-1, 3, 4, 9-tetrahydro-[3-carbolin-2-yl]-3-(3-nitrophenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-[i-carbolin-2-yl]-3-[4-imidazol-1-ylphenyl]propene-1-one (E)-4-[3-(1-(2,3-Dihydrobenzo[1,4]dioxin-6-y!)-1,3,4, 9-tetrahydro-[i-carbolin-yl]-3-oxopropenyl]benzoic acid, methyl ester (E)-1-[1-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-1,3,4,9-tetrahydro-(3-carbolin-2-yl]-3-(3-nitrophenyl)propene-1-one (E)-1-[1-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-1, 3,4,9-tetrahydro-[3-carbolin-2-yl)]-3-(4-(2-dimethylaminoethoxy)phenyl)propene-1-one (E)-1-[1-(3-Fluoro-4-methoxyphenyl)-1, 3,4,9-tetrahydro-[3-carbolin-2-yl)]-3-(4-(2-dimethylaminoethoxy)phenyl)propene-1-one (E)-4-[3-(1-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-1,3,4,9-tetrahydro-~-carbofin-2-yl]-3-oxopropenyl]benzoic acid (E)-(R)-1-(1-(2, 3-Dihydrobenzofuran-5-yl)-1, 3,4, 9-tetrahydro-[3-carbolin-2-yl]-3-phenylpropene-1-one (E)-(S)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-[3-carbolin-2-yl)]-3-(4-(2-dimethylaminoethoxy)phenyl}propane-1-one (E)-1-[1-(2, 3-Dihydrobenzofuran-5-yl )-1, 3,4, 9-tetrahydro-/3-carbolin-2-yl]-3-(4-aminophenyl)propene-1-one ( E)-(S )-1-[ 1-(2, 3-Dihydrobenzofuran-5-yl )-1, 3, 4, 9-tetrahydro-[3-carboi in-2-yl]-3-phenylpropene-1-one (E)-(S)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4, 9-tetrahydro-p-carbolin-2-yl]-(3-nitrophenyl)propene-1-one (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-p-carbolin-2-yl)]-(4-(1-(S}-methyfpyrrolidin-2-yl-methoxy)phenyl)propene-1-one (E)-(R)-1-[1-(2, 3-D ihydrobenzofuran-5-yl )-1, 3,4, 9-tetrahydro-[i-carbolin-2-yl]-3-(3-hydroxyphenyl)propene-1-one ( E)-(R)-1-[1-(2, 3-D ihydrobenzofuran-5-yl}-1, 3,4, 9-tetrahydro-~i-carbolin-2-yl )]-3-(4-(2-dimethylamino-1-methylethoxy)phenyl)propene-1-one (E)-1-( 1-Phenyl-1,3,4,9-tetrahydro-[i-carbolin-2-yl)-3-(4-(4-methylpyperazin-yl)-phenyl)propene-1-one (E)-(R)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-~-carbolin-2-yl)]-3-(4-(1-(S)-methylpyrrolidin-2-yl-methoxy)phenyl)propene-1-one (E)-(R)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4, 9-tetrahydro-~-carbolin-2-yl)]-10 (4-(2-dimethylamino-1-methylethoxy)phenyl)propene-1-one (E)-(R)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-~-carbolin-2-yl)]-3-(4-(2-dimethylaminopropoxy)phenyl)propene-1-one (E}-4-[3-Oxo-3-[1-(3,4-fluorophenyl)-1, 3,4, 9-tetrahydro-[i-carbolin-2-yl]-propenyl]benzoic acid, methyl ester 15 (E)-(R)-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-[i-carbolin-2-yl)]-3-(4-(2-diethylaminoethoxy)phenyl)propene-1-one (E)-(R) 1-[1-(2, 3-Dihydrobenzofuran-5-yl}-1, 3,4, 9-tetrahydro-~-carbol in-2-yl )]-3-(4-(2-dimethylaminopropoxy)phenyl)propene-1-one (E}-4-[3-Oxo-3-[1-(3,4-difluorophenyl)-1,3,4,9-tetrahydro-[i-carbolin-2-yl]propenyl]-benzoic acid (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-[i-carbolin-2-yl]-(4-aminophenyl)propene-1-one (E)-(R)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-[i-carbolin-2-yl]-3-(4-aminophenyl)propene-1-one (E)-(R)-1-[1-(3,4-Methyienedioxyphenyl)-1,3,4,9-tetrahydro-(3-carbolin-2-yl)]-(4-(2-pyrrolidin-1-ylethoxy)phenyl)propene-1-one (E}-(R)-1-[1-(3,4-Methyienedioxyphenyl)-1,3,4, 9-tetrahydro-p-carbolin-2-yl)]-(4-(2-diethylaminoethoxy)phenylpropene-1-one (E)-1-[1-(3-Fluoro-4-methoxyphenyl)-1,3,4,9-tetrahydro-~-carbolin-2-yl)]-3-(3-nitrophenyl)propene-1-one (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-y1)-1,3,4, 9-tetrahydro-[3-carbolin-2-yl]-3-(4-trifluoromethyiphenyl)propene-1-one (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-~-carbolin-2-yl]-(3-trifluoromethylphenyl)propene-1-one (E)-(R)-1-[1-(2, 3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-{i-carbolin-2-yl]-3-(4-(2-morpholin-4-ylethoxy)phenyl)propene-1-one (E)-(R)-1-[1-(2, 3-Dihydrobenzofuran-5-yl)-1, 3,4, 9-tetrahydro-~i-carbolin-2-yl]-3-(4-(2-(ethylmethylamino)ethoxy)phenyl)propene-1-one {E)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-[i-carbolin-2-yl]-3-(4-(3-(dimethylamino)propenyl)phenyl)propene-1-one (E)-(R)-1-[1-(2, 3-Dihydrobenzofuran-5-yl)-1, 3,4, 9-tetrahydro-(3-carbo I in-2-yl]-3-(4-(3-dimethyiamino-2-hydroxypropoxy)phenyl)propene-1-one ( E)-(R)-1-( 1-(2, 3-Dihydrobenzofuran-5-yl)-1, 3, 4, 9-tetrahydro-(3-carboi in-2-yl)-3-(4-formyiphenyl)propene-1-one (E)-(R)-1-[1-{2,3-Dihydrobenzofuran-5-yl}-1,3,4,9-tetrahydro-j3-carbolin-2-ylJ-(4-propylaminomethyl)phenyl)propene-1-one (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-~3-carbolin-2-yl]-[4-(2-dimethylaminoethyiamino)phenylpropene-1-one (E}-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-ji-carbolin-2-yl]-(4-(2-aminoethoxy)phenyl)propene-1-one (E)-(R)-1-[1-(2, 3-Dihydrobenzofuran-5-yl)-1, 3,4, 9-tetrahydro-{i-carbol in-2-yl]-3-(4-hydroxyphenyl)propene-1-one (E)-(R)-1-[1-(2, 3-Dihydrobenzofuran-5-yl)-1, 3,4, 9-tetrahydro-[3-carbolin-2-yl]-3-(4-(4-methylpiperazin-1-yl)phenylpropene-1-one (E)-(R)-1-[1-(2, 3-Dihydrobenzofuran-5-yl)-1,3,4, 9-tetrahydro-~-carbolin-2-yIJ-3-(4-methyiaminomethyl)phenyl)propene-1-one (E)-(R)-1-j1-{2, 3-Dihydrobenzofuran-5-yl)-1, 3,4, 9-tetrahydro-[3-carbol in-2-yl]-3-(4-isopropylaminomethyl)phenyl)propene-1-one (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-~i-carbolin-2-yl]-(4-dimethylaminomethyl)phenyl)propene-1-one (E}-(R)-1-[ 1-(2, 3-Dihydrobenzofuran-5-yl}-1, 3,4, 9-tetrahydro-[i-carbol in-2-yl]-3-[4-(3-dimethylaminopropoxy)phenylJpropene-1-one (E)-(R}-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-~-carbolin-2-yl)-(4-(2-piperidin-1-ylethoxy)phenyl)propene-1-one (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-[i-carbolin-2-yl)-3-(4-(2-piperidin-1-ylethoxy)phenylJpropene-1-one (E}-(R)-[2-(4-{3-[1-(2, 3-Dihydrobenzofuran-5-yl)-1,3,4, 9-tetrahydro-[3-carbolin-2-yl]-3-oxopropenyl)phenoxy)ethyl]methylcarbamic acid, tertbutyl ester ( E)-(R)-1-[ 1-(2, 3-D ihydrobenzofuran-5-yl )-1, 3, 4, 9-tetrahydro-(3-carbolin-2-yl]-3-[4-(2-methylaminoethoxy)phenyl]propene-1-one and pharmaceutically acceptable salts and solvates (e.g. hydrates) thereof.
A specific compound of the invention is:
(E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-~3-carbolin-2-yl)]-3-(4-(2-dimethylaminoethoxy)phenyi)propene-1-one and pharmaceutically acceptable salts and solvates (e.g. hydrates) thereof.
It has been shown that compounds of the present invention are potent and selective inhibitors of cGMP specific PDE. Thus, compounds of formula (!) ace of interest for use in therapy, specifically for the treatment of a variety of conditions where inhibition of cGMP specific PDE is thought to be beneficial.
As a consequence of the selective PDE 5 inhibition exhibited by compounds of the present invention, cGMP levels are elevated, which in turn can give rise to beneficial anti-platelet, anti-neutrophil, anti-vasospastic, vasodilatory, natriuretic~ and diuretic activities as well as potentiation of the effects of endothelium-derived relaxing factor (EDRF), nitrovasodilators, atrial natnuretic factor (ANF), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP) and endothelium-dependent relaxing agents such as bradykinin, acetylcholine and 5-HT~. The compounds of formula (I) therefore have utility in the treatment of a number of disorders, including stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, congestive heart failure, renal failure, atherosclerosis, conditions of reduced blood vessel patency (e.g.
post-percutaneous transluminal coronary angioplasty), peripheral vascular disease, vascular disorders such as Raynaud's disease, inflammatory diseases, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, erectile dysfunction and diseases characterised by disorders of gut motility (e.g.
irritable bowel syndrome).
It will be appreciated that references herein to treatment extend to prophyfaxis as well as treatment of established conditions.
_30 It will also be appreciated that a compound of formula (I), or a physiologically acceptable salt or solvate thereof can be administered as the raw compound, or as a pharmaceutical composition containing either entity.
There is thus provided as a further aspect of the invention a compound of formula (I) for use in the treatment of stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, congestive heart failure, renal failure, atherosclerosis, conditions of reduced blood vessel patency, (e.g. post-PTCA}, peripheral vascular disease, vascular disorders such as Raynaud's disease, inflammatory diseases, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, erectile dysfunction or diseases characterised by disorders of gut motility (e.g. IBS).
According to another aspect of the invention, there is provided the use of a compound of formula (I) for the manufacture of a medicament for the treatment of stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, congestive heart failure, renal failure, atherosclerosis, conditions of reduced blood vessel patency, (e.g.
post-PTCA), peripheral vascular disease, vascular disorders such as Raynaud's disease, inflammatory diseases, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, erectile dysfunction or diseases characterised by disorders of gut motility (e.g. IBS).
In a further aspect, the invention provides a method of treating stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, congestive heart failure, renal failure, atheroscierosis, conditions of reduced blood vessel patency, (e.g.
post-PTCA), peripheral vascular disease, vascular disorders such as Raynaud's disease, inflammatory diseases, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, erectile dysfunction or diseases characterised by disorders of gut motility {e.g. IBS) in a human or non-human animal body which comprises administering to said body a therapeutically effective amount of a compound with formula (I).
Compounds of the invention may be administered by any suitable route, for example by oral, buccal, sub-lingual, rectal, vaginal, nasal, topical or parenteral (including intravenous, intramuscular, subcutaneous and intracoronary) administration. Oral administration is generally preferred.
For administration to man in the curative or prophylactic treatment of the disorders identified above, oral dosages of a compound of formula (1) will generally be in the range of from 0.5-800mg daily for an average adult patient . (70kg). Thus for a typical adult patient, individual tablets or capsules contain from 0.2-400mg of active compound, in a suitable pharmaceutically acceptable -vehicle or carrier, for administration in single or multiple doses, once or several times per day. Dosages for intravenous, buccal or sublingual administration will typically be within the range of from 0.1-400 mg per single dose as required.
In practice the physician will determine the actual dosing regimen which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case but there can be individual instances in which higher or lower dosage ranges may be merited, and such are within the scope of this invention.
For human use, a compound of the formula (I) can be administered alone, but wilt generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, the compound may be administered orally, buccally or sublingually, in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavouring or colouring agents. Such liquid preparations may be prepared with pharmaceutically acceptable additives such as suspending agents (e.g.
methylcellulose, a semi-synthetic glyceride such as witepsol or mixtures of glycerides such as a mixture of apricot kernel oil and PEG-6 esters or mixtures of PEG-8 and capryliclcapric glycerides). A compound may also be injected parenterally, for example intravenously, intramuscularly, subcutaneously or intracoronarily. For parenteral administration, the compound is best used in the form of a sterile aqueous solution which may contain other substances, for example salts, or monosaccharides such as mannitol or glucose, to make the solution isotonic with blood.
Thus, the invention provides in a further aspect a pharmaceutical composition comprising a compound of the formula (I) together with a pharmaceutically acceptable diluent or carrier therefor.
There is further provided by the present invention a process of preparing a pharmaceutical composition comprising a compound of formula (I), which process comprises mixing a compound of formula (I) together with a pharmaceutically acceptable diluent or carrier therefor.
A compound of formula (I) may also be used in combination with other therapeutic agents which may be useful in the treatment of the above-mentioned disease states. The invention thus provides, in another aspect, a combination of a compound of formula (I) together with another therapeutically active agent.
The combination referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical compositions -comprising a combination as defined above together with a pharmaceutically acceptable diluent or carrier comprise a further aspect of the invention.
5 The individual components of such a combination may also be administered either sequentially or simultaneously in separate pharmaceutical formulations.
Appropriate doses of known therapeutic agents for use in combination with a compound of formula (I) will be readily appreciated by those skilled in the art.
Compounds of formula (I) may be prepared by any suitable method known in 10 the art or by the following processes which form part of the present invention. In the methods below R°, R1,R2~ R3, and R4 are are as defined in formula (I) above unless otherwise indicated.
There is a further provided by the present invention a process (A) of preparing a compound of formula (I), which process comprises reacting 15 compounds of formula (II) and (lll) ~R~m x °~~ / I (III) 20 ~R2)"
where X represents a hydroxyl or halogen group.
Suitably the reaction is carried out in the presence of 1,3 dicyclohexylcarbodiimide (DCC) or 1-(3-dimethylaminopropyl)-3 ethylcarbodiimide (EDCI) and 1-hydroxybenzotriazole (HOBT) in a suitable organic solvent, such as dimethylformamide (DMF) or dichloromethane (DCM) for several hours, e.g. 8 hours to 2 days.
Compounds of formula (I) may be prepared as individual enantiomers from the appropriate enantiomer of formula (II) or as a racemic mixture from the appropriate racemic compound of formula (II). Individual enantiomers of the compounds of the invention may be prepared from racemates by resolution using methods known in the art for the separation of racemic mixtures into their constituent enantiomers, for example using HPLC on a chiral column such as Hypersil naphtyl urea or using separation of salts of diastereoisomers.
A compound of formula (II) may be prepared by Pictet-Spengler cyclization between a tryptamine derivative of formula (IV) and an aldehyde of formula (V) / I I CH2CH.,NH~
H
H O
(V) I
(R3)m Re The reaction may conveniently be effected in a suitable solvent such as a halogenated hydrocarbon (e.g. dichloromethane) or an aromatic hydrocarbon (e.g. toluene) in the presence of an acid such as trifluoroacetic acid (TFA).
The reaction may conveniently be carried out at a temperature of from 20 °C
to refiux to provide a compound of formula (Il) in one step. The reaction may also be carried out in a solvent such as an aromatic hydrocarbon (e.g. toluene) under reflux optionally using a Dean-stark apparatus to trap the water produced.
The reaction provides racemic compounds of formula (II). Enantiomers may be obtained from a resolution with N-acetyl leucine using fractional crystallization in EtOAc:MeOH as solvent. (R) and (S) enantiomers may be isolated as salts depending upon whether N-acetyl-(D) and (L)-leucine was used as the starting material.
Compounds of formulae (IV) and (V) are commercially available compounds or prepared by standard synthetic techniques as hereinafter described in the Examples.
A compound of formula (I!I) can be prepared from a corresponding aldehyde of formula (VI) R' H
(VI) O (R2)~
suitably by employing a Wittig reaction followed by basic hydrolysis.
Alternatively a compound of formula (III) may be prepared from a compound of formula (VI) by a Knoevenhagel reaction employing malonic acid.
Compounds of formula {VI) can be prepared from known corresponding alcohol, nitrite, or halide derivatives, using techniques well known in the art of synthetic organic chemistry.
According to a further general process (B) compounds of formula (I) can be converted to alternative compounds of formula (I), employing suitable interconversion techniques such as hereinafter described in the Examples.
Compounds of this invention may be isolated in association with solvent molecules by crystallization from or evaporation of an appropriate solvent.
The pharmaceutically acceptable acid addition salts of the compounds of formula (I) which contain a basic centre may be prepared in a conventional manner. For example, a solution of the free base may be treated with a suitable acid, either neat or in a suitable solution, and the resulting salt isolated either by filtration or by evaporation under vacuum of the reaction solvent.
Pharmaceutically acceptable base addition salts may be obtained in an analogous manner by treating a solution of a compound of formula (I) with a suitable base. Both types of salt may be formed or interconverted using ion-exchange resin techniques.
Thus, according to a further aspect of the invention, we provide a process for preparing a compound of formula (I) or a salt or solvate (e.g. hydrate) thereof which comprises process (A) or (B) as hereinbefore described followed by i) salt formation; or ii) solvate (e.g. hydrate) formation.
WO 97/43287 PCTlEP97/02277 The following additional abbreviations are hereinafter used in the accompanying examples: rt {room temperature), DMSO (dimethylsuiphoxide), NBS (N-bromosuccinimide), THF (tetrahydrofuran), TFA (trifluoroacetic acid), PTSA { p-toluene sulphonic acid), AIBN (2,2'-azobis isobutyronitrile), and TBDMSCI (tert-butyfdimethylsilyl chloride).
Intermediate 1 1-Phenyl-2.3,4,9-tetrahydro-1 H-Q-carboline A solution of tryptamine (15 g, 94.0 mmol) and benzaldehyde (10.9 g, 1.1 equiv.) in DCM (800 mL) was treated with TFA (15 mL, 2 equiv.). The resulting mixture was stirred at rt for one day and then neutralized to pH 7 with a saturated aqueous solution of sodium carbonate. After filtration and concentration to dryness the residue was recrystallized from 2-propanol to give the title compound (11.0 g, 47%) as white crystals.
MP: 175-177 °C.
Intermediate 2 1-(4-Methoxyphenyl)-2.3,4.9-tetrahydro-1 H-Q-carboline This product was prepared using the same procedure as for Intermediate 1 with tryptamine (15 g, 94.9 mrnol), 4-methoxybenzaldehyde (12.9 g, 1.1 equiv.) and TFA (14.6 mL, 2 equiv.) to give the title compound (20.9 g, 80%) as a brownish powder.
MP: 131 °C.
Intermediate 3 1-(4-Nitrophenyl)-2.3.4.9-tetrahydro-1 H-Q-carboline This product was prepared using the same procedure as for Intermediate 1 with tryptamine (2.0 g, 12.5 mmol), 4-nitrobenzaldehyde (1.88 g, 1 equiv.) and TFA
(1.9 mL, 2 equiv.) to give the title compound (3.1 g, 86%) as a yellow powder.
MP: 190 °C.
intermediate 4 1~4-Trifluoromethoxyphenyll-2L3.4,9-tetrahydro-1 H-(~-carboline This product was prepared using the same procedure as for Intermediate 1 with tryptamine (2.0 g, 12.5 mmol), 4-trifluoromethoxybenzaldehyde (2.4 g, 1 equiv.
) and TFA (1.9 mL, 2 equiv.) to give the title compound (1.6 g, 38%) as a white powder.
MP: 68-69 °C.
Intermediate 5 1-(4-Chlorophenyl)-2.3.4.9-tetrahydro-1 H-fi-carboline This product was prepared using the same procedure as for Intermediate 1 with tryptamine {5.0 g, 30 mmol), 4-chlorobenzaldehyde (4.6 g, 1 equiv.) and TFA
(4.6 mL, 2 equiv.) to give the title compound (4.16 g, 49%) as a white powder.
MP: 161 °C.
Intermediate 6 1-(4-Methylphenyl)-2.3.4.9-tetrahydro-1 H-Q-carboline This product was prepared using the same procedure as for Intermediate 1 with tryptamine (1.0 g, 6.2 mmol), 4-methylbenzaidehyde (0.74 g, 1 equiv.) and TFA
(1 mL, 2 equiv.) to give the title compound (1.6 g, 100%) as a white powder.
MP: 207-209 °C.
intermediate 7 1-(3,4-Methylenedioxyphenyl)-2 3 4 9-tetrahydro-1 H-!3-carboline This product was prepared using the same procedure as for Intermediate 1 with tryptamine (20.0 g, 120 mmol), 3,4-methylenedioxybenzaldehyde (20.6 g, 1.1 equiv.) and TFA (18 mL, 2 equiv.) to give the title compound (22 g, 60%) as white crystals after recrystallization from ethanol.
MP: 178 °C.
Intermediate 8 4-(2,3,4.9-Tetrahydro-1H-Q-carbolin-1-yl)benzoic acid methyl ester This product was prepared using the same procedure as for Intermediate 1 with tryptamine (2.8 g, 17.4 mmol), 4-formylbenzoic acid, methyl ester (2.87 g, 1.1 equiv. ) and TFA (2.7 mL, 2 equiv. ) to give the title compound (0.5 g, 9%) as white crystals after recrystallization from isopropanol: H20.
MP: 179 °C.
Intermediate 9 '1-Indan-5-yl-2.3,4.9-tetrahydro-1 H-Q-carboline This product was prepared using the same procedure as for Intermediate 1 with 5 tryptamine (1.28 g, 8.0 mmol), indan-5-carboxaldehyde (1.3 g, 1.1 equiv.) and TFA (1.2 mL, 2 equiv.) to give the title compound (0.36 g, 14%).
~ H NMR (CDC13) b 7.6 (s, 1 H), 7.4 (m, 1 H), 6.9-7.2 (m, 6H), 5.1 (s, 1 H), 3.3-3.4 (m, 1 H), 2.9-3.1 (m, 1 H), 2.7-2.9 (m, 6H), 1.9-2.2 (q, 2H).
10 Intermediate 10 1-(2.3-Dihydrobenzofuran-5-yl)-2.3.4.9-tetrahydro-1 H-a-carboline This product was prepared using a two-step procedure. A solution of tryptamine (32.4 g, 0.2 mol) and 2,3-dihydrobenzofuran-5-carboxaldehyde (30.0 g, 1 equiv.) in toluene (1 L) was heated under reflux for 4 hours. After removal of 15 mL of water and evaporation of toluene the residue was dissolved in DCM (1 L) in the presence of TFA (31 mL, 2 equiv.). The resulting mixture was stirred at rt for 16 hours. Then 1 L of a saturated aqueous solution of NaHC03 was added.
After extraction with DCM and drying over MgS04, the organic solution was evaporated in vacuo. Recrystaflization from DCM:iPrZO (2:30) gave the title 20 compound as white crytals in a 80% yield.
'H NMR (CDC13) 8 7.6 (s, 1 H), 7.5-7.6 (m, 1 H), 7-7.3 (m, 5H), 6.7-6.75 (d, 1 H), 5.1 (s, 1 H), 4.5-4.6 (t, 2H), 3.3-3.45 (m, 1 H), 3.05-3.2 (t, 3H), 2.7-3 (m, 2H).
Intermediate 11 25 1-(4-isopropylphenyl)-2,3.4.9-tetrahydro-1 H-Q-carboline This product was prepared using the same procedure as for Intermediate 1 with tryptamine (5.0 g, 31.2 mmol), 4-isopropylbenzaldehyde (5.08 g, 1.1 equiv.) and TFA (4.8 mL, 2 equiv.) to give the title compound (5.9 g, 67%) as white crystals after recrystallization from iPrZO.
MP: 146 °C.
Intermediate 12 1-(2.3-Benzofuran-5-yl)-2.3.4.9-tetrahydro-1 H-(3-carboline This product was prepared using the same procedure as for Intermediate 1 with tryptamine (2.27 g, 14.1 mmoi), 2,3-benzofuran-S-carboxaldehyde (2.1 g, 1 equiv., prepared according to the procedure of Dorn, C.P et al EP 481671A1) and TFA (2.2 mL, 2 equiv.) to give the title compound (3.0 g, 74%) as white crystals after recrystallization from cyclohexane.
MP: 134-136 °C.
Intermediate 13 1-(2,3-Dihydrobenzof1.41dioxin-6-yl)-2 3 4 9-tetrahydro-1 H-~-carbolin_e This product was prepared using the same procedure as for Intermediate 1 with tryptamine (4.92 g, 30.7 mmol), 2,3-dihydrobenzo[1,4Jdioxin-6-carboxaldehyde (5.05 g, 1.0 equiv.) and TFA (5.0 mL, 2 equiv.) to give the title compound (7.05 g, 75%) as white crystals after recrystallization from iPr20.
MP: 144 °C.
Intermediate 14 1 ~3-Fluoro-4-methoxyphenyl)-2 3 4 9-tetrahydro-1 H-8-carboline This product was prepared using the same procedure as for Intermediate 1 with tryptamine (4.80 g, 30.0 mmol), 3-fluoro-4-methoxybenzaldehyde (4.86 g, 1.05 equiv. ) and TFA (4.6 mL, 2 equiv. ) to give the title compound (5.2 g, 59% ) as white crystals.
MP: 68 °C.
Intermediate 15 1-(3,4-Difluorophenyl)-2.3 4 9-tetrahydro-1 H-Q-carboline This product was prepared using the same procedure as for Intermediate 1 with tryptamine (5.4 g, 33.5 mmol), 3,4-difluorobenzaldehyde (5.0 g, 1.05 equiv.) and TFA (5.2 mL, 2 equiv.) to give the title compound (7.8 g, 82%) as white crystals.
MP: 151 °C.
Intermediate 16 1-(3.4-Methylenedioxyphenyl)-6-fiuoro-2 3 4 9-tetrahydro-1 H ~ carboline This product was prepared using the same procedure as for Intermediate 1 with 5-fluorotryptamine (1.59 g, 8.9 mmol), 3,4-methylenedioxybenzaldehyde (1.47 g, 1.1 equiv.) and TFA (1.4 mL , 2 equiv.) to give the title compound (2.34 g, 85%) as white crystals.
MP: 172 °C.
Analysis for C,aH,sFN20z:
Calculated: C,69.67; H,4.87; N,6.12.
Found: C,69.47; H,4.85; N,6.23%
Intermediate 17 1-(2-Chlorophenyl)-2.3.4.9-tetrahydro-1 H-Q-carboline This product was prepared using the same procedure as for Intermediate 1 with tryptamine (1.0 g, 6.2 mmol), 2-chlorobenzaldehyde (0.7 mL, 1.0 equiv.) and TFA (1.0 mL, 2 equiv.) to give the title compound (1.2 g, 69%).
H NMR (CDC13) b 7.6 (s, 1 H), 7.45 (d, 1 H), 7.40 (d, 1 H), 6.9-7.2 (m, 6H), 5.6 (s, 1 H), 3.2-3.0 (m, 2H), 2.9-2.7 (m, 2H), 2.4 (s, 1 H).
Intermediate 18 (S)-1-(3,4-Methylenedioxyphenyl)-2.3.4,9-tetrahydro-1 H-Q-carboline (S)-1-(3,4-Methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-p-carboline was obtained from the resolution of the corresponding racemic amine with N-acetyl-(L)-Leucine (Sigma) in MeOH followed by a recrystallization from MeOH.
Treatment of the suspension of the recrystallized material in DCM with a saturated aqueous solution of NaHC03 gave the enantiomerically pure (S)-1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1 H-(3-carboline as beige crystals in a 55% yield.
MP: 173 °C.
Analysis for C,8H,6NZ0z. 0.35H20:
Calculated: C,72.39; H,5.64; N,9.38.
Found: C,72.35; H.5.44; N,9.1 %.
ja]p'9~6- -35 (c = 0.53, MeOH).
Intermediate 19 ~1-(3.4-Methylenedioxyphenyl)-2.3.4,9-tetrahydro-1 H-t3-carboline - 30 Following the same protocol as for Intermediate 18 (R)-1-(3,4-methyienedioxyphenyl)-2,3,4,9-tetrahydro-1 H-(3-carboline was obtained from the resolution of the corresponding racemic amine with N-acetyl-(D)-Leucine (Sigma) in MeOH followed by a recrystallization from MeOH. Treatment of the suspension of the recrystallized material in DCM with a saturated aqueous solution of NaHC03 gave the enantiomerically pure (R)-1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1 H-~-carboline as white crystals in a 59% yield.
MP: 92-94 °C.
Analalysis for C,sH,6NZOz:
Calculated: C,73.95; H,5.52; N,9.58.
Found: C,73.72; H,5.52; N,9.52%.
[a]p2''= 34 (c = 0.50, MeOH).
Intermediate 20 (R)-1-(2,3-Dihydrobenzofuran-5-yl)-2 3 4 9-tetrahydro-1 H-Q-carboline Following the same protocol as for Intermediate 18 (R)-1-(2,3-dihydrobenzofuran-5-yl)-2,3,4,9-tetrahydro-1 H-(3-carboline was obtained from the resolution of the corresponding racemic amine with N-acetyl-(D)-Leucine (Sigma) in MeOH:EtOAc followed by a recrystallization from MeOH. Treatment of the suspension of the recrystallized material in DCM with a saturated aqueous solution of NaHC03 gave the enantiomerically pure (R)-1-(2,3-dihydrobenzofuran-5-yl)-2,3,4,9-tetrahydro-1 H-p-carboline as white crystals in a 55% yield.
MP: 98-99 °C.
Analysis for C,9H,eNzO. 0.15H20:
Calculated: C,77.87; H,6.29; N,9.56.
Found: C,77.83; H,6.33; N,9.44%
[a]pz' = 42 (c = 0.50, MeOH).
Intermediate 21 (S)-1-(4-(2.3-Dihydrobenzo(b)furan)-2 3 4 9-tetrahydro-1 H-t3-carboiine Following the same protocol as for Intermediate 18 (S)-1-(2,3-dihydrobenzofuran-5-yl)-2,3,4,9-tetrahydro-1 H-~-carboline was obtained from the resolution of the corresponding racemic amine with N-acetyl-(L)-Leucine (Sigma) in MeOHIEtOAc followed by a recrystallization from MeOH. Treatment of the suspension of the recrystallized material in DCM with a saturated aqueous solution of NaHC03 gave the enantiomerically pure (S)-1-(2,3-dihydrobenzofuran-5-yl)-2,3,4,9-tetrahydro-1 H-/3-carboline as a pale yellow powder in a 45% yield.
MP: 175 °C.
Anaialysis for C,9H,eNzO. 1.OHzO:
Calculated: C,74.0; H,6.54; N,9.08.
Found: C,74.01; H,5.88; N,8.92%.
[a]p'9'= -49 (c = 0.50, MeOH).
Intermediate 22 (E)-3-(4-Ureidovhenyl)acrylic acid A stirred solution of (E)-3-{4-aminophenyl)acrylic acid (1.0 g, 5.0 mmol) and potassium isocyanate (2.0 g, 5 equiv.) in a mixture of water and acetic acid (50 mL) was heated at 100 °C for 12 hours. After cooling, a white solid precipitated out. Filtration, washing of the filter cake with a mixture of water and MeOH, and drying it in vacuo gave the title compound (0.82 g, 80%) as a white solid.
MP > 350 °C.
Intermediate 23 (E)-3-(4-Acetylmethylaminophenyl)acrylic acid A stirred solution of N-(4-formylphenyl)-N-methylacetamide {1.0 g, 5.64 mmol), malonic acid (1.06 g, 1.8 equiv.) and piperidine (0.1 g, catalytic amount) in pyridine (3.5 mL) was heated at 60 °C for 12 hours. Pouring the resulting mixture into HCI (1N) gave a precipitate. Filtration gave the title compound (1.2 g, 98%) as a white solid.
MP: 213-215 °C.
Analysis for C,zH,3N03. 0.2Hz0:
Calculated: C,64.68; H,6.06; N,6.29;
Found: C,64.43; H,6.18; N,6.36%.
N-(4-Formyiphenyl)-N-methylacetamide (1.0 g, 46%) was obtained as an oil from N-{4-formylphenyl)acetamide (2.0 g, 12.2 mmol) in THF in the presence of iodomethane (1.2 mL, 1.5 equiv.) and NaH (0.73 g, 1.5 equiv., 60% in mineral oil).
'H NMR (CDC13, 250 MHz) b 2.0 (s, 3H), 3.4 {s, 3H), 7.4 (d, 2H), 8.0 (d, 2H).
Intermediate 24 (E)-3-(4-(2-Methoxyethylcarbamoyl)phenyllacrylic acid The same method was employed as in the preparation of Intermediate 23 but starting from 4-formyl-N-{2-methoxyethyl)benzamide to give the title compound -as a white powder in a 57% yield.
MP: 205 °C.
5 4-Formyl-N-(2-methoxyethyl)benzamide (158 mg, 48%) was obtained by oxidation of 4-hydroxymethyl-N-(2-methoxyethyl)benzamide (330 mg, 1.6 mmol) in DCM in the presence of Mn02 (3.0 g, 22 equiv.).
'H NMR {CDC13, 250 MHz) b 9.9 (s, 1 H), 7.8 (s, 4H), 6.8 (s, 1 H), 3.4-3.6 (m, 4H), 3.2 (s, 3H).
10 4-Hydroxymethyl-N-(2-methoxyethyl)benzamide (330 mg, 14%) was obtained as an oil (Rf= 0.7, DCM:MeOH (9:1 )) by coupling 4-(hydroxymethyl)benzoic acid (1.0 g, 6.5 mmol) with 2-methoxyethylamine (0.6 mL, 6.5 mmol) in the presence of Et3N (0.95 mL, 1.0 equiv.), EDCI (1.2 g, 1.0 equiv.) and HOBT (0.88 g, 1.0 equiv. ).
Intermediate 25 (E)-(4-(2-Dimethylaminoethoxy)phenyllacrylic acid The same method was employed as in the preparation of Intermediate 23 but starting from 4-(2-dimethylaminoethoxy)benzaldehyde to give the title compound as a white powder in a 100% yield.
MP: 243 °C.
4-(2-Dimethyfaminoethoxy)benzaldehyde (20.6 g, 65%) was obtained by alklylation of 4-hydroxybenzaldehyde (20 g, 164 mmol) in DMF with dimethylaminoethyl chloride (144 g, 8 equiv.) and KzC03 (24.9 g, 1.1 equiv.) for 16 hours at 80 °C.
'H NMR (CDC13, 250 MHz) 8 9.85 (s, 1 H), 7.9-7.8 (d, 2H), 7-6.9 (d, 2H), 4.2 (t, 2H), 2.7 (t, 2H), 2.3 (s, 6H).
Intermediate 26 (E)-3-f4-(2-Morphoiin-4-yl-ethylcarbamoyl)phenyllacrvlic acid The same method was employed as in the preparation of Intermediate 23 but starting from 4-formyl-N-(2-morpholin-4-yl-ethyl)benzamide to give the title compound as a gummy solid.
4-Formyl-N-(2-morpholin-4-yl-ethyl)benzamide (0.14 g, 55%) was obtained by oxidation of 4-hydroxymethyl-N-{2-morpholin-4-yl-ethyl)benzamide (0.24 g, 0.9 mmol) and Mn02 (1.73 g, 20 mmol).
'H NMR (CDC13, 250 MHz) b 10 (s, 1 H), 7.9 (s, 4H), 6.8 (s, 1 H), 3.5 (t, 5H), 2.6 (t, 2H), 2.3 (m, 5H).
4-Hydroxymethyl-N-(2-morpholin-4-yl-ethyl)benzamide (240 mg, 14%) was obtained as a colourless oil (Rf= 0.6, DCM:MeOH (9:1 )) by coupling 4 (hydroxymethyl)benzoic acid (1.0 g, 6.5 mmol) with 2-morpholinethylamine (0.85 g (1.0 equiv.) in the presence of Et3N (0.95 mL, 1.0 equiv.), EDCI (1.2 g, 1.0 equiv.) and HOST (0.88 g, 1.0 equiv.).
Intermediate 27 SE)-3-(4-Cyclohexvlcarbamoylphenyl)acrylic acid The same method was employed as in the preparation of Intermediate 23 but starting from N-cyclohexyl-4-formylbenzamide to give the title compound as a white powder in a 54% yield.
MP: 214 °C.
N-Cyclohexyl-4-formylbenzamide (0.6 g, 60%) was obtained by oxidation of N-cyciohexyl-4-(hydroxymethyl)benzamide (1.0 g, 4.29 mol) with MnOz (0.2 g, 22 equiv. ), as a white powder.
MP: 163 °C.
'H NMR {CDC13, 250 MHz) 8 10 (s, 1 H), 7.95 (s, 4H), 6.6 (s, 1 H), 4.1 {m, 1 H), 3.9-3.7 (m, 3H), 3.4-3.3 (m, 1H), 2.1-1.9 (m, 2H); 1.8-1.7 (m, 2H).
N-Cyclohexyl-4-{hydroxymethyl)benzamide(1.0 g, 66%) was obtained as white crystals by coupling 4-(hydroxymethyl)benzoic acid with cyclohexylamine (0.75 mL, 1 equiv. ) in the presence of Et3N (0.95 mL, 1.0 equiv. ), EDC I ( 1.2 g, 1.0 equiv.} and HOBT (0.88 g, 1.0 equiv.).
MP: 185 °C.
'H NMR (CDC13, 250 MHz} b 7.8-7.7 (d, 2H), 7.5-7.4 (d, 2H), 6.8 (s, 1 H), 4.8 (s, 2H), 4.2 (m, 1 H), 4.0-3.75 (m, 2H), 3.4-3.3 (m, 1 H), 2.7 (m, 1 H), 2-1.9 (m, 2H), 1.6 (m, 1 H), 1.1 (m, 1 H).
Intermediate 28 (E)-3-~4-f(Tetrahydrofuran-2-ylmethyl)carbamoyllphenyl)acrylic acid WO 97/43287 _ The same method was employed as in the preparation of Intermediate 23 but starting from 4-formyl-N-(tetrahydrofuran-2-ylmethyl)benzamide to give the title --compound as a white powder in a 49% yield.
MP: 215 °C.
4-Formyl-N-(tetrahydrofuran-2-ylmethyl)benzamide (0.36 g, 50%) (Rf= 0.3, DCM:MeOH) was obtained as an oil by oxidation of 4-hydroxymethyl-N-(tetrahydrofuran-2-ylmethyl)benzamide (0.72 g, 3.0 mmol) with Mn02 (0.36 g, 22 equiv. ).
4-Hydroxymethyi-N-(tetrahydrofuran-2-ylmethyl)benzamide (0.72 g, 46%) was obtained as a colourless oil (Rf= 0.6, DCM:MeOH (9:1 )) by coupling 4 (hydroxymethyl)benzoic acid (1.0 g, 6.5 mmol) with tetrahydrofuran-2-yl methylamine (0.67 mL, 1.0 equiv.) in the presence of EtsN (0.95 mL, 1.0 equiv.), EDCI (1;2 g, 1.0 equiv.) and HOBT (0.88 g, 1.0 equiv.).
Intermediate 29 (E)-1-(4-(2-Carboxyvinyl)benzoyllpiperidine-4-carboxylic acid ethyl ester The same method was employed as in the preparation of intermediate 23 but starting from 1-(4-formylbenzoyl)piperidine-4-carboxylic acid, ethyl ester to give the title compound as a white powder in a 46% yield.
MP: 165 °C.
1-(4-Formylbenzoyl)piperidine-4-carboxylic acid, ethyl ester (960 mg, 49%) (Rf=
0.6, DCM:MeOH(95:5)) was obtained as an oil by oxidation of 1-(4-hydroxymethylbenzoyl)piperidine-4-carboxylic acid, ethyl ester (2.0 g, 6.8 mmol) with MnOz (13.1 g, 22 equiv.).
'H NMR (CDC13, 250 MHz) b 10.0 (s, 1 H), 7.9 (d, 2H), 7.5 {d, 2H), 4.5 (d, 1 H), 4.1 (q, 2H), 3.6 (d, 1 H), 3.1 (br s, 2H), 2.5 (m, 1 H), 2.1-1.6 {m, 4H), 1.2 (t, 3H).
1-(4-Hydroxymethylbenzoyl)piperidine-4-carboxylic acid, ethyl ester (1.9 g, 100%) was obtained as a colorless oil (Rf= 0.1, DCM:MeOH (95:5)) by coupling 4-(hydroxymethyl)benzoic acid (1.0 g, 6.5 mmol) with 4-piperidine-4-carboxylic acid, ethyl ester (1 mL, 6.5 mmol ) in the presence of Et3N (0.95 mL, 1.0 equiv.), EDCI (1.2 g, 1.0 equiv.) and HOST (0.88 g, 1.0 equiv.).
. 'H NMR (CDC13, 250 MHz) b 7.2 (s, 4H), 4.5 (s, 2H), 4.3 {br s, 1H), 4.1 (q, 2H), 3.6 (br s, 1H),3 (t, 2H), 2.5 {m, 1H), 2.1-1.6 (m, 4H), 1.2 (t, 3H).
Intermediate 30 (E)-3-(4-Ethoxycarbonylmethylphenyl)acrylic acid The same method was employed as in the preparation of intermediate 23 but starting from (4-formylphenyl)acetic acid, ethyl ester gave the title compound as a yellow gum in a 52% yield.
'H NMR (CDC13, 250 MHz) 8 7.8-7.6 (m, 3H), 7.4-7.3 {d, 2H), 6.9-6.8 (d, 1 H), 4.1-3.9 {q, 2H), 3.55 (s, 2H), 1.2 (t, 3H).
4-(4-Formylphenyl)acetic acid, ethyl ester was prepared according to the procedure of Biagi,G.; Livi,O.; Verugi,E. Farmaco-Ed. Sc. 1988, 43, 597-611.
Intermediate 31 -1-(4-(2-Carboxyvinyl)phenyllpiperidine-4-carboxylic acid, ethyl ester The same method was employed as in the preparation of Intermediate 23 but starting from 1-(4-formylphenyl)piperidine-4-carboxylic acid, ethyl ester to give the title compound as a yellow powder in a 86% yield.
MP: 212 °C.
Analysis for C,~HZ,N04. 0.15H20:
Calculated: C,66.71; H,7.01; N,4.58;
Found: C,66.77; H,7.01; N,4.79%.
1-(4-Formylphenyl)piperidine-4-carboxylic acid, ethyl ester was prepared according to the procedure of Duckworth, D.M. HindIey,R.; Richard,M. EP
68669A1.
Intermediate 32 (E)-4-(2-Carboxyvinyl)-3-chlorobenzoic acid, methyl ester The same method was employed as in the preparation of Intermediate 23 but starting from 3-chloro-4-formylbenzoic acid, methyl ester to give the title compound as a white powder in a 58% yield.
MP: 221 °C.
3-Chloro-4-formylbenzoic acid, methyl ester (4.0 g, 81 %) was prepared by reaction of 4-bromomethyl-3-chlorobenzoic acid, methyl ester (6.0 g, 26 mmol) with silver p-toluenesulfonate (15.0 g, 2.0 equiv.) in 100 mL of DMSO in the presence of Et3N (100 mL, 7 equiv.) at rt for 1 hour. Quenching the resulting mixture with 100 mL of water, extraction with 2 x 100 mL of EtOAc, washing with 50 mL of water, drying over Na2S04 and flash chromatography with WO 97!43287 PCT/EP97/02277 cyclohexane:EtOAc (95:5) as eluting solvent, gave the title compound (2.3 g, 42%) as an oil. ..
'H NMR (CDC13, 250 MHz) b.10.5 (s, 1 H), 8.1 (s, 1 H), 7.8-7.7 (d, 1 H), 7.4-7.3 (d, 1 H), 3.8 (s, 3H).
4-Bromomethyl-3-chlorobenzoic acid, methyl ester (6.0 g, 87%) was obtained as an orange oil by refiuxing for 12 hours 4-methyl-3-chlorobenzoic acid, methyl ester (5.7 g, 31 mmol) with NBS (6.4 g, 1.2 equiv.) in the presence of a catalytic amount of AIBN in CC14.
'H NMR (CDC13, 250 MHz) 8 8.0 (s, 1 H), 7.9-7.8 (d, 1 H), 7.45-7.35 {d, 1 H), 4.5 (s, 1 H), 3.9 (s, 3H).
4-Methyl-3-chlorobenzoic acid, methyl ester (5.7 g, 53%) was obtained as an orange oil by refluxing overnight 4-methyl-3-chlorobenzoic acid (9.9 g, 58 mmol) in MeOH in the presence of PTSA.
'H NMR (CDC13, 250 MHz) 8 8.0 (d, 1 H), 7.85 (dd, 1 H), 7.3 (d, 1 H), 4.0 (s, 3H), 2.5 (s, 3H).
Intermediate 33 (E)-5-(2-Carboxyvinyl)-2-chlorobenzoic acid methyl ester The same method was employed as in the preparation of intermediate 32 but starting from 2-chloro-5-formylbenzoic acid, methyl ester to give the title compound as a yellow powder in a 76% yield.
MP: 194 °C.
2-Chloro-5-formylbenzoic acid, methyl ester (0.6 g, 25%) was obtained a gum by reaction of 5-bromomethyl-2-chlorobenzoic acid, methyl ester (3.1 g,11.7 mmol) with silver p-toluenesulfonate (6.4 g, 1.75 equiv.) in DMSO in the presence of Et3N (1.2 mL, 7 equiv.) at rt for 1 hour.
'H NMR (CDC13, 250 MHz) b 10 (s, 1 H), 8.4 (d, 1 H), 7.9 (dd, 1 H), 7.7-7.6 (d, 1 H), 4.0 (s, 3H).
5-Bromomethyl-2-chiorobenzoic acid, methyl ester (3.1 g, 11.7 mmol) was obtained as a gum in a 45% yield by refluxing for 12 hours 5-methyl-2 chlorobenzoic acid, methyl ester (4.78 g, 25.9 mmol) with NBS (5.56, 1.2 equiv.) . in the presence of a catalytic amount of AIBN in CC14.
'H NMR (CDC13, 250 MHz) 8 7.9 (s, 1 H), 7.4 (br s, 2H) 4.5 (s, 2H), 3.9 (s, 3H).
5-Methyl-2-chlorobenzoic acid, methyl ester (4.78 g, 90%) was obtained as a - brown oil, by refluxing overnight 3-methyl-4-chlorobenzoic acid (5.0 g, 29 mmol) in MeOH in the presence of a catalytic amount of PTSA.
'H NMR (CDC13, 250 MHz) 8 7.6 (s, 1 H), 7.25-7.2 (d, 1 H) , 7.15-7.1 (d, 1 H), 3.8 5 (s, 3H), 2.2 (s, 3H).
Intermediate 34 (E)-(3-Hydroxy-4-nitrophenyl)acrylic acid The same method was employed as in the preparation of Intermediate 23 but 10 starting from 3-hydroxy-4-nitrobenzaldehyde to give the title compound as a white powder in a 88% yield.
MP: 237 °C.
Intermediate 35 15 (E)-(3,5-Dimethyl-4-hydroxyphenyl)acryiic acid The same method was employed as in the preparation of Intermediate 23 but starting from 3,5-dimethyl-4-hydroxybenzaldehyde gave the title compound as a white powder in a 94% yield.
MP: 190 °C.
intermediate 36 (E)-(3-Nitro-4-hydroxy-5-methoxphenyl)acrylic acid The same method was employed as in the preparation of Intermediate 23 but starting from 3-vitro-4-hydroxy-5-methoxybenzaldehyde to give the title compound as a white powder in a 75% yield.
MP: 248 °C.
Intermediate 37 (E)-3-(3-Nitro-2-piperidin-1-yl-phenyl)acrylic acid The same method was employed as in the preparation of Intermediate 23 but starting from 2-chloro-3-nitrobenzaldehyde to give the title compound as a . yellow powder in a 100% yield.
'H NMR (CDC13, 250 MHz) 8 10.3 (br s, 1 H), 8.1 (d,1 H), 7.65 (dd, 1 H), 7.55 (dd, 1 H), 7.05 (t, 41 H). 6.3 (d, 1 H), 2.9 (m, 2H), 1.6 (m, 6H).
2-Chloro-3-nitrobenzaldehyde (150 mg, 20%) was prepared by reaction of 1-bromomethyl-2-chloro-3-nitrobenzene (1.0 g, 3.9 mmol) with silver p-toluenesulfonate (1.94 g, 1.75 equiv.) in DMSO in the presence of Et3N (4 mL, equiv.) at rt for 1 hour.
'H NMR (CDC13, 250 MHz) 8.10.5 (s, 1 H), 8.1 (dd, 1 H), 8.0 (dd, 1 H), 7.5 (t, 1 H).
1-Bromomethyl-2-chloro-3-nitrobenzene (13.3 g, 68%} was obtained as a yellow oil by refluxing for 2 hours a mixture of 2-chloro-3-nitrotoluene (10 g, 58 mmol) with NBS (10.3 g, 1 equiv.) in the presence of a catalytic amount of AIBN in CC14.
'H NMR (CDC13, 250 MHz) b 7.75 (dd, 1 H), 7.65 (dd, 1 H), 7.45 (m, 1 H), 4.6 (s, 2H).
Intermediate 38 E)-3-(4-Methyl-3,4-dihydro-2H-benzo(1 4loxazin-6-yl)acrvlic acid The same method was employed as in the preparation of Intermediate 23 but starting from 4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-carboxaldehyde (prepared according to the procedure of Kotha,S.; Bindra,V.; Kuki,A.
Heterocyles 1994, 38, 5-8) to give the title compound as a yellow powder in a 61 % yield MP: 190 °C.
Analysis for C,ZH,3N05:
Calculated: C,65.74; H,5.98; N,6.39;
Found: C,65.85; H,6.04; N,6.33%.
Intermediate 39 (E)-3-(2-Hydroxy-5-nitrophenyl)acrylic acid The same method was employed as in the preparation of Intermediate 23 but starting from 2-hydroxy-5-vitro benzaldehyde to give the title compound as a yellow powder in a 11 % yield.
MP:265-267.°C
Intermediate 40 IE)-3-(3-(Trifiuoromethanesulfonyloxy)phenyllacrylic acid The same method was employed as in the preparation of Intermediate 23 but starting from trifluoromethanesulfonic acid, 3-formylphenyl ester (prepared according to the procedure of Kingsbury,W.D.; Pendrak,l.; Leber,J.D_;
Boehm,J.C.; Mallet,B.; Sarau,H.M.; Foley, J.J.; Schmidt, D.B.; Daines,R.A. J.
Med. Chem. 1993, 36, 3308-3320) to give the title compound as pink crystals in a 36% yield.
MP: 107 °C.
Intermediate 41 (E)-3-(4-(Trifluoromethanesulfonyloxy)phenyllacrylic acid The same method was employed as in the preparation of Intermediate 23 but starting from trifluoromethanesulfonic acid, 4-formylphenyl ester (prepared according to the procedure of Creary,X.; Benage,B.; Hilton,K. J. Org. Chem.
1983, 48(77), 2887-2891 ) to give the title compound as white crystals in a 61 yield.
MP: 194 °C.
Intermediate 42 (E)-3-f4-(2-Pyrrolidin-1-ylethoxy)phenyllacrylic acid The same method was employed as in the preparation of Intermediate 23 but starting from 4-(2-pyrrolidin-1-ylethoxy)benzaldehyde (prepared according to the procedure of Sakaguchi,J.; Nishino, H.; Ogawa,N.; Iwanaga,Y.; Yasuda,S.;
Kato,H.; Ito,Y. Chem. Pharm. Bull. 1992, 40, 202-211 ) to give the title compound as a yellow solid in a 60% yield.
MP: 183 °C.
Intermediate 43 (E)-3-(4-Pyrrolidin-1-yiphenyl)acrylic acid The same method was employed as in the preparation of intermediate 23 but starting from (4-pyrrolidin-1-ylphenyl)benzaldehyde (prepared according to the procedure of Duckworth, D.M. HindIey,R.; Richard,M. EP 68669A1) to give the title compound as a yellow solid in a 65% yield.
MP: 265 °C.
Intermediate 44 -3-(4-ImidaZOl-1-ylphenyl)acrylic acid The same method was employed as in the preparation of Intermediate 23 but starting from 4-imidazol-1-ylbenzaldehyde (prepared according to the procedure -of Sircar,l.; DueII,B.; BristoI,J.A.; Weishaar,R.E.; Evans,D.B. J. Med. Chem.
1987, 30, 1023-1029) to give the title compound as pink crystals in a 5S%
yield.
MP: 326-327 °C.
Intermediate 45 ~E)-(S)-3-(4-(1-Methylpyrrolidin-2-ylmethoxy)phenyllacrylic acid The same method was employed as in the preparation of Intermediate 23 but starting from (S)-4-(1-methylpyrrofidin-2-ylmethoxy)benzaldehyde to give the title compound as a beige powder in a 66% yield.
MP: 251 °C.
[aJp2' _ -9 (c = 0.35, pyridine).
(S}-4-{1-Methyfpyrrolidin-2-ylmethoxy)benzaldehyde (0.96 g, 44%) was obtained as an orange oil by refluxing for 12 hours at 80°C, 4-hydroxybenzaldehyde (1.22 g, 10 mmol) with (S)-2-chloromethy!-1-methylpyrrolidine, hydrochloride (2.55 g, 1.5 equiv. ) in DMF in the presence of K2C03 (3.82 g, 2.8 equiv).
'H NMR (CDC13, 250 MHz) 8 9.9 (s, 1 H), 7.85 (d, 2H), 7.0 (d, 2H), 4.1 (dd, 1 H), 4.0 (dd,1 H), 3.1 {d tr, 1 H), 2.7 (m, 1 H), 2.5 (s, 3H), 2.3 (m, 1 H), 2 (m, 1 H), 1.8 (m, 3H).
(S)-2-Chloromethyl-1-methylpyrrolidine, hydrochloride was prepared according to the procedure of D'Ambra,T.E.; Bacon,E.R.; Edward, R.; BeII,M.R., Carabateas,P.M.; Eissenstat,M.A.; Kumar,V.; Mallamo,J.P,.; Ward,S.J. EP
444451 A2.
Intermediate 46 ~E)-3-(4-(2-Dimethylamino-1-methylethoxy)phenyllacrylic acid The same method was employed as in the preparation of Intermediate 23 but starting from 4-(2-dimethylamino-1-methylethoxy)benzaldehyde to give the title compound as a white powder in a 86% yield.
MP: 235 °C.
Analysis for C,aH,9N03.HC1:
Calculated: C,58.84; H,7.05; N,4.9;
Found C,S8.49; H,7.08; N.5.05%.
4-(2-Dimethylamino-1-methylethoxy)benzaldehyde (2.1 g, 18%) was obtained as an orange oil by refluxing for 12 hours, 4-hydroxybenzaldehyde (7 g, 57 mmoi), K2C03 (8.7 g, 1.1 equiv.) and 2-chloropropyldimethylamine, hydrochloride (13.6 g, 1.5 equiv. ) in DMF.
'H NMR (CDC13, 250 MHz) b 9.7 (s, 1 H), 7.65 (d. 2H), 6.85 (d, 2H), 4.5 (m, 1 H), 2.5 (m, 1 H), 2.3 (m, 1 H), 2.1 (m, 6H), 1.2 (d, 3H).
Intermediate 47 (E)-3-(4-(4-Methylpiperazin-1-yl)phenyljacrylic acid The same method was employed as in the preparation of intermediate 23 but starting from 4-(4-methylpiperazin-1-yl)benzaldehyde (prepared according to the procedure of Sakai,K.; Suzuki,M.; Nunami,K.; Yoneda,N.; Onoda,Y. Iwasawa,Y.
Chem. Pharm. Bull. 1980, 28, 2384-2393) to give the title compound as a white powder in a 65% yield.
MP: 223-226 °C.
Intermediate 48 (E)-3-i4-(2-Dimethylaminopropoxy)phenyllacrylic acid The same method was employed as in the preparation of Intermediate 23 but starting from 4-(2-dimethylaminopropoxy)benzaldehyde (prepared according to the procedure of Mizzoni,R.H. US 3483209) to give the title compound as a beige powder in a 100% yield.
MP: 231 °C.
Intermediate 49 (E)-3-(4-(2-Morpholin-4-ylethoxy)phenyllacrylic acid The same method was employed as in the preparation of Intermediate 23 but starting from 4-(2-morpholin-4-ylethoxy)benzaldehyde (prepared according to the procedure of Naruto,S.; Mizuta,H.; Sawayama,T.; Yoshida,T.; Uno,H.;
Kawashima,K.; Sohji,Y.; Kadokawa,T.; Nishimura,H. J. Med. Chem. 1982, 25, 1240-1245) to give the title compound as a white powder in a 96% yield.
MP: 228 °C.
Intermediate 50 (E)-3-~4-f2-(Ethylmethylamino)ethoxylphenyl~acrylic acid The same method was employed as in the preparation of Intermediate 23 but starting from 4-[2-(ethyimethylamino)ethoxy]benzaldehyde to give the title _ compound as a beige powder in a 73% yield.
MP: 206 °C.
5 Analysis for C,4H,9NOs.HCI:
Calculated: C,58.84; H,7.05; N,4.9;
Found C,59.08; H,7.07; N,5.02%.
4-[2-(Ethylmethylamino)ethoxy]benzaldehyde(5.0 g, 59%) was obtained as a brown oil by refluxing for 12 hours 4-hydroxybenzaldehyde (5 g, 41 mmol), 10 K2C03 (6.2 g, 1.1 equiv.) and (2-chloroethyl)ethylmethylamine, hydrochloride (9.7 g , 1.5 equiv. ) in DMF.
'H NMR (CDC13, 250 MHz) b 9.7 (s, 1 H), 7.7 (d, 2H), 6.9 (d, 2H), 4.1 (t, 2H), 2.6 (t, 2H), 2. (s, 6H).
15 Intermediate 51 ~E)-3-(4-(3-Dimethylaminopropenyl)phenyllacrylic acid This product was prepared by refluxing for .,four hours, (E)-3-[4-(3-dimethylaminopropenyl)phenyl]acrylic acid, methyl ester with NaOH (0.16 g, 2 equiv.) in 10 mL of MeOH. After evaporation of the solvent in vacuo, treatment 20 with 5 mL of HCI (1 N) gave the title compound (0.4 g, 85%) as a gummy orange solid.
'H NMR (CDC13, 250 MHz) 8 7.6 (d, 2H), 7.4 (d, 1 H), 7.2 (d, 2H), 6.6 (d, 1 H), 6.4 (d, 1 H), 5.8 (m, 1 H), 3.7 (d, 2H), 2.6 (s, 6H).
(E)-3-[4-(3-Dimethylaminopropenyl)pheny!]acrylic acid, methyl ester was 25 prepared by the following way: (2-dimethylaminoethyl)triphenylphosphonium bromide (7.2 g, 17.4 mmol) in 30 mL of DMF was treated with KHMDS (27 mL, 1.01 equiv., 0.5 M in toluene) at -78 °C for one hour. At -40 °C, 3-(4-formylphenyl)acrylic acid, methyl ester (2.54 g, 13.3 mmol, prepared according to the procedure of Syper,L.; Miochowski,J. Synthesis, 1984, 9, 747-752) was 30 added dropwise. The resulting mixture was stirred for 12 hours at rt and quenched with water. Extraction with EtOAc, drying over MgS04 and evaporation in vacuo gave a residue that was purified via flash chromatography with DCM:MeOH (90:10) as eluting solvent The title compound (1.1 g, 34%) was obtained as an orange oil.
'H NMR {CDC13, 250 MHz) b 7.6 (d, 1H), 7.4 (d, 2H), 7.2 (d, 2H), 6.5 (d, 1H), 6.4 (d, 1 H), 5.8 (m, 1 H), 3.2 (dd, 2H), 2.1 (s, 6H).
Intermediate 52 (E)-3-f4-(2-(Tertbutyldimethylsilanyloxyl-3-dimethylaminopropenyl)phenyllacrylic acid This product was prepared by refluxing for four hours (E}-3-[4-(2-(tertbutyldimethylsilanyloxy)-3-dirnethylaminopropanyl]phenylJacrylic acid, methyl ester (0.8 g, 2.03 mmol) and NaOH (1 N) (4 mL, 2 equiv. ) in 10 mL of MeOH. Evaporation of the solvent in vacuo and treatment with 5 mL of HCI (1 N) gave the title compound (0.4 g, 60%) as a beige solid solid.
MP: 207 °C.
(E)-3-[4-(2-(Tertbutyldimethyisilanyloxy)-3-dimethylaminopropoxy)phenyl]acrylic acid, methyl ester (0.8 g, 40%) was obtained as a yellow oil by reaction for 4 hours of (E)-3-[4-{3-dimethylamino-2-hydroxypropoxy)phenyl]acrylic acid, methyl ester (1.35 g, 5.13 mmol) with TBDMSCI (0.93 g, 6.2 mmol) in 50 mL of DMF in the presence of imidazole (0.84 g, 2.4 equiv.). After evaporation in vacuo, the residue was taken up in DCM, washed with water, dried over MgS04, evaporated in vacuo and purified via flash chromatography using DCM:MeOH
as eluting solvent.
'H NMR (CDC13, 250 MHz) S 7.5 (d, 1 H), 7.3 (d, 2H), 6.8 (d, 2H), 6.2 (d, 1 H}, 4.0 (m, 2H), 3.8 (m, 1 H), 3.7 (s, 3H), 2.4-2.2 (m, 2H), 2.1 {s, 6H), 0.7 (s, 9H), 0.0 (d, 6H).
(E)-3-(4-(3-Dimethylamino-2-hydroxypropoxy)phenyl]acrylic acid, methyl ester (1.5 g, 60%) was obtained as an oil by reaction of 4-(3-dimethylamino-2 hydroxypropoxy)benzaldehyde (2.0 g, 8.96 mmol) in 80 mL of toluene with triphenylphosphoranylidene methyl acetate (3.6 g, 1.2 equiv.) at 100 °C
for one day. After concentration in vacuo, the residue was taken up in DCM, washed with water, dried over Na2S04, evaporated in vacuo and purified via flash chromatography using DCM:MeOH (95:5) as eluting solvent.
'H NMR (CDCi3, 250 MHz) b 7.6 (d, 1 H}, 7.5 (d, 2H), 7.3 (d, 2H), 6.3 (d, 1 H), 4.2 (m, 1 H), 4.1 (m, 1 H), 3.8 (m, 3H), 3.3 (s, 1 H), 2.8 (dd, 1 H), 2.6 (dd, 1 H), 2.4 (s, 6H).
4-(3-Dimethylamino-2-hydroxypropoxy)benzaldehyde (8.2 g, 61 %) was obtained as an a yellow oil, by reaction of 4-oxiranylmethoxybenzaldehyde (6 g, 33.6 mmol, prepared according to the procedure of Baldwin,J.J.; Hirchmann,R.;
Lumma,W.C.; Ponticello,G.S.; Sweet,C.S.; Scriabine,A. J. Med. Chem. 1977, 20, 1024-1029) in 100 mL of MeOH with dimethylamine (34 mL, 2 equiv. ). The resulting mixture was stirred at reflux for 2 days. Evaporation in vacuo gave a residue that was taken up in DCM, washed with brine and dried over MgS04 and evaporated in vacuo.
'H NMR (CDC13, 250 MHz) 8 9.7 (s, 1H), 7.6 {d, 2H), 7.0 (d, 2H), 4. (m, 3H), 3.6 (s, 1 H), 2.5 (dd, 1 H), 2.3 (dd, 1 H), 2.25 (s, 6H).
Intermediate 53 (E)-3-(4-(2-(Dimethylaminoethylamino)phenyl)acrylic acid The same method was employed as in the preparation of Intermediate 23 but starting from 4-[2-(dimethylaminoethyl)amino]benzaldehyde (prepared according to the procedure of Klaus,M.; Mohr,P.; Weiss,E. EP 331983 A2) to give the title compound as an oil in a 100% yield.
'H NMR (CDC13, 250 MHz) 8 7.5 (d, 1 H), 7.2 (d, 2H), 6.5 (d, 2H), 6.1 (d, 1 H
j, 4.6 (s, 1 H), 3.0 (m, 2H), 2.5 (t, 2H), 2.2 (s, 6H).
Intermediate 54 (E)-3-~4-(2-(1.3-Dioxo-1 3-dihydroisoindol-2-yl)ethoxylphenyl)acryiic acid The same method was employed as in the preparation of intermediate 23 but starting from 4-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethoxy]benzaldehyde (prepared from the procedure of HindIey,R.M.; Haigh,D.; Cottam,G.P. WO
9207839 A1 ) to give the title compound as an oil in a 99% yield.
'H NMR (CDC13, 250 MHz) 8 12.3 (s, 1 H), 7.9 (m, 4H), 7.6 (d, 2H), 7.5 (d, 1 H), 7.0 (d, 2H), 6.4 (d, 1 H), 4.4 (t, 2H), 4.0 (t, 2H).
Intermediate 55 (E)-3-(4-(2-(Piperidin-1-ylethoxy)phenyllacrylic acid The same method was employed as in the preparation of Intermediate 23 but starting from 4-(2-piperidin-1-yl-ethoxy)benzaldehyde (which was prepared . according to the procedure of Naruto,S.; Mizuta,H.; Sawayama,T.; Yoshida,T.;
Uno,H.; Kawashima,K.; Sohji,Y.; Kadokawa,T.; Nishimura,H. J. Med. Chem.
1982, 25, 1240-1245), to give the title compound as a white powder in a 60%
yield.
MP: 231 °C.
Intermediate 56 (E)-3-~4-(2-(Tertbutoxvcarbonyimethvlamino)ethoxvlahenvllacrylic acid (E)-3-[4-(2-Methylaminoethoxy)phenyl]acrylic acid (0.8 g, 3.6 mmol) in dioxane (100 mL) was treated with NaOH (2N) (22 mL, 12 equiv.). After one hour of stirring at 70 °C, ditertbutyldicarbonate (1.6 g, 2 equiv.) was added slowly. The reaction was judged to be complete after 3 hours of stirring at 70 °C.
After filtration of the white precipitate, the filtrate was acidified to pH=1 with HCI (1 N).
A new white solid precipitated out . Filtration and drying in vacuo gave the title compound (0.6 g, 50%) as white crystals.
' H NMR (CDC13, 250 MHz) 8 7.8 (d, 1 H), 7.65 (d, 2H), 7.0 (d, 2H), 6.4 (d, 1 H), 4.25 (t, 2H), 3.7 (t, 2H), 3.1 (s, 3H), 1.5 (s, 9H).
(E)-3-[4-(2-Methylaminoethoxy)phenyl]acrylic acid (1.1 g, 41%) was obtained as a white solid by hydrolysis of (E)-3-[4-(2-methylaminoethoxy)phenyl]acrylic acid, methyl ester (3.0 g, 12.0 mmol) with NaOH (6.0 g, 12 equiv.) in MeOHITHF at 40 °C.
MP: 245 °C.
(E)-3-(4-(2-Methylaminoethoxy)phenyl]acrylic acid, methyl ester (3.0 g, 70%) was obtained as a yellow oil by reaction of trimethylphosphonoacetate (4.2 g, 23.0 mmol) and n-butyl lithium (9.0 mL, 18.0 mmol, 2.0 M in cyclohexane) at -°C, followed by the addition of 4-(2-methylaminoethoxy)benzaidehyde (3.2 g, 18.0 mmol) at - 40 °C. The resulting mixture was stirred at rt for 16 hours, quenched with water, extracted with EtOAc, dried over MgS04 and concentrated in vacuo.
'H NMR (CDC1~, 250 MHz) b 7.65 (d, 1 H), 7.45 (d, 2H), 6.9 (d, 2H), 6.25 (d, 1 H), 4.10 (t, 2H), 3.75 (s, 3H), 2.95 (t, 2H), 2.5 (s, 3H).
4-(2-Methylaminoethoxy)benzaldehyde (3.2 g, 51 °~) was obtained as a yellow oil by reaction of 4-(2-methylaminoethoxy)benzonitrile (7.0 g, 40.0 mmol) with diisobutylaiuminum hydride (40 mL, 1.5 equiv., 1.5 M in toluene) in toluene (400 mL) at - 78°C. After 4 hours of stirring at - 78 °C the resulting mixture was treated with a mixture of waterIMeOH (4 mL). At rt an additional 20 r~L of water was added. The resulting suspension was filtered on a bed of celite~The celite was washed with Et20 (3 x 200 mL). The filtrate was concentrated in vacuo and purified via flash chromatography of silica gel using MeOH:DCM (1:9) as eluting solvent.
'H NMR (CDC13, 250 MHz) b 9.8 {s, 1 H), 7.8 (d, 2H), 7.0 (d, 2H), 4.1 (t, 2H), 2.9 (t, 2H), 2.5 (s, 3H).
4-(2-Methylaminoethoxy)benzonitrile (0.6 g, 15%) was obtained as a yellow oil by reaction of 4-(2-chloroethoxy)benzonitrile (2.0 g, 11.0 mmol, prepared according to the procedure of Mizuno,K.; Kimura,Y.; Otsuji,Y. Synthesis, 1979, 9, 688) with methylamine (4.3 mL, 5 equiv., 40% in water) at 70 °C for 16 hours.
The resulting mixture was extracted with DCM, dried over MgS04, concentrated in vacuo and purified via flash chromatography of silica gel using MeOH:DCM
(2:8) as eluting solvent, to give the title compound.
'H NMR (CDC13, 250 MHz) 8 7.6 (d, 2H), 7.0 (d, 2H), 4.1 (t, 2H), 3.0 (t, 2H), 2.5 (s, 3H).
Example 1 ~E)-1-(1-Phenyl-1.3 4 9-tetrahydro-Q-carboiin-2-yl)-3-phenylpropene 1 one To a solution of intermediate 1 (0.2 g, 0.81 mmol) and NaHC03 {0.08 g, 1.2 equiv.) in 10 mL of DCM was added (E)-cinnamoyl chloride (0.2 g, 1.5 equiv.).
After 4 hours of stirring at rt the reaction was judged to be completed by tlc monitoring (Si02, DCM:MeOH 98:2) and was quenched with 5 mL of a saturated aqueous solution of NaHC03. The reaction mixture was extracted with DCM, washed with brine (5 mL), dried over MgS04 and concentrated in vacuo. Flash chromatography on a 2 x 20 cmz column using DCM:MeOH (98:2) as eluting solvent and removal of the solvent in vacuo gave after recrystallization from propanol, the title compound (0.1 g, 33%) as white crystals.
MP: 130-132 °C.
Analysis for CZ6Hz2N20:
Calculated: C,82.51; H,5.86; N,7.40;
Found: C,82.24; H,5.93; N,7.36%.
Example 2 (El-1-(1-Phenyl-1.3 4.9-tetrahydro-~-carbolin-2-yl)-3-(4-nitrophenyl)propene 1 one The same method as employed as in the preparation of Example 1 but starting from (E)-4-nitrocinnamoyl chloride gave after recrystallization from iPr20:2-propanol (3:1 ), the title compound as a yellow powder in a 47% yield.
MP: 230-231 °C.
5 Analysis for CzsHZ,N303:
Calculated: C,73.74; H,5.00; N,9.92;
Found: C,73.89; H,5.12; N,9.86%.
Example 3 10 (E)-1-(1-Phenyl-1,3,4,9-tetrahydro-a-carbolin-2-yi)-3-(4-trifluoromethylphenyl)-propene-1-one The same method as employed in the preparation of Example 1 but starting from (E)-4-trifluoromethylcinnamoyl chloride gave after recrystallization from pentane, the title compound as a white powder in a 41 % yield.
15 MP: 211 °C.
Analysis for CZ,H2,F3N20. 0.4Hz0:
Calculated: C,71.48; H,4.84; N,6.17;
Found: C,71.84; H,4.81; N,6.19%.
20 Example 4 ~E )-1-( 1-Phenyl-1, 3,4.9-tetrahydro-~-carbol in-2-yl )-3-(4-methoxy-phenyl)propene-1-one The same method as employed in the preparation of Example 1 but starting from (E)-4-methoxycinnamoyl chloride gave after recrystallization from 2-propanol, 25 the title compound as white crystals in a 61 % yield.
MP: 160-163 °C.
Analysis for C2~Hz4N202. 0.5(2-propanol):
Calculated: C,78.06; H,6.44; N,6.39;
Found: C,78.04; H,6.02; N,5.97%.
Example 5 (E)-1-(1-(4-Methoxyphenyl)-1.3.4,9-tetrahydro-Q-carboiin-2-yl~-3-(4-trifluoromethyiphenyl )propene-1-one The same method as employed in the preparation of Example 1 but starting from intermediate 2 and (E)-4-trifluoromethylcinnamoyl chloride gave after recrystallization from pentane, the title compound as a white powder in a 61 yield.
MP: 130-135 °C.
Analysis for CZ8H2sNzOzF3. 0.3H20:
Calculated: C,69.79; H,4.94; N,5.81;
Found: C,69.9; H,4.84; N,5.73%.
Example 6 (E)-N-(4-f3-Oxo-3-(1-phenyl-1 3.4.9-tetrahydro-(3-carbolin-2-yl)propenyllphenyll-acetamide To a solution of Intermediate 1 (0.2 g, 0.81 mmol) in 40 mL of DCM were added Et3N (0.13 mL, 1.1 equiv. ), DCC (0.18 g, 1.1 equiv. ), HOBT (0.12 g, 1.1 equiv. ) and (E)-3-(4-acetylaminophenyl)acrylic acid (0.18 g, 1.1 equiv.). After 24 hours of stirring at rt the reaction was judged to be completed by tlc monitoring (SiOz, DCM:MeOH 95:5) and was quenched with 150 mL of water. A white solid precipitated out and was filtered off. The filtrate was extracted with DCM, washed with brine (5 mL), dried over MgS04 and concentrated in vacuo. Flash chromatography on a 2.5 x 25 cm2 column of silica gel using DCM:MeOH (98:2) as eluting solvent and removal of the solvent in vacuo gave the title compound (0.18 g, 51 %) as yellow crystals after recrystailization from 2-propanol:pentane.
MP: 177-180 °C.
Analysis for CzeH2sN3OzØ7H20:
Calculated: C,75.05; H,5.94; N,9.38;
Found: C,75.01; H,5.81; N,9.22%.
Example 7 ~E)-1-f 1-(4-Methoxyphenyl)-1,3.4,9-tetrahydro-Q-carbolin-2-yl)-3-phenylpropene-1-one The same method as employed in the preparation of Example 1 but starting from Intermediate 2 gave the title compound as white crystals in a 56% yield.
MP: 127 °C.
Analysis for Cz~H24N20z. 0.5Hz0:
Calculated: C,77.67; H,6.04; N,6.71;
Found: C,77.91; H,6.0; N,6.73%.
Example 8 - (E)-1-[1-(3.4-Methylenedioxyphenyl)-1.3.4.9-tetrahydro-ti-carbolin-2-yll-3-phenyl-propene-1-one The same method as employed in the preparation of Example 1 but starting from Intermediate 7 gave after recrystallization from 2-propanol:iPr20 (2:8), the title compound as white crystals in a 38% yield.
MP: 236-238 °C.
Analysis for Cz,H24NZOz. 0.5H20:
Calculated: C,76.76; H,5.25; N,6.63;
Found: C,76.87; H,5.35; N,6.54%.
Example 9 (El-1-( 1-Phenyl-1.3.4,9-tetrahydro-Q-carbolin-2-yl)-3-(4-formylphenyl)propene-one The same method as employed in the preparation of Example 6 but starting from (E)-4-formylcinnamic acid gave after recrystallization from acetone:MeOH
(10:3), the title compound as yellow crystals in a 60% yield.
MP: 146 °C.
Analysis for Cz,H22N202. 0.4H20:
Calculated: C,78.39; H,5.55; N,6.77;
Found: C,78.33; H,5.54; N,6.67%.
Example 10 (E)-N-[4-[3-Oxo-3-(1-(4-nitrophenyl)-1 3 4 9-tetrahydro-Q-carbolin-2-_ yl)propenyll-phenyllacetamide The same method as employed in the preparation of Example 6 but starting from Intermediate 3 gave after recrystallization from 2-propanol, the title compound as white crystals in a 51 % yield.
MP: 185 °C.
Analysis for CzaH2aNa04. 0.6H20:
Calculated: C,68.45; H,5.17; N,11.4;
Found: C,68.37; H,5.06; N,11.26%.
Example 11 (E)-1-(1-(4-Nitrophenyl)-1.3.4.9-tetrahydro-Q-carbolin-2-yl~-3-phenylpropene-1-one The same method as employed in the preparation of Example 1 but starting from Intermediate 3 gave after recrystallization from 2-propanol, the title compound as a yellow powder in a 15% yield.
MP: 205-206 °C.
Analysis for CzsH2,N3O3. 0.2H20:
Calculated: C,73.12; H,5.05; N,9.84;
Found: C,72.95; H,5.15; N,9.81 %.
Example 12 E)-1-(1-(4-Trifluoromethoxyphenyl)-1,3.4 9-tetrahydro-Q-carbofin-2-yll-3-phenyl-propene-1-one The same method as employed in the preparation of Example 1 but starting from Intermediate 4 gave after recrystallization from pentane, the title compound as white crystals in a 44% yield.
MP: 119 °C.
Analysis for CZ,HZ,NZOZF3:
Calculated: C,70.12; H,4.58; N,6.06;
Found: C,70.02; H,4.58; N,6.02%.
Example 13 1 E)-1-( 1-(4-Methylphenyl )-1, 3.4.9-tetrahydro-Q-carbo I i n-2-yll-3-phenylpropene-1-one The same method as employed in the preparation of Example 1 but starting from Intermediate 6 gave after recrystallization from pentane, the title compound as white crystals in a 50% yield.
MP: 125-127 °C.
Analysis for C2,H2aN20. 0.6Hz0:
Calculated: C,80.41; H,6.3; N,6.95;
Found: C,80.49 ; H,6.2 ; N,7.25%.
Example 14 ~E)-N-(4-(3-Oxo-3-(1-(3.4-methylenedioxyphenyl)-1.3 4 9-tetrahydro-(3-_carbolin-2-yl)-propenyllphenyllacetamide The same method as employed in the preparation of Example 6 but starting from Intermediate 7 and {E)-3-(4-acetylaminophenyl)acrylic acid gave after recrystallization from 2-propanol:pentane, the title compound as white crystals in a 85% yield.
MP: 185 °C.
Analysis for Cz9H25N3Oa. 0.4H20:
Calculated: C,71.56; H,5.34; N,8.63;
Found: C,71.59; H,5.32; 8.66%.
Example 15 LE)-4-(3-Oxo-3-(1-phenyl-1 3,4.9-tetrahydro-Q-carbolin-2-yl)-propenyflbenzoic acid. methyl ester To a solution of Example 9 (0.2 g, 0.49 mmol) in 20 mL of MeOH was added activated MnOz {0.59 g, 14 equiv. ), sodium cyanide (0.05 g, 2 equiv. ) and acetic acid (0.05 g, 1.7 equiv.). The resulting mixture was stirred for 5 hours. Tlc monitoring showed a new compound (Si02,DCM:MeOH (95:5), Rf= 0.82). The mixture was filtered through a short column of cefite using 150 mL of a mixture of MeOH:EtOAc:CHCl3 (1:25:25). After evaporation in vacuo the residue was purified via flash chromatography on a 2 x 20 cmz column using DCM as eluting solvent. Evaporation and recrystallization from EtOH gave the title compound (0.15 g, 70%) as yellow crystals.
MP: 222 °C.
Analysis for C28H24NzOs. 0.03H20:
Calculated: C,76.1; H,5.61; N,6.34;
Found: C,76.05; H,5.68; N,6.15%.
Example 16 (E)-1-(1-(2-Chlorophenyl)-1,3.4.9-tetrahydro-(3-carbolin-2-yll-3-phenylpropene-one The same method as employed in the preparation of Example 1 but starting from Intermediate 17 gave after recrystaliization from EtOH, the title compound as white crystals in a 27% yield.
MP: 220-221 °C.
Analysis for CZ6Hz~N20C1:
Calculated: C,75.63; H,5.13; N,6.78;
Found: C,75.4; H,5.21; N,6.79%.
Example 17 E)-1-(1-Phenyl-1,3,4.9-tetrahydro-a-carbolin-2-yl)-3-(3 4-5 methylenedioxyphenyl)-propene-1-one The same method as employed in the preparation of Example 1 but starting from (E)-(3,4-methylenedioxy)cinnamoyl chloride gave after recrystallization from EtOH, the title compound as a white powder in a 65% yield.
MP: 221 °C.
10 Analysis for Cz,HzzNz03. 0.3Hz0:
Calculated: C,75.79; H,5.32; N,6.55;
Found: C,75.76; H,5.37; N,6.53%.
Example 18 15 (E)-1-(1-(3.4-Methylenedioxyphenyl)-1,3.4.9-tetrahydro-(3-carbolin-2-yll-3-(4-bromophenyl)propene-1-one The same method as employed in the preparation of Example 1 but starting from Intermediate 7 and (E)-4-bromocinnamoyl chloride gave after recrystallization from EtOH, the title compound as a white powder in a 10% yield.
20 MP: 188-190 °C.
Analysis for CZ~H2,NzO3Br. 0.3H20:
Calculated: C,63.99; H,4.3; N,5.53;
Found: C,63.53; H,4.23; N,5.38%.
25 Example 19 (E)-1-(1-(4-Chlorophenyl)-1 3.4 9-tetrahydro-(3-carbolin-2-yl)-3-phenylpropene-one The same method as employed in the preparation of Example 1 but starting from Intermediate 5 gave after recrystallization from EtOH, the title compound as 30 white crystals in a 72% yield.
MP: 213-214 °C.
Analysis for CzsHz,N20C1:
Calculated: C,75.63; H,5.13; N,6.78;
Found: C,75.55; H,5.16; N,6.63%
Example 20 ( E )-1-f 1-(3.4-Methylenedioxyphenyl )-1, 3.4.9-tetrahydro-~-carbol i n-2-yll-3-(4-ethoxyphenyl)propene-1-one To a solution of Intermediate 7 (0.2 g,0.68 mmol) in 40 mL of DCM were added Et3N (0.1 mL, 1.1 equiv.), EDCI (0.14 g, 1.1 equiv.), HOBT (0.12 g, 1.1 equiv.) and (E)-4-ethoxycinnamic acid (0.14 g, 1.1 equiv.). After 48 hours of stirring at rt the reaction was judged to be completed by t1c monitoring (Si02, DCM:MeOH
(95:5)) and was quenched with 50 mL of water. The reaction mixture was extracted with DCM, washed with brine (5 mL), dried over MgS04 and concentrated in vacuo. Flash chromatography on a 2.5 x 25 cmz column of silica gel using DCM:MeOH (98:2) as eluting solvent and removal of the solvent in vacuo gave the title compound (0.21 g, 67%) as white crystals after recrystallization from EtOH.
MP: 199-200 °C.
Analysis for Cz9H26Nz04. 0.3Hz0:
Calculated: C,73.8; H,5.68; N,5.94;
Found: C,73.72; H,5.68; N,5.97%.
Example 21 (E)-4-f3-Oxo-3-(1-(3.4-methylenedioxyphenyl)-1.3.4.9-tetrahydro-(i-carbolin-2-yl)propenyllacetic acid, phenyl ester The same method as employed in the preparation of Example 20 but starting from (E)-4-acetoxycinnamic acid gave after recrystallization from MeOH, the title compound as white crystals in a 54% yield.
MP: 216 °C.
Analysis for CzsHz4NzOs:
Calculated: C,72.49; H,5.03; N,5.83;
Found: C,72.3; H,5.11; N,5.84%.
Example 22 (E)-1-f 1-(3,4-Methylenedioxyphenyl)-1.3.4.9-tetrahydro-Q-carbolin-2-yll-3-(4-hydroxyphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-4-hydroxycinnamic acid gave after recrystaltization from EtOH:pentane the title compound as white crystals in a 57% yield.
MP: 175 °C.
Analysis for Cz~HzZN2O4 Ø3H20:
Calculated: C,73.06; H,5.13; N,6.31;
Found: C,73.14; H,5.36; N,6.44%.
Example 23 (E)-1-! 1-(3.4-Methylenedioxyphenyl)-1.3.4.9-tetrahydro-Q-carbol in-2-yll-3-(4-formylphenyl )propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-4-formylcinnamic acid gave after recrystallization from MeOH the title compound as white crystals in a 100% yield.
MP: 208 °C.
Analysis for C28HzzN204. 0.3H20:
Calculated: C,73.77; H,5.00; N,6.15;
Found: C,73.77; H,4.96; N,6.05%.
Example 24 ( E)-1-!4-!3-Oxo-3-( 1-(3.4-methylenedioxyphenyl )-1, 3.4, 9-tetrahydro-(3-carboi in-2-yl)-propenyllphenyll-3-phenylurea The same method as employed in the preparation of Example 20 but starting from (E)-3-[4-(3-(phenylureido)phenyl]acrylic acid (which was prepared in situ by reaction of phenylisocyanate (1 equiv.), (E)-4-aminocinnamic acid (1 equiv.) and Et3N (1 equiv.)), gave after recrystallization from EtOH the title compound as white crystals in a 61 % yield.
MP: 192 °C.
Analysis for C~HzeN4Oa. 0.22(EtOH:H20):
Calculated: C,72.48; H,5.26; N,9.82;
Found: C,72.87; H,5.17; N,9.42%.
Example 25 (E)-1-!1-(3,4-Methyienedioxyphenyl)-1.3.4.9-tetrahydro-Q-carbolin-2-yll-3-(4-aminophenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-4-aminocinnamic acid gave after recrystallization from EtOH:DCM:2 propanol (10:2:2) the title compound as white crystals in a 63% yield.
WO 97/43287 PCT/EP97/02277 _ MP: 262-265 °C.
Analysis for Cz7H23N3O3. 0.3Hz0:
Calculated: C,73.22; H,5.37; N,9.49;
Found: C,72.9; H,5.47; 9.32%.
Example 26 ~E~-1-(1-(3 4-Methylenedioxyphenyl)-1,3.4.9-tetrahydro-Q-carbolin-2-yll-3-(4-nitrophenyl)-propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-4-nitrocinnamic acid gave after recrystallization from EtOH, the title compound as yellow crystals in a 69% yield.
MP: 158° C.
Analysis for CZ~Hz,N30s:
Calculated: C,69.37; H,4.53; N,8.99;
Found: C,69.57; H,4.61; N,8.92%.
Example 27 (El-1-(1-(3 4-Methylenedioxyphenyl)-1,3.4,9-tetrahydro-Q-carbolin-2-yll-3-((4-bis(methylsulfonyl)aminophenyllpropene-1-one This product was prepared by refluxing for two hours a solution of Example 25 (0.2 g, 0.6 mmol), mesyl chloride (0.1 mL, 5 equiv.), Et3N {0.4 mL, 5 equiv.) in 20 mL of THF. The disappearance of the starting material and the formation of a new compound were confirmed by tlc (Si02, DCM:MeOH (95:5), Rf= 0.84). After evaporation of THF the residue was dissolved in DCM (15 mL) and washed with HZO (10 mL). The organic solution was dried over MgSOa and concentrated in vacuo to give a residue which was purified via flash chromatography on a 2.5 x 25 cm2 column using DCM:MeOH (98:2) as eluting solvent. Recrystallization from EtOH gave the title compound (0.09 g, 25%) as a white powder.
MP: 276 °C.
Analysis for C29H27N3O7Sz. 0.3Hz0:
Calculated: C,58.14; H,4.64; N,7.01;
Found: C,57.76; H,4.69; N,6.81%.
Example 28 LE)-4-f 3-Oxo-3-f 1-(3.4-methylenedioxyphenyl)-1.3 4 9-tetrahydro-a-carbolin-2-yll-propenyllbenzoic acid. methyl ester The same method as employed in the preparation of Example 20 but starting from (E)-4-(2-carboxyvinyl)benzoic acid, methyl ester acid (prepared according to the procedure of Taylor,E.C.; Young, W.B.; Chaudhari,R.; PateI,H.
Heterocycles 1993, 36, 1897-1908), gave after recrystallization from MeOH:H20 (99:1 ), the title compound as yellow crystals in a 84% yield.
MP: 211 °C.
Analysis for CZ9Hz4Nz05. 0.3H20:
Calculated: C,71.68; H,5.1; N,5.76;
Found: C,71.76; H,5.02; N,5.68%.
Example 29 (E)-N-f4-f3-Oxo-3-f1-(3.4-methylenedioxyphenyl)-1 3 4 9-tetrahydro-f3-carbolin-2-yllpropenyllphenyilmethanesulfonamide The same method as employed in the preparation of Example 27 but using 1 equiv. of mesyl chloride gave after recrystallization from EtOH the title compound as an off-white powder in a 10% yield.
MP: 203 °C.
Analysis for C2gHz5N3O5S. 0.2H20:
Calculated: C,64.78; H,4.93; N,8.09;
Found: C,64.66; H,5.15; N,7.73%.
Example 30 (E)-4-f3-Oxo-3-f1-(3,4-methytenedioxyphenyl)-1 3 4 9-tetrahydro-(3-carboiin-2-Yllpropenyllbenzamide into a solution of Example 28 (0.2 g, 0.4 mmol) in 50 mL of MeOH was bubbled ammonia and the resulting mixture was stirred at 35°C for two days. The mixture was concentrated in vacuo to give a residue which was washed with 2x30 mL of water. Extraction, drying over MgS04 and concentration in vacuo gave a residue that was purified via radial chromatography using DCM:MeOH (90:10) as eluting solvent and via preparative chromatography (20x20- cm plate, 0.5 mm , SiO~) using the same eluant. The title compound (0.025 g, 13%) was isolated as white crystals after recrystallization from MeOH:H20.
MP: 183 °C.
Analysis for CZ8H23N3O4:
Calculated: C,70.07; H,5.17; N,8.76;
Found: C,69.97; H,5.16; N,8.84%.
5 Example 31 ~E )-4-I3-Oxo-3-f 1-f 3.4-methylenedioxyphenyl )-1, 3,4.9-tetrahydro-(3-carbolin-2-yll-propen~lbenzoic acid This product was prepared by refluxing for four hours a stirred solution of Example 28 (0.5 g, 1.04 mmol) and NaOH (1N) (5.2 mL, 5 equiv.) in 50 mL of 10 MeOH. After evaporation of the solvent in vacuo, the residue was treated with 10 mL of HCI (1 N). A solid precipitated out and was filtered off.
Recrystallization from MeOH gave the title compound (0.35 g, 72%) as white crystals.
MP: 254-256 °C.
Analysis for CzeHZZN20s. 0.2H20:
15 Calculated: C,72.09; H,4.75; N,6.01;
Found: C,71.60; H,4.84; N,5.88%.
Example 32 (E)-1-(1-(3.4-Methylenedioxyphenyl)-1,3.4,9-tetrahydro-Q-carbolin-2-yll-3-(4-20 cyanophenvl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-4-cyanocinnamic acid gave after recrystallization from EtOH the title compound as white crystals in a 69% yield.
MP: 167 °C.
25 Analysis for CzeHz,N303. 0.1 H20:
Calculated: C,74.85; H,4.76; N,9.35;
Found: : C,74.72; H,4.81; N,9.27%.
Example 33 30 (E)-1-f1-(3.4-Methylenedioxyphenyl)-1,3.4.9-tetrahydro-(i-carbolin-2-yll-3-(4-trifluoromethyfphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-4-trifluoromethylcinnamic acid gave after recrystallization from EtOH
the title compound as white crystals in a 73% yield.
35 MP: 233 °C.
Analysis for CzaHz,F3Nz03. 0.2H20:
Calculated: C,68.07; H,4.37; N,5.67;
Found: C,68.04; H,4.32; N,5.65%.
Example 34 ( E )-1-f 1-(3,4-Methylened ioxyphenyl )-1, 3.4. 9-tetrahydro-Q-carbo f in-2-yl l-3-(3.4-methylenedioxyphenyl )propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3,4-methylenedioxycinnamic acid gave after recrystallization from EtOH
the title compound as yellow crystals in a 73% yield.
MP: 233 °C.
Analysis for CzaHzzNzOs:
Calculated: C,72.09; H,4.75; N,6.01;
Found: C,71.79; H,4.76; N,5.93%.
Example 35 (E)-1-(1-(3,4-Methylenedioxyphenyl)-1.3.4.9-tetrahydro-a-carbolin-2-yll-3-(4-chlorophenyl )propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-4-chlorocinnamic acid gave after recrystallization from EtOH the title compound as white crystals in a 55% yield.
MP: 203 °C.
Analysis for Cz~H2,N203C1:
Calculated: C,70.97; H,4.63; N,6.13;
Found: C,71.04; H,4.76; N,6.04%.
Example 36 ( ~ 1-( 1-(3, 4-Methylenedi oxyphenyl)-1, 3,4.9-tetrahydro-Q-carbol in-2-yll-3-(4-trifluoromethoxyphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-4-trifluoromethoxycinnamic acid (prepared according to the procedure of Yagupol'skii, 1_.M., Troitskaya, V.I. Zhurnal Obshchei Khimii 1960, 30, 3104) gave after recrystallization from EtOH the title compound as yellow crystals in a 35% yield.
MP:203-205°C.
Analysis for C2sHz,F3Nz04:
Calculated: C,66.4; H,4.18; N,5.53;
Found: C,66.23; H,4.26; N,5.54.
Example 37 LE)-1-f 1-(3.4-Methylenedioxyphenyl)-1,3.4,9-tetrahydro-Q-carbolin-2-yll-3-(4-methylphenyl )propene-1-one The same method as employed in the preparation of Example 20 but starting from (E}-4-methylcinnamic acid gave after recrystallization from EtOH:DCM
(99:1 ) the title compound as white crystals in a 67% yield.
MP: 240 °C.
Analysis for CZ$H24NzOs. 0.7Hz0:
Calculated: C,74.88; H,5.7; N,6.24;
Found: C,74.83; H,5.45; N,6.35.%.
Example 38 (E)-f4-f3-Oxo-3-(1-(3 4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-t3-carboiin-2-yl)propenyllphenyllurea The same method as employed in the preparation of Example 20 but starting from Intermediate 22 gave after recrystallization from EtOH the title compound as white crystals in a 49% yield.
MP: 208 °C.
Analysis for CZSHz4N4O4. 0.5HzO:
Calculated: C,68.7; H,5.15; N,11.44;
Found: C,68.51; H,5.14; N,11.35%.
Example 39 (E)-1-(1-(3.4-Methylenedioxyphenyl)-1.3,4.9-tetrahydro-(3-carbolin-2-yll-3-(4-hydroxymethylphenyl )propene-1-one This product was prepared by stirring a solution of Example 23 (0.3 g, 0.66 rnmol) in 40 mL of MeOH with NaBH4 (0.1 g, 4 equiv.) at rt for two hours.
Evaporation of the solvent gave a residue which was dissolved in DCM (100 mL) and washed twice with water (50 mL). Extraction with DCM, drying over MgS04 and evaporation in vacuo gave the title compound (0.2 g, 67%) as white crystals after recrystallization from EtOH.
MP: 206 °C.
Analysis for C28Hz4NzO4. 0.3EtOH:
Calculated: C,73.66; H,5.58; N,6.01;
Found: C,73.69; H,5.5; N,6.06%.
Example 40 ~E)-N-Benzyl-4-(3-oxo-3-(1-(3 4-methylenedioxyphenvll-1 3 4 9-tetrahvdro Q
carbolin-2-yl)propenyllbenzamide This product was prepared by stirring a solution of Example 31 (0.2 g, 0.43 mmol) in 50 mL of THF with benzylamine (0.5 mL, 9 equiv.), Et3N (1 mL) and diphenylphosphoryl azide (0.5 mL). After two days the reaction mixture was concentrated in vacuo. The residue was taken up in 100 mL of DCM and washed with 3 x 50 mL of water. Drying over Na2S04 and evaporation of the solvent gave a residue which was purified via flash chromatography with cyclohexane and EtzO. Evaporation in vacuo and recrystallization from EtOH
gave the title compound (0.03 g, 13%) as white crystals.
MP: 203 °C.
Analysis for C35H29N3O4:
Calculated: C,75.66; H,5.26; N,7.56;
Found: C,75.5; H,5.22; N,7.55%.
Example 41 (E)-1-(1-(3,4-Methylenedioxyphenyl)-1 3 4 9-tetrahydro-Q-carbolin-2-yll-3 (2 4 dichlorophenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-2,4-dichlorocinnamic acid gave after recrystallization from EtOH:H20 the title compound as a white powder in a 66% yield.
MP: 194 °C.
Analysis for Cz,H2oNz03C12:
Calculated: C,66.00; H,4.10; N,5.70;
Found: C,65.85; H,4.13; N,5.78%.
Example 42 (E)-1-(1-(3.4-Methylenedioxyphenyl)-1 3 4 9-tetrahydro-Q-carbolin-2-yll 3 (3 methoxy-4-hydroxyphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3-methoxy-4-hydroxycinnamic acid gave after recrystallization from EtOH:H20 (10:1 ) the title compound as an oft-white powder in a 62% yield.
MP: 155 °C.
Analysis for CzsH2aN20s:
Calculated: C,71.78; H,5.16; N,5.98;
Found: C,71.44; H,5.16; N,5.76%.
Example 43 ~,E)-1-f1-(3.4-Methylenedioxyphenyl)-1.3.4.9-tetrahydro-Q-carbolin-2-yll-3-(3-hydroxy-4-methoxyphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3-hydroxy-4-methoxycinnamic acid gave after recrystallization from EtOH:HZO the title compound as an off-white powder in a 47% yield.
MP: 213 °C.
Analysis for CZSHzaNzOs. 0.3H20:
Calculated: C,70.96; H,5.23; N,5.91;
Found: C,71.09; H,5.60; N,5.66%.
Example 44 (E)-1-f 1-(3,4-Methylenedioxyphenyl)-1,3,4.9-tetrahydro-Q-carbolin-2-yl1-3-(4-fluorophenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-4-fluorocinnamic acid gave after recrystallization from EtOH the title compound as white crystals in a 74% yield.
MP: 138-139 °C.
Analysis for C2,Hz,F3N20s:
Calculated: C,73.62; H,4.81; N,6.36;
Found: C,73.78; H,4.81; N,5.97%.
Example 45 (E)-1-( 1-(3.4-Methylenedioxyphenyl )-1.3.4, 9-tetrahydro-(3-carbolin-2-yll-3-indan-5-yl-1-propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3-indane-5-ylacrylic acid gave, after precipitation, the title compound as a yellow powder in a 22% yield.
MP: 115 °C.
5 Analysis for C2pH26N2O3. 0.6Hz0:
Calculated: C,76.12; H,5.79; N,5.92;
Found: C,76.13; H,5.79; N,5.72%.
Example 46 10 ~E)-N-(4-f3-Oxo-3-(1-(3.4-methylenedioxyphenyl)-1 3 4 9-tetrahydro-(3 carbolin 2-yl)propenyllbenzoyllbenzenesulfonamide The same method as employed in the preparation of Example 20 but starting from Example 31 and benzenesulfonamide gave after recrystallization from EtOH:H20 the title compound as white crytals in a 20% yield.
15 MP: 134 °C.
Analysis for C2oHzsNz03. 0.6H20:
Calculated: C,56.13; H,6.67; N,10.91;
Found: C,55.97; H,6.75; N,10.82%.
20 Example 47 (E)-1-f1-(3.4-Methylenedioxyphenyl)-1 3 4 9-tetrahydro-f3-carbolin 2 yll 3 (3 dichlorophenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3,4-dichlorocinnamic acid gave after recrystallization from EtOH:H20 25 (99:1 ) the title compound as a white powder in a 45% yield.
MP: 212 °C.
Analysis for CZ,HZOCIzN203:
Calculated: : C,66.00; H,4.10; N,5.70;
Found: C,65.68; H,4.12; N, 5.68%.
Example 48 (E)-1-f1-(3.4-Methylenedioxyphenyl)-1 3 4 9-tetrahydro-Q-carbolin 2 yll 3 (3 4 dimethoxypheny!)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3,4-dimethoxycinnamic acid gave after recrystallization from EtOH:DCM the title compound as a white powder in a 61 % yield.
MP: 233 °C.
Analysis for CZgHZSN20s. 0.5 H20:
Calculated: C,70.86; H,5.54; N,5.70;
Found. C,70.66; H,5.44; N,5.70%.
Example 49 ~E)-1-f1-(3 4-Methylenedioxyphenyl)-1.3 4 9-tetrahydro-f3-carbolin-2-yll-3-(3,4-dihydroxyphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3,4-dihydroxycinnamic acid gave after recrystallization from EtOH:DMF
the title compound as a white powder in a 41 % yield.
MP: 163-165 °C.
Analysis for Cz,H22N20s. 0.3DMF:
Calculated: C,70.34; H,5.10; N,6.76;
Found: C,70.38; H,5.13; N,6.66%.
Example 50 (E)-N-Methyl-N-~4-(3-oxo-3-( 1-(3 4-methylenedioxyphenyl )-1, 3,4.9-tetrahydro-_ca_rb_olin-2-yl )propenyllphenyllacetamide The same method as employed in the preparation of Example 20 but starting from Intermediate 23 gave after recrystallization from EtOH:H20 (10:0.6) the title compound as an off-white powder in a 86% yield EtOH:HzO.
MP: 165 °C.
Analysis for C3oHz,N304Ø4Hz0:
Calculated: C,71.96; H,5.6; N,8.39;
Found: C,71.8; H,5.57; N,8.28%.
Example 51 (El-2 2-Dimethyl-N-(4-(3-Oxo-3-(1-(3.4-methylenedioxyphenyl)-1.3,4.9-tetrahydro-(3-carbolin-2-yl)propenyllphenyllpropionamide This product was prepared by condensation of Example 25 (0.2 g; 0.46 mmol) with 2,2-dimethylpropionyl chloride (0.09 mL, 1.5 equiv.) and NaOH (1N) (0.7 mL, 1.5 equiv.) in a mixture of EtOAc:DCM (6:1). When starting material had disappeared, 40 mL of a mixture of DCM:H20 (2:1 ) was added. Extraction with DCM, washing with a saturated aqueous solution of NH4C1 and brine, drying over MgS04 and evaporation of the solvent in vacuo gave the title compound (0.2 g, 83%) after recrystallization from EtOH:H20 (1:1 ).
MP: 172-174 °C.
Analysis for C32H3,N3O4. 0.1 H20:
Calculated: C,71.23; H,6.16; N,7.79;
Found: C,70.99; H,6.02 ; N.7.84%.
Example 52 ~E)-1-(1-(3,4-Methylenedioxyphenyl)-1.3,4.9-tetrahydro-a-carbolin-2-yll-3-(3.5-dimethoxyphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3,5-dimethoxycinnamic acid gave after recrystallization from EtOH the title compound as a white powder in a 61 % yield.
MP: 178 °C.
Analysis for C29H2sNz05:
Calculated: C,72.19; H,5.43; N,5.81;
Found: C,72.3; H,5.48; N,5.63%.
Example 53 ~E)-(N)-(4-f 3-(1-(3,4-Methylenedioxyphenyl)-6-fluoro-1, 3.4,9-tetrahydro-~3-carbolin-2-yll-3-oxopropenyflphenyl~-acetamide The same method as employed in the preparation of Example 20 but starting from intermediate 16 and and (E)-3-(4-acetylaminophenyl)acrylic acid gave after recrystallization from MeOH the title compound as a white crystals in a 72%
yield.
MP:179-181 °C.
Analysis for CZSHzaN3OaFØ4H20:
Calculated: C,69.01; H,4.95; N,8.33;
Found: C,68.97; H,4.91; N.8.34%.
Example 54 E)-1-f1-(3,4-Methylenedioxyphenyl)-1 3 4 9-tetrahydro-l3-carbolin-2-yll-3-(3.4.5-trimethoxyphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3,4,5-trimethoxycinnamic acid gave after recrystallization from MeOH
the title compound as a white powder in a 49% yield.
MP: 211 °C.
Analysis for CsoHzsNzOs:
Calculated: C,70.3 ; H,5.51; N,5.47;
Found: C,70.49; H,5.59; N,5.34.%.
Example 55 ~E) N-f4-f3-Oxo-3-(1-(3 4-methylenedioxyphenyl)-1 3 4 9-tetrahydro-Q-carbolin-2-yl )propenyllphenyllisobutyramide The same method as employed in the preparation of Example 51 but starting from isobutyryl chloride gave after recrystallization from EtOH the title compound as a white powder in a 85% yield.
MP: 171 °C.
Analysis for C3,HZSN3Oa. 0.4(HzO:MeOH):
Calculated: C,72.61; H,6.02; N,7.99;
Found: C,72.33; H,5.77; N,8.33%.
Example 56 (El-1-f 1-(3 4-Methylenedioxyphenyl)-6-fluoro-1 3 4.9-tetrahydro-Q-carbolin-2-yll-3-phenylpropene-1-one The same method as employed in the preparation of Example 1 but starting from Intermediate 16 gave after recrystallization from EtOH the title compound as white crystals in a 71 % yield.
MP: 227-228 °C.
Analysis for CZ~Hz,N203F:
Calculated: C,73.63; H,4.81; N,6.36;
Found: C,73.72; H,4.77; N,6.43%.
Example 57 (E)-N-(2-Methoxyethyl)-4-(3-oxo-3-( 1-(3.4-methylenedioxyphenyl)-1.3.4,9-tetrahydro-(3-carbolin-2-yl)propenyllbenzamide The same method as employed in the preparation of Example 20 but starting from Intermediate 24 gave after recrystallization from EtOH the title compound as white crystals in a 43% yield.
MP: 170 °C.
Analysis for CZ,H2,Nz03F. 1.3H20:
Calculated: C,68.07; H,5.82; N,7.68;
Found: C,67.98; H,5.8; N,7.7%.
Example 58 (E)-1-f1-(3,4-Methylenedioxyphenyl)-1,3.4,9-tetrahydro-Q-carbolin-2-yll-3-(3-hydroxyphenyl )propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3-hydroxycinnamic acid gave after recrystallization from EtOH:H20 the title compound as white crystals in a 54% yield.
MP: 248 °C.
Analysis for C2~HZZN204:
Calculated: C,73.96; H,5.06; N,6.39;
Found: C,74.04; H,5.1; N,6.37%.
Example 59 (E)-1-f 1-(3.4-Methylenedioxyphenyl)-1,3.4.9-tetrahydro-a-carbolin-2-yll-3-(3-methoxyphenyl )propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3-methoxycinnamic acid gave after recrystallization from EtOH the title compound as white crystals in a 49% yield.
MP: 218 °C.
Analysis for C28HzaN20a:
Calculated: C,74.32; H,5.35; N,6.19;
Found: C,74.37; H,5.61; N,6.32%.
Example 60 (E)-1-(1-(3.4-Methylenedioxyphenyl)-1.3.4.9-tetrahydro-(3-carbolin-2-yl)-3-(3-nitrophenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3-nitrocinnamic acid gave after recrystallization from EtOH:H20 (20:1 ) the title compound as white crystals in a 91 % yield.
MP: 156-158 °C.
5 Analysis for C2sHzaNz04:
Calculated: C,69.37; H,4.54; N,8.99;
Found: C,69.12; H,4.77; N,8.81 %.
Example 61 10 (E) 1 f 1 (3 4 Methylenedioxyphenyl)-1 3 4 9-tetrahydro-Q-carbolin-2-yll-3-f4-(2-dimethylaminoethoxy)phenyllpropene-1-one The same method as employed in the preparation of Example 20 but starting from intermediate 25 gave after recrystallization from EtOH:H20 the title compound as white crystals in a 45% yield.
15 MP: 157 °C.
Analysis for C3~H3,N3O4:
Calculated: C,73.07; H,6.13; N,8.25;
Found: C,72.7 ; H,6.17; N,8.12%.
20 Example 62 _(E) N (2 Morpholin-4-ylethyl)-4-f3-oxo-3-(1-(3 4-methylenedioxyphenvl)-1.3,4,9-t_etrahydro-(3-carbolin-2-y!)propenyllbenzamide The same method as employed in the preparation of Example 20 but starting from Intermediate 26 gave after recrystallization from EtOH:H~O the title 25 compound as white crystals in a 13% yield.
MP: 145 °C.
Analysis for C~H~,N40s. 0.7Hz0:
Calculated: C,69.07; H,6.03; N9.48;
Found: C,69.08; H, 6.03; N,9.45%.
Example 63 (E) 1 [1 (3 4-Methylenedioxyphenyl)-1 3 4 9-tetrahydro-(3-carbolin-2-yll-3-(4-(1 H-tetrazol-5-yl)phenyllpropene-1-one To a solution of Example 32 (0.25 g, 0.56 mmol) in 10 mL of toluene were added successively trimethylsilylazide (0.30 mL, 4 equiv.} and dibutyltinoxide (0.06 g, 0.4 equiv.). The resulting mixture was stirred at reflux for two days. Tfc monitoring showed formation of a new compound (DCM:MeOH (80:20), Rf=0.35).The reaction mixture was concentrated in vacuo. The resulting yellow gum was dissolved in MeOH and concentrated in vacuo. The residue was partitioned between EtOAc (25 mL) and an aqueous saturated solution of NaHCOs (25 mL).The organic phase was extracted with an additional portion of an aqueous saturated solution of NaHC03 (25 mL). The combined aqueous extracts were acidified to pH= 2 with HCI (1 N) and then extracted with EtOAc (2x25 mL). The combined organic extracts were dried over MgS04, filtered and concentrated to give a yellow powder that was purified via flash chromatography (Si02, DCM:MeOH (90:10)). Recrystallization from 2-propanol:iPr20 (1:1 ) gave the title compound (0.19 g, 70 %} as white crystals.
MP: 232-233 °C.
Analysis for C28HZZNsOs. 0.4H20:
Calculated: C,67.02; H,4.92; N,16.28;
Found: C,66.83; H,4.53; N,15.96%.
Example 64 (E)-1-f 1-(3,4-Methylenedioxyphenyl)-1 3 4 9-tetrahydro-(i-carbolin-2-yll-3-(3 aminophenyl)propene-1-one A solution of Example 60 (1.36 g, 2.9 mmol), SnCIz.H20 (2.8 g, 5 equiv.) in EtOH
was refluxed overnight. After evaporation of the solvent, the residue was taken up in 50 mL of NaOH (1N). The aqueous phase was extracted with 2 x 100 mL
of DCM and 2 x 50 mL of EtOAc. The combined organic layers were dried over NaZS04 and concentrated in vacuo. Flash chromatography (SiOZ, DCM:MeOH
(95:5) and recrystallization from EtOH:DCM gave the title compound (0.27 g, 21 %) as a pale yellow powder.
MP: 139-141 °C.
Analysis for CZ,H23N30s:
Calculated: C,74.13; H,5.30; N,9.60;
Found: C,73.93; H,5.35; N,9.43%.
Example 65 -(E)-N-Cyclohexy!-4-f3-oxo-3-(1-(3.4-methylenedioxyphenyl)-1 3 4 9-tetrahydro ~3-carbolin-2-yl)propenyl~benzamide The same method as employed in the preparation of Example 20 but starting from Intermediate 27 gave after recrystallization from EtOH: H20 the title compound as white crystals in a 6% yield.
MP: 214 °C.
Analysis for CzsH2,N303. 0.1 HzO:
Calculated: C,72.19; H,6.24; N,7.43;
Found: C,72.28; H,6.19; N,6.93%.
Example 66 (E)-N-(Tetrahydrofuran-2-ylmethyl)-4-(3-oxo-3-(1-(3,4-methylenedioxyphenyl)-1 3 4 9-tetrahydro-13-carbolin-2-yl)propenyllbenzamide The same method as employed in the preparation of Example 20 but starting from Intermediate 28 gave after recrystallization from EtOH:HzO (8:2) the title compound as white crystals in a 61 % yield.
MP: 168 °C.
Analysis for C3zH29N3Os. 0.8H20:
Calculated: C,69.88; H,5.61; N,7.64;
Found: C,69.74; H,5.78; N,7.22%.
Example 67 (El-1-(1-(3 4-Methylenedioxyphenyl)-1,3,4.9-tetrahvdro-(3-carbolin-2-yll-3-(3-cyanophenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-cyanocinnamic acid gave after recrystalfization from EtOH:HzO (8:2) the title compound as white crystals in a 46% yield.
MP: 228-230 °C.
Analysis for C2aH2,NsOs. 0.8H20:
Calculated: C,72.81; H,4.93; N,9.10;
Found: C,72.74; H,4.69; N,8.99%.
Example 68 (E)-N-(4-Piperidine-4-carboxylic acid. ethyl ester)-4-(3-oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3.4.9-tetrahydro-t3-carbolin-2-yf)propenyllbenzamide The same method as employed in the preparation of Example 20 but starting from Intermediate 29 gave after recrystallization from iPr20 the title compound as white crystals in a 28% yield.
MP: 144-145 °C.
Analysis for C3gH35N3~6~ 0.7H20:
Calculated: C, 69.93; H,5.93; N,6.8;
Found: C,69.84; H,5.83; N,6.81 %.
Example 69 (E)-N-(4-Piperidine-4-carboxylic acid)-4-(3-oxo-3-(1-(3 4-methylenedioxyphenyl)-1.3.4.9-tetrahydro-(i-carbolin-2-yl)propenyllbenzamide This product was prepared by refluxing a solution of Example 68 (0.21 g, 0.36 mmol) with NaOH (1 N) (0.72 mL, 2 equiv.) in 20 mL of MeOH for 12 hours. After cooling the mixture was poured into Hz0 (100 mL) and acidified with HCI (1 N).
Extraction with 2 x 50 mL of DCM, drying over NaZS04 and concentration in vacuo gave a residue which was recrystallized from MeOH:H20 to give the title compound (0.05 g, 24%) as white crystals.
MP: 204-205 °C.
Analysis for C~H3,N30s. 0.4H20:
Calculated: C,68.56; H,5.58; N,7.05;
Found: C,68.58; H,5.12; N,7.06%.
Example 70 (E)-3-f3-Oxo-3-f1-(3,4-methylenedioxyphenyl)-1 3 4 9-tetrahydro-(3-carboiin-2-yll-propenyllbenzoic acid The same method as employed in the preparation of Example 20 but starting from (E)-3-(2-carboxyvinyl)benzoic acid gave after recrystallization from MeOH, the title compound as a white powder in a 21 % yield.
MP: 156-158 °C.
Analysis for CZeH22N2Os. 0.8HZ0:
Calculated: C,69.93; H,4.95; N,5.83;
Found: C,69.94; H,4.62; N,5.65%.
Example 71 WO 97!43287 PCT/EP97/02277 (E)-1-f1-(3 4-Methylenedioxyphenyl)-1.3.4.9-tetrahydro-a-carbolin-2-yll-3-(3-(4-methylpiperazine-1-carbonyf )phenyl )propene-1-one The same method as employed in the preparation of Example 20 but starting from Example 70 and 4-methylpiperazine gave after recrystallization from MeOH:HzO, the title compound as a white powder in a 30% yield.
MP: 151 °C.
Analysis for C33H3zN4O4. HzO:
Calculated: C,69.95; H,6.05; N,9.89;
Found: C,69.63; H,5.93; N,9.99%.
Example 72 (E)-N-(2-Piperazin-1-ylethyl)-3-[3-oxo-3-( 1-(3.4-methylenedioxyphenyl )-1.3,4, 9-tetrahydro-Q-carbolin-2-yl)propenyllbenzamide The same method as employed in the preparation of Example 20 but starting from Example 70 and 1-(2-aminoethyl)piperazine gave after recrystallization from iPrzO, the title compound as a white powder in a 23% yield.
MP: 138-140 °C.
Analysis for C34H35NSO4. 3.1 HzO:
Calculated: C,64.46; H,6.55; N,11.05;
Found: C,64.46; H,6.25; N,11.00%.
Example 73 ~E )-4-f 3-Oxo-3-( 1-(3 4-methylenedioxyphenyl )-1, 3, 4, 9-tetrahydro-Q-carbof in-2-yl)-propenyllacetic acid ethyl ester The same method as employed in the preparation of Example 20 but starting from Intermediate 30 gave after recrystallization from DCM:pentane, the title compound as a white powder in a 17% yield.
MP: 92-95 °C.
Analysis for C3, HzeNzOs. 0.9Hz0:
Calculated: C,70.95; H,5.72; N,5.34;
Found: C,71.32; H,6.0; N,4.93%.
Example 74 (E)-1-f 1-(3 4-Methylenedioxyphenyl)-1.3,4.9-tetrahydro-t3-carbolin-2-yll-3-(3-tetrazolophenyl)propene-1-one WO 97/43287 _ The same method as employed in the preparation of Example 63 but starting from Example 67 gave after recrystallization from MeOH:HzO, the title .
compound as a white powder in a 5% yield MP: 260-264 °C.
5 Analysis for CZSHzzNs03. 2.2H20:
Calculated: C,63.43; H,5.02; N,15.85;
Found: C,63.31; H,4.37; N,15.47%.
Example 75 10 (E)-2-(3-Oxo-3-(1-(3,4-methylenedioxyphenyl)-1 3 4 9-tetrahydro-(3-carbolin-yll-propenYllbenzoicacid, methyl ester The same method as employed in the preparation of Example 20 but starting from (E)-2-(2-carboxyvinyl)benzoic acid, methyl ester (prepared according to the procedure of Alabaster, R.J.; Cottrell, I.F.; Hands, D.; Humphrey, G.R.;
15 Kennedy, D.J.; Wright, S.H.B. Synthesis 1989, 8, 598-603), gave after recrystallization from MeOH, the title compound as white crystals in a 46%
yield.
MP: 203-204 °C.
Analysis for CZ,HZ,N30s:
Calculated: C,72.49; H,5.03; N,5.83;
20 Found: C,72.59; H,5.1; N,5.67%.
Example 76 (E1-3-(3-Oxo-3-(1-(3.4-methylenedioxyphenyl)-1 3 4 9-tetrahydro-Q-carbolin-2-yll-propenyllbenzoic acid. methyl ester 25 The same method as employed in the preparation of Example 20 but starting from (E)-3-(2-carboxyvinyl)benzoicacid, methyl ester (prepared according to the procedure of Baker,S.R.; Jamieson,W.B; Todd,A. EP 134111 A1), gave after recrystallization from MeOH, the title compound as yellow crystals in a 61 yield.
30 MP: 165-167 °C.
Analysis for CZSH2aNzOs:
Calculated: C,72.49; H,5.03; N,5.83.;
Found: C,72.53; H,5.02; N,5.93%.
35 Example 77 (E)-1-(4-f3-Oxo-3-(1-(3.4-methylenedioxyphenyl)-1,3.4.9-tetrahydro-~-carbolin-2-yl)-propenyllphenyl)piperidine-4-carboxylic acid, ethyl ester The same method as employed in the preparation of Example 20 but starting from Intermediate 31 gave after recrystallization from MeOH, the title compound as yellow crystals in a 45% yield.
MP: 175 °C.
Analyses for C3sHssNsOs.
Calculated: C,72.77; H,6.11; N,7.27;
Found: C,72.99; H,6.16; N,7.03%.
Example 78 (E)-N-(1-Ethylpyrrolidin-2-yl-methyl)-3-f3-oxo-3-(1-(3,4-methylenedioxyphenyl)-1.3.4.9-tetrahydro-Q-carbolin-2-yl)propenyllbenzamide The same method as employed in the preparation of Example 20 but starting from Example 70 and 2-pyrrolidin-1-ylethyiamine gave after recrystallization from iPr20, the title compound as a white powder in a 53% yield.
MP: 128-130 °C.
Analysis for C35H36N404~
Calculated: C,72.9; H,6.29; N,9.72;
Found: C,72.9; H,6.42; N,10.01%.
Example 79 (E)-1-f 1-(3.4-Methylenedioxyphenyl)-1.3.4,9-tetrahydro-~-carbolin-2-yll-3-(3-(2-dimethylaminoethoxy)phenyl)propene-1-one To a solution of Example 58 (0.25 g, 0.57 mmol) in 50 mL of DMF was added KzCOs {0.24 g, 3 equiv.) and an excess of dimethylaminodiethyl chloride (about 15 equiv.). The resulting mixture was heated at 60 °C for four hours until disappearance of the starting material (tlc monitoring, DCM:MeOH (90:10). A
new compound was formed (Rf= 0.20). After evaporation of DMF, the residue was taken up in 150 mL of DCM, washed with 2x50 mL of water, dried over NazSOa and recrystallized from EtOH:HzO.to give the title compound (0.06 g, . 22%) as yellow crystals.
MP: 76-78 °C.
Analysis for C3,H3,N3O4. 0.6Hz0:
Calculated: C,71.55; H,6.24; N,8.07;
WO 97/43287 , Found: C,71.34; H,6.45; N,7.8%.
Example 80 (E)-1-(1-(3,4-Methyienedioxyphenyl)-1,3,4.9-tetrahydro-Q-carbolin-2-yll-3-(3.5-diterbutyl-4-hydroxypheny~propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3,5-ditertbutyl-4-hydroxycinnamic acid gave after recrystallization from cyclohexane, the title compound as yellow crystals in a 45% yield.
MP: 137 °C.
Example 81 (E)-3-f3-Oxo-3-(1-(4-methoxycarbonylphenyl)-1.3 4.9-tetrahydro-Q-carbolin-2-yllpropenyllbenzoic acid. methyl ester The same method as employed in the preparation of Example 20 but starting from Intermediate 8 and (E)-3-{2-carboxy-vinyl)benzoic acid, methyl ester (prepared according to the procedure of Baker,S.R.; Jamieson,W.B; Todd,A. EP
134111 A1 ), gave after recrystallization from 2-propanol, the title compound as white crystals in a 70% yield.
MP: 182 °C.
Analysis for CsoHzsN20s:
Calculated: C,72.86; H,5.3; N,5.66;
Found: C,72.49 ; H,5.31 ; N,5.68%.
Example 82 (E)-2-f3-Oxo-3-f1-(3,4-methylenedioxyphenyl)-1.3 4 9-tetrahydro-Q-carbolin-2-yll-propenyllbenzoic acid The same method as employed in the preparation of Example 31 but starting from Example 75 gave after recrystallization from MeOH the title compound as off-white crystals in a 78% yield.
MP: 174 °C.
Analysis for CzeHZ2N205:
Calculated: C,72.09; H,4.75; N,6.01;
Found: C,72.53; H,4.72; N,5.76%.
Example 83 (E) (4 f3 Oxo-3-(1-(3 4-methylenedioxyphenyl)-1 3.4.9-tetrahydro-~-carbolin-2-1 mr~penyllphenoxy)acetic acid. ethyl ester The same method as employed in the preparation of Example 79 but starting from Example 22 and bromoacetic acid, ethyl ester, gave after recrystallization from EtOH:2-propanol the title compound as yellow crystals in a 28% yield.
MP: 99-98 °C.
Analysis for Cs,H2sNzOs. 2.4Hz0:
Calculated: C,65.57; H,5.82; N,4.93;
Found: C,65.34; H,5.4; N,5.09%.
Example 84 (El (4 (3 Oxo-3-(1-(3 4-methylenedioxyphenyl)-1 3 4 9-tetrahydro-(3-carbolin-2-yl)-propenyllphenyl)acetic acid The same method as employed in the preparation of Example 31 but starting from a solution of Example 73 in EtOH gave after recrystallization from iPrz0:2-propanol the title compound as white crystals in a 51 % yield.
MP: 231 °C.
Analysis for CzgH24N2O5~ 0.25iPrOH:
Calculated: C, 72.11; H, 5.29; N,5.64;
Found: C, 71.9; H, 5.15; N, 5.74%.
Example 85 (E)-(4-(3-Oxo-3-(1-(3 4-methylenedioxyphenyl)-1 3 4.9-tetrahydro-(3-carbolin-2-yl)propenyllphenoxy)acetic acid The same method as employed in the preparation of Example 31 but starting from Example 83 gave after recrystallization from iPr20:2-propanol the title compound as yellow crystals in a 45% yield.
MP: 158-160 °C.
Analysis for CzsHzaN20s . 0.9HzO:
Calculated: C,67.93; H,5.07; N,5.46;
Found: C,68.0; H,4.86; N,5.21 %.
Example 86 (E)-1-f1-(3 4-Methylenedioxyphenyl)-1.3 4.9-tetrahydro-~-carbolin-2-yll-3-(3-nitro-4-chlorophenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3-vitro-4-chlorocinnamic acid gave after recrystallization from EtOH
the title compound as yellow crystals in a 56% yield.
MP: 240 °C.
Analysis for CZ,HZON30sCl:
Calculated: C,64.61; H,4.02; N,8.37;
Found: C,64.5; H,3.97; N,8.28%.
Example 87 (E)-1-f1-(3,4-Methylenedioxyphenyl)-1 3 4 9-tetrahydro-Q-carbolin-2-yll-3-(5 vitro-2-chlorophenyl )propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-5-vitro-2-chiorocinnamic acid gave after recrystallization from EtOH:H20 the title compound as yellow crystals in a 44% yield.
MP: 146 °C.
Analysis for C2,HzoN3OsCl. 0.1 H20:
Calculated: C,64.38; H,4.04; N,8.34;
Found: C,64.12; H,3.81; N,8.35%.
Example 88 (E)-3-Chioro-4-f3-oxo-3-f1-(3 4-methylenedioxyphenyl)-1 3 4 9-tetrahydro-a carbolin-2-ylipropenyllbenzoic acid. methyl ester The same method as employed in the preparation of Example 20 but starting from intermediate 32 gave after recrystallization from EtOH the title compound as a white powder in a 57% yield.
MP: 166 °C.
Analysis for CzsH23N205C1. 0.15EtOH:
Calculated: C,67.43; H,4.62; N,5.37;
Found: C,67.09; H,4.56; N,5.51 %.
Example 89 . (E)-(4-f3-Oxo-3-(1-(3.4-methylenedioxyphenyl)-1 3 4 9-tetrahydro-(~-carbolin y~propenyllbenzyloxy)acetic acid The same method as employed in the preparation of Example 79 but starting from a solution of (E)-(4-(3-oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-~3-carbolin-2-yl)propenyl]benzyloxy)acetic acid, ethyl ester in EtOH
gave after recrystallization from MeOH:HzO the title compound as an off-white solid in a 40% yield.
MP: 162-163 °C.
5 Analysis for C3oHzsN20s. 0.1 H20:
Calculated: C,68.17; H,5.13; N,5.49;
Found: C,68.16; H,5.46; N,5.51 %.
(E)-(4-[3-Oxo-3-(1-(3,4-methyienedioxyphenyl}-1,3,4,9-tetrahydro-[3-carbolin-2-10 yl)propenyl]benzyloxy)acetic acid, ethyl ester:
To a solution of Example 39 (0.7 g, 1.5 mmol) in 50 mL of DMF was added KzC03 (0.25 g, 1.2 equiv.) and ethylbromoacetate (0.2 mL, 1.1 equiv.). The resulting mixture was heated at 60 °C for 16 hours until disappearance of the starting material (tlc monitoring, DCM:MeOH (95:5)) A new compound was 15 formed (Rf= 0.8). After evaporation of DMF, the residue was taken up in 150 mL
of DCM, washed with 2x50 mL of water, dried over Na2S04 and purified via radial chromatography with DCM to give the title compound (0.85 g, 11 %) as a white powder.
1 H NMR (CDC13) b 7.8-6.65 (m, 14H), 5.9 (s, 2H), 4.7 (s, 2H), 4.6-4.3 (q, 2H), 20 4.2-4.0 (m, 4H), 3.6-3.5 (m, 1 H), 3.2-2.9 (m, 2H), 1.3-1.2 (t, 3H).
Example 90 (El-1-(1-(3,4-Methylenedioxyphenyl)-1.3,4,9-tetrahydro-(3-carbolin-2-yl1-3-(5-amino-2-chforophenyl)propene-1-one 25 The same method as employed in the preparation of Example 64 but starting from Example 87 gave after recrystallization from EtOH:DCM, the title compound as a white powder in a 17% yield.
MP: 251-252 °C.
Analysis for Cz~HZ~CIN303. 0.4Hz0:
30 Calculated: C,67.68; H,4.8; N,8.77;
Found: C,67.71; H.4.73; N,8.65%.
Example 91 (E)-3-Chloro-4-(3-oxo-3-(1-(3.4-methylenedioxyphenyl)-1.3.4.9-tetrahydro-(i-35 carbolin-2-yllpropenyllbenzoic acid The same method as employed in the preparation of Example 31 but starting from Example 88 gave after recrystallization from 2-propanol the title compound as a yellow powder in a 40% yield.
MP: 169 °C.
Analysis for C28H2, NZOS. HzO:
Calculated: C,64.8; H,4.47; N,5.40;
Found: C,64.47; H,4.13; N,5.60%.
Example 92 (E)-1-(1-(3.4-Methylenedioxyphenyl)-1.3 4.9-tetrahydro-a-carbolin-2-yll-3-(3 5-dibromo-4-hydroxyphenyt)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3,5-dibromo-4-hydroxy cinnamic acid gave after recrystallization from EtOH: H20 the title compound as white crystals in a 13% yield.
MP: 148-150 °C.
Analysis for C2,HzoNZOaBr2. 1.6EtOH:
Calculated: C,54.14; H,4.45; N,4.18;
Found: C,54.1; H,4.15; N,3.77%.
Example 93 (E)-1-(1-(3,4-Methylenedioxyphenyl)-1.3 4.9-tetrahydro-(3-carbolin-2-yl1-3-(4-(2-dimethylaminopropoxy)phenyl)propene-1-one The same method as employed in the preparation of Example 79 but starting from Example 22 and dimethylaminopropyl chloride gave after recrystallization from cyclohexane:DCM:pentane the title compound as white crystals in a 16%
yield.
MP: 106 °C.
Analysis for C32H33N3O4. 0.3Hz0:
Calculated: C,72.65; H,6.40; N,7.94;
Found: C,72.74 ; H,6.56; N,7.63%.
Example 94 (E)-2-Chloro-5-(3-oxo-3-(1-(3.4-methylenedioxyphenyl)-1 3 4 9-tetrahydro-a-carbolin-2-ytlpropenyllbenzoic acid. methy~ ester The same method as employed in the preparation of Example 20 but starting from Intermediate 33 gave after recrystallization from MeOH:DCM the title compound as a white powder in a 59% yield.
MP: 228 °C.
Analysis for CzsH23CIN20s. 1.05Hz0:
Calculated: C,65.24; H,4.74; N,5.25;
Found: C,64.91; H,4.27; N,5.13%.
Example 95 (E)-1-f1-(3 4-Methylenedioxyphenyl)-1.3,4.9-tetrahydro-a-carbolin-2-yll-3-(4-(2-diisopropylaminoethoxy)phenyl)propene-1-one The same method as employed in the preparation of Example 79 but starting from Example 22 and diisopropylaminodiethyl chloride gave after recrystallization from MeOH:H20 the title compound as pale yellow crystals in a 12% yield.
MP: 92-93 °C.
Analysis for C35H39N3O4:
Calculated: C,74.31; H,6.95; N,7.43;
Found: C,74.34; H,7.16; N,7.10%.
Example 96 ( E)-2-Chloro-5-(3-oxo-3-f 1-(3.4-methylened ioxyphenyl )-1, 3, 4.9-tetrahydro-[i-carbolin-2-yllpropenyl)benzoic acid The same method as employed in the preparation of Example 31 but starting from Example 94 gave after recrystalfization from MeOH the title compound as white crystals in a 78% yield.
MP: 178 °C.
Analysis for C2gH2~N2O5. 0.7Me0H:
Calculated: C,65.86; H,4.58; N,5.35;
Found: C, 65.73 ; H, 4.44 ; N, 5.51 %.
Example 97 (E)-1- 1-(3 4-Methylenedioxyphenyl)-1.3,4.9-tetrahydro-Q-carbolin-2-yll-3-(3-hydroxy-4-nitrophenyl)propene-1-one WO 97/43287 _ The same method as employed in the preparation of Example 20 but starting from Intermediate 34 gave after recrystallization from EtOH the title compound as yellow crystals in a 77% yield.
MP: 172 °C.
Example 98 (E)-1-(1-(3,4-Methylenedioxyphenyl)-1 3 4 9-tetrahydro-Q-carbolin-2-yll-3 (3 5 dimethyl-4-hydroxyphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 35 gave after recrystallization from MeOH:H20 the title compound as a white powder in a 71 % yield.
MP: 151-152 °C.
Analysis for Cz9H26Nz04. 0.4H20:
Calculated: C,73.52; H,5.7; N,5.91;
Found: C,73.56; H,5.59; N 6.29%.
Example 99 (E)-1-11-(3.4-Methylenedioxyphenyl)-1.3 4 9-tetrahydro-(3-carbolin-2-yll-3-(3 (2 dimethylaminoethoxy)-4-nitrophenyl)propene-1-on_e The same method as employed in the preparation of Example 79 but starting from Example 97 and dimethylaminodiethyl chloride gave after recrystallization from MeOH the title compound as a pale yellow powder in a 18% yield.
MP: 189 °C.
Analysis for Cs,H3oN40s. 1.5H20:
Calculated: C,64.02; H,5.72; N,9.63;
Found: C,64.18; H,5.41; N,9.21%.
Example 100 (E)-1-(1-(3.4-Methylenedioxyphenyl)-1 3 4 9-tetrahydro-Q-carbolin-2-yll 3 (3 (2 dimethyiaminoethoxy)-4-aminophenyl)propene-1-one The same method as employed in the preparation of Example 64 but starting from Example 99 gave after recrystallization from iPrzO the title compound as a pale yellow powder in a 17% yield.
MP: 143 °C.
Analysis for C3,H3zN4O4. 0.5H20:
Calculated: C,69.78 ;H,6.23; N,10.5;
Found: C,69.87; H,5.98; N,10.42%.
Example 101 (E)-1-f1-(34-Methylenedioxyphenyl)-1.3.4.9-tetrahydro-t3-carbolin-2-yll-3-(3-nitro-4-hydroxy-5-methoxyphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from intermediate 36 gave after recrystallization from EtOH:DCM the title compound as pale yellow crystals in a 45% yield.
MP: 172 °C.
Analysis for CzeH23N3O,. 0.8H20:
Calculated: C,63.7; H,4.7; N,7.96;
Found: C,63.71; H,4.31; N,7.98%.
Example 102 (E)-1-f1-(3 4-Methylenedioxyphenyl)-1.3.4 9-tetrahydro-(i-carbolin-2-yll-3-(3-chloro-phenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3-chlorocinnamic acid, gave after recrystallization from EtOH the title compound as white crystals in a 48% yield.
MP: 212-213 °C.
Analysis for Cz~H2,CINzO:
Calculated: C,70.97; H,4.63; N,6.13 Found: C,70.65; H,4.63; N,6.16%.
Example 103 (E)-1-(1-(4-Methoxy-phenyl)-1 3 4,9-tetrahydro-t3-carbolin-2-yll-3-(2-chloro-5-nitrophenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 2 and (E)-2-chloro-5-nitrocinnamic acid gave after recrystallization from 2-propanoi the title compound as a yellow powder white in a 18% yield.
MP: 136-138 °C.
Analysis for CZ~HZZCIN304. 0.2Hz0:
Calculated: C,65.98; H,4.59; N,8.55;
Found: C,65.91; H,4.4; N,8.42%.
Example 104 (E)-1-(1-(3.4-Methylenedioxyphenyl)-1,3.4,9-tetrahydro-(3-carbolin-2-yll-3-(2 5 dichlorophenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-2,6-dichlorocinnamic acid gave after recrystallization from cyclohexane the title compound as a white powder in a 41 % yield.
MP: 118-120 °C.
10 Analysis for CZ,HzoCIzN203. 0.2HZ0:
Calculated: C,65.52; H,4.15; N,5.66;
Found: C,65.74; H,4.62; N,5.29%.
Example 105 15 (E)-1-f1-(3.4-Methylenedioxyphenyl)-1349-tetrahydro-(3-carboiin-2-yll-3-(4-methylaminomethylphenyl)propene-1-one A solution of (E)-1-[1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-[3-carbolin-2-yl)-3-(4-methyiiminomethylphenyl)propene-1-one (0.46 g, 1.1 mmol), NaBH3CN (0.14 g, 2.3 mmol) and acetic acid (0.11 mL) in 20 mL of MeOH was 20 stirred at rt for one hour. The reaction mixture was quenched with 50 mL of an aqueous saturated solution of NaHC03. Extraction with 2x30 mL of DCM, washing with brine, drying over NazS04 and concentration in vacuo gave a residue that was purified via flash chromatography of silica gel using DCM:MeOH (97:3) as eluting solvent. Recrystallization from DCM:cyclohexane 25 gave the title compound (0.05 g, 10%) as a white powder.
MP: 201 °C.
Analysis for Cz9HZ,CI2N303. 0.5Hz0:
Calculated: C,73.4; H,5.95; N,8.85;
Found: C,73.66; H,5.82; N,8.57%.
30 A stirred solution of Example 23 (0.5 g, 1.0 mmol) in MeOH was refluxed with methylamine (1.6 mL, 1.5 equiv., 33% in EtOH) for one hour. Evaporation in . vacuo gave (E)-1-[1-(3,4-methylenedioxyphenyl}-1,3,4,9-tetrahydro-~-carbolin-2-yl]-3-(4-methyliminomethylphenyl)propene-1-one (0.46 g, 90%).
'H NMR (CDC13, 250 MHz) 8 8.2 (d, 1 H), 8.1 (s, 1 H), 7.8-7.65 (m, 3H), 7.55-7.5 (m, 3H), 7.4-7.1 (m, 3H), 7.0-6.85 (m, 2H), 6.8-6.6 (dd, 2H), 5.9 (s, 2H), 4.2-(br d, 1 H), 3.5 (s+m, 4H), 3.05-2.85 (m, 2H).
Example 106 ~E)-1-f1-(3 4-Methylenedioxyphenyi)-1.3.4,9-tetrahydro-(i-carbolin-2-yll-3-(3-_methylphenyl)-propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3-methylcinnamic acid gave after recrystallization from MeOH the title compound as a white powder in a 67% yield.
MP: 196 °C.
Analysis for CZaHzaN203:
Calculated: C,77.04; H,5.54; N,6.62;
Found: C,76.76; H,5.56; N,6.33%.
Example 107 (E)-N-Methyl-(4-(3-oxo-3-(1-(3.4-methylenedioxyphenyl)-1.3.4.9-tetrahydro-Q-carbolin-2-yl)propenyllbenzenesulfonamide The same method as employed in the preparation of Example 20 but starting from (E)-4-(N-methylsulfonamide)cinnamic acid gave after recrystallization from EtOH:H20 the title compound as white crystals in a 79% yield.
MP: 162 °C.
Analysis for C28HZSN30s. 0.4EtOH:
Calculated: C,64.78; H,5.17; N,7.87;
Found: C,64.46; H,4.82; N,7.76%.
Example 108 ~E)-1-f1-(3 4-Methylenedioxyphenyl)-1,3,4.9-tetrahydro-p-carbolin-2-yll-3-(3-hydroxy-4-acetylphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-3-hydroxy-4-acetylcinnamic acid gave after recrystaliization from EtOH
the title compound as yellow crystals in a 87% yield.
MP: 217-218 °C.
Analysis for CZSHzaNz05:
Calculated: C,72.49; H,5.03; N,5.83:
Found: C,72.24; H,5.25; N,5.53%.
Example 109 (E)-1-f 1-(2.3-Dihydrobenzofuran-5-yl)-1.3.4.9-tetrahydro-f3-carbolin-2-yll-3-(2-chloro-5-nitrophenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 10 and (E)-2-chloro-5-nitrocinnamic acid gave after recrystallization from EtOH:H20 (95:5) the title compound as yellow crystals in a 62% yield.
MP: 154 °C.
Analysis for CZ~H22CIN3O4. 0.5(HzO:MeOH):
Calculated: C,66.08; H,4.55; N,8.36;
Found: C,66.3; H,4.52; N,7.94%.
Example 110 ~E)-1-f 1-(3.4-Methylenedioxyphenyl)-1.3,4.9-tetrahydro-Q-carbolin-2-yll-3-(2-h~droxyphenyi)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-2-hydroxy cinnamic acid gave after recrystallization from EtOH:HzO, the title compound as white crystals in a 47% yield;
MP: 154 °C.
Analysis for CZ,H2zN204. 0.6H20:
Calculated: C,72.18; H,5.2; N,6.24;
Found: C,72.19; H,4.93; N,6.13%.
Example 111 (E)-1-f 1-(3,4-Methylenedioxyphenyl )-1.3.4, 9-tetrahydro-(3-carbol in-2-yll-3-(3-nitro-2-piperidin-1-ylphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 37 gave after recrystallization from MeOH the title compound as yellow crystals in a 31 % yield.
MP: 162-163 °C.
Analysis for C32H3oN4O$. 0.2H20:
Calculated: C,65.52; H,5.84; N,9.55;
Found: C,65.9; H,5.49; N,9.59%.
Example 112 (E?-1-f1-(2 3-Dihydrobenzofuran-5-yll-1,3.4.9-tetrahydro-~-carbolin-2-yll-3-phenylpropene-1-one The same method as employed in the preparation of Example 1 but starting from Intermediate 10 gave after recrystallization from EtOH the title compound as white crystals in a 52% yield.
MP: 190 °C.
Analysis for Cz8Hz4N202:
Calculated: C,79.98; H,5.75; N,6.66;
Found: C,79.94; H.5.86; N,6.62%.
Example 113 ~E)-1-f 1-(4-Isopropyiphenyl)-1.3,4.9-tetrahydro-~-carbolin-2-yll-3-(3-nitrophenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from intermediate 11 and (E)-3-nitrocinnamic acid gave after recrystallization from EtOH the title compound as yellow crystals in a 54% yield.
MP: 195 °C.
Analysis for CzsH2,N303:
Calculated: C,74.82; H,5.85; N,9.03;
Found: C,74.43; H.5.84; N,9.17%.
Example 114 (E)-1-(1-(2 3-Dihydrobenzofuran-5-yl)-1.3,4,9-tetrahydro-~-carbolin-2-yl]-3-(3-nitrophenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 10 and (E)-3-nitrocinnamic acid gave after recrystallization from EtOH the title compound as white crystals in a 35% yield.
MP: 174-176 °C.
Analysis for CzgH2~N3O4. 0.1 HzO:
Calculated: C,71.97; H,5.0; N,8.99;
Found: C,71.78; H.4.89; N,8.83%.
Example 115 E)-(R)-1-(1-(3,4-Methylenedioxyphenyl)-1.3.4.9-tetrahydro-!3-carbolin-2-yll-3-~henylpropene-1-one The same method as employed in the preparation of Example 1 but starting from Intermediate 19 gave after recrystallization from EtOH the title compound as white crystals in a 60% yield.
MP: 232-233 °C.
Analysis for Cz,HzZN203. 0.2H20:
Calculated: C,76.11; H,5.3; N,6.57;
Found: C,76.2; H,5.27; N,6.77%
[a]pz' _ -336 (c = 0.50, MeOH).
Example 116 (E)-(S)-1-(1-(3.4-Methylenedioxyphenyl)-1.3.4.9-tetrahydro-(i-carbolin-2-yll-3-phenylpropene-1-one The same method as employed in the preparation of Example 1 but starting from Intermediate 18 gave after recrystallization from iPrOH the title compound as white crystals in a 32% yield.
MP: 235-236 °C.
Analysis for Cz7H22NzO3. 0.1 H20:
Calculated: C,76.43; H,5.27; N,6.6;
Found: C,76.26; H,5.21; N,6.61 %.
(a]p2' = 378 (c = 0.5, MeOH).
Example 117 (E)-1-(1-(4-Methoxyphenyl)-1.3.4 9-tetrahydro-(i-carbolin-2-yll-3(3-nitrophenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 2 and (E)-3-nitrocinnamic acid gave after recrystallization from EtOH the title compound as yellow crystals in a 63% yield.
MP: 227 °C.
Analysis for Cz,H23N3O4. 0.1 EtOH:
Calculated: C,71.32; H,5.19; N,9.17;
Found: C,70.96; H,5.14; N,9.23%.
Example 118 ~I~-1-j,1-~4-Met nhen~!~~-1.3.4_9-tetra,~dro-Q-carbolin-2-yu-~-t2-rhloro-5-nitrqBhen~J)~oene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 6 and (E}-2-chloro-5-nitrocinnamic acid gave after 5 recrystallization from EtOH the title compound as a yellow powder in a 57%
yield.
MP: 211-213 °C.
Analysis for Cz,H23CINa03:
Calculated: : C,68.72; H,4.7; N,8.9;
10 Found: C,68.42; H,4.73; N,8.91 %.
Example119 E -N- Tetrah drof ran-2- Im h I -3- o- - 1- 4-m h tetrahydro-f3-carbolin-2-ylloropeny~benzamide 15 The same method as employed in the preparation of Example 20 but starting from Example 70 and tetrahydrofurfurylamine gave after recrystallization from EtOH the title compound as a white powder in a 30% yield.
MP: 172-173 °C.
Analysis for Cg3H3~ N3O5. 0.4H20:
20 Calculated: C,71.18; H,5.76; N,7.55;
Found: C,71.1; H,5.88; N,7.45%.
Example 120 E -1- 1- n -5-25 The same method as employed in the preparation of Example 1 but starting from intermediate 9 and tetrahydrofurfurylamine gave after recrystallization from EtOH the title compound as white crystals in a 51 % yield.
MP: 223 °C.
Analysis far CZ9HzBN20. 0.4H20:
30 Calculated: C,81.81; H,6.34; N,6.58;
Found: C,81.87; H,6.34; N,6.5%.
Example 121 35 ~ ~I~henvlyaropene-1-one 8s The same method as employed in the preparation of Example 20 but starting from 3-acetylcinnamic acid (prepared according to the procedure of Cleland,G.H. J. Org. Chem. 19fi9, 34, 744-747) gave after recrystallization from EtOH the title compound as a yellow powder in a 42% yield.
MP: 191 °C.
Analysis for CzsH24CIN20a:
Calculated: C,74.98; H,5.21; N,6.03;
Found: C,74.85; H,5.28; N,6.1 %.
Example 122 (E )-1-( 1-(2.3-Dihydrobenzofuran-5-yl )-1.3.4, 9-tetrahydro-(3-carbol i n-2-y( )1-3-(4--dimethylaminoethoxylphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 10 and Intermediate 25 gave after recrystallization from CH3CN the title compound as white crystals in a 37% yield.
MP: 146 °C.
Analysis for C3zH3sN3Os. 1.5H20:
Calculated: C,71.89; H,6.79; N,7.86;
Found: C,72.04; H,7.09; N,7.93%.
Example 123 ~E)-4-f 3-Oxo-3-(1-(4-methoxypheny!)-1,3,4, 9-tetrahydro-~-carbolin-2-yllpropenyllbenzoic acid, methyl ester The same method as employed in the preparation of Example 20 but starting from Intermediate 2 and (E)-4-(2-carboxyvinyl)benzoic acid, methyl ester gave after recrystallization from EtOH the title compound as yellow crystals in a 73%
yield.
MP: 189 °C.
Analysis for CZSH2sNz04. 0.1 EtOH:
Calculated: C,74.44; H,5.69; N,5.95;
Found: C,74.1; H, 5.65; N,6.01 %.
Example 124 (E)-1-(1-(3, 4-Methylenedioxyphenyl )-1.3.4, 9-tetrahydro-Q-carbol in-2-yl)-3-(4-methyl-3.4-dihydro-2H-benzof 1,4loxazin-6-yl)propene-1-one WO 97!43287 PCT/EP97/02277 The same method as employed in the preparation of Example 20 but starting from Intermediate 38 gave after recrystallization from EtOH the title compound as yellow crystals in a 69% yield.
MP: 231-232 °C.
Analysis for C2sHz6NzO4. 0.1 EtOH:
Calculated: C,73.01; H,5.51; N, 8.51;
Found: C,72.54; H,5.58; N,8.44%.
Example 125 (E)-1-(1-(3 4-Methylenedioxyphenyl)-1.3.4.9-tetrahydro-Q-carbalin-2-yll-3-(2-hydroxy-5-nitrophenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 39 gave after recrystallization from EtOH the title compound as yellow crystals in a 30% yield.
MP: 205 °C.
Analysis for Cz,HZ,N30s. 0.6EtOH:
Calculated: C,65.78; H,5.14; N,7.94;
Found: C,65.52; H,4.98; N,8.04%.
Example 126 (E)-~-f 3-Oxo-3-f 1-(2.3-dihydrobenzofuran-5-yl )-1. 3,4.9-tetrahydro-8-carbol in-2-yllpropenyllbenzoic acid, methyl ester The same method as employed in the preparation of Example 20 but starting from Intermediate 10 and (E)-4-(2-carboxyvinyl)benzoic acid, methyl ester gave after recrystallization from EtOH the title compound as white needles in a 88%
yield.
MP: 186 °C.
Analysis for CsoHzsNz04. 0.2H20:
Calculated: C,74.73; H,5.52; N,5.81;
Found: C,75.45; H, 5.38; N,6.07%.
Example 127 ( E)-4-f3-Oxo-3-( 1-(4-methoxyphenyl )-1.3.4.9-tetrahydro-!3-carbolin-2-yllpropenyllbenzoic acid The same method as employed in the preparation of Example 31 but starting from Example 123 gave after recrystallization from MeOH: H20 the title compound as a grey powder in a 43% yield.
MP: 147-149 °C.
Analysis for CZ8H24N2O4:
Calculated: C,74.32; H,5.35; N,6.19;
Found: C,74.3; H,5.37; N,6.07%.
Example 128 (E)-4-(3-Oxo-3-(1-(2,3-dihydrobenzofuran-5-yl)-1 3.4 9-tetrahydro->3-carbolin-yllpropenyllbenzoic acid The same method as employed in the preparation of Example 31 but starting from Example 126 gave after recrystallization from MeOH the title compound as white crystals in a 53% yield.
MP: 222-224 °C.
Analysis for C29Hz4Nz04:
Calculated: C,74.98; H,5.21; N,6.03;
Found: C,75.21; H,5.3; N,6.21 %.
Example 129 (E)-1-f 1-(Benzofuran-5-yi)-1.3.4.9-tetrahydro-Q-carbolin-2-yll-3-phenylpropene-1-one The same method as employed in the preparation of Example 1 but starting from Intermediate 12 gave after recrystallization from EtOH the title compound as white crystals in a 35% yield.
MP: 241-242 °C.
Analysis for CZ8H22N20z:
Calculated: C,80.36; H,5.3; N,6.69;
Found: C,80.44; H,5.3; N,6.89%.
Example 130 (E)-3-f3-Oxo-3-(1-(3,4-methylenedioxyphenyl)-1 3 4 9-tetrahydro-Q-carbolin-2-~~-propenyllphenyl)trifluoromethanesuffonic acid phenyl ester The same method as employed in the preparation of Example 20 but starting from Intermediate 40 gave after recrystallization from EtOH the title compound as white crystals in a 38% yield.
MP: 169 °C.
Analysis for CzsHz,FsNzOsS. 0.2HzO:
Calculated: C,58.58; H,3.76; N,4.88;
Found: C,58.84; H,3.71; N,4.3%.
Example 131 (E)-1-[1-(3 4-Methylenedioxyphenyl)-1,3,4.9-tetrahydro-Q-carbolin-2-yll-3-[4-(2-hydroxyethoxylphenyllpropene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-4-(2-hydroxyethoxy)phenyf (prepared according to the procedure of Oku,T.; Kayakiri,H.; Satoh,S.; Abe,Y.; Sawada,Y.; Inoue,T.; Tanaka,H.; EP
622361 ) gave after recrystallization from EtOH the title compound as white crystals in a 57% yield.
MP: 136 °C.
Analysis for CzsHzsNzOs. 1.2EtOH:
Calculated: C,58.58; H,3.76; N,4.88;
Found: C,58.84; H,3.71; N,4.3%.
Example 132 ~E)-1-[1-(Benzofuran-5-yl-1 3 4 9-tetrahydro-Q-carbolin-2-yl)1-3-(4-(2-_dimethylaminoethoxy)phenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 12 and Intermediate 25 gave after recrystallization from CH3CN the title compound as white crystals in a 23% yield.
MP: 159 °C.
Analysis for C32H3~N3O3. 0.1 HzO:
Calculated: C,75.75; H,6.2; N,8.28;
Found: C,75.58; H,5.97; N,8.35%.
Example 133 (E)-1-[1-(3 4-Methylenedioxyphenyl)-1.3.4.9-tetrahydro-f~-carbolin-2-yll-3-(2-dimethylaminophenyl)propene-1-one WO 97!43287 PCT/EP97/02277 The same method as employed in the preparation of Example 20 but starting from (E)-2-dimethylaminocinnamic acid (prepared according to the procedure of Suschitzky,H.; Hollywood,F. Synthesis 1982, 662-665) gave after recrystallization from MeOH:H20 the title compound as a yellow powder in a 5 51 % yield.
MP: 172 °C.
Analysis for C29H2,N3O3:
Calculated: C,74.82; H,5.85; N,9.03;
Found: C,74.75; H,5.85; N,8.9%.
Example 134 (E)-1-(1-(3,4-Methylenedioxyphenyl)-1,3.4.9-tetrahydro-Q-carbolin-2-yl1-3-f2 piperidin-1-ylphenyi)propene-1-one The same method as employed in the preparation of Example 20 but starting from (E)-2-piperidin-1-ylcinnamic acid (prepared according to the procedure of Suschitzky,H.; Hollywood,F. Synthesis 1982, 662-665) gave after recrystallization from MeOH:HzO the title compound as a yellow powder in a 37% yield.
MP: 129 °C.
Analysis for Cs2H3,N3O3:
Calculated: C,76.02; H,6.18; N,8.31;
Found: C,75.66; H,6.18; N,8.29%.
Example 135 (E)-4-(3-Oxo-3-(1-(benzofuran-5-yl-1.3.4.9-tetrahydro-~-carbolin-2-y11-propenyll-benzoic acid. methyl ester The same method as employed in the preparation of Example 20 but starting from Intermediate 12 and (E)-4-(2-carboxyvinyl)benzoic acid methyl ester gave after recrystallization from EtOH the title compound as yellow crystals in a 76%
yield.
MP: 221 °C.
Analysis for C3oHz4Nz04:
Calculated: C,75.62; H,5.08; N,5.88;
Found: C,75.75; H,5.31; N,5.86%.
Example 136 (E)-4 f3 (1-Benzofuran-5-yl-1 3 4 9-tetrahydro-Q-carbolin-2-yll-3-oxo-propenvl~-benzoic acid The same' method as employed in the preparation of Example 31 but starting from Example 135 gave after recrystallization from CH3CN the title compound as yellow crystals in a 66% yield.
MP: 283 °C.
Analysis for C2sHz2NzOa. 0.6H20:
Calculated: C,73.59; H,4.94; N,5.92;
Found: C,73.48; H.4.78; N,5.93%.
Example 137 ,~E)-4 f3 Oxo-3-(1-(3 4-methylenedioxyphenyl)-1 3 4 9-tetrahydro-(i-carbolin-2-yl)propenyllphenylltrifluoromethanesulfonic acid. phenyl ester The same method as employed in the preparation of Example 20 but starting from Intermediate 41 gave after recrystallization from EtOH the title compound as white crystals in a 51 % yield.
MP: 254 °C.
Analysis for CZBH2, F3NzOsS:
Calculated: C,58.95; H,3.71; N,4.91;
Found: C,58.79; H.3.8; N,4.77%.
Example 138 (E)-1-f1-(3 4-Methvlenedioxyphenyl)-1 3 4 9-tetrahydro-l3-carbolin-2-yll-3-(2-(2-'dimethylaminoethoxy)phenyl)propene-1-one The same method as employed in the preparation of Example 79 but starting from Example 110 and dimethylaminodiethyl chloride gave after recrystallization from CH3CN:pentane the title compound as yellow crystals in a 70% yield.
MP: 131 °C.
Analysis for C3,H~,N30a. 1.3Hz0:
Calculated: C,68.95; H,6.35; N,7.88;
Found: C,69.77; H.6.28; N,7.84%.
Example 139 (El-1-f 1-(3-Fluoro-4-methoxyphenyl)-1.3.4.9-tetrahydro-a-carbolin-2-yll-3-~henylpropene-1-one The same method as employed in the preparation of Example 1 but starting from Intermediate 14 gave after recrystallization from DCM:cyclohexane the title compound as white crystals in a 66% yield.
MP: 122 °C.
Analysis for Cz,Hz3FN20z. 0.4CH2C12:
Calculated: C,71.47; H,5.21; N,6.08;
Found: C,71.46; H,5.27; N,6.12%.
Example 140 (E)-(R)-1-f 1-(2.3-Dihydrobenzofuran-5-yl)-1.3.4, 9-tetrahydro-a-carbolin-2-yl )1-3-(4-(2-dimethyiaminoethoxy)phenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and Intermediate 25 gave after recrystallization from CH3CN the title compound as white crystals in a 85% yield.
MP: 187-189 °C.
Analysis for C3zH33N3O3:
Calculated: C,75.71; H,6.55; N,8.20;
Found: C,75.60; H,6.76; N,8.10%.
[aJp2' _ -310 (c = 0.40, CHC13).
Example 141 (E)-1-(2,3-Dihydrobenzof 1.4ldioxin-6-yl)-1,3,4,9-tetrahydro-Q-carbolin-2-yl1-phenylpropene-1-one The same method as employed in the preparation of Example 1 but starting from Intermediate 13 gave after recrystailization from EtOH the title compound as white crystals in a 39% yield.
MP: 216 °C.
Analysis for CzeH24N2O3. 0.6Hz0:
Calculated: C,75.18; H,5.68; N,6.26;
. Found: C,75.17; H,5.41; N,6.4%.
Example 142 (E) 1 f1-(2 3-Dihydrobenzofuran-5-yl)-1 3 4.9-tetrahydro-l3-carbolin-2-yl)1-3-(4-~2-pyrrolidin-1-ylethoxylphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 10 and Intermediate 42 gave after recrystallization from 2-propanol:iPrzO the title compound as white crystals in a 26% yield.
MP: 152 °C.
Analysis for C~H35N3O3. 0.5Hz0:
Calculated: C,75.25; H,6.69; N,7.74;
Found: C,75.31; H,6.6; N,7.69%.
Example 143 (E)-1-f1-(3 4-Methylenedioxyphenyl)-1.3 4.9-tetrahydro-8-carbolin-2-yll-3-f4-pyrrolidin-1-ylphenyllpropene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 43 gave after recrystallization from EtOH:HzO the title compound as white crystals in a 73% yield.
MP: 154 °C.
Analysis for C3,Hz9N3O3. 0.6H20:
Calculated: C,74.11; H,6.06; N,8.36;
Found: C,74.22; H,5.97; N,7.97%.
Example 144 (E)-(R)-1-f1-(2 3-Dihydrobenzofuran-5-yl)-1,3,4.9-tetrahydro-Q-carbolin-2-yll-(3-nitrophenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and (E)-3-nitrocinnamic acid gave after recrystallization from EtOH the title compound as yellow crystals in a 51 % yield.
MP: 155 °C.
Analysis for CzeHZ3N3Oa:
Calculated: C,72.25; H,4.98; N,9.03;
Found: C,72.2; H,5.0; N,9.01 %.
[a]p'9 = -347 (c = 0.33, MeOH).
Example 145 (E)-1-f 1-(3.4-Methylenedioxyphenyl)-1.3,4.9-tetrahydro-Q-carbolin-2-yll-3-f4-imidazol-1-ylphenyllpropene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 44 gave after recrystallization from EtOH the title compound as white crystals in a 69% yield.
MP: 204 °C.
Analysis for C30H24N4O3. 0.6Hz0:
Calculated: C,72.68; H,5.04; N,11.3;
Found: C,72.67; H,4.85; N,11.34%.
Example 146 (E~-4-f3-f 1-(2,3-Dihydrobenzof 1,4ldioxin-6-yl)-1.3,4,9-tetrahydro-Q-carbolin-yll-3-oxopropenyllbenzoic acid, methyl ester The same method as employed in the preparation of Example 20 but starting from Intermediate 13 and (E)-4-(2-carboxyvinyl)benzoic acid, methyl ester gave after recrystallization from MeOH the title compound as a white powder in a 35%
yield.
MP: 136 °C.
Analysis for C3oHzsN20s. 0.1 H20:
Calculated: C,72.6; H,5.32; N, 5.64;
Found: C,72.31; H,5.26; N,5.74%.
Example 147 (E)-1-f 1-(2,3-Dih~drobenzof 1.4ldioxin-6-yl)-1,3.4,9-tetrahydro-~-carbolin-2-yll-3-(3-nitrophenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 13 and (E)-3-nitrocinnamic acid gave after recrystallization from EtOH the title compound as a pale yellow powder in a 93% yield.
MP: 154 °C.
Analysis for CZgH23N3O5. 0.6H20:
Calculated: C,68.31; H,4.95; N,8.54;
Found: C,68.41; H,4.87; N,8.61 %.
Example 148 (E) 1 (1 (2 3 Dihydrobenzo(1 4ldioxin-6-y1)-1 3 4 9-tetrahydro-Q-carbolin-2-yl)1-_3-(4-(2-dimethylaminoethoxy)phenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 13 and Intermediate 25 gave after recrystallization from 5 CH3CN the title compound as a white powder in a 65% yield.
MP: 145 °C.
Example 149 .~E) 1 f1 (3 Fluoro-4-methoxyphenyl)-1 3 4 9-tetrahydro-(3-carbolin-2-yl)1-3-(4-(2-10 dimethylaminoethoxylphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 14 and Intermediate 25 gave after recrystallization from iPr20 the title compound as a white powder in a 60% yield.
MP: 103 °C.
15 Analysis for C31H32FN3O3. 0.4Hz0:
Calculated: C,71.49; H,6.35; N,8.07;
Found: C,71.4; H,6.51; N,8.04%.
Example 150 20 (E)-4 (3 f1-(2 3-Dihydrobenzo(1 4ldioxin-6-yl)-1.3.4.9-tetrahydro-f~-carbolin-2-yll-3-oxopropenyilbenzoic acid The same method as employed in the preparation of Example 31 but starting from Example 146 gave after recrystallization from MeOH the title compound as a white powder in a 93% yield.
25 MP: 253 °C.
Analysis for C2sH24NzOs. 0.7Hz0:
Calculated: C,70.63; H,5.19; N,5.68;
Found: C,70.78; H,5.09; N,5.72%.
30 Example 151 (E) (R) 1 f1 (2 3-Dihydrobenzofuran-5-yl)-1 3 4.9-tetrahydro-13-carbolin-2-yll-phenylpropene-1-one The same method as employed in the preparation of Example 1 but starting from Intermediate 20 gave after recrystallization from MeOH the title compound as 35 white crystals in a 100% yield.
MP: 267 °C.
Analysis for CZeHzaNzOz:
Calculated: C,79.98; H,5.75; N,6.66;
Found: C,79.86; H,5.89; N,6.72%.
[a.]pz2 = -362 (c = 0.35, CHC13).
Example 152 ~E)-(S )-1-f 1-(2.3-Dihydrobenzofuran-5-yll-1.3,4.9-tetrahydro-Q-carbol i n-2-yl )1-3-l4-(2-dimethylaminoethoxy~phenvl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 21 and Intermediate 25 gave after recrystallization from CH3CN the title compound as beige crystals in a 79% yield.
MP: 153 °C.
Analysis for C32H33N3O3. 0.5Hz0:
Calculated: C, ,74.39; H,6.63; N,8.13;
Found: C,74.36; H,6.69; N,8.44%.
[a]pz' = 314 (c = 0.40, CHC13).
Example 153 (El-1-[1-f2.3-Dihydrobenzofuran-5-yl)-1,3.4,9-tetrahydro-a-carbolin-2-yll-3-(4-aminophenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 10 and (E)-4-aminocinnamic acid gave after recrystallization from iPrOH the title compound as white crystals in a 43% yield.
MP: 183 °C.
Analysis for C3pH3~N3O2. 1.6H20:
Calculated: C,76.59; H,5.83; 9.57;
Found: C,76.62; H,5.82; N,9.59%.
Example 154 ( E )-( S )-1-f 1-(2. 3-Dihydrobenzofuran-5-yl )-1, 3,4, 9-tetrahydro-(~-carbo f in-2-yll-3-phenylPropene-1-one The same method as employed in the preparation of Example 1 but starting from Intermediate 21 gave after recrystallization from EtOH the title compound as white crystals in a 98% yield.
MP: 266 °C.
Analysis for C2sH24N20z. 0.2H20:
Calculated: C,79.30; H,5.80; N,6.61;
Found: C,79.24; H,5.92; N,6.48%.
[a]p2°= 356 (c = 0.35, CHC13).
Example 155 ~E )-( S )-1-f 1-(2. 3-D i hydrobenzof ura n-5-yl )-1. 3.4. 9-tetra hydro-Q-carbo t i n-2-y I1-3-~3-nitrophenyl )propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 21 and (E)-3-nitrocinnamic acid gave after recrystallization from 2-propanol the title compound as yellow crystals in a 77% yield.
MP: 143 °C.
Analysis for C28H23N3O4. 0.3H20:
Calculated: C,71.42; H,5.05; N,8.92;
Found: C,71.51; H,4.98; N,9.23%.
[a]p'9 = 294 (c = 0.30, CHC13).
Exameie 156 ~E)-(R)-1-f 1-(2.3-Dihydrobenzofuran-5-yl)-1,3.4.9-tetrahydro-l3-carbolin-2-yl)1-3-~4-( 1-(S)-methylpyrrotidin-2-yl-methoxylphenvl )propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and Intermediate 45 gave after recrystallization from 2-propanol the title compound as white crystals in a 73% yield.
MP: 167 °C.
Analysis for C~H35N3O3:
Calculated: C,76.52; H,6.61; N,7.87;
Found: C,76.13; H, 6.71; N,7.96%.
[ac]D2° _ -344 (c = 0.30, CHC13).
Example 157 ~E)-(R)-1-f 1-(2.3-Dihydrobenzofuran-5-yl)-1.3.4.9-tetrahydro-(3-carbolin-2-yll-3-(3-hydroxyphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and (E)-3-hydroxycinnamic acid gave after recrystallization from EtOH the title compound as white crystals in a 93% yield.
MP: 251 °C.
Analysis for C28H24N2O3. 0.8Hz0:
Calculated: C,74.58; H,5.72; N,6.21;
Found: C,74.58; H,5.65; N,6.17%.
[a]p2' _ -342 (c = 0.53, CHC13).
Example 158 (E)-(R)-1-f 1-(2.3-D ihydrobenzofuran-5-yl)-1.3.4.9-tetrahydro-fi-carbolin-2-vl )1-3-~4-(2-dimethylamino-1-methylethoxy)phenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from intermediate 20 and Intermediate 46 gave after recrystallization from CH3CN the title compound as white crystals in a 100% yield.
MP: 193 °C.
Analysis for C33H35N3~3~ 0.45H20:
Calculated: C,74.82; H,6.83; N,7.93;
Found: C,74.85; H, 6.76; N,8.21 %.
Example 159 (E)-1-( 1-Phenyl-1,3.4, 9-tetrahydro-Q-carbolin-2-yl)-3-(4-(4-methylpyperazin-yl)-phenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 1 and Intermediate 47 gave after recrystallization from EtOH
the title compound as pale yellow crystals in a 26% yield.
MP: 223-226 °C.
Analysis for C32H32N4O3. 0.4H20:
Calculated: C,72.82; H,6.26; N,10.61;
Found C,72.77; H,6.31; N,10.52%.
Example 160 (E)-( R)-1-[ 1-(3,4-Methylenedioxyphenyl )-1.3.4.9-tetrahydro-!3-carbolin-2-of )1-3-(4-( 1-( S )-methylpyrrolidin-2-yl-methoxy)phenyl )propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 19 and Intermediate 45 gave after recrystallization from iPr20 the title compound as white crystals in a 83% yield.
MP: 164 °C.
Analysis for C33H33N3O4. 0.9HZ0:
Calculated: C,71.82; H,6.36; N,7.61;
Found C,72.05; H,6.57; N,7.24%.
[a]p2' _ -285 (c = 0.40, CHC13).
Example 161 (E)-(R)-1-f1-(3 4-Methylenedioxyphenyl)-1.3,4.9-tetrahydro-l3-carbolin-2-yl)1-(4-(2-dimethyiamino-1-methylethoxy)phenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 19 and Intermediate 46 gave after recrystallization from iPrzO
the title compound as white crystals in a 56% yield.
MP: 107 °C.
Analysis for C32Hs3N3O4. 0.7Hz0:
Calculated: C,71.67; H,6.47; N,7.84;
Found: C,71.6; H, 6.53; N,7.97 %.
Example 162 (E)-(R)-1-f1-(3 4-Methylenedioxyphenyl)-1,3.4.9-tetrahydro-Q-carbolin-2-yl)1-3-(4-(2-dimethylaminooropoxy)phenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 19 and Intermediate 48 gave after recrystallization from iPr20 the title compound as white crystals in a 78% yield.
MP: 193 °C.
Analysis for C32H3~N3O4. 1.6H20:
Calculated: : C,69.57; H,6.6; N,7.61;
Found: C,69.46; H. 6.59; N,7.33%.
[a]p2' _ -266 (c = 0.40, CHC13).
Example 163 (E~-4-(3-Oxo-3-(1-(3.4-fluorophenyl)-1.3.4.9-tetrahydro-(3-carbolin-2-yll-propenyllbenzoic acid. methyl ester The same method as employed in the preparation of Example 20 but starting from Intermediate 15 and (E)-4-(2-carboxyvinyl)benzoic acid, methyl ester gave after recrystallization from EtOH:H20 the title compound as a yellow powder in a 100% yield.
MP: 200 °C.
Analysis for Cz8Hz2FzN203:
Calculated: C,71.18; H,4.69; N,5.93;
Found: C,71.21; H,4.77; N,6.03%.
Example 164 (E)-(R)-(1-(2.3-Dihydrobenzofuran-5-yl)-1 3 4 9-tetrah~dro-f3-carbofin-2-yl)1-3-(4 (2-diethylaminoethoxy)phenvl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and (E)-3-(4-(2-diethylaminoethoxy)phenyl)acryfic acid (prepared according to the procedure of Sharpe,C.J.; ShaboIt.R.S.; Brown, G.R.; Ashford,A.; Ross,J.W. J. Med. Chem. 1971, 74, 836-842), gave after recrystallization from CH3CN the title compound as white crystals in a 80%
yield.
MP: 193 °C.
Analysis for C3qH37N3O3. 0.6Hz0:
Calculated: C,74.73; H,7.05; N,7.69;
Found: C,74.53; H, 6.91; N,7.68%.
[a]p2~= -311 (c = 0.30, CHC13).
Example 165 (E)-(R)-1-f1-(2.3-Dihydrobenzofuran-5-yl)-1 34 9-tetrahydro-a-carbolin-2-yl)1-(4-(2-dimethylaminopropoxy)phenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and Intermediate 48 gave after recrystallization from CH3CN the title compound as white crystals in a 79% yield.
MP: 193 °C.
Analysis for C33H35N3O3~
Calculated: C,75.98; H,6.76; N,8.06;
Found: C,76.24; H, 6.76; N,8.21 %.
[oc]p2~ _ -293 (c = 0.40, CHCl3).
Example 166 (E)-4-f3-Oxo-3-f1-(3 4-difluorophenyll-1.3.4.9-tetrahydro-l3-carbolin-2-yllpropenyllbenzoic acid The same method as employed in the preparation of Example 31 but starting from Example 163 gave after recrystalfization from MeOH:H~O the title compound as a white powder in a 100% yield.
MP: 172 °C.
Analysis for CZ~HZOF2Nz03:
Calculated: C,68.06; H,4.65; N,5.88;
Found: C,68.15; H,4.55; N,5.99%.
Example 167 (E)-(R)-1-(1-(2 3-Dihydrobenzofuran-5-yl)-1 3.4.9-tetrahydro-Q-carbolin-2-yl1-(4-aminophenyl )propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and (E)-4-aminocinnamic acid gave after recrystallization from 2-propanol the title compound as white crystals in a 80% yield.
MP: 176 °C.
Analysis for CzsHzsNs02. 0.23H20:
Calculated: C,76.49; H,5.84; N,9.56;
Found: C,76.21; H, 5.61; N,9.96%.
[a]p2' _ -375.3 (c = 0Ø35, CHC13).
Example 168 (E)-(R)-1-f1-(3 4-Methylenedioxyphenyll-1.3,4.9-tetrahydro-f3-carbolin-2-yll-3-(4-arninophenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 19 and (E)-4-aminocinnamic acid gave after recrystallization from 2-propanol:H20 the title compound as white crystals in a 63% yield.
MP: 264 °C.
Analysis for Cz7H23N3O3 0.6H20:
Calculated: C,72.34; H,5.44; N,9.37;
Found: C,72.06; H,5.48; 9.55%.
[a]p2' _ -266 (c = 0.3, MeOH).
Example 169 ~R)-(E)-1-f1-(3,4-Methyienedioxyphenyl)-1 3 4 9-tetrahydro-a-carbolin-2-yl)1 3 ~4-(2-pyrrolidin-1-ylethoxy)phenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from intermediate 19 and Intermediate 42 gave after recrystallization from iPr20 the title compound as brown crystals in a 4% yield.
MP: 116 °C.
Analysis for C33HssNsO4. 1.7H20:
Calculated: C,69.99; H,6.48; N,7.42;
Found: C,70.02; H, 6.47; N,7.59%.
Example 170 ~E)-(Rl-1-f1-(3.4-Methylenedioxyphenyl)-1 3 4 9-tetrahydro-Q-carbolin-2-yl)1 3-(4-(2-diethylaminoethoxy)phenylpropene-1-one The same method as employed in the preparation of Example 20 but starting from 1 Intermediate 19 and (E)-3-(4-(2-diethylaminoethoxy)phenyl)acrylic acid (prepared according to the procedure of Sharpe,C.J.; Shabolt,R.S.; Brown, G.R.; Ashford,A.; Ross,J.W. J. Med. Chem. 1971, 94(9), 836-842) gave after recrystallization from iPrzO the title compound as white crystals in a 67%
yield.
MP: 94 °C.
Analysis for C33H35N3O4. 0.5Hz0:
Calculated: C,72.5; H,6.64; N,7.69;
Found: C,72.48; H,6.64; N,7.58%.
[a]p2~ _ -287 (c = 0.3, CHC13).
Example 171 (E)-1-f1-(3-Fiuoro-4-methoxyphenyl)-1 3 4 9-tetrahydro-(3-carbolin-2-yl)1-3 (3 nitropheny) )propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 14 and (E)-3-nitrocinnamic acid gave after recrystallization from DCM:2-propanol the title compound as a yellow powder in a 90% yield.
MP: 141 °C.
Analysis for C2,Hz2FN304. 0.9CHZCIz:
Calculated: C,61.16; H,4.38; N,7.67;
Found: C,61.1; H,4.39; N,7.56%.
Example 172 (E)-(R)-1-(1-(2.3-Dihydrobenzofuran-5-yl)-1.3.4.9-tetrahydro-l3-carbol in-2-yl)-3-(4-triffuoromethylphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and (E)-4-trifluoromethylcinnamic acid gave after recrystallization from 2-propanol the title compound as white crystals in a 91 yield.
MP: 141 °C.
Analysis for C2sHz3F3NzOz:
Calculated: C,71.3; H,4.75; N,5.73;
Found: C,71.37; H,4.79; N,5.86%.
(oc]pz° _ -326 (c = 0.3, CHC13).
Example 173 (E)-(R)-1-(1-(2.3-Dihydrobenzofuran-5-yl)-1,3.4.9-tetrahydro-(3-carbolin-2-yl1-(3-trifluoromethyiphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and (E)-3-trifluoromethylcinnamic acid gave after recrystallization from 2-propanol:H20 the title compound as white crystals in a 80% yield.
MP: 223 °C.
Analysis for CZSHz3FsN20z:
Calculated: C,71.3; H,4.75; N,5.73;
Found: C,71.44; H,4.73; N,5.85%.
[a]pz° _ -326 (c = 0.3, CHC13).
Example 174 (E)-(R)-1-(1-(2.3-Dihydrobenzofuran-5-yl)-1.3,4.9-tetrahydro-Q-carbolin-2-yll-(4-(2-morpholin-4-ylethoxy)phenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and Intermediate 49 gave after recrystallization from 2-propanol:HzO the title compound as white crystals in a 66% yield.
MP: 148 °C.
Analysis for C34H35N3O4:
Calculated: C,71.3; H,4.75; N,5.73;
Found: C,71.44; H,4.73; N,5.85%.
[a]p'9 = -288 (c = 0.3, CHC13).
Example 175 (E)-(R )-1-f 1-(2, 3-Dihydrobenzofuran-5-yl )-1, 3.4. 9-tetrahydro-Q-carbol in-2-yi1-3-(4-(2-(ethylmethylamino)ethoxy)phenyl )propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and Intermediate 50 gave after recrystallization from iPrZO
the title compound as a white powder in a 66% yield.
MP: 107 °C.
Analysis for C33H3sN3Os~ 0.8Hz0:
Calculated: C,73.94; H,6.88; N,7.84;
Found: C,74.09; H,7.15; N,7.48%.
[a]p2' _ -253 (c = 0.3, CHC13).
Example 176 (E)-1-f 1-(2.3-Dihydrobenzofuran-5-yl)-1.3.4.9-tetrahydro-Q-carbolin-2-yll-3-(4-(3-~dimethylamino)propenyl)phenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and Intermediate 51 gave after recrystallization from EtOH
the title compound as a white powder in a 45% yield.
MP: 216 °C.
Analysis for C33H33N3O2. 0.2H2O:
Calculated: C,78.14; H,6.88; N,7.84;
Found: C,78.03; H,6.74; N,8.21 %.
[a]p~98 = -312 (c = 0.29, CHC13).
Example 177 (E)-(R)-1-f1-(2,3-Dihydrobenzofuran-5-yl)-1.3,4.9-tetrahydro-Q-carbolin-2-yll-(4-(3-dimethylamino-2-hydroxypropoxy)phenyl)propene-1-one At 0 °C to a solution (E)-(R)-1-[1-(2,3-dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-[3-carbolin-2-yl)-3-(4-(2-(tertbutyldimethylsilanyloxy)-3-dimethylamino-2-hydroxy-propoxy)phenyl)propene-1-one (0.4 g, 0.6 mmol) in 50 mL of anhydrous THF was added tetrabutylammonium fluoride (0.6 mL, 1 equiv., 1 M
in THF). The resulting mixture was stirred at rt for one day. Quenching with water, extraction with DCM, washing with brine, drying over MgS04 and concentration in vacuo gave an oil. Recrystallization from iPrOH:HzO gave the title compound (0.2 g, 62%) as an off-white powder.
MP: 138 °C.
Analysis for C33H35N3O4. 0.5Hz0:
Calculated: C,72.5; H,6.64; N,7.69;
Found: C,72.21; H,6.75; N,7.48%.
[a]pz° _ -283 (c = 0.6, CHC13}.
(E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-(3-carbolin-2-yl]-(4-(2-(tertbutyldimethylsilanyloxy)-3-dimethylamino-2-hydroxypropoxy)phenyl)-propene-1-one was obtained in a 89% yield as a yellow oil from the same method as employed in the preparation of Example 20 but starting from Intermediate 20 and intermediate 52.
'H NMR (CDC13,250 MHz) 8 8.1 (s, 1 H), 7.5-7.3 (m, 2H), 6.9-7.2 (m, 7H), 6.8-6.5 (m, 3H), 4.5 (t, 2H), 4.2 (m, 1 H), 4.0 (m, 3H), 3.8 (m, 1 H), 3.3 (m, 1 H), 3.0 (t, 2H), 2.7-2.9 (m, 3H), 2.3-2.15 (m, 2H), 2.1 (s, 6H), 0.8 (s,9H}, 0.05 (d, 6H).
Example 178 (E)-(R)-1-(1-(2 3-Dihydrobenzofuran-5-yl)-1.3.4.9-tetrahydro-f3-carbolin-2-yl)-~,4-formylphenyl )propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and (E)-4-formylcinnamic acid gave after recrystalfization from EtOH the title compound as a white powder in a 53% yield.
MP: 175 °C.
Analysis for CzsHz4NzOs. 0.8Hz0:
Calculated: C,75.24; H,5.57; N,6.05;
Found: C,75.54; H,5.78; N,6.11 %.
[a]p2° _ -340 (c = 0.33, CHC13).
Example 179 (E)-(R)-1-f1-(2 3-Dihydrobenzofuran-5-yl)-1,3,4.9-tetrahydro-Q-carbolin-2-yll-(4-propylaminomethyl)phenyl)propene-1-one To a solution of a solution of Example 178 (0.5 g, 1.1 mmol) in 50 mL of MeOH
was added propylamine {14 rnL, 1.5 equiv.). The resulting mixture was stirred at 50 °C for 4 hours. At rt polymer-supported borohydride (1.2 g, 1.2 equiv., 2.5 mmollg) was added and the resulting mixture was stirred at 50 °C for 6 hours.
After evaporation in vacuo, the residue was washed with 2x50 mL of DCM. After filtration, the filtrate was washed with 2x50 mL of water. Drying over NazS04, evaporation in vacuo and recrystallization from MeOH gave the title compound (0.4 g, 81 %) as a pale yellow powder.
MP: 170 °C.
Analysis for C3zH33N3O2. 0.4H20:
Calculated: C,77.05; H,6.83; N,8.42;
Found: C,77.04; H,6.78; N,8.29%.
[a.]p~9 = -330 {c = 0.4, MeOH).
Example 180 (E)-(R)-1-f1-(2.3-Dihydrobenzofuran-5-yl)-1 3 4.9-tetrahydro-a-carbolin-2-yll-(4-(2-dimethylaminoethyiamino)phenylpropene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and Intermediate 53 gave after recrystallization from EtOH
the title compound as yellow crystals in a 12% yield.
MP: 160 °C.
Analysis for C32H~N40z. 0.2H20:
Calculated: C,75.33; H,6.8; N,10.98;
Found C,75.06; H,6.83; N,10.98%.
(a]p2° _ -214 (c = 0.1, MeOH).
Example 181 ~E)-(Rl-1-!1-(2.3-Dihydrobenzofuran-5-yl)-1 3 4 9-tetrahydro-(3-carbolin-2-yll-~4-(2-aminoethoxy)phenyl )propane-1-one To a solution of (E)-(R)-2-[2-(4-{3-[1-(2,3-dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-~-carbolin-2-ylJ-3-oxo-propenyl~-phenoxy)ethyl]isoindole-1,3-dione (0.85 g, 1.4 mmol) in 50 mL of MeOH:THF was added hydrazine (0.38 mL, 3 equiv., 35% in water). The resulting mixture was stirred at 45 °C for 4 hours.
Evaporation in vacuo and flash chromatography with DCM:MeOH (80:20) as eluting solvent gave the title compound (0.17 g, 26%) as yellow powder.
MP: 186 °C.
Analysis for C3oH29N3Os. 0.3CH2C1z:
Calculated: C,72.06; H,5.91; N,8.32;
Found C,72.12; H,6.08; N,8.67%.
ja,]p2° _ -285 (c = 0.29, MeOH).
(E)-(R)-2-j2-(4-{3-[1-(2, 3-Dihydrobenzofuran-5-yl )-1, 3,4, 9-tetrahydro-ji-carbolin 2-yIJ-3-oxo-propenyl)phenoxy)ethyl]isoindole-1,3-dione was obtained after recrystallization from EtOH, as a gummy solid in a 90% yield using the same method as employed in the preparation of Example 20 but starting from Intermediate 20 and Intermediate 54.
'H NMR (CDC13 250 MHz) 8 8.0-6.7 (m, 19H), 4.5 (t, 2H), 4.2-4.0 (m, 5H), 3.4 (m, 1 H), 3.0 (t, 2H), 2.9 (m, 2H).
Example 182 (E)-(R)-1-f1-(2 3-Dihydrobenzofuran-5-yl)-1,3,4.9-tetrahydro-a-carbolin-2-yll-(4-hydroxyphenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and (E)-4-hydroxycinnamic acid gave after recrystallization from DMF:MeOH the title compound as a white powder in a 90% yield.
MP: 189 °C.
Analysis for C2sHzaN20s. 0.5DMF:
Calculated: C,75.51; H,5.77; N,7.12;
Found: C,75.31; H,5.84; N,6.81 %.
ja]p2° _ _310 (c = 0.32, MeOH).
Example 183 (E)-(R)-1-f1- (2 3-Dihydrobenzofuran-5-yl)-1,3.4.9-tetrahydro-(i-carbolin-2-yl1-3-(4-(4-methylpiperazin-1-yl)phenyipropene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and Intermediate 47 gave after recrystallization from DMF:EtOH the title compound as pale yellow crystals in a 48% yield.
MP: 193 °C.
Analysis for C33H34N4O2. 1.ODMF:
Calculated: C,73.07; H,6.98; N,11.83;
Found C,72.67; H,7.05; N,11.55%.
ja.]p2° _ -330 (c = 0.3, CHC13).
Example 184 (E)-(R)-1-f1-(2.3-Dihydrobenzofuran-5-yl)-1.3.4 9-tetrahydro-8-carbolin-2-yl1-(4-methylaminomethyl )phenyl )propene-1-one The same method as employed in the preparation of Example 179 but starting from methylamine gave after recrystallization from MeOH:H20 the title compound as a white powder in a 52% yield.
MP: 129 °C.
Analysis for C3oH2sNsOz.1.1 H20:
Calculated: C,74.54; H,6.51; N,8.69;
Found: C,74.68; H,6.57; N,8.59%.
[a]p2' _ -288 (c = 0.4, CHC13).
Example 185 (E)-(R)-1-f1-(2.3-Dihydrobenzofuran-5-yl)-1 3 4 9-tetrahydro-a-carbofin-2-yll-(4-isopropylaminomethyl)phenyl)propene-1-one The same method as employed in the preparation of Example 179 but starting from isopropylamine gave after recrystallization from MeOH: H20 the title compound as a white powder in a 47% yield.
MP: 158 °C.
Analysis for C32Hs3N3Oz. 0.3Hz0:
Calculated: C,77.33; H,6.81; N,8.45;
Found: C,77.42; H,6.74; N,8.26%.
[a]p2' _ -319 (c = 0.3, MeOH).
Example 186 (E)-(R)-1-f 1-(2.3-Dihydrobenzofuran-5-yl)-1.3.4.9-tetrahydro-~carboiin-2-yll-(4-dimethylaminomethyl)phenyl)propene-1-one The same method as employed in the preparation of Example 179 but using dimethylamine gave after recrystallization from iPrOH:H20 the title compound as a white powder in a 34% yield.
MP: 153-154 °C.
Analysis for Cs, Hs,NsOzØ2H20:
Calculated: C,77.38; H,6.58; N,8.73;
Found: C,77.4; H,6.49; N,8.61 %.
[a]pz' _ -336 (c = 0.3, MeOH). .
Example 187 (El-(R)-1-f1-(2 3-Dihydrobenzofuran-5-yl)-1.3.4.9-tetrahydro-~-carbolin-2-yl~-L4-(3-dimethylaminopropoxy)phenyllpropene-1-one The same method as employed in the preparation of Example 79 but starting from Example 182 and dimethylaminopropyl chloride gave after recrystalfization from CH3CN the title compound as a white powder in a 53% yield.
MP: 186 °C.
Analysis for C33H35N3O2~ 0.6H20:
Calculated: C,74.44; H,6.85; N,7.89;
Found: C,74.36; H,6.63; N,7.98%.
[a]p2° _ -326 (c = 0.3, MeOH).
Example 188 (E)-(R)-1-f1-(2 3-Dihydrobenzofuran-5-yl)-1.3.4,9-tetrahydro-p-carbolin-2-yll-(4-(2-piperidin-1-ylethoxy)phenyl)propene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and intermediate 55 gave after recrystallization from CH3CN the title compound as white crystals in a 50% yield.
MP: 210 °C.
Analysis for C35H37N3O3.
Calculated: C,76.75; H,6.81; N,7.67;
Found: C,76.68; H,7.11; N,7.93%.
[a]p'8~9 = -290 (c = 0.4, CHC13).
Example 189 (E)-1-f 1-(3 4-Methylenedioxyphenyl)-1 3 4 9-tetrahydro-(3-carbolin-2-yl)-3-(4-(2-piperidin-1-ylethoxy)phenyllpropene-1-one The same method as employed in the preparation of Example 20 but starting from Intermediate 55 gave after recrystallization from MeOH:H20 the title compound as a beige solid in a 32% yield.
MP: 102 °C.
Analysis for C3qH35N3O4. 0.6MeOH:
Calculated: C,73.05; H,6.63; N,7.39;
Found: C,73.24; H,6.87; N,7.02%.
Example 190 (E)-(R)-f2-(4-f3-f 1-(2.3-Dihydrobenzofuran-5-yl)-1.3,4.9-tetrahydro-(3-carbolin-2-yll-3-oxopropenyl)phenoxy)ethyllmethylcarbamic acid, tertbutyl ester The same method as employed in the preparation of Example 20 but starting from Intermediate 20 and Intermediate 56 gave the title compound as a yellow powder in a 95% yield.
MP: 110 °C.
Analysis for C36H39N305~ 0.3H20:
Calculated: C,72.17; H,6.66; N,7.01;
Found; C,71.9; H,6.86; N,7.17%.
Example 191 (E)-(R)-1-f 1-(2.3-Dihydrobenzofuran-5-yl)-1, 3,4.9-tetrahydro-t3-carbolin-2-yll-3-j4-(2-methylaminoethoxy)phenyllpropene-1-one A solution of Example 190 (0.33 g, 0.55 mmol) in DCM (30 mL) was treated with zinc bromide (0.63 g, 5 equiv.) for 16 hours at 30 °C. A gummy solid was formed. Extraction with DCM:MeOH, washing with water, drying over NazS04 and recrystallization from iPrOH gave the title compound as white crystals in a 98% yield.
MP: 145 °C.
Analysis for C3,H3~N3O3. 0.2H20:
Calculated: C,74.89; H,6.37; N,8.45;
Found: C,74.90; H,6.70; N,8.49%.
[a]pz~= -337 (c = 0.4, MeOH).
Example 192 (E)-1-f 1-(3.4-Methylenedioxyphenyl)-1, 3,4,9-tetrahydro-(~-carbolin-2-yll-3-(4-(2-piperidin-1-ylethoxy)phenyllpropene-1-one The same method as employed in the preparation of Example 1 but starting from Intermediate 13 gave after reaystallization from MeOH:HzO the title compound as a beige solid in a 32% yield.
MP: 102 °C.
Analysis for C~,H~NsOa. 0.6MeOH:
Calculated: C,73.05; H,6.63; N,7.39;
Found: C,73.24; H,6.87; N,7.02%.
Inhibitory effect on cGMP-PDE
cGMP-PDE activity of compounds of the present invention was measured using a one-step assay adapted from Wells at al. (Wells, J. N., Baird, C. E., Wu, Y.
J.
and Hardman, J. G., Biochim. Biophys. Acta 384, 430 (1975)). The reaction medium contained 50mM Tris-HCI,pH 7.5, 5mM Mg-acetate, 250uglml 5'-Nucleotidase, 1mM EGTA and 0.15~M 8-[H~j-cGMP. The enzyme used was a human recombinant PDE 5 (ICOS, Seattle USA).
Compounds of the invention were dissolved in DMSO finally present at 2°~6 in the assay. The incubation time was 30 minutes during which the total substrate inversion did not exceed 30°~.
The ICS values for the compounds examined were determined from concentration-response curves using typically concentrations ranging from lOnM to 10~IN. Tests against other PDE enzymes using standard methodology also showed that compounds of the invention are highly selective for the cGMP
specific PDE enzyme.
cGMP level measurements Rat aortic smooth muscle cells (RSMC) prepared according to Chamley et al. in Cell Tissue Res. 177. 503 - 522 (1977) were used between the 10th and 25th SUBSTITUTE SHEET (RULE 26) passage at confluence in 24-well culture dishes. Culture media was aspirated and replaced with PBS (0.5m1) containing the compound tested at the appropriate concentration. After 30 minutes at 37°C, particulates guanylate cyclase was stimulated by addition of ANF (100nM) for 10 minutes. At tt~e end of incubation, the medium was withdrawn and two extractions were performed by addition of 65°h ethanol (0.25m1). The two ethanolic extracts were pooled and evaporated until dryness, using a Speed-vac system. cGMP was measured after acetylation by scintillation proximity immunoassay (AMERSHAM). The ECso values are expressed as the dose giving half of the stimulation at saturating concentrations Biolooical data The compounds according to the present invention were typically found to exhibit an (Cso value of less than 500 nM and an ECso value of less than 5 ErM. In vitro test data for representative compounds of the invention is given in the following table:
SUBSTITUTE SHEET (RULE 26) i aoie ~ . m wrro results Example No. IC~ rsM ECM NM
14 5 0.45 25 72 0.3 28 55 0.3 55 40 0.4 61 20 1.8 140 2 0.1 142 18 1.5 156 15 < 1 164 11 1.5 165 9 < 1 177 12 < 1 180 25 3.5 182 2 < 1 188 24 < 1 191 8 < 1 The hypotensive effects of compounds according to the invention as identified in Table 2 were studied in conscious spontaneously hypertensive rats (SHR). The compounds were admnistered orally at a dose of 5 mglkg in a mixture of 596 DMF and 95% olive oil. Blood pressure was measured from a catheter inserted in the carotid artery and recorded for 5 hours after administration. The results are expressed as Area Under the Curve (AUC from 0 to 5 hours, mmHg.hour) of the fall in blood pressure over time.
SUBSTITUTE SHEET (RULE 26) Table 2. In vivo results Example No. AUC PO (mmHg.h) s1 95 SUBSTITUTE SHEET (RULE 26) The application of which this description and claims forms part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any novel feature or combination of features described herein. They may take the form of product, composition, process or use claims and may include, by way of example and without limitation, the following claim.
Claims (32)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A compound of formula (I) wherein R0 represents -hydrogen or -halogen;
R1 is selected from the group consisting of:
-hydrogen, -NO2, -trifluoromethyl, -trifluoromethoxy, -halogen, -cyano, a 5- or 6- membered heterocyclic group containing at least one heteroatom selected from oxygen, nitrogen and sulphur (optionally substituted by - C(=0)OR a or C1-4alkyl), -C1-6alkyl optionally substituted by -OR a, -C1-3alkoxy, -C(=0)R a, -O-C(=0)R a, -C(=0)OR a, -C1-4alkylene C(=0)OR a, -O-C1-4alkylene -C(=0)OR a, -C1-4alkylene-0-C1-4alkylene-C(=0)OR a, -C(=0)NR a SO2R c, -C(=0)C1-4alkylene Het, wherein Het represents 5- or 6-membered heterocyclic group as defined above, -C1-4alkylene NR a R b, -C2-6alkenyleneNR a R b, -C(=0)NR a R b, -C(=0)NR a R c, -C(=0)NR a C1-4alkylene OR b -C(=0)NR a C1-4alkylene Het, wherein Het represents a 5- or 6-membered heterocyclic group as defined above, -OR a -OC2-4alkylene NR a R b, -OC1-4alkylene-CH(OR a)CH2 NR a R b, -O-C1-4alkylene Het, wherein Het represents a 5- or 6- membered heterocyclic group as defined above, -O-C2-4alkylene-OR a, -O-C2-4alkylene-NR a-C(=0)-OR b, -NR a R b, -NR a C1-4alkyleneNR a R b, -NR a C(=0)R b, -NR a C(=0)NR a R b, -N(SO2C1-4alkyl)2, -NR a(SO2C1-4alkyl), -SO2NR a R b, and -OSO2trifluoromethyl;
R2 is selected from the group consisting of:
-hydrogen, -halogen, -OR a, -C1-6 alkyl, -NO2, and -NR a R b, or R1 and R2, together form a 3- or 4- membered alkylene or alkenylene chain optionally containing at least one heteratom;
R3 is selected from the group consisting of:
-hydrogen, -halogen, -NO2, -trifluoromethoxy, -C1-6alkyl, and -C(=0)OR a;
R4 is hydrogen, or R3 and R4 together form a 3- or 4- membered alkylene or alkenylene chain, optionally containing at least one heteratom;
R a and R b, which may be the same or different, are independently selected from hydrogen and C1-6alkyl;
R c represents phenyl or C4-6cycloalkyl, which phenyl or C4-6cycloalkyl can be optionally substituted by one or more halogen atoms, one or more -C(=0)OR a or one or more -OR a;
n is an integer selected from 1, 2 and 3;
m is an integer selected from 1 and 2;
and pharmaceutically acceptable salts and solvates thereof.
R1 is selected from the group consisting of:
-hydrogen, -NO2, -trifluoromethyl, -trifluoromethoxy, -halogen, -cyano, a 5- or 6- membered heterocyclic group containing at least one heteroatom selected from oxygen, nitrogen and sulphur (optionally substituted by - C(=0)OR a or C1-4alkyl), -C1-6alkyl optionally substituted by -OR a, -C1-3alkoxy, -C(=0)R a, -O-C(=0)R a, -C(=0)OR a, -C1-4alkylene C(=0)OR a, -O-C1-4alkylene -C(=0)OR a, -C1-4alkylene-0-C1-4alkylene-C(=0)OR a, -C(=0)NR a SO2R c, -C(=0)C1-4alkylene Het, wherein Het represents 5- or 6-membered heterocyclic group as defined above, -C1-4alkylene NR a R b, -C2-6alkenyleneNR a R b, -C(=0)NR a R b, -C(=0)NR a R c, -C(=0)NR a C1-4alkylene OR b -C(=0)NR a C1-4alkylene Het, wherein Het represents a 5- or 6-membered heterocyclic group as defined above, -OR a -OC2-4alkylene NR a R b, -OC1-4alkylene-CH(OR a)CH2 NR a R b, -O-C1-4alkylene Het, wherein Het represents a 5- or 6- membered heterocyclic group as defined above, -O-C2-4alkylene-OR a, -O-C2-4alkylene-NR a-C(=0)-OR b, -NR a R b, -NR a C1-4alkyleneNR a R b, -NR a C(=0)R b, -NR a C(=0)NR a R b, -N(SO2C1-4alkyl)2, -NR a(SO2C1-4alkyl), -SO2NR a R b, and -OSO2trifluoromethyl;
R2 is selected from the group consisting of:
-hydrogen, -halogen, -OR a, -C1-6 alkyl, -NO2, and -NR a R b, or R1 and R2, together form a 3- or 4- membered alkylene or alkenylene chain optionally containing at least one heteratom;
R3 is selected from the group consisting of:
-hydrogen, -halogen, -NO2, -trifluoromethoxy, -C1-6alkyl, and -C(=0)OR a;
R4 is hydrogen, or R3 and R4 together form a 3- or 4- membered alkylene or alkenylene chain, optionally containing at least one heteratom;
R a and R b, which may be the same or different, are independently selected from hydrogen and C1-6alkyl;
R c represents phenyl or C4-6cycloalkyl, which phenyl or C4-6cycloalkyl can be optionally substituted by one or more halogen atoms, one or more -C(=0)OR a or one or more -OR a;
n is an integer selected from 1, 2 and 3;
m is an integer selected from 1 and 2;
and pharmaceutically acceptable salts and solvates thereof.
2. A compound represented by formula wherein R5 is selected from the group consisting of -OH, -OC2-4alkylene NR a R b and -O-C1-4alkylene Het, wherein Het represents a 5- or 6- membered heterocyclic group containing at least one heteroatom selected from oxygen, nitrogen, and sulphur, optionally substituted by C1-4alkyl;
R6 represents wherein C represents a 5- or 6-membered ring which may be saturated or partially or fully unsaturated and comprises carbon atoms and optionally one or two heteroatoms selected from oxygen, sulphur and nitrogen, optionally substituted by C1-4alkyl;
R a and R b, which may be the same or different, are independently selected from hydrogen and C1-6alkyl;
and pharmaceutically acceptable salts and solvates thereof.
R6 represents wherein C represents a 5- or 6-membered ring which may be saturated or partially or fully unsaturated and comprises carbon atoms and optionally one or two heteroatoms selected from oxygen, sulphur and nitrogen, optionally substituted by C1-4alkyl;
R a and R b, which may be the same or different, are independently selected from hydrogen and C1-6alkyl;
and pharmaceutically acceptable salts and solvates thereof.
3. The compound of claim 1 wherein R0 represents hydrogen.
4. The compound of claim 1 wherein R1 is selected from the group consisting of:~
-OR a, -O-C2-4alkylene NR a R b, -O-C1-4alkyleneHet, and -O-C2-4alkylene-OR a.
-OR a, -O-C2-4alkylene NR a R b, -O-C1-4alkyleneHet, and -O-C2-4alkylene-OR a.
5. The compound of claim 4 wherein R1 represents -O-C2-4-alkyleneNR a R b.
6. The compound of claim 5 wherein at least one of R a and R b is methyl.
7. The compound of claim 1 wherein R2 represents hydrogen.
8. The compound of claim 1 wherein R1 and R2 together form a methylenedioxy chain, an ethyleneoxy chain, an ethylenedioxy chain, an ethenyleneoxy chain, a propylene chain, a butylene chain, or -NR a ethylene-O-.
9. The compound of claim 1 wherein R1 and R2 together form methylenedioxy, propylene, or -N(CH3)ethylene-O-.
10. The compound of claim 1 wherein R3 and R4 together form a methylenedioxy chain, an ethylenoxy chain, an ethylenedioxy chain, an ethenyleneoxy chain, a propylene chain, a butylene chain, or -NR a ethylene-O-.
11. The compound of claim 1 wherein R3 and R4 together form a methylenedioxy or ethyleneoxy.
12. The compound of claim 2 wherein R5 represents -OC2-4-alkyleneNR a R b, or -O-C1-4 alkyleneHet.
13. The compound of claim 12 wherein Het is selected from the group consisting of piperidyl, pyrrolidinyl, and morpholinyl.
14. The compound of claim 2 wherein R6 represents
15. A compound selected from the group consisting of (E)-1-(1-Phenyl-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)-3-phenylpropene-1-one, (E)-1-(1-Phenyl-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)-3-(4-nitro-phenyl)propene-1-one, (E)-1-(1-Phenyl-1,3,4,9-tetrahydro-.beta.-carbolin-2- yl)-3-(4-trifluoro-methylphenyl)propene-1-one, (E)-1-(1-Phenyl-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)-3-(4-methoxy-phenyl)propene-1-one, (E)-1-[1-(4-Methoxyphenyl)-1,3,9,9-tetrahydro-,.beta.-carbolin-2-yl]-3-(4-trifluoromethylphenyl)propene-1-one, (E)-N-[4-[3-Oxo-3-(1-phenyl-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)propenyl]phenyl]acetamide (E)-1-[1-(4-Methoxyphenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)-3-phenylpropene-1-one, (E)-1-[1-(3,9-Methylenedioxyptienyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl]-3-phenylpropene-1-one, (E)-1-(1-Ploenyl-1,3,4, 9-tetrahydro-.beta.-carbolin-2-yl)-3-.beta.-formylphenyl)propene-1-one, (E)-N-[9-[3-Oxo-3-(1-(4-nitrophenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)propenyl]phenyl]acetamide (E)-1-[1-(4-Nitrophenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl]-3-phenylpropene-1-one, (E)-1-[1-(4-Trifluoromethoxyphenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl]-3-plnenylpropene-1-one, (E)-1-[1-(4-Methylphenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl]-3-phenylpropene-1-one, (E)-N-[4-[3-Oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)-propenyl]-phenyl]acetamide (E)-4-[3-Oxo-3-(1-phenyl-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)-propenyl)benzoic acid, methyl ester (E)-1-[1-(2-Chlorophenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl]-3-phenylpropene-1-one, (E)-1-(1-Phenyl-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)-3-(3,4-methylenedioxyphenyl)-propene-1-one, (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl]-3-(4-bromophenyl)-propene-1-one, (E)-1-[1-(4-Chlorophenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl]-3-phenylpropene-1-one, (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl]-3-(4-ethoxyphen yl)-propene-1-one, (E)-4-(3-Oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)propenyl)acetic acid, phenyl ester (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl]-.beta.-(9-hydroxyphenyl)-propene-1-one, (E) -1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-3-(4-formylphenyl)propene-1-one, (E)-1-[9-[3-Oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)-propenyl]-phenyl)-3-phenylurea (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-3-(4-aminophenyl)-propene-1-one, (E)-1-[1-(3,4-Methylenedioxy-phenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-3-(4-nitrophenyl)-propene-1-one, (E) -1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-3-((4-bis(methylsulfonyl)-aminophenyl]-propene-1-one, (E)-4-(3-Oxo-3-[1-(3,4-methylenedioxyphen yl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl]-propenyl]benzoic acid, methyl ester (E)-N-[4-[3-Oxo-3-[1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)propenyl]phenyl]methanesulfonamide (E)-4-[3-Oxo-3-[1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)propenyl]benzamide) (E)-4-(3-Oxo-3-[1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl]-propenyl]benzoic acid (E)-1-[1-(3,4-Methylenedioxyphen yl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl]-3-(4-cyanophenyl)propene-1-one, (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-3-(4-trifluoromethylphenyl)-propene-1-one, (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)-3-(3,4-methylenedioxy-phenyl)propene-1-one, (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl)-3-(4-chlorophenyl)-propene-1-one, (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-3-(4-trifluoromethoxy-phenyl)propene-1-one, (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-3-(4-methylphenyl)propene-1-one, (E)-[9-[3-Oxo-3-(1-(3,9-methylenedioxyphenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)propenyl]phenyl]urea (E) -1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-3-(9-hydroxymethylphenyl)-propene-1-one, (E)-N-Benzyl-4-[3-oxo-3-(1-(3,4-methylenedioxy-phenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)-propenyl]benzamide (E) -1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-3-(2,4-dichlorophenyl)-propene-1-one, (E)-1-[1-(3,4-Methylenedioxyplnenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-3-(3-methoxy-4-hydroxy-phenyl)propene-1-one, (E) -1-[1-(3,4-Methylenedioxyphenyl)-1, 3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-3-(3-hydroxy-9-methoxy-phenyl)propene-1-one, (E) -1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-3-(4-fluorophenyl)-propene-1-one, (E) -1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-3-indan-5-yl-1-propene-1-one, (E)-N-[4-[3-Oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)propenyl]-benzoyl]benzene-sulfonamide (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-3-(3,4-dichlorophenyl)-propene-1-one, (E) -1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-3-(3,4-dimethoxyphenyl)-propene-1-one, (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-3-(3,4-dihydroxyphenyl)-propene-1-one, (E)-N-Methyl-N-[9-(3-oxo-3-(1-(3,4-methylenedioxy-phenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)-propenyl]phenyl]acetamide, (E)-2,2-Dimethyl-N-[4-[3-Oxo-3-(1-(3,4-methylene-dioxyphenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)propenyl]phenyl]-propionamide, (E) -1-[1-(3, 4-Methylenedioxyphenyl)-1, 3, 4, 9-tetra-hydro-.beta.-carbolin-2-yl]-3-(3,5-dimethoxyphenyl)-propene-1-one, (E)-(N)-(4-[3-[1-(3,4-Methylenedioxyphenyl)-6-fluoro-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl]-3-oxopropenyl]-phenyl}-acetamide, (E) -1-[1-(3,4-Methylenedioxyplienyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-3-(3,4,5-trimethoxyphenyl)-propene-1-one, (E)-N-[4-[3-Oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)propenyl]phenyl]isobutyramide, (E) -1-[1-(3,4-Methylenedioxyphenyl)-6-fluoro-1, 3, 4, 9-tetrahydro-.beta.-carbolin-2-yl]-3-phenylpropene-1-one, (E)-N-(2-Methoxyethyl)-4-[3-oxo-3-(1-(3,4-methylene-dioxyphenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)-propenyl]-benzamide, (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-3-(3-hydroxyphenyl)propene-1-one, (E) -1- [1-(3,4-Methylenedioxyphenyl)-1, 3, 4, 9-tetra-hydro-.beta.-carbolin-2-yl]-3-(3-methoxyphenyl)propene-1-one, (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-3-(3-nitrophenyl)propene-1-one, (E)-1-[1-(3,9-Methylenedioxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-3-[4-(2-dimethylamino-ethoxy)phenyl]propene-1-one, (E)-N-(2-Morpholin-9-ylethyl)-9-[3-oxo-3-(1-(3,9-methylene-dioxyphenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)propenyl]-benzamide, (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-3-[9-(1H-tetrazol-5-yl)-phenyl]propene-1-one, (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,9,9-tetra-hydro-.beta.-carbolin-2-yl]-3-(3-aminophenyl)propene-1-one, (E)-N-Cyclohexyl-4-[3-oxo-3-(1-(3,4-methylenedioxy-phenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)-propenyl]benzamide, (E)-N-(Tetrahydrofuran-2-ylmethyl)-4-[3-oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)propenyl]benzamide, (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-3-(3-cyanophenyl)propene-1-one, (E)-N-(4-Piperidine-4-carboxylic acid, ethyl ester)-4-[3-oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)propenyl]benzamide, (E)-N-(4-Piperidine-4-carboxylic acid)-4-[3-oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)propenyl]benzamide, (E)-3-[3-Oxo-3-[1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl]-propenyl]benzoic acid, (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-3-(3-(4-methylpiperazine-1-carbonyl)-phenyl)propene-1-one, (E)-N-(2-Piperazin-1-ylethyl)-3-[3-oxo-3-(1-(3,4-methylene-dioxyphenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)propenyl]-benzamide, (E)-4-[3-Oxo-3-(1-(3,4-methylenedioxyphenyl)-1, 3, 4, 9-tetrahydro-.beta.-carbolin-2-yl)-propenyl]acetic acid ethyl ester, (E)-1-[1-(3,9-Methylenedioxyphen yl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-3-(3-tetrazolophenyl)-propene-1-one, (E)-2-[3-Oxo-3-[1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-propenyl]benzoicacid, methyl ester, (E)-3-[3-Oxo-3-[1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-propenyl]benzoic acid, methyl ester, (E)-1-(4-[3-Oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)-propenyl]-phenyl)piperidine-4-car-boxylic acid, ethyl ester, (E)-N-(1-Ethylpyrrolidin-2-yl-methyl)-3-[3-oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)propenyl]benzamide, (E) -1-[1-(3,9-Methylenedioxyphenyl)-1, 3, 4, 9-tetrahydro-.beta.-carbolin-2-yl]-3-(3-(2-dimethylamino-ethoxy)phenyl)propene-1-one, (E) -1-[1-(3,4-Methylenedioxyphenyl)-1, 3, 4, 9-tetra-hydro-.beta.-carbolin-2-yl]-3-(3,5-diterbutyl-4-hydroxyphenyl)propene-1-one, (E)-3-[3-Oxo-3-[1-(4-methoxycarbonylphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]propenyl]benzoic acid, methyl ester, (E)-2-[3-Oxo-3-[1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl]propenyl]benzoic acid, (E) -(4- [3-Oxo-3-(1-(3,4-methylenedioxyphenyl)-1, 3, 4, 9-tetrahydro-.beta.-carbolin-2-yl)propenyl]phenoxy)acetic acid, ethyl ester, (E)-(9-[3-Oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl)-propenyl]phenyl)acetic acid, (E) -(4-[3-Oxo-3-(1-(3,4-methylenedioxyphenyl) -1, 3, 4, 9-tetrahydro-.beta.-carbolin-2-yl)propenyl]phenoxy)acetic acid, (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,9,9-tetra-hydro-.beta.-carbolin-2-yl]-3-(3-nitro-9-chlorophenyl)-propene-1-one, (E) -1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-3-(5-nitro-2-chlorophenyl)-propene-1-one, (E)-3-Chloro-4-[3-oxo-3-[1-(3,4-methylenedioxy-phenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl]pro-penyl]benzoic acid, methyl ester, (E) -(4-[3-Oxo-3-(1-(3,4-methylenedioxyphenyl)-1, 3, 4, 9-tetrahydro-.beta.-carbolin-2-yl)propenyl]benzyloxy)acetic acid, (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-3-(5-amino-2-chlorophenyl)-propene-1-one, (E)-3-Chloro-4-[3-oxo-3-[1-(3,4-methylenedioxy-phenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl]propenyl)benzoic acid, (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-3-(3,5-dibromo-9-hydroxy-phenyl)propene-1-one, (E) -1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-3-(9-(2-dimethylamino-propoxy)phenyl)propene-1-one, (E)-2-Chloro-5-[3-oxo-3-[1-(3,4-methylenedioxy-phenyl)-1,3,4,9-tetrahydro-.beta.-carbolill-2-yl]propenyl]benzoic acid, methyl ester, (E)-1-[1-(3,9-Methylenedioxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-3-(4-(2-diisopropylamino-ethoxy)phenyl)propene-1-one, (E)-2-Chloro-5-[3-oxo-3-[1-(3,4-methylenedioxy-phenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl]propenyl)benzoic acid, (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-3-(3-hydroxy-4-vitro-phenyl)propene-1-one, (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-3-(3,5-dimethyl-4-hydroxy-phenyl)propene-1-one, (E) -1-[1-(3,4-Methylenedioxyphenyl)-1, 3, 4, 9-tetra-hydro-.beta.-carbolin-2-yl)-3-(3-(2-dimethylaminoethoxy)-4-nitro-phenyl)propene-1-one, (E) -1-[1-(3, 4-Methylenedioxyphenyl)-1, 3, 4, 9-tetra-hydro-.beta.-carbolin-2-yl)-3-(3-(2-dimeth ylaminoethoxy)-9-amino-phenyl)propene-1-one, (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-3-(3-nitro-4-hydroxy-5-methoxyphenyl)propene-1-one, (E) -1-[1-(3,4-Methylenedioxyphenyl)-1, 3, 4, 9-tetra-hydro-.beta.-carbolin-2-yl]-3-(3-chlorophenyl)propene-1-one, (E) -1- [1-(4-Methoxy-phenyl)-1, 3, 4, 9-tetrahydro-.beta.-carbolin-2-yl]-3-(2-chloro-5-nitrophenyl)propene-1-one, (E) -1- (1-(3,4-Methylenedioxyphenyl)-1, 3, 4, 9-tetra-hydro-.beta.-carbolin-2-yl)-3-(2,6-dichlorophenyl)-propene-1-one, (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl)-3-(4-methylaminomethyl-phenyl)propene-1-one, (E)-1-[1-(3,9-Methylenedioxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl)-3-(3-methylphenyl)propene-1-one, (E)-N-Methyl-(4-[3-oxo-3-(1-(3,4-methylenedioxy-phenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)-propenyl]benzene-sulfonamide, (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl)-3-(3-hydroxy-9-acetylphenyl)-propene-1-one, (E) -1-[1-(2,3-Dihydrobenzofuran-5-yl)-1, 3, 4, 9-tetra-hydro-.beta.-carbolin-2-yl]-3-(2-chloro-5-nitrophenyl)-propene-1-one, (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-3-(2-hydroxyphenyl)propene-1-one, (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-3-(3-nitro-2-piperidin-1-ylphenyl)propene-1-one, (E)-1-(1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-3-phenylpropene-1-one, (E)-1-[1-(4-Isopropylphenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)-3-(3-nitrophenyl)propene-1-one, (E)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl]-3-(3-nitrophenyl)-propene-1-one, (E) - (R) -1-[1-(3,4-Methylenedioxyphenyl)-1, 3, 4, 9-tetrahydro-.beta.-carbolin-2-yl]-3-phenylpropene-1-one, (E) - (S) -1- [1-(3,9-Methylenedioxyphenyl) -1, 3, 4, 9-tetrahydro-.beta.-carbolin-2-yl]-3-phenylpropene-1-one, (E) -1- [1-(4-Methoxyphenyl)-1, 3, 9, 9-tetrahydro-.beta.-carbolin-2-yl]-3(3-nitrophenyl)propene-1-one, (E)-1-[1-(9-Methylphenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl]-3-(2-chloro-5-nitrophenyl)propene-1-one, (E) -N- (Tetrahydrofuran-2-ylmethyl)-3-[3-oxo-3- (1- (3, 4-methylenedioxy)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)propenyl]-benzamide, (E)-1-[1-(Indan-5-yl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl]-3-phenylpropene-1-one, (E) -1-[1-(3,4-Methylenedioxyphenyl)-1, 3, 4, 9-tetra-hydro-.beta.-carbolin-2-yl]-3-(3-acetylphen yl)propene-1-one, (E)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl)]-3-(4-(2-dimethylamino-ethoxy)phenyl)propene-1-one, (E)-9-[3-Oxo-3-[1-(4-methoxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]propenyl]benzoic acid, methyl ester, (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-3-(9-methyl-3,9-dihydro-2H-benzo[1,9]-oxazin-6-yl)propene-1-one, (E)-1-[1-(3,9-Methylenedioxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-3-(2-hydroxy-5-nitrophenyl)-propene-1-one, (E)-4-[3-Oxo-3-[1-(2,3-dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl]propenyl]benzoic acid, methyl ester, (E ) -9- [3-Oxo-3-[1-(9-methoxyphenyl)-1, 3, 4, 9-tetra-hydro-.beta.-carbolin-2-yl]propenyl]benzoic acid, (E)-4-[3-Oxo-3-[1-(2,3-dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl]propenyl]benzoic acid, (E)-1-[1-(Benzofuran-5-yl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl]-3-phenylpropene-1-one, (E) -3-[3-Oxo-3- (1-(3,4-methylenedioxyphenyl ) -1, 3, 4, 9-tetrahydro-.beta.-carbolin-2-yl)-propenyl]-phenyl)trifluoro-methanesulfonic acid, phenyl ester, (E)-1-(1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-3-[4-(2-hydroxyethoxy)-phenyl]propene-1-one, (E)-1-[1-(Benzofuran-5-yl-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)] -3-(4-(2-dimethylaminoethoxy)phenyl)-propene-1-one, (E) -1-[1(3,4-Methylenedioxyphenyl)-1, 3, 4, 9-tetra-hydro-.beta.-carbolin-2-yl] -3- (2-dimethylaminophenyl) -propene-1-one, (E) -1-[1-(3,4-Methylenedioxyplenyl) -1, 3, 4, 9-tetra-hydro-.beta.-carbolin-2-yl]-3-(2-piperidin-1-ylphenyl)-propene-1-one, (E) -4- [3-Oxo-3-[1-(benzofuran-5-yl-1, 3, 4, 9-tetra-hydro-.beta.-carbolin-2-yl]-propenyl]-benzoic acid, methyl ester, (E)-4-[3-(1-Benzofuran-5-yl-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)-3-oxo-propenyl]-benzoic acid, (E ) -4-[3-Oxo-3-(1-(3, 4-methylenedioxyphenyl)-1, 3, 4, 9-tetrahydro-.beta.-carbolin-2-yl)propenyl]-phenyl)trifluoromethane-sulfonic acid, phenyl ester, (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-3-(2-(2-dimethylaminoethoxy)-phenyl)propene-1-one, (E)-1-[1-(3-Fluoro-9-methoxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-3-phenylpropene-1-one, (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)]-3-(4-(2-dimethylamino-ethoxy)phenyl)propene-1-one, (E)-1-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl]-3-phenylpropene-1-one, (E) -1-[1-(2,3-Dihydrobenzofuran-5-yl)-1, 3, 4, 9-tetra-hydro-.beta.-carbolin-2-yl)]-3-(4-(2-pyrrolidin-1-ylethoxy)phenyl)propene-1-one, (E)-1-(1-(3,4-Methylenedioxyploenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-3-[9-pyrrolidin-1-ylphenyl]-propene-1-one, (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,9,9-tetrahydro-.beta.-carbolin-2-yl]-3-(3-nitrophenyl)-propene-1-one, (E) -1- (1- (3,4-Methylenedioxyphenyl) -1, 3, 4, 9-tetra-hydro-.beta.-carbolin-2-yl]-3-(4-imidazol-1-ylphenyl]-propene-1-one, (E) -4-[3-(1-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-1, 3, 4, 9-tetrahydro-.beta.-carbolin-2-yl]-3-oxo-propenyl]benzoic acid, methyl ester, (E)-1-[1-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl]-3-(3-nitrophenyl)-propene-1-one, (E)-1-[1-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)]-3-(4-(2-dimethylamino-ethoxy)phenyl)propene-1-one, (E)-1-[1-(3-Fluoro-9-methoxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl))-3-(4-(2-dimethylamino-ethoxy)phenyl)propene-1-one, (E)-4-[3-[1-(2,3-Dihydrobenzo(1,4]dioxin-6-yl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl]-3-oxopropenyl]benzoic acid, (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl]-3-phenylpropene-1-one, (E)-(S)-1-(1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl))-3-(4-(2-dimethylamino-ethoxy)phenyl)propene-1-one, (E) -1-[1-(2,3-Dihydrobenzofuran-5-yl)-1, 3, 4, 9-tetra-hydro-.beta.-carbolin-2-yl]-3-(4-aminophenyl)propene-1-one, (E) - (S) -1-[1-(2,3-Dihydrobenzofuran-5-yl) -1, 3, 4, 9-tetrahydro-.beta.-carbolin-2-yl]-3-phenylpropene-1-one, (E)-(S)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl]-3-(3-nitrophenyl)-propene-1-one, (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)]-3-(4-(1-(S)-methyl-pyrrolidin-2-yl-methoxy)phenyl)propene-1-one, (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)-3-(3-hydroxyphenyl)-propene-1-one, (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)]-3-(4-(2-dimethylamino-1-methylethoxy)-phenyl)propene-1-one, (E) -1-(1-Phenyl-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)-3-(4-(4-methylpyperazin-1-yl)-phenyl)propene-1-one, (E) -(R)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)]-3-(9-(1-(S)-methyl-pyrrolidin-2-yl-methoxy)-phenyl)propene-1-one, (E)-(R)-1-[1-(3,9-Methylenedioxyphenyl)-1,3,9,9-tetrahydro-.beta.-carbolin-2-yl)]-3-(9-(2-dimethylamino-1-methylethoxy)phenyl)-propene-1-one, (E)-(R)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)]-3-(9-(2-dimethylamino-propoxy)phenyl)propene-1-one, (E)-4-[3-Oxo-3-[1-(3,9-fluorophenyl)-1,3,9,9-tetra-hydro-.beta.-carbolin-2-yl]propenyl]benzoic acid, methyl ester, (E)-(R)-(1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)]-3-(4-(2-diethylamino-ethoxy)phenyl)propene-1-one, (E)-(R)1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)]-3-(4-(2-dimethylamino-propoxy)phenyl)propene-1-one, (E)-4-[3-Oxo-3-[1-(3,4-difluorophenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl]propenyl]benzoic acid, (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl]-3-(4-aminophenyl)-propene-1-one, (E)-(R)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-3-(4-aminophenyl)-propene-1-one, (E)-(R)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)]-3-(4-(2-pyrrolidin-1-ylethoxy)phenyl)propene-1-one, (E)-(R)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)]-3-(4-(2-diethylamino-ethoxy)phenylpropene-1-one, (E)-1-[1-(3-Fluoro-4-methoxyphenyl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl)]-3-(3-nitrophenyl)propene-1-one, (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl]-3-(4-trifluoromethyl-phenyl)propene-1-one, (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)-3-(3-trifluoromethyl-phenyl)propene-1-one, (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl]-3-(4-(2-morpholin-4-ylethoxy)phenyl)propene-1-one, (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl]-3-(4-(2-(ethylmethyl-amino)ethoxy)phenyl)-propene-1-one, (E)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetra-hydro-.beta.-carbolin-2-yl]-3-(4-(3-(dimethylamino)propenyl)phenyl)propene-1-one, (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl]-3-(4-(3-dimethylamino-2-hydroxypropoxy)-phenyl)propene-1-one, (E)-(R)-1-(1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)-3-(4-formylphenyl)-propene-1-one, (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)-3-(4-propylaminomethyl)-phenyl)propene-1-one, (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl]-3-[4-(2-dimethylaminoethylamino)phenyl-propene-1-one, (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)-3-(4-(2-aminoethoxy)-phenyl)propene-1-one, (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl]-3-(4-hydroxyphenyl)-propene-1-one, (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl]-3-(4-(9-methylpiperazin-1-yl)phenylpropene-1-one, (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl]-3-(4-methylaminomethyl)-phenyl)propene-1-one, (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)-3-(4-isopropylamino-methyl)phenyl)propene-1-one, (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl]-3-(4-dimethylamino-methyl)phenyl)propene-1-one, (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl]-3-[4-(3-dimethylamino-propoxy)phenyl]propene-1-one, (E)-(R)-1-(1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-Q-carbolin-2-yl]-3-(4-(2-piperidin-1-yl-ethoxy)phenyl)propene-1-one, (E)-(1)-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)-3-(4-(2-piperidin-1-yl-ethoxy)phenyl]propene-1-one, (E)-(R)-[2-(4-{3-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl]-3-oxopropenyl}-phenoxyl)ethyl]-methylcarbamic acid, tertbutyl ester, (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-carbolin-2-yl]-3-[4-(2-methylamino-ethoxy)phenyl]propene-1-one, and pharmaceutically acceptable salts and solvates thereof.
16. (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-.beta.-carbolin-2-yl)]-3-(4-(2-dimethylamino-ethoxy)phenyl)-propene-1-one, and pharmaceutically acceptable salts and solvates thereof.
17. A pharmaceutical composition comprising a compound of any one of claims 1 to 16, together with a pharmaceutically acceptable diluent or carrier.
18. Use of a compound of any one of claims 1 to 16 for the manufacture of a medicament for the curative or prophylactic treatment of a condition where inhibition of a cGMP-specific PDE is of a therapeutic benefit.
19. The use of claim 18 wherein the condition is selected from the group consisting of stable angina, unstable angina, variant angina, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, congestive heart failure, renal failure, atherosclerosis, a condition of reduced blood vessel patency, a peripheral vascular disease, a vascular disorder, an inflammatory disease, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, and a disease characterized by a disorder of gut motility.
20. The use of claim 18 wherein the condition is erectile dysfunction in an animal.
21. Use of a therapeutically effective amount of a compound of any one of claims 1 to 16 for the treatment of stable angina, unstable angina, variant angina, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, congestive heart failure, renal failure, atherosclerosis, a condition of reduced blood vessel patency, a peripheral vascular disease, a vascular disorder, an inflammatory disease, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, a disease characterized by a disorder of gut motility, in a human or nonhuman animal.
22. The use of claim 21 wherein the animal is a human.
23. Use of an effective amount of a pharmaceutical composition comprising a compound of claim 1, together with a pharmaceutically acceptable diluent or carrier for the treatment of a condition in an animal where inhibition of a cGMP-specific PDE is of a therapeutic benefit.
24. The use of claim 23 wherein the animal is a human.
25. The use of claim 24 wherein the composition is an oral pharmaceutical.
26. Use of an effective dose of a compound of any one of claims 1 to 16, or pharmaceutically acceptable salts and solvates thereof for the curative or prophylactic treatment of erectile dysfunction in an animal.
27. The use of claim 26 wherein the animal is a human.
28. The use of claim 26 wherein the compound is a component of an oral pharmaceutical composition.
29. A combination comprising:
(a) a compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt or solvate thereof, and (b) a second therapeutically active agent, for simultaneous, separate, or sequential use in the treatment of a condition where inhibition of a cGMP-specific PDE is of a therapeutic benefit.
(a) a compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt or solvate thereof, and (b) a second therapeutically active agent, for simultaneous, separate, or sequential use in the treatment of a condition where inhibition of a cGMP-specific PDE is of a therapeutic benefit.
30. The combination of claim 29 wherein the condition is stable angina, unstable angina, variant angina, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, congestive heart failure, renal failure, atherosclerosis, a condition of reduced blood vessel patency, a peripheral vascular disease, a vascular disorder, an inflammatory disease, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, or a disease characterized by a disorder of gut motility.
31. The combination of claim 29 wherein the condition is erectile dysfunction in an animal.
32. A process for preparing a compound of claim 1 comprising reacting a compound of formula (II) with a compound of formula (III) wherein X is hydroxyl or halogen, and R0, R1, R2, R3, R4, n and m are defined in claim 1, optionally followed by one or more of an interconversion step, salt formation, and solvate formation.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9609777.9 | 1996-05-10 | ||
| GB9609820.7 | 1996-05-10 | ||
| GBGB9609777.9A GB9609777D0 (en) | 1996-05-10 | 1996-05-10 | Chemical compounds |
| GBGB9609820.7A GB9609820D0 (en) | 1996-05-10 | 1996-05-10 | Chemical compounds |
| PCT/EP1997/002277 WO1997043287A1 (en) | 1996-05-10 | 1997-05-05 | Carboline derivatives |
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|---|---|
| CA2253948A1 CA2253948A1 (en) | 1997-11-20 |
| CA2253948C true CA2253948C (en) | 2005-07-26 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002253948A Expired - Fee Related CA2253948C (en) | 1996-05-10 | 1997-05-05 | Carboline derivatives |
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| EP (1) | EP0912567B1 (en) |
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| CA (1) | CA2253948C (en) |
| CZ (1) | CZ358598A3 (en) |
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| EA (1) | EA199800907A1 (en) |
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| HU (1) | HUP9901478A3 (en) |
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Families Citing this family (61)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE69711882T2 (en) * | 1996-05-10 | 2002-10-31 | Icos Corp | carboline derivatives |
| US6331543B1 (en) | 1996-11-01 | 2001-12-18 | Nitromed, Inc. | Nitrosated and nitrosylated phosphodiesterase inhibitors, compositions and methods of use |
| DE19837069C1 (en) | 1998-08-17 | 2000-01-05 | Bayer Ag | New cinnamic acid derivatives useful as insecticide intermediates |
| EP1114048A1 (en) * | 1998-09-16 | 2001-07-11 | Agnès Bombrun | Carboline derivatives as cgmp phosphodiesterase inhibitors |
| DE19903087A1 (en) * | 1999-01-27 | 2000-08-10 | Forssmann Wolf Georg | Treatment of erectile dysfunction with C-type natriuretic polypeptide (CNP) as monotherapy or in combination with phosphodiesterase inhibitors |
| ES2213004T3 (en) | 1999-03-24 | 2004-08-16 | Harbor Branch Oceanographic Institution, Inc. | ANTI-INFLAMMATORY USES OF APPLES. |
| US6451807B1 (en) | 1999-04-30 | 2002-09-17 | Lilly Icos, Llc. | Methods of treating sexual dysfunction in an individual suffering from a retinal disease, class 1 congestive heart failure, or myocardial infarction using a PDE5 inhibitor |
| IL135817A0 (en) | 1999-04-30 | 2001-05-20 | Lilly Icos Llc | Phosphodiesterase enzyme inhibitors and their use in pharmaceutical articles |
| CA2407031A1 (en) | 2000-04-19 | 2001-10-25 | Lilly Icos Llc | Use of cyclic gmp-specific phosphodiesterase inhibitors for treatment of parkinson's disease |
| UA74826C2 (en) | 2000-05-17 | 2006-02-15 | Ortho Mcneil Pharm Inc | ?-carboline derivatives as phosphodiesterase inhibitors |
| ATE333457T1 (en) | 2000-06-23 | 2006-08-15 | Lilly Icos Llc | CYCLIC GMP-SPECIFIC PHOSPHODIESTERASE INHIBITORS |
| US6821978B2 (en) | 2000-09-19 | 2004-11-23 | Schering Corporation | Xanthine phosphodiesterase V inhibitors |
| EP1360185B1 (en) * | 2001-02-12 | 2005-08-24 | Lilly Icos LLC | Carboline derivatives |
| WO2002064591A2 (en) * | 2001-02-12 | 2002-08-22 | Lilly Icos Llc | Carboline derivatives |
| ES2278956T3 (en) * | 2001-04-25 | 2007-08-16 | Lilly Icos Llc | CARBOLINE DERIVATIVES AS PHOSPHODIESTERASE 5 (PDE5) INHIBITORS FOR THE TREATMENT OF CARDIOVASCULAR DISEASES AND ERECTILE DYSFUNCTION. |
| MXPA03011081A (en) * | 2001-06-05 | 2004-07-08 | Lilly Icos Llc | Carboline derivatives as pde-5 inhibitors. |
| ES2269679T3 (en) * | 2001-06-21 | 2007-04-01 | Lilly Icos Llc | CARBOLINE DERIVATIVES AS PDEV INHIBITORS. |
| EP1442042A1 (en) | 2001-11-09 | 2004-08-04 | Schering Corporation | Polycyclic guanine derivative phosphodiesterase v inhibitors |
| JP4554931B2 (en) * | 2001-12-20 | 2010-09-29 | メルク セローノ ソシエテ アノニム | Pyrrolidine derivatives as prostaglandin modulators |
| US7595311B2 (en) | 2002-05-24 | 2009-09-29 | Exelixis, Inc. | Azepinoindole derivatives as pharmaceutical agents |
| TWI329111B (en) | 2002-05-24 | 2010-08-21 | X Ceptor Therapeutics Inc | Azepinoindole and pyridoindole derivatives as pharmaceutical agents |
| PL1644021T3 (en) * | 2003-06-13 | 2013-01-31 | Ironwood Pharmaceuticals Inc | Methods and compositions for the treatment of gastrointestinal disorders |
| ES2427166T3 (en) * | 2003-06-23 | 2013-10-29 | Ono Pharmaceutical Co., Ltd. | Novel tricyclic heterocyclic compound |
| US8076353B2 (en) | 2004-03-15 | 2011-12-13 | Ptc Therapeutics, Inc. | Inhibition of VEGF translation |
| US8076352B2 (en) | 2004-03-15 | 2011-12-13 | Ptc Therapeutics, Inc. | Administration of carboline derivatives useful in the treatment of cancer and other diseases |
| US7767689B2 (en) | 2004-03-15 | 2010-08-03 | Ptc Therapeutics, Inc. | Carboline derivatives useful in the treatment of cancer |
| EA201200555A1 (en) | 2004-03-15 | 2013-01-30 | ПиТиСи ТЕРАПЬЮТИКС, ИНК. | DERIVATIVES OF CARBOLINE, USEFUL IN THE INHIBITION OF ANGIOGENESIS |
| CN1972916B (en) * | 2004-05-26 | 2013-03-27 | 卫材R&D管理有限公司 | Cinnamide compound |
| NZ551144A (en) | 2004-05-26 | 2009-12-24 | Eisai R&D Man Co Ltd | Cinnamide compound |
| DE602005019602D1 (en) | 2004-10-26 | 2010-04-08 | Eisai R&D Man Co Ltd | AMORPHIC FORM OF A CINEMA ACID AMID CONNECTION |
| PT1829874E (en) | 2004-12-22 | 2014-04-10 | Ono Pharmaceutical Co | Tricyclic compound and use thereof |
| US8506934B2 (en) | 2005-04-29 | 2013-08-13 | Robert I. Henkin | Methods for detection of biological substances |
| CA2620333A1 (en) | 2005-08-26 | 2007-03-01 | Braincells, Inc. | Neurogenesis by muscarinic receptor modulation |
| EP2258359A3 (en) | 2005-08-26 | 2011-04-06 | Braincells, Inc. | Neurogenesis by muscarinic receptor modulation with sabcomelin |
| CA2625153A1 (en) | 2005-10-21 | 2007-04-26 | Braincells, Inc. | Modulation of neurogenesis by pde inhibition |
| EP1942879A1 (en) | 2005-10-31 | 2008-07-16 | Braincells, Inc. | Gaba receptor mediated modulation of neurogenesis |
| NZ568694A (en) | 2005-11-09 | 2011-09-30 | Zalicus Inc | Method, compositions, and kits for the treatment of medical conditions |
| WO2007058304A1 (en) * | 2005-11-18 | 2007-05-24 | Eisai R & D Management Co., Ltd. | Salts of cynnamide compound or solvates thereof |
| CN101309916A (en) * | 2005-11-18 | 2008-11-19 | 卫材R&D管理有限公司 | Process for production of cinnamamide derivative |
| TWI370130B (en) | 2005-11-24 | 2012-08-11 | Eisai R&D Man Co Ltd | Two cyclic cinnamide compound |
| BRPI0618814A2 (en) | 2005-11-24 | 2014-04-29 | Eisai R&D Man Co Ltd | COMPOUND OR PHARMACOLOGICALLY ACCEPTABLE SALT OF THE SAME, AND PHARMACEUTICAL AGENT |
| US20070117839A1 (en) * | 2005-11-24 | 2007-05-24 | Eisai R&D Management Co., Ltd. | Two cyclic cinnamide compound |
| US20100216734A1 (en) | 2006-03-08 | 2010-08-26 | Braincells, Inc. | Modulation of neurogenesis by nootropic agents |
| TWI378091B (en) | 2006-03-09 | 2012-12-01 | Eisai R&D Man Co Ltd | Multi-cyclic cinnamide derivatives |
| JP2009536669A (en) | 2006-05-09 | 2009-10-15 | ブレインセルス，インコーポレイティド | Neurogenesis by angiotensin regulation |
| JP2009536667A (en) | 2006-05-09 | 2009-10-15 | ブレインセルス，インコーポレイティド | 5HT receptor-mediated neurogenesis |
| AR062095A1 (en) | 2006-07-28 | 2008-10-15 | Eisai R&D Man Co Ltd | CINAMIDE COMPOUND PROFARMACO |
| AU2007292848A1 (en) | 2006-09-08 | 2008-03-13 | Braincells, Inc. | Combinations containing a 4-acylaminopyridine derivative |
| US20100184806A1 (en) | 2006-09-19 | 2010-07-22 | Braincells, Inc. | Modulation of neurogenesis by ppar agents |
| US8293489B2 (en) | 2007-01-31 | 2012-10-23 | Henkin Robert I | Methods for detection of biological substances |
| TW200848054A (en) * | 2007-02-28 | 2008-12-16 | Eisai R&D Man Co Ltd | Two cyclic oxomorpholine derivatives |
| WO2008140111A1 (en) * | 2007-05-16 | 2008-11-20 | Eisai R & D Management Co., Ltd. | One-pot production process for cinnamide derivative |
| US7935815B2 (en) | 2007-08-31 | 2011-05-03 | Eisai R&D Management Co., Ltd. | Imidazoyl pyridine compounds and salts thereof |
| JP5433418B2 (en) | 2007-08-31 | 2014-03-05 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | Polycyclic compound |
| CN101925607A (en) * | 2008-01-28 | 2010-12-22 | 卫材R&D管理有限公司 | Crystalline cinnamide compounds or salts thereof |
| US8580801B2 (en) | 2008-07-23 | 2013-11-12 | Robert I. Henkin | Phosphodiesterase inhibitor treatment |
| WO2010099217A1 (en) | 2009-02-25 | 2010-09-02 | Braincells, Inc. | Modulation of neurogenesis using d-cycloserine combinations |
| US20150119399A1 (en) | 2012-01-10 | 2015-04-30 | President And Fellows Of Harvard College | Beta-cell replication promoting compounds and methods of their use |
| EP2903619B1 (en) | 2012-10-05 | 2019-06-05 | Robert I. Henkin | Phosphodiesterase inhibitors for treating taste and smell disorders |
| US10598672B2 (en) | 2014-02-18 | 2020-03-24 | Cyrano Therapeutics, Inc. | Methods and compositions for diagnosing and treating loss and/or distortion of taste or smell |
| CA2999503A1 (en) | 2015-09-23 | 2017-03-30 | Minerva Biotechnologies Corporation | Method of screening for agents for differentiating stem cells |
Family Cites Families (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3644384A (en) * | 1969-06-09 | 1972-02-22 | Sterling Drug Inc | Certain 2-(alpha-haloacetyl) - 1 2 3 4-tetrahydro - 9h - pyrido(3 4-b)indole-3-carboxylates and derivatives |
| US3717638A (en) * | 1971-03-11 | 1973-02-20 | Sterling Drug Inc | 1,2,3,4,6,7,12,12A-OCTAHYDRO-2-PHENYLPYRAZINO[2',1':6,1]PYRIDO[3,4-b]INDOLES AND INTERMEDIATES THEREFOR |
| US3917599A (en) * | 1973-03-30 | 1975-11-04 | Council Scient Ind Res | 2-Substituted-1,2,3,4,6,7,12,12A-octahydropyrazino(2{40 ,1{40 :6,1)pyrido(3,4-B)indoles |
| GB1454171A (en) * | 1973-10-19 | 1976-10-27 | Council Scient Ind Res | Tetracyclic compounds |
| US4188390A (en) * | 1977-11-05 | 1980-02-12 | Pfizer Inc. | Antihypertensive 4-amino-2-[4-(1,4-benzodioxan-2-carbonyl) piperazin-1-yl or homopiperazin-1-yl]quinazolines |
| GR79603B (en) * | 1982-07-24 | 1984-10-31 | Pfizer | |
| IT1217190B (en) * | 1988-04-22 | 1990-03-14 | Recordati Chem Pharm | USEFUL COMPOUNDS FOR THE TREATMENT AND DIAGNOSIS OF HURRY DYSFUNCTIONS |
| FI892362A (en) * | 1988-06-01 | 1989-12-02 | Eisai Co Ltd | BUTEN- ELLER PROPENSYRADERIVAT. |
| EP0357122A3 (en) * | 1988-08-29 | 1991-10-23 | Duphar International Research B.V | Use of beta-carbolines, their bio-isosteric benzofuran and benzothiophene analogues for the manufacture of a medicament having cytostatic properties |
| DE3830096A1 (en) * | 1988-09-03 | 1990-03-15 | Hoechst Ag | PIPERAZINDIONE WITH PSYCHOTROPER EFFECT |
| FR2649613B1 (en) * | 1989-07-11 | 1991-09-27 | Virag Ronald | VASO-ACTIVE MEDICINE |
| JPH0344324A (en) * | 1989-07-13 | 1991-02-26 | Kazuoki Tsuchiya | Sexual function invigorator |
| EP0459666B1 (en) * | 1990-05-31 | 1994-11-09 | Pfizer Inc. | Medicaments against impotence |
| US5270323A (en) * | 1990-05-31 | 1993-12-14 | Pfizer Inc. | Method of treating impotence |
| GB9013750D0 (en) * | 1990-06-20 | 1990-08-08 | Pfizer Ltd | Therapeutic agents |
| GB9114760D0 (en) * | 1991-07-09 | 1991-08-28 | Pfizer Ltd | Therapeutic agents |
| GB9218322D0 (en) * | 1992-08-28 | 1992-10-14 | Pfizer Ltd | Therapeutic agents |
| GB9311920D0 (en) * | 1993-06-09 | 1993-07-28 | Pfizer Ltd | Therapeutic agents |
| GB9401090D0 (en) * | 1994-01-21 | 1994-03-16 | Glaxo Lab Sa | Chemical compounds |
| DE69711882T2 (en) * | 1996-05-10 | 2002-10-31 | Icos Corp | carboline derivatives |
| US5874437A (en) * | 1996-11-01 | 1999-02-23 | Nitromed, Inc. | Nitrosated and nitrosylated phosphodiesterase inhibitor compounds, compositions and their uses |
| US6043252A (en) * | 1997-05-05 | 2000-03-28 | Icos Corporation | Carboline derivatives |
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1997
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- 1997-05-05 CN CN97194508A patent/CN1067071C/en not_active Expired - Fee Related
- 1997-05-05 ES ES97922960T patent/ES2175404T3/en not_active Expired - Lifetime
- 1997-05-05 KR KR1019980709066A patent/KR20000010918A/en not_active Application Discontinuation
- 1997-05-05 WO PCT/EP1997/002277 patent/WO1997043287A1/en not_active Application Discontinuation
- 1997-05-05 SK SK1544-98A patent/SK154498A3/en unknown
- 1997-05-05 AU AU28910/97A patent/AU711885B2/en not_active Ceased
- 1997-05-05 US US09/155,811 patent/US6117881A/en not_active Expired - Fee Related
- 1997-05-05 TR TR1998/02282T patent/TR199802282T2/en unknown
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- 1997-05-05 EP EP97922960A patent/EP0912567B1/en not_active Expired - Lifetime
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- 1997-05-05 AP APAP/P/1998/001365A patent/AP9801365A0/en unknown
- 1997-05-05 JP JP54045697A patent/JP3418405B2/en not_active Expired - Fee Related
- 1997-05-05 BR BR9709230A patent/BR9709230A/en not_active IP Right Cessation
- 1997-05-05 HU HU9901478A patent/HUP9901478A3/en unknown
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| AU711885B2 (en) | 1999-10-21 |
| PL329875A1 (en) | 1999-04-12 |
| YU49898A (en) | 2000-03-21 |
| EP0912567B1 (en) | 2002-04-10 |
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| IL126951A0 (en) | 1999-09-22 |
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| SK154498A3 (en) | 2000-01-18 |
| DE69711882D1 (en) | 2002-05-16 |
| US6306870B1 (en) | 2001-10-23 |
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| IS4864A (en) | 1998-10-13 |
| JP2000513717A (en) | 2000-10-17 |
| CA2253948A1 (en) | 1997-11-20 |
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