CA1219862A - Thiazine and thiazepine containing compounds - Google Patents
Thiazine and thiazepine containing compoundsInfo
- Publication number
- CA1219862A CA1219862A CA000447163A CA447163A CA1219862A CA 1219862 A CA1219862 A CA 1219862A CA 000447163 A CA000447163 A CA 000447163A CA 447163 A CA447163 A CA 447163A CA 1219862 A CA1219862 A CA 1219862A
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- Prior art keywords
- lower alkyl
- hydrogen
- carbons
- amino
- phenyl
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/04—1,3-Thiazines; Hydrogenated 1,3-thiazines
- C07D279/06—1,3-Thiazines; Hydrogenated 1,3-thiazines not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D281/02—Seven-membered rings
- C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D281/06—Seven-membered rings having the hetero atoms in positions 1 and 4 not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D281/02—Seven-membered rings
- C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/5537—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom the heteroring containing the structure -C(=O)-N-C(=O)- (both carbon atoms belong to the heteroring)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
- C07F9/6544—Six-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Abstract
ABSTRACT THIAZINE AND THIAZEPINE CONTAINING COMPOUNDS This invention is directed to compounds of the formula wherein X is a thiazine or thiazepine selected from These compounds possess angiotensin converting enzyme inhibition activity and are thus useful as hypotensive agents.
Description
HA~6Y
-l- 12~9862 THIAZINE AND THIAZEPINE CONTAINING COMPO~NDS
This invention is directed to the thiazine and thiaze?ine compounds of formula I and salts thereof (I) Rl O
1* 11 R~NH-X-CH- C - OR2 ~19~6~ -2-O O
Il * ll R isR3-C-CH- or R7-P-Rl is hydrogen, lower alkyl, amino substituted lower alkyl, hydroxy substituted lower alkyl, or halo substituted lower alkyl.
X is S
(CH~n ~ 5 ~ N-o R6 ~ or * N N
O o n is one or two.
R5 and R6 are independently selected from hydrogen, lower alkyl, -(CH2)- cycloalkyl and ( 2)m ~
(R14)p ~LZ~9~362 3 R3 is hydroxy, lower alkoxy, di(lower alkyl)-amino-lower alkoxy, lower alkyl-carbonyl-amino-lower alkoxy, lower alkyl-carbonyloxy-lower alkoxy, -O-(CH2)m ~ amlno, ( 14 p lower alkyl-amino, di(lower alkyl)amino, hydroxy-amino, benzylamino,phenethylamino or -O-salt forming ion.
R4 is hydrogen, lower alkyl, ( 2)m ~ ( 14 p ' halo substituted lower alkyl, hydroxy substituted lower alkyl, -(CH2) -cycloalkyl, -(CH2)q-carboxy, -(CH2)q-S-lower alkyl, ~(CH2)q ~ ' H
~(CH2)q~ IS ' ~ NH
N ~(CH2)q~NH~C
~(CH2)q~NH2 , -(CH2)q~N(lower alkyl)2 O O
-(CH2)q-NH-C-lower alkyl, ~(CH2)q~NH~C
~219862 _4_ HA269 -(cH2)q-sHl -(CH2)q-lower alkoxy, S ~ (CH2)q~0~~ (CH2)q~S~
( 14 p 14 p O O
Il 11
-l- 12~9862 THIAZINE AND THIAZEPINE CONTAINING COMPO~NDS
This invention is directed to the thiazine and thiaze?ine compounds of formula I and salts thereof (I) Rl O
1* 11 R~NH-X-CH- C - OR2 ~19~6~ -2-O O
Il * ll R isR3-C-CH- or R7-P-Rl is hydrogen, lower alkyl, amino substituted lower alkyl, hydroxy substituted lower alkyl, or halo substituted lower alkyl.
X is S
(CH~n ~ 5 ~ N-o R6 ~ or * N N
O o n is one or two.
R5 and R6 are independently selected from hydrogen, lower alkyl, -(CH2)- cycloalkyl and ( 2)m ~
(R14)p ~LZ~9~362 3 R3 is hydroxy, lower alkoxy, di(lower alkyl)-amino-lower alkoxy, lower alkyl-carbonyl-amino-lower alkoxy, lower alkyl-carbonyloxy-lower alkoxy, -O-(CH2)m ~ amlno, ( 14 p lower alkyl-amino, di(lower alkyl)amino, hydroxy-amino, benzylamino,phenethylamino or -O-salt forming ion.
R4 is hydrogen, lower alkyl, ( 2)m ~ ( 14 p ' halo substituted lower alkyl, hydroxy substituted lower alkyl, -(CH2) -cycloalkyl, -(CH2)q-carboxy, -(CH2)q-S-lower alkyl, ~(CH2)q ~ ' H
~(CH2)q~ IS ' ~ NH
N ~(CH2)q~NH~C
~(CH2)q~NH2 , -(CH2)q~N(lower alkyl)2 O O
-(CH2)q-NH-C-lower alkyl, ~(CH2)q~NH~C
~219862 _4_ HA269 -(cH2)q-sHl -(CH2)q-lower alkoxy, S ~ (CH2)q~0~~ (CH2)q~S~
( 14 p 14 p O O
Il 11
2 q 2 -(CH2)q-C-lower alkoxy, or (CH2)m-R15 -CH
\ NH-C
O . (R14) m is zero or an integer from 1 to 4.
q is an integer from 1 to 4.
R14 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, halo, trifluoromethyl, or hydroxy.
p is an integer from 1 to 3 provided that p is more than one only if R14 is hydrogen, methyl, methoxy, chloro, or fluoro.
. HA269 ~Z~L9~3~2 5 R15 is lower alkyl, cycloalkyl, or ( 14)p R7 is alkyl of l to lO carbons, -(CH2)5 ~ ~ , -(CH2)5-cycloalkyl, ( 14)p 2 t 2 ' (CH2) ~ ~ , -(CH ) ( 2)s ~ , or R9-c-NH-cH-cH2-s is zero or an integer from 1 to 7.
t is an integer from 1 to 8~
Rg and R12 are independently selected from lower alkyl, halo substituted lower alkyl, -(CH2)m-cycloalkyl, ( 2 m ~ (Rl4)p ( 2)m t ~ ' ~(CH2)m ~ ' and . ~2~862 HA269 ( 2 m ~
R8 and R2 are independently selected from hydrogen, lower alkyl, benzyl, benzhydryl, salt forming ion, or Oj -CH-O-C-R
Rlo Rlo is hydrogen, lower alkyl, cycloalkyl, or phenyl.
Rll is hydrogen, lower alkyl, lower alkoxy, cycloalkyl, phenyl, benzyl, or phenethyl.
This invention in its broadest aspects relates to the thiazine and thiazepine compounds of formula I
above, to compositions contalning such compounds and to the method of using such compounds as anti-hypertensive agents.
The term alkyl used in defining R7 refers to straight or branched chain hydrocarbon radicals having up to ten carbons, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, heptyl, octyl, decyl, etc. The term lower alkyl used in defining various symbols refers to straight or branched chain radicals having up to seven carbons. The preferred lower alkyl groups are up to four carbons with methyl and ethyl most preferred.
12198~i2 _7 HA269 Similarly, the terms lower alkoxy and lower alkylthio refer to such lower alkyl groups attached to an oxygen or sulfur.
The term cycloalkyl refers to saturated rings of 3 to 7 carbon atoms with cyclopentyl and cyclohexyl being most preferred.
The term halogen refers to chloro, bromo, and fluoro.
The term halo substituted lower alkyl refers to such lower alkyl groups described above in which one or more hydrogens have been replaced by chloro, bromo, or fluoro groups such as trifluoromethyl, which is preferred, pentafluoro-ethyl, 2,2,2-trichloroethyl, choromethyl, bromo-methyl, etc. Similarly, the terms amino substitu-ted lower alkyl and hydroxy substituted lower alkyl refer to such lower alkyl groups described above in which one or more hydrogens have been replaced by -NH2 or OH, i.e., aminome~hyl, 2-aminoethyl, 3-hydroxypropyl, etc.
The symbols ~(CH2)m~ ~ , (C 2 ~ S J
( 2)m ~ ~ -(CH2) t ~ ~ (CH2)m ~
12~986Z . HA269 and -(CH2)s ~ represent that the alkylene bridge is attached to an available carbon atom.
The compounds of formula I wherein R is R7-ll- and R7 is alkyl, -(CH2) ~
OR8 ( 14 p -(CH2)5-cycloalkyl, -(CH2) ~ 3 -(C~2) ~ ~ , or (C 2 ~ are prepared by coupling a phosphonochloridate of formula rI
wherein R8 is lower alkyl, benzyl or benzhydryl (II) O
R7-P-Cl with the thiazine or thiazepine ester of the formula (III) H2N- X ~ CH - C - OR2 1~9~
g_ Preferably, the thiazine or-thiazeDine ester of formula III is in its hydrochloride salt form and R2 is lower alkyl, benzyl or benzhydryl.
The products of formula I wherein either or both of R8 and R2 are lower alkyl, benzyl, or benzhydryl can be hydrogenated, for example, by treating with hydrogen in the presence of a ~alladium on carbon catalyst or chemically treated such as with sodium hydroxide in aqueous dioxane or with trimethylsilylbromide in dichloromethane to yield the products of formula I wherein R8 and R2 are hydrogen.
The ester products of formula I wherein 1~
R is -CH-O-C-R
Rlo may be obtained by emploving the thiazine or thia-zepine of formula III in the above reaction with the ester group already in place.
The ester products of formula I wherein R2 is -CH-O-C-Rll can also be obtained by treating R
the product of formula I wherein R2 is hydrogen with a molar equivalent of the compound of the formula . lZ1~62 HA269 (IV) o L-CH-O~C-R
wherein L is a leaving group such as chlorine, bro~ine, tolylsulfonyloxy, etc. The diester products wherein R8 and R2 are the same and are o -CH-O-C-Rll can be obtained by treating the product of formula I wherein R8 and R2 are both hydrogen or an alkali metal salt with two or more equivalents of the compound of formula IV.
The ester products of formula I wherein o R8 is -C~-O-C-Rll can be obtained by treating Rlo the product of formula I wherein R8 is hydrogen or an alkali metal salt and R2 is benæyl or benzhydryl with the compound of formula IV
in the presence of base. Removal of the R2 ester group such as by hydrogenation yields the products of formula I wherein R8 is HA2 6 9 ~1.219l~36;~
-CH-O-C-R
and R~ is hydrogen.
The phosphonochloridates of formula II are described in the literature and in particular by Kosolapoff et al. in Organic Phosphorous Compounds, Vol. 7, Chapter 18 (Wiley, 1972).
~he compounds of formula I wherein R is o R7-P- and R is -~CH ) -NH are prepared by reacting a phthalidyl protected compound of the formula (V) ~ N-(CH2)t- P Cl c OR8 wherein R8 is lower alkyl, benzyl or benzhydryl with the thiazine ester of formula III, preferably wherein R2 is benzyl, in the presence of triethylamine to yield the protected compound of the formula 121~8~i2: `
HA26~ -(VI~
o N - (CH2)~ P ~ H-X-CH - C-OR .
Il OR8 o Treatment with hydrazine removes the ph~halidyl protecting group after which the R8 and R2 ester group can be removed as described previously to yield the corresponding diacid com~ounds of formula I.
The phosphonochloridates of formula V can be prepared by treating a phthalidyl protected alkylbromide of the formula (VII) ~ ~-~CH2)t-Br Il .
o with a trialkylphosphite of the formula (VIII) P(O-alkyl)3 to yield the dles~er of the formula
\ NH-C
O . (R14) m is zero or an integer from 1 to 4.
q is an integer from 1 to 4.
R14 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, halo, trifluoromethyl, or hydroxy.
p is an integer from 1 to 3 provided that p is more than one only if R14 is hydrogen, methyl, methoxy, chloro, or fluoro.
. HA269 ~Z~L9~3~2 5 R15 is lower alkyl, cycloalkyl, or ( 14)p R7 is alkyl of l to lO carbons, -(CH2)5 ~ ~ , -(CH2)5-cycloalkyl, ( 14)p 2 t 2 ' (CH2) ~ ~ , -(CH ) ( 2)s ~ , or R9-c-NH-cH-cH2-s is zero or an integer from 1 to 7.
t is an integer from 1 to 8~
Rg and R12 are independently selected from lower alkyl, halo substituted lower alkyl, -(CH2)m-cycloalkyl, ( 2 m ~ (Rl4)p ( 2)m t ~ ' ~(CH2)m ~ ' and . ~2~862 HA269 ( 2 m ~
R8 and R2 are independently selected from hydrogen, lower alkyl, benzyl, benzhydryl, salt forming ion, or Oj -CH-O-C-R
Rlo Rlo is hydrogen, lower alkyl, cycloalkyl, or phenyl.
Rll is hydrogen, lower alkyl, lower alkoxy, cycloalkyl, phenyl, benzyl, or phenethyl.
This invention in its broadest aspects relates to the thiazine and thiazepine compounds of formula I
above, to compositions contalning such compounds and to the method of using such compounds as anti-hypertensive agents.
The term alkyl used in defining R7 refers to straight or branched chain hydrocarbon radicals having up to ten carbons, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, heptyl, octyl, decyl, etc. The term lower alkyl used in defining various symbols refers to straight or branched chain radicals having up to seven carbons. The preferred lower alkyl groups are up to four carbons with methyl and ethyl most preferred.
12198~i2 _7 HA269 Similarly, the terms lower alkoxy and lower alkylthio refer to such lower alkyl groups attached to an oxygen or sulfur.
The term cycloalkyl refers to saturated rings of 3 to 7 carbon atoms with cyclopentyl and cyclohexyl being most preferred.
The term halogen refers to chloro, bromo, and fluoro.
The term halo substituted lower alkyl refers to such lower alkyl groups described above in which one or more hydrogens have been replaced by chloro, bromo, or fluoro groups such as trifluoromethyl, which is preferred, pentafluoro-ethyl, 2,2,2-trichloroethyl, choromethyl, bromo-methyl, etc. Similarly, the terms amino substitu-ted lower alkyl and hydroxy substituted lower alkyl refer to such lower alkyl groups described above in which one or more hydrogens have been replaced by -NH2 or OH, i.e., aminome~hyl, 2-aminoethyl, 3-hydroxypropyl, etc.
The symbols ~(CH2)m~ ~ , (C 2 ~ S J
( 2)m ~ ~ -(CH2) t ~ ~ (CH2)m ~
12~986Z . HA269 and -(CH2)s ~ represent that the alkylene bridge is attached to an available carbon atom.
The compounds of formula I wherein R is R7-ll- and R7 is alkyl, -(CH2) ~
OR8 ( 14 p -(CH2)5-cycloalkyl, -(CH2) ~ 3 -(C~2) ~ ~ , or (C 2 ~ are prepared by coupling a phosphonochloridate of formula rI
wherein R8 is lower alkyl, benzyl or benzhydryl (II) O
R7-P-Cl with the thiazine or thiazepine ester of the formula (III) H2N- X ~ CH - C - OR2 1~9~
g_ Preferably, the thiazine or-thiazeDine ester of formula III is in its hydrochloride salt form and R2 is lower alkyl, benzyl or benzhydryl.
The products of formula I wherein either or both of R8 and R2 are lower alkyl, benzyl, or benzhydryl can be hydrogenated, for example, by treating with hydrogen in the presence of a ~alladium on carbon catalyst or chemically treated such as with sodium hydroxide in aqueous dioxane or with trimethylsilylbromide in dichloromethane to yield the products of formula I wherein R8 and R2 are hydrogen.
The ester products of formula I wherein 1~
R is -CH-O-C-R
Rlo may be obtained by emploving the thiazine or thia-zepine of formula III in the above reaction with the ester group already in place.
The ester products of formula I wherein R2 is -CH-O-C-Rll can also be obtained by treating R
the product of formula I wherein R2 is hydrogen with a molar equivalent of the compound of the formula . lZ1~62 HA269 (IV) o L-CH-O~C-R
wherein L is a leaving group such as chlorine, bro~ine, tolylsulfonyloxy, etc. The diester products wherein R8 and R2 are the same and are o -CH-O-C-Rll can be obtained by treating the product of formula I wherein R8 and R2 are both hydrogen or an alkali metal salt with two or more equivalents of the compound of formula IV.
The ester products of formula I wherein o R8 is -C~-O-C-Rll can be obtained by treating Rlo the product of formula I wherein R8 is hydrogen or an alkali metal salt and R2 is benæyl or benzhydryl with the compound of formula IV
in the presence of base. Removal of the R2 ester group such as by hydrogenation yields the products of formula I wherein R8 is HA2 6 9 ~1.219l~36;~
-CH-O-C-R
and R~ is hydrogen.
The phosphonochloridates of formula II are described in the literature and in particular by Kosolapoff et al. in Organic Phosphorous Compounds, Vol. 7, Chapter 18 (Wiley, 1972).
~he compounds of formula I wherein R is o R7-P- and R is -~CH ) -NH are prepared by reacting a phthalidyl protected compound of the formula (V) ~ N-(CH2)t- P Cl c OR8 wherein R8 is lower alkyl, benzyl or benzhydryl with the thiazine ester of formula III, preferably wherein R2 is benzyl, in the presence of triethylamine to yield the protected compound of the formula 121~8~i2: `
HA26~ -(VI~
o N - (CH2)~ P ~ H-X-CH - C-OR .
Il OR8 o Treatment with hydrazine removes the ph~halidyl protecting group after which the R8 and R2 ester group can be removed as described previously to yield the corresponding diacid com~ounds of formula I.
The phosphonochloridates of formula V can be prepared by treating a phthalidyl protected alkylbromide of the formula (VII) ~ ~-~CH2)t-Br Il .
o with a trialkylphosphite of the formula (VIII) P(O-alkyl)3 to yield the dles~er of the formula
3~
(IX) O
N-(CH2)t- P-Oalkyl Oalkyl o Treatment of this diester with trimethylsilyl-bromide yields the phosphonic acid of the formula (X) o lS \ N-ICH2)t p-OH
The acid of formula X can then be treated with phosphorous pentachloride and an alcohol of the formula (XI) R -OH
in the presence of triethylamine to give the compound of formula V.
The compounds of formula I wherein R is O
R7-P- and R7 is R -C-NH_CH-CH2- are l~lg~362 . HA269 1~--prepared as follows. A protected amine of the formula (XII) Ts-NH-CH-CH2-O-Ts wherein Ts is tolylsulfonyl, i.e., -S2 ~ CH3 , is reacted with sodium diethvl phos-ll ~honate,i.e., Na-P-OC2H5 , to yield the intermediate of the formula (XIII) o Ts-NH-CH - CH2 P-OC2H5 Treatment with hydrogen bromide (48~) in the presence of phenol with heat yields the aminophosphonic acid of the formula (XIV) O
il Rl2 OH
3~
_15-The aminophosphonic acid of formula XIV isthen reacted with benzoyloxycarbonyl chloride or phthalic anhydride to yield (XV) O
Prot-NH-CH-CH2- P-OH
wherein Prot is benzyloxycarbonyl or phthalidvl.
The acid of formula XV is then converted to the phosphonochloridate of the formula (XVI) O
Il Prot-NH-CH-CH2- P-Cl wherein R8 is lower alkyl, benzyl or benzhydryl by treating XV with triethylorthoformate, benzyl bromide, etc., followed by treatment with thionyl chloride or phosphorus pentachloride.
The acid chloride of formula XVI is then coupled with the thiazine or thiazepine ester of formula III to yield the intermediate of the formula (XVII) 3 Rl Prot-NH-CH-CH - P - NH-X-CH- C-OR2 ~2~3~
Removal of the protecting group such as byhydrogenation where Prot is benzoyloxycarbonyl or by treatment with hydrazine where Prot is phthalidyl followed by reaction with the acid chloride of the formula tXVIII) o Il Rg-C-Cl yields the desired products of formula I.
The thiazine or thiazepine ester of formula III wherein R5 is other than hydrogen can be prepared as follows. A phthaloyl amino acid of the formula (XIX) SH
O . I
~ (I 2 n 1~
O
is reacted with an N-substituted glycine ester of the formula (XX) R5-CH=N-CH2-COOR2 in the presence of a coupling agent such as dicyclohexylcarbodiimide to yield the N-protected thiazine or thiazepine of the formula ~21~38~i2 (XXI) ~ ~N ~ N~R2 o o Treatment of the compound of formula XXI with methylhydrazine removes the phthalimido protecting group and yields the desired thiazine or thiazepine ester of formula III.
The N-protected thiazine or thiazepine of formula XXI can also be prepared by cyclizing a sulfoxide of the formula (XXII) O
~ (CH2) ll C- NH CH2 COOR2 O O
~2~91862 [prepared as set forth by Wolfe et al., Can. J.
Chem., Vol. 57, p. 2412 - 2425 (1979)] by treatment with a mixture of trifluoroacetic acid anhydride and acetic anhydride followed by 2,6-lutidine.
The thiazine or thiazepine ester of formula III wherein R5 is hydrogen can be prepared as follows. A dithiobis amino acid of the formula (XXIII) ~S-(CH ) -CH-COOH]
is reacted with N-carboethoxyphthalimide to give the compound of the formula (XXIV) [S-(CH2)n CH COOH]2 O ~ ~ O
<~
which is treated with a glycine ester hydrochloride in the presence of base and a coupling agent such as carbonyldiimidazole to yield the compound of the formula ~ 8~2 HA269 ( XXv ) O
[S-(CH2) - CH-C-NH-CH -COOR ]
N
~>
The dithiobis compound of formula XXV is treated with zinc dust to yield (XXVI) f HS-(CH2)n CH - C-NH-CH2-COOR2 O ~ ~
,~
which is then treated with bromomethyl methyl ether in the presence of pyridine to give (XXVII) O
H3COCH2~s~(cH2)n CH-C-NH-CH2-COOR2 N
0-~0 <~>
1219~3~2 The compound of formula XXVII is cyclized by treatmentwith camphorsulfonic acid to give the N-protected thiazine or thiazepine of the formula (XXVIII) Il ~S~
~/\ (CH~n I
~ N ~ N-CH2-COOR2 o Treatment of the compound of formula XXVIII
methylhydrazine removes the phthalimido protecting group and yields the desired thiazine or thiazepine ester of formula III~
The thiazepine ester of formula III
20 wherein X is S ~ R5 )- R
~_ N
Il \
O
3L2~86;~
can be prepared as follows. An N-protected serine, for example~ a t-butyloxycarbonyl N-protected serine, is treated with methanol and cesium carbonate to yield the corresponding N-protected serine methyl ester. This methyl ester is then treated with diisopropylcarbodiimide and cuprous chloride to yield the N protected dehydroalanine methyl ester of the formula (XXIX) Prot-NH-C-C02CH3 Treatment of the compound of formula XXIX
with the aminothiol hydrochloride of the formula (xXx) l6 HS - CH - CH-NH2 HCl in the presence of base yields the methyl ester of the formula (XXXI) R5 l6 Prot-NH-CH - CO2CH3 ~ ~.98~2 The compound of formula XXXI is converted to the carboxylic acid and then cyclized by treatment with diphenylphosphoryl azide to yield the compound of the formula (XXXII) /s ~
¦ )- R
Prot-NH ~ NH
ll o The thiazepine of formula XXXII is treated with a bromoacetate of the formula (XXXIII) R O
Br-CH -C-OR2 to yield the compound (XXXIV) Prot-NH ~ ~ 6 1l ~ N - CH - C - OR
O
Removal of the protecting group, for example, by treating with hydroqen chloride in ethyl acetate when Prot is t-butyloxycarbonyl yields the desired thiazepine ester of formula III.
. ~198162 -23- _ HA269 The thiazepine ester of formula III
wherein X is N--o can be prepared as follows. The N-protected dehydroalanine methyl ester of formula XXIX
is reacted with 2-aminothiophenol and 2,6-lutidine to give the compound of formula tXXXV) ~3 Prot-NH - CH C2CH3 The methyl ester of formula XXXV is converted to the carboxylic acid and then cyclized by refluxing in xylene to give the compound of formula (XXXVI) S ~ >
Prot-NH ~ NH
:12~98 6,~
The thiazepine of formula XXXVI i5 treated with the bromoacetate of formula XXXIII and the N-protecting group is removed as described above to give the deslred thiazepine ester.
S The compounds of formula I wherein R is o R3-C-CH- can be prepared as follows. A keto compound of the formula (XXXVII) o R3-C-C=O
is reacted with the thiazine or thiæepine of fon~a III
in the presence of sodium cyanoborohydride to yield the ester of formula I.
If desired, the R2 and R3 ester groups can then be removed to yield the corresponding diacid compound.
The compounds of formula I wherein R3 is lower alkoxy and R2 is hydrogen can be prepared by conver~ing the thiazine or thiazepine ester of formula II wherein R2 is ethyl to the corresponding trimethyl-silylethyl ester prior to reaction with the ketone of formula II. The resulting product can then be treated to remove the R2 trimethylsilylethyl ester group such as by use of tetrabutylammonium fluoride while leaving the R3 ester group in place.
~21~362 HA269 In the above reactions if R4 ls -(CH2)q ~ OH , ~(CH2)q ~ ~ ( 2)q 2' OH
/NH
~(CH2)q ~ ~N , ~(CH2)q~SH, or ~(CH2)q~NH~C
or if Rl is amino or hydroxy substltuted lower alkyl then the hydroxyl, amino, imidazolyl, mercaptan, or guanidinyl function should be ~rotected during the coupling reaction. Suitable protecting groups include benzyloxycarbonyl, t-butoxycarbonyl, benzyl, benzhydryl, trityl, etc., and nitro in the case of guanidinyl. The protecting group is removed by hydrogenation, treatment with acid, or other known methods following completion of the reaction.
Preferred compounds of this invention are those of formula I wherein:
R3 is hydroxy,lower alkoxy of 1 to 4 carbons, or -O-alkali metal salt.
~ (CH2) R4 is -(CH2)m ~ or -CH
NH-C
81~Z
m is zero, one, two or three.
R7 is alkyl of 1 to 10 carbons, -(CH2)s ~ ~ -(CH2)t-NH2, or Rg~C-NH-CH-CH -.
Rg and R12 are selected from lower alkyl of 1 to 4 carbons and ( 2)m ~ , especially wherein Rg is phenyl and R12 is benzyl or phenethyl.
s is zero or an integer from 1 to 7.
t is an integer from 1 to 8.
R14 is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro, or hydroxy.
Rl is hydrogen, lower alkyl of 1 to 4 carbons, or -(CH2)4-NH2 R5 and R6 are independently selected from hydrogen, lower alkyl of 1 to 4 carbons, and (C 2)m ~
~:2~L~8~2 R8 and R2 are independently selected from hydrogen, lower alkyl of 1 to 4 carbons, alkali metal salt, or O
-CH-O-C-R
Rlo is hydrogen, straight or branched chain lower alkyl of 1 to 4 carbons, or cyclohexyl.
R11 is straight or branched chain lower alkyl of 1 to 4 carbons, cyclohexyl or phenyl.
Most preferred compounds of this invention are those of formula I wherein:
~ , ~ N- , O O
~S~ ~
~ N- , or N-O O
g86~
R3 is hydroxy,ethoxy, or -O-alkali metal salt.
R4 is -(CH2)2 ~
R7 is alkyl of 1 to 10 carbons or -(CH2j ~ wherein s is zero or an integer from 1 to 7, especially -(CH2)4 ~ .
R1 is hydrogen.
R5 is hydrogen or phenyl.
R8 and R2 are independently selected from hydrogen, alkali metal salt, and CH-O-C-R provided that only one of R2 and R8 is 11 -CH-O-C-R
Rlo R1o is hydrogen, stralght or branched chain lower alkyl of 1 to 4 carbons, or cyclohexyl.
R11 is straight or branched chain lower alkyl of 1 to 4 carbons.
The compounds of this invention wherein a~ least one of R8 or R2 is hydrogen or R3 is hydroxy, form basic salts with various inorganic and organic bases which are also within the scope of the invention.
~2~L9~
Such salts include ammonium salts, alkali metalsalts like lithium, sodium and potassium salts (which are preferred), alkaline earth metal salts like calcium and magnesium salts, salts with organic bases, e.g., dicyclohexylamine salt, benzathine, N-methyl-D-glucamine, hydrabamine salts, salts with amino acids like arginine, lysine and the like. The nontoxic, physiologically acceptable salts are preferred, although other salts are also useful, e.g., in isolating or purifying the product. The salts are formed using conventional techniques.
The symbol * is used to represent varlous asymmetric centers which may be present in the compounds of formula I. Thus, the compounds of this invention can accordingly exist in diastereoisomeric forms or in mixtures thereof.
The above described processes can utilize racemates, enantiomers or diastereomers as starting materials. When diastereomeric products are prepared, then can be separated by conventional chromatographic OL- fractional crystallization methods.
The compounds of formula I, and the ohysiologically acceptable salts thereof, are hypotensive agents. They inhibit the conversion of the decapeptide angiotensin I to angiotensin II and, therefore, are useful in reducing or relieving angiotensin related hypertension.
The action of the enzyme renin on angiotensinogen, ~215~8~62 a pseudoglobulln in blood plasma, producesangiotensin I. Angiotensin I is converted by angiotensin converting enzyme (ACE) to angio-tensin II. The latter is an active pressor substance which has been implicated as the causative agent in several forms of hyoertension in various mammalian species, e.g., humans. The compounds of this invention intervene in the angiotensinogen ~ (renin) ~ angiotensin I -~
angiotensin II sequence by inhibiting angiotensinconverting enzyme and reducing or eliminating the formation of the pressor substance angio-tensin II. Thus by the administration of a composition containing one (or a combination) of the compounds of this invention, angiotensin dependent hypertension in a species of mammal (e.g., humans) suffering therefrom is alleviated.
A single dose, or preferably two to four divided daily doses, provided on a basis of about 0.1 to 100 mg. per kilogram of body weight per day is appropriate to reduce blood pressure. The substance is preferably administered orally, but parenteral routes such as the subcutaneous, intramuscular, intravenous or intraperitoneal routes can also be employed.
The compounds of this invention can also be formulated in combination with a diuretic for the treatment of hypertension. A combination product comprising a compound of this invention and a diuretic can be administered in an ~986,2 effectlve amount which comprises a total daily dosage of about 30 to 600 mg., preferably about 30 to 330 mg. of a compound of this invention, and about 15 to 300 mg., preferably about 15 to 200 mg. of the diuretic, to a mammalian species in need thereof. Exemplary of the diuretics contemplated for use in combination with a compound of this invention are the thiazide diuretics, e.g., chlorothiazide, hydrochloro-thiazide, flumethiazide, hydroflumethiazide,bendroflumethiazide, methyclo~hiazide, trichlor-methiazide, polythiazide or benzthiazide as well as ethacrynic acid, ticrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamterene, amiloride and spironolactone and salts of such compounds.
The compounds of formula I can be formulated for use in the reduction of blood pressure in compositions such as tablets, capsules or elixirs for oral administration, or in sterile solutions or suspensions for parenteral administration.
About 10 to 500 mg. of a compound of formula I
is compounded with physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is sush that a suitable dosage in the range indicated is obtained.
.1219862 HA269 The following examples are illustrative of the invention. Temperatures are given in degrees centigrade. AG-50W-X8 refers to a crosslinked polystyrene-divinylbenzene sulfonic acid cation exchange resin. HP-20 refers to a porous cross-linked polystyrene-divinylbenzene polymer resin.
* Trade Mark " 12198~i2 Example 1 (R)-Dihvdro-5-[[Hydroxy~4-phenylbutYl)Phosphinvl]
amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, dilithium salt _ a) N-Phthaloyl-L-cysteine A solution of N,N'-diphthaloyl-L-cystine (19.5 g., 38.9 mmole) in a mixture of trifluoroacetic acid (60 ml.) and dry tetra-hydrofuran (200 ml.) is cooled in an ice-bath under nitrogen and treated with zinc dust (15.3 g., 233.4 mmole) in three equal portions over a per~od of 15 minutes. The reaction is stirred cold for 2 hours, then filtered (~elite) and concentrated _ vacuo. The residue is partitioned between 600 ml. of ethyl acetate:ether (5:1) and a water-brine mixture. The organic layer is washed with water, brine and dried (MgSO4). Removal of the solvents in vacuo yields 21.9 g. of crude product which is flash chromatogra-phed on silica gel (400 g.) eluting with toluene:acetic acid (6:1). Fractions containing the desired product are combined to give 12.1 g. of N-phthaloyl-L-cysteine as an oil. []D= -54.2 (c = 1, methanol).
TLC (toluene/acetic acid; 6:1) spot at ~f = 0.30.
b) N-8enzYlidineglYcine, ethyl ester A mixture of glycine, ethyl ester, hydro-chloride (10 g., 71.6 mmole~, triethylamine (14.5 g., 143.2 mmole), and anhydrous MgSO4 (6.0 g., 50.1 mmole) in dry methylene chloride (150 ml.) is treated with a solution of benzaldehyde (7.6 g., 71.6 mmole) in methylene chloride (10 ml.) added * Trade Mark ;2 over a period of 15 minutes. After 5 hours, the reaction mixture is filtered, concentrated in vacuo, and then partltioned between 400 ml. of ether and 50 ml. of water. The organic layer is washed with S water and brine, dried (MgSO4), and concentrated in vacuo to give 12.1 g. of N-benzylidineglycine, ethyl ester.
c) (R)-Dihydro-5-phthalimido-4-oxo-2-phenvl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester To a solution of N-phthaloyl-L-cysteine(15.8 g., 62.8 mmole) and N-benzylidineglycine, ethyl ester (12.3 g., 64.3 mmole) in dry chloroform (160 ml.) cooled in an ice bath under nitrogen is added dicyclo-hexylcarbodiimide (13.0 g., 62.8 mmole) in one porti~.
After 2 hours, the cold reaction mixture is filtered, concentrated in vacuo and redissolved in a mixture of ether (500 ml.) and chloroform (200 ml.). The organic extract is washed with saturated aqueous sodium bicar-bonate, water, 5% potassium bisulfate and brine, dried (MgSO4) and concentrated in vacuo to give 23.8 g. of crude product. Flash chromatography on silica (600 g.) eluting with hexane:ethyl acetate (3:1) yields 15.6 g.
of (R)-dihydro-5-phthalimido-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H) acetic acid, ethyl ester as a diastereomerlc mixture.
d) (R)-Dihydro-5-amino-4-oxo-2-PhenY1-2H-~3-thiaæine-3(4H)-acetic acid, ethyl ester A mixture of (R)-dihydro-5-phthalimido-4-oxo-2-phenyl-2H-l~3-thiazine-3(4H)-acetic acid, ethyl ester (1.5 g., 3.5 mmole), methylhydraæine (0.3 ml., 1.6 eq.), and chloroform (10 ml.) is stirred at 25 in an argon atmosphere for 48 hours. The heterogeneous mixture is diluted with ethyl acetate, filtered,washed with water, ~2~8~2 _35_ HA269 brine, and evaporated. The residue is taken up into 5~ potassium bisulfate and washed with ethyl acetate. The aqueous phase is made basic with saturated sodium bicarbonate, extracted with methylene chloride (twice), dried (MgS04), and evaporated to give 720 mg.
of (R)-dihydro-5-amino-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester as an oil.
TLC (7:2:1, isopropanol/conc. NH40H/water)major spot at Rf = 0.77.
e) Chloro _-phenylbutyl)phosphinic acid, ethyl ester A mixture of 4-phenylbutyl chloride (8.0 g., 47.5 mmole) and triethylphosphite (15.0 ml., 72 mmole) is heated at reflux (bath temperature 185) under argon for 41.5 hours. Distillation of the mixture gives 10.8 g~
of diethyl (4-phenylbutyl)phosphonate as a colorless liquid; b.p. 152-154 (1.0 mm of Hg.).
A mixture of diethyl (4-phenylbutyl) phosphonate (0.73 g., 2.6 mmole), benzene (10 ml.) and phosphorus pentachloride (1.0 eq.) is refluxed under argon for 30 minutes. The benzene and phosphorus oxychloride are removed ln vacuo to give chloro(4-phenylbutyl) phosphinic acid, ethyl ester.
198~
f) (R)-Dihydro-5-[[ethoxy(4-phenylbutyl)phosphinyl]-amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester A mixture of the crude chloro (4-phenyl-butyl)phosphinic acid,ethyl ester (2.6 mmole),dry methylene chloride (9.0 ml.) and (R)-dihydro-5-amino-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester (0.72 g., 2.4 mmole) at 0 (ice bath) in an argon atmosphere is treated dropwise with triethylamine (0.44 ml., 1.3 eq.) in methylene chloride (2 ml.) over 5 mi~utes.
After 30 minutes, the ice bath is removed and the reaction mixture is stirred at room temperature for 16 hours. The mixture is diluted with ethyl acetate and washed successively with saturated sodium bicarbonate, 5% potassium bisulfate, brine, dried (MgSO4), and evaporated.
The residue (1.5 g.) is chromatographed on silica (80 g.) eluting with hexane/acetone (2:1) to give 1.0 g. of (R)-dihydro-5-[[ethoxy(4-phenyl-butyl)phosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester as an oil after evaporation. TLC (hexane/acetone, 2:1) single spot at Rf = 0.5.
g) (R)-Dihydro-5-[[hydroxy(4-phenYlbutyl)phosphi~y~
amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, dilithium salt A mixture of the diethyl ester product from part (f) (1.0 g., 1.93 mmole), methylene chloride (4 ml.) and bromotrimethylsilane (0.5 ml., 2.0 eq.) 1219~3~2 is stirred at room temoerature under argon for16 hours. The methylene chloride and excess bromotrimethylsilane are removed in vacuo and the residue is taken up in acetonitrile (6 ml.) and lN lithium hydroxide (6.0 ml., aoproximately 3.0 eq.). After 2 hours the acetonitrile is evaporated, the aqueous solution is filtered, and chromatographed on an HP-20 (200 ml.) column eluting with a linear gradient of water-acetonitrile (0 -~ 90~ acetonitrile). The desired fractions are combined, evaporated to a small volume, filtered (millipore)~ and lyophilized to give 385 mg. of (R)-dihydro-S-[[(hydroxy(4-phenylbutyl)phosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, dilithium salt as a fluffy white solid. TLC (7:2:1 isopropanol/
concentrated NH40H/water) isomers Rf = 0.66, 0.62. [~]D = ~5 5 (c=l.O,H2O);m.p. 215 (decomp.).
Anal. calc'd. for C22 H25N2O5S 2 2 C, 51.95; H, 5.71; N, 5.51; S, 6.30; P, 6.1 Found: C, 51.92; H, 5.32; N, 5.48; S, 6.40; P, 6.1.
Example 2 5-[[Hydroxy(4-phenylbutYl)phos~hinyl]amino]-tetrahydro-4-oxo-1,3-thiazepine-3(2H)-acetLc acid, dilithium salt a) Bis(phthaloyl)homocystine A mixture of homocystine (5.36, 0.02 mole), soldium carbonate (4.24 g., 0.04 mole) and N-carboethoxyphthalimide (9.7 g., 0.044 mole) in water (50 ml.) is stirred for 4 hours, during which ~2~ 2 ~A269 time it becomes homogeneous. The reaction mixture is washed with ethyl acetate, acidified with concentrated hydrochloric acid, and extracted with methylene chloride. The extracts are dried and evaporated to a residue which is chromatographed on silica gel eluting with methylene chloride/methanol/acetic acid (40:1:1).
The major fraction is crystallized from acetic acid, washed with water and dried to give 7.7 g. of bis(phthaloyl)homocystine as a white solid.
b) gi~(Phthoyl)homocystinyl~Llycine~ ethyl ester A solution of bis(phthaloyl) homocystine (7.0 g., 0.013 mole) and carbonyldiimidazole (4.3 g., 0.026 mole) in tetrahydrofuran (40 ml.) is stirred for 1 hour at 0, then treated with triethylamine (7.4 ml., 0.052 mole) and glycine, ethyl ester, hydrochloride (4.0 g., 0.026 mole).
The mixture is stirred for 4 hours at room temperature, diluted with ethyl acetate, and washed with saturated sodium bicarbonate, 5~
potassium bisulfate, and brine. The solution is dried (MgSO4) and evaporated to a residue which is chromatographed on silica gel eluting with ethyl acetate/hexane (5:4). The major fraction (4.7 g.) is bis(phthaloyl)homocystinylglycine~
ethyl ester.
9~362 c)_ N-Phthaloyl-hOmocysteinvlqlvcine, ethYl ester A mixture of bis(phthaloyl)homocystinylglycine, ethyl ester (2.9 g., 0.041 mole) and acetic acid (8.2 ml.) in ethanol (40 ml.) is treated with zinc dust (1.62 g.) and stirred at room temperature for 1 hour. The mixture is filtered, the filtrate evaporated, and the residue taken up in ethyl acetate and washed with water and brine.
The solution is evaporated to yield 2.9 g. of N~phthaloyl-homocysteinylglycine, ethyl ester as a yellow semi-solid.
d) N-phthaloyl-s-(methoxymethyl)homocysteiny-4LL~
ethyl es_er A solution of N-phthaloylhomocysteinylglycine, ethyl ester (0.97 g., 2.8 mmole) and pyridine (0.67 ml., 8.4 mmole) in methylene chloride (4 ml.) is added dropwise to bromomethyl methyl ether (0.56 ml., 7.0 mmole) in methylene chloride (1.5 ml.) at 0 under argon. The mixture is stirred for 2 hours at room temperature, then additional pyridine (0.67 ml., 8.4 mmole) and bromomethyl methyl ether (0.56 ml., 7.0 mmole) are added and the mixture is stirred 1.5 hours longer. The mixture is washed with water, 5%
potassium bisulfate, dried (MgSO4) and evaporated to yield a residue which is chromatographed on silica gel eluting with ethyl acetate/hexane (1:1) to give 0.78 g. of N-phthaloyl-S-(methoxymethyl) homocysteinylglycine, ethyl ester as an oil.
86~
e) 5-Phthalimido-tetrahydro-4-oxo-1,3-thia-zepine-3(2H)-acetic acid, ethyl ester N-Phthaloyl-S-(methoxymethyl) homocysteinyl-glycine, ethyl ester (0.76 g., 2.0 mmole) and camphorsulfonic acid (0.01 g.) in benzene (15 ml.) are refluxed for 1 hour. Additional camphorsulfonic acid (0.05 g.) is added and reflux is continued for 2 more hours after which anhydrous p-toluenesulfonic acid (0.1 g.) is added and the mixture is refluxed for 20 hours.
The mixture is then diluted with ethyl acetate and washed with saturated sodium bicarbonate, 5 potasslum bisulfate, and brine, dried (MgS04) and evaporated. The residue is chromatographed on silica gel eluting with ethyl acetate to yield a main fraction which is then crystallized from toluene to give 0.51 g. of 5-phthalimido-tetra-hydro-4-oxo-1,3-thiazepine-3(2H)-acetic acid, ethyl ester as a crystalline solid; m.p.
191.5 - 193.5.
f) 5-Amino-tetrahvdro-4-oxo-1,3-thiazepine-3(2H)-acetic acid, ethyl ester A mixture of 5-phthalimido-tetrahydro-4-oxo-1,3-thiazepine-3(2H)-acetic acid, ethyl ester (0.48 g., 1.3 mmole) and methylhydrazine (0.12 ml.) in acetonitrile is stirred at room temperature for 3 days. The reaction mixture is diluted with ethyl acetate, filtered and evaporated to a residue which is taken up in 5~ pot:assium bisulfate and washed with ethyl acetate. The aqueous phase ~2~9~362 is saturated with sodium bicarbonate and extractedwith methylene chloride. The extracts are dried and evaporated to yield 0.2 g. of 5-amino-tetrahydro-4-oxo-1,3-thiazepine-3(2H)-acetic acid, ethyl ester as an oil. TLC (silica gel, 10 methanol in methylene chloride) Rf = 0.19.
g) 5-[[Ethoxy(4-phenylbutyl)phosphinyl]amino]-tetrahydro-4-oxo-1,3-thiazepine-3t2H)-acetic cid, ethyl ester A mixture of crude chloro(4-phenylbutyl) phosphinic acid, ethyl ester, dry methylene chloride and 5-amino-tetrahydro-4-oxo-1,3-th1azepine-3(2H)-acetic acid, ethyl ester are reacted as set forth in Example l(f). Work up of the reaction mixture according to Example l(f) yields 5-[[ethoxy-(4-phenylbutyl)phosphinyl]amino]tetrahydro-4-oxo-1,3-thiazepine-3(2H)-acetic acid, ethyl ester.
- h) 5-[[Hydroxy(4-phenYlbutyl)phosphinyl]amino]-tetrahydro-4-oxo-1,3-thiazepine-3(2H)-acetic acid, dilithium salt The diethyl ester product from part (g) is treated with bromotrimethylsilane according to the procedure of Example 1(~) and the resldue is treated with lN lithium hydroxide and worked up as set forth in Example 1(~) to give 5-[[hydroxy(4-phenylbutyl)phosphinyl]amino]-tetrahydro-4-oxo-1,3-thiazepine-3(2H)-acetic acid, dilithium salt.
386~
.
Examples 3 - 16 Following the procedures of Examples 1 and 2, the thiazine or thiazepine sh~ bel~w in Col.I is reacted with the phosphinic acid ester shown in Col. II to give the ester product shown in Col. III. The R2 and R8 ester groups can be removed to give the corresponding diacid which can then be converted to a salt or in the case of Examples 15 and 1 only the X8 ester group would be removed. The Rl protecting ~roup shown in Examples 6 and 10 would be removed as the last step of the synthesis.
~L2:1~8~i2 -43_ HA269 Col (CH2)n ~/
2 ~/N--ICH-COOR2 o R
Col. II
OR~
- Col. III
(CH2)n~
R7-- p NH--~N--CH-COOR2 8 Rl ~219~3~2: HA2 6 9 ~r) ,f. ~
3~ ~ N
, I N N N N N N
~r ~9 N
N N Nr--~ ~
-- t')t )N N N
,,. N N N N ~_~N
O . ~
"~
~" N
I ~ y ~~, Y Y
N ~ N
~I N _I N ~1 N .--1 a) ~ll2 ~L981~ HA2 6 9 Ln u~u7 n ~ U~ ~
~r D U ~ $
N ~
~iL2~L98~2 U~
C~
U
I
o--o ' o =o ~
~ O~ O a ~ " ~
a) I
_4_ HA269 Example 17 Tetrahydro-6-[[hYdroxy(4-~henylbutyl)~hosphinyl]-amino]-5-oxo-1,4-thiazepine-4(5H)-acetic acid, dilithium salt a) N-~(l,l-Dimethylethoxy)carbonyl]-L-serine, methyl ester To a solution of N-[(l,l-dimethylethoxy)-carbonyl]-L-serine (20.5 g., 0.1 mole), methanol (50 ml.), and water (10 ml.) is added cesium carbonate (16.3 g., 0.5 eq.~. After 5 minutes the solution becomes homogeneous, the methanol is stripped, and the residual water is removed aæeotropically with acetonitrile (three times).
The resulting foam i5 taken up in dry dimethylformamide (250 ml.) and treated with methyl iodide (6.2 ml., 10 eq.) at 25 under argon (slight exotherm). After 25 hours the reaction mixture is taken up in ethyl acetate and washed successively with saturated sodium bicarbonate, 5~ potassium bisulfate, brine, dried ~MgSO4), and evaporated to give 17.5 g.
of N-~(l,l-dimethylethoxy)carbonyl]-L-serine, methyl ester as a light green oil.
TLC (ethyl acetate) single spot at Rf = 0.71.
~Z1~136X
b) 2-[[(l,l-Dimethylethyl)carbonyl]amino]-2-~ropenoic acid, meth~l ester A mixture of N-[(1,1-dimethylethoxycarbonyl]-L-serine, methyl ester (18.4 g., 83.9 mmole), S diisopropylcarbodiimide (14.4 ml., 1.1 eq.) and acetonitrile (30 ml.) is treated with cuprous chloride (2.6 g., 0.3 eq.) at 25 in an argon atmosphere. After stirring the green mixture for 16 hours, ethyl acetate is added and the resulting mixture is filtered (celite bed) and evaporated. The gelatinous residue (19.0 g.) is filtered through a pad of silica (100 g.) eluting with ethyl acetate/hexane (1:16) to give 8.2 g.
of 2-[[~ dimethylethoxy)carbonyl]amlno]-2-propenoic acid, methyl ester as a light green liquid.
TLC (ethyl acetate/hexane; 1:16) major spot at Rf = 0.29.
c) S-(2-Aminoethyl)-N-[(l,l-dimethylethoxy)carbonyl]-L-cysteine, methyl ester A mixture of 2-aminoethanethiol, hydro-chloride (5.5 g., 1.2 eq.), triethylamine (16.6 ml., 2.4 eq.), and methylene chloride (20 ml.) at 0 (ice bath) under argon is treated dropwise with 2-[[(l,l-dimethylethoxy)carbonyl]amino]-2-propenoic acid, methyl ester (8.2 g., 40.8 mmole) in methylene chloride (30 ml.) over a 15 minute period. The ice bath is then removed and the resulting solution is stirred for 20 hours. The reaction mixture is taken up in ethyl acetate, filtered, and washed successively ~ith water (twice), iLZ19~1~i%
-saturated sodium bicarbonate, brine, and evaporated.The gelatinous residue (9.4 g.) is taken up in ether and added dropwise to a solution of oxalic acid (3.6 g.)/ethyl ether (250 ml.) to obtain the oxalate salt as a white solid after filtration.
The oxalate salt is taken up in water and basified with saturated sodium bicarbonate. The resulting oil is extracted into methylene chloride (approximately 20 times) to give 7.5 g. o~
l~ S-(2-aminoethyl)-N-[(l,l-dimethylethoxy)carbonyl]-L-cysteine, methyl ester as an oil after evaporation.
TLC (methylene chloride~methanol/acetic acid;
~:1:1) major spot at Rf = 0.52.
d) (Hexahydro-5-oxo-1,4-thiazepin-6-yl)carbamic acid, (l,l-dimethylethyl) ester A mixture of S-(2-aminoethyl)-N-[(l,l-dimethylethoxy)carbonyl]-L-cysteine, methyl ester (7.5 g., 26.9 mmole), l N sodium hydroxide (31.0 ml., 1.15 eq.), and dioxane (30 ml.) is stirred at room temperature for 2 hours. The reaction is then treated with lN hydrochloric acid (4.1 ml.) to quench excess hydroxide. The dioxane and water are evaporated and the residual water is removed azeotropically with acetonitrile (twice). The resulting foam is taken into dry dimethylformamide (100 ml.), treated with diphenylphosphoryl azide (6.5 ml., 1.1 eq.), and stirred under argon at 25 for 3.5 days. The reaction mixture is diluted with ethyl acetate and washed successively with water, saturated sodium bicarbonate, 12198~i2 5% potassium bisulfate, brine, dried (MgSO4), and evaporated. The residue (3.0 g.) is taken up in hot ethyl acetate and upon cooling 1.1 g.
of the product crystallizes as a colorless solid.
The mother liquor (1.9 g.) is chromatographed on silica (70 g.) eluting with 5~ acetone/methylene chloride to give an additional 0.4 g. of product as a slightly colored solid. A small portion of the product is recrystalli~ed from toluene to give (hexahydro~5-oxo-1,4-thiazepin-6-yl)carbamic acid, (l,l-dimethylethyl) ester as fine colorless needles;
m.p. 199.5 - 201. TLC (10~ acetone/methylene chloride) single spot at Rf = 0.49.
Anal. calc'd. for CloH18N2O3S:
C, 48.76; H, 7.36; N, 11.37; S, 13.02 Found: C, 48.56; H, 7.09; N, 11.35; S, 13.01.
e) 6-[[(1,1-Dimethylethoxy?carbonvl]amino]-tetrahydro-5-oxo-1,4-thiazepine-4(5H)-acetic acid, ethyl ester A suspension of (hexahydro-5-oxo-1,4-thia-zepin-6-yl)carbamic acid, (l,l-dimethylethyl)ester (1.35 g., 5.48 mmole) in dry tetrahydrofuran (10 ml.) under argon at 0 (ice bath) is treated with potassium tert-butoxide (0.68 g., 1.1 eq.) to effect an orange homogeneous solution. After 5 minutes, ethyl bromoacetate (1.1 ml., 1.8 eq.) is added, the ice bath removed, and the reaction mixture is stirred for 2 hours. The reaction mixture is then diluted with ethyl acetate and washed successively with saturated sodium bicar-~lC~2 bonate, 5% potassium bisulfate, brine, dried (MgSO4) and evaporated. The residue is chromato-graphed on silica (85 g.) eluting with 5%
acetone/methylene chloride to give 1.65 g. of 6-[[(1,1-dimethylethoxy)carbonyl]amino]-tetrahydro-5-oxo-1,4-thlazepine-4(5~)-acetic acid, ethyl ester as an oil following evaporation. TLC
(10~ acetone/methylene chloride~ single spot at Rf = 0.71.
f) 6-Amino-tetrahydro-5-oxo-1,4-thiazepine-
(IX) O
N-(CH2)t- P-Oalkyl Oalkyl o Treatment of this diester with trimethylsilyl-bromide yields the phosphonic acid of the formula (X) o lS \ N-ICH2)t p-OH
The acid of formula X can then be treated with phosphorous pentachloride and an alcohol of the formula (XI) R -OH
in the presence of triethylamine to give the compound of formula V.
The compounds of formula I wherein R is O
R7-P- and R7 is R -C-NH_CH-CH2- are l~lg~362 . HA269 1~--prepared as follows. A protected amine of the formula (XII) Ts-NH-CH-CH2-O-Ts wherein Ts is tolylsulfonyl, i.e., -S2 ~ CH3 , is reacted with sodium diethvl phos-ll ~honate,i.e., Na-P-OC2H5 , to yield the intermediate of the formula (XIII) o Ts-NH-CH - CH2 P-OC2H5 Treatment with hydrogen bromide (48~) in the presence of phenol with heat yields the aminophosphonic acid of the formula (XIV) O
il Rl2 OH
3~
_15-The aminophosphonic acid of formula XIV isthen reacted with benzoyloxycarbonyl chloride or phthalic anhydride to yield (XV) O
Prot-NH-CH-CH2- P-OH
wherein Prot is benzyloxycarbonyl or phthalidvl.
The acid of formula XV is then converted to the phosphonochloridate of the formula (XVI) O
Il Prot-NH-CH-CH2- P-Cl wherein R8 is lower alkyl, benzyl or benzhydryl by treating XV with triethylorthoformate, benzyl bromide, etc., followed by treatment with thionyl chloride or phosphorus pentachloride.
The acid chloride of formula XVI is then coupled with the thiazine or thiazepine ester of formula III to yield the intermediate of the formula (XVII) 3 Rl Prot-NH-CH-CH - P - NH-X-CH- C-OR2 ~2~3~
Removal of the protecting group such as byhydrogenation where Prot is benzoyloxycarbonyl or by treatment with hydrazine where Prot is phthalidyl followed by reaction with the acid chloride of the formula tXVIII) o Il Rg-C-Cl yields the desired products of formula I.
The thiazine or thiazepine ester of formula III wherein R5 is other than hydrogen can be prepared as follows. A phthaloyl amino acid of the formula (XIX) SH
O . I
~ (I 2 n 1~
O
is reacted with an N-substituted glycine ester of the formula (XX) R5-CH=N-CH2-COOR2 in the presence of a coupling agent such as dicyclohexylcarbodiimide to yield the N-protected thiazine or thiazepine of the formula ~21~38~i2 (XXI) ~ ~N ~ N~R2 o o Treatment of the compound of formula XXI with methylhydrazine removes the phthalimido protecting group and yields the desired thiazine or thiazepine ester of formula III.
The N-protected thiazine or thiazepine of formula XXI can also be prepared by cyclizing a sulfoxide of the formula (XXII) O
~ (CH2) ll C- NH CH2 COOR2 O O
~2~91862 [prepared as set forth by Wolfe et al., Can. J.
Chem., Vol. 57, p. 2412 - 2425 (1979)] by treatment with a mixture of trifluoroacetic acid anhydride and acetic anhydride followed by 2,6-lutidine.
The thiazine or thiazepine ester of formula III wherein R5 is hydrogen can be prepared as follows. A dithiobis amino acid of the formula (XXIII) ~S-(CH ) -CH-COOH]
is reacted with N-carboethoxyphthalimide to give the compound of the formula (XXIV) [S-(CH2)n CH COOH]2 O ~ ~ O
<~
which is treated with a glycine ester hydrochloride in the presence of base and a coupling agent such as carbonyldiimidazole to yield the compound of the formula ~ 8~2 HA269 ( XXv ) O
[S-(CH2) - CH-C-NH-CH -COOR ]
N
~>
The dithiobis compound of formula XXV is treated with zinc dust to yield (XXVI) f HS-(CH2)n CH - C-NH-CH2-COOR2 O ~ ~
,~
which is then treated with bromomethyl methyl ether in the presence of pyridine to give (XXVII) O
H3COCH2~s~(cH2)n CH-C-NH-CH2-COOR2 N
0-~0 <~>
1219~3~2 The compound of formula XXVII is cyclized by treatmentwith camphorsulfonic acid to give the N-protected thiazine or thiazepine of the formula (XXVIII) Il ~S~
~/\ (CH~n I
~ N ~ N-CH2-COOR2 o Treatment of the compound of formula XXVIII
methylhydrazine removes the phthalimido protecting group and yields the desired thiazine or thiazepine ester of formula III~
The thiazepine ester of formula III
20 wherein X is S ~ R5 )- R
~_ N
Il \
O
3L2~86;~
can be prepared as follows. An N-protected serine, for example~ a t-butyloxycarbonyl N-protected serine, is treated with methanol and cesium carbonate to yield the corresponding N-protected serine methyl ester. This methyl ester is then treated with diisopropylcarbodiimide and cuprous chloride to yield the N protected dehydroalanine methyl ester of the formula (XXIX) Prot-NH-C-C02CH3 Treatment of the compound of formula XXIX
with the aminothiol hydrochloride of the formula (xXx) l6 HS - CH - CH-NH2 HCl in the presence of base yields the methyl ester of the formula (XXXI) R5 l6 Prot-NH-CH - CO2CH3 ~ ~.98~2 The compound of formula XXXI is converted to the carboxylic acid and then cyclized by treatment with diphenylphosphoryl azide to yield the compound of the formula (XXXII) /s ~
¦ )- R
Prot-NH ~ NH
ll o The thiazepine of formula XXXII is treated with a bromoacetate of the formula (XXXIII) R O
Br-CH -C-OR2 to yield the compound (XXXIV) Prot-NH ~ ~ 6 1l ~ N - CH - C - OR
O
Removal of the protecting group, for example, by treating with hydroqen chloride in ethyl acetate when Prot is t-butyloxycarbonyl yields the desired thiazepine ester of formula III.
. ~198162 -23- _ HA269 The thiazepine ester of formula III
wherein X is N--o can be prepared as follows. The N-protected dehydroalanine methyl ester of formula XXIX
is reacted with 2-aminothiophenol and 2,6-lutidine to give the compound of formula tXXXV) ~3 Prot-NH - CH C2CH3 The methyl ester of formula XXXV is converted to the carboxylic acid and then cyclized by refluxing in xylene to give the compound of formula (XXXVI) S ~ >
Prot-NH ~ NH
:12~98 6,~
The thiazepine of formula XXXVI i5 treated with the bromoacetate of formula XXXIII and the N-protecting group is removed as described above to give the deslred thiazepine ester.
S The compounds of formula I wherein R is o R3-C-CH- can be prepared as follows. A keto compound of the formula (XXXVII) o R3-C-C=O
is reacted with the thiazine or thiæepine of fon~a III
in the presence of sodium cyanoborohydride to yield the ester of formula I.
If desired, the R2 and R3 ester groups can then be removed to yield the corresponding diacid compound.
The compounds of formula I wherein R3 is lower alkoxy and R2 is hydrogen can be prepared by conver~ing the thiazine or thiazepine ester of formula II wherein R2 is ethyl to the corresponding trimethyl-silylethyl ester prior to reaction with the ketone of formula II. The resulting product can then be treated to remove the R2 trimethylsilylethyl ester group such as by use of tetrabutylammonium fluoride while leaving the R3 ester group in place.
~21~362 HA269 In the above reactions if R4 ls -(CH2)q ~ OH , ~(CH2)q ~ ~ ( 2)q 2' OH
/NH
~(CH2)q ~ ~N , ~(CH2)q~SH, or ~(CH2)q~NH~C
or if Rl is amino or hydroxy substltuted lower alkyl then the hydroxyl, amino, imidazolyl, mercaptan, or guanidinyl function should be ~rotected during the coupling reaction. Suitable protecting groups include benzyloxycarbonyl, t-butoxycarbonyl, benzyl, benzhydryl, trityl, etc., and nitro in the case of guanidinyl. The protecting group is removed by hydrogenation, treatment with acid, or other known methods following completion of the reaction.
Preferred compounds of this invention are those of formula I wherein:
R3 is hydroxy,lower alkoxy of 1 to 4 carbons, or -O-alkali metal salt.
~ (CH2) R4 is -(CH2)m ~ or -CH
NH-C
81~Z
m is zero, one, two or three.
R7 is alkyl of 1 to 10 carbons, -(CH2)s ~ ~ -(CH2)t-NH2, or Rg~C-NH-CH-CH -.
Rg and R12 are selected from lower alkyl of 1 to 4 carbons and ( 2)m ~ , especially wherein Rg is phenyl and R12 is benzyl or phenethyl.
s is zero or an integer from 1 to 7.
t is an integer from 1 to 8.
R14 is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro, or hydroxy.
Rl is hydrogen, lower alkyl of 1 to 4 carbons, or -(CH2)4-NH2 R5 and R6 are independently selected from hydrogen, lower alkyl of 1 to 4 carbons, and (C 2)m ~
~:2~L~8~2 R8 and R2 are independently selected from hydrogen, lower alkyl of 1 to 4 carbons, alkali metal salt, or O
-CH-O-C-R
Rlo is hydrogen, straight or branched chain lower alkyl of 1 to 4 carbons, or cyclohexyl.
R11 is straight or branched chain lower alkyl of 1 to 4 carbons, cyclohexyl or phenyl.
Most preferred compounds of this invention are those of formula I wherein:
~ , ~ N- , O O
~S~ ~
~ N- , or N-O O
g86~
R3 is hydroxy,ethoxy, or -O-alkali metal salt.
R4 is -(CH2)2 ~
R7 is alkyl of 1 to 10 carbons or -(CH2j ~ wherein s is zero or an integer from 1 to 7, especially -(CH2)4 ~ .
R1 is hydrogen.
R5 is hydrogen or phenyl.
R8 and R2 are independently selected from hydrogen, alkali metal salt, and CH-O-C-R provided that only one of R2 and R8 is 11 -CH-O-C-R
Rlo R1o is hydrogen, stralght or branched chain lower alkyl of 1 to 4 carbons, or cyclohexyl.
R11 is straight or branched chain lower alkyl of 1 to 4 carbons.
The compounds of this invention wherein a~ least one of R8 or R2 is hydrogen or R3 is hydroxy, form basic salts with various inorganic and organic bases which are also within the scope of the invention.
~2~L9~
Such salts include ammonium salts, alkali metalsalts like lithium, sodium and potassium salts (which are preferred), alkaline earth metal salts like calcium and magnesium salts, salts with organic bases, e.g., dicyclohexylamine salt, benzathine, N-methyl-D-glucamine, hydrabamine salts, salts with amino acids like arginine, lysine and the like. The nontoxic, physiologically acceptable salts are preferred, although other salts are also useful, e.g., in isolating or purifying the product. The salts are formed using conventional techniques.
The symbol * is used to represent varlous asymmetric centers which may be present in the compounds of formula I. Thus, the compounds of this invention can accordingly exist in diastereoisomeric forms or in mixtures thereof.
The above described processes can utilize racemates, enantiomers or diastereomers as starting materials. When diastereomeric products are prepared, then can be separated by conventional chromatographic OL- fractional crystallization methods.
The compounds of formula I, and the ohysiologically acceptable salts thereof, are hypotensive agents. They inhibit the conversion of the decapeptide angiotensin I to angiotensin II and, therefore, are useful in reducing or relieving angiotensin related hypertension.
The action of the enzyme renin on angiotensinogen, ~215~8~62 a pseudoglobulln in blood plasma, producesangiotensin I. Angiotensin I is converted by angiotensin converting enzyme (ACE) to angio-tensin II. The latter is an active pressor substance which has been implicated as the causative agent in several forms of hyoertension in various mammalian species, e.g., humans. The compounds of this invention intervene in the angiotensinogen ~ (renin) ~ angiotensin I -~
angiotensin II sequence by inhibiting angiotensinconverting enzyme and reducing or eliminating the formation of the pressor substance angio-tensin II. Thus by the administration of a composition containing one (or a combination) of the compounds of this invention, angiotensin dependent hypertension in a species of mammal (e.g., humans) suffering therefrom is alleviated.
A single dose, or preferably two to four divided daily doses, provided on a basis of about 0.1 to 100 mg. per kilogram of body weight per day is appropriate to reduce blood pressure. The substance is preferably administered orally, but parenteral routes such as the subcutaneous, intramuscular, intravenous or intraperitoneal routes can also be employed.
The compounds of this invention can also be formulated in combination with a diuretic for the treatment of hypertension. A combination product comprising a compound of this invention and a diuretic can be administered in an ~986,2 effectlve amount which comprises a total daily dosage of about 30 to 600 mg., preferably about 30 to 330 mg. of a compound of this invention, and about 15 to 300 mg., preferably about 15 to 200 mg. of the diuretic, to a mammalian species in need thereof. Exemplary of the diuretics contemplated for use in combination with a compound of this invention are the thiazide diuretics, e.g., chlorothiazide, hydrochloro-thiazide, flumethiazide, hydroflumethiazide,bendroflumethiazide, methyclo~hiazide, trichlor-methiazide, polythiazide or benzthiazide as well as ethacrynic acid, ticrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamterene, amiloride and spironolactone and salts of such compounds.
The compounds of formula I can be formulated for use in the reduction of blood pressure in compositions such as tablets, capsules or elixirs for oral administration, or in sterile solutions or suspensions for parenteral administration.
About 10 to 500 mg. of a compound of formula I
is compounded with physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is sush that a suitable dosage in the range indicated is obtained.
.1219862 HA269 The following examples are illustrative of the invention. Temperatures are given in degrees centigrade. AG-50W-X8 refers to a crosslinked polystyrene-divinylbenzene sulfonic acid cation exchange resin. HP-20 refers to a porous cross-linked polystyrene-divinylbenzene polymer resin.
* Trade Mark " 12198~i2 Example 1 (R)-Dihvdro-5-[[Hydroxy~4-phenylbutYl)Phosphinvl]
amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, dilithium salt _ a) N-Phthaloyl-L-cysteine A solution of N,N'-diphthaloyl-L-cystine (19.5 g., 38.9 mmole) in a mixture of trifluoroacetic acid (60 ml.) and dry tetra-hydrofuran (200 ml.) is cooled in an ice-bath under nitrogen and treated with zinc dust (15.3 g., 233.4 mmole) in three equal portions over a per~od of 15 minutes. The reaction is stirred cold for 2 hours, then filtered (~elite) and concentrated _ vacuo. The residue is partitioned between 600 ml. of ethyl acetate:ether (5:1) and a water-brine mixture. The organic layer is washed with water, brine and dried (MgSO4). Removal of the solvents in vacuo yields 21.9 g. of crude product which is flash chromatogra-phed on silica gel (400 g.) eluting with toluene:acetic acid (6:1). Fractions containing the desired product are combined to give 12.1 g. of N-phthaloyl-L-cysteine as an oil. []D= -54.2 (c = 1, methanol).
TLC (toluene/acetic acid; 6:1) spot at ~f = 0.30.
b) N-8enzYlidineglYcine, ethyl ester A mixture of glycine, ethyl ester, hydro-chloride (10 g., 71.6 mmole~, triethylamine (14.5 g., 143.2 mmole), and anhydrous MgSO4 (6.0 g., 50.1 mmole) in dry methylene chloride (150 ml.) is treated with a solution of benzaldehyde (7.6 g., 71.6 mmole) in methylene chloride (10 ml.) added * Trade Mark ;2 over a period of 15 minutes. After 5 hours, the reaction mixture is filtered, concentrated in vacuo, and then partltioned between 400 ml. of ether and 50 ml. of water. The organic layer is washed with S water and brine, dried (MgSO4), and concentrated in vacuo to give 12.1 g. of N-benzylidineglycine, ethyl ester.
c) (R)-Dihydro-5-phthalimido-4-oxo-2-phenvl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester To a solution of N-phthaloyl-L-cysteine(15.8 g., 62.8 mmole) and N-benzylidineglycine, ethyl ester (12.3 g., 64.3 mmole) in dry chloroform (160 ml.) cooled in an ice bath under nitrogen is added dicyclo-hexylcarbodiimide (13.0 g., 62.8 mmole) in one porti~.
After 2 hours, the cold reaction mixture is filtered, concentrated in vacuo and redissolved in a mixture of ether (500 ml.) and chloroform (200 ml.). The organic extract is washed with saturated aqueous sodium bicar-bonate, water, 5% potassium bisulfate and brine, dried (MgSO4) and concentrated in vacuo to give 23.8 g. of crude product. Flash chromatography on silica (600 g.) eluting with hexane:ethyl acetate (3:1) yields 15.6 g.
of (R)-dihydro-5-phthalimido-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H) acetic acid, ethyl ester as a diastereomerlc mixture.
d) (R)-Dihydro-5-amino-4-oxo-2-PhenY1-2H-~3-thiaæine-3(4H)-acetic acid, ethyl ester A mixture of (R)-dihydro-5-phthalimido-4-oxo-2-phenyl-2H-l~3-thiazine-3(4H)-acetic acid, ethyl ester (1.5 g., 3.5 mmole), methylhydraæine (0.3 ml., 1.6 eq.), and chloroform (10 ml.) is stirred at 25 in an argon atmosphere for 48 hours. The heterogeneous mixture is diluted with ethyl acetate, filtered,washed with water, ~2~8~2 _35_ HA269 brine, and evaporated. The residue is taken up into 5~ potassium bisulfate and washed with ethyl acetate. The aqueous phase is made basic with saturated sodium bicarbonate, extracted with methylene chloride (twice), dried (MgS04), and evaporated to give 720 mg.
of (R)-dihydro-5-amino-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester as an oil.
TLC (7:2:1, isopropanol/conc. NH40H/water)major spot at Rf = 0.77.
e) Chloro _-phenylbutyl)phosphinic acid, ethyl ester A mixture of 4-phenylbutyl chloride (8.0 g., 47.5 mmole) and triethylphosphite (15.0 ml., 72 mmole) is heated at reflux (bath temperature 185) under argon for 41.5 hours. Distillation of the mixture gives 10.8 g~
of diethyl (4-phenylbutyl)phosphonate as a colorless liquid; b.p. 152-154 (1.0 mm of Hg.).
A mixture of diethyl (4-phenylbutyl) phosphonate (0.73 g., 2.6 mmole), benzene (10 ml.) and phosphorus pentachloride (1.0 eq.) is refluxed under argon for 30 minutes. The benzene and phosphorus oxychloride are removed ln vacuo to give chloro(4-phenylbutyl) phosphinic acid, ethyl ester.
198~
f) (R)-Dihydro-5-[[ethoxy(4-phenylbutyl)phosphinyl]-amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester A mixture of the crude chloro (4-phenyl-butyl)phosphinic acid,ethyl ester (2.6 mmole),dry methylene chloride (9.0 ml.) and (R)-dihydro-5-amino-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester (0.72 g., 2.4 mmole) at 0 (ice bath) in an argon atmosphere is treated dropwise with triethylamine (0.44 ml., 1.3 eq.) in methylene chloride (2 ml.) over 5 mi~utes.
After 30 minutes, the ice bath is removed and the reaction mixture is stirred at room temperature for 16 hours. The mixture is diluted with ethyl acetate and washed successively with saturated sodium bicarbonate, 5% potassium bisulfate, brine, dried (MgSO4), and evaporated.
The residue (1.5 g.) is chromatographed on silica (80 g.) eluting with hexane/acetone (2:1) to give 1.0 g. of (R)-dihydro-5-[[ethoxy(4-phenyl-butyl)phosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester as an oil after evaporation. TLC (hexane/acetone, 2:1) single spot at Rf = 0.5.
g) (R)-Dihydro-5-[[hydroxy(4-phenYlbutyl)phosphi~y~
amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, dilithium salt A mixture of the diethyl ester product from part (f) (1.0 g., 1.93 mmole), methylene chloride (4 ml.) and bromotrimethylsilane (0.5 ml., 2.0 eq.) 1219~3~2 is stirred at room temoerature under argon for16 hours. The methylene chloride and excess bromotrimethylsilane are removed in vacuo and the residue is taken up in acetonitrile (6 ml.) and lN lithium hydroxide (6.0 ml., aoproximately 3.0 eq.). After 2 hours the acetonitrile is evaporated, the aqueous solution is filtered, and chromatographed on an HP-20 (200 ml.) column eluting with a linear gradient of water-acetonitrile (0 -~ 90~ acetonitrile). The desired fractions are combined, evaporated to a small volume, filtered (millipore)~ and lyophilized to give 385 mg. of (R)-dihydro-S-[[(hydroxy(4-phenylbutyl)phosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, dilithium salt as a fluffy white solid. TLC (7:2:1 isopropanol/
concentrated NH40H/water) isomers Rf = 0.66, 0.62. [~]D = ~5 5 (c=l.O,H2O);m.p. 215 (decomp.).
Anal. calc'd. for C22 H25N2O5S 2 2 C, 51.95; H, 5.71; N, 5.51; S, 6.30; P, 6.1 Found: C, 51.92; H, 5.32; N, 5.48; S, 6.40; P, 6.1.
Example 2 5-[[Hydroxy(4-phenylbutYl)phos~hinyl]amino]-tetrahydro-4-oxo-1,3-thiazepine-3(2H)-acetLc acid, dilithium salt a) Bis(phthaloyl)homocystine A mixture of homocystine (5.36, 0.02 mole), soldium carbonate (4.24 g., 0.04 mole) and N-carboethoxyphthalimide (9.7 g., 0.044 mole) in water (50 ml.) is stirred for 4 hours, during which ~2~ 2 ~A269 time it becomes homogeneous. The reaction mixture is washed with ethyl acetate, acidified with concentrated hydrochloric acid, and extracted with methylene chloride. The extracts are dried and evaporated to a residue which is chromatographed on silica gel eluting with methylene chloride/methanol/acetic acid (40:1:1).
The major fraction is crystallized from acetic acid, washed with water and dried to give 7.7 g. of bis(phthaloyl)homocystine as a white solid.
b) gi~(Phthoyl)homocystinyl~Llycine~ ethyl ester A solution of bis(phthaloyl) homocystine (7.0 g., 0.013 mole) and carbonyldiimidazole (4.3 g., 0.026 mole) in tetrahydrofuran (40 ml.) is stirred for 1 hour at 0, then treated with triethylamine (7.4 ml., 0.052 mole) and glycine, ethyl ester, hydrochloride (4.0 g., 0.026 mole).
The mixture is stirred for 4 hours at room temperature, diluted with ethyl acetate, and washed with saturated sodium bicarbonate, 5~
potassium bisulfate, and brine. The solution is dried (MgSO4) and evaporated to a residue which is chromatographed on silica gel eluting with ethyl acetate/hexane (5:4). The major fraction (4.7 g.) is bis(phthaloyl)homocystinylglycine~
ethyl ester.
9~362 c)_ N-Phthaloyl-hOmocysteinvlqlvcine, ethYl ester A mixture of bis(phthaloyl)homocystinylglycine, ethyl ester (2.9 g., 0.041 mole) and acetic acid (8.2 ml.) in ethanol (40 ml.) is treated with zinc dust (1.62 g.) and stirred at room temperature for 1 hour. The mixture is filtered, the filtrate evaporated, and the residue taken up in ethyl acetate and washed with water and brine.
The solution is evaporated to yield 2.9 g. of N~phthaloyl-homocysteinylglycine, ethyl ester as a yellow semi-solid.
d) N-phthaloyl-s-(methoxymethyl)homocysteiny-4LL~
ethyl es_er A solution of N-phthaloylhomocysteinylglycine, ethyl ester (0.97 g., 2.8 mmole) and pyridine (0.67 ml., 8.4 mmole) in methylene chloride (4 ml.) is added dropwise to bromomethyl methyl ether (0.56 ml., 7.0 mmole) in methylene chloride (1.5 ml.) at 0 under argon. The mixture is stirred for 2 hours at room temperature, then additional pyridine (0.67 ml., 8.4 mmole) and bromomethyl methyl ether (0.56 ml., 7.0 mmole) are added and the mixture is stirred 1.5 hours longer. The mixture is washed with water, 5%
potassium bisulfate, dried (MgSO4) and evaporated to yield a residue which is chromatographed on silica gel eluting with ethyl acetate/hexane (1:1) to give 0.78 g. of N-phthaloyl-S-(methoxymethyl) homocysteinylglycine, ethyl ester as an oil.
86~
e) 5-Phthalimido-tetrahydro-4-oxo-1,3-thia-zepine-3(2H)-acetic acid, ethyl ester N-Phthaloyl-S-(methoxymethyl) homocysteinyl-glycine, ethyl ester (0.76 g., 2.0 mmole) and camphorsulfonic acid (0.01 g.) in benzene (15 ml.) are refluxed for 1 hour. Additional camphorsulfonic acid (0.05 g.) is added and reflux is continued for 2 more hours after which anhydrous p-toluenesulfonic acid (0.1 g.) is added and the mixture is refluxed for 20 hours.
The mixture is then diluted with ethyl acetate and washed with saturated sodium bicarbonate, 5 potasslum bisulfate, and brine, dried (MgS04) and evaporated. The residue is chromatographed on silica gel eluting with ethyl acetate to yield a main fraction which is then crystallized from toluene to give 0.51 g. of 5-phthalimido-tetra-hydro-4-oxo-1,3-thiazepine-3(2H)-acetic acid, ethyl ester as a crystalline solid; m.p.
191.5 - 193.5.
f) 5-Amino-tetrahvdro-4-oxo-1,3-thiazepine-3(2H)-acetic acid, ethyl ester A mixture of 5-phthalimido-tetrahydro-4-oxo-1,3-thiazepine-3(2H)-acetic acid, ethyl ester (0.48 g., 1.3 mmole) and methylhydrazine (0.12 ml.) in acetonitrile is stirred at room temperature for 3 days. The reaction mixture is diluted with ethyl acetate, filtered and evaporated to a residue which is taken up in 5~ pot:assium bisulfate and washed with ethyl acetate. The aqueous phase ~2~9~362 is saturated with sodium bicarbonate and extractedwith methylene chloride. The extracts are dried and evaporated to yield 0.2 g. of 5-amino-tetrahydro-4-oxo-1,3-thiazepine-3(2H)-acetic acid, ethyl ester as an oil. TLC (silica gel, 10 methanol in methylene chloride) Rf = 0.19.
g) 5-[[Ethoxy(4-phenylbutyl)phosphinyl]amino]-tetrahydro-4-oxo-1,3-thiazepine-3t2H)-acetic cid, ethyl ester A mixture of crude chloro(4-phenylbutyl) phosphinic acid, ethyl ester, dry methylene chloride and 5-amino-tetrahydro-4-oxo-1,3-th1azepine-3(2H)-acetic acid, ethyl ester are reacted as set forth in Example l(f). Work up of the reaction mixture according to Example l(f) yields 5-[[ethoxy-(4-phenylbutyl)phosphinyl]amino]tetrahydro-4-oxo-1,3-thiazepine-3(2H)-acetic acid, ethyl ester.
- h) 5-[[Hydroxy(4-phenYlbutyl)phosphinyl]amino]-tetrahydro-4-oxo-1,3-thiazepine-3(2H)-acetic acid, dilithium salt The diethyl ester product from part (g) is treated with bromotrimethylsilane according to the procedure of Example 1(~) and the resldue is treated with lN lithium hydroxide and worked up as set forth in Example 1(~) to give 5-[[hydroxy(4-phenylbutyl)phosphinyl]amino]-tetrahydro-4-oxo-1,3-thiazepine-3(2H)-acetic acid, dilithium salt.
386~
.
Examples 3 - 16 Following the procedures of Examples 1 and 2, the thiazine or thiazepine sh~ bel~w in Col.I is reacted with the phosphinic acid ester shown in Col. II to give the ester product shown in Col. III. The R2 and R8 ester groups can be removed to give the corresponding diacid which can then be converted to a salt or in the case of Examples 15 and 1 only the X8 ester group would be removed. The Rl protecting ~roup shown in Examples 6 and 10 would be removed as the last step of the synthesis.
~L2:1~8~i2 -43_ HA269 Col (CH2)n ~/
2 ~/N--ICH-COOR2 o R
Col. II
OR~
- Col. III
(CH2)n~
R7-- p NH--~N--CH-COOR2 8 Rl ~219~3~2: HA2 6 9 ~r) ,f. ~
3~ ~ N
, I N N N N N N
~r ~9 N
N N Nr--~ ~
-- t')t )N N N
,,. N N N N ~_~N
O . ~
"~
~" N
I ~ y ~~, Y Y
N ~ N
~I N _I N ~1 N .--1 a) ~ll2 ~L981~ HA2 6 9 Ln u~u7 n ~ U~ ~
~r D U ~ $
N ~
~iL2~L98~2 U~
C~
U
I
o--o ' o =o ~
~ O~ O a ~ " ~
a) I
_4_ HA269 Example 17 Tetrahydro-6-[[hYdroxy(4-~henylbutyl)~hosphinyl]-amino]-5-oxo-1,4-thiazepine-4(5H)-acetic acid, dilithium salt a) N-~(l,l-Dimethylethoxy)carbonyl]-L-serine, methyl ester To a solution of N-[(l,l-dimethylethoxy)-carbonyl]-L-serine (20.5 g., 0.1 mole), methanol (50 ml.), and water (10 ml.) is added cesium carbonate (16.3 g., 0.5 eq.~. After 5 minutes the solution becomes homogeneous, the methanol is stripped, and the residual water is removed aæeotropically with acetonitrile (three times).
The resulting foam i5 taken up in dry dimethylformamide (250 ml.) and treated with methyl iodide (6.2 ml., 10 eq.) at 25 under argon (slight exotherm). After 25 hours the reaction mixture is taken up in ethyl acetate and washed successively with saturated sodium bicarbonate, 5~ potassium bisulfate, brine, dried ~MgSO4), and evaporated to give 17.5 g.
of N-~(l,l-dimethylethoxy)carbonyl]-L-serine, methyl ester as a light green oil.
TLC (ethyl acetate) single spot at Rf = 0.71.
~Z1~136X
b) 2-[[(l,l-Dimethylethyl)carbonyl]amino]-2-~ropenoic acid, meth~l ester A mixture of N-[(1,1-dimethylethoxycarbonyl]-L-serine, methyl ester (18.4 g., 83.9 mmole), S diisopropylcarbodiimide (14.4 ml., 1.1 eq.) and acetonitrile (30 ml.) is treated with cuprous chloride (2.6 g., 0.3 eq.) at 25 in an argon atmosphere. After stirring the green mixture for 16 hours, ethyl acetate is added and the resulting mixture is filtered (celite bed) and evaporated. The gelatinous residue (19.0 g.) is filtered through a pad of silica (100 g.) eluting with ethyl acetate/hexane (1:16) to give 8.2 g.
of 2-[[~ dimethylethoxy)carbonyl]amlno]-2-propenoic acid, methyl ester as a light green liquid.
TLC (ethyl acetate/hexane; 1:16) major spot at Rf = 0.29.
c) S-(2-Aminoethyl)-N-[(l,l-dimethylethoxy)carbonyl]-L-cysteine, methyl ester A mixture of 2-aminoethanethiol, hydro-chloride (5.5 g., 1.2 eq.), triethylamine (16.6 ml., 2.4 eq.), and methylene chloride (20 ml.) at 0 (ice bath) under argon is treated dropwise with 2-[[(l,l-dimethylethoxy)carbonyl]amino]-2-propenoic acid, methyl ester (8.2 g., 40.8 mmole) in methylene chloride (30 ml.) over a 15 minute period. The ice bath is then removed and the resulting solution is stirred for 20 hours. The reaction mixture is taken up in ethyl acetate, filtered, and washed successively ~ith water (twice), iLZ19~1~i%
-saturated sodium bicarbonate, brine, and evaporated.The gelatinous residue (9.4 g.) is taken up in ether and added dropwise to a solution of oxalic acid (3.6 g.)/ethyl ether (250 ml.) to obtain the oxalate salt as a white solid after filtration.
The oxalate salt is taken up in water and basified with saturated sodium bicarbonate. The resulting oil is extracted into methylene chloride (approximately 20 times) to give 7.5 g. o~
l~ S-(2-aminoethyl)-N-[(l,l-dimethylethoxy)carbonyl]-L-cysteine, methyl ester as an oil after evaporation.
TLC (methylene chloride~methanol/acetic acid;
~:1:1) major spot at Rf = 0.52.
d) (Hexahydro-5-oxo-1,4-thiazepin-6-yl)carbamic acid, (l,l-dimethylethyl) ester A mixture of S-(2-aminoethyl)-N-[(l,l-dimethylethoxy)carbonyl]-L-cysteine, methyl ester (7.5 g., 26.9 mmole), l N sodium hydroxide (31.0 ml., 1.15 eq.), and dioxane (30 ml.) is stirred at room temperature for 2 hours. The reaction is then treated with lN hydrochloric acid (4.1 ml.) to quench excess hydroxide. The dioxane and water are evaporated and the residual water is removed azeotropically with acetonitrile (twice). The resulting foam is taken into dry dimethylformamide (100 ml.), treated with diphenylphosphoryl azide (6.5 ml., 1.1 eq.), and stirred under argon at 25 for 3.5 days. The reaction mixture is diluted with ethyl acetate and washed successively with water, saturated sodium bicarbonate, 12198~i2 5% potassium bisulfate, brine, dried (MgSO4), and evaporated. The residue (3.0 g.) is taken up in hot ethyl acetate and upon cooling 1.1 g.
of the product crystallizes as a colorless solid.
The mother liquor (1.9 g.) is chromatographed on silica (70 g.) eluting with 5~ acetone/methylene chloride to give an additional 0.4 g. of product as a slightly colored solid. A small portion of the product is recrystalli~ed from toluene to give (hexahydro~5-oxo-1,4-thiazepin-6-yl)carbamic acid, (l,l-dimethylethyl) ester as fine colorless needles;
m.p. 199.5 - 201. TLC (10~ acetone/methylene chloride) single spot at Rf = 0.49.
Anal. calc'd. for CloH18N2O3S:
C, 48.76; H, 7.36; N, 11.37; S, 13.02 Found: C, 48.56; H, 7.09; N, 11.35; S, 13.01.
e) 6-[[(1,1-Dimethylethoxy?carbonvl]amino]-tetrahydro-5-oxo-1,4-thiazepine-4(5H)-acetic acid, ethyl ester A suspension of (hexahydro-5-oxo-1,4-thia-zepin-6-yl)carbamic acid, (l,l-dimethylethyl)ester (1.35 g., 5.48 mmole) in dry tetrahydrofuran (10 ml.) under argon at 0 (ice bath) is treated with potassium tert-butoxide (0.68 g., 1.1 eq.) to effect an orange homogeneous solution. After 5 minutes, ethyl bromoacetate (1.1 ml., 1.8 eq.) is added, the ice bath removed, and the reaction mixture is stirred for 2 hours. The reaction mixture is then diluted with ethyl acetate and washed successively with saturated sodium bicar-~lC~2 bonate, 5% potassium bisulfate, brine, dried (MgSO4) and evaporated. The residue is chromato-graphed on silica (85 g.) eluting with 5%
acetone/methylene chloride to give 1.65 g. of 6-[[(1,1-dimethylethoxy)carbonyl]amino]-tetrahydro-5-oxo-1,4-thlazepine-4(5~)-acetic acid, ethyl ester as an oil following evaporation. TLC
(10~ acetone/methylene chloride~ single spot at Rf = 0.71.
f) 6-Amino-tetrahydro-5-oxo-1,4-thiazepine-
4(5H)-acetic_acid, _ hyl ester, hydrochloride A mixture of 6-[[(1,1-dimethylethoxy) carbonyl]amino]-tetrahydro-5-oxo-1,4-thiazepine-4(5H)-acetic acid, ethyl ester ~1.65 g., 4.96 mmole) lS and ethyl acetate (10 ml.) at 0 (ice bath) is treated with cold saturated hydrochloric acid/
ethyl acetate (20 ml.). After stirrlng for 2 hours at 0, nitrogen is passed through the solution to remove excess hydrochloric acid; The ethyl acetate is evaporated and the residue is triturated with ether (three times) to give 1.35 g. of 6-amino-tetrahydro-S-oxo-1,4-thiazepine-4(5H)-acetic acid, ethyl ester, hydrochloride as a yellow solid. TLC (methylene chloride/methanol/acetic acid; 8:1:1) sing}e spot at Rf = 0.5 (visualized with ninhydrin and heat).
~Z~ 6~ HA269 Anal- calc'd. for C9H16N23S HCl 0.5 H2O:
C, 38.98; H, 6.52; N, 10.10; S, 11.56;
Cl, 12.78 Found: C, 38.98; H, 6.73; N, 9.66; S, 11.32;
Cl, 12.80.
g) Tetrahvdro-6-[[ethoxy(4-phenylbutyl)phosphinyl]-amino]-5-oxo-1,4-thlazepine-4(5H)-acetic acid, ethyl ester A mixture of crude chloro (4-phenylbutyl)-phosphinic acid, ethyl ester (4.09 mmole), dry tetrahydrofuran (5 ml.), and 6-amino-tetrahydro-
ethyl acetate (20 ml.). After stirrlng for 2 hours at 0, nitrogen is passed through the solution to remove excess hydrochloric acid; The ethyl acetate is evaporated and the residue is triturated with ether (three times) to give 1.35 g. of 6-amino-tetrahydro-S-oxo-1,4-thiazepine-4(5H)-acetic acid, ethyl ester, hydrochloride as a yellow solid. TLC (methylene chloride/methanol/acetic acid; 8:1:1) sing}e spot at Rf = 0.5 (visualized with ninhydrin and heat).
~Z~ 6~ HA269 Anal- calc'd. for C9H16N23S HCl 0.5 H2O:
C, 38.98; H, 6.52; N, 10.10; S, 11.56;
Cl, 12.78 Found: C, 38.98; H, 6.73; N, 9.66; S, 11.32;
Cl, 12.80.
g) Tetrahvdro-6-[[ethoxy(4-phenylbutyl)phosphinyl]-amino]-5-oxo-1,4-thlazepine-4(5H)-acetic acid, ethyl ester A mixture of crude chloro (4-phenylbutyl)-phosphinic acid, ethyl ester (4.09 mmole), dry tetrahydrofuran (5 ml.), and 6-amino-tetrahydro-
5-oxo-1,4- ~hiazepi~-4(5H)-acetic acid,ethyl ester, hydrochloride (1.10 g., 4.09 mmole) at 0~ (ice bath) in an argon atmosphere is treated dropwise with triethylamine (1.25 ml., 2.2 eq.) in tetrahydrofuran (5 ml.) over a 2 minute period.
After 20 minutes the ice bath is removed, and the reaction mixture is stirred for an additional 2 hours. The reaction mixture is diluted with ethyl acetate and washed successively with saturated sodium bicarbonate, 5~ potassium bisulfate, brine, dried (MgSO4), and evaporated. The residue (2.0 g.) is chromatographed on silica (75 g.) eluting with 3:1 toluene/acetone to give 1.45 g.
of tetrahydro-6-[[ethoxy(4-phenylbutyl)phosphinyl]-amino]-5-oxo-1,4-thiazepine-4(5H)-acetic acid, ethyl ester as an oil. TLC (toluene/acetic acid;
3:1) single spot at Rf = 0.16.
~2~9862 h) Tetrahydro-6 [[hydroxy(4-phenvlbutyl)phos~hinvl]-amino]-5-oxo-1,4-thiaze~ine-4(5H)-acetic acid, dilithium salt A mixture of the diester product from S part (g) (1.45 g., 3.17 mmole), methylene chloride (5 ml~), and bromotximethylsilane (1.3 ml., 3.0 eq.) is stirred under argon at 25. After 16 hours additional bromotrimethylsilane (1.0 eq.) is added. After an additional 3 hours the methylene chloride and excess bromotrimethyl-silane are removed ln vacuo and the residue is treated with dry acetonitrile (10 ml.) and lN sodium hydroxide (10 ml., approximately 3 eq.). After 3 hours the acetonitrile is evaporated and the resulting aqueous phase is applied to an HP-20 (200 ml. bed) column eluting with a linear gradient water ~ acetonitrile (0/90~). The desired fractions are combined, evaporated to a small volume, and applied to an AG50W X 8 ~Li ) ~40 ml.) column eluting with water. The desired fractions are combined, filtered (millipore), and lyophilized to give 0.85 g. of tetrahydro-6-[[hydroxy(4-phenylbutyl)phosphinyl]-amino]-5-oxo-1,4-thiazepine-4(5H)-acetic acid, dilithium salt as a white solid; m.p. darkens at 233~. TLC (isopropanol/conc. NH40H/water;
7:2:1) single spot at Rf = 0.71.
Anal. calc'd. for C17H23N2O5PS 2 2 C, 45.05; H, 6.12; N, 6.18; S, 7.07; P, 6.83 Found: C, 45.05; H, 5.77; N, 6.19; S, 6.92; P, 6.7.
~ 6~ ~A269 Exam~les 18 - 28 Following the procedure of Example 17 but employing substituted 2-aminoethanethiol shown below in Col. I in part (c) one obtains the thiazepine shown below in col. II. This thiazepine is then reacted with the phosphinic acid ester shown in Col. III to give the ester oroduct shown in Col. IV. The R2 and R8 ester groups can be removed to give the corresponding diacid which can then be converted to a salt or in the case of Examples 27 and 28 only the R8 ester group would be removed. The Rl protecting group shown in Examples 24 and 25 would be removed as the last step of the synthesis.
:3 21~62 _5 5-Col. I
IR5 lR6 Col. II
2 ~ N-CH IC-OR2 Rl Col. III
o R7 P Cl Co 1 . IV
O ~ ~
~19~362 X I Y '' y y N y Z
x~l Y y y y y y . ..
T y (~1 ~ ~) X ¦ I Y
~ y ~ T (~ --~ a~ ci) o X
~2:~L9862 E~A 2 5 9 u~ ~n Ln u~ In a~ I O U U
~ ~ ~N 1~
~1 ~ U r U
x~l ~, u O _ U ~
O=U I ~
3 ~ O U
~1 u u u ~ o ~ _ u Z
I U
1 5 ~ U
x~
~1 C
t3 ~21986;~
5%-Exam~le 29 (+)~Dihydro-3-[[hYdroxy(4-phenYlbutvl)3hosphinyl]
amino]-4-oxo-1,5-benzothiazepine-5(2H)-acetic acid, dilithium salt a) S-(2-Aminophenyl)-N-[(l,l-dimethylethoxy)-carbonyl]-L-cysteine, methyl ester To a mixture of 2-amino-thiophenol (1.9 g., 15.4 mmole), methylene chloride (15 ml.), and 2,6-lutidine (1.8 ml., l.0 eq.) at -20 (chloroform dry ice) is added 2-[[(l,l~methylethoxy)carbonyl]amino]-2-propenoic acid, methyl ester (3.0 g., l.0 eq.) dropwise over 5 minutes. After one hour the cooling bath is removed and the reaction mix'ure is stirred for an additional 16 hours. The reaction mixture is diluted with ethyl acetate and washed with saturated sodium bicarbonate, water, brine, dried (MgSO4), and evaporated. The residue (4.1 g.) is chromatographed on silica (125 g.) eluting with hexane/ethyl acetate (5:1) to give 2.5 g. of S-(2-aminophenyl)-N-[~ dimethylethoxy)carbonyl]-L-cysteine, methyl ester as an oil after evaporation.
b) 5-(2-Aminophen~)-N-[(1,l-dimethylethoxY)-carbonyl]-L-cysteine A mixture of S-(2-aminophenyl)-N-[(l,l-dimethylethoxy)carbonyl]-L-cysteine, methyl ester (1.0 g., 3.1 mmole), lN sodium hydroxide (3.1 ml., l.0 eq.), and dioxane (6 ml.) is stirred at room temperature in an argon atmosphere for one hour.
The reaction mixture is washed with ethyl acetate, :~21~86~:
neutralized with lN hydrochloric acid (3.1 ml.)and extracted with methylene chloride (twice).
The combined extracts are dried (MgSO4) and evaporated to give 1.0 g. of S-(2-aminophenyl)-N-[(l,l-dimethylethoxy)carbonyl]-L-cysteine as a foa~. TLC (methylene chloride/acetic acid/
methanol; 100:5:5) major spot at Rf = 0.5. The product crystallizes from xylene to give S-(2-aminophenyl)-N-[(1,1-dimethylethoxy)carbonyl]-L-cysteine as a fluffy crystalline solid; m.p. 109-111~.
Anal. calc'd. for C14H20N2O4S:
C, 53.83; H, 6.45; N, 8.97; S, 10.26 Found: C, 53.51; H, 6.28; N, 8.99; S, 10.26.
c) (~)-(2,3,4,5-TetrahYdro-4-oxo-1,5-benzo-thiazepin-3-vl)carbamic acid,l,l-dimethylethyl ester A suspension of S-(2-aminophenvl)-N-[(l,1-dimethylethoxy)carbonyl]-L-cysteine (0.65 g., 2.1 mmole) in xylene (15 ml.) is refluxed in a flask equipped with a Dean-Stark trap for 7 hours. Upon cooling of the reaction mixture the product crystallizes. The solid is collected by filtration, washed with xylene, and dried (high vacuum) to give 0.4 g. of (I)-(2,3~4~5-tetrahydro-4-oxo-1,5-benzothiazepin-3-yl)carbamic acid, l,l-dimethylethyl ester as an off-white crystalline solid; m.p. 197-200 (decomp.).
Anal. calc'd. for C14H18N2O3S:
C, 57.12; H, 6.16; N, 9.52; S, 10.89 Found: C, 56.88; H, 6.l7; N, 9.40; S, 10.87.
12~386X
d) (+)-3-[[(1,1-Dimethylethoxy)carbonYl]amino]-3,4-dihydro-4-oxo-1,5-benzothiazepine-5(2H)-acetic acid~ ethyl ester A mixture of (+)-(2,3,4,5-tetrahydro-4-oxo-1,5-benzothiazepin-3-yl)carbamic acid, 1,1-dimethylethyl ester (0.8 g., 2.7 mmole), tetrahydro-furan (10 ml.) and potassium tert-butoxide (0.4 g., 1.3 eq.) is stirred at 0 (ice bath) under argon for 10 minutes and then treated with ethyl bromoacetate (0.5 g., 1.7 eq.). After 3 minutes the ice bath is removed and the mixture is stirred for one hour. The reaction mixture is then diluted with ethyl acetate and washed successively with saturated sodium bicarbonate, 5~ potassium bisulfate, and brine, dried (MgSO4) and evaporated.
The residue (1.3 g.) is chromatographed on silica (60 g.) eluting with hexane/ethyl acetate (4:1) to give 1.0 g. of (+)-3-[[(1,1-dimethylethoxy)-carbonyl]amino]-3,4-dihydro-4-oxo-1,5-benzothia-zepine-5(2H)-acetic acid, ethyl ester as a foam.
TLC (hexane/ethyl acetate; 4:1) single spot at Rf = 0.21.
e) (+)-3-Amino-3,4-dihYdro-4-oxo-1,5-benzothia-zepine-5(2H)-acetic acid, ethvl ester A mixture of (+)-3-[[(1,1-dimethylethoxy)-carbonyl]amino]-3,4-dihydro-4-oxo-1,5-benzo-thiazepine-5(2H)-acetic acid, ethyl ester (1.0 g., 2.6 mmole), methylene chloride (5 ml.), and trifluoroacetic acid (3 ml.) is stirred under argon at 25 for 30 minutes. The methylene chloride and ~Z~ 2 O trifluoroacetic acid are removed ln vacuo and the residue is taken up in ethyl acetate and the hydrochloride salt is precipitated with saturated hydrochloric acid/ethyl ether. The white solid is collected by filtration and washed with 2:1 ethyl acetate/ethyl ether to yield 0.7 g. of (+)-3-amino-3,4-dihydro-4-oxo-1,5-benzothiazepine-5(2H)-acetic acid, ethyl ester as a white solid;
m.p. 231-233 (decomp.). TLC tmethylene chloride/
acetic acid/methanol; 100:5:5) single s~ot at Rf = 0.08.
Anal- calc'd. for C13H16N23S HC1:
C, 49.29; H, 5.41; N, 8.84; S, 10.12;
Cl, 11.37 Found: C, 48.87; H, 5.31; N, 8.80; S, lO.OS;
C1, 11.37~
f) (+)-Dihydro-3-[[ethoxy(4 phenylbutyl)phosphinyl]-amino~-4-oxo-1,5-benzothiazepine-5_2H)-acetic acid, ethyl ester A mixture of crude chloro (4-phenylbutyl)-phosphinic acid, ethyl ester (2.44 mmole), dry tetrahydrofuran (10 ml.), and (+)-3-amino-3,4-dihydro-4-oxo-1,5-benzothiazepine-5(2H)-acetic acid, ethyl ester (0.65 g., 2.05 mmole) at 0 (ice bath) in an argon atmosphere is treated dropwise with ; triethylamine (0.86 ml., 3.0 eq.) in tetrahydrofuran (5 ml.) over 1 minute. After standing at 0 for 20 minutes the ice bath is removed and the reaction mixture is stirred for 16 hours. The reaction mixture is diluted with ethyl acetate and washed ~;219862 successively with saturated sodium bicarbonate, 5~ potassium bisulfate and brine, dried (MgSO4), and evaporated. The residue (1.2 g.) is chromatographed on silica (60 g.) eluting with acetone/hexane (1:1) to give 0.8 g. of (+)-dihydro-3-[[ethoxy(4-phenylbutyl)phosphinyl]amino]-4-oxo-1,5-benzothiazepine-5(2H)-acetic acid, ethyl ester as an oil after evaporation. TLC (acetone/hexane;
2:1) two spots at Rf=0.59,0.65(isomers at phosphorus).
g) (+)-Dihydro-3-[[hydroxY(4-phenylbut~ hosphinyl]-amino]-4-oxo-1,5-benzothiazepine-5(2H)-acetic acid, dilithium salt A mixture of the diester product from part (f) (0.8 g., 1.59 mmole), dry methylene lS chloride (5 ml.), and bromotrimethylsilane (0.63 ml., 3.0 eq.) is stirred at room temperature in an argon atmosohere for 16 hours. The methylene chloride and bromotrimethylsilane are removed in vacuo and the residue is taken up in acetonitrile (approximately 5 ml.) and lN lithium hydroxide (5.6 ml., 3.5 eq.) and stirred for 2 hours. The acetonitrile is stripped, the aqueous solution is filtered, and apolied to an HP-20 (200 ml.) column eluting with a linear gradient water-acetonitrile (0 ~ 90% acetonitrile). The desired fractions are combined, filtered (millipore), and lyophilized to give 0.5 g. of (+)-dihydro-3-[[hydroxy(4-phenylbutyl)phos?hinyl]amino]-4-oxo-1,5-benzo-thiazepine-5(2H)-acetic acid, dilithium salt as a fluffy white solid; m.p. 245 (decomp.).
~2~8~2 HA269 TLC (isopropanol/conc. NH4OH/water; 7:2:1)single spot at Rf = 0.48.
Anal. calc'd. for C21H23N2O5SPL 2 2 C, 51.19; H, 5.44; N, 5.68; S, 6.51; P, 6.3 Found: C, 51.24; H, 5.12; N, 5.53; S, 6.57; P, 6.2.
Similarly, by following the procedure of Example 29 but employing the various chloro (substituted) phosphinic acid esters shown in Col. II of Examples 3 to 16 and 18 to 28, other compounds within the scope of this invention are obtai~ed.
Example 30 (R?-Dihydro-5-[[(6-aminohexYl)hYdroxyphosphin~l]-amino]-4-oxo-2-phenyl-2H-1,3-thiazepine-3(4H)-acetic acid, dilithium salt a) N-(6-Bromohexyl)phthalimide A mixture of crystalline 6-aminohexanol (11.7 g., 0.1 mole) and phthalic anhydride (14.8 g., 0.1 mole) is heated at 170 for 1.5 hours in an argon atmosphere. The evolved water is then removed with heat and argon flow.
The reaction mixture is cooled to 100 and phosphorus tribromide (7.2 ml., 0.086 mole) is added in portions via gas tight syringe to the reaction mixture. A vigorous reaction occurs with each addition. After addition is complete, the reaction mixture is heated at 100 for an additional 30 minutes. The cooled reaction mixture is diluted with ethanol (20 ml.) then poured over ice-water ~3~62 and refrigerated overnight. A yellow solid is Eiltered and washed several times with cold water until the filtrate is nearly neutral.
The crude solid is recrystallized from ethanol to give 21.0 g. of N-(6~bromohe~yl)phthalLmide as a pale yellow solid; m.p. 54-55. TLC (hexane-ethyl acetate; 1:1) shows a major spot at Rf = 0.8.
b) (6-Phthalimidohexyl)phosphonic acid, diethyl ester A mixture of N-(6-bromohexyl)phthalimide (5.5 g., 17.7 mmole) and triethylphosphite (10.0 ml., 58.4 mmole) is refluxed (bath temperature 160-165) under argon for 16 hours.
The volatiles are removed by distillation at 100 (bath temperature), 0.5 mm. of Hg to leave a pale yellow viscous oil. The crude product is purified by flash chromatography on silica gel (100 g.) eluting with acetone-hexane (1:2) to give
After 20 minutes the ice bath is removed, and the reaction mixture is stirred for an additional 2 hours. The reaction mixture is diluted with ethyl acetate and washed successively with saturated sodium bicarbonate, 5~ potassium bisulfate, brine, dried (MgSO4), and evaporated. The residue (2.0 g.) is chromatographed on silica (75 g.) eluting with 3:1 toluene/acetone to give 1.45 g.
of tetrahydro-6-[[ethoxy(4-phenylbutyl)phosphinyl]-amino]-5-oxo-1,4-thiazepine-4(5H)-acetic acid, ethyl ester as an oil. TLC (toluene/acetic acid;
3:1) single spot at Rf = 0.16.
~2~9862 h) Tetrahydro-6 [[hydroxy(4-phenvlbutyl)phos~hinvl]-amino]-5-oxo-1,4-thiaze~ine-4(5H)-acetic acid, dilithium salt A mixture of the diester product from S part (g) (1.45 g., 3.17 mmole), methylene chloride (5 ml~), and bromotximethylsilane (1.3 ml., 3.0 eq.) is stirred under argon at 25. After 16 hours additional bromotrimethylsilane (1.0 eq.) is added. After an additional 3 hours the methylene chloride and excess bromotrimethyl-silane are removed ln vacuo and the residue is treated with dry acetonitrile (10 ml.) and lN sodium hydroxide (10 ml., approximately 3 eq.). After 3 hours the acetonitrile is evaporated and the resulting aqueous phase is applied to an HP-20 (200 ml. bed) column eluting with a linear gradient water ~ acetonitrile (0/90~). The desired fractions are combined, evaporated to a small volume, and applied to an AG50W X 8 ~Li ) ~40 ml.) column eluting with water. The desired fractions are combined, filtered (millipore), and lyophilized to give 0.85 g. of tetrahydro-6-[[hydroxy(4-phenylbutyl)phosphinyl]-amino]-5-oxo-1,4-thiazepine-4(5H)-acetic acid, dilithium salt as a white solid; m.p. darkens at 233~. TLC (isopropanol/conc. NH40H/water;
7:2:1) single spot at Rf = 0.71.
Anal. calc'd. for C17H23N2O5PS 2 2 C, 45.05; H, 6.12; N, 6.18; S, 7.07; P, 6.83 Found: C, 45.05; H, 5.77; N, 6.19; S, 6.92; P, 6.7.
~ 6~ ~A269 Exam~les 18 - 28 Following the procedure of Example 17 but employing substituted 2-aminoethanethiol shown below in Col. I in part (c) one obtains the thiazepine shown below in col. II. This thiazepine is then reacted with the phosphinic acid ester shown in Col. III to give the ester oroduct shown in Col. IV. The R2 and R8 ester groups can be removed to give the corresponding diacid which can then be converted to a salt or in the case of Examples 27 and 28 only the R8 ester group would be removed. The Rl protecting group shown in Examples 24 and 25 would be removed as the last step of the synthesis.
:3 21~62 _5 5-Col. I
IR5 lR6 Col. II
2 ~ N-CH IC-OR2 Rl Col. III
o R7 P Cl Co 1 . IV
O ~ ~
~19~362 X I Y '' y y N y Z
x~l Y y y y y y . ..
T y (~1 ~ ~) X ¦ I Y
~ y ~ T (~ --~ a~ ci) o X
~2:~L9862 E~A 2 5 9 u~ ~n Ln u~ In a~ I O U U
~ ~ ~N 1~
~1 ~ U r U
x~l ~, u O _ U ~
O=U I ~
3 ~ O U
~1 u u u ~ o ~ _ u Z
I U
1 5 ~ U
x~
~1 C
t3 ~21986;~
5%-Exam~le 29 (+)~Dihydro-3-[[hYdroxy(4-phenYlbutvl)3hosphinyl]
amino]-4-oxo-1,5-benzothiazepine-5(2H)-acetic acid, dilithium salt a) S-(2-Aminophenyl)-N-[(l,l-dimethylethoxy)-carbonyl]-L-cysteine, methyl ester To a mixture of 2-amino-thiophenol (1.9 g., 15.4 mmole), methylene chloride (15 ml.), and 2,6-lutidine (1.8 ml., l.0 eq.) at -20 (chloroform dry ice) is added 2-[[(l,l~methylethoxy)carbonyl]amino]-2-propenoic acid, methyl ester (3.0 g., l.0 eq.) dropwise over 5 minutes. After one hour the cooling bath is removed and the reaction mix'ure is stirred for an additional 16 hours. The reaction mixture is diluted with ethyl acetate and washed with saturated sodium bicarbonate, water, brine, dried (MgSO4), and evaporated. The residue (4.1 g.) is chromatographed on silica (125 g.) eluting with hexane/ethyl acetate (5:1) to give 2.5 g. of S-(2-aminophenyl)-N-[~ dimethylethoxy)carbonyl]-L-cysteine, methyl ester as an oil after evaporation.
b) 5-(2-Aminophen~)-N-[(1,l-dimethylethoxY)-carbonyl]-L-cysteine A mixture of S-(2-aminophenyl)-N-[(l,l-dimethylethoxy)carbonyl]-L-cysteine, methyl ester (1.0 g., 3.1 mmole), lN sodium hydroxide (3.1 ml., l.0 eq.), and dioxane (6 ml.) is stirred at room temperature in an argon atmosphere for one hour.
The reaction mixture is washed with ethyl acetate, :~21~86~:
neutralized with lN hydrochloric acid (3.1 ml.)and extracted with methylene chloride (twice).
The combined extracts are dried (MgSO4) and evaporated to give 1.0 g. of S-(2-aminophenyl)-N-[(l,l-dimethylethoxy)carbonyl]-L-cysteine as a foa~. TLC (methylene chloride/acetic acid/
methanol; 100:5:5) major spot at Rf = 0.5. The product crystallizes from xylene to give S-(2-aminophenyl)-N-[(1,1-dimethylethoxy)carbonyl]-L-cysteine as a fluffy crystalline solid; m.p. 109-111~.
Anal. calc'd. for C14H20N2O4S:
C, 53.83; H, 6.45; N, 8.97; S, 10.26 Found: C, 53.51; H, 6.28; N, 8.99; S, 10.26.
c) (~)-(2,3,4,5-TetrahYdro-4-oxo-1,5-benzo-thiazepin-3-vl)carbamic acid,l,l-dimethylethyl ester A suspension of S-(2-aminophenvl)-N-[(l,1-dimethylethoxy)carbonyl]-L-cysteine (0.65 g., 2.1 mmole) in xylene (15 ml.) is refluxed in a flask equipped with a Dean-Stark trap for 7 hours. Upon cooling of the reaction mixture the product crystallizes. The solid is collected by filtration, washed with xylene, and dried (high vacuum) to give 0.4 g. of (I)-(2,3~4~5-tetrahydro-4-oxo-1,5-benzothiazepin-3-yl)carbamic acid, l,l-dimethylethyl ester as an off-white crystalline solid; m.p. 197-200 (decomp.).
Anal. calc'd. for C14H18N2O3S:
C, 57.12; H, 6.16; N, 9.52; S, 10.89 Found: C, 56.88; H, 6.l7; N, 9.40; S, 10.87.
12~386X
d) (+)-3-[[(1,1-Dimethylethoxy)carbonYl]amino]-3,4-dihydro-4-oxo-1,5-benzothiazepine-5(2H)-acetic acid~ ethyl ester A mixture of (+)-(2,3,4,5-tetrahydro-4-oxo-1,5-benzothiazepin-3-yl)carbamic acid, 1,1-dimethylethyl ester (0.8 g., 2.7 mmole), tetrahydro-furan (10 ml.) and potassium tert-butoxide (0.4 g., 1.3 eq.) is stirred at 0 (ice bath) under argon for 10 minutes and then treated with ethyl bromoacetate (0.5 g., 1.7 eq.). After 3 minutes the ice bath is removed and the mixture is stirred for one hour. The reaction mixture is then diluted with ethyl acetate and washed successively with saturated sodium bicarbonate, 5~ potassium bisulfate, and brine, dried (MgSO4) and evaporated.
The residue (1.3 g.) is chromatographed on silica (60 g.) eluting with hexane/ethyl acetate (4:1) to give 1.0 g. of (+)-3-[[(1,1-dimethylethoxy)-carbonyl]amino]-3,4-dihydro-4-oxo-1,5-benzothia-zepine-5(2H)-acetic acid, ethyl ester as a foam.
TLC (hexane/ethyl acetate; 4:1) single spot at Rf = 0.21.
e) (+)-3-Amino-3,4-dihYdro-4-oxo-1,5-benzothia-zepine-5(2H)-acetic acid, ethvl ester A mixture of (+)-3-[[(1,1-dimethylethoxy)-carbonyl]amino]-3,4-dihydro-4-oxo-1,5-benzo-thiazepine-5(2H)-acetic acid, ethyl ester (1.0 g., 2.6 mmole), methylene chloride (5 ml.), and trifluoroacetic acid (3 ml.) is stirred under argon at 25 for 30 minutes. The methylene chloride and ~Z~ 2 O trifluoroacetic acid are removed ln vacuo and the residue is taken up in ethyl acetate and the hydrochloride salt is precipitated with saturated hydrochloric acid/ethyl ether. The white solid is collected by filtration and washed with 2:1 ethyl acetate/ethyl ether to yield 0.7 g. of (+)-3-amino-3,4-dihydro-4-oxo-1,5-benzothiazepine-5(2H)-acetic acid, ethyl ester as a white solid;
m.p. 231-233 (decomp.). TLC tmethylene chloride/
acetic acid/methanol; 100:5:5) single s~ot at Rf = 0.08.
Anal- calc'd. for C13H16N23S HC1:
C, 49.29; H, 5.41; N, 8.84; S, 10.12;
Cl, 11.37 Found: C, 48.87; H, 5.31; N, 8.80; S, lO.OS;
C1, 11.37~
f) (+)-Dihydro-3-[[ethoxy(4 phenylbutyl)phosphinyl]-amino~-4-oxo-1,5-benzothiazepine-5_2H)-acetic acid, ethyl ester A mixture of crude chloro (4-phenylbutyl)-phosphinic acid, ethyl ester (2.44 mmole), dry tetrahydrofuran (10 ml.), and (+)-3-amino-3,4-dihydro-4-oxo-1,5-benzothiazepine-5(2H)-acetic acid, ethyl ester (0.65 g., 2.05 mmole) at 0 (ice bath) in an argon atmosphere is treated dropwise with ; triethylamine (0.86 ml., 3.0 eq.) in tetrahydrofuran (5 ml.) over 1 minute. After standing at 0 for 20 minutes the ice bath is removed and the reaction mixture is stirred for 16 hours. The reaction mixture is diluted with ethyl acetate and washed ~;219862 successively with saturated sodium bicarbonate, 5~ potassium bisulfate and brine, dried (MgSO4), and evaporated. The residue (1.2 g.) is chromatographed on silica (60 g.) eluting with acetone/hexane (1:1) to give 0.8 g. of (+)-dihydro-3-[[ethoxy(4-phenylbutyl)phosphinyl]amino]-4-oxo-1,5-benzothiazepine-5(2H)-acetic acid, ethyl ester as an oil after evaporation. TLC (acetone/hexane;
2:1) two spots at Rf=0.59,0.65(isomers at phosphorus).
g) (+)-Dihydro-3-[[hydroxY(4-phenylbut~ hosphinyl]-amino]-4-oxo-1,5-benzothiazepine-5(2H)-acetic acid, dilithium salt A mixture of the diester product from part (f) (0.8 g., 1.59 mmole), dry methylene lS chloride (5 ml.), and bromotrimethylsilane (0.63 ml., 3.0 eq.) is stirred at room temperature in an argon atmosohere for 16 hours. The methylene chloride and bromotrimethylsilane are removed in vacuo and the residue is taken up in acetonitrile (approximately 5 ml.) and lN lithium hydroxide (5.6 ml., 3.5 eq.) and stirred for 2 hours. The acetonitrile is stripped, the aqueous solution is filtered, and apolied to an HP-20 (200 ml.) column eluting with a linear gradient water-acetonitrile (0 ~ 90% acetonitrile). The desired fractions are combined, filtered (millipore), and lyophilized to give 0.5 g. of (+)-dihydro-3-[[hydroxy(4-phenylbutyl)phos?hinyl]amino]-4-oxo-1,5-benzo-thiazepine-5(2H)-acetic acid, dilithium salt as a fluffy white solid; m.p. 245 (decomp.).
~2~8~2 HA269 TLC (isopropanol/conc. NH4OH/water; 7:2:1)single spot at Rf = 0.48.
Anal. calc'd. for C21H23N2O5SPL 2 2 C, 51.19; H, 5.44; N, 5.68; S, 6.51; P, 6.3 Found: C, 51.24; H, 5.12; N, 5.53; S, 6.57; P, 6.2.
Similarly, by following the procedure of Example 29 but employing the various chloro (substituted) phosphinic acid esters shown in Col. II of Examples 3 to 16 and 18 to 28, other compounds within the scope of this invention are obtai~ed.
Example 30 (R?-Dihydro-5-[[(6-aminohexYl)hYdroxyphosphin~l]-amino]-4-oxo-2-phenyl-2H-1,3-thiazepine-3(4H)-acetic acid, dilithium salt a) N-(6-Bromohexyl)phthalimide A mixture of crystalline 6-aminohexanol (11.7 g., 0.1 mole) and phthalic anhydride (14.8 g., 0.1 mole) is heated at 170 for 1.5 hours in an argon atmosphere. The evolved water is then removed with heat and argon flow.
The reaction mixture is cooled to 100 and phosphorus tribromide (7.2 ml., 0.086 mole) is added in portions via gas tight syringe to the reaction mixture. A vigorous reaction occurs with each addition. After addition is complete, the reaction mixture is heated at 100 for an additional 30 minutes. The cooled reaction mixture is diluted with ethanol (20 ml.) then poured over ice-water ~3~62 and refrigerated overnight. A yellow solid is Eiltered and washed several times with cold water until the filtrate is nearly neutral.
The crude solid is recrystallized from ethanol to give 21.0 g. of N-(6~bromohe~yl)phthalLmide as a pale yellow solid; m.p. 54-55. TLC (hexane-ethyl acetate; 1:1) shows a major spot at Rf = 0.8.
b) (6-Phthalimidohexyl)phosphonic acid, diethyl ester A mixture of N-(6-bromohexyl)phthalimide (5.5 g., 17.7 mmole) and triethylphosphite (10.0 ml., 58.4 mmole) is refluxed (bath temperature 160-165) under argon for 16 hours.
The volatiles are removed by distillation at 100 (bath temperature), 0.5 mm. of Hg to leave a pale yellow viscous oil. The crude product is purified by flash chromatography on silica gel (100 g.) eluting with acetone-hexane (1:2) to give
6.00 g. of (6-phthalimidohexyl)phosphonic acid, diethyl ester as a colorless viscous oil. TLC
(acetone-hexane; 1:1) shows a single spot at Rf = 0.40.
c) Chloro(6-phthalimidohexYl)phosphinic acid, ethyl ester A mixture of (6-phthalimidohexyl)phosphonic acid, diethyl ester, benzene, and phosphorus pentachloride is refluxed according to the procedure of Example l(e) to give chloro(6-phthalimidohexyl~
phosphinic acid, ethyl ester.
~21986;~
d) IR)-Dihydro-5-[[ethoxy(6-phthalimidohexyl) phosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester Chloro(6-phthalimidohexyl)phosohinic acid, ethyl ester and (R)-dihydro-5-amino-4-oxo-2-phenyl-2H~1,3-thiazine-3(4H)-acetic acid,ethyl ester are reacted according to the procedure of Example l(f) to give (R)-dihydro-5-[[ethoxy(6-phthalimido-hexyl)phosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester.
e) (R)-Dihydro-5-[[(6-aminohexYl)ethoxyphosphinyl]-amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester A solution of (R)-dihydro-5-[[ethoxy(6-phthal-imidohexyl)phosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester in dioxane is treated with hydrazine hydrate and stirred at room temperature under argon. After the reaction is completed, the mixture is diluted with toluene and the solvents decanted. The residue is triturated with methylene chloride and filtered.
The combined filtrate is evaporated to dryness to give (R)-dihydro-5-~[(6-aminohexyl)ethoxy-phosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4Hj acetic acid, ethyl ester.f) (R)-Dihydro-5-[[(_-aminohexyl)hydroxv~hosphinyl]
amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, dilithium salt The diethyl ester product from part (e) is treated with bromotrimethylsilane in methylene ` :~X1~38~
chloride and the residue is taken up inacetonitrile and treated with lN lithium hydroxide according to the procedure of Example l(g) Work-up of the product according to the procedure 5 of Example l(g) gives (R)-dihydro-5-[[(6-aminohexyl)-hydroxyphosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, dilithium salt.
ExamPles 31 - 34 Following the procedure of Example 30 but employing the aminoalcohol listed in Col. I
one obtains the product listed in Col. II.
Example Col. I Col. II
31 3-aminopropanol (R)~Dihydro-5-[[(3-aminopropyl)hydroxy-phosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid,dilithium salt 32 2-aminoethanol (R)-Dihydro-5-[[(2-aminoethyl)hydroxyphos-phinyl]amino]-4-oxo-2-phenyl-2H-1,3-thia-zine-3~4H)-acetic acid, dilithium salt 33 4-aminobutanol (R)-Dihydro 5-[[(4-aminobutyl)hydroxyphos-phinyl]amino]-4-oxo-2-phenyl-2~1-1,3-thiazine-3(4H)-acetic acid, dilithium salt lZ1~ 2 _ -67-Example Col. I Col. II
34 8-aminooctanol (R)-Dihydro-5-[[(8-aminooctyl)hydroxyphos-phinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, di-lithium salt Similarly, by employing the thiazine or thia-zepine esters of Examples 2 to 29 within the pro-cedure of Examples 30 to 34, other compoands within the scope of the invention are obtained.
Example 35(R)-Dihydro-5-[[[2-(benzoylamino)-3-phenyl~ropyl]-hydroxyphosphinyl]amino]-4-oxo-2-phenvl-2H-1,3-thiazine-3(4H)-acetic acid, dilithium salt a) 4-Methylbenzenesulfonic acid, 2-[[(4-methyl-phenyl)sulfonyl]amino]-3-Phenylpropyl ester A solution of d,l-phenylalaninol, hydro-chloride (9.4 g., 50.1 mmole) in dry pyridine (35 ml.) at 0 (ice bath) is treated with p-toluenesulfonyl chloride (19.4 g., 102 mmole) in small portions over a 15 minute period. The mixture is allowed to come to room temperature and stirred overnight. The mixture is evaporated to dryness and the residue partitioned between ethyl acetate and 5% potassium bisulfate. The ethyl acetate layer is washed successively with 5%
potassium bisulfate, saturated sodium bicarbonate and saturated sodium chloride, dried (Na2SO4), and evaporated. The dark residue is filtered ~2198~2 through a pad of silica gel eluting with methylene chloride then methylene chloride-ethyl acetate (1:1). Evaporation of the solvents and trituration of the residue with ether gives 13.93 g. of 4-methylbenzenesulfonic acid, 2- E [ (4-methylphenyl)-sulfonyl]amino]-3-phenylpropyl ester as white crystals; m.p. 95-96; TLC (ethyl acetate/hexane;
1:2) spot at Rf = 0.39. A sample recrystallized from diisopropyl ether has m.p. 96-98.
b) [2-[[(4-Methylphenyl)sulfonyl]amino]-3-phenyl~
propyl]phosphonic acid, diethyl ester A solution of diethylphosphite (7.3 g., 52.9 mmole) in dry tetrahydrofuran (100 ml.) is treated with sodium hydride 50% oil dispersion lS (2.20 g., 45.8 mmole) in small portions under argon.
The mixture is then refluxed for 30 minutes, cooled to room temperature, and treated with 4-methyl-benzenesulfonic acid, 2-[[(4-methylphenyl)sulfonyl]-amino]-3-phenylpropyl ester (6.9 g., 15 mmole).
After lS minutes, a white solid separates; additional tetrahydrofuran (75 ml.) is added and stirring continued overnight. After stirring at room temperature overnight, the mixture is refluxed for one hour, cooled and partitioned between ethyl acetate (75 ml.) and 5% potassium bisulfate (50 ml.).
The ethyl acetate phase is washed successively with 5% potassium bisulfate, saturated sodium bicarbonate and saturated sodium chloride, dried (Na2SO4), and evaporated. The residue is ~riturated with hexane to give 5.9 g. of [2-[[(4-methyl-:1219862 phenyl)sulfonyl]amino]-3-phenylpropyl]phosphonic acid, diethyl ester as an off-white solid;
m.p. 86-89; TLC (ethyl acetate) spot at Rf = 0.48.
A sample recrystallized from diisopropyl ether has m.p. 94-95.
c) t2-Amino-3-phenylpropyl)phosphinic acid A mixture of i2-[[(4-methYlPhenYl)sulfonyl]-amino]-3-phenylpropyl]phosphonic acid, diethyl ester (5.9 g., 13.9 mmole), phenol (8.0 g., 85.1 mmole), and 48% aqueous hydrobromic acid (50 ~1.) is refluxed for 5.5 hours. The cooled mixture is diluted with water (50 ml.) and washed with ethyl acetate (2 x S0 ml.). The aqueous phase is evaporated to dryness, taken up in water (30 ml.) and evaporated again. This is repeated twice more. Finally, the residue is taken up in water and applied to an AG 50 W - X2 (H ~orm) column (50 ml. bed volume) and eluted first with water then with 5% pyridine-water. The fractions containing the desired product are combined and evaporated to dryness. The solid residue is triturated with acetonitrile to give 2.55 g. of (2-amino-3-phenylpropyl)phosphinic acid as an off-white crystalline solid; m.p. 347 (dec.);
TLC (isopropanol/conc. NH40H/water; 7:2:1) spot at Rf = 0.27.
d) (2-Phthalimido-3-phenylpropy~ hosphinic acid A mixture of (2-amino-3-phenylpropyl) phosphinic acid (2.0 g., 9.3 mmole) and phthalic anhydride (1.55 g., 10.5 mmole) is fused in a _70_ HA269 flask under argon at 195-200 (bath temperature) for 1.5 hours. The glassy dark residue is refluxed with ethyl acetate (25 ml.) until the glassy residue dissolves and a fluffy crystalline 5 solid separates. The cooled mixture is diluted with diethyl ether (25 ml.) and filtered. The solid is washed thoroughly with diethyl ether and dried to give 2.37 g. of (2-phthalimido-3-phenylpropyl)phosphinic acid as an off-white crystalline solid; m.p. 127 - 130. A sample crystallized from ethyl acetate m.p. 129 - 131;
TLC (isopropanollconc. NH40H/water; 7:2:1) spot at Rf = 0.33.
e) (R~Dihydro-5-[~[2-Phthalimido-3-Phenylpropvl]-ethoxyphosphinvl]amino]-4-oxo-2-phenyl-2H-l~3 thiazine-3(4H)-acetic acid, ethyl ester A suspension of (2-phthalimido-3-phenylpropyl) phosphinic acid in dry benzene is treated with phosphorus pentachloride and stirred at room temperature under argon for an hour. The mixture is then refluxed for 15 minutes, cooled and evaporated to dryness at room temperature (0.5 mm.
of Hg). The residue is taken up in dry methylene chloride and reacted successively with a mixture of ethanol(l eq.) and triethylamine (1 eq.) in methylene chloride and (R)-dihydro-5-amino-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester in the presence of triethylamine according to the procedure of Example l(f). Work up of the reaction mixture according to the procedure of Example l(f) yields (R)-dihydro-5-[[[2-phthalimido-3-phenylpropyl]ethoxyphosphinyl~-~.Z~9~36%
amino]-4-oxo-2-phenyl-2H-l~3-thiazine-3(4H)-acetic acid, ethyl ester.
f) (R)-Dihydro-S-[[[2-(benzoYlamino)-3-phenyl~ropyl]-ethoxyphosphinyl]amino]-4-oxo-3-phenyl-2H-1,3-thia_ zine-3(4H)-acetic acid, ethyl ester A solution of (R)-dihydro-5-[[[2-phthalimido-3-phenylpropyl]ethoxyphosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester in dioxane is treated with hydrazine hydrate and stirred for 24 hours at room temperature.
The mixture is then partitioned between ethyl acetate-water and the ethyl acetate phase was washed with water and saturated sodium chloride, dried (Ma2SO4), and evaporated. The residue is taken lS up in dry toluene and refluxed for one hour. The mixture is filtered, treated with triethylamine and benzoyl chloride and stirred at room temperature for 30 minutes. The mixture is diluted with ethyl acetate, washed successively with 5~ potassium bisul-fate, saturated sodium bicarbonate, and saturatedsodium chloride, dried (Na2SO4), and evaporated.
The residue is chromatographed on silica gel to give (R)-dihydro-5-[[[2-(benzoylamino)-3-phenylpropyl]-ethoxyphosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester.
q) (R)-Dihydro-5-_~_[[2-(benzoylamino)-3-phenylpropyl~-hydroxyphosphinyl]amino]-4-oxo-2-phenyl-2~-1,3-thiazine-3(4H)-acetic acid, dilithium salt The diethyl ester product from part (f) is treated with bromotrimethylsilane in methylene ~Z1~62 HA269 - -chloride and the residue is taken up in acetonitrile and treated with lN lithium hydroxide according to the procedure of Example l(g). Work uo of the product according to the orocedure of Example l(g) gives (R)-dihydro-5-[[[2-(benzoylamino)-3-phenyl-propyl]hydroxyphosphinyl]amino]-4-oxo-2-ohenyl-2H-1,3-thiazine-3(4H)-acetic acid, dilithium salt.
Examples 36 - 45 Following the procedure of Example 35 but employing the protected amine shown in Col. I and the phosphinic diester shown in Col. II, one obtains, after removal of the tosyl protecting group and reaction with phthalic anhydride, the phosphinic acid shown in Col. III. The acid of lS Col. III is then converted to the phosphinic acid ester chloride shown in Col. IV which is then coupled with the thiazine ester shown in Col. V
to yield the intermediate shown in Col. VI.
Removal of the phthalidyl group and reaction with the acid chloride shown in Col. VII
yields the ester product shown in Col. VIII.
The ~2 and R8 ester groups can be removed to give the corresponding diacid which can then be converted to a salt or in the case of Example 45 only the R8 ester group would be removed. The Rl protecting group shown in Example 40 would be removed as the last step of the synthesis.
Col. I Col. II
o Ts-NH-CH-CH2-OTs Na-P-OC H
Rl 2 2 5 Col._III Col. IV
[~N-cH-cH2-p-oH ~N-CH-CH2-P-Cl Col. V Col. VI
H2N~ 5-CH-COOR2 ~N-CH-CH2-P--NE~nN-C11~COR2 ~2~ 86~
~A269 Col. VII
o Rg C--C1 Col. VIII
2 ) n~
Rg-C-NH-CH- CH2-- P NH~ N-cH-cooR2 :~LX~ 2 n u~ Irl ~n In :r ~ I ~ S' o -N
~ I .
N
x I ~ ~o a) I
~ o N N
,~ o =
y _~
~ t~
~J
~ ~ Ln ," 3 Ul Ll') X~ I Y ~ y N ~ U
~ I
E~ ~I N
X
.~219l362 _ _77-O Similarly, by employing the thiazine esters of Examples 17 ~o 29 within the procedure of Examples 35 to 45, other compounds within the scope of the invention are obtained.
Example 46 (R)-Dihydro-5-[[1-(ethoxvcarbonyl)-3-phenylpropyl]-amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid a) (R)-Dihydro-5-phthalimido-4-oxo-2-phenyl-2H-1,3-thiazine-3t4H)-acetic acid, ethyl ester (isomer A) and (isomer B) The diastereomeric mixture of (R)-dihydro-5-phthalimido-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester (15.6 g.) from Example l(c) is refluxed in ether (500 ml.) for 4 hours, then cooled in an ice-bath and filtered to give 5.9 g. of isomer A at least 90~ free of isomer B; m.p. 166-168. ~]D = -72.9 (c = 1, chloroform). TLC (hexane/ethyl acetate; 1:1) shows spot at Rf = 0.40.
Anal. calc'd. for C22~20O5N2S:
C, 62.25; H, 4.75; N, 6.60; S, 7.55 Found: C, 62.21; H, 4.82; N, 6.63; S, 7.52.
A second, lower melting sample of isomer A
(0.9 g., m.p. 162-164) is obtained by refluxing the remaining mixture in 125 ml. of ether and collecting the solid product. The remaining mixture (8 g.) is refluxed in 50 ml. of ether affording 250 mg.
of insoluble material and 7.1 g. of soluble product enriched in isomer B. 5.8 g. of this ~ 86~, HA269 material is purified chromatographically on two Waters Prep LC columns run with hexane:ethyl acetate (3:1~. By this route, 4.8 g. of isomer B
is obtained; m.p. 66 - 68; [~]D = -101.2~
(c = 1, chloroform). TLC same as for isomer A.
Anal. calc d- for C22 20 5 2 C, 61.83; H, 4.79; N, 6.55; S, ?.50 Found: C, 61.83; H! 5-07; N, 6.25; S, 7.42.
b) (R)-Dihydro-5-phthalimido-4-oxo-2-phenyl-2H-1,3-thiazine-3~4H)-acetic acid, 2-(trimethylsilyl) ethyl ester (R)-Dihydro-5-phthalimido-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester (isomer A) (l.o g., 2.36 mmole) is heated in 2-trLmethylsilylethanol (5.58 g., 47.2 mmole) in the presence of titanium (IV) ethoxide (135 mg., 0.59 mmole). Upon completion of the reaction, the reaction mixture is diluted with ether, washed with lN hydrochlor~c acid, water, 2~ saturated aqueous sodium bicarbonate, and brine, dried (MgSO4), and concentrated in vacuo. The residue is purified chromatographically on silica gel eluting with hexane/ethyl acetate (3:1) to give (R)-dihydro-5-phthalimido-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)ethyl ester.
* Trade Mark ~ .
~21.9~62 HA269 c) (R)-Dihydro-5-amino-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)ethyl ester A solution of the trimethylsilyl ester product from part (b) (1.17 g., 2.36 mmole) in 4 ml. of dry chloroform is treated with N-methylhydrazine (217 mg., 4.72 mmole). The stop~ered reaction is stirred at room temperature overnight, then diluted with ether and filtered to remove N-methyl-phthalhydrazide. Removal of organic solvents ln vacuo yields (R)-dihydro-5-amino-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2~(trimethylsilyl)ethyl ester.
~ ~l]-amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)ethyl ester A solution of (R)-dihydro-5-amino-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(tri-methylsilyl)ethyl ester (9 mmole) in dry isopropanol (12 ml.) under nitrogen is treated with sodium bicarbonate ~2.25 mmole) followed by ethyl-2-oxo-4-phenylbutyrate (9.3 g., 45 mmole) dissolved in isopropanol (8 ml.). To the resulting susoension is added powdered 3A molecular sieves (8 g.). The reaction mixture is stirred for one hour while the pH is maintained at around 7Ø Next a solution of sodium cyanoborohydride (1.13 g., 18 mmole) in isopropanol (14 ml.) is added incrementally over a 5 hour period while continuing to maintain neutral pH. The reaction mixture is ~L~19~6~
then stirred overnight at room temperature, thenfiltered (celite), concentrated in vacuo, and partitioned between ether and water. Normal work up of the organic extract followed by column chromatography on silica gel yields (R)-dihydro-5-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)ethyl ester as a mixture of diastereomers.
e) (R)-Dihydro-5-~[l-(ethoxvcarbonYl)-3-phenyl-pro~l]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic_acid A solution of (R~-dihydro-5-[[l-(ethoxy-carbonyl)-3-phenylpropyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl) ethyl ester (1.47 mmole) in dry dimethylformamide (4.5 ml.) is cooled in an ice-bath and reacted with a solution of n-tetrabutylammonium fluoride tri-hydrate (0.928 g., 2.94 mmole) in dimethylformamide (1.5 ml.). Upon disappearance of starting material, the reaction mixture is diluted with ethyl acetate (200 ml.) and washed with water (30 ml., twice). Normal work-up of the organic extract followed by chromatography affords (R)-dihydro-5-[[1-(ethoxycarbonyl)-3-phenylpropyl]-amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid as a mixture of diastereomers.
Similarly, the diastereomic mixture of (R)-dihydro-5-phthalimido-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester or its isomer B
~2~ 9~
could be employed in place of isomer A in the above procedure to yield other compounds within the scope of the invention.
Example 47 (R)-Dihydro-5-[[1-carboxy-3-phenylpropyl]amino~-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, dilithium salt A solution of (R)-dihydro-5-[[1-(ethoxy-carbonyl)-3-phenylpropyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid (1 mmole), prepared as set forth in Example 46, in methanol (4 ml.) is treated with lN aqueous lithium hydroxide (2 ml.). Upon completion of the reaction, the aqueous solution is filtered and chromatographed on an HP-20 (200 ml.) column eluting with a linear gradient of water -acetonitrile(10 ~ 90% acetonitrile). The desired fractions are combined, evaporated to a small volume, filtered (millipore) and lyophilized to give (R)-dihydro-5-[[1-carboxy-3-phenylpropyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, dilithium salt.
Examples 48 - 70 Following the procedure of Examole 46 but employing the keto compound shown in Col. I
and the thiazine ester shown in Col. II, one obtains the product shown in Col. III. The R3 and R4 protecting groups shown in Examples 59, 61, and 63 to 65 are removed as the last step of the synthesis. The R2 and R3 ester groups can be lX~L9862 . HA269 - 82- _ removed to give the corresponding diacid which can then be converted to a salt. When it is desired to remove only the R2 ester group and leave the R3 ester group in place, then the thiazine ethyl ester is converted to its trimethylsilylethyl ester prior to reaction with the keto compound.
~198~
Col. I
O O
Il 11 R-- C-- C--R
Col. II
S R
(CH2 ) ~ O
2 ~ N-CH-C-OR2 R
Col. III
~ S ~R
(I 2 ) n~
R3 C--CH--NH~ N--CH--C--OR
4 O Rl ~986~
~ N N~N3~N ~ N X
xl Y Y Y Y Y Y
x~
~ I I I I I I I
N N T
O I I N
-E ¢1 ~ ~I N t~
121'9~362 ~r 2 N ¦ N N N N N N
II: I I I l I l I
~ T
1~:; 1 1 1 1 1 1 l Y ~
N~I N _I N
~ N ~ N
~1 I Y Y I I Y
~ U N I ~,3 O ~ ~
~ I æN ~ o Z z 8 ~, ~ Z
o Z
~r ~ ~D 1` ~ u x ~LZ 'L98~2 :r 2 3: ~r N I N UN U UN UN
~S; I I I I I I
U~
~r:
N 5~
~ I I I I I I
z c; I N _I N ~ ~
Z~
N N U O -- U
~_) C) N ~ Z
¦ I o ~ N _~
X 15 ~ N
C~I I ~
U~Ul Ln U'~ U~
o U o U o O.--1 N ~ ~r a~
Ll N N
S =~ ~CN ¦ z _ T ~ = O
N N
N N
~ I O ~ C,) ~1 E ~D ' ~D
x ~Z151862 HA2 6 9 tX; ¦ C) N
~ ~: V ~:
~ I I I t t- I '`t ~ ~\t ~ ~0 ~ ~=0 t.~ Z
\ ~ /
~ ~t '`t tY I I O
Q. a) al o .~t r~
a6~
Similarly, by employing the thiazineesters of Examples 17 to ~9 within the procedure of Examples 46 to 70,other compounds within the scope of the invention are obtained.
Example 71 (R)-Dihvdro-5-~[[2-methYl-l-(l-OXoDroPoXy)propoxy](4 p}lenYlbutyl)~hosphinYl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid,monolithium salt 10 d) (R)-Dihydro-5-phthalimido-4-oxo-2-Dhenyl-2H-1,3-thiazine-3(4H)-acetic acid, trimethvlsilyl-ethyl ester (R)-Dihydro-5-phthalimido-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester is heated in trimethylsilylethanol in the presence of titani~m (IV) ethoxide. Upon completion of the reaction, the reaction mixture is diluted with ether, washed Wit}l lN hydrochloric acid, water, saturated aqueous sodium bicarbonate, and brine, dried (MgSO4), and concentrated ln vacuo. The residue is purified chromatographically on silica gel to yield (R)-dihydro-5-phthalimido-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, trimethyl-silylethyl ester.
b) (R)-Dihydro-5-amino-4-oxo-2-~henyl-2H-1,3-thia-zine-3(4H)-acetic acid, trimethylsilvlethyl ester A solution of the trimethylsilylethyl ester product from part (a) in dry chloroform is treated with N-methylhydrazine according to the procedure of Example l(d) to give (R)-dihydro-5-amino-4-'lZ19~6;;~
. HA269 oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, trimethylsilylethyl ester.
c) (R)-Dihydro-5-[[ethox~(4-phenylbutyl)~hosphinyl]-amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, trimethylsilylethyl ester Chloro(4-phenylbutyl)phosphinic acid, ethyl ester is reacted with (R)-dihydro-5-amino-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, trimethylsilylethyl ester according to the procedure of Example l(f) to yield (R)-dihydro-5-[[ethoxy-(4-phenylbutyl)phosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-aceticacid,trimethylsilylethyl ester.
d) (R)-DihYdro-5-[[[2-methvl-1-(1-oxopropoxy)-propoxy](4-phen~lbutyl)phosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, trimethvl-silylethyl ester A mixture of the diester product from ~art (c) and bis(trimethylsilyl~acetamide in methylene chloride is stirred at ambient temperature for several hours. After concentration in vacuo at 30, methylene chloride is added followed by bromotrimethyl-silane. The mixture is stirred at room temperature for several hours and concentrated ln vacuo overnight. The residue is dissolved in methylene chloride and treated with triethylamine and water and again concentrated ln vacuo. The residue is taken up in chloroform and treated with triethylamine, l-chloroisobutyl propanoate, sodium chloride, and tetrabutylammonium iodide. The mixture is stirred at reflux temperature overnight. The reaction 9~3~i2 . HA269 mixture is then concentrated ln vacuo and ether is added to the residue. The water soluble solids separatlng from solution are filtered off and the ethereal filtrate is washed with water, 2% sodium thiosulfate, and brine, dried (MgSO4), and concentrated ln vacuo to give (R)-dihydro-5-[[[2-methyl-1-(1-oxopropoxy)propoxy](4-phenvlbutyl) phosphinyl]amino~-4-oxo-2-phenyl-2H-l~3-thiazine 3(4H)-acetic acid, trimethylsilylethyl ester.
e) (R)-Dihydro-5-[[[2-methyl-1-(1-oxopropoxy)-propoxy](4-phenylbutyl)phosphinYl]amino]-4-oxo-2-2~ 1-2H-1,3-thiazine~3(4H)-acetic acid, monolithium salt The diester product from part (d) in dry di-methylformamide is treated with a solution of n-tetrabutylammonium fluoride in dimethylformamide.
Upon disappearance of the starting material, the reaction mixture is diluted with ethyl acetate, washed with water, and concentrated in vacuo. The residue is dissolved in water and applied to an AG50 X 8(Li ) column eluting with water. Fractions containing the desired product are combined and lyophilized. The iyophilate is chromatographed on an HP-20 column eluting with a linear gradient of acetonitrile/water (0 ~ 90%). Fractions containing the desired product are combined, concentrated ln vacuo and the residue is dissolved in water, filtered, and lyophilized to give (R)-dihydro-5-[[[2-methyl-1-(1-oxopropoxy)propoxy]-~1386~ HA269 (4-phenylbutyl)phosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3l4H)-acetic acid, monolithium salt.
Examples 72 - 77 Following the proc:edure of Example 71 but substituting for the l-chloroisobutyl propanoate the alkylating agents listed below in Col. I, the products listed in Col. II are obtained.
~xampleCol. I Col. II
Cl-CH-O-C-C H (R)-Dihydro-5-[[[cyclo-hexyl!l-oxopropoxy)methoxy]
(4-phenylbutyl)phosphinyl]-amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ll monolithium salt 73Cl-CH-O-C-C2H5 (R)-Dihydro-5-[[[1-(1-CH3 oxopropoxy)ethoxy](4-phenyl-butyl)phosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, mono-lithium salt 74Cl-CH -O-C-C(CH ) (R)-Dihydro-5-[[[(2,2-dimethyl-1-oxopropoxy)methoxy]-(4-phenylhutyl)phosphinyl]-amino]-4 oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, monolithium salt ~219~3~,2 ~ 93-Example Col. I Col. II
Cl-CH-O-C-(CH ) -CH (R)-Dihydro-5-[[[2-methyl-1-CH(CH3)2 (1-oxobutoxy)propoxy](4-phenylbutyl)phosphinyl]-amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, monolithium salt 76 2 ~ (R)-Dihydro-5-[[[(phenyl-carbonyloxy)methoxy](4-phenylbutyl)phosphinyl]-amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic ll acid, monolithium salt 77 Cl-CH2-0-C-OC2H5 (R)-Dihydro-5-[[[(ethoxy-carbonyloxy)methoxy](4-phenylbutyl)phosphinyl~-amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, monolithium salt ~219~62 Similarly, the alkylating agents ofExamples 71 to 77 can be employed with the ester products of Examples 2 to 45 to yield other compounds within the scope of this invention.
ExamDle 78 (R)-Dihydro-5-[[hydroxy(4-phenylbutyl)phosphinyl]-amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, disodium salt Following the procedure of Example l but substituting sodium hydroxide for the lithium hydroxide in part (g), one obtains (R)-dihydro-5-[[hydroxy(4-phenylbutyl)-phosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, disodium salt.
This procedure can be employed generally to give the corresponding mono or disodium salt. In a similar manner, the corresponding mono or dipotassium salt can be obtained.
121986~ ~269 Example 79 (5R)-5-[(1-Carboxy-3-phenylpro~yl)amino]dihydro-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid (B-slow isomer) a) N-Phthaloyl-L-cysteine A solution of N,N'-diphthaloyl-L-Cystine (19.5 g., 38.9 mmole) in a mixture of trifluoro-acetic acid (60 ml.) and dry tetrahydrofuran (200 ml.) is cooled in an ice-bath under nitrogen and treated with zinc dust (15.3 g., 233.4 mmole) in three equal portions over a period of 15 minutes.
The reaction is stirred cold for 2 hours, then filtered (celite) and concentrated in vacuo. The residue is partitioned between 600 ml. of ethyl acetate:ether (5:1) and a water-brine mixture.
The organic layer is washed with water, brine and dried (MgSO4). Removal of the solvents in vacuo yields 21.9 g. of crude product which is flash chromatographed on silica gel (400 g.) eluting with toluene:acetic acid (6:1). Fractions containing the desired product are combined to give 12.1 g. of N-phthaloyl-L-cysteine ~s an oil.
[a]D = -54.2 (c=l, methanol). TLC (toluene/
acetic acid; 6:1) spot at Rf = 0.30.
b) N-Benzylidineglycine, ethyl ester A mixture of glycine, ethyl ester, hydro-chloride (10 g., 71.6 mmole), triethylamine (14.5 g., 143.2 mmole) and anhydrous MgSO4 (6.0 g., 50.1 mmole) in dry methylene chloride (150 ml.) is treated with a solution of benzaldehyde (7.6 g., 1~ 9~ 2 . IIA269 _ -96-71.6 mmole) in methylene chloride (lO ml.) added over a period of 15 minutes. After 5 hours, the reaction mixture is filtered, concentrated ln vacuo, and then partitioned between 400 ml. of ether and 50 ml. of water. The organic layer is waslled with water and brine, dried (MgSO4), and concentrated ln vacuo to give 12.1 g. of N-benzyli-dineglycine, ethyl ester.
c) (5R)-Dihydro-5-phthalimido-4-oxo-2-ph~ 2~-1,3-thiazine-3(4H)-acetic acid, ethyl ester (isomers A and B) To a solution of N-phthaloyl-L-cysteine (15.8 g., 62.8 mmole) and N-benzylidineglycine, ethyl ester (12.3 g., 64.3 mmole) in dry chloroform (160 ml.) cooled in an ice bath under nitrogen is added dicyclohexylcarbodiimide (13.0 g., 62.8 mmole) in one portion. After 2 hours, the cold reaction mixture is filtered, concentrated in vacuo and redissolved in a mixture of ether (500 ml.) and chloroform (200 ml.). The organic extract is washed with saturated aqueous sodium bicarbonate, water, 5% potassium bisulfate and brine, dried (MgSO4) and concentrated ln vacuo to give 23.8 g. of crude product. Flash chroma-tography on silica (600 g.) eluting with llexane:
ethyl acetate (3:1) yields 15.6 g. of (5R)-dihydro-5-phthalimido-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester as a diastereomeric mixture.
9~
This mixture is refluxed in 500 ml. ofether for 4 hours, then cooled in an ice-bath and fi]tered to yield 5.9 g. of (5R)-dihydro-5-phthalimido-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester ~isomer A); m.p.
166~168; [a]D = -72.9 (c = 1, chloroform).
TLC (hexane/ethyl acetate; l:l)spot at Rf = 0.40.
Anal. calc'd. for C22H20N2O5S:
C, 62.25; H, 4.75; N, 6.60; S, 7.55 Found: C, 62.21; H, 4.82; N, 6.63; S, 7.52.
Trituration of the remainder of the diastereomeric product mixture with 125 ml. of refluxing ether affords a second batch of isomer A
(0.9 g., m.p. 162-164). The residue is triturated with ether to give 0.75 g. of insoluble substance (presumably largely isomer A) and 7.1 g. of material enriched in isomer B. The enriched isomer B
(6.0 g.) is chromatographed on two connected Waters Prep LC columns eluted with hexane:ethyl acetate (3:1). Pooling of the product containing fractions yields 4.8 g. of purified (5R)-dihydro-5-phthalimido-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester (isomer B);m.p 66-68; [a]D = -101.2 (c = 1, chloroform).
TLC same as isomer A.
Anal. c . 22 20 2 5 2 C, 61.83; H, 4.79; N, 6~55; S, 7.50 Found: C, 61.83; H, 5.07; N, 6.25; S, 7.42.
86~
H~2G9 d) (5R)-Dihydro-5-Phthalimido-4-oxo-2-pheny~
_-1,3-thiazine-3(4~1)-acetic acid, 2-(trimet~
silyl)ethyl ester (isomer ~) A mixture of (5R)-dihydro-5-phthalimido-4-oxo-2~phenyl-2~-1,3-thiazine-3(4H)-acetic acid, ethyl ester (isomer B) (2.5 g., 5.9 mmole), 2-trimethylsilylethanol (14.0 g., 118 mmole), and titanium (IV) ethoxide (338-mg., 1.48 mmole) is heated at 100 under nitrogen for 5 hours and then cooled to room temperature. The reaction mixture is then diluted with 200 ml. of ether and stirred with 25 ml. of lN hydrochloric acid for 10 minutes. Next, the organic solution is separated, rinsed with water, saturated sodium bicarbonate, water, and brine, dried (MgSO4), and concentrated in vacuo. I~ost of the excess 2-trimethylsilylethanol is removed by distillation using a 40 oil bath and an ice-cooled receiving flask. After further pumping in vacuo, the residue (3.2 g.) is flash chromatographed on 160 g. of LPS-l silica gel eluted with hexane:ethyl acetate (5:1) to give 2.2 g. of (SR)-dihydro-5-phthalimido-4-oxo-2-phenyl-2H-1,3-thia~ine-3(411)-acetic acid, 2-(trime-thylsilyl)ethyl ester (isomer B); m.p. 65-66;
[~]D = ~75 0 (C = 1, chloroform). TLC (he~ane:
ethyl acetate; 2:1) spot at Rf = 0.46.
Anal. calc'd. for C25H28N2O5SSi:
C, 60.46; H, 5.68; N, 5.64; S, 6.46 Found: C, 60.44; H, 5.69; N, 5.50; S, 6.43.
i2 _99_ e) (5R)-Dihydro-5-amino-4-oxo-2-Phenyl- 2H-I~3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)_ ethyl ester (isomer B) A solution of (5R)-dihydxo-5-phthalimido-4-S oxo-2-phenyl-2H-1,3-thiazine-3(4Ii)-acetic acid, 2-(trime-thylsilyl)ethyl ester (isomer B) (2.01 g., 4.05 mmole) in dry chloroform (9 ml.) under nitrogen at room temperature is treated with methylhydrazine (317 mg., 6.88 mmole).
After 12 hours, an additional 0.1 ml. of methyl-hydrazine is added and the reaction is stoppered and stirred overnight. The reaction mixture is then diluted with an additional 100 ml. of ether and the solution is rinsed with 25 ml. portions of saturated sodium bicarbonate, water, and brine, dried (MgSO4), and concentrated ln vacuo to give 1.55 g. of crude (5R)-dihydro-5-amino-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)ethyl ester (isomer B);
[~]D = ~47~3 (c = 1, chloroform).
f) ~5R)-5-[[1-(Ethoxycarbonyl)-3-phenylpropyl]-amino]dihydro-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)ethyl ester (B fast and slow isomers) To a solution of (5R)-dihydro-5-amino-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)ethyl ester (isomer B) (1.55 g., 4.05 mmole) in 11 ml. of isopropanol is added ethyl-2-oxo-4-phenylbIltyrate (4.18 g., 20.2 mmole).
The above mixture, at room temperature under . ~21986~ !IA269 nitrogen, is treated with p-toluenesulfonic acid, monohydrate (386 mg., 2.03 mmole) followed by 4.5 g. of freshly pulverized 3A~ molecular sieves. This mixture is stirred for 1 hour while keepiny the pH between 6 and 8 by adding solid sodium bicarbonate. Next, a solution of sodium cyanoborohydride (509 mg., 8.1 mmole) in isopropanol (8.1 ml.) is added over a period of 5 hours while keeping the pH between 6 and 8 by adding p-toluenesulfonic acid, monohydrate. Upon completion of the addltion, the reaction is stirred at room temperature overnight, diluted with 150 ml.
of ether, and filtered. The filtrate is rinsed with ~ 30 ml. portions of water, 10~ potassium bisulfate, water, saturated sodium bicarbonate, water, and brine, then dried (MgSO4), and concentrated in vacuo to give 5.4 g. of crude product. Removal of most of the by-product, ethyl-2-hydroxy-4-phenylbutyrate, is accomplished by chromatography.
The resulting crude mixture of diastereomers (1.6 ~.) is flash chromatographed on 100 g. of LPS-l silica gel eluted with petroleum ether:ether (7:2). This yields 821 mg. of (5R)-5-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]dihvdro-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)ethyl ester (B-slow isomer), [~]D = -29.8 (C = 1, chloroform).
Anal. Calc'd. for C29H40N205SSi:
C, 62.55; H, 7.24; N, 5.03; S, 5.76 Found: C, 62.25; H, 7.30; N, 4.91; S, 5.56.
`~21986~
The fraction from the above flash column contains 525 mg. of the fast moving diastereomer.
This material is further purified by hydrogenation in 40 ml. of ethyl acetate at 50 psi in the presence of 125 mg. of 10~ palladium/carbon catalyst.
After 20 hours, the solution is filtered, concentrated in vacuo and the residue (450 mg.) is flash chromatographed on 22 g. of LPS-l silica gel eluting with petroleum ether:ether (3:1). Pooling of the product containing fractions yields 325 mg.
of (5R)-5-[[1-(ethoxycarbonyl)-3-phenylpropyl~-amino]dihydro-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)ethyl ester tB-fast isomer), r~]D = -22.4 (c = 1, chloroform).
Anal. calc'd. for C29H40N2osssi:
C, 62.55; H, 7.24; N, 5.03; S, 5.76 Found: C, 62.73; H, 7.43; N, 4.82; S, 5.47.
q) (5R)-5-l[l-(Ethoxycarbonyl)-3-phenyl~ropyl]
amino]dihydro-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid (B-slow isomer) A mixture of trifluoroacetic acid (8 ml.) and anisole (0.4 ml.) is cooled in an ice-water bath under nitrogen and treated with (5R)-5-[[l-(ethoxycarbonyl)-3-phenylpropyl]amino]
dihydro-4-oxo-2-phenyl-2H-1,3-thiazine~3~4H)-acetic acid, 2-(trimethylsilyl)ethyl ester (B-slow isomer) (400 mg., 0.72 mmole) dissolved in dry methylene chloride (4 ml.). The cooling bath is removed and the reaction is stirred at ambient temperature for 3 hours, then concentrated * Trade Mark ~L21~;2 in v cuo and azeotroped with toluene. The crude product (440 mg.) is chromatographed on 150 ml.
of ~IP-20 eluted with a graclient from 400 ml.
of water:acetonitrile (5:4) to 400 ml. of 100%
acetonitrile. The product containing fractions are pooled, evaporated, then precipitated from ethanol (10 ml.) by the addition of water (300 ml.). By this method 171 mg. of (5R)-5-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]dihydro-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid (B-slow isomer) are obtained; m.p. 130-135; [~]D = -36.1 (c = 1, methanol). TLC (ethyl acetate:pyridine:acetic acid:
water; 100:20:6:11) spot at Rf = 0.79.
Anal. calc'd. for C24H28N2O5s:
C, 63.13; H, 6.18; N, 6.14; S, 7.02 Found: C, 63.20; H, 6.26; N, 6.12; S, 6.97.
h) (5R)-5-[(1-Carboxy-3-phenylpropyl)amino]dihydro-4-oxo-2-phenyl-2H-1,3-thia~ine-3(4I~)-acetic acid (B-slow isomer) A solution of the product from part (g) (50 mg., 0.11 mmole) in methanol (0.2 ml.) is cooled in an ice-water bath under argon and treated with lN aqueous sodium hydroxide (0.241 ml.). The cooling bath is removed and the reaction is stirred at room temperature for 5 hours. The reaction is then quenched directly onto a 2 ml.
AG 50W-X2(H ) column and eluted with water. The elution solvent is then changed to 3~ aqueous pyridine to elute about 40 mg. of crude product.
Final purification is carried out on a 15 x 180 mm.
~Z~9~2 I-IA269 HP-20 column eluted with a gradient from 200 ml.
of acetonitrlle:water (1:1) to 200 ml. of 100%
acetonitrile. Pooling of the product containing fractions yields 34 mg. of (5R)-5-[(1-carboxy-3-phenylpropyl)amino]dihydro-4-oxo-2-phenyl-2II-1,3-thiazine-3(4H)-acetic acid (B-slow isomer) as a mono-hydrate; m.p. 132-138; [~]D = 40.8 (c = 0.5, 5~
aqueous sodium bicarbonate). TLC (isopropanol:N~40H:
water; 7:2:1) spot at Rf = 0.63.
C, 59.17; H, 5.87; N, 6.28; S, 7.18 Found: C, 59.36; H, 5.53; N, 6.35; S, 7.18.
Example 80 (5R)-5-[(1-Carboxy-3-phenylpropyl)amino]dihydro-4-oxo-2-phenyl-2H-l~3-thiazine-3(4H)-acetic acid (B-fast isomer) a) (5R)-5-[[1-(Ethox~carbonyl)-3-phenyl ropyl]amino]
ih o-4-oxo-2-phenyl-2H-1~3-thiazine-3(4H)-acetic acid (B-fast isomer) A mixture of trifluoroacetic acid (6 ml.) and anisole (0.3 ml.) is cooled in an ice-bath under nitrogen and treated with (5R)-5-[[l-(ethoxycarbonyl)-3-phenylpropyl]amino]-dihydro-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trime~hylsilyl)ethyl ester (B-fast isomer) (315 mg., 0.57 mmole) dissolved in dry methylene chloride (4 ml.). The cooling bath is removed andthe reaction is stirred at room temperature under nitrogen for 3 hours, then concentrated in vacuo and azeotro~ed with toluene -~X1986~, ~A269 to yield 363 mg. of crude product. Chromatography on 150 ml. of HP-20 eluted with a gradient from 400 ml. of water:acetonitrile (5:4) to 400 ml.
of 100% acetonitrile yields 200 mg. of (5R)-5-[[(1-(ethoxycarbonyl)-3-phenylproPyl]amino]-dihydro-4-oxo-2-phenyl--2H-1,3-thiazine-3(4H)-acetic acid (B-fast isomer); m.p. 160-165;
[~]D = -24.4 (c = 0.5, methanol).
TLC (ethyl acetate:pyridine:acetic acid:water;
100:20:6:11) spot at Rf = 0.70 (minor spo-t at Rf = 0.80).
Anal. calc'd. for C24H28N2O5S:
C, 63.13; H, 6.18; N, 6.14; S, 7.02 Found: C, 63.39; H, 6.37; N, 5.94; S, 6.92.
_) (5R)-5-[(1-Carboxy-3-phenylpropyl)amino]dihydro_ -oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid (B-fast isomer) A solution of the product from part (a) (50 mg., 0.11 mmole) in methanol (0.2 ml.) is cooled in an ice-water bath under argon and treated with lN aqueous sodium hydroxide (0.241 ml.). The cooling bath is removed and the reaction is stirred at room tcmperature for 7 hours, then quenched directly onto a 2 ml. AG50W-X2(H ) column. The exchange column is initially eluted with several ml. of water then with 3~ aqueous pyridine to give 42 mg. of crude product after removal of solvents. The crude product is purified by gradient elution on a 15 x 180 mm.
HP-20 column run from 210 ml. of water:acetonitrile ~2~91~
(2:1) to 210 ml. of 100~ acetonitrile taking about 3ml/2min. fractions. The product containing fractions are pooled with methanol rinses and evaporated to give 31.3 mg. of (5R)-5-[(1-carboYy-3-phenylpropyl)amino]dihydro-4-oxo-2-phenyl-211-1,3-thiazine-3(4H)-acetic acid(B-fast isomer) as a monohydrate; m.p. 131-134; [~D = ~40 4 (c = 0.5, 5Qo aqueous sodium bicarbonate). TLC
(isoproDanol:NH3:water; 7:2:1) spot at Rf = 0.51.
C, 59.17; H, 5.87; N, 6.28; S, 7.18 Found: C, 59.24; H, 5.58; N, 6.32; S, 7.00.
Example 81 (5R)-5-[(1-Carboxy-3-phenylpropyl)amino]dihydro-4-lS oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid (A-slow isomer) a) (5R)-Dihydro-5-phthalimido-4-oxo-2-phen~
2H-1,3-thiazine-3(4H)-acetic acid, 2-(-trimethyl-silyl)ethyl ester (isomer A) A mixture of (5R)-dihydro-5-phthalimido-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester (isomer A), from Example l(c), (2.8 g., 6.6 mmole), 2-trimethylsilylethanol (15.37 g., 130 mmole), and titanium (IV) ethoxide (376 mg., 1.65 mmole) is heated at 100 under nitrogen for 5.5 hours, then cooled to room temperature overnight. The reaction mixture is diluted with ether (200 ml.), and stirred with lN hydrochloric acid (25 ml.) for 10 minutes. The organic layer is separated, rinsed with saturated ~219~6'~ 269 aqueous sodium bicarbonate, water, and brine,dried (MgSO4), and concentrated in vacuo. Most of the excess 2-trimethylsilylethanol is removed by distillation using a 40 oil bath and an ice-cooled receiving flask. After continued pumping overnight in vacuo, the residue~4.3 g.) is flash chromatographed on 215 g. of LPS-l silica gel eluted with hexane:ethyl acetate (5:1) to yield 2.7 g. of (5R)-dihydro-5-phthalimido-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)ethyl ester (isomer A);
m.p. 58-60; [~]D = -53.6 (c = 1, chloroform).
TLC (hexane:ethyl acetate; 2:1) spot at Rf = 0.32.
~nal. calc'd. for C25H28N2O5ssi C, 60.46; H, 5.68; N, 5.64; S, 6.46 Found: C, 60.20; H, 5.71; N, 5.56; S, 6.42.
b) (5R)-Dihydro-5-amino-4-oxo-2-~henyl-2~-1,3_ thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)-~ 1 ester (isomer A) A solution of 15R)-dihydro-5-phthalimido-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)ethyl ester(isomer A) (2.7 g., 5.43 mmole) in dry chloroform (12 ml.) under nitrogen at room temperature is treated with 425 mg. of methylhydrazine (9.24 mmole) and the reaction is stoppered. After 48 hours, an additional 0.15 ml. of methylhydrazine is added, and the reaction is stoppered and stirred overnight. The reaction mixture is then diluted . I-IA269 ~X198~2 with 70 ml. of ether, stirred for 10 minutes, and filtered. The filtrate is diluted with ether (150 ml.) , washed with 35 ml. portions of aqueous sodium bicarbonate, water, and brine, dried tMgSO4), and concentrated in vacuo to give 2.1 g. of (5R)-dihydro-5-amino-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trimethyl-silyl)ethyl ester (isomer A); [~]D = +35.2 (c = 1, chloroform).
c) (5R)-5-[[1-(Ethoxycarbonyl)-3-phenylprop~l]-amino]dihydro-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)ethyl ester (A-fast and slow isomers) To a solution of (5R)-dihydro-5-amino-4-lS oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)ethyl ester (isomer A) (2.1 g., 5.43 mmole) in iso?ropanol (15 ml.) under nitrogen at room temperature is added ethyl-2-oxo-4-phenylbutyrate (5.6 g., 27.15 mmole) followed by p-toluenesulfonic acid, monohydrate (518 mg., 2.72 mmole) and finally freshly pulverized 3A molecular sieves (6.0 g.). The mixture is stirred for one hour while the pH is kept between 6 and 8 by adding solid sodium bicarbonate. A solution of sodium cyanoboro-hydride (682 mg., 10.86 mmole) in isopropanol t10.9 ml.) is added to the reaction over a 5 hour period while keeping the pH between 6 and 8 by adding p--toluenesulfonic acid, monohydrate.
After the addition is completed, the reaction /~1 ~2~63~
I~A269 is stirred at room temperature overnight, then diluted with ether (200 rnl.), and filtered.
The filtrate is rinsed with 40 ml. portions of 10o potassium bisulfate, ~ater, saturated sodium bicarbonate, water, and brine, dried (MgSO4), and concentrated ln vacuo to yield 8.6 g. of crude product. Further purification is accomplished chromatographically using 350 g. of Activity II
neutral alumina eluted with ether:acetonitrile (20:1). The resulting crude product obtained (800 mg.) is hydrogenated by dissolving in ethyl acetate (70 ml.), adding 200 mg. of 10~ palladium/
carbon catalyst and shaking on a Parr apparatus at an initial hydrogen pressure of 50 psi overnight. The resulting crude mixture of diastereomers (760 mg.) is flash chromatographed on 50 9. of LPS-l silica gel elu-ting with petroleum ether:ether (3:1).
This column yields 240 mg. of (5R)-5-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]dihydro-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)ethyl ester (A-fast isomer);
[~]D = +26.1 (c = 1, chloroform). TLC (petroleum ether:ether; 3:1) spot at Rf = 0.10.
Anal. Calc'd. for C29H40N2O5SSi C, 62.55; H, 7.24; N, 5.03; S, 5.76 Found: C, 62.31; H, 7.50; N, 4.94; S, 5.74.
3~
~Z19862 ~269 The column also yields 400 mg. of (5R)-S-[[l-(ethoxycarbonyl)-3-phenylpropyl]amino]dihydro-4-oxo-2-phenyl-2H-1 r 3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)ethyl ester (A-slow isomer);
S [a]D = +14.5 (c = 1, chloroform). TLC
(petroleum ether:ether; 3:1) spot at Rf = 0.06.
Anal. Calc'd. for C29H40N2O5SSi C,62.55; H, 7.24; N, 5.03; S, 5.76 Found: C,62.46; H, 7.32; N, 4.94; S, 5.64.
d) (5R)-5-[[l-(Ethoxycarbonyl)-3-phenylpropyl]
amino]dihydro-4-oxo-2-phenyl-2H-lr3-thiazine 3(4H)-acetic acid (A-slow isomer) A solution of trifluoroacetic acid (8 ml.) and anisole (0.4 ml.) is cooled in an ice-water bath under nitrogen and treated with (5R)-5-[[l-(ethoxycarbonyl)-3-phenylpropyl]amino]dihydro-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)ethyl ester (A-slow isomer) (400 mg., 0.72 mmole) dissolved in dry methylene chloride (4 ml.). The cooling bath is removed, and the reaction is stirred at room temperature for 3 hours, concentrated in vacuo and azeotroped with toluene. The crude product (398 mg.) is chromatographed on 150 ml. ofHP-20 eluted with a gradient from 400 ml. of water:acetonitrile (5:4) to 400 ml. of 100~ acetonitrile. The product containing fractions are pooled and concentrated ln vacuo to give 275 mg. of (5R)-5-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]
dihydro-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-~Z~9~36;2 acetic acid (A-slow isomer); m.p. 47-52;
[~]D = +21.4 (c = 0.5, methanol). TLC
(ethyl acetate:pyridine:acetic acid:water;
100:20:6:11) spot at Rf = 0.83.
Anal. Calc d. 24 28 2 5 2 C, 61.20; H, 6.34; N, 5.95; S, 6.81 Found: C, 61.20; H, 6.07; N, 5.94; S, 6.68.
_) (5R)-5-[(1-Carboxy-3-~henylpropyl)amino]-dih~dro-4-oxo-2-phenyl-2H-l~3-thiazine-3(4H) acetic acid (A-slow isomer) A solution of the product from part(d) (50 mg., 0.11 mmole) in methanol (0.2 ml.) is cooled in an ice-water bath under nitrogen and treated with lN sodium hydroxide (0.24 ml.).
The ice bath is removed, and the reaction is stirred at ambient temperature for 5 hours. The reaction is then quenched directly onto a 2 ml.
AG50W-X2(H ) column and washed with water. The desired product is eluted with 3% aqueous pyridine to give 46 mg. of crude product. Final purifica-tion is carried out on a 50 ml. HP-20 column eluted with a gradient from 200 ml. of water:
acetonitrile (2:1) to 200 ml. of 100% acetonitrile.
The product containing fractions are concentrated ln vacuo, triturated with cold water, and filtered to give 24 mg. of (5R)-5-[(1-carboxy-3-phenyl-propyl)amino]dihydro-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid (A-slow isomer) as a monohydrate;
m.p. 190-192; [~]D = +55 4 (c -- 0-5, 5g aqueous sodium bicarbonate). TLC (isopropanol:
~L21986~
NH40H:water; 7:2:1)spot at ~f = 0.56.
C, 59.07; H, 5.86; N, 6.26; S, 7.16 Found: C, 59.07; H, 5.58; N, 6.10; S, 7.05.
Example 82 _5R)-5-[(1-Carb_ y-3-phenylprop~71)amino]dihydro-4-oxo-2-~henyl-2H-1,3-thiazine-3(4H)-acetic acid (A-fast isomer) -a) (5R)-5-[[1-(Ethoxycarbonyl)-3-phenylpropyl]-amino]dihydro-4-oxo-2-phen~1-2H-1,3-thiazine-3(4H)-acetic acid (A-fast isomer) A solution of trifluoroacetic acid ~4 ml.) and anisole (0.3 ml.) is cooled in an ice-~ater bath under nitrogen and treated with a solution of (5R)-5-[[1-(ethoxycarbonyl)-3-phenylpropyl]
amino]dihydro-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)ethyl ester (A-fast isomer), from Example 3(c)7 (223 mg., 0.4 mmo]e) in dry methylene chloride (2 ml.). The cooling bath is removed and the reaction mixture is stirred at ambient temperature under nitrogen for 3 hours, concentrated in vacuo, and azeotroped with toluene to give 240 mg. of crude product.
Chromatography on 150 ml. of HP-20 eluting with a gradient from 400 ml. water:acetonitrile (5:4) to 400 ml. of 100% acetonitrile yields 169 mg.
of (5R)-5-[[1-(ethoxycarbonyl)-3-phenylpropyl]-amino]dihydro-4-oxo-2-phenyl-2H-1,3-thiazine-3(41~)-acetic acid (A fast isomer); m.p.
45-52; [a]D = +25.2 (c = 0.5, methanol).
12~9~3~jz TLC (ethyl acetate:pyridine:acetic acid:water;
100:20:6:11) spot at Rf = 0.56.
. C24 28 2 5S 0.3 H2O
C, 62.39; H, 6.24; N, 6.06; S, 6.94 Found: C, 62.61; H, 6.07; N, 5.61; S, 6.91.
b) (5R)-5-[(1-Carboxy-3-phenylpropyl)amino]
dihydro-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid (A-fast isomer) A solution of the product from part (a) (49 mg., 0.11 mole) in methanol (0.2 ml.) is cooled in an ice-water bath under nitrogen and treated with lN sodium hydroxide (0.24 ml., 0.241 mmole). The cooling bath is removed, the reaction is stirred for 6 hours at room temperature, and then quenched directly onto 2 m~. AG50W-X2(H ) column. The column is initially washed with a few volumes of water, then the product is eluted with 3% aqueous pyridine to give 35 mg.
of (5R)-S-[(l-carboxy-3-phenylpropyl)amino]
dihydro-4-oxo-2-phenyl-2H-1,3-thiazine-3t4H)-acetic acid (A-fast isomer) as a 1.2 hydrate;
m.p. 146-150; []D = +52.8 (c = 0.5, 5~ aqueous sodium bicarbonate). TLC (isopropanol:NH4OH:
water; 7:2:1) spot at Rf = 0.52.
C, 58.70; H, 5.91; N, 6.22; S, 7.12 Found: C, 58.70; H, 5.70; N, 6.22; S, 7.16.
1~269 Example 83 (+)-Dihydro-3-[(1-Carboxy-3-phenylpropyl)amino]-4-oxo-1~5-benzothiazepine-5(2H)-acetic acid a) S-(2-Aminophenyl)-N-[(l,l-dimethylethoxy)-carbonyl]-L-cysteine, methyl ester To a mixture of 2-amino-thiophenol (1.9 g., 15.4 mmole), methylene chloride (15 ml.), and 2,6-lutidine (1.8 ml., 1.0 eq.) at -20 (chloroform dry ice) is added 2-[[(l,l-dimethylethoxy)G~r~onyl]anuno]-2-propenoic acid, methyl ester (3.0 g., 1.0 eq.) dropwise over 5 minutes. After one hour the cooling bath is removed and the reaction mixture is stirred for an additional 16 hours. The reaction mixture is diluted with ethyl acetate and washed with saturated sodium bicarbonate, ~ater, brine, dried (rlgSO4), and evaporated. Tlle residue (4.1 g.) is chromatograplled on silica (125 g.) eluting with hexane/ethyl acetate (5:1) to give 2.5 g. of S-(2-aminophenyl)-N-~(l,l-dimethylethoxy)carbonyl]-L-cysteine, methyl ester as an oil after evaporation.
b) S-(2-Aminophenyl)-N-~(l,l-dimethvlethoxy)-carbon~ ystein A mixture of S-(2-aminophenyl)-N-[(l,l-dimethylethoxy)carbonyl]-L-cysteine, methyl ester (1.0 g., 3.1 mmole), lN sodium hydroxide (3.1 ml., 1.0 eq.), and dioxane (6 ml.) is stirred at room temperature in an argon atmosphere for one hour.
The reaction mixture is washed with cthyl ~cetate, . ~2~9862 I~A269 neutralized with lN hydrochloric acid (3.1 ml.)and extracted with methylene chloride (twice).
The combined extracts are dried (MgSO4) and evaporated to give 1.0 g. of S-(2-aminophenyl)~N-[(l,l-dimethylethoxy)carbonyl]-L-cysteine as a foam. TLC (methylene chloride/acetic acid/
methanol; 100:5:5) major spot at Rf = 0.5. The product crystallizes from xylene to give S-(2-aminophenyl)-N-[(l,l-dimetllylethoxy)carbonyl]-L-cysteine as a fluffy crystalline solid; m.p. 109-111.
Anal. calc'd. for C14H20N2O4S:
C, 53.83t H, 6.45; N, 8.97; S, 10.26 Found: C, 53.51; H, 6.28; N, 8.99; S, 10.26.
c) (i)-(2,3,4,5-Tetrahyd o-4-oxo-1,5-benzo-thiazepin-3-yl)carbamic acid,l,l-dimethylethyl c_ter A suspension of S-(2-aminophenvl)-N-[(l,l-dimethylethoxy)carbonyl]-L-cysteine (0.65 g., 2.1 mmole) in xylene (15 ml.) is reflu~ed in a flask equipped with a Dean-Stark trap for
(acetone-hexane; 1:1) shows a single spot at Rf = 0.40.
c) Chloro(6-phthalimidohexYl)phosphinic acid, ethyl ester A mixture of (6-phthalimidohexyl)phosphonic acid, diethyl ester, benzene, and phosphorus pentachloride is refluxed according to the procedure of Example l(e) to give chloro(6-phthalimidohexyl~
phosphinic acid, ethyl ester.
~21986;~
d) IR)-Dihydro-5-[[ethoxy(6-phthalimidohexyl) phosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester Chloro(6-phthalimidohexyl)phosohinic acid, ethyl ester and (R)-dihydro-5-amino-4-oxo-2-phenyl-2H~1,3-thiazine-3(4H)-acetic acid,ethyl ester are reacted according to the procedure of Example l(f) to give (R)-dihydro-5-[[ethoxy(6-phthalimido-hexyl)phosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester.
e) (R)-Dihydro-5-[[(6-aminohexYl)ethoxyphosphinyl]-amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester A solution of (R)-dihydro-5-[[ethoxy(6-phthal-imidohexyl)phosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester in dioxane is treated with hydrazine hydrate and stirred at room temperature under argon. After the reaction is completed, the mixture is diluted with toluene and the solvents decanted. The residue is triturated with methylene chloride and filtered.
The combined filtrate is evaporated to dryness to give (R)-dihydro-5-~[(6-aminohexyl)ethoxy-phosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4Hj acetic acid, ethyl ester.f) (R)-Dihydro-5-[[(_-aminohexyl)hydroxv~hosphinyl]
amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, dilithium salt The diethyl ester product from part (e) is treated with bromotrimethylsilane in methylene ` :~X1~38~
chloride and the residue is taken up inacetonitrile and treated with lN lithium hydroxide according to the procedure of Example l(g) Work-up of the product according to the procedure 5 of Example l(g) gives (R)-dihydro-5-[[(6-aminohexyl)-hydroxyphosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, dilithium salt.
ExamPles 31 - 34 Following the procedure of Example 30 but employing the aminoalcohol listed in Col. I
one obtains the product listed in Col. II.
Example Col. I Col. II
31 3-aminopropanol (R)~Dihydro-5-[[(3-aminopropyl)hydroxy-phosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid,dilithium salt 32 2-aminoethanol (R)-Dihydro-5-[[(2-aminoethyl)hydroxyphos-phinyl]amino]-4-oxo-2-phenyl-2H-1,3-thia-zine-3~4H)-acetic acid, dilithium salt 33 4-aminobutanol (R)-Dihydro 5-[[(4-aminobutyl)hydroxyphos-phinyl]amino]-4-oxo-2-phenyl-2~1-1,3-thiazine-3(4H)-acetic acid, dilithium salt lZ1~ 2 _ -67-Example Col. I Col. II
34 8-aminooctanol (R)-Dihydro-5-[[(8-aminooctyl)hydroxyphos-phinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, di-lithium salt Similarly, by employing the thiazine or thia-zepine esters of Examples 2 to 29 within the pro-cedure of Examples 30 to 34, other compoands within the scope of the invention are obtained.
Example 35(R)-Dihydro-5-[[[2-(benzoylamino)-3-phenyl~ropyl]-hydroxyphosphinyl]amino]-4-oxo-2-phenvl-2H-1,3-thiazine-3(4H)-acetic acid, dilithium salt a) 4-Methylbenzenesulfonic acid, 2-[[(4-methyl-phenyl)sulfonyl]amino]-3-Phenylpropyl ester A solution of d,l-phenylalaninol, hydro-chloride (9.4 g., 50.1 mmole) in dry pyridine (35 ml.) at 0 (ice bath) is treated with p-toluenesulfonyl chloride (19.4 g., 102 mmole) in small portions over a 15 minute period. The mixture is allowed to come to room temperature and stirred overnight. The mixture is evaporated to dryness and the residue partitioned between ethyl acetate and 5% potassium bisulfate. The ethyl acetate layer is washed successively with 5%
potassium bisulfate, saturated sodium bicarbonate and saturated sodium chloride, dried (Na2SO4), and evaporated. The dark residue is filtered ~2198~2 through a pad of silica gel eluting with methylene chloride then methylene chloride-ethyl acetate (1:1). Evaporation of the solvents and trituration of the residue with ether gives 13.93 g. of 4-methylbenzenesulfonic acid, 2- E [ (4-methylphenyl)-sulfonyl]amino]-3-phenylpropyl ester as white crystals; m.p. 95-96; TLC (ethyl acetate/hexane;
1:2) spot at Rf = 0.39. A sample recrystallized from diisopropyl ether has m.p. 96-98.
b) [2-[[(4-Methylphenyl)sulfonyl]amino]-3-phenyl~
propyl]phosphonic acid, diethyl ester A solution of diethylphosphite (7.3 g., 52.9 mmole) in dry tetrahydrofuran (100 ml.) is treated with sodium hydride 50% oil dispersion lS (2.20 g., 45.8 mmole) in small portions under argon.
The mixture is then refluxed for 30 minutes, cooled to room temperature, and treated with 4-methyl-benzenesulfonic acid, 2-[[(4-methylphenyl)sulfonyl]-amino]-3-phenylpropyl ester (6.9 g., 15 mmole).
After lS minutes, a white solid separates; additional tetrahydrofuran (75 ml.) is added and stirring continued overnight. After stirring at room temperature overnight, the mixture is refluxed for one hour, cooled and partitioned between ethyl acetate (75 ml.) and 5% potassium bisulfate (50 ml.).
The ethyl acetate phase is washed successively with 5% potassium bisulfate, saturated sodium bicarbonate and saturated sodium chloride, dried (Na2SO4), and evaporated. The residue is ~riturated with hexane to give 5.9 g. of [2-[[(4-methyl-:1219862 phenyl)sulfonyl]amino]-3-phenylpropyl]phosphonic acid, diethyl ester as an off-white solid;
m.p. 86-89; TLC (ethyl acetate) spot at Rf = 0.48.
A sample recrystallized from diisopropyl ether has m.p. 94-95.
c) t2-Amino-3-phenylpropyl)phosphinic acid A mixture of i2-[[(4-methYlPhenYl)sulfonyl]-amino]-3-phenylpropyl]phosphonic acid, diethyl ester (5.9 g., 13.9 mmole), phenol (8.0 g., 85.1 mmole), and 48% aqueous hydrobromic acid (50 ~1.) is refluxed for 5.5 hours. The cooled mixture is diluted with water (50 ml.) and washed with ethyl acetate (2 x S0 ml.). The aqueous phase is evaporated to dryness, taken up in water (30 ml.) and evaporated again. This is repeated twice more. Finally, the residue is taken up in water and applied to an AG 50 W - X2 (H ~orm) column (50 ml. bed volume) and eluted first with water then with 5% pyridine-water. The fractions containing the desired product are combined and evaporated to dryness. The solid residue is triturated with acetonitrile to give 2.55 g. of (2-amino-3-phenylpropyl)phosphinic acid as an off-white crystalline solid; m.p. 347 (dec.);
TLC (isopropanol/conc. NH40H/water; 7:2:1) spot at Rf = 0.27.
d) (2-Phthalimido-3-phenylpropy~ hosphinic acid A mixture of (2-amino-3-phenylpropyl) phosphinic acid (2.0 g., 9.3 mmole) and phthalic anhydride (1.55 g., 10.5 mmole) is fused in a _70_ HA269 flask under argon at 195-200 (bath temperature) for 1.5 hours. The glassy dark residue is refluxed with ethyl acetate (25 ml.) until the glassy residue dissolves and a fluffy crystalline 5 solid separates. The cooled mixture is diluted with diethyl ether (25 ml.) and filtered. The solid is washed thoroughly with diethyl ether and dried to give 2.37 g. of (2-phthalimido-3-phenylpropyl)phosphinic acid as an off-white crystalline solid; m.p. 127 - 130. A sample crystallized from ethyl acetate m.p. 129 - 131;
TLC (isopropanollconc. NH40H/water; 7:2:1) spot at Rf = 0.33.
e) (R~Dihydro-5-[~[2-Phthalimido-3-Phenylpropvl]-ethoxyphosphinvl]amino]-4-oxo-2-phenyl-2H-l~3 thiazine-3(4H)-acetic acid, ethyl ester A suspension of (2-phthalimido-3-phenylpropyl) phosphinic acid in dry benzene is treated with phosphorus pentachloride and stirred at room temperature under argon for an hour. The mixture is then refluxed for 15 minutes, cooled and evaporated to dryness at room temperature (0.5 mm.
of Hg). The residue is taken up in dry methylene chloride and reacted successively with a mixture of ethanol(l eq.) and triethylamine (1 eq.) in methylene chloride and (R)-dihydro-5-amino-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester in the presence of triethylamine according to the procedure of Example l(f). Work up of the reaction mixture according to the procedure of Example l(f) yields (R)-dihydro-5-[[[2-phthalimido-3-phenylpropyl]ethoxyphosphinyl~-~.Z~9~36%
amino]-4-oxo-2-phenyl-2H-l~3-thiazine-3(4H)-acetic acid, ethyl ester.
f) (R)-Dihydro-S-[[[2-(benzoYlamino)-3-phenyl~ropyl]-ethoxyphosphinyl]amino]-4-oxo-3-phenyl-2H-1,3-thia_ zine-3(4H)-acetic acid, ethyl ester A solution of (R)-dihydro-5-[[[2-phthalimido-3-phenylpropyl]ethoxyphosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester in dioxane is treated with hydrazine hydrate and stirred for 24 hours at room temperature.
The mixture is then partitioned between ethyl acetate-water and the ethyl acetate phase was washed with water and saturated sodium chloride, dried (Ma2SO4), and evaporated. The residue is taken lS up in dry toluene and refluxed for one hour. The mixture is filtered, treated with triethylamine and benzoyl chloride and stirred at room temperature for 30 minutes. The mixture is diluted with ethyl acetate, washed successively with 5~ potassium bisul-fate, saturated sodium bicarbonate, and saturatedsodium chloride, dried (Na2SO4), and evaporated.
The residue is chromatographed on silica gel to give (R)-dihydro-5-[[[2-(benzoylamino)-3-phenylpropyl]-ethoxyphosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester.
q) (R)-Dihydro-5-_~_[[2-(benzoylamino)-3-phenylpropyl~-hydroxyphosphinyl]amino]-4-oxo-2-phenyl-2~-1,3-thiazine-3(4H)-acetic acid, dilithium salt The diethyl ester product from part (f) is treated with bromotrimethylsilane in methylene ~Z1~62 HA269 - -chloride and the residue is taken up in acetonitrile and treated with lN lithium hydroxide according to the procedure of Example l(g). Work uo of the product according to the orocedure of Example l(g) gives (R)-dihydro-5-[[[2-(benzoylamino)-3-phenyl-propyl]hydroxyphosphinyl]amino]-4-oxo-2-ohenyl-2H-1,3-thiazine-3(4H)-acetic acid, dilithium salt.
Examples 36 - 45 Following the procedure of Example 35 but employing the protected amine shown in Col. I and the phosphinic diester shown in Col. II, one obtains, after removal of the tosyl protecting group and reaction with phthalic anhydride, the phosphinic acid shown in Col. III. The acid of lS Col. III is then converted to the phosphinic acid ester chloride shown in Col. IV which is then coupled with the thiazine ester shown in Col. V
to yield the intermediate shown in Col. VI.
Removal of the phthalidyl group and reaction with the acid chloride shown in Col. VII
yields the ester product shown in Col. VIII.
The ~2 and R8 ester groups can be removed to give the corresponding diacid which can then be converted to a salt or in the case of Example 45 only the R8 ester group would be removed. The Rl protecting group shown in Example 40 would be removed as the last step of the synthesis.
Col. I Col. II
o Ts-NH-CH-CH2-OTs Na-P-OC H
Rl 2 2 5 Col._III Col. IV
[~N-cH-cH2-p-oH ~N-CH-CH2-P-Cl Col. V Col. VI
H2N~ 5-CH-COOR2 ~N-CH-CH2-P--NE~nN-C11~COR2 ~2~ 86~
~A269 Col. VII
o Rg C--C1 Col. VIII
2 ) n~
Rg-C-NH-CH- CH2-- P NH~ N-cH-cooR2 :~LX~ 2 n u~ Irl ~n In :r ~ I ~ S' o -N
~ I .
N
x I ~ ~o a) I
~ o N N
,~ o =
y _~
~ t~
~J
~ ~ Ln ," 3 Ul Ll') X~ I Y ~ y N ~ U
~ I
E~ ~I N
X
.~219l362 _ _77-O Similarly, by employing the thiazine esters of Examples 17 ~o 29 within the procedure of Examples 35 to 45, other compounds within the scope of the invention are obtained.
Example 46 (R)-Dihydro-5-[[1-(ethoxvcarbonyl)-3-phenylpropyl]-amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid a) (R)-Dihydro-5-phthalimido-4-oxo-2-phenyl-2H-1,3-thiazine-3t4H)-acetic acid, ethyl ester (isomer A) and (isomer B) The diastereomeric mixture of (R)-dihydro-5-phthalimido-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester (15.6 g.) from Example l(c) is refluxed in ether (500 ml.) for 4 hours, then cooled in an ice-bath and filtered to give 5.9 g. of isomer A at least 90~ free of isomer B; m.p. 166-168. ~]D = -72.9 (c = 1, chloroform). TLC (hexane/ethyl acetate; 1:1) shows spot at Rf = 0.40.
Anal. calc'd. for C22~20O5N2S:
C, 62.25; H, 4.75; N, 6.60; S, 7.55 Found: C, 62.21; H, 4.82; N, 6.63; S, 7.52.
A second, lower melting sample of isomer A
(0.9 g., m.p. 162-164) is obtained by refluxing the remaining mixture in 125 ml. of ether and collecting the solid product. The remaining mixture (8 g.) is refluxed in 50 ml. of ether affording 250 mg.
of insoluble material and 7.1 g. of soluble product enriched in isomer B. 5.8 g. of this ~ 86~, HA269 material is purified chromatographically on two Waters Prep LC columns run with hexane:ethyl acetate (3:1~. By this route, 4.8 g. of isomer B
is obtained; m.p. 66 - 68; [~]D = -101.2~
(c = 1, chloroform). TLC same as for isomer A.
Anal. calc d- for C22 20 5 2 C, 61.83; H, 4.79; N, 6.55; S, ?.50 Found: C, 61.83; H! 5-07; N, 6.25; S, 7.42.
b) (R)-Dihydro-5-phthalimido-4-oxo-2-phenyl-2H-1,3-thiazine-3~4H)-acetic acid, 2-(trimethylsilyl) ethyl ester (R)-Dihydro-5-phthalimido-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester (isomer A) (l.o g., 2.36 mmole) is heated in 2-trLmethylsilylethanol (5.58 g., 47.2 mmole) in the presence of titanium (IV) ethoxide (135 mg., 0.59 mmole). Upon completion of the reaction, the reaction mixture is diluted with ether, washed with lN hydrochlor~c acid, water, 2~ saturated aqueous sodium bicarbonate, and brine, dried (MgSO4), and concentrated in vacuo. The residue is purified chromatographically on silica gel eluting with hexane/ethyl acetate (3:1) to give (R)-dihydro-5-phthalimido-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)ethyl ester.
* Trade Mark ~ .
~21.9~62 HA269 c) (R)-Dihydro-5-amino-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)ethyl ester A solution of the trimethylsilyl ester product from part (b) (1.17 g., 2.36 mmole) in 4 ml. of dry chloroform is treated with N-methylhydrazine (217 mg., 4.72 mmole). The stop~ered reaction is stirred at room temperature overnight, then diluted with ether and filtered to remove N-methyl-phthalhydrazide. Removal of organic solvents ln vacuo yields (R)-dihydro-5-amino-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2~(trimethylsilyl)ethyl ester.
~ ~l]-amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)ethyl ester A solution of (R)-dihydro-5-amino-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(tri-methylsilyl)ethyl ester (9 mmole) in dry isopropanol (12 ml.) under nitrogen is treated with sodium bicarbonate ~2.25 mmole) followed by ethyl-2-oxo-4-phenylbutyrate (9.3 g., 45 mmole) dissolved in isopropanol (8 ml.). To the resulting susoension is added powdered 3A molecular sieves (8 g.). The reaction mixture is stirred for one hour while the pH is maintained at around 7Ø Next a solution of sodium cyanoborohydride (1.13 g., 18 mmole) in isopropanol (14 ml.) is added incrementally over a 5 hour period while continuing to maintain neutral pH. The reaction mixture is ~L~19~6~
then stirred overnight at room temperature, thenfiltered (celite), concentrated in vacuo, and partitioned between ether and water. Normal work up of the organic extract followed by column chromatography on silica gel yields (R)-dihydro-5-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)ethyl ester as a mixture of diastereomers.
e) (R)-Dihydro-5-~[l-(ethoxvcarbonYl)-3-phenyl-pro~l]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic_acid A solution of (R~-dihydro-5-[[l-(ethoxy-carbonyl)-3-phenylpropyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl) ethyl ester (1.47 mmole) in dry dimethylformamide (4.5 ml.) is cooled in an ice-bath and reacted with a solution of n-tetrabutylammonium fluoride tri-hydrate (0.928 g., 2.94 mmole) in dimethylformamide (1.5 ml.). Upon disappearance of starting material, the reaction mixture is diluted with ethyl acetate (200 ml.) and washed with water (30 ml., twice). Normal work-up of the organic extract followed by chromatography affords (R)-dihydro-5-[[1-(ethoxycarbonyl)-3-phenylpropyl]-amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid as a mixture of diastereomers.
Similarly, the diastereomic mixture of (R)-dihydro-5-phthalimido-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester or its isomer B
~2~ 9~
could be employed in place of isomer A in the above procedure to yield other compounds within the scope of the invention.
Example 47 (R)-Dihydro-5-[[1-carboxy-3-phenylpropyl]amino~-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, dilithium salt A solution of (R)-dihydro-5-[[1-(ethoxy-carbonyl)-3-phenylpropyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid (1 mmole), prepared as set forth in Example 46, in methanol (4 ml.) is treated with lN aqueous lithium hydroxide (2 ml.). Upon completion of the reaction, the aqueous solution is filtered and chromatographed on an HP-20 (200 ml.) column eluting with a linear gradient of water -acetonitrile(10 ~ 90% acetonitrile). The desired fractions are combined, evaporated to a small volume, filtered (millipore) and lyophilized to give (R)-dihydro-5-[[1-carboxy-3-phenylpropyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, dilithium salt.
Examples 48 - 70 Following the procedure of Examole 46 but employing the keto compound shown in Col. I
and the thiazine ester shown in Col. II, one obtains the product shown in Col. III. The R3 and R4 protecting groups shown in Examples 59, 61, and 63 to 65 are removed as the last step of the synthesis. The R2 and R3 ester groups can be lX~L9862 . HA269 - 82- _ removed to give the corresponding diacid which can then be converted to a salt. When it is desired to remove only the R2 ester group and leave the R3 ester group in place, then the thiazine ethyl ester is converted to its trimethylsilylethyl ester prior to reaction with the keto compound.
~198~
Col. I
O O
Il 11 R-- C-- C--R
Col. II
S R
(CH2 ) ~ O
2 ~ N-CH-C-OR2 R
Col. III
~ S ~R
(I 2 ) n~
R3 C--CH--NH~ N--CH--C--OR
4 O Rl ~986~
~ N N~N3~N ~ N X
xl Y Y Y Y Y Y
x~
~ I I I I I I I
N N T
O I I N
-E ¢1 ~ ~I N t~
121'9~362 ~r 2 N ¦ N N N N N N
II: I I I l I l I
~ T
1~:; 1 1 1 1 1 1 l Y ~
N~I N _I N
~ N ~ N
~1 I Y Y I I Y
~ U N I ~,3 O ~ ~
~ I æN ~ o Z z 8 ~, ~ Z
o Z
~r ~ ~D 1` ~ u x ~LZ 'L98~2 :r 2 3: ~r N I N UN U UN UN
~S; I I I I I I
U~
~r:
N 5~
~ I I I I I I
z c; I N _I N ~ ~
Z~
N N U O -- U
~_) C) N ~ Z
¦ I o ~ N _~
X 15 ~ N
C~I I ~
U~Ul Ln U'~ U~
o U o U o O.--1 N ~ ~r a~
Ll N N
S =~ ~CN ¦ z _ T ~ = O
N N
N N
~ I O ~ C,) ~1 E ~D ' ~D
x ~Z151862 HA2 6 9 tX; ¦ C) N
~ ~: V ~:
~ I I I t t- I '`t ~ ~\t ~ ~0 ~ ~=0 t.~ Z
\ ~ /
~ ~t '`t tY I I O
Q. a) al o .~t r~
a6~
Similarly, by employing the thiazineesters of Examples 17 to ~9 within the procedure of Examples 46 to 70,other compounds within the scope of the invention are obtained.
Example 71 (R)-Dihvdro-5-~[[2-methYl-l-(l-OXoDroPoXy)propoxy](4 p}lenYlbutyl)~hosphinYl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid,monolithium salt 10 d) (R)-Dihydro-5-phthalimido-4-oxo-2-Dhenyl-2H-1,3-thiazine-3(4H)-acetic acid, trimethvlsilyl-ethyl ester (R)-Dihydro-5-phthalimido-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester is heated in trimethylsilylethanol in the presence of titani~m (IV) ethoxide. Upon completion of the reaction, the reaction mixture is diluted with ether, washed Wit}l lN hydrochloric acid, water, saturated aqueous sodium bicarbonate, and brine, dried (MgSO4), and concentrated ln vacuo. The residue is purified chromatographically on silica gel to yield (R)-dihydro-5-phthalimido-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, trimethyl-silylethyl ester.
b) (R)-Dihydro-5-amino-4-oxo-2-~henyl-2H-1,3-thia-zine-3(4H)-acetic acid, trimethylsilvlethyl ester A solution of the trimethylsilylethyl ester product from part (a) in dry chloroform is treated with N-methylhydrazine according to the procedure of Example l(d) to give (R)-dihydro-5-amino-4-'lZ19~6;;~
. HA269 oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, trimethylsilylethyl ester.
c) (R)-Dihydro-5-[[ethox~(4-phenylbutyl)~hosphinyl]-amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, trimethylsilylethyl ester Chloro(4-phenylbutyl)phosphinic acid, ethyl ester is reacted with (R)-dihydro-5-amino-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, trimethylsilylethyl ester according to the procedure of Example l(f) to yield (R)-dihydro-5-[[ethoxy-(4-phenylbutyl)phosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-aceticacid,trimethylsilylethyl ester.
d) (R)-DihYdro-5-[[[2-methvl-1-(1-oxopropoxy)-propoxy](4-phen~lbutyl)phosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, trimethvl-silylethyl ester A mixture of the diester product from ~art (c) and bis(trimethylsilyl~acetamide in methylene chloride is stirred at ambient temperature for several hours. After concentration in vacuo at 30, methylene chloride is added followed by bromotrimethyl-silane. The mixture is stirred at room temperature for several hours and concentrated ln vacuo overnight. The residue is dissolved in methylene chloride and treated with triethylamine and water and again concentrated ln vacuo. The residue is taken up in chloroform and treated with triethylamine, l-chloroisobutyl propanoate, sodium chloride, and tetrabutylammonium iodide. The mixture is stirred at reflux temperature overnight. The reaction 9~3~i2 . HA269 mixture is then concentrated ln vacuo and ether is added to the residue. The water soluble solids separatlng from solution are filtered off and the ethereal filtrate is washed with water, 2% sodium thiosulfate, and brine, dried (MgSO4), and concentrated ln vacuo to give (R)-dihydro-5-[[[2-methyl-1-(1-oxopropoxy)propoxy](4-phenvlbutyl) phosphinyl]amino~-4-oxo-2-phenyl-2H-l~3-thiazine 3(4H)-acetic acid, trimethylsilylethyl ester.
e) (R)-Dihydro-5-[[[2-methyl-1-(1-oxopropoxy)-propoxy](4-phenylbutyl)phosphinYl]amino]-4-oxo-2-2~ 1-2H-1,3-thiazine~3(4H)-acetic acid, monolithium salt The diester product from part (d) in dry di-methylformamide is treated with a solution of n-tetrabutylammonium fluoride in dimethylformamide.
Upon disappearance of the starting material, the reaction mixture is diluted with ethyl acetate, washed with water, and concentrated in vacuo. The residue is dissolved in water and applied to an AG50 X 8(Li ) column eluting with water. Fractions containing the desired product are combined and lyophilized. The iyophilate is chromatographed on an HP-20 column eluting with a linear gradient of acetonitrile/water (0 ~ 90%). Fractions containing the desired product are combined, concentrated ln vacuo and the residue is dissolved in water, filtered, and lyophilized to give (R)-dihydro-5-[[[2-methyl-1-(1-oxopropoxy)propoxy]-~1386~ HA269 (4-phenylbutyl)phosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3l4H)-acetic acid, monolithium salt.
Examples 72 - 77 Following the proc:edure of Example 71 but substituting for the l-chloroisobutyl propanoate the alkylating agents listed below in Col. I, the products listed in Col. II are obtained.
~xampleCol. I Col. II
Cl-CH-O-C-C H (R)-Dihydro-5-[[[cyclo-hexyl!l-oxopropoxy)methoxy]
(4-phenylbutyl)phosphinyl]-amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ll monolithium salt 73Cl-CH-O-C-C2H5 (R)-Dihydro-5-[[[1-(1-CH3 oxopropoxy)ethoxy](4-phenyl-butyl)phosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, mono-lithium salt 74Cl-CH -O-C-C(CH ) (R)-Dihydro-5-[[[(2,2-dimethyl-1-oxopropoxy)methoxy]-(4-phenylhutyl)phosphinyl]-amino]-4 oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, monolithium salt ~219~3~,2 ~ 93-Example Col. I Col. II
Cl-CH-O-C-(CH ) -CH (R)-Dihydro-5-[[[2-methyl-1-CH(CH3)2 (1-oxobutoxy)propoxy](4-phenylbutyl)phosphinyl]-amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, monolithium salt 76 2 ~ (R)-Dihydro-5-[[[(phenyl-carbonyloxy)methoxy](4-phenylbutyl)phosphinyl]-amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic ll acid, monolithium salt 77 Cl-CH2-0-C-OC2H5 (R)-Dihydro-5-[[[(ethoxy-carbonyloxy)methoxy](4-phenylbutyl)phosphinyl~-amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, monolithium salt ~219~62 Similarly, the alkylating agents ofExamples 71 to 77 can be employed with the ester products of Examples 2 to 45 to yield other compounds within the scope of this invention.
ExamDle 78 (R)-Dihydro-5-[[hydroxy(4-phenylbutyl)phosphinyl]-amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, disodium salt Following the procedure of Example l but substituting sodium hydroxide for the lithium hydroxide in part (g), one obtains (R)-dihydro-5-[[hydroxy(4-phenylbutyl)-phosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, disodium salt.
This procedure can be employed generally to give the corresponding mono or disodium salt. In a similar manner, the corresponding mono or dipotassium salt can be obtained.
121986~ ~269 Example 79 (5R)-5-[(1-Carboxy-3-phenylpro~yl)amino]dihydro-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid (B-slow isomer) a) N-Phthaloyl-L-cysteine A solution of N,N'-diphthaloyl-L-Cystine (19.5 g., 38.9 mmole) in a mixture of trifluoro-acetic acid (60 ml.) and dry tetrahydrofuran (200 ml.) is cooled in an ice-bath under nitrogen and treated with zinc dust (15.3 g., 233.4 mmole) in three equal portions over a period of 15 minutes.
The reaction is stirred cold for 2 hours, then filtered (celite) and concentrated in vacuo. The residue is partitioned between 600 ml. of ethyl acetate:ether (5:1) and a water-brine mixture.
The organic layer is washed with water, brine and dried (MgSO4). Removal of the solvents in vacuo yields 21.9 g. of crude product which is flash chromatographed on silica gel (400 g.) eluting with toluene:acetic acid (6:1). Fractions containing the desired product are combined to give 12.1 g. of N-phthaloyl-L-cysteine ~s an oil.
[a]D = -54.2 (c=l, methanol). TLC (toluene/
acetic acid; 6:1) spot at Rf = 0.30.
b) N-Benzylidineglycine, ethyl ester A mixture of glycine, ethyl ester, hydro-chloride (10 g., 71.6 mmole), triethylamine (14.5 g., 143.2 mmole) and anhydrous MgSO4 (6.0 g., 50.1 mmole) in dry methylene chloride (150 ml.) is treated with a solution of benzaldehyde (7.6 g., 1~ 9~ 2 . IIA269 _ -96-71.6 mmole) in methylene chloride (lO ml.) added over a period of 15 minutes. After 5 hours, the reaction mixture is filtered, concentrated ln vacuo, and then partitioned between 400 ml. of ether and 50 ml. of water. The organic layer is waslled with water and brine, dried (MgSO4), and concentrated ln vacuo to give 12.1 g. of N-benzyli-dineglycine, ethyl ester.
c) (5R)-Dihydro-5-phthalimido-4-oxo-2-ph~ 2~-1,3-thiazine-3(4H)-acetic acid, ethyl ester (isomers A and B) To a solution of N-phthaloyl-L-cysteine (15.8 g., 62.8 mmole) and N-benzylidineglycine, ethyl ester (12.3 g., 64.3 mmole) in dry chloroform (160 ml.) cooled in an ice bath under nitrogen is added dicyclohexylcarbodiimide (13.0 g., 62.8 mmole) in one portion. After 2 hours, the cold reaction mixture is filtered, concentrated in vacuo and redissolved in a mixture of ether (500 ml.) and chloroform (200 ml.). The organic extract is washed with saturated aqueous sodium bicarbonate, water, 5% potassium bisulfate and brine, dried (MgSO4) and concentrated ln vacuo to give 23.8 g. of crude product. Flash chroma-tography on silica (600 g.) eluting with llexane:
ethyl acetate (3:1) yields 15.6 g. of (5R)-dihydro-5-phthalimido-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester as a diastereomeric mixture.
9~
This mixture is refluxed in 500 ml. ofether for 4 hours, then cooled in an ice-bath and fi]tered to yield 5.9 g. of (5R)-dihydro-5-phthalimido-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester ~isomer A); m.p.
166~168; [a]D = -72.9 (c = 1, chloroform).
TLC (hexane/ethyl acetate; l:l)spot at Rf = 0.40.
Anal. calc'd. for C22H20N2O5S:
C, 62.25; H, 4.75; N, 6.60; S, 7.55 Found: C, 62.21; H, 4.82; N, 6.63; S, 7.52.
Trituration of the remainder of the diastereomeric product mixture with 125 ml. of refluxing ether affords a second batch of isomer A
(0.9 g., m.p. 162-164). The residue is triturated with ether to give 0.75 g. of insoluble substance (presumably largely isomer A) and 7.1 g. of material enriched in isomer B. The enriched isomer B
(6.0 g.) is chromatographed on two connected Waters Prep LC columns eluted with hexane:ethyl acetate (3:1). Pooling of the product containing fractions yields 4.8 g. of purified (5R)-dihydro-5-phthalimido-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester (isomer B);m.p 66-68; [a]D = -101.2 (c = 1, chloroform).
TLC same as isomer A.
Anal. c . 22 20 2 5 2 C, 61.83; H, 4.79; N, 6~55; S, 7.50 Found: C, 61.83; H, 5.07; N, 6.25; S, 7.42.
86~
H~2G9 d) (5R)-Dihydro-5-Phthalimido-4-oxo-2-pheny~
_-1,3-thiazine-3(4~1)-acetic acid, 2-(trimet~
silyl)ethyl ester (isomer ~) A mixture of (5R)-dihydro-5-phthalimido-4-oxo-2~phenyl-2~-1,3-thiazine-3(4H)-acetic acid, ethyl ester (isomer B) (2.5 g., 5.9 mmole), 2-trimethylsilylethanol (14.0 g., 118 mmole), and titanium (IV) ethoxide (338-mg., 1.48 mmole) is heated at 100 under nitrogen for 5 hours and then cooled to room temperature. The reaction mixture is then diluted with 200 ml. of ether and stirred with 25 ml. of lN hydrochloric acid for 10 minutes. Next, the organic solution is separated, rinsed with water, saturated sodium bicarbonate, water, and brine, dried (MgSO4), and concentrated in vacuo. I~ost of the excess 2-trimethylsilylethanol is removed by distillation using a 40 oil bath and an ice-cooled receiving flask. After further pumping in vacuo, the residue (3.2 g.) is flash chromatographed on 160 g. of LPS-l silica gel eluted with hexane:ethyl acetate (5:1) to give 2.2 g. of (SR)-dihydro-5-phthalimido-4-oxo-2-phenyl-2H-1,3-thia~ine-3(411)-acetic acid, 2-(trime-thylsilyl)ethyl ester (isomer B); m.p. 65-66;
[~]D = ~75 0 (C = 1, chloroform). TLC (he~ane:
ethyl acetate; 2:1) spot at Rf = 0.46.
Anal. calc'd. for C25H28N2O5SSi:
C, 60.46; H, 5.68; N, 5.64; S, 6.46 Found: C, 60.44; H, 5.69; N, 5.50; S, 6.43.
i2 _99_ e) (5R)-Dihydro-5-amino-4-oxo-2-Phenyl- 2H-I~3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)_ ethyl ester (isomer B) A solution of (5R)-dihydxo-5-phthalimido-4-S oxo-2-phenyl-2H-1,3-thiazine-3(4Ii)-acetic acid, 2-(trime-thylsilyl)ethyl ester (isomer B) (2.01 g., 4.05 mmole) in dry chloroform (9 ml.) under nitrogen at room temperature is treated with methylhydrazine (317 mg., 6.88 mmole).
After 12 hours, an additional 0.1 ml. of methyl-hydrazine is added and the reaction is stoppered and stirred overnight. The reaction mixture is then diluted with an additional 100 ml. of ether and the solution is rinsed with 25 ml. portions of saturated sodium bicarbonate, water, and brine, dried (MgSO4), and concentrated ln vacuo to give 1.55 g. of crude (5R)-dihydro-5-amino-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)ethyl ester (isomer B);
[~]D = ~47~3 (c = 1, chloroform).
f) ~5R)-5-[[1-(Ethoxycarbonyl)-3-phenylpropyl]-amino]dihydro-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)ethyl ester (B fast and slow isomers) To a solution of (5R)-dihydro-5-amino-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)ethyl ester (isomer B) (1.55 g., 4.05 mmole) in 11 ml. of isopropanol is added ethyl-2-oxo-4-phenylbIltyrate (4.18 g., 20.2 mmole).
The above mixture, at room temperature under . ~21986~ !IA269 nitrogen, is treated with p-toluenesulfonic acid, monohydrate (386 mg., 2.03 mmole) followed by 4.5 g. of freshly pulverized 3A~ molecular sieves. This mixture is stirred for 1 hour while keepiny the pH between 6 and 8 by adding solid sodium bicarbonate. Next, a solution of sodium cyanoborohydride (509 mg., 8.1 mmole) in isopropanol (8.1 ml.) is added over a period of 5 hours while keeping the pH between 6 and 8 by adding p-toluenesulfonic acid, monohydrate. Upon completion of the addltion, the reaction is stirred at room temperature overnight, diluted with 150 ml.
of ether, and filtered. The filtrate is rinsed with ~ 30 ml. portions of water, 10~ potassium bisulfate, water, saturated sodium bicarbonate, water, and brine, then dried (MgSO4), and concentrated in vacuo to give 5.4 g. of crude product. Removal of most of the by-product, ethyl-2-hydroxy-4-phenylbutyrate, is accomplished by chromatography.
The resulting crude mixture of diastereomers (1.6 ~.) is flash chromatographed on 100 g. of LPS-l silica gel eluted with petroleum ether:ether (7:2). This yields 821 mg. of (5R)-5-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]dihvdro-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)ethyl ester (B-slow isomer), [~]D = -29.8 (C = 1, chloroform).
Anal. Calc'd. for C29H40N205SSi:
C, 62.55; H, 7.24; N, 5.03; S, 5.76 Found: C, 62.25; H, 7.30; N, 4.91; S, 5.56.
`~21986~
The fraction from the above flash column contains 525 mg. of the fast moving diastereomer.
This material is further purified by hydrogenation in 40 ml. of ethyl acetate at 50 psi in the presence of 125 mg. of 10~ palladium/carbon catalyst.
After 20 hours, the solution is filtered, concentrated in vacuo and the residue (450 mg.) is flash chromatographed on 22 g. of LPS-l silica gel eluting with petroleum ether:ether (3:1). Pooling of the product containing fractions yields 325 mg.
of (5R)-5-[[1-(ethoxycarbonyl)-3-phenylpropyl~-amino]dihydro-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)ethyl ester tB-fast isomer), r~]D = -22.4 (c = 1, chloroform).
Anal. calc'd. for C29H40N2osssi:
C, 62.55; H, 7.24; N, 5.03; S, 5.76 Found: C, 62.73; H, 7.43; N, 4.82; S, 5.47.
q) (5R)-5-l[l-(Ethoxycarbonyl)-3-phenyl~ropyl]
amino]dihydro-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid (B-slow isomer) A mixture of trifluoroacetic acid (8 ml.) and anisole (0.4 ml.) is cooled in an ice-water bath under nitrogen and treated with (5R)-5-[[l-(ethoxycarbonyl)-3-phenylpropyl]amino]
dihydro-4-oxo-2-phenyl-2H-1,3-thiazine~3~4H)-acetic acid, 2-(trimethylsilyl)ethyl ester (B-slow isomer) (400 mg., 0.72 mmole) dissolved in dry methylene chloride (4 ml.). The cooling bath is removed and the reaction is stirred at ambient temperature for 3 hours, then concentrated * Trade Mark ~L21~;2 in v cuo and azeotroped with toluene. The crude product (440 mg.) is chromatographed on 150 ml.
of ~IP-20 eluted with a graclient from 400 ml.
of water:acetonitrile (5:4) to 400 ml. of 100%
acetonitrile. The product containing fractions are pooled, evaporated, then precipitated from ethanol (10 ml.) by the addition of water (300 ml.). By this method 171 mg. of (5R)-5-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]dihydro-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid (B-slow isomer) are obtained; m.p. 130-135; [~]D = -36.1 (c = 1, methanol). TLC (ethyl acetate:pyridine:acetic acid:
water; 100:20:6:11) spot at Rf = 0.79.
Anal. calc'd. for C24H28N2O5s:
C, 63.13; H, 6.18; N, 6.14; S, 7.02 Found: C, 63.20; H, 6.26; N, 6.12; S, 6.97.
h) (5R)-5-[(1-Carboxy-3-phenylpropyl)amino]dihydro-4-oxo-2-phenyl-2H-1,3-thia~ine-3(4I~)-acetic acid (B-slow isomer) A solution of the product from part (g) (50 mg., 0.11 mmole) in methanol (0.2 ml.) is cooled in an ice-water bath under argon and treated with lN aqueous sodium hydroxide (0.241 ml.). The cooling bath is removed and the reaction is stirred at room temperature for 5 hours. The reaction is then quenched directly onto a 2 ml.
AG 50W-X2(H ) column and eluted with water. The elution solvent is then changed to 3~ aqueous pyridine to elute about 40 mg. of crude product.
Final purification is carried out on a 15 x 180 mm.
~Z~9~2 I-IA269 HP-20 column eluted with a gradient from 200 ml.
of acetonitrlle:water (1:1) to 200 ml. of 100%
acetonitrile. Pooling of the product containing fractions yields 34 mg. of (5R)-5-[(1-carboxy-3-phenylpropyl)amino]dihydro-4-oxo-2-phenyl-2II-1,3-thiazine-3(4H)-acetic acid (B-slow isomer) as a mono-hydrate; m.p. 132-138; [~]D = 40.8 (c = 0.5, 5~
aqueous sodium bicarbonate). TLC (isopropanol:N~40H:
water; 7:2:1) spot at Rf = 0.63.
C, 59.17; H, 5.87; N, 6.28; S, 7.18 Found: C, 59.36; H, 5.53; N, 6.35; S, 7.18.
Example 80 (5R)-5-[(1-Carboxy-3-phenylpropyl)amino]dihydro-4-oxo-2-phenyl-2H-l~3-thiazine-3(4H)-acetic acid (B-fast isomer) a) (5R)-5-[[1-(Ethox~carbonyl)-3-phenyl ropyl]amino]
ih o-4-oxo-2-phenyl-2H-1~3-thiazine-3(4H)-acetic acid (B-fast isomer) A mixture of trifluoroacetic acid (6 ml.) and anisole (0.3 ml.) is cooled in an ice-bath under nitrogen and treated with (5R)-5-[[l-(ethoxycarbonyl)-3-phenylpropyl]amino]-dihydro-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trime~hylsilyl)ethyl ester (B-fast isomer) (315 mg., 0.57 mmole) dissolved in dry methylene chloride (4 ml.). The cooling bath is removed andthe reaction is stirred at room temperature under nitrogen for 3 hours, then concentrated in vacuo and azeotro~ed with toluene -~X1986~, ~A269 to yield 363 mg. of crude product. Chromatography on 150 ml. of HP-20 eluted with a gradient from 400 ml. of water:acetonitrile (5:4) to 400 ml.
of 100% acetonitrile yields 200 mg. of (5R)-5-[[(1-(ethoxycarbonyl)-3-phenylproPyl]amino]-dihydro-4-oxo-2-phenyl--2H-1,3-thiazine-3(4H)-acetic acid (B-fast isomer); m.p. 160-165;
[~]D = -24.4 (c = 0.5, methanol).
TLC (ethyl acetate:pyridine:acetic acid:water;
100:20:6:11) spot at Rf = 0.70 (minor spo-t at Rf = 0.80).
Anal. calc'd. for C24H28N2O5S:
C, 63.13; H, 6.18; N, 6.14; S, 7.02 Found: C, 63.39; H, 6.37; N, 5.94; S, 6.92.
_) (5R)-5-[(1-Carboxy-3-phenylpropyl)amino]dihydro_ -oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid (B-fast isomer) A solution of the product from part (a) (50 mg., 0.11 mmole) in methanol (0.2 ml.) is cooled in an ice-water bath under argon and treated with lN aqueous sodium hydroxide (0.241 ml.). The cooling bath is removed and the reaction is stirred at room tcmperature for 7 hours, then quenched directly onto a 2 ml. AG50W-X2(H ) column. The exchange column is initially eluted with several ml. of water then with 3~ aqueous pyridine to give 42 mg. of crude product after removal of solvents. The crude product is purified by gradient elution on a 15 x 180 mm.
HP-20 column run from 210 ml. of water:acetonitrile ~2~91~
(2:1) to 210 ml. of 100~ acetonitrile taking about 3ml/2min. fractions. The product containing fractions are pooled with methanol rinses and evaporated to give 31.3 mg. of (5R)-5-[(1-carboYy-3-phenylpropyl)amino]dihydro-4-oxo-2-phenyl-211-1,3-thiazine-3(4H)-acetic acid(B-fast isomer) as a monohydrate; m.p. 131-134; [~D = ~40 4 (c = 0.5, 5Qo aqueous sodium bicarbonate). TLC
(isoproDanol:NH3:water; 7:2:1) spot at Rf = 0.51.
C, 59.17; H, 5.87; N, 6.28; S, 7.18 Found: C, 59.24; H, 5.58; N, 6.32; S, 7.00.
Example 81 (5R)-5-[(1-Carboxy-3-phenylpropyl)amino]dihydro-4-lS oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid (A-slow isomer) a) (5R)-Dihydro-5-phthalimido-4-oxo-2-phen~
2H-1,3-thiazine-3(4H)-acetic acid, 2-(-trimethyl-silyl)ethyl ester (isomer A) A mixture of (5R)-dihydro-5-phthalimido-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester (isomer A), from Example l(c), (2.8 g., 6.6 mmole), 2-trimethylsilylethanol (15.37 g., 130 mmole), and titanium (IV) ethoxide (376 mg., 1.65 mmole) is heated at 100 under nitrogen for 5.5 hours, then cooled to room temperature overnight. The reaction mixture is diluted with ether (200 ml.), and stirred with lN hydrochloric acid (25 ml.) for 10 minutes. The organic layer is separated, rinsed with saturated ~219~6'~ 269 aqueous sodium bicarbonate, water, and brine,dried (MgSO4), and concentrated in vacuo. Most of the excess 2-trimethylsilylethanol is removed by distillation using a 40 oil bath and an ice-cooled receiving flask. After continued pumping overnight in vacuo, the residue~4.3 g.) is flash chromatographed on 215 g. of LPS-l silica gel eluted with hexane:ethyl acetate (5:1) to yield 2.7 g. of (5R)-dihydro-5-phthalimido-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)ethyl ester (isomer A);
m.p. 58-60; [~]D = -53.6 (c = 1, chloroform).
TLC (hexane:ethyl acetate; 2:1) spot at Rf = 0.32.
~nal. calc'd. for C25H28N2O5ssi C, 60.46; H, 5.68; N, 5.64; S, 6.46 Found: C, 60.20; H, 5.71; N, 5.56; S, 6.42.
b) (5R)-Dihydro-5-amino-4-oxo-2-~henyl-2~-1,3_ thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)-~ 1 ester (isomer A) A solution of 15R)-dihydro-5-phthalimido-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)ethyl ester(isomer A) (2.7 g., 5.43 mmole) in dry chloroform (12 ml.) under nitrogen at room temperature is treated with 425 mg. of methylhydrazine (9.24 mmole) and the reaction is stoppered. After 48 hours, an additional 0.15 ml. of methylhydrazine is added, and the reaction is stoppered and stirred overnight. The reaction mixture is then diluted . I-IA269 ~X198~2 with 70 ml. of ether, stirred for 10 minutes, and filtered. The filtrate is diluted with ether (150 ml.) , washed with 35 ml. portions of aqueous sodium bicarbonate, water, and brine, dried tMgSO4), and concentrated in vacuo to give 2.1 g. of (5R)-dihydro-5-amino-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trimethyl-silyl)ethyl ester (isomer A); [~]D = +35.2 (c = 1, chloroform).
c) (5R)-5-[[1-(Ethoxycarbonyl)-3-phenylprop~l]-amino]dihydro-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)ethyl ester (A-fast and slow isomers) To a solution of (5R)-dihydro-5-amino-4-lS oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)ethyl ester (isomer A) (2.1 g., 5.43 mmole) in iso?ropanol (15 ml.) under nitrogen at room temperature is added ethyl-2-oxo-4-phenylbutyrate (5.6 g., 27.15 mmole) followed by p-toluenesulfonic acid, monohydrate (518 mg., 2.72 mmole) and finally freshly pulverized 3A molecular sieves (6.0 g.). The mixture is stirred for one hour while the pH is kept between 6 and 8 by adding solid sodium bicarbonate. A solution of sodium cyanoboro-hydride (682 mg., 10.86 mmole) in isopropanol t10.9 ml.) is added to the reaction over a 5 hour period while keeping the pH between 6 and 8 by adding p--toluenesulfonic acid, monohydrate.
After the addition is completed, the reaction /~1 ~2~63~
I~A269 is stirred at room temperature overnight, then diluted with ether (200 rnl.), and filtered.
The filtrate is rinsed with 40 ml. portions of 10o potassium bisulfate, ~ater, saturated sodium bicarbonate, water, and brine, dried (MgSO4), and concentrated ln vacuo to yield 8.6 g. of crude product. Further purification is accomplished chromatographically using 350 g. of Activity II
neutral alumina eluted with ether:acetonitrile (20:1). The resulting crude product obtained (800 mg.) is hydrogenated by dissolving in ethyl acetate (70 ml.), adding 200 mg. of 10~ palladium/
carbon catalyst and shaking on a Parr apparatus at an initial hydrogen pressure of 50 psi overnight. The resulting crude mixture of diastereomers (760 mg.) is flash chromatographed on 50 9. of LPS-l silica gel elu-ting with petroleum ether:ether (3:1).
This column yields 240 mg. of (5R)-5-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]dihydro-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)ethyl ester (A-fast isomer);
[~]D = +26.1 (c = 1, chloroform). TLC (petroleum ether:ether; 3:1) spot at Rf = 0.10.
Anal. Calc'd. for C29H40N2O5SSi C, 62.55; H, 7.24; N, 5.03; S, 5.76 Found: C, 62.31; H, 7.50; N, 4.94; S, 5.74.
3~
~Z19862 ~269 The column also yields 400 mg. of (5R)-S-[[l-(ethoxycarbonyl)-3-phenylpropyl]amino]dihydro-4-oxo-2-phenyl-2H-1 r 3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)ethyl ester (A-slow isomer);
S [a]D = +14.5 (c = 1, chloroform). TLC
(petroleum ether:ether; 3:1) spot at Rf = 0.06.
Anal. Calc'd. for C29H40N2O5SSi C,62.55; H, 7.24; N, 5.03; S, 5.76 Found: C,62.46; H, 7.32; N, 4.94; S, 5.64.
d) (5R)-5-[[l-(Ethoxycarbonyl)-3-phenylpropyl]
amino]dihydro-4-oxo-2-phenyl-2H-lr3-thiazine 3(4H)-acetic acid (A-slow isomer) A solution of trifluoroacetic acid (8 ml.) and anisole (0.4 ml.) is cooled in an ice-water bath under nitrogen and treated with (5R)-5-[[l-(ethoxycarbonyl)-3-phenylpropyl]amino]dihydro-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)ethyl ester (A-slow isomer) (400 mg., 0.72 mmole) dissolved in dry methylene chloride (4 ml.). The cooling bath is removed, and the reaction is stirred at room temperature for 3 hours, concentrated in vacuo and azeotroped with toluene. The crude product (398 mg.) is chromatographed on 150 ml. ofHP-20 eluted with a gradient from 400 ml. of water:acetonitrile (5:4) to 400 ml. of 100~ acetonitrile. The product containing fractions are pooled and concentrated ln vacuo to give 275 mg. of (5R)-5-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]
dihydro-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-~Z~9~36;2 acetic acid (A-slow isomer); m.p. 47-52;
[~]D = +21.4 (c = 0.5, methanol). TLC
(ethyl acetate:pyridine:acetic acid:water;
100:20:6:11) spot at Rf = 0.83.
Anal. Calc d. 24 28 2 5 2 C, 61.20; H, 6.34; N, 5.95; S, 6.81 Found: C, 61.20; H, 6.07; N, 5.94; S, 6.68.
_) (5R)-5-[(1-Carboxy-3-~henylpropyl)amino]-dih~dro-4-oxo-2-phenyl-2H-l~3-thiazine-3(4H) acetic acid (A-slow isomer) A solution of the product from part(d) (50 mg., 0.11 mmole) in methanol (0.2 ml.) is cooled in an ice-water bath under nitrogen and treated with lN sodium hydroxide (0.24 ml.).
The ice bath is removed, and the reaction is stirred at ambient temperature for 5 hours. The reaction is then quenched directly onto a 2 ml.
AG50W-X2(H ) column and washed with water. The desired product is eluted with 3% aqueous pyridine to give 46 mg. of crude product. Final purifica-tion is carried out on a 50 ml. HP-20 column eluted with a gradient from 200 ml. of water:
acetonitrile (2:1) to 200 ml. of 100% acetonitrile.
The product containing fractions are concentrated ln vacuo, triturated with cold water, and filtered to give 24 mg. of (5R)-5-[(1-carboxy-3-phenyl-propyl)amino]dihydro-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid (A-slow isomer) as a monohydrate;
m.p. 190-192; [~]D = +55 4 (c -- 0-5, 5g aqueous sodium bicarbonate). TLC (isopropanol:
~L21986~
NH40H:water; 7:2:1)spot at ~f = 0.56.
C, 59.07; H, 5.86; N, 6.26; S, 7.16 Found: C, 59.07; H, 5.58; N, 6.10; S, 7.05.
Example 82 _5R)-5-[(1-Carb_ y-3-phenylprop~71)amino]dihydro-4-oxo-2-~henyl-2H-1,3-thiazine-3(4H)-acetic acid (A-fast isomer) -a) (5R)-5-[[1-(Ethoxycarbonyl)-3-phenylpropyl]-amino]dihydro-4-oxo-2-phen~1-2H-1,3-thiazine-3(4H)-acetic acid (A-fast isomer) A solution of trifluoroacetic acid ~4 ml.) and anisole (0.3 ml.) is cooled in an ice-~ater bath under nitrogen and treated with a solution of (5R)-5-[[1-(ethoxycarbonyl)-3-phenylpropyl]
amino]dihydro-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)ethyl ester (A-fast isomer), from Example 3(c)7 (223 mg., 0.4 mmo]e) in dry methylene chloride (2 ml.). The cooling bath is removed and the reaction mixture is stirred at ambient temperature under nitrogen for 3 hours, concentrated in vacuo, and azeotroped with toluene to give 240 mg. of crude product.
Chromatography on 150 ml. of HP-20 eluting with a gradient from 400 ml. water:acetonitrile (5:4) to 400 ml. of 100% acetonitrile yields 169 mg.
of (5R)-5-[[1-(ethoxycarbonyl)-3-phenylpropyl]-amino]dihydro-4-oxo-2-phenyl-2H-1,3-thiazine-3(41~)-acetic acid (A fast isomer); m.p.
45-52; [a]D = +25.2 (c = 0.5, methanol).
12~9~3~jz TLC (ethyl acetate:pyridine:acetic acid:water;
100:20:6:11) spot at Rf = 0.56.
. C24 28 2 5S 0.3 H2O
C, 62.39; H, 6.24; N, 6.06; S, 6.94 Found: C, 62.61; H, 6.07; N, 5.61; S, 6.91.
b) (5R)-5-[(1-Carboxy-3-phenylpropyl)amino]
dihydro-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid (A-fast isomer) A solution of the product from part (a) (49 mg., 0.11 mole) in methanol (0.2 ml.) is cooled in an ice-water bath under nitrogen and treated with lN sodium hydroxide (0.24 ml., 0.241 mmole). The cooling bath is removed, the reaction is stirred for 6 hours at room temperature, and then quenched directly onto 2 m~. AG50W-X2(H ) column. The column is initially washed with a few volumes of water, then the product is eluted with 3% aqueous pyridine to give 35 mg.
of (5R)-S-[(l-carboxy-3-phenylpropyl)amino]
dihydro-4-oxo-2-phenyl-2H-1,3-thiazine-3t4H)-acetic acid (A-fast isomer) as a 1.2 hydrate;
m.p. 146-150; []D = +52.8 (c = 0.5, 5~ aqueous sodium bicarbonate). TLC (isopropanol:NH4OH:
water; 7:2:1) spot at Rf = 0.52.
C, 58.70; H, 5.91; N, 6.22; S, 7.12 Found: C, 58.70; H, 5.70; N, 6.22; S, 7.16.
1~269 Example 83 (+)-Dihydro-3-[(1-Carboxy-3-phenylpropyl)amino]-4-oxo-1~5-benzothiazepine-5(2H)-acetic acid a) S-(2-Aminophenyl)-N-[(l,l-dimethylethoxy)-carbonyl]-L-cysteine, methyl ester To a mixture of 2-amino-thiophenol (1.9 g., 15.4 mmole), methylene chloride (15 ml.), and 2,6-lutidine (1.8 ml., 1.0 eq.) at -20 (chloroform dry ice) is added 2-[[(l,l-dimethylethoxy)G~r~onyl]anuno]-2-propenoic acid, methyl ester (3.0 g., 1.0 eq.) dropwise over 5 minutes. After one hour the cooling bath is removed and the reaction mixture is stirred for an additional 16 hours. The reaction mixture is diluted with ethyl acetate and washed with saturated sodium bicarbonate, ~ater, brine, dried (rlgSO4), and evaporated. Tlle residue (4.1 g.) is chromatograplled on silica (125 g.) eluting with hexane/ethyl acetate (5:1) to give 2.5 g. of S-(2-aminophenyl)-N-~(l,l-dimethylethoxy)carbonyl]-L-cysteine, methyl ester as an oil after evaporation.
b) S-(2-Aminophenyl)-N-~(l,l-dimethvlethoxy)-carbon~ ystein A mixture of S-(2-aminophenyl)-N-[(l,l-dimethylethoxy)carbonyl]-L-cysteine, methyl ester (1.0 g., 3.1 mmole), lN sodium hydroxide (3.1 ml., 1.0 eq.), and dioxane (6 ml.) is stirred at room temperature in an argon atmosphere for one hour.
The reaction mixture is washed with cthyl ~cetate, . ~2~9862 I~A269 neutralized with lN hydrochloric acid (3.1 ml.)and extracted with methylene chloride (twice).
The combined extracts are dried (MgSO4) and evaporated to give 1.0 g. of S-(2-aminophenyl)~N-[(l,l-dimethylethoxy)carbonyl]-L-cysteine as a foam. TLC (methylene chloride/acetic acid/
methanol; 100:5:5) major spot at Rf = 0.5. The product crystallizes from xylene to give S-(2-aminophenyl)-N-[(l,l-dimetllylethoxy)carbonyl]-L-cysteine as a fluffy crystalline solid; m.p. 109-111.
Anal. calc'd. for C14H20N2O4S:
C, 53.83t H, 6.45; N, 8.97; S, 10.26 Found: C, 53.51; H, 6.28; N, 8.99; S, 10.26.
c) (i)-(2,3,4,5-Tetrahyd o-4-oxo-1,5-benzo-thiazepin-3-yl)carbamic acid,l,l-dimethylethyl c_ter A suspension of S-(2-aminophenvl)-N-[(l,l-dimethylethoxy)carbonyl]-L-cysteine (0.65 g., 2.1 mmole) in xylene (15 ml.) is reflu~ed in a flask equipped with a Dean-Stark trap for
7 hours. Upon cooling of the reaction mixture the product crystallizes. The solid is collected by filtration, washed with xylene, and dried (high vacuum) to give 0.4 g. of (+)-(2,3,4,5-tetrahydro-4-oxo-1,5-benzothiazepin-3-yl)carbamic acid, l,l-dimethylethyl ester as an off-white crystalline solid; m.p. 197-200 (decomp.).
Anal. calc'd. for C14H18N2O3S:
C, 57.12; H, 6.16; N, 9.52; S, 10.89 Found: C, 56.88; H, 6.17; N, 9.40; S, 10.87.
-. ~219~62 HA269 d) (+)-3-[[(1,1-Dimethylethoxy)carbonvl]amino]-3,4-dihydro-4-oxo-1,5-benzothiazepine-5(2H)-ace_ic acid, ethyl ester A mixture of (+)-(2,3,4,5-tetrahydro-4-oxo-1,5-benzothiazepin-3-yl)carbamic acid, 1,1-dimethylethyl ester (0.8 g., 2.7 mmole), tetrahydro-furan (10 ml.) and potassium tert-butoxide (0.4 g., 1.3 eq.) is stirred at 0 (ice bath) under argon for 10 minutes and then treated with ethyl bromoacetate (O.S g., 1.7 eq.). After 3 minutes the ice bath is removed and the mixture is stirred for one hour. The reaction mixture is then - diluted with ethyl acetate and washed successively with saturated sodium bicarbonate, 5% potassium bisulfate, and brine, dried (~gSO4) and evaporated.
The residue (1.3 g.) is chromatographed on silica (60 g.) eluting with hexane/ethyl acetate (4:lJ to give 1.0 g. of (+)-3-[[(1,1-dimethyletlloxy)-carbonyl]amino]-3,4-dihydro-4-oxo-1,5-benzothia-zepine-5(2H)-acetic acid, ethyl ester as a foam.
TLC (hexane/ethyl acetate; 4:1) single spot at Rf = 0.21.
e) (+)-3-Amino-3,4-dihydro-4-oxo-1,5-benzothia-zepine-5(2H)-acetic acid, ethyl ester A mixture of (+)-3-[[(1,1-dimethylethoxy)-carbonyl]amino]-3,4-dihydro-4-oxo-1,5-benzo-thiazepine-5~2H)-acetic acid, ethyl ester (1.0 g., 2.6 mmole), methylene chloride (5 ml.), and trifluoroacetic acid (3 ml.) is stirred under aryon at 25 for 30 minutes. The methylene chloride and lZ19~36;~
trifluoroacetic acid are removed ln vacuo and the residue is taken up in ethyl acetate and the hydrochloride salt is precipitated with satu~rated hydrochloric acid/ethyl ether. The white solid' is collected by filtration and washed with 2:1 ethyl acetate/ethyl ether to yield 0.7 g. of (+)-3-amino-3,4-dihydro-4-oxo-1,5-benzothiazepine-5(2H)-acetic acid, ethyl ester as a white solid;
m.p. 231-233 (decomp.). TLC (methylene chloride/
acetic acid/methanol; 100:5:5) single spot at Rf = 0.08.
Anal. calc'd. for C13Hl6N2O3s HCl:
C, 49.29; H, 5.41; N, 8.84; S, 10.12;
Cl, 11.37 Found: C, 48.87; H, 5.31; N, 8.80; S, 10.05;
Cl, 11.37.
f) (+)-Dihydro-3-[[1-(Ethoxycarbonyl)-3-phenyl-propyl]amino]-4-oxo-1,5-benzothiazepine-5(2H~-acetic acid, ethvl ester (+)-3-Amino-3,4-dihydro-4-oxo-1,5-benzothia-zepine-5(2H)-acetic acid, ethyl ester is reacted with ethyl-2-oxo-4-phenylbutyrate in the presence of sodium cyanoborohydride according to the pro-cedure of Exam21e l(f) to yield (+)-dihydro-3-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-4-oxo-1,5-benzothiazepine-5(2~)-acetic acid, ethyl ester.
~__(+)-Dihydro-3-[(1-Carboxy-3-phenylpropyl) amino]-4-oxo-1,5-benzothiazepine-5(2H)-acetic acid The diethyl ester product from part ~f) is treated with sodium hydroxide according to the ~Z1~86~ HA269 - procedure of Example l(h) to yield (+)-dihydro-3-[(1-carboxy-3-phenylpropyl)amino]-4-oxo-1,5-benzothiazepine-5(2H)-acetic acid.
In a similar manner, the keto compounds shown in Col. I of Examples 5 to 31 can be employed in the above procedure to yield other compounds within the scope of the invention.
Example 84 (5R)-5-[(1-Carbox~-3-phenylpropyl)amino]dihvdro-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid (s-slow isomer), disodium salt The diacid product from Example 1 (1 mmole) is dissolved in water (50 ml.). Aqueous sodium bicarbonate (0.1 N, 20 ml.) is added and the aqueous solution is lyophilized. The residue is dissolved and purified chromatographicallv to give (5R)-5-[(1-carboxy-3-phenylpropyl)amino]-dihydro-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid (B-slow isomer~, disodium salt.
In a similar manner disodium or monosodium salts ofthe products of Examples 2 to 32 can be prepared.
Anal. calc'd. for C14H18N2O3S:
C, 57.12; H, 6.16; N, 9.52; S, 10.89 Found: C, 56.88; H, 6.17; N, 9.40; S, 10.87.
-. ~219~62 HA269 d) (+)-3-[[(1,1-Dimethylethoxy)carbonvl]amino]-3,4-dihydro-4-oxo-1,5-benzothiazepine-5(2H)-ace_ic acid, ethyl ester A mixture of (+)-(2,3,4,5-tetrahydro-4-oxo-1,5-benzothiazepin-3-yl)carbamic acid, 1,1-dimethylethyl ester (0.8 g., 2.7 mmole), tetrahydro-furan (10 ml.) and potassium tert-butoxide (0.4 g., 1.3 eq.) is stirred at 0 (ice bath) under argon for 10 minutes and then treated with ethyl bromoacetate (O.S g., 1.7 eq.). After 3 minutes the ice bath is removed and the mixture is stirred for one hour. The reaction mixture is then - diluted with ethyl acetate and washed successively with saturated sodium bicarbonate, 5% potassium bisulfate, and brine, dried (~gSO4) and evaporated.
The residue (1.3 g.) is chromatographed on silica (60 g.) eluting with hexane/ethyl acetate (4:lJ to give 1.0 g. of (+)-3-[[(1,1-dimethyletlloxy)-carbonyl]amino]-3,4-dihydro-4-oxo-1,5-benzothia-zepine-5(2H)-acetic acid, ethyl ester as a foam.
TLC (hexane/ethyl acetate; 4:1) single spot at Rf = 0.21.
e) (+)-3-Amino-3,4-dihydro-4-oxo-1,5-benzothia-zepine-5(2H)-acetic acid, ethyl ester A mixture of (+)-3-[[(1,1-dimethylethoxy)-carbonyl]amino]-3,4-dihydro-4-oxo-1,5-benzo-thiazepine-5~2H)-acetic acid, ethyl ester (1.0 g., 2.6 mmole), methylene chloride (5 ml.), and trifluoroacetic acid (3 ml.) is stirred under aryon at 25 for 30 minutes. The methylene chloride and lZ19~36;~
trifluoroacetic acid are removed ln vacuo and the residue is taken up in ethyl acetate and the hydrochloride salt is precipitated with satu~rated hydrochloric acid/ethyl ether. The white solid' is collected by filtration and washed with 2:1 ethyl acetate/ethyl ether to yield 0.7 g. of (+)-3-amino-3,4-dihydro-4-oxo-1,5-benzothiazepine-5(2H)-acetic acid, ethyl ester as a white solid;
m.p. 231-233 (decomp.). TLC (methylene chloride/
acetic acid/methanol; 100:5:5) single spot at Rf = 0.08.
Anal. calc'd. for C13Hl6N2O3s HCl:
C, 49.29; H, 5.41; N, 8.84; S, 10.12;
Cl, 11.37 Found: C, 48.87; H, 5.31; N, 8.80; S, 10.05;
Cl, 11.37.
f) (+)-Dihydro-3-[[1-(Ethoxycarbonyl)-3-phenyl-propyl]amino]-4-oxo-1,5-benzothiazepine-5(2H~-acetic acid, ethvl ester (+)-3-Amino-3,4-dihydro-4-oxo-1,5-benzothia-zepine-5(2H)-acetic acid, ethyl ester is reacted with ethyl-2-oxo-4-phenylbutyrate in the presence of sodium cyanoborohydride according to the pro-cedure of Exam21e l(f) to yield (+)-dihydro-3-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-4-oxo-1,5-benzothiazepine-5(2~)-acetic acid, ethyl ester.
~__(+)-Dihydro-3-[(1-Carboxy-3-phenylpropyl) amino]-4-oxo-1,5-benzothiazepine-5(2H)-acetic acid The diethyl ester product from part ~f) is treated with sodium hydroxide according to the ~Z1~86~ HA269 - procedure of Example l(h) to yield (+)-dihydro-3-[(1-carboxy-3-phenylpropyl)amino]-4-oxo-1,5-benzothiazepine-5(2H)-acetic acid.
In a similar manner, the keto compounds shown in Col. I of Examples 5 to 31 can be employed in the above procedure to yield other compounds within the scope of the invention.
Example 84 (5R)-5-[(1-Carbox~-3-phenylpropyl)amino]dihvdro-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid (s-slow isomer), disodium salt The diacid product from Example 1 (1 mmole) is dissolved in water (50 ml.). Aqueous sodium bicarbonate (0.1 N, 20 ml.) is added and the aqueous solution is lyophilized. The residue is dissolved and purified chromatographicallv to give (5R)-5-[(1-carboxy-3-phenylpropyl)amino]-dihydro-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid (B-slow isomer~, disodium salt.
In a similar manner disodium or monosodium salts ofthe products of Examples 2 to 32 can be prepared.
Claims (14)
1. A process for preparing a compound of the formula and pharmaceutically acceptable salts thereof wherein:
X is R1 is hydrogen, lower alkyl, amino substituted lower alkyl, hydroxy substituted lower alkyl, or halo substituted lower alkyl;
n is one or two;
R5 and R6 are independently selected from the group consisting of hydrogen, lower alkyl, -(CH2)m-cycloalkyl and ;
R3 is hydroxy, lower alkoxy, di(lower alkyl)-amino-lower alkoxy, lower alkyl-carbonyl-amino-lower alkoxy, lower alkyl-carbonyloxy-lower alkoxy, , amino, lower alkyl-amino, di(lower alkyl)amino, hydroxy-amino, benzylamino, phenethylamino, or -O-salt forming ion;
R4 is hydrogen, lower alkyl , halo substituted lower alkyl, hydroxy substituted lower alkyl, -(CH2)q-cycloalkyl, -(CH2)q-carboxy, -(CH2)q-S-lower alkyl, -(CH2)q-NH2 , -(CH2)q-N(lower alkyl)2, -(CH2)q-NH-?-lower alkyl , -(CH2)q-SH, (CH2)q-lower alkoxy, -(CH2)q-?-NH2 , -(CH2)q-?-lower alkoxy, or ;
m is zero or an integer from 1 to 4;
q is an integer from 1 to 4;
R14 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, halo, trifluoromethyl, or hydroxy;
p is an integer from 1 to 3 provided that p is more than one only if R14 is hydrogen, methyl, methoxy, chloro, or fluoro;
R15. is lower alkyl, cycloalkyl, or ;
R7 is alkyl of 1 to 10 carbons, , -(CH5)s-cycloalkyl, -(CH2)t-NH2 , s is zero or an integer from 1 to 7;
t is an integer from 1 to 8;
R9 and R12 are independently selected from the group consisting of lower alkyl, halo substitu-ted lower alkyl -(CH2)m-cycloalkyl, ;
R8 and R2 are independently selected from the group consisting of hydrogen, lower alkyl, benzyl, benzhydryl, salt forming ion, and ;
R10 is hydrogen, lower alkyl, cycloalkyl, or phenyl: and R11 is hydrogen, lower alkyl, lower alkoxy, cycloalkyl, phenyl, benzyl, or phenethyl, characterized by reacting a compound of the formula with a compound of the formula
X is R1 is hydrogen, lower alkyl, amino substituted lower alkyl, hydroxy substituted lower alkyl, or halo substituted lower alkyl;
n is one or two;
R5 and R6 are independently selected from the group consisting of hydrogen, lower alkyl, -(CH2)m-cycloalkyl and ;
R3 is hydroxy, lower alkoxy, di(lower alkyl)-amino-lower alkoxy, lower alkyl-carbonyl-amino-lower alkoxy, lower alkyl-carbonyloxy-lower alkoxy, , amino, lower alkyl-amino, di(lower alkyl)amino, hydroxy-amino, benzylamino, phenethylamino, or -O-salt forming ion;
R4 is hydrogen, lower alkyl , halo substituted lower alkyl, hydroxy substituted lower alkyl, -(CH2)q-cycloalkyl, -(CH2)q-carboxy, -(CH2)q-S-lower alkyl, -(CH2)q-NH2 , -(CH2)q-N(lower alkyl)2, -(CH2)q-NH-?-lower alkyl , -(CH2)q-SH, (CH2)q-lower alkoxy, -(CH2)q-?-NH2 , -(CH2)q-?-lower alkoxy, or ;
m is zero or an integer from 1 to 4;
q is an integer from 1 to 4;
R14 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, halo, trifluoromethyl, or hydroxy;
p is an integer from 1 to 3 provided that p is more than one only if R14 is hydrogen, methyl, methoxy, chloro, or fluoro;
R15. is lower alkyl, cycloalkyl, or ;
R7 is alkyl of 1 to 10 carbons, , -(CH5)s-cycloalkyl, -(CH2)t-NH2 , s is zero or an integer from 1 to 7;
t is an integer from 1 to 8;
R9 and R12 are independently selected from the group consisting of lower alkyl, halo substitu-ted lower alkyl -(CH2)m-cycloalkyl, ;
R8 and R2 are independently selected from the group consisting of hydrogen, lower alkyl, benzyl, benzhydryl, salt forming ion, and ;
R10 is hydrogen, lower alkyl, cycloalkyl, or phenyl: and R11 is hydrogen, lower alkyl, lower alkoxy, cycloalkyl, phenyl, benzyl, or phenethyl, characterized by reacting a compound of the formula with a compound of the formula
2. A process according to claim 1 wherein R is
3. A process according to claim 1 wherein R is and R7 is alkyl of 1 to 10 carbons.
, -(CH2)t-NH2 or ;
R9 and R12 are independently selected from the group consisting of lower alkyl of 1 to 4 carbons and s is zero or an integer from 1 to 7;
t is an integer from 1 to 8;
m is zero, one, two or three;
R14 is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro, or hydroxy;
R1 is hydrogen, lower alkyl of 1 to 4 carbons, or -(CH2)4-NH2;
R5 and R6 are independently selected from the group consisting of hydrogen, lower alkyl of 1 to 4 carbons and ;
R8 and R2 are independently selected from the group consisting of hydrogen, lower alkyl of 1 to 4 carbons, alkali metal salt, and ;
R10 is hydrogen, straight or branched chain lower alkyl of 1 to 4 carbons, or cyclohexyl;
and R11 is straight or branched chain lower alkyl of 1 to 4 carbons, cyclohexyl or phenyl.
, -(CH2)t-NH2 or ;
R9 and R12 are independently selected from the group consisting of lower alkyl of 1 to 4 carbons and s is zero or an integer from 1 to 7;
t is an integer from 1 to 8;
m is zero, one, two or three;
R14 is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro, or hydroxy;
R1 is hydrogen, lower alkyl of 1 to 4 carbons, or -(CH2)4-NH2;
R5 and R6 are independently selected from the group consisting of hydrogen, lower alkyl of 1 to 4 carbons and ;
R8 and R2 are independently selected from the group consisting of hydrogen, lower alkyl of 1 to 4 carbons, alkali metal salt, and ;
R10 is hydrogen, straight or branched chain lower alkyl of 1 to 4 carbons, or cyclohexyl;
and R11 is straight or branched chain lower alkyl of 1 to 4 carbons, cyclohexyl or phenyl.
4. A process according to claim 1 wherein R is X is ;
R7 is alkyl of l to 10 carbons or .
;
s is zero or an integer from 1 to 7;
R1 is hydrogen;
R5 is hydrogen or phenyl;
R8 and R2 are independently selected from the group consisting of hydrogen, alkali metal salt, and provided that only one of R2 and R8 is ;
R10 is hydrogen, straight or branched chain lower alkyl of 1 to 4 carbons, or cyclohexyl; and R11 is straight or branched chain lower alkyl of 1 to 4 carbons.
R7 is alkyl of l to 10 carbons or .
;
s is zero or an integer from 1 to 7;
R1 is hydrogen;
R5 is hydrogen or phenyl;
R8 and R2 are independently selected from the group consisting of hydrogen, alkali metal salt, and provided that only one of R2 and R8 is ;
R10 is hydrogen, straight or branched chain lower alkyl of 1 to 4 carbons, or cyclohexyl; and R11 is straight or branched chain lower alkyl of 1 to 4 carbons.
5. A process according to claim 1 wherein R is
6. A process according to claim 1 wherein R is ; R3 is hydroxy, lower alkoxy of 1 to 4 carbons, or -O-alkali metal salt;
;
m is zero, one, two or three;
R1 is hydrogen. lower alkyl of 1 to 4 carbons, or -(CH2)4-NH2;
R5 and R6 are independently selected from hydrogen, lower alkyl of 1 to 4 carbons, and ;
R14 is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro, or hydroxy;
R2 is hydrogen, lower alkyl of 1 to 4, alkali metal salt, or ;
R10 is hydrogen, straight or branched chain lower alkyl of 1 to 4 carbons, or cyclohexyl; and R11 is straight or branched chain lower alkyl of 1 to 4 carbons, cyclohexyl or phenyl.
;
m is zero, one, two or three;
R1 is hydrogen. lower alkyl of 1 to 4 carbons, or -(CH2)4-NH2;
R5 and R6 are independently selected from hydrogen, lower alkyl of 1 to 4 carbons, and ;
R14 is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro, or hydroxy;
R2 is hydrogen, lower alkyl of 1 to 4, alkali metal salt, or ;
R10 is hydrogen, straight or branched chain lower alkyl of 1 to 4 carbons, or cyclohexyl; and R11 is straight or branched chain lower alkyl of 1 to 4 carbons, cyclohexyl or phenyl.
7. A process according to claim 1 wherein R is ; X is ;
R3 is hydroxy, ethoxy, or -O-alkali metal salt;
R4 is ;
R1 is hydrogen;
R5 is hydrogen or phenyl;
R2 is hydrogen, alkali metal salt, or ;
R10 is hydrogen, straight or branched chain lower alkyl of 1 to 4 carbons, or cyclohexyl; and R11 is straight or branched chain lower alkyl of 1 to 4 carbons.
R3 is hydroxy, ethoxy, or -O-alkali metal salt;
R4 is ;
R1 is hydrogen;
R5 is hydrogen or phenyl;
R2 is hydrogen, alkali metal salt, or ;
R10 is hydrogen, straight or branched chain lower alkyl of 1 to 4 carbons, or cyclohexyl; and R11 is straight or branched chain lower alkyl of 1 to 4 carbons.
8. A compound of the formula and pharmaceutically acceptable salts thereof wherein:
X is ;
R1 is hydrogen, lower alkyl, amino substituted lower alkyl, hydroxy substituted lower alkyl, or halo substituted lower alkyl;
n is one or two;
R5 and R6 are independently selected from the group consisting of hydrogen, lower alkyl, -(CH2)m-cycloalkyl and ;
R3 is hydroxy, lower alkoxy, di(lower alkyl)-amino-lower alkoxy, lower alkyl-carbonyl-amino-lower alkoxy, lower alkyl-carbonyloxy-lower alkoxy, amino, lower alkyl-amino, di(lower alkyl)amino, hydroxy-amino! benzylamino, phenethylamino, or -O-salt forming ion;
R4 is hydrogen, lower alkyl , halo substituted lower alkyl, hydroxy substituted lower alkyl, -(CH2)q-cycloalkyl, -(CH2)q-carboxy, -(CH2)q-S-lower alkyl, , , , -(CH2)q-NH2 , -(CH2)q-N(lower alkyl)2 , -(CH2)q-NH-?-lower alkyl, , -(CH2)q-SH, (CH2)a-lower alkoxy, , -(CH2)q-?-NH2 , -(CH2)q-?-lower alkoxy, or ;
m is zero or an integer from 1 to 4;
q is an integer from 1 to 4;
R14 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, halo, trifluoromethyl, or hydroxy;
p is an integer from 1 to 3 provided that p is more than one only if R14 is hydrogen, methyl, methoxy, chloro, or fluoro;
R15. is lower alkyl, cycloalkyl, or ;
R7 is alkyl of 1 to 10 carbons, , -(CH2)s-cycloalkyl, -(CH2)t-NH2 , , ;
s is zero or an integer from 1 to 7;
t is an integer from 1 to 8;
R9 and R12 are independently selected from the group consisting of lower alkyl, halo substitu-ted lower alkyl -(CH2)m-cycloalkyl, ;
R8 and R2 are independently selected from the group consisting of hydrogen, lower alkyl, benzyl, benzhydryl, salt forming ion, and ;
R10 is hydrogen, lower alkyl, cycloalkyl, or phenyl; and R11 is hydrogen, lower alkyl, lower alkoxy, cycloalkyl, phenyl, benzyl, or phenethyl, whenever prepared by the process of claim 1.
X is ;
R1 is hydrogen, lower alkyl, amino substituted lower alkyl, hydroxy substituted lower alkyl, or halo substituted lower alkyl;
n is one or two;
R5 and R6 are independently selected from the group consisting of hydrogen, lower alkyl, -(CH2)m-cycloalkyl and ;
R3 is hydroxy, lower alkoxy, di(lower alkyl)-amino-lower alkoxy, lower alkyl-carbonyl-amino-lower alkoxy, lower alkyl-carbonyloxy-lower alkoxy, amino, lower alkyl-amino, di(lower alkyl)amino, hydroxy-amino! benzylamino, phenethylamino, or -O-salt forming ion;
R4 is hydrogen, lower alkyl , halo substituted lower alkyl, hydroxy substituted lower alkyl, -(CH2)q-cycloalkyl, -(CH2)q-carboxy, -(CH2)q-S-lower alkyl, , , , -(CH2)q-NH2 , -(CH2)q-N(lower alkyl)2 , -(CH2)q-NH-?-lower alkyl, , -(CH2)q-SH, (CH2)a-lower alkoxy, , -(CH2)q-?-NH2 , -(CH2)q-?-lower alkoxy, or ;
m is zero or an integer from 1 to 4;
q is an integer from 1 to 4;
R14 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, halo, trifluoromethyl, or hydroxy;
p is an integer from 1 to 3 provided that p is more than one only if R14 is hydrogen, methyl, methoxy, chloro, or fluoro;
R15. is lower alkyl, cycloalkyl, or ;
R7 is alkyl of 1 to 10 carbons, , -(CH2)s-cycloalkyl, -(CH2)t-NH2 , , ;
s is zero or an integer from 1 to 7;
t is an integer from 1 to 8;
R9 and R12 are independently selected from the group consisting of lower alkyl, halo substitu-ted lower alkyl -(CH2)m-cycloalkyl, ;
R8 and R2 are independently selected from the group consisting of hydrogen, lower alkyl, benzyl, benzhydryl, salt forming ion, and ;
R10 is hydrogen, lower alkyl, cycloalkyl, or phenyl; and R11 is hydrogen, lower alkyl, lower alkoxy, cycloalkyl, phenyl, benzyl, or phenethyl, whenever prepared by the process of claim 1.
9. A compound of Claim 8 wherein R is whenever prepared by the process of claim 2.
10. A compound of Claim 8 wherein R is and R7 is alkyl of 1 to 10 carbons, , -(CH2)t-NH2 or ;
R9 and R12 are independently selected from the group consisting of lower alkyl of 1 to 4 carbons and ;
s is zero or an integer from 1 to 7;
t is an integer from 1 to 8;
m is zero, one, two or three;
R14 is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro, or hydroxy;
R1 is hydrogen, lower alkyl of 1 to 4 carbons, or -(CH2)4-NH2;
R5 and R6 are independently selected from the group consisting of hydrogen, lower alkyl of 1 to 4 carbons and ;
R8 and R2 are independently selected from the group consisting of hydrogen, lower alkyl of 1 to 4 carbons, alkali metal salt, and ;
R10 is hydrogen, straight or branched chain lower alkyl of 1 to 4 carbons, or cyclohexyl;
and R11 is straight or branched chain lower alkyl of 1 to 4 carbons, cyclohexyl or phenyl, whenever prepared by the Process of claim 3.
R9 and R12 are independently selected from the group consisting of lower alkyl of 1 to 4 carbons and ;
s is zero or an integer from 1 to 7;
t is an integer from 1 to 8;
m is zero, one, two or three;
R14 is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro, or hydroxy;
R1 is hydrogen, lower alkyl of 1 to 4 carbons, or -(CH2)4-NH2;
R5 and R6 are independently selected from the group consisting of hydrogen, lower alkyl of 1 to 4 carbons and ;
R8 and R2 are independently selected from the group consisting of hydrogen, lower alkyl of 1 to 4 carbons, alkali metal salt, and ;
R10 is hydrogen, straight or branched chain lower alkyl of 1 to 4 carbons, or cyclohexyl;
and R11 is straight or branched chain lower alkyl of 1 to 4 carbons, cyclohexyl or phenyl, whenever prepared by the Process of claim 3.
11. A compound of Claim 8 wherein R is ; X is , ;
R7 is alkyl of 1 to 10 carbons or ;
s is zero or an integer from 1 to 7;
R1 is hydrogen;
R5 is hydrogen or phenyl;
R8 and R2 are independently selected from the group consisting of hydrogen, alkali metal salt, and provided that only one of R2 and R8 is ;
R10 is hydrogen, straight or branched chain lower alkyl of 1 to 4 carbons, or cyclohexyl; and R11 is straight or branched chain lower alkyl of 1 to 4 carbons, whenever prepared by the process of claim 4.
R7 is alkyl of 1 to 10 carbons or ;
s is zero or an integer from 1 to 7;
R1 is hydrogen;
R5 is hydrogen or phenyl;
R8 and R2 are independently selected from the group consisting of hydrogen, alkali metal salt, and provided that only one of R2 and R8 is ;
R10 is hydrogen, straight or branched chain lower alkyl of 1 to 4 carbons, or cyclohexyl; and R11 is straight or branched chain lower alkyl of 1 to 4 carbons, whenever prepared by the process of claim 4.
12. A compound of Claim 8 wherein R is .
whenever prepared by the process of claim 5.
whenever prepared by the process of claim 5.
13. A compound of Claim 8 wherein R is ; R3 is hydroxy, lower alkoxy of 1 to 4 carbons, or -O-alkali metal salt;
;
m is zero, one, two or three, R1 is hydrogen, lower alkyl of 1 to 4 carbons, or -(CH2)4-NH2;
R5 and R6 are independently selected from hydrogen, lower alkyl of 1 to 4 carbons, and ;
R14 is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro, or hydroxy;
R2 is hydrogen, lower alkyl of 1 to 4, alkali metal salt, or ;
R10 is hydrogen, straight or branched chain lower alkyl of 1 to 4 carbons, or cyclohexyl; and R11 is straight or branched chain lower alkyl of 1 to 4 carbons, cyclohexyl or phenyl, whenever prepared by the process of claim 6.
;
m is zero, one, two or three, R1 is hydrogen, lower alkyl of 1 to 4 carbons, or -(CH2)4-NH2;
R5 and R6 are independently selected from hydrogen, lower alkyl of 1 to 4 carbons, and ;
R14 is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro, or hydroxy;
R2 is hydrogen, lower alkyl of 1 to 4, alkali metal salt, or ;
R10 is hydrogen, straight or branched chain lower alkyl of 1 to 4 carbons, or cyclohexyl; and R11 is straight or branched chain lower alkyl of 1 to 4 carbons, cyclohexyl or phenyl, whenever prepared by the process of claim 6.
14. A compound of Claim 8 wherein R is ; X is , R3 is hydroxy, ethoxy, or -O-alkali metal salt;
R4 is ;
R1 is hydrogen;
R5 is hydrogen or phenyl;
R2 is hydrogen, alkali metal salt, or R10 is hydrogen, straight or branched chain lower alkyl of 1 to 4 carbons, or cyclohexyl; and R11 is straight or branched chain lower alkyl of 1 to 4 carbons, whenever prepared by the process of claim 7.
R4 is ;
R1 is hydrogen;
R5 is hydrogen or phenyl;
R2 is hydrogen, alkali metal salt, or R10 is hydrogen, straight or branched chain lower alkyl of 1 to 4 carbons, or cyclohexyl; and R11 is straight or branched chain lower alkyl of 1 to 4 carbons, whenever prepared by the process of claim 7.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/470,882 US4460579A (en) | 1983-02-28 | 1983-02-28 | Thiazine and thiazepine containing compounds |
| US470,882 | 1983-02-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1219862A true CA1219862A (en) | 1987-03-31 |
Family
ID=23869447
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000447163A Expired CA1219862A (en) | 1983-02-28 | 1984-02-10 | Thiazine and thiazepine containing compounds |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US4460579A (en) |
| EP (1) | EP0120728B1 (en) |
| JP (1) | JPS59167577A (en) |
| AT (1) | ATE34388T1 (en) |
| CA (1) | CA1219862A (en) |
| DE (1) | DE3471305D1 (en) |
Families Citing this family (31)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1985004402A1 (en) * | 1984-03-24 | 1985-10-10 | Takeda Chemical Industries, Ltd. | Fused 7-membered ring compounds and process for their preparation |
| WO1984004306A1 (en) * | 1983-04-22 | 1984-11-08 | Takeda Chemical Industries Ltd | Fused 7-membered ring compounds and process for their preparation |
| US4564612A (en) * | 1983-04-22 | 1986-01-14 | Takeda Chemical Industries, Ltd. | Condensed, seven-membered ring compounds and their use |
| JPS608284A (en) * | 1983-06-29 | 1985-01-17 | Mitsui Toatsu Chem Inc | Benzothiazepine derivative and its preparation |
| JPS608283A (en) * | 1983-06-29 | 1985-01-17 | Mitsui Toatsu Chem Inc | Benzothiazepine derivative and its preparation |
| US4638000A (en) * | 1983-08-12 | 1987-01-20 | Takeda Chemical Industries, Ltd. | Condensed seven-membered ring compounds, their production and use |
| JPS60174775A (en) * | 1984-02-21 | 1985-09-09 | Mitsui Toatsu Chem Inc | Benzothiazepine derivative |
| US4512988A (en) * | 1984-03-01 | 1985-04-23 | E. R. Squibb & Sons, Inc. | Acylamino oxo or hydroxy substituted alkylamino thiazines and thiazepines |
| SU1435151A3 (en) * | 1984-04-10 | 1988-10-30 | Санкио Компани Лимитед (Фирма) | Method of producing derivatives of perhydrothiazepin or acid-additive pharmaceutically acceptable salts thereof |
| JPS6165894A (en) * | 1984-09-08 | 1986-04-04 | Shionogi & Co Ltd | Thiazine phosphonic acid derivative, its preparation and insecticide |
| JPS61148171A (en) * | 1984-12-21 | 1986-07-05 | Mitsui Toatsu Chem Inc | Benzothiazepine derivative |
| JPH07113020B2 (en) * | 1985-09-12 | 1995-12-06 | 三共株式会社 | Process for producing perhydro-1,4-thiazepine derivative |
| ES2061490T3 (en) * | 1986-04-04 | 1994-12-16 | Sankyo Co | PERHYDROTIAZEPINE AND PERHYDROAZEPINE DERIVATIVES, THEIR PREPARATION AND USE IN THERAPEUTICS. |
| JPH07116224B2 (en) * | 1987-12-29 | 1995-12-13 | 吉富製薬株式会社 | Benzolactam compound |
| US5646276A (en) * | 1992-05-13 | 1997-07-08 | Bristol-Myers Squibb Co. | Diazepine containing dual action inhibitors |
| US5552397A (en) * | 1992-05-18 | 1996-09-03 | E. R. Squibb & Sons, Inc. | Substituted azepinone dual inhibitors of angiotensin converting enzyme and neutral exdopeptidase |
| RU2124503C1 (en) | 1992-05-18 | 1999-01-10 | И.Р.Сквибб энд Санз, Инк. | Heterocyclic nitrogen-containing derivatives of carboxylic acid, method of their synthesis, pharmaceutical composition |
| US5504080A (en) * | 1992-10-28 | 1996-04-02 | Bristol-Myers Squibb Co. | Benzo-fused lactams |
| US5508272A (en) | 1993-06-15 | 1996-04-16 | Bristol-Myers Squibb Company | Compounds containing a fused bicycle ring and processes therefor |
| US5362727A (en) * | 1993-07-26 | 1994-11-08 | Bristol-Myers Squibb | Substituted azepino[2,1-a]isoquinoline compounds |
| US5525723A (en) * | 1993-11-18 | 1996-06-11 | Bristol-Myers Squibb Co. | Compounds containing a fused multiple ring lactam |
| JP2664865B2 (en) * | 1994-01-13 | 1997-10-22 | 三共株式会社 | Method for producing perhydro-1,4-thiazepine derivative |
| US5616775A (en) * | 1994-05-05 | 1997-04-01 | Bristol-Myers Squibb Co. | Process for preparing homocystein analogs useful as intermediates for compounds containing a fused bicyclic ring |
| US5587375A (en) * | 1995-02-17 | 1996-12-24 | Bristol-Myers Squibb Company | Azepinone compounds useful in the inhibition of ACE and NEP |
| US5877313A (en) | 1995-05-17 | 1999-03-02 | Bristol-Myers Squibb | Benzo-fused azepinone and piperidinone compounds useful in the inhibition of ACE and NEP |
| US5650408A (en) * | 1995-06-07 | 1997-07-22 | Karanewsky; Donald S. | Thiazolo benzazepine containing dual action inhibitors |
| US5635504A (en) * | 1995-06-07 | 1997-06-03 | Bristol-Myers Squibb Co. | Diazepine containing dual action inhibitors |
| US6635632B1 (en) | 1996-12-23 | 2003-10-21 | Athena Neurosciences, Inc. | Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds |
| US6683075B1 (en) | 1996-12-23 | 2004-01-27 | Athena Neurosciences, Inc. | Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use |
| US6958330B1 (en) | 1998-06-22 | 2005-10-25 | Elan Pharmaceuticals, Inc. | Polycyclic α-amino-ε-caprolactams and related compounds |
| FR2781483A1 (en) * | 1998-07-21 | 2000-01-28 | Hoechst Marion Roussel Inc | Thioazepinone derivatives having Src domain SH2 inhibiting and osteoclast-mediated calcium resorption from bone inhibiting activity, for treatment of osteoporosis |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BR6915295D0 (en) * | 1969-01-25 | 1973-04-12 | Tanabe Seiyaku Co | CHRONOLOGICAL INDICATOR OF EVENT IN TELEVISED TRANSMISSION |
| US3691163A (en) * | 1970-08-03 | 1972-09-12 | Exxon Research Engineering Co | Certain phosphorus-containing thiomorpholinones |
| PT73522B (en) * | 1980-08-18 | 1983-07-14 | Merck & Co Inc | Process for preparing substituted caprylolactam derivatives as antihypertensives |
| IL63540A0 (en) * | 1980-08-18 | 1981-11-30 | Merck & Co Inc | Substituted enantholactam derivatives as antihypertensives |
| GR74635B (en) * | 1980-08-18 | 1984-06-29 | Merck & Co Inc | |
| US4379146A (en) * | 1981-02-17 | 1983-04-05 | Merck & Co., Inc. | Substituted phosphonamides as antihypertensives |
| DE3260831D1 (en) * | 1981-06-05 | 1984-10-31 | Merck & Co Inc | Perhydro-1,4-thiazepin-5-one and perhydro-1,4-thiazocin-5-one derivatives, process for preparing and pharmceutical composition containing the same |
| JPS58116477A (en) * | 1981-06-05 | 1983-07-11 | メルク・エンド・カムパニ−・インコ−ポレ−テツド | Antihypertensive perhydro-1,4-thiazepin-5-one and perhydro-1,4-thiazocin-5-one derivative |
| US4474955A (en) * | 1981-06-17 | 1984-10-02 | Vincenzo Iannella | Process for preparing 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-[N-(2-pyridinyl)carboxamide]-1,1-dioxide, and its phosphoric ester |
-
1983
- 1983-02-28 US US06/470,882 patent/US4460579A/en not_active Expired - Fee Related
-
1984
- 1984-02-10 CA CA000447163A patent/CA1219862A/en not_active Expired
- 1984-02-14 AT AT84400293T patent/ATE34388T1/en active
- 1984-02-14 DE DE8484400293T patent/DE3471305D1/en not_active Expired
- 1984-02-14 EP EP84400293A patent/EP0120728B1/en not_active Expired
- 1984-02-28 JP JP59038452A patent/JPS59167577A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| JPS59167577A (en) | 1984-09-21 |
| EP0120728A1 (en) | 1984-10-03 |
| EP0120728B1 (en) | 1988-05-18 |
| US4460579A (en) | 1984-07-17 |
| ATE34388T1 (en) | 1988-06-15 |
| DE3471305D1 (en) | 1988-06-23 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry | ||
| MKEX | Expiry |
Effective date: 20040331 |