WO1999037625A1 - 2,3,4,5-tetrahydro-1h-[1,4]-benzodiazepine-3-hydroxamic acids as matrix metalloproteinase inhibitors - Google Patents

2,3,4,5-tetrahydro-1h-[1,4]-benzodiazepine-3-hydroxamic acids as matrix metalloproteinase inhibitors Download PDF

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Publication number
WO1999037625A1
WO1999037625A1 PCT/US1999/001325 US9901325W WO9937625A1 WO 1999037625 A1 WO1999037625 A1 WO 1999037625A1 US 9901325 W US9901325 W US 9901325W WO 9937625 A1 WO9937625 A1 WO 9937625A1
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alkyl
tetrahydro
benzodiazepine
methoxybenzenesulfonyl
carboxylic acid
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PCT/US1999/001325
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French (fr)
Inventor
Jay Donald Albright
Efren Guillermo Delos Santos
Xuemei Du
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American Cyanamid Company
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Priority to HU0100277A priority Critical patent/HUP0100277A3/en
Priority to AU22402/99A priority patent/AU2240299A/en
Priority to PL99342045A priority patent/PL342045A1/en
Priority to CA002317546A priority patent/CA2317546A1/en
Priority to IL13716299A priority patent/IL137162A0/en
Priority to JP2000528549A priority patent/JP2002501056A/en
Priority to BR9907746-9A priority patent/BR9907746A/en
Priority to EP99902417A priority patent/EP1051407A1/en
Priority to KR1020007008171A priority patent/KR20010034406A/en
Publication of WO1999037625A1 publication Critical patent/WO1999037625A1/en
Priority to NO20003828A priority patent/NO20003828L/en

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    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D213/56—Amides
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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
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    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Definitions

  • This invention relates to 4-(4-substituted-benzenesulfonyl)-2,3,4,5-tetrahydro- lH-[l,4]benzodiazepine-3-hydroxyamic acids which act as matrix metalloproteinase
  • the compounds of the present invention are useful in disease conditions mediated by matrix metalloproteinases, such as tumor growth, osteoarthritis, rheumatoid arthritis and degenerative cartilage loss.
  • MMPs Matrix metalloproteinases
  • These zinc-containing endopeptidases consist of several subsets of enzymes, including collagenases, stromelysins and gelatinases. Of these, the gelatinases have been shown to be the MMPs most intimately involved with the growth
  • gelatinase For example, it is known that the level of expression of gelatinase is elevated in malignancies, and that gelatinase can degrade the basement membrane which leads to tumor metastasis.
  • Angiogenesis required for the growth of solid tumors, has also 25 recently been shown to have a gelatinase component to its pathology as reported in "Matrix Metalloproteinases, Novel Targets for Directed Cancer Therapy", Drugs and Aging. 11:229-244 (1997).
  • MMPs diseases mediated by MMPs
  • Other conditions mediated by MMPs include restenosis, MMP-mediated 30 osteopenias, inflammatory diseases of the central nervous system, skin aging, osteoarthritis, rheumatoid arthritis, septic arthritis, corneal ulceration, abnormal wound healing, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system, cirrhosis of the liver, glomerular disease of the kidney, premature rupture of fetal 35 membranes, inflammatory bowel disease, periodontal disease, age-related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of - 2 -
  • TNF- ⁇ converting enzyme catalyzes the formation of TNF- from membrane bound TNF- ⁇ precursor protein.
  • TNF- ⁇ is a pro-inflammatory cytokine that is believed to have a role in rheumatoid arthritis, septic shock, graft rejection, cachexia, anorexia, inflammation, congestive heart failure, inflammatory disease of the central nervous system, inflammatory bowel disease, insulin resistance and HIN infection, in addition to its well-documented antitumor properties.
  • Research with anti-T ⁇ F- ⁇ antibodies in transgenic animals has demonstrated that blocking the formation of T ⁇ F- ⁇ inhibits the progression of arthritis. This observation has recently been extended to humans as described in "T ⁇ F- ⁇ in Human Diseases", Current Pharmaceutical Design. 2:662-667 (1996).
  • MMPs and TACE small molecule inhibitors of MMPs and TACE would have the potential for treating a variety of disease states. Although a variety of MMP and TACE inhibitors are known, many of these molecules are peptidic and peptide-like which demonstrate bioavailability and pharmacokinetic problems. Long acting, orally bioavailable non-peptide inhibitors of MMPs and/or TACE would thus be highly desirable for the treatment of the disease states discussed above.
  • U.S. Patent No, 5,455,258 discloses 2-substituted-2-(arylsulfonylamino) hydroxyamic acids and their use as MMP inhibitors.
  • WO 97/18194 discloses N- (arylsulfonyl)tetrahydroisoquinolone-hydroxyamic acids and related bicyclic derivatives thereof and their use as MMP inhibitors.
  • WO 97/20824 discloses l-(arylsulfonyl)-4- (substituted)piperazine-2-hydroxyamic acids, 4-(arylsulfonyl) morpholine-3- hydroxyamic acids, 4-(arylsulfonyl)-tetrahydro-2HJ,4-thiazine-3-hydroxyamic acids, 3-(substituted-l-(arylsulfonyl)hexahydro-2 -hydroxyamic acids and related compounds as useful MMP inhibitors. - 3 -
  • This invention relates to novel derivatives of substituted 2.3,4.5-tetrahydro-lH- [l,4]benzodiazepine-3-carboxylic acid hydroxyamide which exhibit inhibitory activity against MMPs.
  • the compounds of the present invention are represented by the following formula 1
  • R is selected from hydrogen, (Cj - C 3 ) alkyl, -CN, -OR', -SR', -CF 3 -OCF 3 , Cl, F, NH 2 , NH(C j - C 3 )alkyl, -N ⁇ CO ⁇ - C 3 )alkyl, -N(R')(R'), NO 2 , -CONH 2 , -SO 2 NH 2 , -SO 2 N(R')(R'), or -N(R')COCH 2 O-(C 1 - C 3 )alkyl, wherein R' is (C l - C 3 ) alkyl or hydrogen;
  • R 4 is (Ci - C 6 ) alkyl-O-, (C, - C 6 ) alkyl-S-, o ⁇ s -R.
  • R is hydrogen, halogen, cyano, methyl or -OCH 3 ;
  • Rl and R 2 are each, independently, hydrogen or CH 3 ;
  • R 3 is (C, - C 8 )alkyl, NH 2 CH 2 CO-, (Cj - C 6 )alkylNHCH 2 CO-. HO(CH 2 ) m CO-,
  • HCO- Aryl(CH 2 ) n CO-, Heteroaryl(CH 2 ) n CO-, (C x - C 3 )alkyl-O-(CH 2 ) n CO-,
  • L is hydrogen, (C r C 3 )alkyl, -CN, -OR', -SR', -CF 3 , -OCF 3 , Cl , F, NH 2 , -NH-(C, - C 3 )alkyl, -N(R')CO(C ⁇ - C 3 )alkyl, N(R')(R'), -NO 2 , -CONH 2 , -SO 2 NH 2 , -SO 2 N(R')(R'), -N(R')COCH 2 O-(C ⁇ - C 3 )alkyl,
  • W is O, S, NH or N(C, - C 3 )alkyl
  • Y is hydrogen, F, Cl, CF 3 or OCH 3 ; and X' is halogen, hydrogen, (C j - C 3 )alkyl, O-
  • (C ! - C 3 )alkyl or -CH 2 OH; and pharmaceutically acceptable salts thereof.
  • -C3 alkyl covers methyl, ethyl, n-propyl and i-propyl groups.
  • -C6 alkyl covers, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl and pentyl groups.
  • C3-C7 cycloalkyl covers saturated and unsaturated cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-cyclopropenyl, 2-cyclopropenyl, 1-cyclobutenyl and 2-cyclobutenyl.
  • R is suitably hydrogen, halogen or (Ci-C3)alkyl, for example hydrogen, chloro or methyl.
  • Rl is suitably hydrogen.
  • R2 is suitably hydrogen.
  • R4 is suitably ( -C alkyl)-O-, for example methoxy.
  • R3 is suitably selected from the group: (C ⁇ -C3)alkyl- SO2-, aryl(CH2)nSO2-, (C ⁇ -C3)alkyl-CO-, aryl(CH2)nCO-, heteroaryl(CH2)nCO-, - 7 -
  • the compounds of the present invention are those of formula 1 wherein R is hydrogen, (C ⁇ - C 3 ) alkyl, -CN, -OR', -SR', -CF 3; -OCF 3 , Cl, F, NH 2 , NH(C ⁇ - C 3 )alkyl, -N(R')CO(C ⁇ - C 3 )alkyl, -N(R')(R'), NO 2 ,
  • R 4 is (C, - C 6 ) alkyl-O-, (Ci - C 6 ) alkyl-S-,
  • R is hydrogen, halogen, cyano, methyl or -OCH 3 ;
  • Rl and R 2 are each, independently, hydrogen or CH 3 ;
  • X is hydrogen, halogen, (C ⁇ - C 3 ) alkyl or -OCH 3 wherein R and R' are as defined above; and pharmaceutically acceptable salts thereof.
  • the compounds of the present invention are those of formula 1 wherein R is hydrogen, (C ⁇ - C 3 ) alkyl, -CN, -OR', -SR', -CF 3 -OCF 3 , Cl, F, NH 2 ,
  • R 4 is (C j - C 6 ) alkyl-O-, (C, - C 6 ) alkyl-S-, - 9 -
  • R is hydrogen, halogen, cyano, methyl or -OCH 3 ;
  • R l and R 2 are each, independently, hydrogen or CH 3 ; R 3 is
  • the compounds of the present invention include those of formula 1 wherein R is hydrogen, (C, - C 3 ) alkyl, -CN, -OR', -SR'. -CF 3 ⁇ -OCF 3 , Cl, F, NH 2 , NH(C ⁇ - C 3 )alkyl, -N(R')CO(C 1 - C 3 )alkyl, -N(R')(R'), NO 2 , -CONH 2 , -SO 2 NH 2 , -SO 2 N(R')(R'), or -N(R')COCH 2 O-(C ⁇ - C 3 )alkyl, wherein R' is (C j - C 3 ) alkyl or hydrogen;
  • R 4 is ( - C 6 ) alkyl-O-, (C ] - C 6 ) alkyl-S-,
  • R is hydrogen, halogen, cyano, methyl or -OCH 3 ;
  • R ] and R 2 are each, independently hydrogen or CH 3 ;
  • R' R' wherein X is hydrogen, halogen, (Ci - C 3 ) alkyl or -OCH 3 and R and R' are as defined above; and pharmaceutically acceptable salts thereof.
  • a further, more preferred embodiment of the present invention includes compounds represented by formula 1 wherein
  • R is selected from hydrogen, (Cj - C 3 ) alkyl, -CN, -OR', -SR', -CF 3
  • R 4 is (C j - C 6 ) alkyl-O-, (Ci - C 6 ) alkyl-S-,
  • R is hydrogen, halogen, cyano, methyl or -OCH 3 ;
  • R ] and R 2 are each, independently hydrogen or CH 3 ;
  • R' R' wherein X is hydrogen, halogen, (C j - C 3 ) alkyl or -OCH 3 and R and R' are as defined above; and pharmaceutically acceptable salts thereof.
  • R is hydrogen, ( - C 3 ) alkyl, -CN, -OR', -SR', -CF 3 -OCF 3 , Cl, F, NH 2 .
  • R 4 is (C j - C 6 ) alkyl-O-, (Ci - C 6 ) alkyl-S-,
  • R is hydrogen, halogen, cyano, methyl or -OCH 3 ;
  • Ri and R 2 are each, independently hydrogen or CH 3 ; 13 -
  • L is hydrogen, (C x - C 3 )alkyl, -CN, -OR', -SR', -CF 3 , -OCF 3 , Cl, F, NH 2 ,
  • W is O, S, NH or N(C, - C 3 )alkyl
  • Y is hydrogen, F, Cl, CF 3 or OCH 3 ; and X' is halogen, hydrogen, (Ci - C 3 )alkyl, O- (Ci - C3)alkyl, or -CH 2 OH; and pharmaceutically acceptable salts thereof.
  • the compounds of the invention may be prepared by reacting an appropriate acid halide such as the acid chloride or bromide with hydroxylamine.
  • the acid halide may be prepared by reacting the corresponding acid or a metal salt thereof with an activating agent such as oxalyl chloride, oxalyl bromide, thionyl chloride, thionyl bromide, (chloromethylene)dimethylammoniumchloride or (bromomethylene)dimethyl ammonium bromide.
  • an activating agent such as oxalyl chloride, oxalyl bromide, thionyl chloride, thionyl bromide, (chloromethylene)dimethylammoniumchloride or (bromomethylene)dimethyl ammonium bromide.
  • the subsequent reaction of the acid halide with hydroxylamine may suitably be performed in situ.
  • Metal salts may be prepared by reacting a ester of formula I
  • R 2J is (C ⁇ alkyl, benzyl or arylalkyl and all other groups are as defined above, with a base such as lithium hydroxide, potassium hydroxide, sodium hydroxide or barium hydroxide.
  • a base such as lithium hydroxide, potassium hydroxide, sodium hydroxide or barium hydroxide.
  • This may suitably be performed in a solvent such as a (C j -Cg) alcohol, tetrahydrofuran, N,N-dimethylformide or p-dioxane in the presence or absence of water.
  • the resulting metal salt may be directly converted to the desired product or it may first be converted to the acid, e.g. by treating it with aqueous hydrochloric acid or acetic acid.
  • the ester of formula I a may be converted to its acid by treatment with an aqueous mineral acid such as hydrochloric acid, hydrobromic acid or trifluoroacetic acid and the acid converted to the desired product as described
  • the compounds of formula 1 may be advantageously prepared according to Reaction Schemes 1 to 7. Variations in these schemes may be made to improve productivity without negatively impacting the amount and nature of the product, by - 15 -
  • reactive groups may be blocked with suitable blocking moieties which may then be deblocked under standard conditions (for instance, hydroxy groups may be protected with trimethylsilyl or t-butyl-dimethylsilyl moieties which are then removed in a later reaction step).
  • suitable blocking moieties for instance, hydroxy groups may be protected with trimethylsilyl or t-butyl-dimethylsilyl moieties which are then removed in a later reaction step.
  • the compounds of Formula 1 are synthesized from an alkyl ester
  • Ester derivatives 8 (where the ester function is a t-butyl ester) are converted to the acid with trifluoroacetic acid under standard conditions.
  • Rj (Ci - C 3 )alkyl;
  • R Hydrogen; halogen; OCH 3 ; NO 2 ; NH 2 ; CF 3 ; NHCOCH 3 ; NHCOCH 2 OCH 3 ; CONH 2 ; -N(R')(R'), -N(R')CO(C ⁇ - C 3 )alkyl; (C!
  • R 3 Ar(CH 2 ) n CO-; Heteroaryl(CH 2 ) n CO-, Ar(CH 2 ) n SO 2 -; Heteroaryl(CH 2 ) n SO 2 -: Alkyl-O-CH 2 ) n CO-; Alkyl-O-(CH 2 ) m SO 2 -; AlkylCO-; AlkylSO 2 -; AlkylCO- NHCH 2 CO-; and cycloalkyl(C 3 - C 7 )CO-; and R 4 is as defined herein. 17
  • R 5 -N0 2 t-BocNH- CH OCONH-
  • R 6 Ar(CH 2 ) n -; Alkyl-; Heteroaryl(CH 2 ) n -;Alkyl-O-(CH 2 ) n -; Cycloalkyl(C 3 - C 7 );
  • R 7 Ar(CH 2 ) n -; Alkyl-; Heteroaryl(CH 2 ) n -; Alkyl-O-(CH 2 ) m -;
  • Rg Ar(CH 2 ) n CO-; Ar(CH 2 ) n SO 2 -; AlkylCO-; AlkylSO 2 -; Heteroaryl(CH 2 ) n CO-;
  • arylmethyl-2,3,4,5-tetrahydro-lH [1.4]-benzodiazepines may be prepared in the manner illustrated in Reaction Schemes 3 and 4.
  • Reaction Scheme 3 the methyl 3-hydroxy-2-[4-methoxybenzenesulfonyl)-(2-aminobenzyl)amino]- propionates 6 are subjected to reductive alkylation with arylcarboxaldehydes and heteroaiylcarboxaldehydes to provide intermediates 17.
  • Standard reaction conditions such as reactions with triphenylphosphine and diethyl azodicarboxylate (DEAD) or triplenylphosphine with either carbon tetrachloride or carbon tetrabromide, results in the
  • N- aroyl derivatives 22 are reduced with reducing agents such as borane or lithium aluminum hydride to reduce both the ester and amide functions.
  • R 9 Ar R ° t rfllA ⁇ R i ⁇ o or
  • R-o ; and 9 and R 10 are: Cl, Br, F, OCH 3 , OEt , SCH 3 , CO CH
  • R 9 and RJO are hydrogen ,C1, Br, F, OCH3 , OEt
  • R 8 alkyl, arylalkyi, aryloxyalkyl, heterocyclicalkyl, or alkyloxyalkyloxyalkyl.
  • preferred compounds of the present invention are those with basic moieties in the 1 -(substituted carbonyl) group which may be prepared in the manner shown in Reaction Scheme 5.
  • the intermediates 25 may also be synthesized by reaction of methyl 2-[(2-aminobenzyl)-(4- methoxybenzenesulfonyl) amino]-3-hydroxypropionates 6 with acid chlorides to give "dehydroalanine" derivatives 28.
  • mild bases such as NaHCO3 can be reacted with these derivatives to cause ring closure via a 1.4- addition to the double bond in intermediate 28 to provide the 7-membered 2,3.4,5-tetrahydro- 1H-[1 ,4] diazepines 25.
  • R 8 o N- ⁇ CH.)- ⁇ / 2 n -(CH 2 )-
  • aryl-heteroarylcarbonyl, heteroaryl-heteroarylcarbonyl derivatives 30 may be synthesized by standard palladium catalysed coupling of bromoaiOyl or bromheteroaroyl derivatives 29 with appropriate arylstannanes, heteroarylstannanes, arylboronic acids, heteroarylboronic acids, aryl triflates, heteroaryl triflates and the like. under known conditions. For example, see Synthesis. 563-566 (1997); J. Org. Chem.. 62:3405-3406, (1997); Tetrahedron Lett.. 36:5247-5250, ( 1995);
  • aryl-aryl, heteroaryl-aryl, aryl- heteroaryl and heteroaryl-heteroaryl carboxylic ester derivatives can be prepared and these derivatives converted to carboxylic acid intermediates.
  • the acids are then converted to acid chlorides which are reacted with esters of 2- [(2-aminobenzyl)-(4- substituted-benzenesulfonyl)amino]-3-hydroxypropionate as illustrated for conversion of derivatives 6 to intermediates 31.
  • esters of 2- [(2-aminobenzyl)-(4- substituted-benzenesulfonyl)amino]-3-hydroxypropionate as illustrated for conversion of derivatives 6 to intermediates 31.
  • the following references describe procedures for the synthesis of methyl 3-arylpyrrole-4-carboxylates as in J. Org. Chem..
  • Y is H, F, Cl, CF 3 , CH 3 , or OCH 3 ;
  • X is halogen, hydrogen, or (C j - C 3 )alkyl
  • R and R' are as defined herein; and R4 is as defined herein. - 25
  • the intermediates 2.4,5.6-tetrahydro- l H-[ l J]benzod ⁇ azep ⁇ nes 39 and 38 may be prepared from glycine esters in the manner exemplified in Reaction Scheme 7
  • 10.160-161, 8 194 affords the dimethylaminomethyl (Mannich type) compounds as intermediates for elimination to the "dehydroalanine" derivatives 37 or direct ring closure of 36 to 39 via an e minauon- addition reaction Ring closure of compounds 37 provides intermediates 38 for conversion to hydroxamic acids Variations of the reactions conditions for conversion of 36 to 39 involve heating in the presence of Lewis acids, such as BF3, or heating an acid salt of 36 to effect the elimination-addition reacuon.
  • Lewis acids such as BF3
  • an acid salt of 36 to effect the elimination-addition reacuon.
  • inte ⁇ nediate carboxylic acids for conversion to the tetrahydro[ 1 ,4]benzodiazepine-3-carboxylic acid, hydroxyamides may be synthesized via different routes as shown in Schemes 1-8.
  • alternate routes may be preferred as shown in Scheme 8.
  • intermediate carboxylate esters of Intermediate 41 or acids of Intermediate 44 wherein the R 4 substituent is an OH group are prepared.
  • Intermediates with R 4 an OH group may be prepared from derivatives wherein the OH group is protected by a group which can be selectively removed.
  • Derivatives 40 wherein R 4 is an OCH 3 moiety are suitable precursors to the desired phenolic compounds 41 and 44 through cleavage of the oxygen methyl bond.
  • the anion of the phenolic OH group may be prepared in situ and then alkylated.
  • Suitable bases are alkaline metal carbonates, hydrides, alkoxides and organic bases.
  • Reaction with an alkylating moiety represented by the Formula (C r C 6 )alkyl-X wherein X is a reactive leaving group such as a chloride, bromide, iodide, O-mesylate of an O-to.sylate gives the derivatives 42 and 45.
  • the alkylation reaction may be carried out with caboxylate esters such as 41 or with the carboxylic acids such as 44.
  • the phenolic compounds 41 and 44 may be reacted under Mitsunobe Reaction conditions to afford the O-alkylated derivatives 42 and 45.
  • Standard Mitsunobe Reaction conditions such as those described in the following literature references, may be used in the coupling reactions: J. Heterocvclic Chem. 34:349 (1997); Tetrahedron Lett. 37:6439 (1996); J. Org. Chem.. 56:7173 (1991); Tetrahedron Lett. 5709 (1989); Synthesis 1:28 (1981).
  • the compounds of the present invention which have a basic moiety may be used in the form of salts derived from pharmaceutically or physiologically acceptable acids.
  • These salts include, but are not limited to, salts with inorganic acids (such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid) or organic acids (such as acetic acid, oxalic acid, succinic acid, and maleic acid).
  • Other salts of compounds with an acidic moiety include those with alkali metals or alkaline earth metals (such as sodium, potassium, calcium, and magnesium) or organic bases.
  • compositions containing the present compounds may be administered orally, in the form of tablets, capsules, dispersible powders, granules, suspensions, syrups or elixirs; parentally, in the form of a sterile injectable solution or suspension; or topically, in the form of creams, lotions, ointments, etc.
  • Such pharmaceutical compositions may contain from about 1 to about 100 mg of active in "gt>r A edient in combination with the carrier.
  • the effective dosage of the present compounds utilized to treat a specific condition will vary depending upon the particular compound employed, the mode of administration and the type and severity of the condition being treated. However, in general, satisfactory results are obtained when the present compounds are administered at a dosage of about 0.001 to 1000 mg kg of body weight.
  • the compounds of the present invention may be administered orally, as well as by intravenous, intramuscular, subcutaneous or topical routes.
  • Solid carriers useful for preparing tablets, capsules, etc. include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin.
  • Liquid carriers useful for preparing compositions of the present compounds include sterile water, polyethylene, glycols, non-ionic surfactants, and edible oils such as corn, sesame, and peanut oils.
  • Adjuvants conventionally used in the preparation of pharmaceutical compositions may also be included, such as flavoring agents, coloring agents, preservatives and antioxidants.
  • the compounds of the present invention were tested for biological activity according to the following procedures. - 30 -
  • the assay is based on the cleavage of the thiopeptide substrate ((Ac-Pro-Leu- Gly(2-mercapto-4-methyl-pentanoyl)-Leu-Gly-OEt), available from Bachem Bioscience) by the enzyme gelatinase, releasing the substrate product which reacts colorimetrically with DTNB ((5,5'-dithio-bis(2-nitro-benzoic acid)).
  • DTNB (5,5'-dithio-bis(2-nitro-benzoic acid)
  • the thiopeptide substrate was made up fresh as a 20 mM stock in 100% DMSO and the DTNB was dissolved in 100% DMSO as a 100 mM stock and stored in the dark at room temperature.
  • the substrate and the DTNB were diluted together to 1 mM with substrate buffer (50 mM HEPES, pH 7.5, 5 mM CaCl2) before use.
  • substrate buffer 50 mM HEPES, pH 7.5, 5 mM CaCl2
  • the stock of human neutrophil gelatinase B was diluted with assay buffer (50 mM HEPES, pH 7.5, 5 mM CaCl2, 0.02% Brij) to a final concentration of 0J5 nM.
  • the assay buffer, enzyme, DTNB/substrate (500 ⁇ M final concentration) and vehicle or inhibitor were added to a 96 well plate (total reaction volume of 200 ⁇ l) and the increase in color was monitored spectrophotometrically for 5 minutes at 405 nm on a plate reader.
  • the increase in OD405 was plotted and the slope of the line was calculated.
  • the slope represents the reaction rate.
  • the lineaiity of the reaction rate was confirmed (fi >0.85) and the mean (x ⁇ sem) of the control rate was calculated and compared for statistical significance (p ⁇ 0.05) with drug-treated rates using Dunnett's multiple comparison test.
  • Dose-response relationships were generated using multiple doses of drug and IC50 values with 95% CI were estimated using linear regression (IPRED, HTB).
  • This assay was based on the cleavage of a peptide substrate ((Dnp-Pro-Cha- Gly-Cys(Me)-His-Ala-Lys(NMa)-NH2), available from Peptide International, Inc.) by collagenase releasing the fluorescent NMa group which was quantitated on the fluorometer as disclosed in Bickett et al., "A High Throughput Fluorogenic Substrate - 31 -
  • MMP-1 Interstitial Collagenase
  • MMP-2 Gelatinase
  • Dnp quenches the NMa fluorescence in the intact substrate.
  • the substrate was dissolved in methanol and stored frozen in 1 mM aliquots. Collagenase was stored frozen in buffer in 25 ⁇ M aliquots.
  • the substrate was dissolved in HCBC buffer to a final concenttation of 10 ⁇ M and collagenase to a final concentration of 5 nM.
  • the compounds being examined were dissolved in methanol, DMSO, or HCBC.
  • the methanol and DMSO were diluted in HCBC to ⁇ 1.0%.
  • the compounds were added to a 96 well plate containing enzyme and the reaction was started by the addition of substrate.
  • the reaction was read (excitation 340 nm. emission 444 nm) for 10 min. and the increase in fluorescence over time was plotted as a linear line. The slope of the line was calculated representing the reaction rate. The linearity of the reaction rate was confirmed (r ⁇ >0.85). The mean (x ⁇ sem) of the control rate was calculated and compared for statistical significance (p ⁇ 0.05) with drug-treated rates using Dunnett's multiple comparison test. Dose-response relationships were generated using multiple doses of drug and IC50 values with 95% CI were estimated using linear regression.
  • each well received a solution composed of 10 ⁇ L TACE (available from Immunex) at a final concentration of l ⁇ g/mL, 70 ⁇ L Tris buffer, have a pH of 7.4 and containing 10% glycerol (final concentration 10 mM), and 10 ⁇ L of test compound solution in DMSO (final concentration l ⁇ M, DMSO concentration ⁇ 1%).
  • the plates were incubated for 10 minutes at room temperature.
  • the reaction was initiated by addition of a fluorescent peptidyl substrate (final concentration 100 ⁇ M) to each well with shaking on a shaker for 5 sec.
  • the reaction was read (excitation 340 nm, emission 420 nm) for 10 min. and the increase in fluorescence over time was plotted as a linear line. The slope of the line was calculated and this represents the reaction rate. The linearity of the reaction rate was confirmed (r ⁇ >0.85). The mean (x ⁇ sem) of the control rate was calculated and compared for statistical significance (p ⁇ 0.05) with drug-treated rates using Dunnett's -32-
  • the following intermediate compounds can be prepared from the appropriately unsubstituted methyl 2- [(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate or the appropriately substituted methyl 2-[(substituted-2-aminobenzyl)-(4-methoxybenzene- sulfonyl)amino]-3-hydroxypropionate.

Abstract

Compounds are provided having formula (I), wherein R, R1, R2, R3 and R4 are defined in the specification, which have matrix metalloproteinase inhibiting activity.

Description

- 1
2,3,4,5-TETRAHYDRO-lH-[l,4]-BENZODIAZEPINE-3-HYDROXAMIC ACIDS AS MATRIX METALLOPROTEINASE INHIBITORS
5
FIELD OF INVENTION
This invention relates to 4-(4-substituted-benzenesulfonyl)-2,3,4,5-tetrahydro- lH-[l,4]benzodiazepine-3-hydroxyamic acids which act as matrix metalloproteinase
10 inhibitors. The compounds of the present invention are useful in disease conditions mediated by matrix metalloproteinases, such as tumor growth, osteoarthritis, rheumatoid arthritis and degenerative cartilage loss.
BACKGROUND OF THE INVENTION
15 Matrix metalloproteinases (MMPs) are a group of enzymes that have been implicated in the pathological destruction of connective tissue and basement membranes. These zinc-containing endopeptidases consist of several subsets of enzymes, including collagenases, stromelysins and gelatinases. Of these, the gelatinases have been shown to be the MMPs most intimately involved with the growth
20 and spread of tumors.
For example, it is known that the level of expression of gelatinase is elevated in malignancies, and that gelatinase can degrade the basement membrane which leads to tumor metastasis. Angiogenesis, required for the growth of solid tumors, has also 25 recently been shown to have a gelatinase component to its pathology as reported in "Matrix Metalloproteinases, Novel Targets for Directed Cancer Therapy", Drugs and Aging. 11:229-244 (1997).
Other conditions mediated by MMPs include restenosis, MMP-mediated 30 osteopenias, inflammatory diseases of the central nervous system, skin aging, osteoarthritis, rheumatoid arthritis, septic arthritis, corneal ulceration, abnormal wound healing, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system, cirrhosis of the liver, glomerular disease of the kidney, premature rupture of fetal 35 membranes, inflammatory bowel disease, periodontal disease, age-related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of - 2 -
prematurity, ocular inflammation, keratoconus, Sjogren's syndrome, myopia, ocular tumors. ocular angiogenesis/ neo-vascularization and corneal graft rejection. Studies relating to these conditions are set forth, e.g., in "Recent Advances in Matrix Metalloproteinase Inhibitor Research", R. P. Beckett et al., Research Focus. 1 : 16-26, (1996); Curr. Opin. Ther. Patents. 4(1): 7-16, (1994); Curr. Medicinal Chem.. 2: 743- 762, (1995); Exp. Opin. Ther. Patents. 5(2): 1087-1 10, ( 1995); Exp. Opin. Ther. Patents. 5(12): 1287-1196, (1995); "Inhibition of Matrix Metallo-proteinases: Structure Based Design", Current Pharmaceutical Design. 2:524-661 , (1996). "Matrix Metalloproteinase Inhibitor Drugs", Emerging Drugs. 2:205-230 (1997).
TNF-α converting enzyme (TACE) catalyzes the formation of TNF- from membrane bound TNF-α precursor protein. TNF-α is a pro-inflammatory cytokine that is believed to have a role in rheumatoid arthritis, septic shock, graft rejection, cachexia, anorexia, inflammation, congestive heart failure, inflammatory disease of the central nervous system, inflammatory bowel disease, insulin resistance and HIN infection, in addition to its well-documented antitumor properties. Research with anti-TΝF-α antibodies in transgenic animals has demonstrated that blocking the formation of TΝF-α inhibits the progression of arthritis. This observation has recently been extended to humans as described in "TΝF-α in Human Diseases", Current Pharmaceutical Design. 2:662-667 (1996).
It is expected that small molecule inhibitors of MMPs and TACE would have the potential for treating a variety of disease states. Although a variety of MMP and TACE inhibitors are known, many of these molecules are peptidic and peptide-like which demonstrate bioavailability and pharmacokinetic problems. Long acting, orally bioavailable non-peptide inhibitors of MMPs and/or TACE would thus be highly desirable for the treatment of the disease states discussed above.
U.S. Patent No, 5,455,258 discloses 2-substituted-2-(arylsulfonylamino) hydroxyamic acids and their use as MMP inhibitors. WO 97/18194, discloses N- (arylsulfonyl)tetrahydroisoquinolone-hydroxyamic acids and related bicyclic derivatives thereof and their use as MMP inhibitors. WO 97/20824 discloses l-(arylsulfonyl)-4- (substituted)piperazine-2-hydroxyamic acids, 4-(arylsulfonyl) morpholine-3- hydroxyamic acids, 4-(arylsulfonyl)-tetrahydro-2HJ,4-thiazine-3-hydroxyamic acids, 3-(substituted-l-(arylsulfonyl)hexahydro-2 -hydroxyamic acids and related compounds as useful MMP inhibitors. - 3 -
SUMMARY OF THE INVENTION
This invention relates to novel derivatives of substituted 2.3,4.5-tetrahydro-lH- [l,4]benzodiazepine-3-carboxylic acid hydroxyamide which exhibit inhibitory activity against MMPs. The compounds of the present invention are represented by the following formula 1
HOHN
Figure imgf000005_0001
1
wherein R is selected from hydrogen, (Cj - C3) alkyl, -CN, -OR', -SR', -CF3 -OCF3, Cl, F, NH2, NH(Cj - C3)alkyl, -N^CO^ - C3)alkyl, -N(R')(R'), NO2, -CONH2, -SO2NH2, -SO2N(R')(R'), or -N(R')COCH2O-(C1 - C3)alkyl, wherein R' is (Cl - C3) alkyl or hydrogen;
R4 is (Ci - C6) alkyl-O-, (C, - C6) alkyl-S-, o ^s -R.
S
-c^J Λ
Figure imgf000005_0002
-O- \-R" , —S-ζ V- R or
\ ) *\ wherein R is hydrogen, halogen, cyano, methyl or -OCH3;
Rl and R2 are each, independently, hydrogen or CH3;
R3 is (C, - C8)alkyl, NH2CH2CO-, (Cj - C6)alkylNHCH2CO-. HO(CH2)mCO-,
HCO-, Aryl(CH2)nCO-, Heteroaryl(CH2)nCO-, (Cx - C3)alkyl-O-(CH2)nCO-,
(Cj - C3)alkylCO-, (Cλ - C3)alkylCO-NHCH2CO-, (C3 - C7)cycloalkylCO-, - 4 -
(C[ - C3)alkyISO2-. Aryl(CH2)nSO2-, Heteroaryl(CH2)nSO2-. (C, - C3)alkyl-O- (CH2)m-SO2-, (C, - C3)alkyl-O-(CH2)m, (C, - C3)alkyl-O-(C, - C3)alkyl-O-(C, - C3)alkyl. HO-(C , - C3)alkyl-O-(Cι - C3)alkyl. Aryl-O-CH2CO-. Heteroaryl-O-CH2CO-, ArylCH=CHCO-. HeteroarylCH=CHCO-. (C, - C3)alkylCH=CHCO-,
O O
II II
CH^OC- . or CH OC-NHCHoCO-
Aryl(C, - C3)alkyl, Heteroaryl(Cι - C3)alkyl, ArylCH=CHCH2-, HeteroarylCH=CHCH2-. (C, - C6)alkylCH=CHCH2-,
A\ Y ^ M
,V_ 7 CO-
Mμ 0- CO¬
^A
CO-
Figure imgf000006_0001
Figure imgf000006_0002
R'OCH2 CH(OR')CO-, (R'OCH2)2C(R')CO-,
CH3-N N(C, - C3)alkylCH=CH-CO- , O N-(C, - C6)alkylCO-
J N-(C, - C6)alkylCO- . (C, - C3)alkylCONHCO-, N-(C , -Chalky 1CO-
O N-(C, - C6)alkylCO- N-(C,-C6)alkylCO- ,N-(C|-C6)alkyiCO-
/
N N
- C6)alkylCO- , t-Boc-N N-(C, - C^alkylCO-
O ll
EtOC \J N(C, - C6)alkylCO-
Figure imgf000006_0003
- 5
N_ R" -(C] - C6)alkylCO-
Figure imgf000007_0001
CH3
Figure imgf000007_0002
CO-
[(C, - C6)alkyl]2-N-(Cι - C6)alkyl CO-, or (C, - C6)alkyl-NH-(Cι - C6)alkylCO-; wherein m = 1 to 3; n = 0 to 3;
Aryl is
X and
Figure imgf000007_0003
R
Heteroaryl is
X X
S>
'N o
X* • N v>
V £ ■ ■ N
N I> o
R'
X or
O I N A , N
I \ IAX R' R' wherein X is hydrogen, halogen, (Cj - C3) alkyl or -OCH3 and R and R' are as defined above;
L is hydrogen, (CrC3)alkyl, -CN, -OR', -SR', -CF3, -OCF3, Cl , F, NH2, -NH-(C, - C3)alkyl, -N(R')CO(Cι - C3)alkyl, N(R')(R'), -NO2, -CONH2, -SO2NH2, -SO2N(R')(R'), -N(R')COCH2O-(Cι - C3)alkyl,
X=\ Y^Γ-^CONH- Y. ^-^CONH-
7 §-J-∞ - . X? -r XQ ; - 6 -
M is
Figure imgf000008_0001
N A?
n
N
Ό 'N N I
R'
^ • x >γ
N 1 > ~ R' R'
R'- N N-
Figure imgf000008_0002
tBoc — N N—
Figure imgf000008_0003
' DN- '
N— , or N(R')(R') where R' is as defined above;
W is O, S, NH or N(C, - C3)alkyl;
Y is hydrogen, F, Cl, CF3 or OCH3; and X' is halogen, hydrogen, (Cj - C3)alkyl, O-
(C! - C3)alkyl, or -CH2OH; and pharmaceutically acceptable salts thereof. When used herein the term -C3 alkyl covers methyl, ethyl, n-propyl and i-propyl groups. When used herein the term -C6 alkyl covers, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl and pentyl groups. When used herein the term C3-C7 cycloalkyl covers saturated and unsaturated cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-cyclopropenyl, 2-cyclopropenyl, 1-cyclobutenyl and 2-cyclobutenyl.
R is suitably hydrogen, halogen or (Ci-C3)alkyl, for example hydrogen, chloro or methyl. Rl is suitably hydrogen. R2 is suitably hydrogen. R4 is suitably ( -C alkyl)-O-, for example methoxy. R3 is suitably selected from the group: (Cι-C3)alkyl- SO2-, aryl(CH2)nSO2-, (Cι-C3)alkyl-CO-, aryl(CH2)nCO-, heteroaryl(CH2)nCO-, - 7 -
(Cι-C3)alkyl-O-(CH2)nCO-, (C3-C7)cycloalkyl-CO-, (Cι-C3)alkyl-O-(CH2)m- or aryl(Cι-C3)alkyl-) for example methyl sulphonyl, n-propylsulphonyl, 4-methyl- phenylsulphonyl, 4-methoxyphenylsulponyl, methylcarbonyl, 3- trifluormethylcarbonyl, 2-phenylethylcarbonyl, methoxymethylcarbonyl, cyclopropylcarbonyl, cyclohexylcarbonyl, 2-methoxyethyl? phenylcarbonyl, 2-methyl-
5-fluorophenylcarbonyl, 4-biphenylcarbonyl, 2-biphenylcarbonyl, 2,4- dichlorophenylcarbonyl, phenoxymethylcarbonyl, phenylcarbonyl, 4- trifluoromethylphenylcarbonyl, 2-imidazol- 1 -yl-phenylcarbonyl, 2-morpholin-4-yl- phenylcarbonyl, 4-ethoxyphenylcarbonyl, 4-(4-methyl-imidazol- 1 -yl)-2-choloro- phenylcarbonyl, 2,4-dimethoxyphenylcarbonyl, 4-methyl-piperazin-l- ylmethylcarbonyl, 3-pyridinylcarbonyl, 2-thienylcarbonyl, 4-pyridinylcarbonyl, 2- furanylcarbonyl or benzyl.
Preferably, the compounds of the present invention are those of formula 1 wherein R is hydrogen, (C} - C3) alkyl, -CN, -OR', -SR', -CF3; -OCF3, Cl, F, NH2, NH(Cι - C3)alkyl, -N(R')CO(Cι - C3)alkyl, -N(R')(R'), NO2,
-CONH2, -SO2NH2, -SO2N(R')(R'), or -N(R')COCH2O-(Cι - C3)alkyl, wherein R ' is (Ci - C3) alkyl or hydrogen;
R4 is (C, - C6) alkyl-O-, (Ci - C6) alkyl-S-,
_^
Figure imgf000009_0001
yn -R
V >
R K,ι - .R R., R,
S ^Λ
N J -^ AΛ
"N
R- , - —J S— ( l , or
Figure imgf000009_0003
Figure imgf000009_0004
Γ
Figure imgf000009_0005
R" , wherein R is hydrogen, halogen, cyano, methyl or -OCH3;
Rl and R2 are each, independently, hydrogen or CH3;
R3 is (Ci - C8)alkyl, NH2CH2CO-, (Cj - C6)alkylNHCH2CO-, HO(CH2)mCO-, HCO-, Aryl(CH2)nCO-, Heteroaryl(CH2)nCO-, (Cj - C3)alkyl-O-(CH2)nCO-, (Cj - C3)alkylCO-, (Ci - C3)alkylCO-NHCH2CO-, (C3 - C7)cycloalkylCO-, Aryl-O-CH2CO-, HeteroarylOCH2CO-, ArylCH=CHCO-, HeteroarylCH=CHCO-, (Ci - C3)alkylCH=CHCO-, - 8
O
A II ϊ?
CH2OC- CH^OC-NHCH CO-
Figure imgf000010_0001
wherein m = 1 to 3; n = 0 to 3;
Aryl is
and
Figure imgf000010_0002
Heteroaryl is
X
C -X > y> O x
T A AΪ~ N
N O
Ii
R'
X s A .
.N or
O N N
I
R' R'
wherein X is hydrogen, halogen, (C\ - C3) alkyl or -OCH3 wherein R and R' are as defined above; and pharmaceutically acceptable salts thereof.
More preferably, the compounds of the present invention are those of formula 1 wherein R is hydrogen, (Cλ - C3) alkyl, -CN, -OR', -SR', -CF3 -OCF3, Cl, F, NH2,
NH(C, - C3)alkyl, -N(R')CO(C, - C3)alkyl, -N(R*)(R'), NO2, -CONH2, -SO2NH2, -SO2N(R')(R'), -N(R')COCH2O-(Cι - C3)alkyl, wherein R' is (Cx - C3) alkyl or hydrogen;
R4 is (Cj - C6) alkyl-O-, (C, - C6) alkyl-S-, - 9 -
Figure imgf000011_0001
R, R,
Figure imgf000011_0002
AΛ.
Figure imgf000011_0003
• - ^
N J A
^
N J
, -S-CS-Ϊ ,or
Figure imgf000011_0004
-O wherein R is hydrogen, halogen, cyano, methyl or -OCH3;
Rl and R2 are each, independently, hydrogen or CH3; R3 is
CH3-N N(C, - C3)alkylCH=CH-CO- , O N-(C, - C6)alkylCO- ,
S N-(C, - C6)alkylCO- JCι - C3)alkylCONHCO-, N-(C j -Chalky ICO- ,
CN-(Cι - C6)alkylCO- , N-(C,-C6)alkylCO- , | NJCr alkylCO- ,
^N N=/
/ \ / \ N(Cj - C6)alkylCO- , t-Boc-N N-(Cj - C^alkylCO- >
O
EtOCN N(Cj - C^alkylCO- ,
Figure imgf000011_0005
R- O ' CO-
[(C, - C6)alkyl]2-N-(Cι - C6)alkyl CO-, or (Ci - C6)alkyl-NH-(Cι - C6)alkylCO-, wherein R' is as defined above; and pharmaceutically acceptable salts thereof. - 10 -
It is more preferred that the compounds of the present invention include those of formula 1 wherein R is hydrogen, (C, - C3) alkyl, -CN, -OR', -SR'. -CF3ι -OCF3, Cl, F, NH2, NH(Cι - C3)alkyl, -N(R')CO(C1 - C3)alkyl, -N(R')(R'), NO2, -CONH2, -SO2NH2, -SO2N(R')(R'), or -N(R')COCH2O-(Cι - C3)alkyl, wherein R' is (Cj - C3) alkyl or hydrogen;
R4 is ( - C6) alkyl-O-, (C] - C6) alkyl-S-,
O ^ rV\ιirTl s_ ■,Rι- - -OrvA Ii
^s ■R
O
Ri . .Ri R,
-
Figure imgf000012_0001
A ■ ) --ø N
-^Tγ_ „- . R , or
Figure imgf000012_0002
Figure imgf000012_0003
\ ) R, wherein R is hydrogen, halogen, cyano, methyl or -OCH3;
R] and R2 are each, independently hydrogen or CH3;
R3 is (Cj - C3)alkylSO2-, Aryl(CH2)nSO2-, Heteroaryl(CH2)nSO2-, or (Cj - C3)alkyl- O-(CH2)m-SO2, wherein m = 1 to 3; n = 0 to 3; Aryl is
Figure imgf000012_0004
- 11 -
Heteroaryl is
X X
N
X Έ> N v O
• >
N O sfi— N
O
I
R'
X
\Γ ^ y^x
O N N i i
R' R' wherein X is hydrogen, halogen, (Ci - C3) alkyl or -OCH3 and R and R' are as defined above; and pharmaceutically acceptable salts thereof.
A further, more preferred embodiment of the present invention includes compounds represented by formula 1 wherein
R is selected from hydrogen, (Cj - C3) alkyl, -CN, -OR', -SR', -CF3
-OCF3, Cl, F. NH2, NH(Cι - C3)alkyl, -N(R')CO(Cι - C3)alkyl, -N(R')(R'), NO2, -CONH2, -SO2NH2, -SO2N(R')(R'), or -N(R')COCH2O-(Cι " C3)alkyl, wherein R ' is (Ci - C3) alkyl or hydrogen;
R4 is (Cj - C6) alkyl-O-, (Ci - C6) alkyl-S-,
^ — / 0 -R, , C \ —= / »;s^ ~Rι
. ./Ri ^ .Ri Ri
Figure imgf000013_0001
_/ Ns^N • - --,,
N J - "N'
■R , — S— R , or
Figure imgf000013_0002
Figure imgf000013_0003
~" \. / " R, wherein R is hydrogen, halogen, cyano, methyl or -OCH3;
R] and R2 are each, independently hydrogen or CH3; R3 is (Cλ - C8)alkyl, Aryl(Cj - C3)alkyl, Heteroaryl(Cι - C3)alkyl, ArylCH=CHCH2, HeteroarylCH=CHCH2-, or (Cj - C6)alkylCH=CHCH2-, wherein 12
Aryl is
and
Figure imgf000014_0001
Heteroaryl is
X X
O x A
T \,— N
N O
Ii
R'
X or O N N
I x
I
R' R' wherein X is hydrogen, halogen, (Cj - C3) alkyl or -OCH3 and R and R' are as defined above; and pharmaceutically acceptable salts thereof.
Additionally preferred compounds of the present invention include those of formula 1 wherein R is hydrogen, ( - C3) alkyl, -CN, -OR', -SR', -CF3 -OCF3, Cl, F, NH2. NH(Cι - C3)alkyl, -N(R')CO(Cι - C3)alkyl, -N(R')(R'), NO2, -CONH2, - SO2NH2, -SO2N(R')(R'), or -N(R')COCH2O-(Cι - C3)alkyl, wherein R' is (Ci - C3) alkyl or hydrogen;
R4 is (Cj - C6) alkyl-O-, (Ci - C6) alkyl-S-,
A il •R,
Figure imgf000014_0002
ι= R, .R,
Figure imgf000014_0003
N^ A}
R
Figure imgf000014_0004
-O " or
■R , wherein R is hydrogen, halogen, cyano, methyl or -OCH3;
Figure imgf000014_0005
Ri and R2 are each, independently hydrogen or CH3; 13 -
R is
Y y M co- CO- CO-
,X—
Figure imgf000015_0001
Figure imgf000015_0002
^
M *N
M CO-
YJT '"JL CO.
Figure imgf000015_0004
Figure imgf000015_0005
M
CO- II ' _ιi_
, or CO-
Figure imgf000015_0003
s wherein m = 1 to 3; n = 0 to 3;
L is hydrogen, (Cx - C3)alkyl, -CN, -OR', -SR', -CF3, -OCF3, Cl, F, NH2,
-NH-(Cι - C3)alkyl, -N(R')CO(Cι - C3)alkyl, N(R')(R'), -NO2, -CONH2, -SO2NH2,
-SO2N(R')(R'), -N(R')COCH2O-(Cι - C3)alkyl,
T\ Yχ^^ 0NH- Y. r- CONH
O
M is
Figure imgf000015_0006
J ATA: N
^ > N • A N Ny ■ O'
I
R'
N I N
I R' R'
R,_Nv ,N" . \\ -rOCO-N N , < V - 14 -
tBoc — N-
Figure imgf000016_0001
Figure imgf000016_0002
— , or N(R')(R') where R' is as defined above;
W is O, S, NH or N(C, - C3)alkyl;
Y is hydrogen, F, Cl, CF3 or OCH3; and X' is halogen, hydrogen, (Ci - C3)alkyl, O- (Ci - C3)alkyl, or -CH2OH; and pharmaceutically acceptable salts thereof.
The compounds of the invention may be prepared by reacting an appropriate acid halide such as the acid chloride or bromide with hydroxylamine. The acid halide may be prepared by reacting the corresponding acid or a metal salt thereof with an activating agent such as oxalyl chloride, oxalyl bromide, thionyl chloride, thionyl bromide, (chloromethylene)dimethylammoniumchloride or (bromomethylene)dimethyl ammonium bromide. The subsequent reaction of the acid halide with hydroxylamine may suitably be performed in situ. Metal salts may be prepared by reacting a ester of formula Ia
Figure imgf000016_0004
la wherein R2J is (C^alkyl, benzyl or arylalkyl and all other groups are as defined above, with a base such as lithium hydroxide, potassium hydroxide, sodium hydroxide or barium hydroxide. This may suitably be performed in a solvent such as a (Cj-Cg) alcohol, tetrahydrofuran, N,N-dimethylformide or p-dioxane in the presence or absence of water. The resulting metal salt may be directly converted to the desired product or it may first be converted to the acid, e.g. by treating it with aqueous hydrochloric acid or acetic acid. Alternatively the ester of formula Ia may be converted to its acid by treatment with an aqueous mineral acid such as hydrochloric acid, hydrobromic acid or trifluoroacetic acid and the acid converted to the desired product as described above.
The compounds of formula 1 may be advantageously prepared according to Reaction Schemes 1 to 7. Variations in these schemes may be made to improve productivity without negatively impacting the amount and nature of the product, by - 15 -
means that will be recognized by those skilled in the art. For example, reactive groups may be blocked with suitable blocking moieties which may then be deblocked under standard conditions (for instance, hydroxy groups may be protected with trimethylsilyl or t-butyl-dimethylsilyl moieties which are then removed in a later reaction step). In general, the compounds of Formula 1 are synthesized from an alkyl ester
(such as methyl, ethyl, t-butyl and the like) of serine, threonine, or 3,3-dimethyl-3- hydroxypropionic acids. One reaction pathway is shown in Reaction Scheme 1. It is noted that methyl esters are shown in all of the Reaction Schemes, however, it is to be understood that the use of methyl esters is for puiposes of illustration only, and other suitable alkyl esters or benzyl esters may similarly be used.
In Reaction Scheme 1, serine, threonine, beta-hydroxyvaline and related derivatives are converted to the corresponding N-(4-substituted-benzenesulfonyl) derivatives 3 and alkylated with suitable substituted or unsubstituted 2-nitrobenzyl bromides or 2-nitrobenzyl chlorides to provide the corresponding nitro derivatives 5 . Reduction under conventional reducing conditions, such as catalytic hydrogeneration (with Pd/C) or chemical reduction (e.g., with SnCl2 or FeC^) results in amino derivatives 6. Reaction of the N- (2-aminobenzyl) derivatives 6 with alkanoyl chlorides, alkylsulfonyl chlorides, aroyl chlorides, heteroaroyl chlorides, aryl sulfonyl chlorides, heteroarylsulfonyl chlorides and the like, in the presence of trialkylamines or pyridene, provides the dihydroalanine derivatives 7. Ring closure to the [l,4]benzodiazepine compounds 9 is carried out by reaction with a mild base such as sodium or potassium bicarbonate in an alcohol solvent such as methanol or ethanol. Standard conditions which involve hydrolysis of the ester (NaOH), acid chloride formation and reaction of the acid chloride with hydroxylamine are then used to convert the ester derivatives 8 to the hydroxamic acids 9. Ester derivatives 8 (where the ester function is a t-butyl ester) are converted to the acid with trifluoroacetic acid under standard conditions.
As illustrated in Reaction Scheme 2, derivatives 10, which contain a blocked hydroxyl group, are alkylated with 2-nitro or 2-amino benzyl alcohol derivatives 11 by application of the Mitsunobu reaction to give intermediates 12. Reduction of the 2-nitro group and removal of the hydroxy blocking group with derivatives 12. where the R4 group is a protected amino moiety with simultaneous deblocking of the amino and hydroxyl functions, gives intermediate compounds 13. The intermediate 13 may then be reacted with benzyl oxycarbonyl chloride to give the closed ring [1.4] benzodiazepine 14. Reaction of this compound with acyl chlorides, aroyl chlorides, heteroaroyl chlorides, alky.sulfonyl chlorides, arylsulfonyl chlorides and heteroarylsulfonyl chlorides and the like results in the intermediates 15. 16 -
1
Figure imgf000018_0001
Ar(CH2^COCl Heteroaryl(CH 2
Ar(CH2)nS02Cl Alkyl-O-CH^COCl Alkyl-0-(CH2)S0
AlkylCOCl AlkylS02Cl Cycloalkyl( C3to C7) CO
Figure imgf000018_0003
8
( 1) OH * (2) C1COCOC1 , r (3) NH2OH
Figure imgf000018_0002
O I I SO
-T
HOHN Y' LO R
R,^
R2 ¥
Figure imgf000018_0004
R3
9 wherein n = 0 to 3; m = 1 to 3;
Rj = (Ci - C3)alkyl; R = Hydrogen; halogen; OCH3; NO2; NH2; CF3; NHCOCH3; NHCOCH2OCH3; CONH2; -N(R')(R'), -N(R')CO(Cι - C3)alkyl; (C! - C3)alkyl; R3 = Ar(CH2)nCO-; Heteroaryl(CH2)nCO-, Ar(CH2)nSO2-; Heteroaryl(CH2)nSO2-: Alkyl-O-CH2)nCO-; Alkyl-O-(CH2)mSO2-; AlkylCO-; AlkylSO2-; AlkylCO- NHCH2CO-; and cycloalkyl(C3 - C7)CO-; and R4 is as defined herein. 17
Scheme 2
o so o SO 4 II ,A\«,
II I Hη CH3OC\^i NH
CH ,OC NH o R
HO
Figure imgf000019_0001
0 M 1 CH2OH
Figure imgf000019_0004
10
11
R5 = -N02 t-BocNH- CH OCONH-
O o so7 R5 = N02 II
II I (l)H2;Pd/C
(2) H+
HO R5 = t-BocNH- (1)H+ ;TFA
12
Figure imgf000019_0005
Figure imgf000019_0002
Rs=^CH2OCONH-
Figure imgf000019_0003
or
Figure imgf000019_0006
14 -^SO 2C1 15 wherein n = 0 to 3; m= 1 to 3;
0 = phenyl;
DEAD = diethylazodicarboxylate;
R6 = Ar(CH2)n-; Alkyl-; Heteroaryl(CH2)n-;Alkyl-O-(CH2)n-; Cycloalkyl(C3 - C7);
R7 = Ar(CH2)n-; Alkyl-; Heteroaryl(CH2)n-; Alkyl-O-(CH2)m-;
Rg = Ar(CH2)nCO-; Ar(CH2)nSO2-; AlkylCO-; AlkylSO2-; Heteroaryl(CH2)nCO-;
Heteroaryl(CH2)nSO2-; Alkyl-O-(CH2)nCO-; Alkyl-O-(CH2)mSO2-. - 18 -
1 -substituted arylmethyl-2,3,4,5-tetrahydro-lH [1.4]-benzodiazepines may be prepared in the manner illustrated in Reaction Schemes 3 and 4. In Reaction Scheme 3. the methyl 3-hydroxy-2-[4-methoxybenzenesulfonyl)-(2-aminobenzyl)amino]- propionates 6 are subjected to reductive alkylation with arylcarboxaldehydes and heteroaiylcarboxaldehydes to provide intermediates 17. Standard reaction conditions such as reactions with triphenylphosphine and diethyl azodicarboxylate (DEAD) or triplenylphosphine with either carbon tetrachloride or carbon tetrabromide, results in the
"dehydroalanine" derivatives 18 which are then ring closed to the [l,4]benzodiazepines
20.
In an alternative route to the 3-hydroxamic acid derivatives 21 (Scheme 4), N- aroyl derivatives 22 are reduced with reducing agents such as borane or lithium aluminum hydride to reduce both the ester and amide functions. The 3-
(hydroxymethyl)-l-(arylmethyl)-2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine 23 are oxidized with stardard reagents known to convert a hydroxymethyl group to a carboxy lie acid:reagents such as NaIO4 with catalyst Ruθ2 (e.g., see J. Or . Chem..
46:3936 (1981); Synlett, p. 143, (1996)). Coupling the acids (via the acid chlorides) to hydroxylamine then gives products 21. Certain intermediates as exemplified by formula 25 may be reduced with borane under mild conditions to give derivatives 25a in which the amide carbonyl is selectively reduced. These intermediates 25a are then converted to hydroxamic acid derivatives via hydrolysis of the ester to the acid and coupling the acid chloride with hydroxylamine.
19
Scheme 3
SO ft 2Q>-R4
CH3OC ^" N
R
HO y" .
R2 H
Figure imgf000021_0001
Figure imgf000021_0002
NaCNBH3 HOAc
ft SO I 2 v // ΛR44
HO ^ Rl K2
Figure imgf000021_0004
CH2Ar
17
(C6H5 )3P
CC1
Figure imgf000021_0003
CH.O
O °2 KN R-i HO, ^N.
Figure imgf000021_0005
8 RΛ ^ R wherein 21 CH-^Ar
R9 Ar = R° t rfllA^^ R i ιo or
R9 N R9 S ' O
R-o ; and 9 and R 10are: Cl, Br, F, OCH3 , OEt , SCH 3 , COCH
<? — *-'
I' o II
COEt, CF3 ,OCF3 ,CNH2 . -NHCOCH3 ,orMe2N-. -20
Scheme 4
f? SO R4
&
CH3OC. N. HOCH2\^N
BH. R "1 o
RA^ R R, I.J^ CH2Ar
23
O SO- RΛ
HO 11
\ N- H o- R
R? Λ N- /
I
CH^r 21
Figure imgf000022_0001
wherein R RQ
/ 10 \ R -10 RQ
RQ Rt R,
Ar = •Ό 7* • β or
R9 R« S °
f - fh'29 R , and R9 and RJO are hydrogen ,C1, Br, F, OCH3 , OEt
^ > O o
II
SCH 3 , COCH COEt , CF3 , OCF3 , or Me2N-.
fj> ?°2 R4
CH3OC- N i. α RΛ f? SO
J
CH.OC^
R BH„
R>
Figure imgf000022_0002
A A
R2
Figure imgf000022_0003
O^^Rg CH2R8
25 25a wherein R8 = alkyl, arylalkyi, aryloxyalkyl, heterocyclicalkyl, or alkyloxyalkyloxyalkyl. - 21 -
Other, preferred compounds of the present invention are those with basic moieties in the 1 -(substituted carbonyl) group which may be prepared in the manner shown in Reaction Scheme 5. Reaction of the 2.3.4,5-tetrahydro- lH-[ 1.4]- benzodiazepines 14 (without a substituent at the 1 -position) with carbonyl chloride derivatives in the manner depicted in Reaction Scheme 5, results in intermediates 25 which are then converted to acid 26 and hydroxamic acids 27. The intermediates 25 may also be synthesized by reaction of methyl 2-[(2-aminobenzyl)-(4- methoxybenzenesulfonyl) amino]-3-hydroxypropionates 6 with acid chlorides to give "dehydroalanine" derivatives 28. As previously described, mild bases such as NaHCO3 can be reacted with these derivatives to cause ring closure via a 1.4- addition to the double bond in intermediate 28 to provide the 7-membered 2,3.4,5-tetrahydro- 1H-[1 ,4] diazepines 25.
22
Scheme 5
i? SO 4 so
&
CH„OC CH30 iC? N-
RoCOCl Ό^
R ■X > -
R N
Figure imgf000024_0001
o
Et3N or pyridine R<7 R
14 o
25
Wherein R8= o N-<CH.)- \ / 2 n -(CH2)-
OH-
S N-(CH0)- \_J 2 " N- N~(CH2) n-
CH3- _ JKCH2)n- N-(CH2)-
CH3
[CH3(CH2)n]2^CH2)- O t-BocN N-(CH-)-
EtOC-N |-<CH2)- x ' O
0CH2OC- and n
Figure imgf000024_0002
- 23 -
As illustrated in Reaction Scheme 6, aryl-arylcarbonyl, heteroaryl-arylcarbonyl. aryl-heteroarylcarbonyl, heteroaryl-heteroarylcarbonyl derivatives 30 may be synthesized by standard palladium catalysed coupling of bromoaiOyl or bromheteroaroyl derivatives 29 with appropriate arylstannanes, heteroarylstannanes, arylboronic acids, heteroarylboronic acids, aryl triflates, heteroaryl triflates and the like. under known conditions. For example, see Synthesis. 563-566 (1997); J. Org. Chem.. 62:3405-3406, (1997); Tetrahedron Lett.. 36:5247-5250, ( 1995);
Heterocycles. 45:467, (1997); Tetrahedron Lett.. 38: 11 18-1 182, (1997); Heterocycles.
42: 189-194, (1996); Tetrahedron Lett.. 5005-5006, (1993); Synthesis. 843, ( 1987);
Heterocycles. 2711-2716, (1987); and Tetrahedron Lett.. 4407-4410, (1986).
By coupling with such palladium catalysts, aryl-aryl, heteroaryl-aryl, aryl- heteroaryl and heteroaryl-heteroaryl carboxylic ester derivatives can be prepared and these derivatives converted to carboxylic acid intermediates. The acids are then converted to acid chlorides which are reacted with esters of 2- [(2-aminobenzyl)-(4- substituted-benzenesulfonyl)amino]-3-hydroxypropionate as illustrated for conversion of derivatives 6 to intermediates 31. The following references describe procedures for the synthesis of methyl 3-arylpyrrole-4-carboxylates as in J. Org. Chem.. 62:2649- 2651, (1997); methyl (2-methylphenyl) benzoates as in J. Ore. Chem.. 62:3405-3406, (1997); and methyl benzoates substitued with heterocyclic moieties such as furanyl, thienyl or pyridinyl groups as in Tetrahedron Lett.. 27:4407-4410, (1986).
24
Scheme 6
O SO W II r * W
W
CH OC. .N
R
R Ώ etc
+ W= B(OH)2 ; SnMe- ; Sn(n-butyl)3 ;
0 Ar"
O-Triflate; ZnCl ; or ZnBr; 29
Br
Λ Λ//YY
Ar'- 1
-:0 c T Y\τh ^ , or O o
Br
Pd(PPh3)4 or Pd(PPh3) Cl2 or
Figure imgf000026_0001
j equivalent Pd catalyst
Cl
0 SO O SO II I II O CH3OC- ,N CH,OC
Figure imgf000026_0003
Rι Y o- R,
R ~ Et3N
V,v o- L or
R N- 2 I Cl
O" Ar" A
O Ar"
30
Figure imgf000026_0002
M
Y where Ar' >r\ or (Λ -^
O
T M
X ^_ Y Lis ~~ YN^ -CONH- CONH-. ^J^CONH- , oorr - ^^
M is
Y N Λ Y ^ γ\r ^ v^ SΓ1!
N I R' V N I R'
Y is H, F, Cl, CF3, CH3, or OCH3;
X is halogen, hydrogen, or (Cj - C3)alkyl;
R and R' are as defined herein; and R4 is as defined herein. - 25
The intermediates 2.4,5.6-tetrahydro- l H-[ l J]benzodιazepιnes 39 and 38 may be prepared from glycine esters in the manner exemplified in Reaction Scheme 7 In this synthetic route, N-(4-substιtuted-benzenesulfonyl) denvatives of glycine ethyl ester, glycine t-butyl ester or glycine methyl ester 33 are alkylated with a substituted (R) or unsubstituted (R=H) 2-nιtrobenzyl bromide in N.N-dtmethylformamide or 1-methyl- 2-pyrrolιdιnone in the presence of potassium carbonate to give intermediates 34 Alternatively, the esters of N-(4-substιtuted-benzenesulfonyl) glycines. such as the methyl ester 33. are first reacted with sodium hydride in N. N-dimethylformamide or 1- methyl-2-pyrrolιdιnone and the resulting anion reacted with substituted or unsubstituted 2-nιtrobenzylbromιdes to provide compounds 34 Reaction of deπvates 34 with N,N- dιmethyl(methylene)ammonιum chloπde or the iodide salts under standard reaction conditions (e g , as set forth in Fieser and Fieser. 10.160-161, 8 194 affords the dimethylaminomethyl (Mannich type) compounds as intermediates for elimination to the "dehydroalanine" derivatives 37 or direct ring closure of 36 to 39 via an e minauon- addition reaction Ring closure of compounds 37 provides intermediates 38 for conversion to hydroxamic acids Variations of the reactions conditions for conversion of 36 to 39 involve heating in the presence of Lewis acids, such as BF3, or heating an acid salt of 36 to effect the elimination-addition reacuon.
-26
Scheme 7
O O _
CH3OCCH9NH9 + C1SO D^ 4 O^OCCT^NHSO VR4
33 CH2Br
32 ' .NO?
^
O
II R
CH3OCCH2JxJ- SO2— ^ RΛ CH2
NH2 HZ CH3OCCH2N-SO2-^ ~R4
ZAZ CH, Pd/C NO,
35
+
Figure imgf000028_0002
CH2 = N(CH3)2C1- or 34 CH2 = N(CH3)2I-
O
O SO^ R,
CT OCCH-N-SO r _ R4
I I CE^OC^^ (CH3)2N-CH2 CH2
R
NH2- j ^
Figure imgf000028_0003
36 R
37
.
.
CH XJ N-, C^OC. N-
R
^JAR R3
39 Ah 38 - 27 -
The inteπnediate carboxylic acids for conversion to the tetrahydro[ 1 ,4]benzodiazepine-3-carboxylic acid, hydroxyamides may be synthesized via different routes as shown in Schemes 1-8. For the synthesis of some of the desired products of Formula 1 , alternate routes may be preferred as shown in Scheme 8. Under these conditions, intermediate carboxylate esters of Intermediate 41 or acids of Intermediate 44 wherein the R4 substituent is an OH group are prepared. Intermediates with R4 an OH group may be prepared from derivatives wherein the OH group is protected by a group which can be selectively removed. Derivatives 40 wherein R4 is an OCH3 moiety are suitable precursors to the desired phenolic compounds 41 and 44 through cleavage of the oxygen methyl bond. As shown in Scheme 8. the anion of the phenolic OH group may be prepared in situ and then alkylated. Suitable bases are alkaline metal carbonates, hydrides, alkoxides and organic bases. Reaction with an alkylating moiety represented by the Formula (CrC6)alkyl-X wherein X is a reactive leaving group such as a chloride, bromide, iodide, O-mesylate of an O-to.sylate gives the derivatives 42 and 45.
The alkylation reaction may be carried out with caboxylate esters such as 41 or with the carboxylic acids such as 44. Alternatively, the phenolic compounds 41 and 44 may be reacted under Mitsunobe Reaction conditions to afford the O-alkylated derivatives 42 and 45. Standard Mitsunobe Reaction conditions, such as those described in the following literature references, may be used in the coupling reactions: J. Heterocvclic Chem. 34:349 (1997); Tetrahedron Lett. 37:6439 (1996); J. Org. Chem.. 56:7173 (1991); Tetrahedron Lett. 5709 (1989); Synthesis 1:28 (1981).
28
Scheme 8
O SO A_ ° €H3
O -SO;
CH ,oJrN f^0"
.R BBr3
A f
R ACό ^ CH30^ R . Rf? 3
Figure imgf000030_0001
R? R J.
3
40 41 l)OH (C^alkylOH 2) BBr3 (CδHs^P 1 DEAD
Figure imgf000030_0002
O 0-alkyl(C,-C6)
Figure imgf000030_0003
Figure imgf000030_0005
44
42 or
Base (C,-C6)alkyl-X
Figure imgf000030_0004
OH
O
O S02"(~)-0-alkyl(C1-C6)
(C,-C6)alkyl OH
Figure imgf000030_0006
K2 D-
45
(CrC6)alkyl-X X = halogen, OTs, OMs
- 29 -
The compounds of the present invention which have a basic moiety may be used in the form of salts derived from pharmaceutically or physiologically acceptable acids. These salts include, but are not limited to, salts with inorganic acids (such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid) or organic acids (such as acetic acid, oxalic acid, succinic acid, and maleic acid). Other salts of compounds with an acidic moiety include those with alkali metals or alkaline earth metals (such as sodium, potassium, calcium, and magnesium) or organic bases.
When the present compounds are utilized in pharmaceutical compositions, they may be combined with one or more pharmaceutically acceptable carriers, e.g., solvents, diluents and the like. Such compositions containing the present compounds may be administered orally, in the form of tablets, capsules, dispersible powders, granules, suspensions, syrups or elixirs; parentally, in the form of a sterile injectable solution or suspension; or topically, in the form of creams, lotions, ointments, etc. Such pharmaceutical compositions may contain from about 1 to about 100 mg of active in "gt>rAedient in combination with the carrier.
The effective dosage of the present compounds utilized to treat a specific condition will vary depending upon the particular compound employed, the mode of administration and the type and severity of the condition being treated. However, in general, satisfactory results are obtained when the present compounds are administered at a dosage of about 0.001 to 1000 mg kg of body weight.
As noted above, the compounds of the present invention may be administered orally, as well as by intravenous, intramuscular, subcutaneous or topical routes. Solid carriers useful for preparing tablets, capsules, etc., include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin. Liquid carriers useful for preparing compositions of the present compounds include sterile water, polyethylene, glycols, non-ionic surfactants, and edible oils such as corn, sesame, and peanut oils. Adjuvants conventionally used in the preparation of pharmaceutical compositions may also be included, such as flavoring agents, coloring agents, preservatives and antioxidants.
The compounds of the present invention were tested for biological activity according to the following procedures. - 30 -
In Vitro Gelatinase Assay
The assay is based on the cleavage of the thiopeptide substrate ((Ac-Pro-Leu- Gly(2-mercapto-4-methyl-pentanoyl)-Leu-Gly-OEt), available from Bachem Bioscience) by the enzyme gelatinase, releasing the substrate product which reacts colorimetrically with DTNB ((5,5'-dithio-bis(2-nitro-benzoic acid)). This assay is disclosed in Weingarten et al., "Spectrophotometric Assay for Vertebrate Collegenase", Anal. Biochem.. 147:437-440, (1985). The enzyme activity is measured by the rate of the color increase.
The thiopeptide substrate was made up fresh as a 20 mM stock in 100% DMSO and the DTNB was dissolved in 100% DMSO as a 100 mM stock and stored in the dark at room temperature. The substrate and the DTNB were diluted together to 1 mM with substrate buffer (50 mM HEPES, pH 7.5, 5 mM CaCl2) before use. The stock of human neutrophil gelatinase B was diluted with assay buffer (50 mM HEPES, pH 7.5, 5 mM CaCl2, 0.02% Brij) to a final concentration of 0J5 nM.
The assay buffer, enzyme, DTNB/substrate (500 μM final concentration) and vehicle or inhibitor were added to a 96 well plate (total reaction volume of 200μl) and the increase in color was monitored spectrophotometrically for 5 minutes at 405 nm on a plate reader.
The increase in OD405 was plotted and the slope of the line was calculated. The slope represents the reaction rate. The lineaiity of the reaction rate was confirmed (fi >0.85) and the mean (x ± sem) of the control rate was calculated and compared for statistical significance (p <0.05) with drug-treated rates using Dunnett's multiple comparison test. Dose-response relationships were generated using multiple doses of drug and IC50 values with 95% CI were estimated using linear regression (IPRED, HTB).
In Vitro Collagenase Assay
This assay was based on the cleavage of a peptide substrate ((Dnp-Pro-Cha- Gly-Cys(Me)-His-Ala-Lys(NMa)-NH2), available from Peptide International, Inc.) by collagenase releasing the fluorescent NMa group which was quantitated on the fluorometer as disclosed in Bickett et al., "A High Throughput Fluorogenic Substrate - 31 -
for Interstitial Collagenase (MMP-1) and Gelatinase (MMP-9)", Anal. Biochem.. 212:58-64, (1993). Dnp quenches the NMa fluorescence in the intact substrate.
The assay was run in HCBC assay buffer (50 mM HEPES, pH 7.0, 5 mM Ca+2, 0.02% Brij, 0.5% Cysteine), with human recombinant fibroblast collagenase (truncated, mw= 18,828, from Wyeth-Ayerst Research, Radnor, PA). The substrate was dissolved in methanol and stored frozen in 1 mM aliquots. Collagenase was stored frozen in buffer in 25 μM aliquots. In conducting the assay, the substrate was dissolved in HCBC buffer to a final concenttation of 10 μM and collagenase to a final concentration of 5 nM. The compounds being examined were dissolved in methanol, DMSO, or HCBC. The methanol and DMSO were diluted in HCBC to < 1.0%. The compounds were added to a 96 well plate containing enzyme and the reaction was started by the addition of substrate.
The reaction was read (excitation 340 nm. emission 444 nm) for 10 min. and the increase in fluorescence over time was plotted as a linear line. The slope of the line was calculated representing the reaction rate. The linearity of the reaction rate was confirmed (r^ >0.85). The mean (x ± sem) of the control rate was calculated and compared for statistical significance (p <0.05) with drug-treated rates using Dunnett's multiple comparison test. Dose-response relationships were generated using multiple doses of drug and IC50 values with 95% CI were estimated using linear regression.
Procedure for Measurin eg- TACE Inhibition
In a 96- well black microtiter plate, each well received a solution composed of 10 μL TACE (available from Immunex) at a final concentration of lμg/mL, 70μL Tris buffer, have a pH of 7.4 and containing 10% glycerol (final concentration 10 mM), and 10 μL of test compound solution in DMSO (final concentration lμM, DMSO concentration <1%). The plates were incubated for 10 minutes at room temperature. The reaction was initiated by addition of a fluorescent peptidyl substrate (final concentration 100 μM) to each well with shaking on a shaker for 5 sec.
The reaction was read (excitation 340 nm, emission 420 nm) for 10 min. and the increase in fluorescence over time was plotted as a linear line. The slope of the line was calculated and this represents the reaction rate. The linearity of the reaction rate was confirmed (r^ >0.85). The mean (x±sem) of the control rate was calculated and compared for statistical significance (p<0.05) with drug-treated rates using Dunnett's -32-
multiple comparison test. Dose-response relationships were generated using multiple doses of dmg and IC50 values with 95% CI were estimated using linear regression.
The results obtained following these standard experimental test procedures are presented in Table 1.
Table 1
O
N- O ■R4
HOHIsT "■
R^ HR R;
Compound of
_R3 Example R l R2 4 IC50 (nM)
MMP-1 MMP-9 MMP- 13 TACE
-SO^-CH3 2 H H H -OCH3
- 14.1 5.1 391 t 1
-S02CH3 3 H H H -OCH3 156.5 7.9 3.0 104+ 8
-S02CH2CH2CH3 10 H H H -OCH3 183 7.0 2.8 91 ± 10
-Sθ ^-OCH3 4 H H H -OCH3 224.1 12.2 4.3 101 + 3
-COCH3 6 H H H -OCH3 18.4 1.4 1.0 103 ± 7 coO 5 H H H -OCH3 15.8(23) 0.56(1.7; ) 0.4 (1.1) 95+ 10
Figure imgf000034_0001
33
Compound of R3 Example R R, R2 R4 IC50 (nM)
MMP-1 MMP-9 MMP- 13 TACE
-co-Q 7 H H H -OCH3 20.4 (34) 0.6 (1.9) 0.4 (1.3) 77.7 + 7
C0I 8 H H H -OCH3 19.7 1.1 1.1 12.8 + 1.2
13 H H H -OCH3 54.9 9.8
■co-o 2.0 154 + 27
COCH OCH3 9 H H H -OCH3 34.1 1.34 1.19 95.2 ± 14.8
-∞^- 12 H H H -OCH3 523 17.9 25.7 207 + 21
Figure imgf000035_0002
C0 1 H H H -OCH3 96.2 5.1 3.7 352 ± 34
CH .
11 H H H -OCH, 55.4 3.9 2.3 271 + 20
-CO
Figure imgf000035_0001
15 H H H _0CH3 52.7 0.7 0.4 199 + ] 9
■cς D-0
^ _J 14 H H H -OCH 3 542 12.6 3.7 45% (luM)
-coA 55 H H H -0CH3 171 4.0 3.3 68.5 + 7.2
cov^ 57 H H H -OCH3 465 12.7 7.2 318 ± 27
-co- cι 31 H H H -OCH3 75.5 3.0 2.6 36%(luM)
Cl
-cof 40
0} H H H -OCH 3 16.6 1.4 1.2 28.5 + 6.6
58 H H H -OCH3
COCH .0- 65.5 4.4
Figure imgf000035_0003
2.9 154 + 20 - 34 -
Compound of 3 Example R Rl R2 R4 IC50 (nM_) MMP-1 MMP-9 MMP- 13 TACE
-COCH2OCH3 59 7-CH, H H -OCH3 105 2.6 1-8 125 + 6
-coø 60 7-CH3 H H -OCH3 22.7 1.4 1.3 143 ± 4
-CO^-0CF3 61 8-Cl H H -OCH3 239 (265) 1.3 (3.9) 0.4 (4.3) 1248 ± 69
Figure imgf000036_0002
CH2CH2OCH3 62 H H H -OCH3 1000 100 100 51 (lμM)
CI 63 7-CH3 H H -OCH3 130 5.6 3.1 6 ± 8 cc ^
64 8-Cl H H -OCH3 157 3.4 384 +
N.
-CO-Q>
-CO-ζJ-OC2H5 65 H H H -OCH3 23.5 1.5 1.5 157 + 13
Cl
-CO Γ=/ΠNN...N.^^"CH,3 66 H H H -OCH3 83.4 3.4 2.6 148 + 14
-CH 2~ 67 H H H -OCH3 ι323 50.8 73.9 551 + 29
-CO 71 H H H -OCH3 41.3 2.4 1.3 136 + 15
Figure imgf000036_0001
OCH3
-CO-CH— I^N-CHj 72 H H H -OCH3 4982 187 317 808 ± 90
The present invention will now be illustrated with reference to the following, non-limiting examples.
Reference Example 1 (L) N-(BenzyIoxycarbonyl)-O-benzylserine, t-butyl ester
Into a solution of 25 g (0.076 mol) of N-(benzyloxycarbonyl)-O-benzylserine in 600 ml of CH2CI2 cooled to -6°C in an ice-salt bath was bubbled isobutylene, while
4J ml of concentrated sulfuric acid was added dropwise thereto. The mixture was stirred for 4 hours and worked up as described in Synthetic Commun.. 26:2723 (1996) to give 29.24 g of product as a yellow oil. - 35 -
Reference Example 2 L-Serine, t-butyl ester
A mixture of 29.24 g (0.076 mol) of (L) N-(benzyloxycarbonyl)-O- benzylserine, t-butyl ester from Reference Example 1, 24.1 g (038 mol) of ammonium formate and 38.3 g of 10% palladium on carbon in 600 ml of methanol was heated at 65°C for 20 hours and stirred at room temperature overnight. The mixture was filtered through diatomaceous earth and the filter pad was washed with methanol. The filtrate was concentrated to give 12.18 g (99.6%) of product as described in Synthetic Commun.. 26:2723 (1996).
Reference Example 3 N-(4-Methoxybenzenesulfonyl)-L-serine, t-butyl ester (3-hydroxy-2-(4- methoxybenzenesulfonylamino)propionic acid, tert-butyl ester) To a solution of 12.18 g (0.0756 mol) of L-serine, t-butyl ester, 26.52 ml of triethylamine in 160 ml of CH2CI2 (cooled in an ice bath) was added, in small portions,
16J g (0.0771 mol) of 4-methoxybenzene-sulfonyl chloride. The mixture was stirred at 0°C for 0.5 hours and at room temperature overnight. The mixture was washed with H2O, 2N citric acid, brine and dried with Na2SO4. The solvent was removed under vacuum to give 25.34 g of solid which was triturated with hexane. The solid was recrystallized from 120 ml of toluene to give 12.18 g (48.7%) of product as a white solid. The filtrate was concentrated and the residue chromatographed on silica gel with hexane-ethyl acetate (7:3) as eluent to give 5.71 g (22.8%) of white solid, m.p. 70- 75°C. Anal, for C14H21NO6S:
Calc'd: C, 50.7; H.6.4; N,4J; Found: C, 50.4; H.6.3; N.4.4.
Reference Example 4
3-Hydroxy-2-[(4-methoxybenzenesuIfonyl)-(2-nitrobenzyl)amino] propionic acid, tert-butyl ester To 6.16 g (18.6 mmol) of 3-hydroxy-2-(4-methoxybenzenesulfonylamino)- propionic acid tert-butyl ester in 50 ml of N,N-dimethylformamide, cooled in an ice bath, was added 0.781 g (19.5 mmol) of sodium hydride. After gas evolution ceased, a solution of 4.02 g (18.6 mmol) of 2-nitrobenzylbromide in 18 ml of N,N- dimethylformamide was added dropwise. The mixture was stirred under nitrogen at room temperature for 4 hours and 1.0 g of 2-nitrobenzyl bromide was added. The mixture was stirred at room temperature overnight and the solvent removed under vacuum. The residue was diluted with water and extracted with CH2CI2. The organic - 36 -
extract was washed with H2O, brine and dried with Na2SO4. The solvent was removed to give 11.2 g of solid which was chromatographed on silica gel with hexane- ethyl acetate (1 : 1) as eluent followed by hexane-ethyl acetate (35:65) as eluent. The fractions containing product were combined and the solvent was then removed to gave 1.1 g (89%) of solid. A sample from a 3 mmol run gave a gum. Anal, for C21H26N2O8S:
Calc'd: C,54J ; H.5.6; N.6.0; Found: C.54.0; H,5J; N,6.0.
Reference Example 5
2-[(2-Aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3- hydroxypropionic acid, tert-butyl ester
A mixture of 0.60 g (1.28 mmol) of 3-hydroxy-2-[(4-methoxybenzene- sulfonyl)-(2-nitrobenzyl)amino] propionic acid, tert-butyl ester and 1.45 g (6.45 mmol) of SnCb'2H2θ in 20 ml of methanol was heated in an oil bath at 90°C for 2 hours.
The solvent was removed under vacuum and ethyl acetate added to the residue. The mixture was neutralized with saturated sodium bicarbonate solution and filtered through diatomaceous earth. The ethyl acetate layer was separated and washed with H2O, brine and dried with Na2SO. The solvent was removed under vacuum to give 030 g (53%) of a gum. Anal, for C21H28 2O6S:
Calc'd: C, 57.8; H,6.5; N.6.4;
Found: C, 57.8; H,7.0; N.6.2.
Reference Example 6 2-[(2-Aminobenzyl)-(4-methoxybenzenesulfonyI)amino]-3- hydroxypropionic acid
A solution of 0.75 g (1.72 mmol) of 2-[(2-aminobenzyl)-(4-methoxybenzene- sulfonyl)amino]-3-hydroxypropionic acid, tert-butyl ester and 6 ml of trifluoroacetic acid in 6 ml of CH2CI2 was stirred at room temperature for 3 hours and then concentrated to dryness under vacuum. To the residue was added H2O, CH2CI2 and IN NaOH until the aqueous layer reached pH 8. The aqueous layer was then separated, acidified with 2 N citric acid and extracted with ethyl acetate. The extract was washed with H2O, brine and dried Na2SO4. The solvent was removed under vacuum to give 0.35 g (54%) of a solid. Anal, for C17H20N2O6S: Calc'd: C, 53.7: H,5.3; N.7.4;
Found: C, 53.0; H,53; N.6.9. - 37 -
Reference Example 7
2-{(2-[3-(Trifluoromethylbenzoyl)aminobenzyl]-(4- methoxybenzenesulfonyl)amino}acrylic acid, tert-butyl ester
A mixture of 0.431 g (1 mmol) of 2-[(2-amino-benzyl)-(4-methoxybenzene- sulfonyl)amino]-3-hydroxy-propionic acid, tert-butyl ester, 0.474 g (2.2 mmol) of 3- (trifluoromethyl)benzoyl chloride and 1 ml of pyridine in 2 ml of CH2CI2 was stirred at room temperature for 3.5 hours. The mixture was poured into H2O and extracted with CH2CI2. The extract was washed with H2O, 2 N citric acid. H2O. 1 N NaHCO3, brine and dried with Na2SO4. The solvent was removed to give 0J2 g of solid. The solid was dissolved in 2 ml of tetrahydrofuran and 1.5 ml of triethylamine was added thereto. The solution was heated at 65°C overnight and concentrated to dryness under vacuum. The residue was extracted with CH2Q2 and the extract washed with H2O and dried with Na2SO4. The solvent was removed under vacuum to give 0.55 g of product as a solid. From a similar run the product was chromatographed on silica gel with hexane-ethyl acetate to give a solid, m.p. 65-72°C. Anal, for C29H29F3N2O6S:
Calc'd: C, 59.0; H,5.0; N.4.7; Found: C, 59.2; H.5.2; N.4.4.
Reference Example 8 4-(4-Methoxybenzenesulfonyl)-l-(3-trifluoromethylbenzoyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid, tert-butyl ester
A mixture of 0.55 g (0.932 mmol) of 2-{(2-[3-(trifluoromethyl)benzoyl]- aminobenzoyl]-(4-methoxybenzenesulfonyl)amino} acrylic acid, tert-butyl ester and 0J02 g (1.21 mmol) of NaHCO3 in 4 ml of methanol was stirred at room temperature overnight and the solvent removed. The residue was extracted with CH2CI2 and the extract washed with H2O, brine and dried with Na2SO4. The solvent was removed to give 0.57 g of solid. The solid was chromatographed on thick layer silica gel plates with hexane-ethyl acetate (1:1) as solvent to give 0.30 g of a light yellow solid, m.p. 57-60°C. Anal, for C29H29F3N2O6S: Calc'd: C,59.0; H,5.0; N.4.7;
Found: C,58.8; N,5.0; N.4.6. - 38 -
Reference Example 9
4-(4-Methoxybenzenesulfonyl)- l-(3-trif luoromethylbenzoyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid
A mixture of 0.36 g (0.61 mmol) of 4-(4-methoxybenzenesulfonyl)-l-(3- trifluoromethylbenzoyl)-2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid, tert-butyl ester and 3 ml of trifluoroacetic acid in 3 ml of CH2CI2 was stirred at room temperature for 3 hours. The mixture was concentrated to dryness under vacuum and the residue extracted with CH2CI2. The CH2CI2 was washed with 1 N NaHCO3 and the aqueous layer (pH 8) was acidified with 2 N citric acid and extracted with ethyl acetate. The extract was dried (Na2SO4). The original CH2CI2 extract was washed with 2 N citric acid, H2O, brine and dried with Na2SO4. The CH2CI2 extract and the ethyl acetate extract were combined and the solvent removed under vacuum to give 0.31 g of solid, m.p. 105-110°C. Anal, for C25H21F3N2O6S:
Calc'd: C,56J; H,4.0; N.5.2; Found: C.55.1; H.3.7; N.5.O.
Reference Example 10
Methyl l-([l,l '-Biphenyl]-2-carbonyl)-4-(4-methoxybenzenesulfonyl)-
2,3,4, 5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate To a mixture of 1.5 g (3.8 mmol) of methyl 2-[(2-aminobenzyl)-(4- methoxybenzenesulfonyl)amino]-3-hydroxypropionate and 2.65 ml of triethylamine in 12 ml of CH2CI2 chilled at 0°C was added a solution of [l J'-biphenyl]-2-carbonyl chloride in 6 ml of CH2CI2. The mixture was stirred at room temperature overnight and diluted with CH2CI2 and H2O. The organic layer was separated and washed with 2 N citric acid, brine and dried with Na2SO4, The solvent was removed under vacuum to give 2.2 g of a white foam. Anal, for C31H28N2O S:
Calc'd: C,66.9; H.5.1; N,5.0; Found: C.67.3; H,5.2;N,4.7.
Reference Example 11
Methyl 4-(4-MethoxybenzenesulfonyI)-l-(2-methyl-5-fIuorobenzoyl)- 2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
To a mixture of 1.5 g (3.80 mmol) of methyl 2-[(2-aminobenzyl)-(4- methoxybenzenesulfonyl)amino]-3-hydroxypropionate and 2.64 ml (18.97 mmol) of triethylamine in 15 ml of CH2CI2, chilled to 0°C, was added 136 g ( 11.4 mmol) of 2- methyl-5-fluorobenzoyl chloride. The mixture was stirred at room temperature overnight. The solution was then diluted with CH2CI2 and water and the organic layer - 39 -
separated. The organic layer was washed with 2 N citric acid, brine and dried with Na2SO4. The solvent was removed under vacuum to give 2J g of a white foam. Anal, for C26H25FN2O6S:
Calc'd: C,60.9; H,4.9; N,5.5; Found: C,60.9; H,5.0; N,5.0;
Mass spectrum (ES) 513.4 (M+H).
Reference Example 12 Methyl 4-(4-MethoxybenzenesuIfonyI)-2,3,4,5-tetrahydro-lH-[l,4] benzodiazepine- 3-carboxylate
To a mixture of 5.0 g (12.68 mmol) of methyl 2-[(2-aminobenzyl)-(4- methoxybenzenesulfonyl)amino]-3-hydroxypropionate and 17.7 ml (26.8 mmol) of triethylamine in 50 ml of CH2CI2 chilled to 0°C was added 9.05 ml (63.4 mmol) of benzyl chloroformate. The mixture was stirred overnight and then cooled to 0°C and .8 ml of triethylamine and 9.05 ml (63.4 mmol) of benzyl chloroformate were added thereto. The mixture was stirred overnight and then washed with H2O, 2 N citric acid, brine and dried with Na2SO4. The solvent was removed under vacuum to give 6.95 g of solid. The solid was chromatographed on silica gel with hexane-ethyl acetate ( 1 : 1 ) to give 2.1 g of product as a viscous yellow oil. From a similar 0.5 g run, there was obtained 0J78 g of an oil. Anal, for C] 8H20N2O5S:
Calc'd: C,57.4; H,5.4; N/7.4; S,8.5; Found: C,57.9; H.5.4; N.6.7; S,7.9; Mass spectrum (ES) 377.2 (M+H).
Reference Example 13
Methyl 3-Hydroxy-2-(4-methoxybenzenesulfonylamino)propionate
To a mixture of 5.0 g (32.14 mmol) of D,L-serine, methyl ester and 15J ml (0.012 mol) of triethylamine in 100 ml of CH2CI2, cooled to 0°C, was added portionwise 6.64 g (32.14 mmol) of 4-methoxybenzenesulfonyl chloride. The mixture was then stirred under argon at room temperature for 2 days. The mixture was diluted with 100 ml of CH2CI2 and then washed with 60 ml each of H2O, 2 N citric acid, brine and dried with Na2SO4. The solvent was removed under vacuum to give a solid.
Crystallization from ethyl acetate gave 5.0 g (54%) of white crystals, m.p. 92-94°C. Anal, for C1 1H15NO6S: Calc'd: C.45.7; H.5.2; N,4.8; SJ 1J;
Found: C,45.6; H,5J; N,4.8; SJ 1J . - 40 -
Reference Example 14 Methyl 3-Hydroxy-2-[(4-methoxybenzenesulfonyl)-(2-nitrobenzyl) aminojpropionate
To a .solution of 15.0 g (51.85 mmol) of methyl 3-hydroxy-2-(4- methoxybenzenesulfonylamino)propionate in 125 ml of N,N-dimethylformamide, cooled in an ice bath, was added portionwise 2J9 g (57.03 mmol) of NaH (60% in oil). The mixture was stirred at 0°C for 20 minutes and then a solution of 12.32 g (57.03 mmol) of 2-nitrobenzyl bromide in 25 ml of dry N.N-dimethylformamide was added dropwise. The solution was stirred at room temperature for 48 hours and diluted with 500 ml of ethyl acetate and water. The organic layer was separated and the aqueous layer extracted with 250 ml of ethyl acetate. The combined organic layer and extract was washed with 200 ml each of H2O, 1 N NaHCO3, brine and dried with Na2SO4. The solvent was removed and the residual solid was triturated with ethyl acetate, cooled and filtered to give 13.5 g (61%) of white crystals, having a m.p. 127- 129°C. From a small scale run (3.0 g) there was obtained 2.32 g of white crystals, having a m.p. 127-129°C. Anal, for C18H20N2O8S:
Calc'd: C.50.9; H.4.8; N,6.6; Found: C,50.9; H.4.8; N,6.5.
Reference Example 15
Methyl 2-[(2-Aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-
3-hydroxypropionate
To a mixture under nitrogen of 1.5 g (3.53 mmol) of methyl 3-hydroxy-2-[(4- methoxybenzenesulfonyl)-(2-nitrobenzy])amino]propionate in 5 ml of dry ethanol was added 1J2 g (17.69 mmol) of ammonium formate followed by the addition of 0.50 g of 10% palladium on carbon. The mixture was stirred overnight at room temperature and heated at 80°C for 2 hours. The mixture was filtered through diatomaceous earth and the filtrate concentrated to dryness under vacuum to give a semisolid. Trituration with ethyl acetate gave 0.65 g (47%) of white crystals, m.p. 138-140°C; Anal, for C18H22N2O6S:
Calc'd: C,54.8; H,5.6; N,7J; Found: C,53.0; H,5.6; N,6.8. - 41 -
Reference Example 16
Methyl 3-Hydroxy-2-{(4-methoxybenzenesulfonyl)-[2-(2,2,2- trifluoroacetylamino)benzyl]amino}propionate
To a solution of 0.50 g (1.27 mmol) of methyl 2-[(2-aminobenzyl)-(4- methoxybenzenesulfonyl)amino]-3-hydroxypropionate in 5 ml of CH2CI2 was added
1.8 ml ( 12.7 mmol) of trifluoroacetic anhydride. The solution was stirred for 1 hour and concentrated to dryness under vacuum. Methanol was added to the residue and the solvent was removed under vacuum. The addition of methanol and concentration to dryness was repeated twice. The residue was chromatographed on silica gel thick layer plates with hexane-ethyl acetate (1 : 1) to give 0.50 g of a colorless glass. Anal, for C20H21F3N2O7S:
Calc'd: C,49.0; H,43; N.5.7; Found: C.49.0; H.4.5; N,5.4.
Reference Example 17
Methyl 2-[(4-Methoxybenzenesulfonyl)-(2-nitrobenzyl)amino] acrylate
To a solution of 1.0 g (2.356 mmol) of methyl 3-hydroxy-2-[(4- methoxybenzenesulfonyl)-(2-nitrobenzyl) amino]propionate in 2 ml of pyridine, cooled to -10°C was added 0.539 g (2.83 mmol) of 4-methylbenzeuesulfonyl chloride. The solution was chilled overnight and 4 ml of pyridine and 0.539 g (2.83 mmol) of 4- methylbenzene-sulfonyl chloride were added. The mixture was stirred and chilled at -10°C for 24 hours and diluted with H2O. The mixture was extracted with ethyl acetate and the extract washed with H2O, 2 N citric acid, and brine and then dried (Na2SO4). The solvent was removed under vacuum to give 1.2 g of an oil. The oil was dissolved in 6 ml of pyridine and 1.08 g of 4-methylbenzenesulfonyl chloride was added thereto. The mixture was stirred at room temperature overnight and diluted with H2O. The mixture was extracted with ethyl acetate and the extract was washed with H2O, 2 N citric acid, and brine and then dried with Na2SO4. The solvent was removed to give 1.0 g of brown oil. The oil was crystallized from ethanol to give white crystals, m.p. 65- 67°C. Anal, for C18HI8N2O7S:
Calc'd: C53.2; H,4.5; N.6.9; Found: C,53.7; H,4.5; N.7.2. - 42 -
Reference Example 18
Methyl 2-{(4-Methoxybenzenesulfonyl)-[2-(4-pyridiny arbonyl) aminobenzyl]amino}acrylate
To a mixture of 1.5 g (3.80 mmol) of methyl 2-[(2-aminobenzyl)-(4- methoxybenzenesulfonyl)amino]-3-hydroxypropionate and 3.0 ml (21.6 mmol) of triethylamine in 15 ml of CH2CI2. cooled to 0°C was added 1.7 g (9.5 mmol) ml of 4- pyridinecarbonyl chloride (isonicotinoyi chloride). The mixture was stirred at room temperature overnight and diluted with CH2CI2. The mixture was washed with H2O, 2 N citric acid, and brine and then dried with Na2SO4. The solvent was removed to give 1.8 g of a light tan solid; Anal, for C24H23N3O6S:
Calc'd: C,59.9; H,4.8; N,8J; S,6.6;
Found: C,59.0; H,4.8; N,8.5; S,6.9;
Mass spectrum (ES) 482.6(M+H).
Utilizing the procedure described in Reference Example 18. the following intermediate compounds can be prepared from the appropriately unsubstituted methyl 2- [(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate or the appropriately substituted methyl 2-[(substituted-2-aminobenzyl)-(4-methoxybenzene- sulfonyl)amino]-3-hydroxypropionate.
Reference Example 19 Methyl 2-{(4-Methoxybenzenesulfonyl)-[2-(2,2,2- trifluoroacetylamino)benzyl]amino}acrylate white crystals, m.p. 120-121 °C. Anal, for C20H19F3N2O6S: Calc'd: C,50.9; H,4J; N,5.9;
Found: C,50.8; H,4J; N,5.6.
Reference Example 20 Methyl 2-[(2-Benzoylaminobenzyl)-(4-methoxybenzenesulfonyl) aminojacrylate yellow oil. Anal, for C25H24N2O6S:
Calc'd: C,62.5; H,5.0; N,5.8; Found: C,62J; H,53; N,5.0.
Reference Example 21
Methyl 2-[(2-Acetylaminobenzyl)-(4-methoxybenzenesuIfonyl) aminojacrylate - 43 -
Reference Example 22 Methyl 2-((4-Methoxybenzenesulfonyl)-{2-[(3- pyridinylcarbonyI)aminoJbenzyl}amino)acrylate off-white solid. Anal, for C24H23N3O6S:
Calc'd: C.59.9; H,4.8; N,8.7; S,6.6; Found: C,58.9; H,4.8; N,8.4; S,6.4; Mass spectrum (ES) 482.8(M+H).
Example 23
Methyl 2-((4-Methoxybenzenesulfonyl)-{[(2- thienylcarbonyl)amino]benzyl}amino)acrylate tan solid. Anal, for C23H22 2O6S2:
Calc'd: C.56.8; H,4.6; N,5.8; Found: C,55J; H,4.4; N,4.9.
Reference Example 24 Methyl 2-{[2-(-Methoxyacetylamino)benzyI]-(4- methoxybenzenesulfonyl)amino}acrylate yellow oil. Anal, for C21H24N2O7S:
Calc'd: C,56J; H,5.4; N,63; Found: C.55.3; H,5.6; N.5.8.
Reference Example 25 Methyl 2-{(4-Methoxybenzenesulfonyl)-[2-(n- propylsulfonylamino)benzylJamino}acryIate light brown oil. Anal, for C21H26 2O7S2:
Calc'd: C.52.3; H,5.4; N,5.8; Found: C.51.9; H,5.4; N.5.7.
Reference Example 26 Methyl 2-{[2-(3-Phenylpropionyl)aminobenzyl]-(4- methoxybenzenesulfonyl)amino}acrylate light brown oil. Anal, for C27H28N2O6S: Calc'd: C,63.8; H,5.6; N.5.5;
Found: C.66.7; H,5.8; N,4J. - 44 -
Reference Example 27 tert-Butyl 2-{[2-(3-Trifluoromethylbenzoyl)aminobenzyl]-(4- methoxybenzenesulfonyl)amino}acrylate yellow solid; m.p. 65-72°C.
Reference Example 28 Methyl 2-{[2-(4-Biphenylcarbonyl)aminobenzyl]-(4- methoxybenzenesulfonyl)amino}acrylate white solid. Anal for C31H28N2O6S: Calc'd: C,66.9; H,5J ; N,5.0;
Found: C,66J; H,5.0; N,5J.
Reference Example 29 Methyl 2-{[2-(Cyclopropylcarbonyl)aminobenzyl]-(4- methoxybenzenesulfonyl)amino}acrylate yellow oil. Anal, for C22H24N2O6S:
Calc'd: C,59.5; H,5.4; N,63; Found: C,60.0; H,5J; N,6.0; Mass spectrum (ES) 445.5 (M+H).
Reference Example 30 Methyl 2-{[2-(Cyclohexylcarbonyl)aminobenzyl]-(4- methoxybenzenesulfonyl)amino}acrylate white foam. Anal, for C25H30N2O6S: Calc'd: C,61J; H,6J; N,5.8;
Found: C,59J ; H,6.0; N.5.4; Mass spectrum (ES) 487.5 (M+H).
Reference Example 31 Methyl 2-{[2-(3-Fluorobenzoyl)aminobenzyl]-(4- methoxybenzenesulfonyl)amino}acrylate
Reference Example 32 Methyl 2-{[2-(3-Chlorobenzoyl)aminobenzyIJ-(4- methoxybenzenesulfonyl)amino}acrylate - 45 -
Reference Example 33
Methyl 2-{[2-(2,4-Dichlorobenzoyl)aminobenzyl]-(4- methoxybenzenesulfonyl)amino}acrylate
Reference Example 34
Methyl 2-{[2-(2,3-Difluorobenzoyl)aminobenzyI]-(4- methoxybenzenesulfonyl)amino}acrylate
Reference Example 35 Methyl 2-{[2-(2-Chloro-4-fluorobenzoyl)aminobenzyl]-(4- methoxybenzenesulfonyl)amino}acrylate
Reference Example 36 Methyl 2-{ [2-(2-FuranyIcarbonyl)aminobenzyl]-(4- methoxybenzenesuIfonyl)amino}acrylate off-white solid. Anal, for C23H22N2O7S.
Calc'd: Q58.7; H,4J; N.6.0; Found: C.58.0; H,4J ; N,3.8; Mass Spectrum (ES) 470.9 (M+H).
Reference Example 37
Methyl 2-((4-Methoxybenzenesulfonyl)-{2-[(3- thienylcarbonyl)amino]benzyl}amino)acrylate
Reference Example 38
Methyl 2-{[2-(2-Acetylaminoacetyl)aminobenzyl]-(4- methoxybenzenesulfonyl)amino}acrylate
Reference Example 39 Methyl 2-{[2-(2-Dimethylacetyl)aminobenzyl]-(4- methoxybenzenesulfonyl)amino}acrylate
Reference Example 40 Methyl 2-{[2-(Cyclobutylcarbonyl)aminobenzylJ-(4- methoxybenzenesulfonyl)amino}acrylate - 46 -
Reference Example 41
Methyl 1 -Methoxy acetyl-4-(4-methoxybenzenesulfonyl)-2,3, 4,5- tetrahydro-lH-[l,4Jbenzodiazepine-3-carboxy!ate
To a mixture of 0.449g (1 mmol) of methyl 2-[[2-(2-methoxyacetamido)- benzyl]-(4-methoxybenzene-sulfonyl]amino]acrylate in 5 ml of anhydrous methanol was added 0J09 g (1.3 mmol) of anhydrous sodium bicar-bonate. The mixture was stirred at room temperature overnight and the solvent removed under vacuum. To the residue was added ethyl acetate and water. The organic layer was separated and washed with H2O and brine and then dried with Na2SO4. The solvent was removed to give 0.41 g of solid. The solid was crystallized from ethyl acetate to give 0J8 g of white crystals, m.p. 160-163°C. Anal, for C21H24N2O7S:
Calc'd: C,56J; H.5.4; N,63;
Found: C,56J; H,53; N,63; S,6.9;
Mass spectrum (ES) 449J (M+H).
Utilizing the procedure in Reference Example 41, the following intermediate compounds can be prepared from the appropriate methyl 2-{(4-methoxybenzene- sulfonyl)-[2-(substituted amino)benzyl]amino}acrylates.
Reference Example 42
Methyl 4-(4-Methoxybenzenesulfonyl)-l-(4-methylphenylsulfonyl)- 2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate white foam. Anal, for C25H26 2O7S2:
Calc'd: C,56.6; H,4.9; N.5.3 Found: C.56.2; H,5J; N.5.2.
Reference Example 43
Methyl l,4-Bis-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH-
[l,4Jbenzodiazepine-3-carboxylate white solid. Anal, for C25H26N2O8S2:
Calc'd: C,54.9; H,4.8; N.5.1; Found: C,54.8; H,4.9; N,5J. - 47 -
Reference Example 44
Methyl l-Methanesulfonyl-4-(4-methoxybenzeuesulfonyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate white crystals, m.p. 136-137°C. Anal, for C19H22N2O7S2: Calc'd: C.50.2; H.4.9; N.6.2;
Found: C,50J; H.4.9; N,6.4.
Reference Example 45 Methyl l-Benzoyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- lH-[l,4]benzodiazepine-3-carboxylate tan solid. Anal, for C25H24N2O2S:
Calc'd: C,62.2; H,5.4; N,5.8; Found: Q62.3; H.5.2; N,5.6.
Reference Example 46
Methyl l-Acetyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH- [l,4Jbenzodiazepine-3-carboxylate white crystals, m.p. 150-155°C. Anal, for C20H22 2O6S:
Calc'd: C,57.4; H,53; N.6.7; Found: C,56.6; H.5.2; N.6.5.
Reference Example 47
Methyl 4-(4-Methoxybenzenesulfonyl)-l-(3-pyridinylcarbonyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate off-white solid; Anal, for C24H23N3O6S:
Calc'd: C,59.9; H,4.8; N,8.7; Found: C.59J; H.4.8; N,83; Mass spectrum (ES) 482.2 (M+H).
Reference Example 48
Methyl 4-(4-Methoxybenzenesulfonyl)-l-(2-thienylcarbonyI)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate off-white solid. Anal, for C23H22 2O6S2:
Calc'd: C.56.8; H,4.6; N.5.8; Found: C,56.0; H.4.6; N,5.2. - 48 -
Reference Example 49
Methyl 4-(4-Methoxybenzenesulfonyl)-l-(4-pyridinylcarbonyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate off-white crystals, m.p. 162-164°C. Anal, for C24H23N3O6S: Calc'd: C.59.9; H,4.8; N,8J;
Found: C,59.9; H.4.8; N,8J.
Reference Example 50 Methyl l-(4-Biphenylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate white solid; Anal, for C31H28N2O6S:
Calc'd: C,66.9; H,5J ; N,5.0; Found: C,65.8; H.5J; N,5.0; Mass spectrum (ES) 557.6 (M+H).
Reference Example 51 Methyl 4-(4-MethoxybenzenesulfonyI)-l-(propane-l-sulfonyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate yellow oil. Anal, for C21H26N2O7S2: Calc'd: C,523; H,5.4; N,5.8;
Found: C.51.8; H,5.4; N,5.6.
Reference Example 52 Methyl l-([l,l'-BiphenyIJ-2-carbonyl)-4-(4-methoxybenzenesulfonyl)- 2,3,4, 5-tetrahydro-lH-[l,4Jbenzodiazepine-3-carboxylate white foam. Anal, for C31H28 2O6S:
Calc'd: C,66.9; H,5J; N,5.0; Found: C,673; H,5J; N,4J; Mass spectrum (ES) 557.6 (M+H).
Reference Example 53
Methyl l -(3-Fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate - 49 -
Reference Example 54
Methyl 4-(4-Methoxybenzenesulfonyl)-l-(2-methyl-5-fluorobenzoyl)-
2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate white solid; Anal, for C26H25FN2O6S: Calc'd: C,60.9; H.4.9; N.5.5;
Found: C,60.9; H,5.0; N,5.0.
Reference Example 55 Methyl 4-(4-MethoxybenzenesulfonyI)-l-(2-methyl-3-fluorobenzoyl)- 2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Reference Example 56
Methyl 4-(4-Methoxybenzenesulfonyl)-l-(3-phenylpropionyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate white solid; Anal, for C27H28N2O6S:
Calc'd: C,63.8; H.5.6; N,5.5; Found: C,64.0; H,5J; N.5.3; S,6.5.
Reference Example 57 Methyl 4-(4-MethoxybenzenesulfonyI)-l-(2-trifluoromethylbenzoyl)-
2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Reference Example 58 Methyl l-(2-Chloro-6-trifluoromethylbenzoyl)-4(4- methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3- carboxylate
Reference Example 59 Methyl l-(4-Fluoro-2-trifluoromethylbenzoyl)-4-(4- methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3- carboxylate
Reference Example 60 Methyl l-(2-Fluoro-6-trifluoromethylbenzoyl)-4-(4- methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH-[l,4Jbenzodiazepine-3- carboxylate - 50 -
Reference Example 61
Methyl 4-(4-MethoxybenzenesuIfonyl)-l-(2-methyIbenzoyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Reference Example 62
Methyl 4-(4-Methoxybenzenesulfonyl)-l -(2-methyl-6-chlorobenzoyl)- 2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Reference Example 63 Methyl l-(2,4-Dimethylbenzoyl)-4-(4-methoxybenzenesuIfonyl)-
2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Reference Example 64 Methyl l-(2,5-Dimethylbenzoyl)-4-(4-methoxybenzenesulfonyl)- 2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Reference Example 65 Methyl l-(2-Chloro-4-fluorobenzoyl)-4-(4-methoxybenzenesulfonyI)- 2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Reference Example 66
Methyl l-(2-Chlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-
2,3,4,5-tetrahydro-lH-[l,4Jbenzodiazepine-3-carboxylate
Reference Example 67
Methyl l-(2-Fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Reference Example 68 Methyl 1 -(2-Chloro-6-fluorobenzoyl)-4-(4-methoxybenzenesulfonyI)- 2,3,4, 5-tetrahydro-lH-[l,4Jbenzodiazepine-3-carboxylate
Reference Example 69 Methyl l-(2,3-Difluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5- tetrahydro-lH-[l,4Jbenzodiazepine-3-carboxylate - 51 -
Reference Example 70
Methyl l-(2,4-Dichlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Prepared according to the procedure set forth in Reference Example 10; white solid. Anal, for C25H22CI2N2O6S:
Calc'd: C.54J; H,4.0; N,5J; Found: C.54.4; H.3.8: N.4.9; Mass spectrum (548.9) (M+H); 550.9 (M+H).
Reference Example 71
Methyl l-(2,3-Dichlorobenzoyl)-4-(4-methoxybenzenesuIfonyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Reference Example 72 Methyl l-(2,5-Dichlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Reference Example 73 Methyl l-(2-Methoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxy!ate
Reference Example 74 Methyl l-(4-Chloro-2-methoxybenzoyl)-4-(4-methoxybenzenesulfonyl)- 2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Reference Example 75
Methyl 4-(4-Methoxybenzenesulfonyl)-l-(2-methylthiobenzoyl)-2,3,4,5- tetrahydro-lH-[l ,4]benzodiazepine-3-carboxylate
Reference Example 76
Methyl 4-(4-Methoxybenzenesulfonyl)-l-(3-methyl-2-thienylcarbonyl)- 2,3,4,5-tetrahydro-lH-[1.4Jbenzodiazepine-3-carboxylate
Reference Example 77 Methyl 4-(4-Methoxybenzenesulfonyl)-l-(4-methyl-2-thienylcarbonyl)- 2,3,4, 5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate - 52 -
Reference Example 78
Methyl l-(3-Chloro-2-thienylcarbonyl)-4-(4-methoxybenzenesulfonyl)-
2,3,4,5-tetrahydro-lH-[l,4Jbenzodiazepine-3-carboxylate
Reference Example 79
Methyl l-(2-Furanylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate off-white solid, m.p. 165-167°C. Anal, for C23H22N2O7S:
Calc'd: C,58.7; H.4.7; N,6.0; Found: C,58.4; H,4.6; N,5J;
Mass spectrum (ES) 470.9 (M+H).
Reference Example 80 Methyl 4-(4-Methoxybenzenesulfonyl)-l-(3-methyl-2-furanylcarbonyl)- 2,3,4,5-tetrahydro-lH-[l,4Jbenzodiazepine-3-carboxylate
Reference Example 81 Methyl 4-(4-Methoxybenzenesulfonyl)-l-(4-methyl-2-furanylcarbonyl)- 2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Reference Example 82
Methyl l-(5-Chloro-2-furanylcarbonyI)-4-(4-methoxybenzenesulfonyl)-
2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Reference Example 83
Methyl l-(5-Chloro-2-thienyIcarbonyl)-4-(4-methoxybenzenesulfonyl)- 2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Reference Example 84 Methyl l-Propionyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- lH-[l,4]benzodiazepine-3-carboxy!ate
Reference Example 85 Methyl l-Hexanoyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- lH-[l,4Jbenzodiazepine-3-carboxylate - 53 -
Reference Example 86
Methyl l -(3-Methoxypropionyl)-4-(4-methoxybenzenesulfonyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Reference Example 87
Methyl 4-(4-MethoxybenzenesuIfonyl)-l -(3-thienylcarbonyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Reference Example 88 Methyl l-(3-Furanylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Reference Example 89 Methyl l-(trans-Crotonyl)-4-(4-methoxybenzenesulfonyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Reference Example 90
Methyl l-(Methacryloyl)-4-(4-methoxybenzenesulfonyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Reference Example 91
Methyl l-(ChIoroacetyl)-4-(4-methoxybenzenesulfonyI)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Following the method described for Reference Example 18, 3.0 g (7.61 mmol) of methyl 2-[2-aminobenzyl)-(4-methoxy-benzenesulfonyl)-aminoJ-3-hydroxy- propionate was reacted with 1.82 ml (22.8 mmol) of chloroacetylchloride to give 4.0 g of solid. Chromatography on silica gel with ethyl acetate-hexane ( 1 : 1) as a solvent gave 1.5 g of methyl 2-[(2-chloroacetylaminobenzyl)-(4-methoxybenzenesulfonyl)-amino]- acrylate. A 1.3 g sample of the preceding compound was reacted with 0.312 g of anhydrous NaHCO3 in 10 ml of anhydrous methanol at room temperature overnight and the mixture was then heated at 80°C for 5 hours. The solvent was removed and the residue partitioned between H2O and ethyl acetate. The ethyl acetate extract was washed with brine, dried with Na2SO4 and the solvent removed. The residue was triturated with hexane-ethyl acetate, chilled and filtered to give the product; Mass spectrum (ES) 453.1 (M+H). - 54 -
Reference Example 92
Methyl l-(Acetylaminoacetyl)-4-(4-methoxybenzenesulfonyI)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Reference Example 93
Methyl l-(N,N-Dimethylaminoacetyl)-4-(4-methoxybenzenesulfonyl)- 2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Reference Example 94 Methyl l-(Cyclopropylcarbonyl)-4-(4-methoxybenzenesulfonyl)-
2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate white crystals, m.p. 98-100°C. Anal, for C22H24N2O6S:
Calc'd: C,59.5; H,5.4; N,63; Found: C,593; H,5.6; N,6J; Mass spectrum (ES) 445J (M+H).
Reference Example 95
Methyl l-(Cyclobutylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Reference Example 96
Methyl 4-(4-MethoxybenzenesulfonyI)-l-(trifluoroacetyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
To a solution of 1.0 g (2.54 mmol) of methyl 3-hydroxy-2-{(4- methoxybenzenesulfonyl)-[2-(2JJ-trifluoroacetylamino)benzyl]amino jpropionate in
10 ml of CH2CI2 was added 1.8 ml (12.7 mmol) of trifluoroacetic anhydride. After 1 hour at room temperature, the solvent was removed. Dichloromethane was added several times and the solvent removed under vacuum after each addition. Methanol was then added 2 times and the solvent removed under vacuum to give methyl 2-{(4- methoxybenzenesulfonyl)-[2-(2JJ-trifluoroacetylamino)benzyl]-amino} acrylate as a glass. The glass was dissolved in methanol and 0.213 g of anhydrous NaHCO3 was added. The mixture was stirred at room temperature overnight and concentrated under vacuum to dryness. To the residue was added ethyl acetate and water. The organic layer was separated, washed with H2O, brine and dried with Na2SO4. The solvent was removed and the residue ( 1.0 g) was chromatographed on silica gel thick layer - 55 -
plates with hexane-ethyl acetate (1 : 1) as solvent to give 0.365 g of product as a glass. Anal, for C20H19F3N2O6S:
Calc'd: C,50.9; H,4J ; N,5.9; FJ2J; S,6J; Found: C.50.8; H,4.4; N,5.5; FJ 1 J; S,6J; Mass spectrum (ES) 473.1 (M+H).
Reference Example 97
Methyl 4-(4-Methoxybenzenesulfonyl)-l-(4-methylphenylsulfonyl)-
2,3,4,5-tetrahydro-lH-[l,4Jbenzodiazepine-3-carboxylate To 0.50 g ( 1.26 mmol) of 2-[(2-aminobenzyl)-(4-methoxybenzene- sulfonyl)amino]-3-hydroxypropionate in 5 ml of pyridine cooled to 0°C was added 0J84 g (2.59 mmol) of tosyl chloride. The mixture was stirred at 0°C for 2 hours and then concentrated to remove the solvent. To the residue was added 8 ml of anhydrous ethanol and the mixture refluxed for 2 days. The mixture was concentrated to dryness and ethyl acetate added. The mixture was washed with H2O. 2 N citric acid, brine and dried with Na2SO4. The filtrate was filtered through a thin pad of hydrous magnesium silicate and the filter pad washed with ethyl acetate. The filtrate was concentrated to dryness to give 0.60 g of a foam. Anal, for C25H26N2O7S2:
Calc'd: C,56.6; H,4.9; N.5.3; S.12.1 ; Found: C,56J; H.5.2; N,5J; SJ 1.4;
Mass spectrum (ES) 531.6 (M+H).
Reference Example 98 Methyl 2-[(4-Methoxybenzenesulfonyl)-(2- methylsulfonylaminobenzyl)amino]acrylate
To a solution of 1.0 g (2.54 mmol) of methyl [(2-aminobenzyl)-(4- methoxybenzenesulfonyl)amino]-3-hydroxypropionate in 10 ml of pyridine cooled to -5°C was added 0.432 ml (5.58 mmol) of methanesulfonyl chloride. The mixture was stirred at 0°C for 48 hours. To the mixture was added ice and H2O and the mixture was extracted with ethyl acetate. The extract was washed with H2O, 2 N citric acid, brine and dried with Na2SO4. The solvent was removed under vacuum and the residue triturated with ethyl acetate-hexane to give 0.90 g of a solid, 128-142°C. Anal, for C19H22N2O7S2:
Calc'd: C,50J; H,4.9; N,6.2; SJ4J ; Found: C.49.6; H,5.0; N,6.9; SJ4.0;
Mass spectrum (ES) 455.5 (M+H). - 56 -
Reference Example 99
Methyl l,4-Bis-(4-Methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH-
[l,4]benzodiazepine-3-carboxylate
To a solution of 1.0 g (2.34 mmol) of methyl 2-[(2-aminobenzyl)-(4- methoxybenzenesulfonyl)amino]-3-hydroxypropionate in 6 ml of pyridine cooled to 0°C to -5°C was added 1.07 (5.18 mmol) of 4-methoxybenzenesulfonyl chloride. After 2 hours, the mixture was concentrated to dryness under vacuum. To the residue was added 12 ml of ethanol and the mixture refluxed overnight. The solvent was removed under vacuum and the residue chromatographed on silica gel thick layer plates with ethyl acetate-hexane (1 :1 ) as solvent to give 0.83 g (60%) of product as a white foam; Anal, calc'd for C25H26N2O8S2: C,54.9; H.4.8; N.5.1; SJ 1.7. Found: C.54.8;
H,4.9; N,5.0; SJ 1.5; Mass spectrum (ES) 547 J (M+H); and a second component (0.38 g) methyl 2-{ [2-(4-methoxybenzenesulfonyl)aminobenzyl]-(4-methoxybenzene- sulfonyl)amino}-3-hydroxypropionate. Anal, for C25H28N2O9S2: Calc'd: C.53.2; H,5.0; N,5.0; SJ 1.4;
Found: C,51.8; H,5J ; N.4.7; SJ 1.3; Mass spectrum (ES) 565.2 (M+H).
Reference Example 100 Methyl 1 -Acetyl-4-(4-methoxybenzenesuIfonyl)-2,3,4,5-tetrahydro- lH-[l,4]benzodiazepine-3-carboxylate
To a solution of 070 g (1.52 mmol) of methyl 2-[(2-diacetylaminobenzyl)-(4- methoxybenzenesulfonyl) aminojacrylate in 5 ml of anhydrous methanol was added 0.332 g (3.95 mmol) of anhydrous sodium bicarbonate. The mixture was stirred at room temperature overnight and the solvent removed under vacuum. To the residue was added ethyl acetate and H2O. The organic layer was separated, washed with brine and dried with Na2SO4. The solvent was removed and the residue dried under vacuum to give 0.59 g of white crystals, m.p. 150-155°C. Anal, for C20H22N2O6S:
Calc'd: C,57.4; H,53; N,6.7; S.7.7; Found: C,56.6; H,5J; N,6.5; S.7.5;
Mass spectrum (ES) 419.9 (M+H).
Reference Example 101 Methyl 3-Acetoxy-2-[(2-diacetylaminobenzyl)-(4- methoxybenzenesulfonyl)aminoJpropionate
A mixture of 1.0 g (2.54 mmol) of methyl 2-[(2-aminobenzyl)-(4- methoxybenzenesulfonyl)amino]-3-hydroxypropionate and 13 ml of acetic anhydride - 57 -
in 8 ml of toluene was heated at 100°C for 2 hours. The mixture was concentrated and 3 ml of acetic anhydride added thereto. The mixture was heated at 100°C overnight and concentrated to dryness under high vacuum to give an oil. The oil was dried at 75°C under vacuum for 48 hours to give 1J g of a yellow oil. Anal, for C24H28N2O9S: Calc'd: C.54.5; H,5.2; N,5.5; S.6.2;
Found: C,54.6; H,5J ; N.5.4; S,6.4; Mass spectrum (ES) 520.8 (M+H).
Reference Example 102 Methyl 2-[(2-Diacetylaminobenzyl)-(4- methoxybenzenesulfonyl)amino]acrylate
A mixture of 1.0 g (1.97 mmol) of methyl 3-acetoxy-2-[(2-diacetyl- aminobenzyl)-(4-methoxybenzenesulfonyl)amino]propionate and 0.826 ml (5.92 mmol) of triethylamine in 5 ml of CH2O2 was stirred at room temperature overnight. The solution was diluted with 30 ml of CH2CI2 and washed with 20 ml each of H2O, 2 N. citric acid, brine and dried with Na2SO4. The solvent was removed under vacuum to give a brown oil. Anal, for C22H24N2O7S: Calc'd: C,57.4; H,53; N,6J ; S,7.0; Found: C,56J; H,5.5; N,5.6; S,7J.
Reference Example 103 Methyl 2-{(4-MethoxybenzenesulfonyI)-[2-(2,2,2- trifluoroacetylamino)benzyl]amino}acrylate To a suspension of 1.0 g (2.54 mmol) of methyl 2-[(2-aminobenzyl)-(4- methoxybenzenesulfonyl)amino]-3-hydroxypropionate in 10 ml of toluene was added 1.8 ml (12.7 mmol) of trifluoroacetic anhydride (solid dissolves). The solution was stirred for 2 hours at room temperature and heated at 100°C overnight. The mixture was then concentrated to dryness under vacuum. To the residue was added 0.9 ml of trifluoroacetic anhydride and the solution stirred at room temperature for 1.5 hours and concentrated to dryness. To the residue was added 10 ml of toluene and the mixture refluxed for 2 hours. The solution was cooled to room temperature and 2.5 ml of triethylamine added and the mixture stirred at room temperature overnight. The solution was concentrated to dryness and the residue dissolved in ethyl acetate. The ethyl acetate was washed with H2O, brine and dried (Na2SO4). The solvent was removed under vacuum to give 1.0 g of colorless oil. Crystallization from ethyl acetate - hexane - 58 -
gave 0.625 g of colorless crystals, m.p. 120- 121 °C. Anal, for C20H19F3N2O6S:
Calc'd: C.50.9; H,4J; N.5.9; S.6.7; FJ2J; Found: C.50.8; H.4.2; N,5.6; S,6.8; FJ 1.9; Mass spectrum (ES) 473.1 (M+H).
Reference Example 104
4-(4-Methoxybenzenesulfonyl)-l -(2-methyl-5-f luorobenzoyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic Acid To a mixture of 1.9 g (3.71 mmol) of methyl 4-(4-methoxybenzenesulfonyl)-l-
(2-methyl-5-fluorobenzoyl)-2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate in 10 ml of tetrahydrofuran was added 5 ml (4.82 mmol) of 1 N NaOH. The mixture was stirred at room temperature for 1.5 hours and the solvent removed under vacuum. To the residue was added ethyl acetate and the mixture neutralized with 1 N HCl. The organic layer was separated, washed with brine and dried with Na2SO4. The solvent was removed under vacuum to give 1.41 g of white solid. Anal, for C25H23FN2O6S: Calc'd: C.60.2: H.4.7; N,5.6; Found: C.60.2; H,4.8; N,5.4 S,6.4; F,3.6; Mass spectrum (ES) 497.5 (M-H).
Utilizing the method described in Reference Example 104, the following benzodiazepine-3-carboxylic acids can be prepared.
Reference Example 105 4-(4-Methoxybenzenesulfonyl)-l-(4-methylphenylsulfonyI)-2,3,4,5- tetrahydro-lH-[l,4Jbenzodiazepine-3-carboxylic acid white foam. Anal, for C24H24N2O7S2:
Calc'd: C,55.8; H,4.7; N,5.4; Found: C,53.9; H.5.1; N,4.8; Mass spectrum (ES) 512.2 (M+H). - 59 -
Reference Example 106 l,4-Bis-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH-
[l,4Jbenzodiazepine-3-carboxylic acid off-white solid. Anal, for C24H24N2O8S2: Calc'd: C,54J ; H.4.5; N.5.3;
Found: C,52.4; H,4.8; N.4.7; Mass spectrum (ES) 533J (M+H).
Reference Example 107 l-MethanesulfonyI-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- lH-[l,4]benzodiazepine-3-carboxylic acid white solid. Anal, for C 18H20N2O7S2:
Calc'd: C,49J; H.4.6; N,63; Found: C,47.5; H,5.0; N.5.5; Mass spectrum (ES) 441.1 (M+H).
Reference Example 108 l-Benzoyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH-
[l,4]benzodiazepine-3-carboxylic acid white foam. Anal, for C24H22N2O6S:
Calc'd C61.5; H,5J; N,6.0; Found: C,60.8; H,5J; N.5.7; Mass spectrum (ES) 467.9 (M+H).
Reference Example 109 l-Acetyl-4-(4-methoxybenzenesuIfonyl)-2,3,4,5-tetrahydro-lH- [l,4Jbenzodiazepine-3-carboxylic acid white solid; Anal, for C19H22N2O6S:
Calc'd: C.56.4; H.5.0; N,6.9; Found: C.55.2; H.4.9; N.6.6; S,7.8;
Mass spectrum (ES) 404.9 (M+H). - 60 -
Reference Example 110
4-(4-Methoxybenzenesulfonyl)- l -(3-pyridiny Icarbonyl)-2, 3,4,5- tetrahydro-lH-[l,4Jbenzodiazepine-3-carboxylic acid white solid; m.p. 250-255. Anal, for C23-H2] N3θ6S: Calc'd: C,59J; H.4.5; N,9.0;
Found: C,583; H,4.7; N,83; Mass spectrum (ES); 468J (M+H).
Reference Example 111 4-(4-Methoxybenzenesulfonyl)- l-(2-thieny lcarbonyl)-2, 3,4,5- tetrahydro-lH-[l,4Jbenzodiazepine-3-carboxylic acid white solid; Anal, for C22H20N2O6S2:
Calc'd: C,55.9; H.4.3; N,5.9; Found: C,54.9; H,4.4; N,5.4; Mass spectrum (ES) 473J (M+H).
Reference Example 112 l-Methoxyacetyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH-
[l,4]benzodiazepine-3-carboxylic acid white crystals, m.p. 193-194°C. Anal, for C20H22N2O7S:
Calc'd: C,553; H,5J; N,6.5; Found: C,55J ; H,4.9; N.6.2; Mass spectrum (ES) 433.1 (M-H).
Reference Example 113
4-(4-Methoxybenzenesulfonyl)-l -(4-pyridinylcarbonyI)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid white crystals, m.p. 258-261°C. Anal, for C23H21N3O6S:
Calc'd: C,59J; H,4.5; N.9.0; Found: C,58.8; H,4.5; N,8.8;
Mass spectrum (ES) 4833 (M+H). - 61 -
Reference Example 114 l-(4-Biphenylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2, 3,4,5- tetrahydro-lH-[l,4Jbenzodiazepine-3-carboxylic acid white foam. Anal, for C30H26N2O6S: Calc'd: C,66.4; H.4.8; N,5.2;
Found: C,64.7; H,5J; N,4.8; Mass spectrum (ES) 543.6 (M+H).
Reference Example 115 4-(4-Methoxybenzenesulfonyl)-l -(propane- l-sulfonyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid white foam. Anal, for C20H24N2O7S2:
Calc'd: C,513; H,5.2; N,6.0; Found: C.50.3; H.5.3; N,5.7; Mass spectrum (ES) 467.3 (M-H).
Reference Example 116 l-([l, -Biphenyl]-2-carbonyl)-4-(4-methoxybenzenesulfonyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid white foam; m.p. 106-145°C. Anal, for C30H26N2O6S:
Calc'd: C,66.4; H,4.8; N.5.2; Found: C,65.7; H.5.0; N,4.8; Mass spectrum (ES) 541 J (M-H).
Reference Example 117 l-(3-Fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- lH-[l,4Jbenzodiazepine-3-carboxylic acid
Reference Example 118 4-(4-Methoxybenzenesulfonyl)- l -(2-methyl-3-fluorobenzoyl)-2, 3,4,5- tetrahydro-lH-[l,4Jbenzodiazepine-3-carboxylic acid - 62 -
Reference Example 119
4-(4-Methoxybenzenesulfonyl)-l -(3-phenylpropionyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid white solid. Anal, for C26H26N2O6S: Calc'd: C,63J; H,53; N,5.7;
Found: C.61.5; H,5.4; N.5.2; Mass spectrum (ES) 493.2 (M-H).
Reference Example 120 4-(4-Methoxybenzenesulfonyl)-l-(2-trifluoromethylbenzoyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxyIic acid
Reference Example 121 l-(2-Chloro-6-trifluoromethylbenzoyl)-4-(4-methoxybenzenesulfonyl)- 2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid
Reference Example 122 l-(4-Fluoro-2-trifluoromethylbenzoyl)-4-(4-methoxybenzenesulfonyl)- 2,3,4, 5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid
Reference Example 123 l-(2-Fluoro-6-trifluoromethylbenzoyl)-4-(4-methoxybenzenesulfonyl)-
2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid
Reference Example 124 -(4-Methoxybenzenesulfonyl)-l-(2-methylbenzoyl)-2,3,4,5-tetrahydro- lH-[l,4]benzodiazepine-3-carboxylic acid
Reference Example 125 4-(4-Methoxybenzenesulfonyl)-l-(2-methyl-6-chlorobenzoyl)-2,3,4,5- tetrahydro-lH-[l,4Jbenzodiazepine-3-carboxylic acid
Reference Example 126 l-(2,4-Dimethylbenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid - 63 -
Reference Example 127 l -(2,5-DimethylbenzoyI)-4-(4-methoxybenzenesulfonyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid
Reference Example 128 l-(2-Chloro-4-fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid
Reference Example 129 l-(2-Chlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- lH-[l,4]benzodiazepine-3-carboxylic acid
Reference Example 130 l-(2-Fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- lH-[l,4Jbenzodiazepine-3-carboxylic acid
Reference Example 131 l-(2-Chloro-6-fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2, 3,4,5- tetrahydro-lH-[l,4Jbenzodiazepine-3-carboxylic acid
Reference Example 132 l -(2,3-Difluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5- tetrahydro-lH-[l,4Jbenzodiazepine-3-carboxylic acid
Reference Example 133 l-(2,4-Dichlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid white solid. Anal, for C24H20CI2 2O6S:
Calc'd: C,53.8; H,3.8; N,5.2; Found: C,52.8; H,3.9; N,4.9;
Mass spectrum (ES) 533 (M-H).
Reference Example 134 l-(2,3-Dichlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid - 64 -
Reference Example 135 l-(2,5-Dichlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid
Reference Example 136 l-(2-Methoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid
Reference Example 137 l-(4-Chloro-2-methoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2, 3,4,5- tetrahydro-lH-[l,4Jbenzodiazepine-3-carboxyIic acid
Reference Example 138 4-(4-Methoxybenzenesulfonyl)-l -(2-methylthiobenzoyl)-2, 3,4,5- tetrahydro-lH-[l,4Jbenzodiazepine-3-carboxylic acid
Reference Example 139 4-(4-Methoxybenzenesulfonyl)-l-(3-methyl-2-thienylcarbonyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid
Reference Example 140
4-(4-Methoxybenzenesulfonyl)-l -(4-methyl-2-thienylcarbonyl)-2, 3,4,5- tetrahydro-lH-[l,4Jbenzodiazepine-3-carboxylic acid
Reference Example 141 l-(3-Chloro-2-thienylcarbonyl)-4-(4-methoxybenzenesuIfonyl)-2,3,4,5- tetrahydro-lH-[l,4Jbenzodiazepine-3-carboxylic acid
Reference Example 142 l-(2-Furanylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxyIic acid white solid. Anal, for C22H20N2O7S:
Calc'd: C, 57.9; H, 4.4; N, 6.1; Found: C, 56.5; H, 4.5; N, 5.7; Mass spectrum (ES) 455.1 (M-H). - 65 -
Reference Example 143 -(4-Methoxybenzenesulfonyl)-l-(3-methyl-2-furanylcarbonyI)-2,3,4,5- tetrahydro-lH-[l,4Jbenzodiazepine-3-carboxylic acid
Reference Example 144 -(4-Methoxybenzenesulfonyl)-l -(4-methyl-2-f uranylcarbonyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid
Reference Example 145 l-(5-Chloro-2-furanylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2, 3,4,5- tetrahydro-lH-[l,4Jbenzodiazepine-3-carboxylic acid
Reference Example 146 l-(5-Chloro-2-thienylcarbonyl)-4-(4-methoxybenzenesuIfonyl)-2,3,4,5- tetrahydro-lH-[l,4Jbenzodiazepine-3-carboxylic acid
Reference Example 147 l-Propionyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH- [l,4]benzodiazepine-3-carboxylic acid
Reference Example 148 l -Hexanoyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH-
[l,4]benzodiazepine-3-carboxylic acid
Reference Example 149 l-(3-Methoxypropionyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid
Reference Example 150 4-(4-Methoxybenzenesulfonyl)-l-(3-thienylcarbonyI)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid
Reference Example 151 4-(3-Furanylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid - 66 -
Reference Example 152 l-(trans-Crotonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- lH-[l,4]benzodiazepine-3-carboxylic acid
Reference Example 153 l-(MethacryIoyl)-4-(4-methoxybenzenesuIfonyl)-2,3,4,5-tetrahydro-lH- [l,4]benzodiazepine-3-carboxylic acid
Reference Example 154 l-(Pyrrolidinoacetyl)-4-(4-methoxybenzenesuIfonyl)-2,3,4,5-tetrahydro- lH-[l,4]benzodiazepine-3-carboxylic acid
Reference Example 155 l-(Acetylaminoacetyl)-4-(4-methoxybenzenesulfonyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid
Reference Example 156 l -(Cyclopropylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid white crystals, m.p. 131-135°C. Anal, for C21H22N2O6S:
Calc'd: C,58.6; H,5J; N,6.5; Found: C,58J ; H,5.5; N,5.8; Mass spectrum (ES) 431.5 (M+H).
Reference Example 157 l-(Cyclobutylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid
Reference Example 158 l-(Cyclohexylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid white solid. Anal, for C24H28N2O6S:
Calc'd: C,61.0; H,6.0; N,5.9; Found: C,57.0; H,5.7; N,5.4; Mass spectrum (ES) 471.5 (M-H). - 67 -
Reference Example 159 (D,L)N-(4-Methoxybenzenesulfonyl)-O-(2-tetrahydropyranyl)serine,
Methyl ester
A mixture of 1.44 g (5 mmol) of N-(4-methoxybenzenesulfonyl)serine, methyl ester; 1.05 g (12.5 mmol) of 3,4-dihydro-2H-pyran and 9.5 mg of 4-methyl- benzenesulfonic acid monohydrate in 5 ml of tetrahydrofuran was refluxed overnight and the mixture was concentrated to dryness under vaccum. The residue was extracted with CH2CI2 and the extract washed with 2 N NaHCO3, brine and dried with Na2SO4. The solution was filtered through a thin pad of hydrous magnesium silicate and the filter pad washed with CH2C12- The filtrate was concentrated to dryness and the residue (2.3 g) was extracted with three 50 ml portions of hot hexane to give 1.92 g of product as a yellow oil; Mass spectrum (ES) 374.4 (MH+).
Reference Example 160 Methyl 3-Hydroxy-2-{[4-methoxybenzenesulfonyl]-[2-(4- morpholinocarbonylamino)benzyl]amino}propionate
To a mixture of 1.0 g (2.54 mmol) of methyl 2-[(2-aminobenzyl)-(4- methoxybenzenesulfonyl)amino]-3-hydroxypropionate in 8 ml of pyridine chilled at 0° to -10°C was added 740 μL (6.34 mmol) of morpholinocarbonyl chloride. The mixture was kept at 0° to 5°C overnight. The mixture was concentrated under vacuum and diluted with ethyl acetate. The solution was washed with H2O, 2 N citric acid, and brine and dried with Na2SO4. The solvent was removed under vacuum to give 1.61 g of solid (yellow-orange foam). The solid was chromatographed on thick layer silica gel plates with hexane-ethyl acetate (1 :3) as solvent to give 0.86 g of solid. Anal, for C23H29N3O8S:
Calc'd: C,54.4; H,5.8; N,83; Found: C.53.9; H,5.7; N,8J; Mass spectrum (ES) 508.4 (M+H).
Reference Example 161
Methyl 2-{(4-Methoxybenzenesulfonyl)-[2-(4- morpholinocarbonylamino)benzyl]amino}acrylate
To a solution of 0.70 g (1.38 mmol) of methyl 3-hydroxy-2-{ [4-methoxy- benzenesulfonyl]-[2-(4-mo holinocarbonylamino)benzyl]amino }propionate and 769 μL (5.54 mmol) of triethylamine in 8 ml of CH2CI2, cooled to 0°C, was added 0.386 g (2.03 mmol) of 4-methylbenzenesulfonyl chloride. The mixture was stirred at room temperature for 2 hours, diluted with water and extracted with CH2CI2. The extract - 68 -
was washed with 2 N citric acid, brine and dried with Na2SO4. The solvent was removed to give 0.67 g of a yellow oil. Anal, for C23H27N3O7S: Calc'd: C56.4; H.5.6; N,8.6; S,6.6; Found: C.56.1 ; H,5.8; N.8.3; S.6.6.
Reference Example 162
Methyl 4-(4-Methoxybenzenesulfonyl)-l-(4-morpholinocarbonyl)-
2,3,4, 5-tetrahydro-lH-[l,4]-benzodiazepine-3-carboxy late
A mixture of 0.50 g (1.02 mmol) of methyl 2-{(4-methoxybenzenesulfonyl)-[2- (4-moφholinocarbonyl-amino)benzyl]amino} acrylate and 0.1 1 1 g (1.32 mmol) of anhydrous NaHCO3 in 5 ml of anhydrous methanol was stirred at room temperature for
16 hours. An additional 55 mg of NaHCO3 was added and the mixture stirred at room temperature for 2 hours. The solvent was removed under vacuum and the residue diluted with H2O and extracted with ethyl acetate. The extract was washed with brine and dried with Na2SO4. The solvent was removed and the residue triturated with hexane-ethyl acetate to give 0.36 g of a yellow solid; Anal, calc'd for C23H27N3O7S: C56.4; H,5.6; N,8.6; S,6.6. Found: C,56.5; H,5.7; N.8.4; S.6.7; Mass spectrum (ES) 490.3 (M+H).
Reference Example 163
4-(4-Methoxybenzenesulfonyl)- l-(4-morpholinocarbonyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic Acid
A mixture of 0.36 g (0.735 mmol) of methyl 4-(4-methoxybenzenesulfonyl)-l- (4-morpholinocarbonyl)-2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate and 1 ml (0.95 mmol) of 1 N NaOH in 5 ml of tetrahydrofuran was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum and the acidified with 1 N HCl and cooled. The mixture was filtered and the solid washed with water to give 0.26 g of white solid. Anal, for C22H25N3θ7S:
Calc'd: C,55.6; H.5.3; N,8.8; Found: C,53.5; H,5.6; N,83;
Mass spectrum (ES) 474.3 (M-H). - 69 -
Reference Example 164
Methyl 3-[(2-Tetrahydropyranyl)oxy]-2-[(4-methoxybenzenesulfonyl)-
(2-nitro-4-chlorobenzyl)amino]propionate
To a mixture of 1.67 g (4.4 mmol) of (D,L) N-(4-methoxybenzenesulfonyl)- - (2-tetrahydropyranyl) serine, methyl ester, 0.825 g (4.4 mol) of 4-chloro-2-nitrobenzyl alcohol and 1 J6 g (4.4 mmol) of triphenylphosphine in 4.5 ml of tetrahydrofuran was added dropwise a solution of 0.766 g (4.4 mmol) of diethyl azodicarboxylate in 1 ml of tetrahydrofuran. The mixture was stirred at room temperature overnight and the solvent removed under vacuum. The residue was triturated with diethyl ether, filtered and the filtrate passed through a thin pad of hydrous magnesium silicate. The pad was washed with ethyl acetate and the total filtrate concentrated to dryness under vacuum to give
4.54 g of solid. The solid was chromatographed on silica gel with hexane-ethyl acetate
(55:45) as solvent. The fractions containing product were combined and the solvent removed to give 0.55 g of oily solid; Mass spectrum (ES) 543J (M+H).
Reference Example 165 Methyl 2-{[2-(4-Pyridinylmethyleneamino)benzyl]-[4- methoxybenzenesulfonyI]amino}-3-hydroxypropionate A mixture of 0.50 g (1J68 mmol) of methyl 2-[(2-aminobenzyl)-(4- methoxybenzenesulfonyl)amino]-3-hydroxypropionate and 1 J68 mmol of 4- pyridinecarboxaldehyde in 7 ml of anhydrous ethanol was refluxed for 1.5 hours and the mixture concentrated under vacuum to dryness. To the residue was added H2O and ethyl acetate. The ethyl acetate layer was separated and concentrated to dryness under vacuum. The solid was purified by thick layer chromatography on silica gel with hexane-ethyl acetate as solvent to give 0.40 g of solid product (plus a small amount of starting material). Anal, for C24H25N3O6S:
Calc'd: C,59.6; H,5J; N.8.7; Found: Q57.6; H,5.7; N.7.4;
Mass spectrum (ES) 484 (M+H)-product; 395J (M+H)-starting material.
Reference Example 166
Methyl l-(Cyclohexylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
To a solution of 0.80 g (1.64 mmol) of methyl 2-{ [2-(cyclohexylcarbonyl)- aminobenzyl]-(4-methoxybenzenesulfonyl)amino} acrylate in 10 ml of methanol was added 0J07 g (2.46 mmol) of anhydrous sodium bicarbonate. The mixture was stirred for 2 days and then an additional 0J07 g of NaHCO3 added. The mixture was stirred - 70 -
ovemight and the solvent removed under vacuum. To the residue was added H2O and ethyl acetate and the organic layer separated. The ethyl acetate extract was washed with brine, dried with Na2SO4 and the solvent removed under vacuum to give 0.83 g of the product as a yellow oil. Anal, for C25H30N2O6S: Calc'd: C,61 J; H,6J; N,5.8; Found: C,61.0; H.6.4; N.5.3;
Mass spectrum (ES) 487.0 (M+H).
Reference Example 167 Methyl 3-Hydroxy-2-[(4-methoxybenzenesulfonyl)-(4-chloro-2- nitrobenzyl)amino]propionate
To a solution of 0J89 g (1 mmol) of methyl 3-hydroxy-2-(4- methoxybenzenesulfonylamino)propionate in 4 ml of N,N-dimethylformamide cooled in an ice bath was added 40 mg of NaH (60% in oil) (1 mmol). After the gas evolution ceased, 0J65 g (1 J mmol) of sodium iodide was added, followed by the addition of 0J26 g (1J mmol) of 4-chloro-2-nitrobenzyl chloride in 1 ml of dimethylformamide. The solution became purple and was stirred at room temperature over the weekend. The solvent was removed under vacuum and the residue extracted with CH2CI2. The extract was washed with H2O, brine and dried with Na2SO4. The solvent was removed to give 0.53 g of solid which was chromatographed on thick layer silica gel plates with hexane-ethyl acetate (2:1) as solvent to give 0J43 g (31 %) of product, as crystals, m.p. 112°-114°C. Anal, for C18H19CIN2O8S:
Calc'd: C.47.2; H,4J; N,6J; Found: C.47.0; H,4J; N,6.0; Mass spectrum (ES) 459J (M+H).
Reference Example 168
Methyl 3-Hydroxy-2-[(4-methoxybenzenesulfonyl)-(4-chloro-2- aminobenzyl)amino]propionate
A mixture of 0.454 g (1 mmol) of methyl 3-hydroxy-2-[(4-methoxy- benzenesulfonyl)-(4-chloro-2-nitrobenzyl)amino]propionate and 0.451 g (2 mmol) of
SnCl2*2H2O in 12 ml of methanol was refluxed for 2 hours. An additional 0.451 g (2 mmol) of SnCl2*2H2O was added and the mixture refluxed for 2 hours. The solvent was removed and ethyl acetate added. The mixture was neutralized with 1 N NaHCO3 and then stirred for 1 hour and filtered. The ethyl acetate layer was separated and washed with H2O, brine and dried with Na2SO4. The solvent was removed to give
0.42 g of solid which was chromatographed on thick layer silica gel plates with hexane- - 71 -
ethyl acetate (45:55) as solvent to give 60 mg of product (Rp 0.66) as a glass, m.p. 99°-1 12°C. Anal, for C18H21CIN2O6S:
Calc'd: C.50.4; H.4.9; N,6.5;
Found: C,49J; H.4.9; N,6.4; Mass spectrum (ES) 429.1 (M+H).
Reference Example 169
Methyl 3-Hydroxy-2-[(4-methoxybenzenesulfonyl)-(4-chloro-2- aminobenzyl)amino]propionate To a solution of 0.458 g (1 mmol) of methyl 3-hydroxy-2-[(4- methoxybenzenesulfonyl)-(4-chloro-2-nitrobenzyl)amino]propionate in 25 ml of ethanol and 25 ml of ethyl acetate was added 0.045 g of 10% Pd/C (wet - 50% H2O).
The mixture was shaken in a Parr hydrogenator under 35 pounds per square inch of hydrogen for 3 hours. The mixture was filtered through diatomaceous earth and the filtrate was concentrated to dryness under vacuum to give 0.47 g of the product as a solid (approximately 90% pure). Thin layer chromatography on silica gel, NMR and Mass spectrum (ES) 429.1 (M+H) 395 J (M+H) indicated approximately 10% of deschloro derivative.
A mixture of 4.74 g of methyl 3-hydroxy-2-[(4-methoxybenzenesulfonyl)-(4- chloro-2-aminobenzyl)amino} propionate, and 0.470 g of 10% Pd/C (wet-50% H2O) in 200 ml of ethyl acetate-ethanol (1: 1) was shaken in a Parr hydrogenator under 35 psi of hydrogen for 4 hours. The mixture was filtered through diatomaceous earth and the solvent removed to give 4.5 g of solid. The solid was chromatographed by HPLC on a Waters Prep machine with a 4 x 30 cm silica gel column with a step gradient of hexane- ethyl acetate (9: 1 to 6:4 to 1: 1 to 0:100) to give 1.56 g of a glass, m.p. 110°-123°C. Anal, for C18H21CIN2O6S:
Calc'd: C, 50.4; H, 4.9; N, 6.5; Cl, 8.3; Found: C, 50.3; H, 4.8; N, 6.5; Cl, 7.8.
Reference Example 170 N-(4-Methoxybenzenesulfonyl)-glycine, Methyl Ester To a mixture of 12.5 g (0J mol) of glycine, methyl ester hydrochloride in 120 ml of CH2CI2, cooled in an ice bath was added 417 ml (0.3 mol) of triethylamine, followed by the dropwise addition of a solution of 20.65 g (0J mol) of 4- methoxybenzenesulfonyl chloride in 40 ml of CH2CI2. The mixture was stirred at room temperature overnight and poured into water. The organic layer was separated - 72 -
and washed with 2 N citric acid, H2O, 1 N NaHCO3. brine and dried with Na2SO4.
The solvent was removed under vacuum to give 24.6 g of residue which was triturated with ethyl acetate to give 19.9 g of crystals, m.p. 59°-61°C. Anal, for 0H13NSO5:
Calc'd: C.46.3; H.5.1 ; N.5.4; Found: C.46J; H.5.0; N.5.2.
Reference Example 171 Methyl 2-[(4-methoxybenzenesuIfonyl)-(2-nitrobenzyl)amino]acetate
To a stirred and cooled mixture of 1 J g (30 mmol) of NaH (58% in oil) in 50 ml of N,N-dimethylformamide was added dropwise a solution of 7.78 g (30 mmol) of N-(4-methoxybenzenesulfonyl)glycine, methyl ester in 40 ml of N,N-dimethyl- formamide. After gas evolution ceased, a solution of 6.80 g (32 mmol) of 2- nitrobenzyl bromide in 40 ml of N,N-dimethylformamide was added dropwise to the mixture. The mixture was then stirred at room temperature overnight under nitrogen and the solvent removed under vacuum. The residue was extracted with CH2CI2 and the extract washed with H2O, 2 N citric acid, H2O, 1 N NaHCO3, brine and dried with Na2SO4, The solution was filtered through a thin pad of hydrous magnesium silicate and the filter pad washed with CH2CI2. The filtrate was concentrated under vacuum to give 1 1.79 g of solid. Trituration with ethyl acetate gave 2.64 g (22%) of crystals, m.p. 114°C-116°C. Anal, for C17H18N2O7S:
Calc'd: C.51.8; H,4.6; N,7J ; Found: C,517; H,4.6; N,7J .
From the mother liquors an additional 6.49 g (55%) of product as crystals was obtained by chilling at 0°C and filtering the mother liquors.
Reference Example 172 Methyl 2-[(2-Aminobenzyl)-(4-methoxybenzenesulfonyl)amino]acetate
(A) To a mixture of 2J5 g (5.45 mmol) of methyl-2-[(4-methoxy- benzenesulfonyl)-(2-nitrobenzyl)amino]acetate and 1.57 g (25 mmol) of ammonium formate in 10 ml of anhydrous methanol was added 0.42 g of 10% palladium on carbon. The mixture was stirred at room temperature for 1.5 hours and then filtered through diatomaceous earth. The filtrate was concentrated to dryness under vacuum and the residue diluted with H2O (25 ml) and extracted with CH2CI2 (75 ml). The extract was washed with brine, dried with Na2SO4 and the solvent removed to give
0.45 g of solid. Crystallization from ethyl acetate gave 0J24 g of white crystals, m.p. 100°-102°C. Anal, for C17H20N2O5S: - 73 -
Calc'd: C,56.0; H,5.5; N,77; Found: C,56J ; H,5.6; N,7.6.
(B) To a solution of 4J g of methyl 2-[(4-methoxybenzenesulfonyl)-(2- nitrobenzyl)amino]acetate in 200 ml of ethanol-ethyl acetate (1: 1) was added 0.42 g of
10% Pd on carbon (wet -50% H2O) and the mixture shaken in a Parr hydrogenator under 35 pounds per square inch of hydrogen for 4.5 hours at room temperature. The mixture was filtered through diatomaceous earth and the filtrate concentrated to dryness under vacuum to give 4.0 g of crystals, m.p. 100°-102°C.
Reference Example 173 2-[(2-Aminobenzyl)-(4-methoxybenzenesulfonyl)amino]acetic Acid To a solution of 5J4 g (14J mmol) of methyl 2-[(2-aminobenzyl)-(4- methoxybenzenesulfonyDamino] acetate in 50 ml of methanol-tetrahydrofuran (1 : 1) was added 2.86 ml of 10 N NaOH and the mixture refluxed for 2 hours. The solvent was removed under vacuum and the residue partitioned between water and ether. The water layer was separated and acidified with 2 N citric acid. The solid was filtered, washed with H2O and dried in a vacuum oven at room temperature to give 4.45 g (91%) of crystals, m.p. 145°-147°C. Anal, for C16H18N2O5S: Calc'd: C,54.9; H,5J; N,8.0;
Found: C,55J; H,5J; N,7.9.
Reference Example 174 Methyl 4-(4-Methoxybenzenesulfonyl)-l -(phenoxyacetyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
To a cooled (0°C) mixture of 1.5 g (3.8 mmol) of methyl 2-[(2-aminobenzyl)- (4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate and 27 ml (19 mmol) of triethylamine in 15 ml of CH2CI2 was added 1.58 g (1 1.4 mol) of phenoxyacetyl chloride. The mixture was stirred at room temperature overnight and filtered. The filtrate was washed with H2O, 2 N citric acid, and brine and dried with Na2SO4. The solvent was removed to give 2.4 g of crude methyl 2-{(4-methoxybenzenesulfonyl)-[2- (phenoxyacetylamino)benzyl]amino} acrylate as an oil. Anal, for C26H26N2O7S:
Calc'd: C,61J; H,5J; N.5.5; Found: C,62.6; H,5J ; N,4.0; Mass spectrum (ES) 511 (M+H). - 74 -
To a 2.0 g (3.92 mmol) sample of the preceding compound in 15 ml of methanol was added 0.494 g of anhydrous NaHCO3 and the mixture stirred for 5 hours. The mixture was concentrated under vacuum and ethyl acetate and H2O were added to the residue. The mixture was filtered and the organic layer of the filtrate separated, washed with brine and dried with Na2SO4. The solvent was removed to give 0.36 g of product as off-white crystals, m.p. 151°-153°C. Anal, for C26H26N2O7S:
Calc'd: C.61.2; H.5.1; N.5.5; Found: C.61.1 ; H.5.1 ; N.5.4; Mass spectrum (ES) 51 1 (M+H).
Reference Example 175
3-hydroxymethyl-4-(4-Methoxybenzenesulfonyl)-l-
(3-pyridinylmethyl)-2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine A mixture of 0J00 g (0.208 mmol) of methyl 4-(4-methoxybenzenesulfonyl)-
1 -(3-pyridinylcarbonyl)-2,3,4,5-tetrahydro- 1 H-[ 1 ,4]benzodiazepine-3-carboxylate and 3 ml of borane-tetrahydroforan complex in tetrahydrofuran (1.0 M) was refluxed overnight. The solution was cooled to room temperature, diluted with methanol and the solvent removed. Methanol was added several times and, after each addition, the solvent was removed. To the residue was added IN NaHCO3. The mixture was stirred for 45 minutes and then extracted with ethyl acetate. The extract was concentrated and then washed with H2O, brine and dried with Na2SO4. The solvent was removed under vacuum and the residue chromatographed on thick layer silica gel plates with 10% methanol in ethyl acetate as solvent to give 60 mg of solid (Rp 0.26). Crystallization from ethyl acetate gave 30 mg of white crystals. Anal, for C23H25N3O4S:
Calc'd: C,62.8; H.5.7; N,9.6; S.7.3;
Found: C.61.1; H,5.6; N,9.2; S,73;
Mass spectrum (ES) 440.2 (M+H).
Reference Example 176
Methyl 4-(4-Methoxybenzenesulfonyl)-l-(2-methoxypyridinyl-3- carbonyl)-2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
To a cooled (0°C) mixture of 1.0 g (2.54 mmol) of methyl 2-[(2-aminobenzyl)- (4-methoxybenzenesulfonyl) amino]-3-hydroxypropionate and 1.8 ml (12.68 mmol) of triethylamine in 10 ml of CH2CI2 was added 0.957 g (5.58 mmol) of 2- methoxypyridine-3-carbonyl chloride in 4 ml of CH2O2. The solution was stirred at - 75 -
room temperature overnight, diluted with H2O and CH2CI2 and the organic layer separated. The organic layer was washed with H2O, 2 N citric acid, and brine and dried with Na2SO4. The solvent was removed under vacuum to give 1.2 g of solid.
The solid was chromatographed on thick layer silica gel plates with ethyl acetate-hexane (3:1) as solvent to give 0J7 g of yellow foam. Anal, for C25H25N3O7S:
Calc'd: C,587, H,4.93; N,8.21 ; Found: C.57.8; H.4.5; N.8.3; S,6J.
Reference Example 177 5-Methyl-2-nitrobenzyl Bromide
To a cooled (ice-water bath) mixture of 30% HBr in acetic acid (3 ml) was added 2.5 g 5-methyl-2-nitrobenzyl alcohol and the chilled solution stirred for 2 hours. The mixture was poured into ice-water and extracted with diethyl ether. The extract was washed with H2O, brine and the solvent removed under vacuum to give a mixture of product (50%) and starting material (50%).
Reference Example 178
Methyl 3-Hydroxy-2-[(4-methoxybenzenesulfonyl)-(5-methyl-2- nitrobenzyl)amino]propionate A solution of 23.14 g (0.08 mol) of methyl 3-hydroxy-2-(4- methoxybenzenesulfonylamino)proρionate in 120 ml of dry N,N-dimethylformamide was added dropwise to a stirred suspension of 3J g (0.08 mol) of sodium hydride (57% in oil) in 120 ml of N,N-dimethylformide. When gas evolution ceased, the mixture was chilled in an ice bath and a solution of 16.4 g (0.084 mol) of 5-methyl-2- nitrobenzyl chloride in 100 ml of N,N-dimethylformamide was added. To the mixture was added 12.6 g (0.084 mol) of anhydrous sodium iodide and the mixture was chilled in an ice bath and stirred for 20 minutes. The mixture was allowed to warm to room temperature and was stirred overnight. The solvent was removed under vacuum and the residue diluted with 200 ml of H2O and extracted with 500 ml of ethyl acetate. The aqueous layer was extracted with an additional 200 ml of ethyl acetate. The combined extract was washed with H2O, brine and dried with Na2SO4. The solvent was removed to give 41.18 g of crude product. The product was chromatographed on silica gel with hexane-ethyl acetate (1:1) as solvent to give 8J4 g (RF 0.38) of product as a yellow semi-solid. From a small scale run ( 1 mmol) the product was chromatographed twice on thick silica gel plates with hexane-ethyl acetate ( 1 : 1 ) to give 0J2 g of a yellow semi-solid. Anal, for C19H22 2SO8: - 76 -
Calc'd: C.52.0: H.5J ; N.6.4; Found: C,517; H.5J ; N,6.0.
Reference Example 179 Methyl 3-Hydroxy-2-[(4-methoxybenzenesulfonyl)-(2-amino-5- methylbenzyl)amino]propionate
To a solution of 3.4 g of methyl 3-hydroxy-2-[(4-methoxybenzenesulfonyl)-(5- methyl-2-nitrobenzyl)-amino]propionate in 200 ml of ethanol-ethyl acetate (1 : 1) was added 0.34 g of 10% palladium on carbon (wet - 50% H2O). The mixture was then shaken in a Parr hydrogenator under 35 psi of hydrogen for 2.5 hours. The mixture was filtered through diatomaceous earth and the filtrate concentrated under vacuum to give 2.86 g of a brown oil. Anal, for C19H24N2O6S:
Calc'd: C,55.9; H,5.9; N,6.9; Found: Q55.6; H,5.9; N.6.4; Mass spectrum (ES) 409 (M+H).
Reference Example 180
Methyl 3-[(2-Tetrahydropyranyl)oxy]-2-[(-4-methoxybenzenesulfonyl)-
(5-methyI-2-nitrobenzyl)amino]propionate To a mixture of 175 g (4.68 mmol) of (D,L)N-(4-methoxybenzenesulfonyl)-O-
(2-tetrahydropyranyl) serine, methyl ester, 0.790 g (4.68 mmol) of 5-methyl-2- nitrobenzyl alcohol and 1.23 g (4.68 mmol) of triphenylphosphine in 4.5 ml of anhydrous tetrahydrofuran was added dropwise (over 15 minutes) a solution of 0.815 g (4.68 mmol) of diethyl azodicarboxylate (DEAD) in 1 ml of tetrahydrofuran. The mixture was stirred at room temperature overnight and the solvent removed under vacuum. The residue was triturated with diethyl ether and the solid filtered off. The filtrate was concentrated to dryness under vacuum to give 4.67 g of solid. The solid was chromatographed on silica gel with hexane-ethyl acetate (1 : 1) to give 0.56 g of product (RF 0.48).
Reference Example 181
Methyl l-Methoxyacetyl-4-(4-methoxybenzenesulfonyl)-
7-methyl-2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
To a cooled (0°C) mixture of 1.598 g (3.91 mmol) of methyl 3-hydroxy-2-[(4- methoxybenzenesulfonyl)-(2-amino-5-methylbenzyl)amino]propionate and 1.97 g
(19.5) mmol) of triethylamine in 15 ml of dichloromethane was added 0.787 ml (8.60 mmol) of methoxy acetylchloride. The mixture was stirred at room temperature - 77 -
overnight. The mixture was then diluted with CH2CI2 and washed with H2O. 2 N citric acid. H2O. brine and dried with Na2SO4. The solution was filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to give 1.94 g of crude methyl 2-{ [2-(methoxyacetylamino)-5-methylbenzyl]-(4-methoxy-benzene- sulfonyl)-amino} acrylate as a brown oil. Mass spectrum (ES) 463.4 (M+H).
To a solution of 1.62 g (3.5 mmol) of the preceding compound in 15 ml of anhydrous methanol was added 0.382 g (4.50 mmol) of anhydrous NaHCO3 and the mixture was stirred overnight at room temperature. The solvent was removed under vacuum and the residue partitioned between 100 ml of ethyl acetate and 20 ml of water. The ethyl acetate layer was separated and washed with H2O. brine and dried with Na2SO4. The solution was filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated under vacuum to give a yellow oil. Trituration with ethyl acetate-hexane gave 1.26 g (78%) of tan crystals, m. p. 122°-124°C. Anal, for C22H26N2O7S:
Calc'd: C,57J; H,57; N,6J; Found: C,57.4; H,57; N,6.0.
Reference Example 182 Methyl l-Benzoyl-4-(4-methoxybenzenesulfonyl)-7-methyl-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazeprine-3-carboxylate
To a cooled (0°C) mixture of 1.465 g (3.586 mmol) of methyl 3-hydroxy-2-[4- methoxybenzenesulfonyl)-(2-amino-5-methylbenzyl)amino]propionate and 2.49 ml (17.93 mmol) of triethylamine in 20 ml of CH2CI2 was added 0.915 ml (7.89 mmol) of benzoyl chloride. The mixture was stored at room temperature overnight, diluted with CH2CI2 and washed with H2O, 2 N citric acid, H2O, brine and dried with Na2SO4. The solution was filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated under vacuum to give 1.8 g of crude methyl 2-[(2- benzoylamino-5-methylbenzyl)-(4-methoxybenzenesulfonyl)amino]acrylate as a brown oil. Anal, for C26H26N2O6S:
Calc'd: C,63J ; H,53; N,57; Found: C,63.9; H,5J; N.5.2.
As described for Reference Example 181, 1.825 g (3.68 mmol) of the preceding compound was stirred with 0.402 g (478 mmol) of NaHCO3 in 1.5 ml of methanol to give an oil. Trituration with hexane (plus several drops of ethyl acetate) gave crystals, m. p. 58°-62°C. - 78 -
Reference Example 183
Methyl l-(trans-Crotonyl)-4-(4-methoxybenzenesulfonyl)-7-methyl-
2,3,4,5-tetrahydro-lH-[l,4]benzadiazepine-3-carboxylate As described for Reference Examples 181 and 182. a mixture of 1.41 g (3.455 mmol) of methyl 3-hydroxy-2-[-(4-methoxybenzenesulfonyl)-(2-amino-5-methyl- benzyl)amino]propionate, 1.75 g (173 mmol) of triethylamine and 0.809 ml of trans- crotonyl chloride in 15 ml of CH2CI2 was stirred overnight to give 1.52 g of methyl 2-
{ [2-(trans-crotonylamino)-5-methylbenzyl]-(4-methoxybenzenesulfonyl) aminojacrylate as a brown oil; Mass spectrum (ES) 459.4 (M+H).
As described in Reference Example 181, 1.52 g (3.31 mmol) of the preceding product was stirred with 0.362 g (4.3 mmol) of NaHCO3 in 15 ml of methanol at room temperature overnight. To the mixture was added 0.056 g of NaHCO3 and the mixture was heated at 80°C for 3 hours and worked up as for Reference Example 181 to give a
1.05 g of a yellow glass, m. p. 75°-84°C. Mass spectrum (ES) 459.4 (M+H).
Reference Example 184 l-(trans-Crotonyl)-4-(4-methoxybenzenesulfonyl)-7-methyl-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepene-3-carboxylic acid
A mixture of 1J6 g (2.72 mmol) of methyl l-(trans-crotonyl)-4-(4- methoxybenzenesulfonyl)-7-methyl-2,3,4,5-tetrahydro- 1 H-[ 1 ,4]benzodiazepine-3- carboxylate and 3.53 ml (3.53 mmol) of 1 N NaOH in 10 ml of tetrahydrofuran was stirred at room temperature for 3 hours. The solvent was removed under vacuum and the residue dissolved in H2O and the solution extracted with ethyl acetate. The aqueous layer was acidified with IN HCl (pH 2) and extracted with CH2CI2. The CH2CI2 extract was dried with Na2SO4 and the solvent removed to give 1.06 g (after drying under vacuum) of solid, m. p. 101°-105° C.
Reference Example 185 l-(Benzoyl)-4-(4-methoxybenzenesulfonyl)-7-methyl-2, 3-4,5- tetrahydro-lH[l,4]benzodiazepine-3-carboxylic acid
A mixture of lJ8g (2.38 mml) of methyl l-(benzoyl)-4-(4- methoxy - benzenesulfonyl)-7-methyl-2,3,4,5-tetrahydro- 1 H-[ 1 ,4]benzodiazepine-3-carboxylate and 3.09 ml (3.09 mmol) of IN NaOH in 10 ml of tetrahydrofuran was stored at room temperature overnight and the solvent removed under vacuum. The residue was diluted with H2O. extracted with ethyl acetate and the aqueous layer acidified with 2N citric - 79 -
acid. The mixture was extracted with CH2CI2 and the CH2CI2 extracts were washed with H2O, brine and dried with Na2SO4. The solvent was removed to give 0.82g of a light yellow glass, m.p. 95°-100°C; Mass spectrum (ES) 481.4 (M+H).
Reference Example 186
Methyl 4-(4-Methoxybenzenesulfonyl)-l-(2-methoxyethyI)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
A mixture of 1.6 g (3.57 mmol) of methyl l-(methoxyacetyl)-4-(4- methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1 H-[ 1 ,4]benzodiazepine-3-carboxylate and 32 ml of borane in tetrahydrofuran (1.0 M) was refluxed under nitrogen overnight. Methanol was added and the solvent removed. To the residue was added 25 ml of CH2CI2 and 25 ml of 2 N HCl and the mixture stirred at room temperature for 1 hour. The organic layer was separated and washed with H2O and concentrated to dryness. The residue was triturated with ethyl acetate-hexane, cooled and filtered to give 1 J g of white crystals, m.p. 86°-90°C; Mass spectrum (ES) 435.4 (M+H). Anal, for C2lH26N2θ6S:
Calc'd: C,58J ; H.6.0; N,6.5; Found: C,58.5; H,6.0; N,6.5.
Reference Example 187
4-(4-Methoxybenzenesulfonyl)-l-(2-methoxyethyl)-2,3,4,5-tetrahydro- lH[l,4]benzodiazepine-3-carboxylic acid
A mixture of 1.0 g (2.3 mmol) of methyl 4-(4-methoxybenzenesulfonyl)-l-(2- methoxyethyl)-2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate and 3.0 ml of I N NaOH in 10 ml of tetrahydrofuran was stirred at room temperature for 2 hours and the solvent removed. To the residue was added water and the mixture acidified with 1 N HCl. The mixture was extracted with ethyl acetate and the extract was washed with brine and dried with Na2SO4. The solvent was removed and the residue triturated with ethyl acetate-hexane, cooled and filtered to give 0.65 g of white crystals, m.p. 164°- 165°C; Mass spectrum (ES) 421.4 (M+H). Anal, for C20H24N2O6S:
Calc'd: C.57J; H,5.8; N,67; Found: C,573; H,57; N,6.4. - 80 -
Reference Example 188
Methyl l-(Benzyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- lH-[l,4]benzodiazepine-3-carboxylate
A mixture of 0J0 g (0.416 mmol) of methyl 1 -(benzoyl )-4-(4- methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate and 4 ml of borane in tetrahydrofuran ( 1.0 M) was refluxed overnight and the solvent removed. To the residue was added 5 ml of CH2CI2 and 5 ml of 2N HCl and the mixture stirred for 1 hour. The organic layer was separated and concentrated to dryness. The residue was chromatographed on thick layer silica gel plates with hexane- ethyl acetate (2: 1 ) as solvent to give 0J40 g of a colorless oil; Mass spectaim (ES) 467.5 (M+H).
Reference Example 189 4-(4-Methoxybenzenesulfonyl)-l -[4-(trifluoromethoxy)benzoyl]-8- chloro-2,3,4,5-tetrahydro-lH[l,4]benzodiazepine-3-carboxylic acid
As described for Reference Example 18, 1.46 g (3.40 mmol) of methyl 2-[(2- amino-4-chlorobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxyproρionate was reacted with 4-(trifluoromethoxy)benzoyl chloride to give 2.59 g of methyl 2-{2-[4- (trifluoromethoxy) benzoyl]amino-4-chlorobenzyl]amino} acrylate as a yellow oil; Mass spectrum (ES) 599.3 (M+H). The preceding compound was stirred with 0.445 g (5.29 mmol) of anhydrous NaHCO3 in 15 ml of methanol at room temperature for 16 hours and then was heated at 80°C for 2 hours. The solvent was removed and the residue extracted with ethyl acetate. The extract was washed with H2O. brine, and dried (Na2SO4). The solvent was removed and the residue crystallized from ethyl acetate- hexane to give methyl 4-(4-methoxybenzenesulfonyl)- 1 -[4-(trifluoromethoxy)benzoyl } - 8-chloro-2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate as yellow crystals, m.p. 149°-151°C. Anal, for C26H22CIF3O7S:
Calc'd: C,52J; H,37; N.4.7; Cl.6.0; F.9.5; Found: C.51.8; H,3.6; N.4.7; Cl,5.9; F.9.4.
1.58g (2.64 mmol) of the preceding compound was stirred with 3.43 ml of IN NaOH in 10 ml of tetrahydrofuran at room temperature for 2 hours and worked up as for Reference Example 104 to give 1.52 g of product. Crystallization from ethyl acetate-hexane gave 1.2 g of white crystals, m.p. 184°-186°C. - 81 -
Reference Example 190
Methyl 4-(4-MethoxybenzenesuIfonyl)-l-(4-morpholinoacetyl)-2,3,4,5- tetrahydro-lH[l,4]benzodiazepine-3-carboxylate
A mixture of 0J0 g (0J2 mmol) of methyl l-(chloroacety])-4-(4- methoxybenzenesulfonyl)-2,3,4.5-tetrahydro-lH-[l,4]benzodiazepine-3-caι-boxylate, 21 J El of morpholine and 125.4 El of N.N-diisopropylethylamine in 3 ml of CH2CI2 was stirred overnight at room temperature. An additional 2J El of moφholine was added and the solution stirred for 2 days at room temperature. The mixture was diluted with CH2CI2 and washed with H2O, brine and dried with Na2SO4. The solvent was removed to give the product as a solid, Mass spectrum (ES) 504.3 (M+H). Anal, for C24H29N3O7S:
Calc'd: C.57.2; H.5.8; N.8.3; Found: C,56.5; H.5.6; N,8J .
Reference Example 191
Methyl 4-(4-Methoxybenzenesulfonyl)-l-[2-(l- pyrazolyI)phenylcarbonyl]-7-methyl-2,3,4,5-tetrahydro-lH-
[l,4]benzodiazepine-3-carboxylate
As described for the general reaction of ethyl 2-fluorobenzoate with amines set forth in Tetrahedron. 53:7557-7576 (1997), ethyl 2-fluorobenzoate was reacted with pyrazole by refluxing N,N-dimethylformamide to give ethyl 2-(l-pyrazolyl)benzoate, as a thick yellow oil. Anal. Calc'd: for C12 H12 N2O2: C, 667; H, 5.6; N 13.0: Found: C, 66.5: H, 5.4: N, 12.9; Mass spectrum (ES) 217.2 (M+H). A sample (7.02g) of this compound and 8.42 ml of 5N NaOH in 40 ml of ethanol-tetrahydrofuran (2: 1) was refluxed for 2 hrs and the solvent removed. The residue was made acidic (pH6) with 2N citric acid and the precipated solid was filtered to obtain 37g of product. The pH of the filtrate was adjusted to 4.5 and extracted with ethyl acetate. The extract was concentrated to dryness to give 1.5g of product. The two crops were combined to give 5Jg of 2-(l-pyrazolyl)benzoic acid, mp 140-142°C. To the preceding compound (2.07 g) in 5 ml CH2C12 (chilled in an ice bath )was added 11.1 ml of a 2 Molar solution of oxalyl chloride in CH2C12 and 0.085 ml of N,N-dimethylformamide. The mixture was allowed to warm to room temperature and stirred for 4 hours. The solvent was removed and 25 ml of toluene added (twice) and removed under vacuum to give 2- (l-pyrazolyl)benzoyl chloride as a yellow solid.
A 2.3 g sample of the preceding compound was reacted with 1.5g of the compound of Reference Example 179 in 15 ml of CH2C12 and 5J2 ml of triethylamine - 82 -
in the manner described for Reference Example 181 to give methyl 2-[(4- methoxybenzenesulfonyl)-{2-[2-(l-pyrazolyl)phenylcarbonyl]amino-5-methylbenzyl}- amino]acrylate. This compound was cyclized with NaHCO3 in methanol in the manner described in Reference Example 181 to give methyl 4-(4-methoxybenzenesulfonyl)-l- [2-( 1 -pyrazolyl)phenylcarbonyl]-7-methyl-2,3 ,4,5-tetrahydro- 1 H-[ 1 ,4]benzodiazepine- 3-carboxylate (m.p. 240-242° C).
A 1J6 g sample of the preceding compound was hydrolysed with 2.69 ml of
IN NaOH in 10 ml of tetrahydrofuran in the manner described for Reference Example 104 to give 0.71 g of 4-(4-methoxybenzenesulfonyl)-l-[2-(l-pyrazolyl)phenyl- carbonyl)-7-methyl-2,3,4,5-tetrahydro-lH[l,4]benzodiazepine-3- carboxylic acid (mp
149-151°C).
Reference Example 192 Methyl 4-(4-Methoxybenzenesulfonyl)-l-[2-(4- morpholino)phenylcarbonyl}-8-chloro-2,3,4,5-tetrahydro-lH- [l,4]benzodiazepine-3-carboxylate
Ethyl 2-moφholinobenzoate prepared in the manner described in Tetrahedron. 53:7557, (1997) was refluxed with 10 N NaOH in tetrahydrofuran-ethanol (8:2) for 1.5 hrs to give 2-moφholinobenzoic acid, mp 156-157°C. A 1.8 g sample of this compound in 5 ml of CH2C12 (chilled) was added to a solution of 7.9 ml of oxalyl chloride in CH2C12 (2M) followed by the addition of 0.058 ml of N,N- dimethylformamide. The solution was stirred at room temperature for 6 hrs and the solvent removed. Toluene was added (2 times) and removed to give 2-(4- moφholino)benzoyl chloride as a yellow solid.
The preceding 2-(4-moφholino)benzoyl chloride was reacted with methyl 2-[(2- amino-4-chlorobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate in the manner described in Reference Examples 181 and 189, and the product was stirred with NaHCO3 in methanol to give methyl 4-(4-methoxybenzenesulfonyl)-l-[2-(4- moφholino)phenylcarbonyl]-8-chloro-2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3- carboxylate, as a white solid having a mp 100-105°C.
To 0.90g of this compound in 10 ml of tetrahydrofuran was added 1.95 ml of 1 N NaOH and the solution was stirred at room temperature overnight. Acidification with
2N citric acid gave 0.82 g of 4-(4-methoxybenzenesulfonyl)-l-[2-(4-moφholino)- - 83 -
phenylcarbonyl]-8-chloro-2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid (mp 136-143 °C).
Reference Example 193 Methyl l-(4-Ethoxybenzoyl)-4-(4-methoxybenzenesulfony!) -
2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
A mixture of 0.270 g of methyl 4-(4-methoxybenzenesulfonyl)-2,3,4,5- tetrahydro- 1H-[1, 4] benzodiazepine-3-carboxylate of Reference Example 12, 0J91 g of 4-ethoxybenzoyl chloride and 500 μl of triethylamine in 5 ml of CH2C12 was stirred at room temperature overnight. The mixture was diluted with CH2C12 and H2O and the CH2C12 layer was separated and concentrated to dryness. The residue was triturated with ethyl acetate to give 0J76g of methyl l-(4-ethoxybenzoyl)-4-(4-methoxy- benzenesulfonyl)-2,3,4,5tetrahydro-lH-[l ,4]benzodiazepine-3-carboxylate as white crystals, (mp 187-190°C).
A 0.47 g sample of this compound was hydrolyzed with 1 J ml of IN NaOH in 4 ml of tetrahydrofuran. Dilution with H2O and acidification with IN HCl gave 0.40 g of the acid as a white solid, mp 144-152°C.
Reference Example 194
Methyl 4-(4-Methoxybenzenesulfonyl) -l-[2-chloro-4-(3-methyl-l- pyrazolyl)phenylcarbonyl}-2,3,4,5-tetrahydro -1H-
[l,4]benzodiazepine-3-carboxylate
As described in Example 65, methyl 4-(4-methoxybenzenesulfonyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate was reacted with 4-(3-methyl-l- pyrazolyl)-2-chlorobenzoyl chloride to give methyl 4-(4-methoxybenzenesulfonyl)-l-
[2-chloro-4-(3-methyl-l-pyrazolyl)phenylcarbonyl]-2,3,4,5-tetrahydro-lH-[l,4]benzo- diazepine-3-carboxylate as a white solid. Anal, for C29H27ClN4O6S:
Calc'd: C, 58.3; H, 4.6; N, 9.4. Found: C,58J; H, 4.9; N, 8.9.
This compound was hydrolysed with IN NaOH in tetrahydrofuran as described in Reference Example 185 to give the benzodiazepine-3-carboxylic acid derivative as a white solid. - 84 -
Reference Example 195 l-Benzyl-4-(4-methoxybenzenesulfonyl) -2,3,4, 5-tetrahydro-lH-
[l,4]benzodiazepine-3-carboxy!ic acid
A mixture of 17 g of the compound of Reference Example 45 and 25 ml of borane in tetrahydrofuran ( 1.0 Molar) was refluxed under nitrogen overnight. To the solution was added 5 ml of CH3OH, CH2C12 (40 ml) and 30 ml of 2N HCl and the mixture stirred at room temperature for 1.5 hr. The organic layer was separated, washed with brine, dried with Na2SO4 and the solvent removed. The residue was crystallized from ethanol-hexane to give lJ5g of methyl l-benzyl-4-(4- methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- lH-[ 1 ,4]benzodiazepine-3-carboxylate as white crystals, mp 120-122°C. A sample (1.0 g) of this compound was hydrolysed with 2.8 ml of 1 N NaOH in 7 ml of tetrahydrofuran as described in Reference Example 104 to give 0.64 g of the 2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid derivative as white crystals (mp 183-185°C).
Reference Example 196 Methyl l-(2,4-Dimethoxybenzoyl)-4-(4-methoxybenzenesuIfonyl)- 2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate To a cooled (0°C) solution of 1.0 g (2.66 mmol) of 4-(4- methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate from Reference Example 12 and 1.85 ml (13.3 mmol) of triethylamine in 8 ml of CH2CI2 was added 1J7 g (6.65 mmol) of 2,4-dimethoxybenzoyl chloride. The mixture was stirred at room temperature overnight, diluted with CH2CI2 and washed with 2 N citric acid. The organic layer was washed with H2O, 1 N Na2CO3, brine and dried over Na2SO4- The solvent was removed and the residue was chromatographed on thick layer silica gel plates with ethyl acetate-hexane (1: 1) as an eluent to give 1.0 g of methyl l-(2,4-dimethoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate as a white foam. Anal, for 27H28H2°8S: Calc'd: C,60.0; H,5J; N.5.2;
Found: C.60.0; H.5.2; N.5.1;
Mass Spectrum (ES): 541.0 (M+H).
A 0.80 g (1.48 mmol) sample of the preceding compound and 1.92 ml (1.92 mmol) of 1 N NaOH in 5 ml of tetrahydrofuran was stirred at room temperature for 1.5 hours. The solvent was removed and the residue diluted with water. The solution was acidified with 1 N HCl, chilled and filtered to give 0.70 g of l-(2,4-dimethoxy- - 85 -
benzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine- 3-carboxylic acid as a white solid. Anal, for C26H26N2O8S:
Calc'd: C.59.3; H,5.0; N.5.3; Found: C.56J ; H,4.8; N.5.0; Mass Spectrum (ES): 527.0 (M+H).
Reference Example 197 Methyl 4-(4-Methoxybenzenesulfonyl)-l-[2-(4-methylpiperazin-l- yl)acetyl]-2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate To a mixture of 2.5 g (6.64 mmol) of methyl 4-(4-methoxybenzenesulfonyl)-
2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate (Reference Example 12) and 4.63 ml (33J mmol) of triethylamine in 40 ml of CH2CI2 cooled to 0°C was added to
1.65 g (14.63 mmol) of chloroacetyl chloride. The solution was stirred at room temperature for 2 days, chilled to 0°C and 926 μl of triethylamine and 750 mg of chloroacetyl chloride were added thereto. The mixture was stirred at room temperature overnight, diluted with CH2CI2 and H2O. The insoluble solid was filtered off. The organic layer of the filtrate was separated , washed with brine, dried with Na2SO4 and filtered through diatomaceous earth. The solvent was removed and the residue triturated with ethyl acetate and a trace of ethanol. Chilling and filtering gave 0.75 g of methyl 1 -(chloroacetyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1 H-
[l,4]benzo-diazepine-3-carboxylate (Reference Example 91). Anal. for C2oH2iClN2O6S:
Calc'd: C,53.0; H,47; N.6.2; Found: C,51.6; H.4.6; N.5.7; Mass Spectrum (ES): 453.0 (M+H).
To a solution of 1.4 g (3.09 mmol) of the preceding compound in 12 ml of CH2CI2 cooled to 0°C was added 1.2 ml (6.79 mmol) of N,N-diisopropylethylamine followed by the addition of 753J μl (6.79 mmol) of 1-methylpiperazine. The mixture was stirred at room temperature overnight, diluted with CH2CI2, and washed with 2 N citric acid, H2O, 1 M NaHCO3, brine and dried (Na2SO4). The citric acid wash was made basic with saturated NaHCO3 and then extracted with CH2CI2. The extract was dried over Na2SO4 and the solvent removed under vacuum to give 1 JO g of methyl 4-
(4-methoxybenzenesulfonyl)- 1 -[2-(4-methylpiperazin- 1 -yl)acetyl]-2,3,4,5-tetrahydro- lH-[l,4]benzodiazepine-3-carboxylate as a white glass. - 86 -
A mixture of 1.0 g ( 1.94 mmol) of the preceding compound and 2.3 ml (2.3 mmol) of 1 N KOH in 5 ml of methanol was stirred at room temperature for 2 hours. The solvent was removed under vacuum. To the residue was added toluene (2 times) and the solvent removed under vacuum after each addition. The solid was dried at 65°C under vacuum for 6 hours to give 1J g of potassium 4-(4-methoxybenzenesulfonyl)-l- [2-(4-methylpiperazin- 1 -yl)acetyl]-2,3,4,5-tetrahydro- 1 H-[ 1 ,4]benzodiazepine-3- carboxylate as a white solid.
Reference Example 198 Methyl l-Acetyl-4-(4-hydroxybenzenesu!fonyI)-2,3,4,5- tetrahydro-lH-[l,4] benzodiazepine-3-carboxylate
To a cooled (0°) solution of 2.0g (4.78 mmol) of methyl l-acetyl-4-(4- methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate in 14 ml of CH2 C12 was added dropwise 143.3ml (143mmol) of a 1.0 molar solution of BBr3 in CH2 Cl2 The mixture was stirred at room temperature for 1.5 hours. Ice and H2O were added to the reaction mixture and the insolubles filtered off. The filtrate was diluted with CH2C12 and H2O and the CH2C12 layer separated, washed with brine and dried (Na2 SO4). The solvent was removed under vacuum to give 1.5 g of a white foam. The solid was chromatographed on silica gel with hexane-ethyl acetate (1:1) as solvent to give a foam which was dried under vacuum to give 0.52 g of product as a white foam; Anal. Calc'd for Cι9H20N2O6S: C, 56 4:H, 5.0; N, 6.9 Found: C 55J ; H, 4.7: N, 6.5.
Reference Example 199 Methyl 4-(4-Hydroxybenzenesulfonyl)-l-(2-thienylcarbonyI)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
To a solution of 4.0 g (8.22 mmol) of methyl 4-(4 methoxybenzenesulfonyl)-l- (2-thienylcarbonyl)-2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate in 17 ml of CH2C12 chilled to 0°C, was added slowly 16.4 ml (16.44 mmol) of 1.0 molar solution of boron tribromide in CH2C12. The mixture was stirred at room temperature overnight and diluted with CH2C12. The mixture was filtered and the solid washed with CH2C12. and H2O. The filtrate was diluted with H2O and the organic layer separated. The solvent was removed under vacuum and the solid chromatographed on silica gel with hexane-ethyl acetate (1:1) as solvent to give 0.80 g of off white foam; Mass Spectrum (ES) 473.5 (M+H); Anal. Calc'd for C22 H2Q N2O6 S2: C, 55.9; H, 4.3; N, 5.9. Found: C, 54.5; H, 4.4; N, 5.5. - 87 -
Reference Example 200
Methyl l-Benzoyl-4-(4-hydroxybenzenesu!fonyI)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
To a solution of 9.8 g (20.39 mmol) of methyl l-benzoyl-4-(4- methoxybenzenesulfonyl)-2,3,4,5-tetraydro-lH-[l,4]benzodiazepine in 50 ml of
CH2C12 cooled to 0°, was added slowly 40.8 ml (40.8 mmol) of a 1.0 molar solution of BBr3 in CH2C12 The mixture was stirred under nitrogen at room temperature overnight. Ice and H2O were added and the mixture diluted with CH2C12. The organic layer was separated and the aqueous layer extracted with ethyl acetate. The combined organic extracts (CH2Cl +ethyl acetate) were concentrated under vacuum and the residue dissolved in ethyl acetate. The solution was washed with H2O, brine and dried
(Na2SO4). The solution was filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness. The residue was chromatographed on silica gel with hexane-ethyl acetate as solvent to give 8 g of product as an off-white foam; Mass Spectrum (ES) 467 (M+H); Anal Calc'd for C24H22N2O6S: C, 61.8; H, 4.8; N, 6.0.
Found: C, 61.3; H, 4.6; N, 5.8.
Utilizing the method described in Reference Examples 191-193, the following methyl- 1 -substituted-4-hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro- lH-[ 1 ,4] benzodiazepine-3-carboxylates can be prepared.
Reference Example 201
Methyl 4-(4-Hydroxybenzenesulfonyl)-l-(4-methylphenylsuIfonyl)-
2,3,4, 5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate.
Reference Example 202
Methyl l-Methanesulfonyl-4-(4-hydroxybenzenesulfonyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepinef-3-carboxylate
6.0 g (13.2 mmol) of Reference Example 44 and 22.6 ml (22.6 mmol) of BBr3 in CH2C12 (solution) gave, after chromatography on silica with ethyl acetate-hexane (1: 1), 0.82g of a white foam; Mass spectrum (ES) 440.9 (M + H).
Reference Example 203 Methyl 4-(4-Hydroxybenzenesulfonyl)-l-(3-pyridinylcarbonyl) 2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate - 88 -
Reference Example 204
Methyl 4-(4-Hydroxybenzenesulfonyl)-l-(4-pyridiny lcarbony 1-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Reference Example 205
Methyl l-(4-Biphenylcarbonl)-4-(4-hydroxybenzenesulfonyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Reference Example 206 Methyl 4-(4-Hydroxybenzenesulfonyl)-l-(propane-l-sulfonyI)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxy!ate
Reference Example 207 Methyl l-([l,I'-Biphenyl]-2-carbonyl)-4-(4-hydroxybenzenesulfonyI)- 2,3,4, 5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Reference Example 208 Methyl l-(3-FIuorobenzoyl)-4-(4-hydroxybenzenesulfonyI)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Reference Example 209 Methyl 4-(4-Hydroxybenzenesulfonyl)-l-(2-methyl-5-fluorobenzoyl)- 2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Reference Example 210
Methyl 4-(4-Hydroxybenzenesulfonyl)-l-(2-methyI-3-fluorobenzoyl)- 2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Reference Example 211 Methyl 4-(4-HydroxybenzenesulfonyI)-l-(3-phenylpropionyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate - 89 -
Reference Example 212
Methyl 4-(4-Hydroxybenzenesulfonyl)-l-(2-trifluoromethyIbenzoyI)-
2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Reference Example 213
Methyl l-(2-Chloro-6-trifluoromethyIbenzoyl)-4-(4- hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3- carboxylate
Reference Example 214
Methyl l-(4-Fluoro-2-trifluoromethylbenzoyl)-4-(4- hydroxybenzenesulfonyI)-2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3- carboxylate
Reference Example 215
Methyl l-(2-Fluoro-6-trifluoromethybenzoyl)-4-(4- hydroxybenzenesulfonyI)-2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3- carboxylate
Reference Example 216
Methyl 4-(4-Hydroxybenzenesulfonyl)-l-(2 methy!benzoyI)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Reference Example 217 Methyl 4-(4-Hydroxybenzenesulfonyl)-l-(2-methyI-6-chlorobenzoyI)- 2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylateReference
Example 218 Methyl l-(2,4-Dimethylbenzoyl)-4-(4-hydroxybenzenesulfonyI)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Reference Example 219
Methyl l-(2,5-Dimethylbenzoyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate - 90 -
Reference Example 220
Methyl l-(2-Chloro-4-fluorobenzoyl)-4-(4-hydroxybenzenesulfonyl)-
2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Reference Example 221
Methyl l-(2-Chlorobenzoyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Reference Example 222 Methyl l-(2-Fluorobenzoyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxy!ate
Reference Example 223 Methyl l-(2-Chloro-6-fluorobenzoyl)-4-(4-hydroxybenzenesulfonyl)- 2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Reference Example 224 Methyl l-(2,3-Dif!uorobenzoyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Reference Example 225
Methyl l-(2,4-Dich!orobenzoyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Reference Example 226
Methyl l-(2,3-Dichlorobenzoyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Reference Example 227 Methyl-l-(2,5-Dichlorobenzoyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Reference Example 228 Methyl 4-(4-Hydroxybenzenesulfonyl)-l-(2-methylthiobenzoyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate - 91 -
Reference Example 229
Methyl 4-(4-HydroxybenzenesulfonyI)-l-(3-methyl-2-thienyIcarbonyl)-
2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Reference Example 230
Methyl 4-(4-HydroxybenzenesuIfonyl)-l-(4-methyI-2-thienylcarbonyl)- 2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxy!ate
Reference Example 231 Methyl l-(3-Chloro-2-thienylcarbonyl)-4-( hydroxybenzenesulfonyl)- 2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Reference Example 232 Methyl l-(2-Furanylcarbonyl)-4-(4-hydroxybenzenesulfonyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
To a solution of 3.0g (6.38 mmol) of methyl l-(2 furanylcarbonyl)-4-(4- methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1 H-[ 1 ,4]benzodiazepine-3-carboxylate in., 15 ml of CH2C12 (cooled to 0°C ) was added dropwise 12.8ml (2.8 mmol) of BBr3 in CH2C12 (1.0 M in CH2Cl2).The mixture was stirred at room temperature for 3 days, diluted with CH2C12 and then ice was added. The organic layer was separated, washed with H2O, brine and dried (Na2SO4). The solvent was removed and the residue chromatographed on silica gel (flash column) with ethyl acetate-hexane (1:1) as solvent. The fractions containing product were combined, the solvent removed and the residue triturated with ethyl acetate. Chilling and filtering gave 072g of methyl l-(2- furanyl- carbonyl)-4-hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3- carboxylate as a white solid, mp 204-206°C; Anal Cal'd for C22H20N2O7S: C, 57.9; H,
4.2; N, 6.1. Found: C.57.2; H.4.3; N, 6.0.;Mass spectrum (ES) 457.1 (M+H).
Reference Example 233 Methyl 4-(4-Hydroxybenzenesulfonyl)-l-(3-methyl-2- furanylcarbonyl)-2,3,4,5- tetrahydro-lH-[-l,4]benzodiazepine-3- carboxylate - 92 -
Reference Example 234 Methyl 4-(4-HydroxybenzenesulfonyI)-l-(4-methyI-2- furany!carbonyI)-2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3- carboxylate
Reference Example 235 Methyl l-(5-Chloro-2-furanylcarbonyI)-4-(4- hydroxybenzenesulfonyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-
3-carboxylate
Reference Example 236 Methyl l-(5-Chloro-2-thienylcarbonyI)-4-(4- hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH-[l,4]benzodeiazepine-
3-carboxylate
Reference Example 237 Methyl 1- Propionyl-4-(4-hydroxybenzenesulfonyI)-2,3,4,5- tetrahydro-lH-[l,4]benzodeiazepine-3-carboxylate
Reference Example 238
Methyl l-Hexanoyl-4-(4-hydroxybenzenesulfonyI)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Reference Example 239 Methyl 4-(4-HydroxybenzenesulfonyI)-l-(3-thienylcarbonyl)-
2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Reference Example 24 Methyl l-(3-FuranylcarbonyI)-4-(4-hydroxybenzenesulfonyI)- 2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate
Reference Example 241 Methyl l-(Acetylaminoacetyl)-4-(4-hydroxybenzenesulfonyl)- 2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate - 93 -
Reference Example 242 Methyl 1-(N,N Dimethylaminoacetyl)-4-(4- hydroxybenzenesulfonyl)- 2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-
3-carboxylate
Reference Example 243 Methyl l-(Cyclopropylcarbonyl)-4-(4-hydroxybenzenesu!fonyl)- 2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine
To a solution of 4..44g(10 mmol) of methyl l-cyclopropylcarbonyl-4-(4- methoxybenzenefulfonyl)-2,3,4-tetrahydro-lH-[l,4]benzodiaxepine -3-carboxylate in
25 ml of CH2C12 chilled to 0 C was added dropwise 22 ml (22 mmol) of BBr3 in CH2C12 (1.0 molar solution). The mixture was stirred overnight, cooled and diluted with ice and H2O. Dichloromethane was added and the organic layer separated and washed with H2O, brine and dried (Na2SO4). The solvent was removed under vacuum to give a solid which was chromatographed on silica gel with the solvent ethyl acetate- hexane (1:1) to give 1.0 g of methyl l-cyclopropylcarbonyl-4-(4-hydroxybenzene- sulfonyl)-2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate as a foam; Mass spectrum (ES) 431.3 (M+H).
Reference Example 244
Methyl 4-(4-Hydroxybenzenesulfonyl)-l-(trifluoroacetyl) -2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine
Example 1 4-(4-Methoxybenzenesulfonyl)- l-(3-trif luoromethylbenzoyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide
To a solution of 0J97 g (0.556 mmol) of 4-(4-methoxybenzenesulfonyl)-l-(3- trifluoromethylbenzoyl)-2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid from Reference Example 9 in 5 ml of CH2CI2, was added 0.556 ml (1.11 mmol) of 2.0 M oxalyl chloride in CH2CI2 and 0.044 ml of N,N-dimethylformamide. The mixture was stirred under nitrogen at room temperature for 1.5 hours and cooled in an ice bath. To this solution was added a chilled mixture of 0J56 g (2.24 mmol) of hydroxylamine hydrochloride and 4.68 ml (3.36 mmol) of triethylamine in 1.39 ml of tetrahydrofuran and 0.33 ml of H2O. The mixture was stirred at room temperature overnight and diluted with CH2CI2. The mixture was washed with 2 N citric acid, H2O, 1 N NaHCO3, brine and dried with Na2SO4. The solvent was removed under vacuum to give 0J9 g of solid. Chromatography on thick layer silica gel plates with - 94 -
ethyl acetate-methanol (9: 1) gave 60 mg of solid, m.p. 128-130°C. Anal, for C25H22F3N3O6S:
Calc'd: C,54.6; H,4.0; N,77;
Found: C,54J ; H.4J; N.7.3.
Utilizing the procedure described in Example 1, the following compounds are prepared from the appropriately l-substituted-4(4-methoxybenzenesulfonyl)-23,4,5- tetrahydro- 1 H-[ 1 ,4]benzodiazepine-3-carboxylic acids.
Example 2
4-(4-Methoxybenzenesulfonyl)-l-(4-methylphenylsulfonyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide
Solid. Anal, for C24H25N3O7S2:
Calc'd: C,54J; H,47; N,7.9; Found: C,53.5; H,5J; N.7.3.
Example 3 l-Methanesulfonyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Solid. Anal, for C18H21N3O7S2:
Calc'd: C,47.5; H.4.7; N,9.2; Found: C,46.8; H.4.8; N.8.5.
Example 4 l,4-Bis-(4-Methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH-
[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide
Solid. Anal, for C24H25N3O8S2:
Calc'd: C,52.6; H,4.6; N.7.7; Found: C.52.2; H,4.8; N.7.3.
Example 5 l-Benzoyl-4-(4-methoxybenzenesuIfonyl)-2,3,4,5-tetrahydro-lH- [l,4]benzodiazepine-3-carboxyIic acid, Hydroxyamide White solid. Anal, for C24H23N3O6S: Calc'd: C,59.9; H,4.8; N.8.7.;
Found: C.59.2; H,4.6; N,8.6; S, 6.4; Mass spectrum (ES) 482.3 (M+H). - 95 -
Example 6 l-AcetyI-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH-
[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide White crystals, m.p. 195-197°C. Anal, for C19H21N3O6S:
Calc'd: Q54.4; H,5J ; NJO.O; Found: C,52.6; H.4.9; N.9.4.
Example 7 4-(4-Methoxybenzenesulfonyl)- l -(3-py ridinylcarbonyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxy!ic acid, Hydroxyamide
White crystals, m.p. 167-169°C. Anal, for C23H22N4O6S:
Calc'd: C,573; H,4.6; NJ 1.6; Found: 55.3; H.4.6; N.10.6.
Example 8 4-(4-Methoxybenzenesulfonyl)- 1 -(2-thienylcarbonyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide White solid. Anal, for C22H21N3O6S2: Calc'd: C.54.2; H,4.3; N,8.6;
Found: C,537; H,4.4; N,8J.
Example 9 l-Methoxyacetyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH- [l,4]benzodiazepine-3-carboxyIic acid, Hydroxyamide
White crystals, m.p. 143-145°C. Anal, for C20H23N3O7S:
Calc'd: C,53.4; H,5J; N,9.4; Found: C,53.9; H,5.6; N.8.5.
Example 10
4-(4-Methoxybenzenesulfonyl)-l -(propane-1-sulf onyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide
Off-white solid. Anal, for C20H25N3O7S2:
Calc'd: C,497; H,5J; N.8.7; Found: C,48.9; H,53; N.8.4. - 96 -
Example 11
4-(4-Methoxybenzenesulfonyl)-l -(2-methyl-5-fluorobenzoyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide
Off-white solid. Anal, for C25H24FN3O6S: Calc'd: C,58.5; H.4.7; N,8.2;
Found: C,57J ; H.4.8; N,7.6.
Example 12 4-(4-Methoxybenzenesulfonyl)- l-(3-phenylpropionyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide
Solid. Anal, for C26H27N3O6S:
Calc'd: C,613; H,5.3; N,8.3; Found: C.59.8; H,5.3; N.7.5.
Example 13
4-(4-Methoxybenzenesulfonyl)- l-(4-pyridiny lcarbonyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide
White crystals, m.p. 155-165°C. Anal, for C23H22N4O6S:
Calc'd: C.57.3; H,4.6; NJ 1.6; Found: C,56.8; H.4.9; NJ0.9.
Example 14
1 -([1,1' -Biphenyl]-2-carbonyl)-4-(4-methoxybenzenesulfonyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Purified by chromatography on silica gel thick layer plates with hexane-ethyl acetate as solvent to give a white solid; m.p. 176-178°C. Anal, for C30H27N3O6S:
Calc'd: C,64.6; H.4.9; N.7.5; Found: C.63.7; H,4.6; N,7J.
- 97 -
Example 15 l-(4-BiphenylcarbonyI)-4-(4-methoxybenzenesulfonyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide
Purified by chromatography on silica gel thick layer plates with hexane-ethyl acetate (1: 1) as solvent to give a white solid, m.p. 160-168°C. Anal, for C30H27N3O6S:
Calc'd: C,64.6; H,4.9; N,7.5; Found: C,61 J; H.4.9; N.7.0; Mass spectrum (ES) 558.1 (M+H).
Example 16 l -(3-Fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- lH-[l,4]benzodiazepine-3-carboxyIic acid, Hydroxyamide
Example 17
4-(4-Methoxybenzenesulfonyl)- l-(2-methyl-3-f luorobenzoyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide
Example 18 4-(4-Methoxybenzenesulfonyl)-l-(2-methyl-3-trifluoromethylbenzoyl)- 2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid,
Hydroxyamide
Example 19 l-(2-Chloro-6-trifluoromethylbenzoyl)-4-(4-methoxybenzenesulfonyl)- 2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid,
Hydroxyamide
Example 20 l-(4-FIuoro-2-trifluoromethylbenzoyl)-4-(4-methoxybenzenesulfonyl)- 2,3,4, 5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxyIic acid,
Hydroxyamide
Example 21 l-(2-Fluoro-6-trifluoromethylbenzoyl)-4-(4-methoxybenzenesulfonyl)- 2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid,
Hydroxyamide - 98 -
Example 22 -(4-MethoxybenzenesulfonyI)-l-(2-methylbenzoyl)-2,3,4,5-tetrahydro- lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide
Example 23
4-(4-Methoxybenzenesulfonyl)-l-(2-methyl-6-chlorobenzoyl) -2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide
Example 24 l-(2,4-Dimethylbenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide
Example 25 l-(2,5-Dimethylbenzoyl)-4-(4-methoxybenzenesuIfonyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxy!ic acid, Hydroxyamide
Example 26 l-(2-Chloro-4-fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide
Example 27 l-(2-Chlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide
Example 28 l-(2-Fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide
Example 29 l-(2-Chloro-6-fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide
Example 30 l-(2,3-Difluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide - 99 -
Example 31 l -(2,4-DichlorobenzoyI)-4-(4-methoxybenzenesulfonyI)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide white crystals, m.p. 158-162°C. Anal, for C24H21CI2N3O6S: Calc'd: C,52.4; H.3.9; N,7.6;
Found: C,52J ; H,3.8; N,7.5; Mass spectrum (ES) 549.9 (M+H); 552.0 (M+H).
Example 32 l -(2,3-Dichlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide
Example 33 1 -(2,5 -Dichlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide
Example 34 l-(2-Methoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxy!ic acid, Hydroxyamide
Example 35 l-(4-Chloro-2-methoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid, hydroxyamide
Example 36
4-(4-Methoxybenzenesulfonyl)-l-(2-methylthiobenzoyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide
Example 37 4-(4-Methoxybenzenesulfonyl)-l-(3-methyl-2-thienylcarbonyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide
Example 38 4-(4-(MethoxybenzenesulfonyI)-l-(4-methyl-2-thienylcarbonyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide - 100 -
Example 39 l-(3-Chloro-2-thienylcarbonyl)-4-(4-methoxybenzenesu!fonyI)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide
Example 40 l-(2-Furanylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide white solid. Anal, for C22H21N3O7S:
Calc'd: C, 56.0; H, 4.5; N, 8.9; Found: C, 55.6; H, 4.8; N, 83;
Mass spectrum (ES) 472.0 (M+H).
Example 41 4-(4-Methoxybenzenesulfonyl)-l-(3-methyl-2-furanylcarbonyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide
Example 42 4-(4-Methoxybenzenesulfonyl)-l-(4-methyl-2-furanylcarbonyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide
Example 43 l-(5-Chloro-2-furanylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide
Example 44 l-(5-Chloro-2-thienylcarbonyI)-4-(4-methoxybenzenesulfonyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide
Example 45 l-Propionyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH-
[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide
Example 46 l-Hexanoyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH- [l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide - 101 -
Example 47 l-(3-Methoxypropionyl)-4-(4-methoxybenzenesulfonyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide
Example 48
4-(4-Methoxybenzenesulfonyl)- l-(3-thieny lcarbonyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide
Example 49 l-(3-Furanylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide
Example 50 l-(trans-Crotonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide
Example 51 l-(Methacryloyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH- [l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide
Example 52 l-(Acetylaminoacetyl)-4-(4-methoxybenzenesulfonyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide
Example 53 l-(Aminoacetyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH- [l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide
Example 54 l-(N,N-Dimethylaminoacetyl)-4-(4-methoxybenzenesulfonyI)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide - 102 -
Example 55 l -(Cyclopropylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide off-white solid. Anal, for C21H23 3O S: Calc'd: C,56.6; H.5J; N,9.4;
Found: C,55J ; H,5J; N,8.8; Mass spectrum (ES) 446.5 (M+H).
Example 56 l-(CyclobutylcarbonyI)-4-(4-methoxybenzenesulfonyl)-2, 3,4,5 - tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide
Example 57 l-(Cyclohexylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide off-white solid. Anal, for C24H29N3O6S:
Calc'd: C,59J; H,6.0; N,8.6; Found: C,58.0; H,6.0; N,8J; Mass spectrum (ES) 488.6 (M+H).
Example 58
4-(4-MethoxybenzenesuIfonyl)-l -(phenoxyacetyl)-2,3,4,5-tetrahydro- lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxamide
A mixture of 0.70 g (137mmol) of methyl 4-(4-methoxybenzenesulfonyl)-l- (phenoxyacetyl)-2,3,4-5-tetrahydro-lH[l,4]benzodiazepine-3-carboxylate and 1.8 ml
(1.78 mmol) of IN NaOH in 3 ml of tetrahydrofuran was stirred at room temperature for 2 hours. The mixture was diluted with 3 ml of H2O and acidified with IN HCl to give a gummy solid. Ethyl acetate was added thereto and the mixture was chilled overnight. Filtration gave 4-(4-methoxybenzenesulfonyl)-l-(phenoxyacetyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid as crystals, m.p. 188°-191°C.
To a 0.496 g (1 mmol) sample of the preceeding compound in 5 ml of CH2CI2 cooled to 0°C, was added 1 ml (2 mmol) of oxalyl chloride followed by the addition of
77.4 μl (1 mmol) of N,N-dimethylformamide. The mixture was stirred at room temperature under nitrogen for 1 hour (referred to as solution A). In a separate flask was added 0J78 g (4 mmol) of hydroxyamine hydrochloride, 0.5 ml of H2O and
836.3 μl (5 mmol) of triethylamine. The mixture was stirred for 20 minutes and then - 103 -
cooled to 0°C (referred to as solution B). The cooled solution B was added to the cooled (0°C) and stirred solution A and then this mixture was allowed to warm to room temperature and was stirred overnight. The mixture was concentrated under vacuum, diluted with CH2CI2 and washed with H2O, 2N citric acid, IN NaHCO3, and brine and dried with Na2SO4. The solvent was removed and the residue crystallized from hexane-ethyl acetate (3:97) to give 0.396 g of white crystals, m.p. 159°-163°C. Anal, for C25H25N3O7S;
Calc'd: C.58.7; H.4.9, N,8.2; Found: C.58.4; H.5.1 : N.7.8; Mass spectrum (ES) 512 (M+H).
Example 59 l-Methoxyacetyl-4-(4-methoxybenzenesulfonyl)-7-methyl-2, 3-4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid, hydroxyamine A mixture of 1.26 g (272 mmol) of methyl l-methoxyacetyl-4-(4- methoxybenzenesulfonyl)-7-methyl-2,3.4,5-tetrahydro-lH-[l,4]benzodiazepine-3- carboxylate from Reference Example 181, 3.53 ml of IN NaOH and 10 ml of tetrahydrofuran was stirred at room temperature for 3 hours. The solvent was then removed under vacuum and the residue dissolved in H2O and extracted with ethyl acetate. The aqueuous layer was acidified with IN HCl and then extracted with CH2Cl2. The CH2CI2 layer was dried over Na2SO and the solvent removed to provide a solid. This material was dried in a vacuum oven and given 1.06 of solid, m.p. 101-105°C.
A 1.02 g (2.27 mmol) sample of l-methoxyacetyl-4-(4-methoxy- benzenesulfonyl)-7-methyl-2,3-4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid prepared above was dissolved in 2.57 ml of IN KOH. Toluene was added several times and the solvent was removed after each addition. The residue was dried in a vacuum oven to give 1 J g of potassium salt. A mixture of 2J6 ml (4.52 mmol) of oxalyl chloride in 20 ml of CH2CI2 was cooled at 0°C and 0.351 ml (4.52 mmol) of
N,N-dimethylformamide (DMF) was added dropwise. The mixture was stirred for 5 minutes and the potassium salt (1J g) was added. The mixture was allowed to warm to room temperature and was stirred for 2 hours under nitrogen. The mixture was cooled (0°C) and this mixture was added to a cooled (0°C) mixture of 0.628 g (9.04 mmol) of hydroxylamine hydrochloride, 1.89 ml (13.56 mmol) of triethylamine in 1 ml of tetrahydrofuran-water (8:2). The mixture was stirred and chilled at 0°C for 10 minutes and then stirred at room temperature overnight. The solvent was removed - 104 -
under vacuum and the residue diluted with CH2CI2-H2O and acidified with 2 N citric acid (pH 4). The CH2CI2 layer was separated and washed with H2O. IN NaHCO3. H2O. and brine and dried with Na2SO4. The solution was filtered through a thin pad of hydrous magnesium silicate and the solvent removed under vacuum to give 0.73 g of solid. Crystallization from ethyl acetate gave 0.32 g of crystals, m.p. 146°-148°C.
Example 60 l-Benzoyl-4-(4-methoxybenzenesulfonyl)-7-methyl-2,3,4,5-tetrahydro- lH[l,4]benzodianzepine-3-carboxylic acid, Hydroxyamide In the manner described in Example 59, 0.83 g (1.71 mmol) of 1 -benzoyl-4-(4- methoxybenzene-sulfonyl)-7-methyl-2,3,4,5-tetrahydro-lH[l,4]benzodianzepine-3- carboxylic acid from Reference Example 185 was converted to the potassium salt with 1.87 ml of IN KOH and the salt reacted with oxalyl chloride-DMF to give the acid chloride which was reacted with hydroxylamine. The solid from the reaction gave from CH2CI2 0.20 g. of yellow solid, m.p. 137°- 139°C.
Example 61 4-(4-Methoxybenzenesulfonyl)-l-[4-(trifluoromethoxy)benzoyl]-8- chloro-2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide
In the manner described for Example 59, the potassium salt was prepared from 1.20 g of 4-(4-methoxybenzenesulfonyl)-l-[4-(trifluoromethoxy)benzoyl)-8-chloro- 2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid from Reference Example 189, m.p. 184°-186°C and reacted with oxalyl chloride-DMF and the acid chloride reacted with hydroxylamine to give 1 JO g of solid. Chromatography on thick layer silica gel plates with ethyl acetate-methanol (95:5) gave 0.58 g of solid m.p. 134° dec; Mass spectrum (ES) 601 (M+H).
Example 62 4-(4-MethoxybenzenesuIfonyl)-l-(2-methoxyethyl)-2,3,4,5-tetrahydro- lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide
In the manner described for Example 1, 0.55 g of 4-(4-methoxy- benzenesulfonyl)-l-(2-methoxyethyl)-2,3,4,5-tetrahydro-lH-[l,4]-benzodiazepine-3- carboxylic acid from Reference Example 187 was reacted with oxalyl chloride and the resulting acid chloride reacted with hydroxylamine to 0.40 g of solid. Chromatography on thick layer silica gel plates with ethyl acetate-methanol (7:3) gave 0J50 g of product - 105 -
as an off-white foam; Mass spectrum (ES) 434.3 (M-H) Anal, for C20H25N3O6S:
Calc'd: C,55.2; H,5.8; N.9.7; Found: C,54.0; H,5.8; N.9.3.
Example 63 4-(4-MethoxybenzenesuIfonyl)-l-[2- ( 1 - pyrazo!yl)phenylcarbonyl]2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3- carboxylic acid, Hydroxyamide. As described for the general reaction of ethyl 2-fluorobenzoate with amines set forth in Tetrahedron. 53, 7557-7576 (1997), ethyl 2-fluorobenzoate was reacted with pyrazole by refluxing N, N-dimethylformamide to give ethyl 2-(l-pyrazolyl)benzoate, as a thick yellow oil. Anal. Calc'd: for C,2 H12 N2O2: C, 66.7; H, 5.6; N 13.0: Found:
C, 66.5: H, 5.4: N, 12.9; Mass spectrum (ES) 217.2 (M+H). A sample (7.02g) of this compound and 8.42 ml of 5N NaOH in 40 ml of ethanol-tetrahydrofuran (2: 1) was refluxed for 2 hrs and the solvent removed.The residue was made acidic (pH6) with 2N citric acid and the precipated solid was filtered to obtain 37g of product. The pH of the filtrate was adjusted to 4.5 and extracted with ethyl acetate. The extract was concentrated to dryness to give 1.5g of product. The two crops were combined to give 5Jg of 2-(l-pyrazolyl)benzoic acid, mp 140-142°C. To the preceding compound
(2.07 g) in 5 ml CH2C12 (chilled in an ice bath )was added 11.1 ml of a 2 Molar solution of oxalyl chloride in CH2C12 and 0.085 ml of N,N-dimethylformamide. The mixture was allowed to warm to room temperature and stirred for 4 hours. The solvent was removed and 25 ml of toluene added (twice) and removed under vacuum to give 2- (l-pyrazolyl)benzoyl chloride as a yellow solid.
A 2.3 g sample of the preceding compound was reacted with 1.5g of the compound of Reference Example 179 in 15 ml of CH2C12 and 5J2 ml of triethylamine in the manner described for Reference Example 181 to give methyl 2-[ (4- methoxybenzenesulfonyl)- { 2-[2-( 1 -pyrazolyl)phenylcarbonyl]amino-5-methylbenzyl } - amino]acrylate. This compound was cyclized with NaHCO3 in methanol in the manner described in Reference Example 181 to give methyl 4-(4-methoxybenzenesulfonyl)-l- [2-( 1 -pyrazolyl)phenylcarbonyl]-7-methyl-2,3,4,5-tetrahydro- 1 H-[ 1 ,4]benzodiazepine- 3-carboxylate, m.p. 240-242° C.
A 1J6 g sample of the preceding compound was hydrolysed with 2.69 ml of IN NaOH in 10 ml of tetrahydrofuran in the manner described for Reference Example - 106 -
104 to give 0.71 g of 4-(4-methoxybenzenesulfonyl)-l-[2-(l-pyrazolyl)phenyl- carbonyl)-7-methyl-2,3,4,5-tetrahydro-lH[l,4]benzodiazeρine-3- carboxylic acid, mp 149-151°C.
In the manner described in Example 59, 1J g of the preceding compound was converted to the potassium salt and reacted with oxalyl chloride and then hydroxylamine to give the above-identified product as white crystals, mp 194-196°C.
Example 64 4-(4-Methoxybenzenesulfonyl)-l-[2-(4- morpholino)phenylcarbonyl}-8-chloro-2,3,4,5-tetrahydro-lH- [l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide
Ethyl 2-moφholinobenzoate prepared in the manner described in Tetrahedron.
53:7557, (1997) was refluxed with 10 N NaOH in tetrahydrofuran-ethanol (8:2) for 1.5 hrs to give 2-moφholinobenzoic acid, mp 156-157°C. A 1.8 g sample of this compound in 5 ml of CH2C12 (chilled) was added a solution of 7.9 ml of oxalyl chloride in CH2C12 (2M) followed by the addition of 0.058 ml of N, N-dimethylformamide.
The solution was stirred at room temperature for 6 hrs and the solvent removed.
Toluene was added (2 times) and removed to give 2-(4- moφholino)benzoyl chloride as a yellow solid.
In the manner described in Reference Examples 181 and 189, the preceding 2-
(4-moφholino)benzoyl chloride was reacted with methyl 2-[(2-amino-4-chlorobenzyl)-
(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate and the product was stirred with NaHCO3 in methanol to give methyl 4-(4-methoxybenzenesulfonyl)-l-[2-(4- moφholino)phenylcarbonyl]-8-chloro-2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3- carboxylate, as a white solid having a mp 100-105°C.
To 0.90g of this compound in 10 ml of tetrahydrofuran was added 1.95 ml of 1 N NaOH and the solution was stirred at room temperature overnight. Acidification with 2N citric acid gave 0.82 g of solid, mp 136-143°C. This compound, 4-(4- methoxybenzenesulfonyl)-l-[2-(4-moφholino)phenylcarbonyl]-8-chloro-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid (0.78g) was converted to the potassium salt and reacted first with oxalyl chloride and then with hydroxylamine as described in Example 63 to give 0.276g of product as a light yellow solid, mp 132° C. - 107 -
Example 65 l-(4-Ethoxybenzoyl)-4-(4-methoxybenzenesuIfonyl) -2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxyIic acid, Hydroxyamide
A mixture of 0.270 g of methyl 4-(4-methoxybenzenesulfonyl)-2,3,4,5- tetrahy dro-lH-[l, 4] benzodiazepine-3-carboxylate of Reference Example 12, 0J91 g of 4-ethoxybenzoyl chloride and 500 μl of triethylamine in 5 ml of CH2C12 was stirred at room temperature overnight. The mixture was diluted with CH2C12 and H O and the CH2C12 layer was separated and concentrated to dryness. The residue was triturated with ethyl acetate to give 0J76g of methyl l-(4-ethoxybenzoyl)-4-(4-methoxybenzene- sulfonyl)-2,3,4,5tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate as white crystals, mp 187-190°C.
A 0.47 g sample of this compound was hydrolyzed with 1 J ml of IN NaOH in
4 ml of tetrahydrofuran. Dilution with H2O and acidification with IN HCl gave 0.40 g of the acid as a white solid, mp 144-152°C. The preceding compound (035g) was converted to the above-titled compound in the manner described in Example 1 to provide 0J95g of solid, mp 136-142°C.
Example 66 4-(4-MethoxybenzenesulfonyI) -l-[2-chloro-4-(3-methyl-l- pyrazolyl)phenylcarbonyl}-2,3,4,5-tetrahydro -1H- [l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide
As described in Example 65, methyl 4-(4-methoxybenzenesulfonyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate was reacted with 4-(3-methyl-l- pyrazolyl)-2-chlorobenzoyl chloride to give methyl 4-(4-methoxybenzenesulfonyl)-l-
[2-chloro-4-(3-methyl- 1 -pyrazolyl)phenylcarbonyl]-2,3,4,5-tetrahydro- lH-[ 1 ,4]benzo- diazepine-3-carboxylate as a white solid. Anal, for C29H27ClN4O6S:
Calc'd: C, 58.3; H, 4.6; N, 9.4. Found: C,58J; H, 4.9; N, 8.9.
This compound was hydrolysed with IN NaOH in tetrahydrofuran as described in Reference Example 185 to give the benzodiazepine-3-carboxylic acid derivative as a white solid. This compound was reacted with oxalyl chloride and then reacted with hydroxylamine as described in Example 1 to give the product as white crystals, mp 189-191°C. - 108 -
Example 67 l-Benzyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH-
[l,4]benzodiazepine-3-carboxylic acid, Hydroxylamide
A mixture of 17 g of the compound of Reference Example 45 and 25 ml of borane in tetrahydrofuran ( 1.0 Molar) was refluxed under nitrogen overnight. To the solution was added 5 ml of CH3OH, CH2C12 (40 ml) and 30 ml of 2N HCl and the mixture stirred at room temperature for 1.5 hr. The organic layer was separated, washed with brine, dried with Na2SO4 and the solvent removed. The residue was crystallized from ethanol-hexane to give lJ5g of methyl l-benzyl-4-(4- methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate as white crystals, mp 120-122°C. A sample (1.0 g) of this compound was hydrolysed with 2.8 ml of 1 N NaOH in 7 ml of tetrahydrofuran as described in Reference Example
104 to give 0.64 g of the 2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid derivative as white crystals, mp 183-185°C.
A 0.55 g sample of this compound was converted to the acid chloride which was reacted with hydroxylamine as described in Example 1 to give the product as a light brown foam; Mass spectrum (ES) 468J (M +H).
Utilizing the procedure described in Example 65 above, the following compounds may be prepared.
Example 68 4-(4-Methoxybenzenesulfonyl)-l-(4-(2-thienyl)phenyl-carbonyl)- 2,3,4, 5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid,
Hydroxyamide
Example 69 4-(4-Methoxybenzenesulfonyl)-l-(4-(3-thienyl)phenyl-carbonyl)- 2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid,
Hydroxyamide - 109 -
Example 70
4-(4-MethoxybenzenesuIfonyI)-l-[2-(3-pyrazol)phenyl-carbonyl]-
2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid,
Hydroxyamide
Example 71 l-(2,4-Dimethoxybenzoyl)-4-(4-methoxybenzenesuIfonyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide To a cooled (0°C) solution of 1.0 g (2.66 mmol) of 4-(4- methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- lH-[ 1 ,4]benzodiazepine-3-carboxylate from Reference Example 12 and 1.85 ml (13.3 mmol) of triethylamine in 8 ml of CH2Cl2 was added 1 J7 g (6.65 mmol) of 2,4-dimethoxybenzoyl chloride. The mixture was stirred at room temperature overnight, diluted with CH2C12 and washed with 2 N citric acid. The organic layer was washed with H2O, 1 N Na2CO3, brine and dried over Na2SO4- The solvent was removed and the residue was chromatographed on thick layer silica gel plates with ethyl acetate-hexane (1: 1) as an eluent to give 1.0 g of methyl 1 -(2,4-dimethoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate as a white foam. Anal, for C27H28H2OgS:
Calc'd: C,60.0; H.5.2; N.5.2; Found: C,60.0; H.5.2; N,5J; Mass Spectrum (ES): 541.0 (M+H).
A 0.80 g ( 1.48 mmol) sample of the preceding compound and 1.92 ml ( 1.92 mmol) of 1 N NaOH in 5 ml of tetrahydrofuran was stirred at room temperature for 1.5 hours. The solvent was removed and the residue diluted with water. The solution was acidified with 1 N HCl, chilled and filtered to give 0.70 g of l-(2,4-dimethoxy- benzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine- 3-carboxylic acid as a white solid. Anal, for C26H26N2O8S:
Calc'd: Q59.3; H.5.0; N,53; Found: C,56J; H,4.8; N,5.0; Mass Spectrum (ES): 527.0 (M+H).
A 0.80 g (1.52 mmol) sample of the preceding compound in 10 ml of CH2C12
(chilled to 0°C) was added to 1.52 ml (3.04 mmol) of oxalyl cholride (2.0 M solution in CH2C12). To the solution was added 118 μl (1.52 mmol) of N,N-dimethylformamide - 1 10 -
and the solution stirred at 0°C for 1.5 hours (Mixture A). A mixture of 0.422 g (6.08 mmol) of hydroxylamine hydrochloride, 1J7 ml (9J4 mmol) of triethylamine, 5 ml of N,N-dimethyformamide and 0.5 ml of water was prepared in a separate flask, stirred for 20 minutes at room temperature and then cooled to 0°C in an ice bath (Mixture B). The cooled solution of Mixture A was added to the cooled Mixture B and then stirred at room temperature overnight. The mixture was diluted with CH2CI2 and 2 N citric acid added. The organic layer was separated, washed with H2O, brine and dried with Na2SO . The solvent was removed and the residue crystalized from ethanol to give 0.40 g of product as white crystals, mp 189-191°C. Anal, for C26H27N3O8S: Calc'd: C.57.7; H,5.0; N,77;
Found: C,57.6; H,4.9; N.7.7;
Mass Spectrum (ES): 542.2 (M+H).
Example 72 4-(4-Methoxybenzenesulfonyl)-l-[2-(4-methylpiperazin-l-yl)acetyl]-
2,3,4, 5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid,
Hydroxyamide
To a mixture of 2.5 g (6.64 mmol) of methyl 4-(4-methoxybenzenesulfonyl)-
2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate (Reference Example 12) and 4.63 ml (33.2 mmol) of triethylamine in 40 ml of CH2C12 cooled to 0°C was added to
1.65 g (14.63 mmol) of chloroacetyl chloride. The solution was stirred at room temperature for 2 days, chilled to 0°C and 926 μl of triethylamine and 750 mg of chloroacetyl chloride were added thereto. The mixture was stirred at room temperature overnight, diluted with CH2Cl2 and H2O. The insoluble solid was filtered off. The organic layer of the filtrate was separated , washed with brine, dried with Na2SO4 and filtered through diatomaceous earth. The solvent was removed and the residue triturated with ethyl acetate and a trace of ethanol. Chilling and filtering gave 0.75 g of methyl l-(chloroacetyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1 H-[ 1 ,4]- benzodiazepine-3-carboxylate (Reference Example 91). Anal, for C20H21CIN2O6S: Calc'd: C,53.0; H,47; N.6.2;
Found: C.51.6; H,4.6; N.5.7; Mass Spectrum (ES): 453.0 (M+H).
To a solution of 1.4 g (3.09 mmol) of the preceding compound in 12 ml of CH2C12 cooled to 0°C was added 1.2 ml (6.79 mmol) of N,N-diisopropylethylamine followed by the addition of 753.2 μl (6.79 mmol) of 1-methylpiperazine. The mixture was stirred at room temperature overnight, diluted with CH2Cl2, and washed with 2 N - I l l -
citric acid, H2O, 1 M NaHCO3, brine and dried (Na2SO4). The citric acid wash was made basic with saturated NaHCO3 and then extracted with CH2C12. The extract was dried over Na2SO4 and the solvent removed under vacuum to give 1J0 g of methyl 4-
(4-methoxybenzenesulfonyl)-l-[2-(4-methylpiperazin-l-yl)acetyl]-2,3,4,5-tetrahydro- lH-[l,4]benzodiazepine-3-carboxylate as a white glass.
A mixture of 1.0 g (1.94 mmol) of the preceding compound and 2.3 ml (2.3 mmol) of 1 N KOH in 5 ml of methanol was stirred at room temperature for 2 hours. The solvent was removed under vacuum. To the residue was added toluene (2 times) and the solvent removed under vacuum after each addition. The solid was dried at 65°C under vacuum for 6 hours to give 1J g of potassium 4-(4-methoxybenzenesulfonyl)-l- [2-(4-methylpiperazin- 1 -yl)acetyl]-2,3,4,5-tetrahydro- 1 H-[ 1 ,4]benzodiazepine-3- carboxylate as a white solid.
To 1.85 ml (3.69 mmol) of a 2.0 molar solution of oxalyl chloride in CH2C12, cooled to 0°C, was added slowly 286 μl (3.69 mmol) of N,N-dimethylformamide (precipitate formed). To this stirred mixture was 1.0 g (1.85 mmol) of the preceding compound in 5 ml of CH2CI2. The mixture was stirred under nitrogen for two hours
(Mixture A).
In a separate flask, a mixture of 0.514 g (7.4 mmol) of hydroxylamine hydrochloride, 1.55 ml (11.1 mmol) of triethylamine in tetrahydrofuran-water (4: 1) was stirred at room temperature and then cooled to 0°C and stirred for 5 minutes. To this mixture was added the cooled (0°C) Mixture A and then the resulting solution stirred at room temperature overnight. The mixture was concentrated under vacuum and CH2Cl2 added. The organic layer was separated and concentrated to dryness to give 1.4 g of product. The product was chromatographed on thick layer silica gel plates with CH2Cl2-CH3OH-NH4OH(45:6: l) as a solvent to give 65 mg of brown solid:
Mass Spectrum (ES): 518.3 (M + H). - 112 -
Example 73
4-[4-(4-Chlorophenyloxy)benzenesulfonyl] -l-(methoxyacety I)-2, 3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide
A. N-[4-(4-Chlorophenyloxybenzenesulfonyl)serine. methyl ester (methyl-
3-hydroxy-2-r4-(4-chlorophenoxy')benzenesulonylaminolpropionate'). To a mixture of 3.42 g (22 mmol) of serine, methyl ester, hydrochloride and 10.7 ml (77.0 mmol) of triethylamine in 60 ml of CH C12, chilled to 0°C, was added 6.063 g (20 mmol) of 4-
(4-chlorophenyloxy)benzenesulfonyl chloride. The mixture was stirred at room temperature overnight, diluted with CH2C12 and washed with 2 N citric acid, H2O, 1 N
NaHCO3, brine and dried with Na2SO . The solvent was removed to give an oil which was dried under vacuum at 68 °C to give a solid. Trituration with hexane-ethyl acetate gave 5.85 g of off-white crystals, mp 90-94°C. Anal, for C16H16ClNO6S:
Calc'd: C.49.8; H.4.2; N.3.6; Found: C,50J; H,4J ; N,3.8;
Mass Spectrum (ES): 385.9 (M+H).
B. Methyl 3-hydroxy-2- { r4-(4-chlorophenyloxy)benzene-sulfonyll -(2- nitrobenzyllamino Iproprionate. To a cooled (0°C) solution of 5.5 g (14.76 mmol) of compound from part A in 60 ml of dry N,N-dimethylformamide was added (portionwise), 0.682 g (17 mmol) of sodium hydride (60% in oil). After gas evolution ceased, 3.7 g (17 mmol) of 2-nitrobenzylbromide in 15 ml of N,N-dimethylformamide was added slowly. The mixture was stirred at room temperature overnight and diluted with 200 ml of ethyl acetate and 150 ml of water. The organic layer was separated and washed with H2O, brine and dried with Na2SO4. The solvent was removed under vacuum and the residue chromatographed on a silica gel column with hexane-ethyl acetate (2:1) as an eluent to give 4.7 g of a brown oil. Anal, for C2 H2iClN2O8S:
Calc'd: C,53.0; H,4J; N,5.4; Found: C,53.2; H.4.2; N.5.1; Mass Spectrum (ES): 521.2 (M+H).
C. Methyl 2-( (2-aminobenzyl)-r4-(4-chlorophenyloxy)benzene- sulfonyllamino I -3-hydroxypropionate. A mixture of 3.0 g (5.77 mmol) of the compound from part B and 0.300 g of 10% wet palladium on carbon (50% in H2O) in 300 ml of ethyl acetate-ethanol (1:1) was shaken in a Parr hydrogenator under 35 psi of hydrogen for 4 hours. The mixture was filtered through diatomaceous earth and the - i n ¬
solvent removed under vacuum. The residue was dried at 65°C under vacuum to give 2.63 g of an off-white solid. Anal, for C23H23ClN2O6S:
Calc'd: C.56.3; H.4.7; N,57; Found: C,56.6; H,4.6; N.5.6; Mass Spectrum (ES): 491J (M+H).
D. Methyl 2-\ I4-(4-chlorophenyloxy)benzenesulfonyll-r2-("methoxy- acetylamino)benzyllamino } acrylate. To a mixture of 0.80 g (1.63 mmol) of the compound from Part C and 1J4 ml (8J5 mmol) of triethylamine in 8 ml of CH2C12, cooled to 0°C, was added 328 μl (3.58 mmol) of methoxyacetyl chloride. The mixture was stirred at room temperature overnight, diluted with CH2C12 and washed with H2O, 2 N citric acid, brine and dried (Na2SO4). The solvent was removed under vacuum and the residue chromatographed on thick layer silica gel plates with hexane-ethylacetate (2: 1) as a solvent to give 0.48 g of a white foam. Anal, for C26H25CIN2O7S: Calc'd: C.57.3; H.4.6; N.5.1;
Found: C.56.7; H,47; N.5.0; Mass Spectrum (ES): 545.2 (M+H).
E. Methyl 4-[4-(4-chlorophenyloxy')benzenesulfonyll- 1 -. methoxyacetylV 23.4.5-tetrahydro-lH-[J.41benzodiazepine-3-carboxylate. A mixture of 0.45 g (0.827 mmol) of the compound from part D and 0.09 g of anhydrous NaHCO3 in 5 ml of dry methanol was stirred at room temperature overnight. The solvent was removed, ethyl acetate added and the mixture washed with H2O, brine and dried with Na2SO . The solvent was removed to give 0.43 g of an off-white solid. Anal, for C26H25CIN2O7S: Calc'd: C.57.3; H,4.6; N.5.1;
Found: C,57.6; H,4.6; N,5.0;
Mass Spectrum (ES): 545.2 (M+H).
F. 4-r(4-Chlorophenyloxy)benzenesulfonyll-l-(methoxyacetyI)-23.4.5- tetrahydro- 1 H-11.41benzodiazepine-3-carboxylic acid. A mixture of 0.52g (0.956 mmol) of the compound from Part F and 1.2 ml (1.2 mmol) of IN KOH in 8 ml of methanol was stirred at room temperature for 2 hours. An additional 0.6 ml of IN KOH was added and the mixture was stirred at room temperature overnight. The mixture was concentrated, diluted with H2O and extracted with ethyl acetate. The extract was washed with brine and dried over Na2SO4. The solvent was removed and the product dried at 65°C under vacuum to give 0.49 g of off-white foam. Anal, for C25H23ClN2O7S: - 1 14 -
Calc'd: C,56.6; H.4.4; N.5.3; Found: Q56.6; H.4.3; N,5.0; Mass Spectrum (ES): 531.2 (M+H).
To a solution of 0.45 g (0.848 mmol) of the compound from Part F in 4 ml of
CH2C12 cooled to 0°C was added 850 μl (1.69 mmol) of oxalyl chloride (2.0 molar solution in CH2C12) and then 50.2 μl (0.848 mmol) of N,N-dimethylflormamide. This mixture was stirred under nitrogen for 2 hours (Solution A). In a separate flask a mixture of 2J2 g (5.0 mmol) of hydroxylamine hydrochloride, 1.07 ml (7.65 mmol) of triethylamine, 4 ml of tetrahydroforan and 0.4 ml of H2O was stirred for 15 minutes and cooled to 0°C. To this mixture was added the cooled (0°C) Solution A and the mixture was stirred at room temperature overnight. The mixture was concentrated under vacuum, diluted with ethyl acetate and washed with H2O, IN NaHCO3 2 N citric acid, brine and dried over Na2SO4. The solvent was removed under vacuum and the residue chromatographed on thick layer silica gel plates with 2% methanol in ethyl acetate to give 0.20 g of the product of the Example as a brown solid. Anal, for C25H24ClN3O7S:
Calc'd: Q55.0; H,4.4; N,77; Found: C.53.1; H.5.0; N,67; Mass Spectrum (ES): 546.3 (M+H).
Example 74 4-[4-(4-Chlorophenyloxy)benzenesulfonyl]-l-(2-thienylcarbonyl)- 2,3,4,5-tetrahydro-lH[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide
The following reactions were carried out in the manner described for Example 73, Parts D, E, and F. A 1.4 g (2.85 mmol) sample of methyl 2-{(2-aminobenzyl)-[4- (4-chlorophenyloxy)benzenesulfonyl]amino}-3-hydroxypropionate (the compound of Part C of Example 73) was reacted with 1.25 g (8.55 mmol) of 2-thiophenecarbonyl chloride to give 1.7 g of methyl 2-{ [4-(4-chlorophenyloxy)benzyenesulfonyl]-[2-(2- thienylcarbonyl-amino)benzyl]amino} acrylate as a yellow oil. Mass Spectrum (ES): 583.1 (M+H).
The reaction of 1.5 g of the preceding compound with 0.251 g of NaHCO3 in 8 ml methanol gave 1.6 g of methyl 4-[4-(4-chlorophenyloxy)benzenesulfonyl)-l-(2- thienylcarbonyl)-2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate as a yellow oil. - 115 -
Mass Spectrum (ES): 583J (M+H).
The hydrolysis of 1.5 g of the preceding compound with 3.3 ml of 1 N NaOH in 6 ml of tetrahydroforan gave 1 J g of 4-[4-(4-chlorophenyloxy)benzenesulfonyl]-l- (2-thienylcarbonyl)-2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid as an off-white foam. As described for Example 73, 1.0 g of the preceding benzodiazepine- 3-carboxylic acid was reacted with oxalyl chloride and then with hydroxylamine to give the product of the Example as a solid (off-white foam). Mass Spectrum (ES): 584.2 (M+H).
Example 75
4-[4-(4-Chlorophenyloxy)benzenesulfonyl]-l -(benzoyl)-2, 3,4,5- tetrahydro-lH[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide
The following reactions were carried out in the manner described for Example
73, Parts D, E, and F. A 1.0 g (2.04 mmol) sample compound C of Example 73 was reacted with 710 μl (6J0 mmol) of benzoyl chloride to give 1.25 g of methyl 2-{[4-(4- chlorophenyloxy)benzenesulfonyl]-[2-(benzoylamino)benzyl]amino } acrylate as a brown oil. Mass Spectrum (ES): 577 J (M+H).
The reaction of 1J g (1.9 mmol) of the preceding compound with 0J08 g (2.48 mmol) of NaHCO3 in 8 ml of methanol gave 1J g of methyl 4-[4-(4- chlorophenyloxy)benzenesulfonyl]-l-(benzoyl)-2,3,4,5-tetrahydro-lH- [ 1 ,4]benzodiazepine-3-carboxylate as a brown oil. Mass Spectrum (ES): 577.1 (M+H).
A 1.0 g (1.73 mmol) sample of the preceding compound was hydrolysed with 2.3 ml (2.75 mmol) of 1 N NaOH in 5 ml of tetrahydrofuran to give 0.50 g of 4-[4-(4- chlorophenyloxy)benzenesulfonyl]-l-(benzoyl)-2,3,4,5-tetrahydro-lH-
[l,4]benzodiazepine-3-carboxylic acid as a white foam. As described for Example 73, 0.460 g (0.817 mmol) of the preceding benzodiazepine-3-carboxylic acid was reacted with oxalyl chloride and then with hydroxylamine to give 0.04 g of the product of the Example as a light brown solid. Mass Spectrum (ES): 578.2 (M+H). - 1 16 -
Example 76
4-[4-(4-Pyridinyloxy)benzenesulfonyl]-l-(methoxyacetyl)-2, 3,4,5- tetrahydro-lH[l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide
A. To a cooled mixture of 6.84 g (44 mmol) of D, L-serine, methyl ester hydrochloride and 21.4 (144 mmol) of triethylamine in 90 ml of CH2C12 was added a solution of 10.78 g (40 mmol) of 4-(4-pyridinyloxy)benzenesulfonyl chloride in 50 ml of CH2C1 . The mixture was stirred at room temperature overnight, diluted with 50 ml of CH2C1 and the solution washed with H2O, IN NaHCO3, 2 N citric acid, brine and dried (with Na2SO4). The solvent was removed under vacuum to give a solid. The aqueous 2 N citric acid wash was made basic with saturated NaHCO3 and then extracted with CH2C12. The solvent was removed to give a solid. The two crops of solid were combined, washed with H2O and then hexane. The solid was dried at 80°C to give 10.95 g of methyl 3-hydroxy-2-[4-(4-pyridinyloxy)-benzenesulfonylamino] propionate as white crystals, mp. 137-139°C.
B . To a solution of 4.5 g (12,78 mmol) of the product from Part A in 35 ml of dry N,N-dimethylformamide cooled to 0°C was added (portionwise) 0.662 g (16.61 mmol) of NaHCO3 (60% in oil). The mixture was stirred 15 minutes and 3.59 g (16.61 mmol) of 2-nitrobenzylbromide in 15 ml of N,N-dimethylformamide was added hereto. The mixture was stirred at room temperature overnight, diluted with ethyl acetate (200 ml) and H2O (100 ml). The organic layer was separated and washed with H2O, brine and dried (with Na2SO4). The solvent was removed to give 5.9 g of solid. Column chromatography on silica gel with ethyl acetate-hexane (10: 1) as an eluant gave 1.4 g of methyl 2-{(2-nitrobenzyl)-[4-(4-pyridinyloxy) benzenesulfonyl]- amino}-3-hydroxypropionate as an off-white solid. Mass Spectrum (ES): 488.1 (M+H).
The compound from Part B was converted to the product of the Example in the manner described for Example 73 in Parts D, E, and F. - 117 -
Example 77 l-(BenzoyI)-4-(4-pentyloxybenzenesu!fonyl)-2, 3,4,5 -tetrahydro-lH- [l,4]-benzodiazepine-3-carboxylic Acid, Hydroxyamide
To a stirred solution of 1J4 g (4.82 mmol) of triphenylphosphine in 12 ml of toluene and 3 ml of N,N-dimethylformamide was added 524 μL (4.82 mmol) of 1- pentanol and 1.5 g (3.22 mmol) of methyl l-(benzoyl)-4-(4-hydroxybenzenesulfonyl)- 2,3,4, 5-tetrahydro-lH-[l,4]benzodiazepine-3-carboxylate. To this stirred mixture was added 259 μL (4.82 mmol) of diethyl azodicarboxylate and the mixture was stirred overnight. The solvent was removed and the residue chromatographed on silica gel with ethyl acetate-hexane (1:3) as solvent. Concentration of the fractions containing product gave 1.59 g of a white solid; mp 170-172°C; Anal. Calcd for C29H 2N206: C, 64.9; H, 6.0; N, 5.2. Found: C, 64.7; H, 6.0; H, 5.4.
A mixture of a 1.4 g (2.61 mmol) sample of the preceding compound and 3.4 ml (3.4 mmol) of IN KOH in 7 ml of tetrahydrofuran was stirred at room temperature for 2 hrs and the solvent removed under vacuum. To the residue was added toluene and the solvent removed (repeated two times). The residue was dried at 85°C under vacuum overnight to give 1.5 g of l-(benzoyl)-4-(4-pentyloxybenzenesulfonyl)- 2,3,4,5- tetrahydro- lH-[l,4]benzodiazepine-3-carboxylic acid as the potassium salt. To 10 ml of CH2C12 was added 4.8 ml (9.6 mmol) of oxalyl chloride in CH2C12 (2.0 molar) and the solution chilled to 0°C. To the chilled solution was added 740 μL (9.56 mmol) of N,N-dimethylformamide and 134g (2.39 mmol) of the preceding potassuim salt in 5 ml of dry N,N-dimethylformamide. The mixture was stirred at room temperature for 1.5 hr, cooled to 0°C ,and added to a chilled (0°C) solution of 2.2 ml (35.9 mmol) of 50% aqueous hydroxylamine in 10 ml of tetrahydrofuran. The mixture was stirred at room temperature overnight and diluted with CH2C12. The CH2C12 layer was separated, washed with H2O and concentrated to dryness under vacuum. The residue was chromatographed on silica gel with ethyl acetate-hexane (1:1) as solvent. Fraction containing product was concentrated to dryness and the residue dissolved in ethyl acetate. The solution was washed with three times with H2O and once with brine and dried (Na2SO4). The solvent was removed and the residue dried at 85°C under vacuum overnight to give 0.96 g of product as a white foam; Mass spectrum (ES) 538.0 (M+H). - 118 -
Example 78 l-Acetyl-4-(4-Hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH- [l,4]benzodiazepine-3-carboxylic acid, Hydroxyamide
To a crude mixture of l-acetyl-4-(4-hydroxybenzenesulfonyl)-2,3,4,5- tetrahy dro-lH-[l,4]benzodiazepine-3-carboxylic acid (0.55g) and N-hydroxy- benzotriazole (0.414g) in 5 ml of N,N-dimethylformamide was added 0.684 g of l-[3- (dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride. The mixture was stirred at room temperature for 1 hr and then 750 μL of hydroxylamine in water (50%) was added and the mixture stirred at room temperature overnight. The mixture was diluted with ethyl acetate and then washed with H2O, 2N citric acid, brine and dried (Na2SO4). The solvent was removed under vacuum to give a solid. Chromatography on silica gel with 10% methanol in ethyl acetate as solvent gave a solid which was dried at 78°C under vacuum overnight to give an off-white foam; Mass spectrum (ES) 406J (M+H); Anal. Calcd. For C18HI9N3O6S; C, 53.3; H, 4.7; N, 10.4. Found: C, 52.6; H, 5.2; N, 10.4.
The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof and, accordingly, reference should be made to the appended claims, rather than to the foregoing specification, as indicating the scope of the invention.

Claims

119
WHAT IS CLAIMED IS:
A compound of Formula 1 :
HOHN'
Figure imgf000121_0001
wherein
R is selected from hydrogen, (Cj - C3) alkyl, -CN, -OR", -SR', -CF3> -OCF3, Cl, F, NH2, NH(Cj - C3)alkyl, -N(R')CO(C! - C3)alkyl, -N(R')(R'), NO2, -CONH2, -SO2NH2, -SO2N(R')(R"), -N(R')COCH2O-(C1 - C3)alkyl, wherein R' is (Cj - C3) alkyl or hydrogen; R4 is hydroxy, (C, - C6) alkyl-O-, (Cj - C6) alkyl-S-,
-R, /r > -R,
R. .Ri R,
AΛ
Figure imgf000121_0002
N ►ø N
R
Figure imgf000121_0003
-*J
Figure imgf000121_0004
\ R , or
"*\ wherein R is hydrogen, halogen, cyano, methyl or -OCH3;
Figure imgf000121_0005
R\ and R2 are each, independently, hydrogen or CH3; R3 is (C, - C8)alkyl, NH2CH2CO-, (Qx - C6)alkylNHCH2CO-, HO(CH2)mCO-, HCO-, Aryl(CH2)nCO-, Heteroaryl(CH2)nCO-, (Cj - C3)alkyl-O-(CH2)nCO-, (Cj - C3)alkylCO-, (Cλ - C3)alkylCO-NHCH2CO-, (C3 - C7)cycloalkylCO-, (Cj - C3)alkylSO2-, Aryl(CH2)nSO2-, Heteroaryl(CH2)nSO2-, (Cj - C3)alkyl-O- (CH2)m-SO2-, (Cj - C3)alkyl-O-(CH2)m, (C, - C3)alkyl-O-(C, - C3)alkyl-O-(C1 - C3)- - 120 -
alkyl, HO- Cj - C3)alkyl-O-(C] - C3)alkyl. Aryl-O-CH2CO-, Heteroaryl-O-CH2CO-, ArylCH=CHCO-, HeteroarylCH=CHCO-, (Cj - C3)alkylCH=CHCO-.
O O II II CH2OC- CH2OC-NHCH2CO-
Figure imgf000122_0001
Figure imgf000122_0002
Aryl(C, - C3)alkyl, Heteroaryl(CrC3)alkyl, ArylCH=CHCH2- HeteroarylCH=CHCH2-, (Cl - C6)alkylCH=CHCH2-,
Y M
£> CO- CO- CO-
Figure imgf000122_0003
^
M N
M Y^' ^CO-
Figure imgf000122_0005
Figure imgf000122_0004
CO- w
M
CO-
Figure imgf000122_0006
Y ΓC°- s R'OCH2 CH(OR')CO-, (R'OCH2)2C(R')CO-,
CH3- N N(C! - C3)alkylCH=CH-CO- , Ω N-(C, - C6)alkylCO-
AJ N-(Cj - C6)alkylCO- , (C, - C3)alkylCONHCO-, ^-(C C^alkylCO- ,
O N-(C! - C6)alkylCO- , N-(C!-C6)alkylCO- N-(C,-C6)alkylCO- ,
" N N
CH3- N(C] - C6)alkylCO- , t-Boc-N N-(C, - C^alkylCO-
R' CO- O . ,
II / \ EtOCN - C^alkylCO- ,
R' o- \_A N(C, 121 -
(Cj - C6)alkylCO-
Figure imgf000123_0001
CH3
Figure imgf000123_0002
Figure imgf000123_0003
R' O
[(Cj - C6)alkyl]2-N-(C1 - C6)alkyl CO-, or (Cj - C6)alkyl-NH-(C1 - C6)alkylCO-; wherein m = 1 to 3; n = 0 to 3; Aryl is
X
] and
R
Heteroaryl is
X
O x
T η— N
N O
Ii
R'
N. 1 1 X Λ. ■ N or X
O N A N
I I
R' R'
wherein X is hydrogen, halogen, (Cj - C3) alkyl or -OCH3 and R and R' are as defined above; L is hydrogen, (CrC3)alkyl, -CN, -OR', -SR', -CF3, -OCF3, Cl, F, NH2, -NH-(C, C3)alkyl, -N(R')CO(C! - C3)alkyl, N(R')(R'), -NO2, -CONH2, -SO2NH2, -SO2N(R')(R'), -N(R')COCH2O-(C1 - C3)alkyl,
-^CONH- Y^ -_-_C0NH- ξ ∞™- .Y . - ^ 122
Mis
A
Y J N s
ϊl
N
N ^O'
I
R' s!T- N
^ \
N AT
I "1 3Y
N I
R' R'
R'-N N- OCO-N N
Figure imgf000124_0002
tBoc — N N- O N— N- ,
V N — , or N(R')(R') where R' is as defined above;
W is O, S, NH or N^ - C3)alkyl;
Y is hydrogen, F, Cl, CF3 or OCH3; and X' is halogen, hydrogen, (Cx - C3)alkyl,
O-(Cj - C3)alkyl, or -CH OH; and pharmaceutically acceptable salts thereof.
123 -
2. A compound according to claim 1 , wherein
R is hydrogen, (C, - C3) alkyl, -CN, -OR', -SR', -CF3>
-OCF3, Cl, F, NH2, NH(Cj - C3)alkyl, -N(R')CO(C! - C3)alkyl, -N(R')(R'), NO2,
-CONH2, -SO2NH2, -SO2N(R')(R'), or -N(R,)COCH2O-(C1 - C3)alkyl, wherein R ' is (Cj - C3) alkyl or hydrogen;
R4 is (Cj - C6) alkyl-O-, (Cj - C6) alkyl-S-,
-^ - ~\_£ 1 -R R.> ■R,
^A
.R, R. R,
O- - N -HT "N'
- R" , — S— V- R" , or
Figure imgf000125_0001
\ / R, wherein R is hydrogen, halogen, cyano, methyl or -OCH3;
R] and R2 are each, independently, hydrogen or CH3;
R3 is (Cj - C8)alkyl, NH2CH2CO-, (Cj - C6)alkylNHCH2CO-, HO(CH2)mCO- HCO-, Aryl(CH2)nCO-, Heteroaryl(CH2)nCO-, (Cj - C3)alkyl-O-(CH2)nCO-, (Cj - C3)alkylCO-, (C, - C3)alkylCO-NHCH2CO-, (C3 - C7)cycloalkylCO-, Aryl-O-CH2CO-, HeteroarylOCH2CO-, ArylCH=CHCO-, HeteroarylCH=CHCO- (C, - C3)alkylCH=CHCO-,
II (ϋ^ , II > or -j7-CH2OC-NHCH2CO-
Figure imgf000125_0002
Figure imgf000125_0003
wherein m = 1 to 3; n = 0 to 3; Aryl is
Figure imgf000125_0004
- 124 -
Heteroaryl is
X
N V ' S> H O
X
■ N
N
I O S'>
R'
\p ,\N , γ »v X \Λ— N ,N , or ^ ; _ ^^ x
O N ^N
I i
R' R.
wherein X is hydrogen, halogen, (Cj - C3) alkyl or -OCH3 wherein R and R' are as defined above; and pharmaceutically acceptable salts thereof.
3. A compound according to claim 1 , wherein
R is hydrogen, (C, - C3) alkyl, -CN, -OR', -SR', -CF3ι -OCF3, Cl, F, NH2, NH(C, - C3)alkyl, -N(R')CO(C1 - C3)alkyl, -N(R')(R'), NO2, -CONH2. -SO2NH2, -SO2N(R')(R'), -N(R')COCH2O-(C] - C3)alkyl, wherein R' is (Cj - C3) alkyl or hydrogen; R4 is (Cj - C6) alkyl-O-, (Cj - C6) alkyl-S-,
. / Rl ^ .Ri Rj
Figure imgf000126_0001
- , — s- \-R" , or
Figure imgf000126_0002
~~ \. / , wherein R is hydrogen, halogen, cyano, methyl or -OCH3; R] and R2 are each, independently, hydrogen or CH3; 125
R^ is
/ \
CH J N(Cj - C3)alkylCH=CH-CO- , O N-(C, - C6)alkylCO-
A N-(C, - C6)alkylCO- , (C, - C3)alkylCONHCO-, N-(C, -Chalky 1CO-
O N-(C! - C6)alkylCO- N-(Cι-C6)alkylCO- , N-(Cι-C6)alkylCO-
' N N=
CH3-N N(Cj - C6)alkylCO- , t-Boc-N N-(Cj - C^alkylCO-
o
EtOCN N(Cj - Chalky ICO- ,
- C6)alkylCO-
Figure imgf000127_0001
Figure imgf000127_0002
[(Ci - C6)alkyl]2-N-(Cι - C6)alkyl CO-, or (Cj - C6)alkyl-NH-(C, - C6)alkylCO-, where R' is as defined above; and pharmaceutically acceptable salts thereof.
4. A compound according to claim 1. wherein
R is hydrogen, (Cj - C3) alkyl, -CN, -OR', -SR', -CF3>
-OCF3, Cl, F, NH2, NH(Cι - C3)alkyl, -N(R')CO(C1 - C3)alkyl, -N(R')(R'), NO2, -CONH2, -SO2NH2, -SO2N(R')(R'), -N(R')COCH2O-(Cι - C3)alkyl, wherein R' is (Ci - C3) alkyl or hydrogen;
- 126
R4 is (Cj - C6) alkyl-O-, (C, - C6) alkyl-S-.
-O Rι • -o-o a =/ yny ■R,
R,
/ \ V € Nf • -^ Nf
-θA -R -^S Λ -R or
Figure imgf000128_0001
Figure imgf000128_0002
, wherein R is hydrogen, halogen, cyano, methyl or -OCH3;
Figure imgf000128_0003
Rj and R2 are each, independently, hydrogen or CH3; R3 is (Ci - C3)alkylSO2-, Aryl(CH2)nSO2-, Heteroaryl(CH2)nSO2-, or (Cj - C3)alkyl- O-(CH2)m-SO2, wherein m = 1 to 3; n = 0 to 3; Aryl is
and
Figure imgf000128_0004
Heteroaryl is
X
N S O x \,7— N
N O
I I >
R"
X
Jι ■ N
, or irX
O N ^ N7
I I
R' R' wherein X is hydrogen, halogen, (C] - C3) alkyl or -OCH3 and R and R' are as defined above; and pharmaceutically acceptable salts thereof. - 127 -
5. A compound according to claim 1 , wherein
R is hydrogen, (Cj - C3) alkyl, -CN, -OR', -SR', -CF3( -OCF3, Cl, F. NH2, NH(Cι - C3)alkyl. -N(R')CO(C! - C3)alkyl, -N(R')(R'), NO2,
-CONH2, -SO2NH2, -SO2N(R')(R'), or -N(R')COCH2O-(C! - C3)alkyl, wherein R ' is (Ci - C3) alkyl or hydrogen;
R4 is (Ci - C6) alkyl-O-, (C] - C6) alkyl-S-,
_ HK ^_R, , _(> - -_Rι ,
\=/ 0 \ — / \s/
r^, r R' ^ R| ^/R|
, →A R or
Figure imgf000129_0001
Figure imgf000129_0002
"R, wherein R is hydrogen, halogen, cyano, methyl or -OCH3; Rj and R2 are each, independently, hydrogen or CH3;
R3 is (C, - C8)alkyl, Aryl(Cj - C3)alkyl, Heteroaryl(Cj - C3)alkyl, ArylCH=CHCH2, HeteroarylCH=CHCH2-, or (C, - C6)alkylCH=CHCH2-, wherein Aryl is
Figure imgf000129_0003
- 128 -
Heteroaryl is
X x
X
O x • N \T-N
N O
I V>
R"
X
O N ^N
R' R- wherein X is hydrogen, halogen, (Ci - C3) alkyl or -OCH3 and R and R' are is as defined above; and pharmaceutically acceptable salts thereof.
6. A compound according to claim 1 , wherein
R is hydrogen, (Cj - C3) alkyl, -CN, -OR', -SR', -CF3 -OCF3, Cl, F, NH2, NH(Cι - C3)alkyl, -N(R')CO(Cι - C3)alkyl, -N(R')(R'), NO2,
-CONH2, -SO2NH2, -SO2N(R')(R'), or -N(R')COCH2O-(Cι - C3)alkyl, wherein R ' is (Cj - C3) alkyl or hydrogen;
R4 is (Cj - C6) alkyl-0-, (Cj - C6) alkyl-S-,
-o^f JTl. -R, 0 ~\JΓ -R. o N — ' s
_/-^> .κι Ri f I ΓK ^ x
oA^ R , — \-R , or
Figure imgf000130_0001
R , wherein R is hydrogen, halogen, cyano, methyl or -OCH3:
Figure imgf000130_0002
Rj and R are each, independently, hydrogen or CH3; 129
R^is
Y M
> ^ - CO- Vi co- ' CO-
M N:
M _l. γ_! i-co- IL -Jl
Figure imgf000131_0001
Figure imgf000131_0002
M
■CO-
Figure imgf000131_0003
S wherein m = 1 to 3; n = 0 to 3;
L is hydrogen, (C, - C3)alkyl, -CN, -OR', -SR', -CF3, -OCF3, Cl, F, NH2,
-NH-(Cι - C3)alkyl, -N(R')CO(Cι - C3)alkyl, N(R')(R'), -NO2, -CONH2, -SO2NH2,
-SO2N(R')(R'), -N(R')COCH2O-(Cι - C3)alkyl,
γ jr^'CONH- Y---/T- , CONH
'
Figure imgf000131_0004
. .« \ oy .
Mis
rT^i
Figure imgf000131_0005
Ύ N7 X STi
Tv .T f - • C0.N
N N N
I
R'
\Λ— N γ
N I < I
R' R' 130
/ \
R'- N N- OCO-N N
Figure imgf000132_0001
Figure imgf000132_0002
tBoc — N N— N- N-
N— , or N(R')(R') where R' is as defined above;
W is O, S, NH or N(Cj - C3)alkyl;
Y is hydrogen, F, Cl. CF3 or OCH3; and X' is halogen, hydrogen. (Cj - C3)alkyl.
O-(Cι - C3)alkyl, or -CH2OH; and pharmaceutically acceptable salts thereof.
7. A compound as claimed in any one of Claims 1 to 6 which is selected from
4-(4-Methoxybenzenesulfonyl)-l-(3-trifluoromethylbenzoyl)-2,3,4,5-tetrahydro-lH- [l,4]benzodiazepine-3-carboxylic acid, hydroxyamide,
4-(4-Methoxybenzenesulfonyl)-l-(4-methylphenylsulfonyl)-2,3,4,5-tetrahydro-lH- [l,4]benzodiazepine-3-carboxylic acid, hydroxyamide,
l-(Methanesulfonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH- [1 ,4]benzodiazepine-3-carboxylic acid, hydroxyamide,
l,4-Bis-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3- carboxylic acid, hydroxyamide,
l-Benzoyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine- 3-carboxylic acid, hydroxyamide,
l-Acetyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH-[l,4]benzodiazepine-3- carboxylic acid, hydroxyamide,
4-(4-Methoxybenzenesulfonyl)-l-(3-pyridinylcarbonyl)-2,3,4,5-tetrahydro-lH- [l,4]benzodiazepine-3 -carboxy lie acid, hydroxyamide, - 131 -
4-(4-Methoxybenzenesulfonyl)-l-(2-thienylcarbonyl)-2,3,4,5-tetrahydro-lH- [ 1 ,4]benzodiazepine-3-carboxylic acid, hydroxyamide,
1 -Methoxyacetyl-4-(4-methoxybenzenesulfony l)-23,4,5-tetrahydro- 1 H- [l,4]benzodiazepine-3-carboxylic acid, hydroxyamide.
4-(4-Methoxybenzenesulfonyl)- 1 -(propane- 1 -sulfonyl)-2,3,4,5-tetrahydro- 1 H- [l,4]benzodiazepine-3-carboxylic acid, hydroxyamide,
4-(4-Methoxybenzenesulfonyl)-l-(2-methyl-5-fluorobenzoyl)-2,3,4,5-tetrahydro-lH- [l,4]benzodiazepine-3-carboxylic acid, hydroxyamide,
4-(4-Methoxybenzenesιιlfonyl)-l-(4-pyridinylcarbonyl)-2,3.4,5-tetrahydro-lH- [ 1 ,4]benzodiazepine-3-carboxylic acid, hydroxyamide,
4-(4-Methoxybenzenesulfonyl)-l-(3-phenylpropionyl)-2,3,4,5-tetrahydro-lH- [l,4]benzodiazepine-3-carboxylic acid, hydroxyamide,
1 -( [ 1 J '-Bipheny l]-2-carbonyl)-4-(4-methoxybenzene-sulfonyl)-2,3,4,5-tetrahydro- lH-[1.4]benzodiazepine-3-carboxylic acid, hydroxyamide,
l-(4-Biphenylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH- [l,4]benzodiazepine-3-carboxylic acid, hydroxyamide,
l-(3-Fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3.4,5-tetrahydro-lH- [ 1 ,4]benzodiazepine-3-carboxylic acid, hydroxyamide,
4-(4-Methoxybenzenesulfonyl)- 1 -(2-methyl-3-fluorobenzoyl)-2,3,4,5-tetrahydro- 1 H- [l,4]benzodiazepine-3-carboxylic acid, hydroxyamide,
4-(4-Methoxybenzenesulfonyl)-l-(2-methyl-3-trifluoromethylbenzoyl)-2, 3,4.5- tetrahydro- 1 H-[ 1 ,4]benzodiazepine-3-carboxylic acid, hydroxyamide,
l-(2-Chloro-6-trifluoromethylbenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5- tetrahydro- lH-[ 1.4]benzodiazepine-3-carboxylic acid, hydroxyamide, - 132 -
l-(4-Fluoro-2-trifluoromethylbenzoyl)-4-(4-methoxybenzenesulfonyl)-2.3,4,5- tetrahydro-lH-[l ,4]benzodiazepine-3-carboxylic acid, hydroxyamide,
l-(2-Fluoro-6-trifluoromethylbenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5- tetrahydro- lH-[l,4]benzodiazepine-3-carboxylic acid, hydroxyamide.
4-(4-Methoxybenzenesulfonyl)-l-(2-methylbenzoyl)-2,3.4,5-tetrahydro-lH- [1.4]benzodiazepine-3-carboxylic acid, hydroxyamide,
4-(4-Methoxybenzenesulfonyl)-l-(2-methyl-6-chlorobenzoyl)-2,3,4,5-tetrahydro-lH- [1.4]benzodiazepine-3-carboxylic acid, hydroxyamide,
l-(2,4-Dimethylbenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH- [ 1 ,4]benzodiazepine-3-carboxylic acid, hydroxyamide,
1 -(2,5-Dimethylbenzoyl)-4-(4-methoxybenzenesulfonyl)-23,4,5-tetrahydro- 1 H- [l,4]benzodiazepine-3-carboxylic acid, hydroxyamide,
l-(2-Chloro-4-fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3.4,5-tetrahydro-lH- [ 1 ,4]benzodiazepine-3-carboxylic acid, hydroxyamide,
1 -(2-Chlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3.4,5-tetrahydro- 1 H- [1.4]benzodiazepine-3-carboxylic acid, hydroxyamide,
l-(2-Fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3.4,5-tetrahydro-lH- [l,4]benzodiazepine-3-carboxylic acid, hydroxyamide,
1 -(2-Chloro-6-fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3 ,4,5-tetrahydro- 1 H- [l,4]benzodiazepine-3-carboxylic acid, hydroxyamide,
l-(2,3-Difluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2.3,4,5-tetrahydro-lH- [l,4]benzodiazepine-3-carboxylic acid, hydroxyamide,
l-(2,4-Dichlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH- [l,4]benzodiazepine-3-carboxylic acid, hydroxyamide, - 133 -
l-(2.3-Dichlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-23-,4,5-tetrahydro-lH- [ l ,4]benzodiazepine-3-carboxylic acid, hydroxyamide,
1 -(2,5-Dichlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3.4,5-tetrahydro- 1 H- [l,4]benzodiazepine-3-carboxylic acid, hydroxyamide.
l-(2-Methoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH- [l,4]benzodiazepine-3-carboxylic acid, hydroxyamide,
l-(4-Chloro-2-methoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- lH-[l,4]benzodiazepine-3-carboxylic acid, hydroxyamide,
4-(4-Methoxybenzenesulfonyl)-l-(2-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH- [ 1 ,4]benzodiazepine-3-carboxylic acid, hydroxyamide,
4-(4-Methoxybenzenesulfonyl)-l-(3-methyl-2-thienylcarbonyl)-2,3,4,5-tetrahydro-lH- [ 1 ,4]benzodiazepine-3 -carboxylic acid, hydroxyamide.
4-(4-Methoxybenzenesulfonyl)-l-(4-methyl-2-thienylcarbonyl)-2,3,4,5-tetrahydro-lH- [l ,4]benzodiazepine-3-carboxylic acid, hydroxyamide,
l-(3-Chloro-2-thienylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH- [1.4]benzodiazepine-3-carboxylic acid, hydroxyamide,
l-(2-Furanylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH- [l ,4]benzodiazepine-3-carboxylic acid, hydroxyamide,
4-(4-Methoxybenzenesulfonyl)-l-(3-methyl-2-furanylcarbonyl)-2,3,4,5-tetrahydro-lH- [l,4]benzodiazepine-3 -carboxy lie acid, hydroxyamide.
4-(4-Methoxybenzenesulfonyl)-l-(4-methyl-2-furanylcarbonyl)-2,3,4,5-tetrahydro-lH- [l ,4]benzodiazepine-3-carboxylic acid, hydroxyamide,
l-(5-Chloro-2-furanylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH- [l,4]benzodiazepine-3-carboxylic acid, hydroxyamide, - 134 -
l-(5-Chloro-2-thienylcarbonyl)-4-(4-methoxybenzenesulfonyl)-23.4,5-tetrahydro-lH- [l ,4]benzodiazepine-3-carboxylic acid, hydroxyamide,
l -Propionyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH- [l,4]benzodiazepine-3-carboxylic acid, hydroxyamide.
l-Hexanoyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH- [l ,4]benzodiazepine-3-carboxylic acid, hydroxyamide,
l-(3-Methoxypropionyl)-4-(4-methoxybenzenesulfonyl)-2,3,4.5-tetrahydro-lH- [1.4]benzodiazepine-3-carboxylic acid, hydroxyamide,
4-(4-Methoxybenzenesulfonyl)-l-(3-thienylcarbonyl)-2,3,4,5-tetrahydro-lH- [l ,4]benzodiazepine-3-carboxylic acid, hydroxyamide,
l -(3-Furanylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH- [l,4]benzodiazepine-3 -carboxylic acid, hydroxyamide,
l-(trans-Crotonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH- [l ,4]benzodiazepine-3-carboxylic acid, hydroxyamide,
1 -(Methacryloyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1 H- [l,4]benzodiazepine-3-carboxylic acid, hydroxyamide,
l-(Acetylaminoacetyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH- [l,4]benzodiazepine-3-carboxylic acid, hydroxyamide,
l-(Aminoacetyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH- [l,4]benzodiazepine-3-carboxylic acid, hydroxyamide,
l-(N,N-Dimethylaminoacetyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH- [l,4]benzodiazepine-3-carboxylic acid, hydroxyamide,
1 -(Cyclopropylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1 H- [1.4]benzodiazepine-3-carboxylic acid, hydroxyamide, - 135 -
4-(4-Methoxybenzenesulfonyl)-l-(4-(2-thienyl)phenyl-carbonyl)-23,4,5-tetrahydro- lH-[l ,4]benzodiazepine-3-carboxylic acid, hydroxyamide,
4-(4-Methoxybenzenesulfonyl)-l-(4-(3-thienyl)phenylcarbonyl)-2,3,4.5-tetrahydro- lH-[l,4]benzodiazepine-3-carboxylic acid, hydroxyamide,
4-(4-Methoxybenzenesulfonyl)-l-[2-(l-pyrazolyl)phenylcarbonyl]-23,4,5-tetrahydro- lH-[l,4]benzodiazepine-3-carboxylic acid, hydroxyamide,
4-(4-Methoxybenzene.sulfonyl)-l-[2-(3-pyrazolyl)phenylcarbonyl]-2,3,4,5-tetrahydro- lH-[l,4]benzodiazepine-3-carboxylic acid, hydroxyamide,
l-(Cycloyhexylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH-[1.4]- benzodiazepine-3-carboxylic acid, hydroxyamide,
l-Methoxyacetyl-4-(4-methoxybenzenesulfonyl)-7-methyl-23,4,5-tetrahydro-lH- [l,4]-benzodiazepine-3-carboxylic acid, hydroxyamide,
l-Benzoyl-4-(4-methoxybenzenesulfonyl)-7-methyl-2,3,4.5-tetrahydro-lH-[l,4]- benzodiazepine-3-carboxylic acid, hydroxyamide,
4-(4-Methoxybenzenesulfonyl)-l-[(4-trifluoromethoxy)benzoyl]-8-chloro-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid, hydroxyamide,
4-(4-methoxybenzenesulfonyl)-l-[2-chloro-4-(3-methyl-l-pyrazolyl)phenylcarbonyl]- 2,3,4,5-tetrahydro-lH[l,4]-benzodiazepine-3-carboxylic acid, hydroxyamide,
4-(4-Methoxybenzenesulfonyl)-l-[2-(l-pyrazolyl)phenylcarbonyl]-7-methyl-2,3,4,5- tetrahydro- lH-[ 1 ,4]benzodiazepene-3-carboxylic acid, hydroxyamide,
4-(4-Methoxybenzenesulfonyl)-l-[2-(4-morpholino)phenylcarbonyl]-8-chloro-23,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-caι-boxylic acid, hydroxyamide,
l-(4-Ethoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3.4,5-tetrahydro-lH- [l,4]benzodiazepine-3-carboxylic acid, hydroxyamide, - 136 -
l-(Cyclobutylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3.4.5-tetrahydro-lH- [l ,4]benzodiazepine-3-carboxylic acid, hydroxyamide,
4-(4-Methoxybenzenesulfonyl)-l-(phenoxyacetyl)-23.4,5-tetrahydro-lH- [l,4]benzodiazepine-3-carboxylic acid, hydroxyamide.
4-(4-Methoxybenzenesulfonyl)- 1 -(2-methoxyethyl)-2,3,4.5-tetrahydro- 1 H- [l,4]benzodiazepine-3-carboxylic acid, hydroxyamide,
l-Benzyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH-[ 1 ,4]benzodiazepine- 3-carboxylic acid, hydroxyamide,
l-(2.4-Dimethoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-23,4,5-tetrahydro-lH- [l,4]benzodiazepine-3-carboxylic acid, hydroxyamide,
4-(4-Methoxybenzenesulfonyl)-l-[2-(4-methylpiperazin-l-yl)acetyl]-2,3,4,5- tetrahydro-lH-[l,4]benzodiazepine-3-carboxylic acid, hydroxyamide.
4-[4-(4-Chlorophenyloxy)benzenesulfonyl]-l-(methoxyacetal)-2,3,4,5-tetrahydro-lH- [l ,4]benzodiazepine-3-carboxylic acid, hydroxyamide,
4-[4-(4-Chlorophenyloxy)benzenesulfonyl]-l-(2-thienylcarbonyl)-2,3,4,5-tetrahydro- lH-[l,4]benzodiazepine-3-carboxylic acid, hydroxyamide,
4-[4-(4-Chlorophenyloxy)benzenesulfonyl]-l-(benzoyl-2,3,4,5-tetrahydro-lH- [l,4]benzodiazepine-3-carboxylic acid, hydroxyamide
and 4-[4-(4-Pyridinyloxy)benzenesulfonyl]-l-(methoxyacetyl)-2,3,4,5-tetrahydiO-lH- [l,4]benzodiazepine-3-carboxylic acid, hydroxyamide. - 137
8. A pharmaceutical composition comprising a compound of Formula 1
-RΛ
HOHN
Figure imgf000139_0001
wherein
R is selected from hydrogen, (C, - C3) alkyl, -CN. -OR', -SR', -CF3
-OCF3, Cl, F, NH2, NH(C] - C3)alkyl, -N(R')CO(Cι - C3)alkyl, -N(R')(R'), NO2,
-CONH2, -SO2NH2, -SO2N(R')(R'), -N(R')COCH2O-(C! - C3)alkyl, wherein R' is
(Ci - C3) alkyl or hydrogen:
R4 is hydroxy (Ci - C6) alkyl-O-, (Ci - C6) alkyl-S-,
_ _D_ ■ DR, -r^J~ JL -R,
^
.Ri .Ri Ri
{ V A SA
N 3 -^ N
R R , or
Figure imgf000139_0002
Figure imgf000139_0003
"R, wherein R is hydrogen, halogen, cyano, methyl or -OCH3;
Figure imgf000139_0004
Rl and R2 are each, independently, hydrogen or CH3;
R3 is (Cj - C8)alkyl, NH2CH2CO-, (Cj - C6)alkylNHCH2CO-, HO(CH2)mCO-,
HCO-, Aryl(CH2)nCO-, Heteroaryl(CH2)nCO-, (Cj - C3)alkyl-O-(CH2)nCO-,
(Ci - C3)alkylCO-, (Ci - C3)alkylCO-NHCH2CO-, (C3 - C7)cycloalkylCO-,
(Ci - C3)alkylSO2-, Aryl(CH2)nSO2-, Heteroaryl(CH2)nSO2-, (Cj - C3)alkyl-O-
(CH2)m-SO2-, (Cj - C3)alkyl-O-(CH2)m, (Cι-C3)alkyl-O-(C,-C3)alkyl-O-(Cι-C3)- alkyl, HO-(C! - C3)alkyl-O-(C! - C3)alkyl, Aryl-O-CH2CO-, Heteroaryl-O-CH2CO-.
ArylCH=CHCO-, HeteroarylCH=CHCO-, (Ci - C3)alkylCH=CHCO-, 138
Ay O O II II ■CH2OC- ■ CH9OC-NHCH-,CO-
Aryl(C, - C3)alkyl, Heteroaryl(Cι - C3)alkyl, ArylCH=CHCH2- HeteroarylCH=CHCH2-, ( - C6)alkylCH=CHCH2-,
Y M fy CO- VAτ\ CO- c CO-
M N
M I γ_!!_ JL-CO- O
Figure imgf000140_0001
Figure imgf000140_0002
M
CO- II
Y— CO-
Figure imgf000140_0003
s
R'OCH2 CH(OR')CO-, (R'OCH2)2C(R')CO-,
CH3-N N(C, - C3)alkylCH=CH-CO- , O N-(C, - C6)alkylCO-
N-(Cj - C6)alkylCO- , (Cj - C3)alkylCONHCO-, N-(C, -Chalky ICO-
0 -<cι - C6)alkylCO- , N-(d-C6)alkylCO- , N-(Cι-C6
/ >-.n )alkylCO-
" N N=
CH3-N N(Cj - C6)alkylCO- , t-Boc-N N-(C, - C^alkylCO-
■\J
O ll
EtOC \NA N(C, - Chalky ICO- ,
Figure imgf000140_0004
- 139 -
R' N- (C C ij -- CC66))aallkkyy IlCCOO-
CH3
Figure imgf000141_0001
CO
[(C, - C6)alkyl]2-N-(Cι - C6)alkyl CO-, or (Ci - C6)alkyl-NH-(C, - C6)alkylCO- wherein m = 1 to 3; n = 0 to 3; Aryl is
X and
«s>* R
Heteroaryl is
Q~ . τy . τ> .
A I
R'? ■ V ■ V ■ V. — λ — X \T~ N
O N ^N
I I R' R'
wherein X is hydrogen, halogen, (Cj - C3) alkyl or -OCH3 and R and R' are as defined above;
L is hydrogen, (CrC3)alkyl, -CN, -OR', -SR', -CF3, -OCF3, Cl , F, NH2, -NH-(Cr C3)alkyl, -N(R')CO(Cι - C3)alkyl, N(R')(R'), -NO2, -CONH2, -SO2NH2,-SO2N(R')(R'), -N(R')COCH2O-(C! - C3)alkyl,
X"' Y^ /r-vCONH- Y^ _. rONH-
■CONH- , ^\ S:> .« t ^O 140 -
M is
JJ
Y y_j >y sry
* N
N Λo-N I
R'
0 N I R' ■ X X3 N I R'
R'- N N- , || - OCO-N
tBoc — N N— Q N
\ N — , or N(R')(R') where R' is as defined above;
W is O, S, NH or N(Cj - C3)alkyl;
Y is hydrogen. F, Cl, CF3 or OCH3; and X' is halogen, hydrogen, (C - C3)alkyl,
O-(Cj - C3)alkyl, or -CH2OH; and pharmaceutically acceptable salts thereof.
9. A method of treating disease conditions mediated by matrix metalloproteinase in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula 1
HOHN
Figure imgf000142_0001
- 141 -
wherein
R is selected from hydrogen, Ci - C3) alkyl. -CN, -OR'. -SR', -CF3 -OCF3, Cl, F. NH2, NH(C] - C3)alkyl, -N(R')CO(Cι - C3)alkyl, -N(R')(R'), NO2, -CONH2, -SO2NH2, -SO2N(R')(R'), -N(R')COCH2O-(C! - C3)alkyl, wherein R' is (Cj - C3) alkyl or hydrogen;
R4 is hydroxy. (Ci - C6) alkyl-O-, (C - C6) alkyl-S-,
_^ΛX1 ■R,
Figure imgf000143_0001
n^ ■R,
R, r=λ
Figure imgf000143_0002
R" , — S- - R . or
Figure imgf000143_0003
" X / , wherein R is hydrogen, halogen, cyano, methyl or -OCH3;
Rl and R2 are each, independently, hydrogen or CH3;
R3 is (C! - C8)alkyl, NH2CH2CO-, (Cj - C6)alkylNHCH2CO-, HO(CH2)mCO-, HCO-, Aryl(CH2)nCO-, Heteroaryl(CH2)nCO-, (C] - C3)alkyl-O-(CH2)nCO-, (Ci - C3)alkylCO-, (Ci - C3)alkylCO-NHCH2CO-, (C3 - C7)cycloalkylCO-, (Ci - C3)alkylSO2-, Aryl(CH2)nSO2-, Heteroaryl(CH2)nSO2-, (Ci - C3)alkyl-O- (CH2)m-SO2-, (Ci - C3)alkyl-O-(CH2)m, (C - C3)alkyl-O-(Cι - C3)alkyl-0-(C, - C3)alkyl, HO-(Cι - C3)alkyl-O-(Cι - C3)alkyl, Aryl-O-CH2CO-, Heteroaryl-O- CH2CO-, ArylCH=CHCO-, HeteroarylCH=CHCO-, (Ci - C3)alkylCH=CHCO-,
O
11 CH2OC-NHCH2CO-
Figure imgf000143_0004
Figure imgf000143_0005
Ai Cj - C3)alkyl, Heteroary Cj - C3)alkyl, ArylCH=CHCH2-, HeteroarylCH=CHCH2-, (Cλ - C6)alkylCH=CHCH2-, 142
Y Y M
£> CO- CO-
^>»-
M N
M I.
Y÷ -jrco- o
Figure imgf000144_0001
Figure imgf000144_0002
M
CO- i > I
CO-
Figure imgf000144_0003
k S J
R'OCH2 CH(OR')CO-, (R'OCH2)2C(R')CO-,
/
CH3-NJ N(Cj - C3)alkylCH=CH-CO- , O N-(Cj - C6)alkylCO-
J N-(C, - C6)alkylCO- ,(Cj - C3)alkylCONHCO-, N-(CrC6)alkylCO-
O N^d-C^alkylCO- , N-(C!-C6)alkylCO- , ,N-(C!-C6)alkylCO- ,
/
N N
/ \
CH, J N(C!-C6)alkylCO- , t-Boc-N N-(Cj - C^alkylCO-
O II
EtOCN
Figure imgf000144_0004
J N(Cj - C^alkylCO-
rv. R'
N-(Cι -C6)alkylCO- έH3
Figure imgf000144_0005
R' O- CO-
[(C, - C6)alkyl]2-N-(C, - C6)alkyl CO-, or (C{ - C^alkyl-NH^Cj - C6)alkylCO-; wherein m= 1 to3;n = 0to 3; - 143 -
Aryl is x and
R
Heteroaryl is
C <f>
N O
X
V Ny O
R"
■ N y . A . X
O N or N^
I I R' R'
wherein X is hydrogen, halogen, (Ci - C3) alkyl or -OCH3 and R and R' are as defined above;
L is hydrogen, (CrC3)alkyl, -CN, -OR', -SR', -CF3, -OCF3, Cl, F, NH2, -NH-(Cr C3)alkyl, -N(R')CO(C! - C3)alkyl, N(R')(R'), -NO2, -CONH2, -SO2NH2, -SO2N(R')(R'), -N(R')COCH2O-(Cι - C3)alkyl,
Y^-^ 0NH" Y^^^CONH-
144 -
M is
J Y- 5^ k N ^
X 11
N N • < k N
O N N N I R'
\Λ—N
N I I X N Ii •
R' R'
/ \
R'-N N- OCO-N N
Figure imgf000146_0001
• " ' tBoc — N N— , O N— , N-
J N- , or N(R')(R') where R' is as defined above;
W is O, S, NH or N(Q - C3)alkyl;
Y is hydrogen, F, Cl, CF3 or OCH3; and X' is halogen, hydrogen, (C - C3)alkyl,
O-(C] - C3)alkyl, or -CH2OH; and pharmaceutically acceptable salts thereof.
10. A compound as claimed in any one of Claims 1 to 7 for use as a medicament.
1 1. Use of a compound as claimed in any one of Claims 1 to 7 in the preparation of a medicament for the treatment of a disease condition mediated by matrix metalloproteinases.
12. A process for the preparation of a compound of Formula 1 as claimed in any one of Claims 1 to 7 which comprises reacting the corresponding acid halide with hydroxylamine.
PCT/US1999/001325 1998-01-27 1999-01-22 2,3,4,5-tetrahydro-1h-[1,4]-benzodiazepine-3-hydroxamic acids as matrix metalloproteinase inhibitors WO1999037625A1 (en)

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HU0100277A HUP0100277A3 (en) 1998-01-27 1999-01-22 2,3,4,5-tetrahydro-1h-[1,4]-benzodiazepine-3-hydroxamic acids as metalloproteinase inhibitors, process for their preparation and pharmaceutical compositions containing them
AU22402/99A AU2240299A (en) 1998-01-27 1999-01-22 2,3,4,5-tetrahydro-1h-(1,4)-benzodiazepine-3-hydroxamic acids as matrix metalloproteinase inhibitors
PL99342045A PL342045A1 (en) 1998-01-27 1999-01-22 2,3,4,5-tetrahydro-1h-[1,4]-benzdiazepin-3-hydroxamic acids as inhibitors of matrix metaloproteinases
CA002317546A CA2317546A1 (en) 1998-01-27 1999-01-22 2,3,4,5-tetrahydro-1h-¬1,4|-benzodiazepine-3-hydroxamic acids as matrix metalloproteinase inhibitors
IL13716299A IL137162A0 (en) 1998-01-27 1999-01-22 2,3,4,5-tetrahydro -1h- [1,4]-benzodiazepine -3- hydroxamic acids as matrix metalloproteinase inhibitors
JP2000528549A JP2002501056A (en) 1998-01-27 1999-01-22 2,3,4,5-tetrahydro-1H- [1,4] -benzodiazepine-3-hydroxamic acid as matrix metalloproteinase inhibitor
BR9907746-9A BR9907746A (en) 1998-01-27 1999-01-22 2,3,4,5-tetrahydro-1h [1,4] -benzodiazepine-3-hydroxamic acids as metalloproteinase matrix inhibitors
EP99902417A EP1051407A1 (en) 1998-01-27 1999-01-22 2,3,4,5-tetrahydro-1h-[1,4]-benzodiazepine-3-hydroxamic acids as matrix metalloproteinase inhibitors
KR1020007008171A KR20010034406A (en) 1998-01-27 1999-01-22 2,3,4,5-Tetrahydro-1H[1,4]-benzodiazepine-3-hydroxamic acids as matrix metalloproteinase inhibitors
NO20003828A NO20003828L (en) 1998-01-27 2000-07-26 2,3,4,5-tetrahydro-1H- [1,4] benzodiazepine-3-hydroxamic acids as matrix metalloproteinase inhibitors

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WO2000044730A1 (en) * 1999-01-27 2000-08-03 American Cyanamid Company 2,3,4,5-tetrahydro-1h-[1,4]benzodiazepine-3-hydroxamic acid as matrix metalloproteinase inhibitors
WO2001081322A1 (en) * 2000-04-21 2001-11-01 Bristol-Myers Squibb Company Non-imidazole benzodiazepine inhibitors of farnesyl protein transferase
US6544984B1 (en) 1999-01-27 2003-04-08 American Cyanamid Company 2,3,4,5-tetrahydro-1H-(1,4)benzodiazepine-3-hydroxamic acids
EP1992636A2 (en) 1999-11-12 2008-11-19 Amgen Inc. Process for correction of a disulfide misfold in Fc molecules
EP2087908A1 (en) 2001-06-26 2009-08-12 Amgen, Inc. Antibodies to opgl
WO2011033010A1 (en) 2009-09-17 2011-03-24 Galderma Research & Development 4-alkoxy-n- (2-hydroxycarbamoyl-2-piperidinyl-ethyl) -benzamide compounds as selective tace-inhibitors for the treatment of inflammatory diseases
WO2011033009A1 (en) 2009-09-17 2011-03-24 Galderma Research & Development N- [2-hydroxycarbamoyl-2- (piperazinyl) ethyl] benzamide compounds, their preparation and their use as tace inhibitors
US8955512B2 (en) 2001-06-05 2015-02-17 Alexza Pharmaceuticals, Inc. Method of forming an aerosol for inhalation delivery
US9211382B2 (en) 2001-05-24 2015-12-15 Alexza Pharmaceuticals, Inc. Drug condensation aerosols and kits
WO2020070239A1 (en) 2018-10-04 2020-04-09 INSERM (Institut National de la Santé et de la Recherche Médicale) Egfr inhibitors for treating keratodermas
US11642473B2 (en) 2007-03-09 2023-05-09 Alexza Pharmaceuticals, Inc. Heating unit for use in a drug delivery device

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WO1997020824A1 (en) * 1995-12-08 1997-06-12 Agouron Pharmaceuticals, Inc. Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses, and methods and intermediates useful for their preparation

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WO1997020824A1 (en) * 1995-12-08 1997-06-12 Agouron Pharmaceuticals, Inc. Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses, and methods and intermediates useful for their preparation

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6458783B1 (en) 1997-09-29 2002-10-01 Bristol-Myers Squibb Company Non-imidazole benzodiazepine inhibitors of farnesyl protein transferase
WO2000044730A1 (en) * 1999-01-27 2000-08-03 American Cyanamid Company 2,3,4,5-tetrahydro-1h-[1,4]benzodiazepine-3-hydroxamic acid as matrix metalloproteinase inhibitors
US6544984B1 (en) 1999-01-27 2003-04-08 American Cyanamid Company 2,3,4,5-tetrahydro-1H-(1,4)benzodiazepine-3-hydroxamic acids
EP1992636A2 (en) 1999-11-12 2008-11-19 Amgen Inc. Process for correction of a disulfide misfold in Fc molecules
WO2001081322A1 (en) * 2000-04-21 2001-11-01 Bristol-Myers Squibb Company Non-imidazole benzodiazepine inhibitors of farnesyl protein transferase
US10350157B2 (en) 2001-05-24 2019-07-16 Alexza Pharmaceuticals, Inc. Drug condensation aerosols and kits
US9440034B2 (en) 2001-05-24 2016-09-13 Alexza Pharmaceuticals, Inc. Drug condensation aerosols and kits
US9211382B2 (en) 2001-05-24 2015-12-15 Alexza Pharmaceuticals, Inc. Drug condensation aerosols and kits
US8955512B2 (en) 2001-06-05 2015-02-17 Alexza Pharmaceuticals, Inc. Method of forming an aerosol for inhalation delivery
US9308208B2 (en) 2001-06-05 2016-04-12 Alexza Pharmaceuticals, Inc. Aerosol generating method and device
US9439907B2 (en) 2001-06-05 2016-09-13 Alexza Pharmaceutical, Inc. Method of forming an aerosol for inhalation delivery
US9687487B2 (en) 2001-06-05 2017-06-27 Alexza Pharmaceuticals, Inc. Aerosol forming device for use in inhalation therapy
US11065400B2 (en) 2001-06-05 2021-07-20 Alexza Pharmaceuticals, Inc. Aerosol forming device for use in inhalation therapy
EP3492100A1 (en) 2001-06-26 2019-06-05 Amgen Inc. Antibodies to opgl
EP2087908A1 (en) 2001-06-26 2009-08-12 Amgen, Inc. Antibodies to opgl
US11642473B2 (en) 2007-03-09 2023-05-09 Alexza Pharmaceuticals, Inc. Heating unit for use in a drug delivery device
WO2011033009A1 (en) 2009-09-17 2011-03-24 Galderma Research & Development N- [2-hydroxycarbamoyl-2- (piperazinyl) ethyl] benzamide compounds, their preparation and their use as tace inhibitors
WO2011033010A1 (en) 2009-09-17 2011-03-24 Galderma Research & Development 4-alkoxy-n- (2-hydroxycarbamoyl-2-piperidinyl-ethyl) -benzamide compounds as selective tace-inhibitors for the treatment of inflammatory diseases
WO2020070239A1 (en) 2018-10-04 2020-04-09 INSERM (Institut National de la Santé et de la Recherche Médicale) Egfr inhibitors for treating keratodermas

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