MXPA01007575A - 2,3,4,5-tetrahydro-1h-[1,4]benzodiazepine-3-hydroxamic acid as matrix metalloproteinase inhibitors - Google Patents

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

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Publication number
MXPA01007575A
MXPA01007575A MXPA/A/2001/007575A MXPA01007575A MXPA01007575A MX PA01007575 A MXPA01007575 A MX PA01007575A MX PA01007575 A MXPA01007575 A MX PA01007575A MX PA01007575 A MXPA01007575 A MX PA01007575A
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Mexico
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alkyl
tetrahydro
carboxylic acid
benzodiazepine
hydrogen
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MXPA/A/2001/007575A
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Spanish (es)
Inventor
Jay Donald Albright
Jeremy Ian Levin
Santos Efren Guillermo Delos
James Ming Chen
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Wyeth Holdings Corporation
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Publication of MXPA01007575A publication Critical patent/MXPA01007575A/en

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Abstract

Compounds having formula (1) are useful in treating disease conditions mediated by matrix metalloproteinases and TACE, such as tumor growth, osteoarthritis, rheumatoid arthritis and degenerative cartilage loss.

Description

CIDOS 2, 3,, 5-TETRAHYDRO-1H- [1, 4] BENZODIAZEPIN-3-HYDROXAMIC AS INHIBITORS OF METALOPROTEINASE MATRIX FIELD OF THE INVENTION This invention relates to 4- (4-substituted-benzenesulfonyl) acids - 2,3,4, 5-tetrahydro-lH- [1,4] benzodiazepin-3-hydroxamics which act as inhibitors of the matrix metalloproteinase and as inhibitors of the enzyme (TACE) that converts TNF-a. The compounds of the present invention are useful in disease conditions mediated by matrix metalloproteinases and TACE, such as tumor growth, osteoarthritis, rheumatoid arthritis and degenerative cartilage loss.
BACKGROUND OF THE INVENTION 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. From this, it has been shown that gelatinases are the most MMPs REF: 131001 intimately involved with the growth and expansion of tumors. For example, it is known that the level of expression of gelatinase is elevated in malignancies, and this gelatinase can degrade the basement membrane which leads to tumor metastasis. Angiogenesis, required for the growth of solid tumors, has also recently been shown to have a gelatinase component for 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, osteopenias mediated by MMP, 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 loss of cartilage followed by traumatic joint damage, demyelinating diseases of the nervous system, cirrhosis of the liver, glomerular disease of the kidney, premature rupture of fetal membranes, inflammatory bowel disease, periodontal disease, age-related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren's syndrome, myopia, ocular tumors, ocular angiogenesis / neovascularization and rejection of the cornea graft. Studies related to these conditions have been described in, for example, "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): 1087-110, (1995); Exp. Opin. Ther. Patents, 5 (12): 1287-1196, (1995); "Inhibition of Matrix Metalloproteinases: Structure Based Design", Current Pharmaceutical Design, 2: 524-661, (1996). "Matrix Metalloproteinase Inhibitor Drugs", Emerginq Drugs, 2: 205-230 (1997). The enzyme (TACE) that converts TNF-a, catalyzes the formation of TNF-a from the precursor protein of TNF-a membrane. TNF-a is a proinflammatory 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, resistance to insulin and HIV infection, in addition to its well-documented antitumorigenic properties. The search with anti-TNF-a antibodies in transgenic animals, has shown that blocking the formation of TNF-a inhibits the progress of arthritis. This observation has recently been extended to humans as described in "TNF-a in Human Diseases," Current Pharmaceutical Design, 2: 662-667 (1996). It is expected that the small molecule inhibitors of MMPs and TACE may have the potential to treat 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 problems of bioavailability and pharmacokinetics. Accordingly, non-peptidic, orally bioavailable, long-acting MMPs and / or TACE inhibitors could be highly desirable for the treatment of the disease states described above. U.S. Patent No. 5,455,258 describes 2-substituted-2- (arylsulfonylamino) hydroxyamic acids and their uses as inhibitors of MMP. WO 97/18194 describes the N- (arylsulfonyl) tetrahydroisoquinolone-hydroxamic acids and related bicyclic derivatives thereof and their uses as MMP inhibitors. WO 97/20824 and the Patent North American 5,753,653 describe 1- (arylsulfonyl) -4- (substituted) piperazine-2-hydroxamic acids, 4- (arylsulfonyl) morpholin-3-hydroxamic acids, 4- (arylsulfonyl) -tetrahydro-2H, 1, -thiazin-3 acids -hydroxamics, 3- (substituted-1- (arylsulfonyl) hexahydro-2-hydroxamic acids and related compounds as useful MMP inhibitors, WO 98/08822, WO 98/08823 and WO 98/08825, describe the 1- (arylsulfonyl ) 6-element hexahydropyrimidine-2-hydroxamics, l-substituted-3- [(4-methoxybenzenesulfonyl)] hexahydropyrimidine-4-hydroxamics, 4- (arylsulfonyl) -tetrahydro-1,2-thiazine-3-hydroxamic acids and acids (arylsulfonyl) -4-substituted-piperazine-2-hydroxamics, WO 98/08827 describes 4- (arylsulfonyl) -hexahydrothiazepine-3-hydroxamic acids and 4- (aryl sulfonyl) -hexahydro [1,4] -diazepin-3 acids -hydroxamics.
BRIEF DESCRIPTION OF THE INVENTION This invention relates to new derivatives of substituted 2,3,4,5-tetrahydro-lH [1,4] benzodiazepine-3-carboxylic acid, hydroxamide which exhibits inhibitory activity against MMPs. The compounds of the present invention are represented by the following formula I wherein R is selected from hydrogen, (C1-C3) alkyl, -CN, -OR ', -SR', -CF3, -OCF3, Cl, F, NH2, -NH (C? -C3) alkyl, -N (R ') CO (C? -C3) alkyl, -N (R') (R '), N02, -CONH2, -S02NH2, -S02N (R') (R '), or -N (R') C0CH20- (C1-C3) alkyl, wherein R 'is (C1-C3) alkyl or hydrogen; R4 is (Ci-Cβ) alkyl-0- containing a triple bond, for example, C2-C6; wherein R "is hydrogen, -CH20H, (C? -C6) alkyl, (Cx-C6) alkyl-0-CH2-, (C? -C6) alkyl-S-CH2-, (C? -C6) alkyl -NH-CH2-, [(C1-C3) alkyl] 2-NCH2-, (C? -C6) cycloalkyl-0-CH2-, [(C? ~ C3) alkyl] 2-N- (CH2) 2- 4NHCH2-, ( Ri and R2 are each, independently, hydrogen or CH3; R3 is (C? -C8) alkyl, NH2CH2CO-, (C? -C6) alkylNHCH2CO-, HO (CH2) mCO-, HCO-, Aryl (CH2) nCO-, Heteroaryl (CH2) nCO-, (C? ~ C3) alkyl-O- (CH2) nC0-, (C1-C3) alkylCO-, (C1-C3) alkylCO-NHCH2CO-, (C3-C7) cycloalkylCO-, (C1-C3) alkylS02-, Aryl (CH2) nS02-, Heteroaryl (CH2) nS02-, (C1-C3) alkyl-O- (CH2) m-S02-, (C1-C3) alkyl-O- (CH2) m-, (C1-C3) alkyl-O - (C1-C3) alkyl-O- (C1-C3) alkyl, HO- (C1-C3) alkyl-O- (C1-C3) alkyl, Aril-O-CH2CO-, Heteroaryl-0-CH2CO-, ArilCH = CHCO-, HeteroarilCH = CHCO-, (Cx-C3) alkylCH = CHCO-, O -p-CH2OC-, 0 - -CH2OC-NHCH2CO- Aryl (C1-C3) alkyl, Heteroaryl (C1-C3) alkyl, ArilCH = CHCH2-, HeteroarylCH = CHCH2-, (C? -C6) alkylCH = CHCH2-, R'OCH2 CH (OR ') CO-. (ROCH2) 2C (R ') CO-, CO-. uil CO-, CH3- (Cj -C6) alkyl CO-, 1-B? C- ^ - (Ci-Cfi) alkyl CO- \ V JC0", EtOC? ^ ^ íCi-CßJiuqiiiiCO-. R 'o [(C? -C6) alkyl] 2-N- (C? -C6) alkyl CO-, or (C? -C6) alkyl-NH- (C6) alkylCO-; where m 1 to 3; n = 0 to 3; Arilo is Heteroaryl is wherein X is hydrogen, halogen, (C1-C3) alkyl or -0CH3 and R and R 'are as defined above; L is hydrogen, (C1-C3) alkyl, -CN, -OR ', -SR', -CF3, -0CF3, Cl, F, NH2, -NH- (C? -C3) alkyl, -N (R ' ) CO (C1-C3) alkyl, N (R ') (R'), -N02, -CONH2, -S02NH2, -S02N (R ') (R'), -N (R ') C0CH20- (C1-) C3) alkyl, Month it is as defined above; W is 0, S, NH or N (C1-C3) alkyl; And it is hydrogen, F, Cl, CF3 or OCH3; and X 'is halogen, hydrogen, (C1-C3) alkyl, 0- (C1-C3) alkyl, or -CH20H; and pharmaceutically acceptable salts thereof.
DETAILED DESCRIPTION OF THE INVENTION Preferably, the compounds of the present invention are those of the formula 1 wherein R is hydrogen, (C1-C3) alkyl, -CN, -OR ', -SR', -CF3, -0CF3, Cl , F, NH2, NH (C? -C3) alkyl, -N (R ') CO (C1-C3) alkyl, -N (R') (R '), N02,' -CONH2, -S02NH2, -S02N (R ') (R'), or -N (R ') COCH2-0- (C? -C3) alkyl, wherein R' is (C1-C3) alkyl or hydrogen; R4 is (C? ~ C6) alkyl-O- containing a triple bond, wherein R "is hydrogen, -CH2OH, (C? -C6) alkyl, (Ci- C6) alkyl-0-CH2-, (C? -C6) alkyl-S-CH2-, (C? -C6) alkyl -NH-CH2-, [(C? -C3) alkyl] -NCH2-, (C? -C6) cycloalkyl-0-CH2-, [(Ci-C3) alkyl] 2-N- (CH2) 2-4 NHCH2 -, 0- \. { (Cl-C3) ai ui ') 2 ^ - (CH2) 3- ^ l (CH3) CH2-. -CHrO- ^ \.
Ri and R2 are each, independently, hydrogen or CH3; R3 is (C? -C8) alkyl, NH2CH2C0-, (C? -C6) alkylNHCH2C0-, H0 (CH2) mC0-, HCO-, Aryl (CH2) nC0-, Heteroaryl (CH2) nC0-, (Ci-C3) ) alkyl-O- (CH2) nC0-, (C? ~ C3) alkylCO-, (C1-C3) alkylCO-NHCH2CO-, (C3-C7) cycloalkylCO-, Aryl-0-CH2CO-, HeteroarylOCH2CO-, where m = 1 to 3; n = 0 to 3; Arilo is Heteroaryl is wherein X is hydrogen, halogen, (C1-C3) alkyl or -OCH3 and R and R 'are as defined above; and pharmaceutically acceptable salts thereof. It is more preferred that the compounds of the present invention include those of formula 1 wherein R is hydrogen, (C1-C3) alkyl, -CN, -OR ', -SR', -CF3, -OCF3, Cl, F, NH2, NH (C? -C3) alkyl, -N (R ') CO (C1-C3) alkyl, -N (R') (R '), N02, -CONH2, -SO2NH2, -S02N (R') (R '), or -N (R') COCH20- (C? -C3) alkyl, wherein R 'is (C1-C3) alkyl or hydrogen; R4 is (C? -C6) alkyl-O- which contains a triple bond, wherein R "is hydrogen, -CH2OH, (C? -C6) alkyl, (C? -C6) alkyl-0-CH2-, (C? -C6) alkyl-S-CH2-, (C? -C6) alkyl-NH-CH2-, [(C? -C3) alkyl] 2-NCH2-, (C? -C6) cycloalkyl-0-CH2-, [(C1-C3) alkyl] 2-N- (CH2) 2.4 NHCH2-, { Ri and R2 are each, independently, hydrogen or CH3; R3 is (C1-C3) alkylCO-, (C1-C3) alkyl-O- (CH2) mCO-, ArylCO- where m = l to 3; n = 0 to 3; Arilo is Heteroaryl is wherein X is hydrogen, halogen, (C1-C3) alkyl or -OCH3 and R and R 'are as defined above; and pharmaceutically acceptable salts thereof.
It is more preferred that the compounds of the present invention include those of formula 1 wherein R is hydrogen, (C1-C3) alkyl, -CN, -OR, -SR, -CF3, OCF3, Cl, F, NH2, NH (C? -C3) alkyl, -N (R ') CO (C1-C3) alkyl, -N (R') (R '), N02, -CONH2, -SO2NH2, S02N (R') (R ') or -N (R ') COCH20- (Ci-C3) alkyl, wherein R' is (C1-C3) alkyl or hydrogen; R4 is (C? -C6) alkyl-O- which contains a triple bond, wherein R "is hydrogen, -CH2OH, (C? -C6) alkyl, (Ci-C6) alkyl-0-CH2-, (C? -C6) alkyl-S-CH2-, (C? -C6) alkyl -NH-CH2-, [(C1-C3) alkyl] 2-NCH2-, (C? -C6) cycloalkyl-0-CH2-, [(Ci-C3) alkyl] 2-N- (CH2) 2-4 NHCH2 -, ((C? -C3) aiqui.) 2 ^ - (CH2) 2- M (CH3) CH2-. -CHrOY ~ S / Ri and R are each, independently, hydrogen or CH3; R3 is (C? -C3) alkylS02-, Aryl (CH2) nS02-, Heteroaryl (CH2) nS02-, or (C1-C3) alkyl-O- (CH2) nS02-, where m = l to 3; n = 0 to 3; Arilo is A further, more preferred embodiment of the present invention includes compounds represented by formula 1 wherein R is selected from hydrogen, (C1-C3) alkyl, -CN, -OR ', - SR', -CF3, -OCF3 , Cl, F, NH2, NH (C? -C3) alkyl, -N (R ') CO (C? ~ C3) alkyl, -N (R') (R '), N02, -CONH2, -S02NH2, -S02N (R ') (R'), or -N (R ') COCH20- (C1-C3) alkyl, wherein R' is (C1-C3) alkyl or hydrogen; R4 is (Ci-Ce) alkyl-O- which contains a triple bond, wherein R "is hydrogen, -CH2OH, (C? -C6) alkyl, (Cx-C6) alkyl-0-CH2-, (C? -C6) alkyl-S-CH2-, (C? -C6) alkyl -NH-CH2-, [(C? -C3) alkyl] 2-NCH2-, (C? -C6) cycloalkyl-0-CH2-, [(Cx-C3) alkyl] 2-N- (CH2) 2- 4NHCH2-, • ^ aR: - ^^ '. Ri and R2 are each, independently, hydrogen or CH3; R3 is (C? -C3) alkylCO-, (C1-C3) alkyl-CO-, (C? ~ C7) cycloalkylCO-, (C1-C3) alkyl-O- (CH2) m-CO-, Ar (CH2 ) n-CO-, HO- (CH2) mCO-, Heteroaryl (CH2) m -CO- where Aryl is Heteroaryl is . t $ where X is hydrogen, halogen, (C1-C3) alkyl or -0CH3 and R and R 'are as defined above; and pharmaceutically acceptable salts thereof. Additionally the highly preferred compounds of the present invention include those of the formula I wherein R is hydrogen, (C1-C3) alkyl, -CN, -OR ', -SR', -CF3, -0CF3, Cl, F, NH2, NH (C1-C3) alkyl, -N (R ') C0 (Cx-C3) alkyl, -N (R') (R '), N02, -C0NH2, -S02NH2, -S02N (R') ( R '), or -N (R') C0CH20- (C1-C3) alkyl, wherein R 'is (C1-C3) alkyl or hydrogen; R4 is -0-CH2-C = C-R; wherein R "is hydrogen, -CH20H, (C? -C6) alkyl, (C? -C6) alkyl-0-CH2-, (C? -C6) alkyl-S-CH2-, (C? -C6) alkyl-NH-CH2-, [(C1-C3) alkyl] 2-NCH2-, (C? -C6) cycloalkyl-0-CH2-, [(d-C3) alkyl] 2-N- (CH2) 2- 4NHCH2-, ( Ri and R2 are each, independently, hydrogen or CH3; R3 is where m = 1 to 3; n = 0 to 3; L is hydrogen, (C1-C3) alkyl, -CN, -OR ', -SR', -CF3, -OCF3, Cl, F, NH2, -NH- (C? -C3) alkyl, -N (R ' ) CO (C1-C3) alkyl, N (R ') (R'), -N02, -CONH2, -SO2NH2, -S02N (R ') (R'), -N (R ') COCH20- (C1- C3) alkyl, Month it is as defined above; W is O, S, NH or N (C1-C3) alkyl; And it is hydrogen, F, Cl, CF3 or OCH3; and X 'is halogen, hydrogen, (C1-C3) alkyl, O- (C1-C3) alkyl, or -CH2OH; and pharmaceutically acceptable salts thereof. In accordance with this invention, there is provided a process for preparing compounds of formula 1, as defined above, which comprises one of the following: a) reacting a compound of formula II < p) wherein R, Ri, R2, R3 and R are as defined above, and A is COOH or a reactive derivative thereof, with a compound of formula III NH2OH (III) to give a corresponding compound of formula 1; b) re-dissolving a mixture (for example racemate) of optically active isomers of a compound of the formula I to isolate a substantially free enantiomer or diastereomer of the other enantiomer or diastereomers; c) acidifying a base compound of formula I with a pharmaceutically acceptable acid to give a pharmaceutically acceptable salt. With respect to process a) the reaction can be carried out by processes known in the art, for example, by the reaction with the acid chloride to form a reactive derivative before the reaction with the hydroxylamine.
With respect to process b) standard separation techniques can be used to isolate particular enantiomeric or diastereomeric forms. For example, a racemic mixture can be converted to a mixture of optically active diastereoisomers by reaction with a single or single enantiomer of a "resolving agent" (for example by diastereomeric salt formation or formation of a covalent bond). The resulting mixture of optically active diastereoisomers can be separated by standard techniques (e.g., crystallization or chromatography) and then the individual optically active diastereomers are treated to remove the resolving agent, whereby the simple enantiomer of the compound is released. of the invention. Chiral chromatography (using a chiral support, eluent or coupling agent or ion bond) can also be used to directly separate enantiomer mixtures. The compounds of the formula I can be isolated in the form of a salt of a pharmaceutically acceptable acid, for example, an organic or inorganic acid by treatment with an acid as described above. Some of the intermediate compounds for the preparation of derivatives of formula 1 are those wherein R 4 is OCH 3 and they can be advantageously prepared according to the illustrated Reaction Schemes. The ester derivatives of the formulas 8, 14, 15, 20, 22, 23, 24, 25, 29 and 30 wherein R 4 is OCH 3 are used to prepare derivatives wherein R 4 is OH (via the cleavage of the 0-CH 3 group) ). As illustrated in Scheme 8, derivatives with a phenolic OH group are reacted under standard organic synthetic conditions to convert the OH moiety to substituents R4 (previously defined). Variations can be made in these schemes to improve productivity without causing negative effects on the quantity and nature of the product, by means that will be recognized by those skilled in the art. For example, the reactive groups can be blocked with suitable blocking portions which can then be deblocked under standard conditions (for example, the hydroxy groups can be protected with portions of trimethylsilyl or t-butyl-dimethylsilyl which are then removed in a subsequent reaction step). In addition, those skilled in the art will recognize that catalytic hydrogenation conditions are inappropriate for preparing intermediates with a R4 portion that contains a triple bond.; the portion R4 is then introduced into intermediates that do not require a reduction 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. A reaction path is shown in Reaction Scheme I. It is noted that methyl esters are shown in all Reaction Schemes, however, it is understood that the use of methyl esters is for purposes of illustration only, and other suitable alkyl esters, benzyl esters and the like can be used similarly. In Reaction Scheme 1, serine, threonine, beta-hydroxy valine 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. The reduction under conventional reduction conditions, such as catalytic hydrogeneration (with Pd / C) or chemical reduction (for example, with SnCl 2 or FeCl 3) results in amino derivatives 6. The reaction of the N- (2-aminobenzyl) derivatives with alkanoyl chlorides, alkylsulfonyl chlorides, aroyl chlorides, heteroaroyl chlorides, aryl sulfonyl chlorides, heteroarylsulfonyl chlorides and the like, in the presence of trialkylamines or pyriden, provides the dehydroalanin derivatives 7. The ring closure for the compounds [1,4] benzodiazepine 9 is carried out by reaction with a weak base such as sodium or potassium bicarbonate in an alcohol solvent such as methanol or ethanol. Standard conditions involving ester hydrolysis (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. The ester derivatives (wherein the function ester 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 the application of the Mitsunobu reaction to give intermediates 12. The reduction of the 2-nitro group and removal of the hydroxy blocking group with derivatives 12, wherein the R4 group is a protected amino moiety with simultaneous unblocking of the amino and hydroxyl functions, gives the intermediary compounds 13. Intermediates 13 can be then react with benzyloxycarbonyl chloride to give the closed ring [1,4] benzodiazepines 14. The reaction of derivatives 14 with acyl chlorides, aroyl chlorides, heteroaroyl chlorides, alkylsulfonyl chlorides, arylsulfonyl chlorides and chlorides of heteroaryl sulfonyl and the like produce intermediates 15.
Reaction Scheme 1 where n = 0 to 3; m = 1 to 3; Ri = R2 = (C1-C3) alkyl; R = Hydrogen; halogen; OCH; N02; NH2; CF3, NHCOCH3; NHCOCH2OCH3; CONH2; -N (R ') (R'); -N (R ') C0 (C? ~ C3) alkyl; (C1-C3) alkyl; R3 = Ar (CH2) nCO-; Heteroaryl (CH2) nC0-; Ar (CH2) nS02-; Heteroaryl (CH2) nS02-; Alkyl-0-CH2) nC0-; Alkyl-O- (CH2) mS02-; AlkylCO-; Alkyls02-; AlkylC0-NHCH2C0-; and (C3-C7) C0- cycloalkyl; and R4 is as defined herein.
Reaction Scheme 2 where 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 (C -C7); R7 = Ar (CH2) n-; Alkyl-; Heteroaryl (CH2) p-; Alkyl-O- (CH2) m-; R8 = Ar (CH2) nC0-; Ar (CH2) nS02-; AlkylCO-; Alkyls02-; Heteroaryl (CH2) nCO-; Heteroaryl (CH2) nS02-; Alkyl-O- (CH2) nC0-; Alqüil-O- (CH2) mS02-. The 1-substituted arylmethyl-2, 3, 4, 5-tetrahydro-1H [1,4] -benzodiazepines can be prepared in the manner illustrated in Reaction Schemes 3 and. In Reaction Scheme 3, methyl 3-hydroxy-3-hydroxy-2- [4-methoxybenzenesulfonyl) - (2-amino-benzyl) -amino] propionates 6 are subjected to reductive alkylation with arylcarboxaldehydes and heteroarylcarboxaldehydes to provide intermediates. standard reactions such as reactions with triphenylphosphine and diethyl azodicarboxylate (DEAD) or triphenylphosphine with either carbon tetrachloride or carbon tetrabromide, result in the derivatives of "dehydroalanine" 18 which are then the closed ring for the [1, 4 ] benzodiazepines 20. In an alternative route to the 3-hydroxamic acid derivatives 21 (Scheme 4), the N-aroyl derivatives 22 are reduced with reducing agents such as borane or lithium aluminum hydride to reduce both the functions of ester as amide. The 3- (hydroxymethyl) -1- (arylmethyl) -2, 3, 4, 5-tetrahydro-lH- [1,] benzodiazepines 23 are oxidized with known standard reagents to convert a hydroxymethyl group to a carboxylic acid: reagents such as NaI04 with RuÜ2 catalyst (for example, see J. Org. Chem., 46: 3936 (1981); Synlett, p.143, (1996)). The coupling of the acids (via the acid chlorides) to hydroxylamine then gives the products 21. Certain intermediates that are exemplified by the formula 25 can be reduced with borane under mild or non-severe conditions to give the 25a derivatives in which it is selectively reduced the amide carbonyl. These intermediates 25a are then converted to hydroxamic acid derivatives via hydrolysis of the ester to the acid and coupling of the acid chloride with hydroxylamine.
Reaction Scheme 3 Reaction Scheme A wherein R8 = alkyl, arylalkyl, aryloxyalkyl, heterocyclic alkyl, or alkyloxyalkyloxyalkyl. Other preferred compounds of the present invention are those with basic portions in the group 1- (substituted carbonyl) which can be prepared in the manner shown in Reaction Scheme 5. The reaction of 2, 3, 4, 5- tetrahydro-lH- [1,4] -benzo-diazepines 14 (without a substituent in the 1-position) with carbonyl chloride derivatives in the form shown in Reaction Scheme 5, results in the intermediates which then become to acid 26 and hydroxamic acids 27. Intermediates 25 can also be synthesized by the reaction of 2- [(2-aminobenzyl) - (4-methoxy-benzenesulfonyl) amino] -3-hydroxypropionates 6 with acid chlorides to give the derivatives of "dehydroalanine" 28. As previously described, weak bases such as NaHCO 3 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 2, 3, 4, 5-tetrahydro-1H- [1, ] diazepines 25 of 7 elements. As illustrated in Reaction Scheme 6, aryl-arylcarbonyl, heteroaryl-arylcarbonyl, aryl-heteroarylcarbonyl, heteroaryl-heteroarylcarbonyl derivatives, can be sintered by standard palladium-catalyzed coupling of bromoaroyl or bromheteroaroyl derivatives with suitable arylstannans, heteroaryltannanes, 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: 1118-1182, (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, the aryl-aryl, heteroaryl-aryl, aryl-heteroaryl and heteroaryl-heteroaryl carboxylic ester derivatives can be prepared and these derivatives are 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 the conversion of derivatives 6 to intermediates. The following references describe processes 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. Org. Chem., 62: 3405-3406, (1997); and methyl benzoates substituted with heterocyclic portions such as furanyl, thienyl or pyridinyl groups as in Tetrahedron Lett., 27: 4407-4410, (1986). Reaction Scheme 5 Reaction Scheme 6 Y is H, F, Cl, CF3, CH3, or 0CH3; X is halogen, hydrogen, or (C1-C3) alkyl; R and R 'are as defined here; Ri and R2 are as defined here; and R4 is as defined here. Intermediates 2, 4, 5, 6-tetrahydro-lH- [1,] benzodiazepines 39 and 38 can be prepared from glycine esters in the manner exemplified in Reaction Scheme 7. In this synthetic route, the derivatives of N- (4-substituted-benzenesulfonyl) of glycine ethyl ester, glycine t-butyl ester or glycine methyl ester 33 are alkylated with an unsubstituted 2-nitrobenzyl (R = H) bromide or N-substituted (R) , N-dimethylformamide or 1-methyl-2-pyrrolidinone in the presence of potassium carbonate to give intermediates 34. Alternatively, esters of N- (4-substituted-benzenesulfonyl) glycines, such as methyl ester 33, are first they react with sodium hydride in N, N-dimethylformamide or l-methyl-2-pyrrolidinone and the resulting anion reacts with substituted or unsubstituted 2-nitrobenzylbromides to provide the compounds 34. Reaction of the derivatives 34 with N-chloride, N-dimethyl (methylene) ammonium or the salts of iodide or under standard reaction conditions (e.g., as described in Fieser and Fieser, 10: 160-161; 8: 194 produces the dimethylaminomethyl compounds (Mannich type) as intermediates for the removal of "dehydroalanine" derivatives 37 or direct ring closure from 36 to 39 via an elimination-addition reaction. Ring closure of compounds 37 provides intermediates 38 for the conversion to hydroxamic acids. Variations in the conditions • of reactions for the conversion from 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 reaction. Reaction Scheme 7 Intermediate carboxylic acids for conversion to tetrahydro [1,4] -benzodiazepine-3-carboxylic acid, hydroxyamides can be synthesized via different routes as shown in Schemes 1-8. For the syntheses of some of the desired products of Formula 1, the alternative routes shown in Scheme 8 are preferred. These routes may be preferred when the R 4 group contains a triple bond or when it is preferred to introduce the R 4 group to the group. end of the synthetic sequence. Under these conditions, the intermediate carboxylate esters of the formula 41 or acids of the formula 44 are prepared in which the substituent R4 is an OH group. The intermediates with R4 any OH group is prepared from derivatives wherein the OH group is protected by a group which can be removed selectively. The derivatives 40 wherein R 4 is an OCH 3 moiety are suitable precursors for the desired phenolic compounds 41 and 44 through the cleavage of the methyl oxygen bond. As shown in Scheme 8 the anion of the phenolic OH group can be prepared in situ and then alkylated. Suitable bases are alkali metal carbonates, hydrides, alkoxides and organic bases. The reaction with an alkylation moiety represented by the formula R? 5CH2X wherein X is a reactive separation group such as chloride, bromide, iodide, O-mesylate or an O-tosylate, gives derivatives 42 and 45. The reaction of Alkylation can be carried out with carboxylate esters such as 41 or with the carboxylic acids represented by the formula 44. Alternatively, the phenolic compounds 41 and 44 can be reacted under the Mitsunobe Reaction conditions to produce the O-alkylated derivatives 42 and 45. Mitsunobe Reaction conditions, standards, which as described in the following literature references, can be used in coupling reactions, (a) J. Heterocyclic Chem. 34, 349 (1997); (b) Tetrahedron Lett 37, 6439 (1996); (c) J. Org Chem, 56, 7173 (1991); (d) Tetrahedron Lett 5709 (1989); (e) Synthesis 1-28 (1981).
Reaction Scheme 8 45 43 RJJCHJX R < CH < > 0 = 4 (co or * • defined above) X = halogen, OTs, RI 3CH2OH = R H OMs The compounds of the present invention which have a basic portion, can 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 portion include those with alkali metals or alkaline earth metals (such as sodium, potassium, calcium, and magnesium) or organic bases. When the present compounds are used in the pharmaceutical compositions, they can be combined with one or more pharmaceutically acceptable carriers, for example, solvents, diluents and the like. Such compositions containing the present compounds can be administered orally, in the form of tablets, capsules, dispersible powders, granules, suspensions, syrups or elixirs; mainly, in the form of a suspension or injectable, sterile solution; or topically, in the form of creams, lotions, ointments, etc. Such pharmaceutical compositions may contain from about 1 to about 100 mg of the active ingredient in combination with the carrier. The effective dosage of the present compounds used to treat a specific condition will vary depending on the particular compound employed, the mode of administration and the type and severity of the condition to be treated. However, in general, satisfactory results are obtained when the present compounds are administered in a dosage of about 0.001 mg / kg body weight. As noted above, the compounds of the present invention can be administered orally, as well as intravenously, intramuscularly, subcutaneously or topically. Solid carriers useful for the preparation of tablets, capsules, etc., include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin. Useful liquid carriers for the preparation of compositions of the present compounds include sterile water, polyethylene, glycols, nonionic surfactants, and edible oils such as corn, sesame, and peanut oils. Conventionally useful adjuvants may also be included in the preparation of pharmaceutical compositions, 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.
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 described in Weingarten et al., "Spectrophotometric Assay for Vertébrate Collegenase ", Anal. Biochem., 147: 437-440, (1985) .The activity of the enzyme is measured by the speed of the increase in color.The substrate of thiopeptide was recently produced as a concentrated base of 20 mM in 100%. of DMSO and DTNB is dissolved in 100% DMSO as a 100 mM concentrated base and stored in the dark at room temperature.The substrate and DTNB were co-diluted to 1 mM with substrate buffer solution (50 M HEPES , pH 7.5, 5 mM CaCl2) before use The concentrated base of neutrophil gelatinase B human, was diluted with assay buffer (50 mM HEPES, pH 7.5, 5 mM CaCl2, 0.02% Brij) to a final concentration of 0.15 nM.
The assay buffer, enzyme, DTNB / substrate (500 μM final concentration) and the vehicle or inhibitor were added to a 96-well plate (total reaction volume of 200 μl) and the increase in color was observed spectrophotometrically for 5 hours. minutes at 405 nm on a plate reader. The increase in OD405 was plotted and the deviation of the line was calculated. The deviation represents the reaction speed. The linearity of the reaction rate was confirmed (R2 >; 0.85) and the average (x + sem) of the control rate was calculated and compared by statistical significance (p <0.05) with drug-treated rates using Dunnett's multiple comparison tests. The dose-response relationships were generated using multiple doses of drug and IC 50 values with 95% Cl 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 that releases the fluorescent NMa group which was quantified in the fluorometer as described in Bickett et al., "A High Throughput Fluorogenic Substrate for Interstitial Collagenase (MMP-1) and Gelatinase (MMP-9)", Anal . Biochem., 212: 58-64; (1993). Dnp extinguishes NMa fluorescence in the intact substrate. The assay was run in HCBC buffer (50 mM HEPES, pH 7.0, 5 mM Ca + 2, 0.02% Brij, 0.5% Cysteine), with collagenase from human recombinant fibroblasts (truncated, mw = 18.828, from yeth-Ayerst Research, Radnor, PA). The substrate was dissolved in methanol and stored cooled in 1 mM aliquots. The collagenase was stored cold in buffer solution in 25 μM aliquots. In the conduct of the assay, the substrate was dissolved in HCBC buffer at a final concentration of 10 μM and collagenase at a final concentration of 5 nM. The compounds that were 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 initiated 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 deviation of the line was calculated by representing the reaction rate. The linearity of the reaction rate was confirmed (r> 0.85). The average (x + sem) of the control rate was calculated and compared by statistical significance (p <0.05) with drug-treated rates using Dunnett's multiple comparison test. Dose-response relationships were generated using multiple doses of drugs and IC 50 values with 95% Cl were estimated using linear regression.
Procedure for Measuring TACE Inhibition In a 96-well black microtiter plate, each well receives a solution composed of 10 μL of TACE (available from I munex) at a final concentration of 1 μg / mL, 70 μL of buffer solution Tris, has a pH of 7. and contains 10% glycerol (final concentration mM), and 10 μL of the test compound solution in DMSO (final concentration 1 μM, concentration of DMSO <1%).
The plates were incubated for 10 minutes at room temperature. The reaction was initiated by the addition of a fluorescent peptidyl substrate (final concentration 100 μM) to each cavity 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 deviation of the line was calculated and this represents the reaction rate. The linearity of the reaction rate was confirmed (r2> 0.85). The average (x + sem) of the control rate was calculated and compared by the 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 IC 50 values with 95% Cl were estimated using linear regression. Some results obtained followed by these experimental test procedures, standards, are presented in Table 1.
Table 1 Compound of R 3 Ex R R, R 2 R < MMP-1 MMP-9 MP-13 TACE -COCH 3 1 H H H -OCH 2 C = CCH 3 835 228 77 16 -CO-? 2 H H H -OCH2C = CCH3 250 24 8 38 3 H H H -OCH 2 C == CCH 3 165 36 10 59 33 _C0-57 H H H -? CH 2 C = CCH 3 125 .CO-? 58 H H H. -OOCCHH2, CC "" == CCCCHH33 841 33 29 10 Some intermediary compounds for the synthesis of derivatives of formula 1 are presented in Table 2 (Reference Examples 10, 11, 41, 43-90, 92-97, 99, 100, 162, 166, 176, 181, 182 , 186, 188, 190) Table 2 R, R2 R4 H H H H H H -COCH2OCH3 7-CH3 H H -OCH3 -ccO 7-CH3 H H -OCH3"CC -0CF3 8-C1 H H -OCH3 -CH2CH20CH3 H H H -OCH3 • CH2-0 H H H -OCH3 C0-CH2 - N N -CH3 H H H -OCH3 R3 R _R? _R2_ i • C? H H H -0CH3 -8-ú H H H -OCH3 ^ o H H H -OCH3 COCH OCH-, H H H -OCH 3 The present invention will now be illustrated with reference to the following non-limiting examples.
Reference Example 1 (L) N- (Benzyloxycarbonyl) -O-benzyl-serine t-butyl ester In a solution of 25 g (0.076 mol) of N- (benzyloxycarbonyl) -O-benzyl serine in 600 ml of CH2CI2 cooled to -6 ° C in an ice-bath with an isobutylene bubble, while 4.1 ml of concentrated sulfuric acid was bubbled. it was drip added to it. The mixture was stirred for 4 hours and worked up as described in Synthetic Co. , 26: 2723 (1996) to give 29.24 g of the product as a yellow oil.
Reference Examples 2 T-butyl ester of L-Serine A mixture of 29.24 g (0.076 mol) of (L) N- (benzyloxycarbonyl) -O-benzyl-serine t-butyl ester of the Reference Example 1, 24.1 g (0.38 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 the product as described in Synthetic Co., 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 t-butyl ester of L-serine, 26.52 ml of triethylamine in 160 ml of CH2Cl2 (cooled in an ice bath) was added, in small portions, 16.1 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 H20, 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 the product as a white solid. The filtrate was concentrated and the residue was 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 C14H2? N06S: Cale: C, 50.7; H, 6.4; N, 4.2; Found: C, 50.4; H, 6.3; N, 4.4.
Reference Example 4 3-Hydroxy-2- [(4-methoxybenzenesulfonyl) - (2-nitrobenzyl) amino] propionic acid tert-butyl ester To 6.16 g (18.6 mmol) of the 3-hydroxy-2- (4-methoxybenzenesulfonylamino) propionic acid tert-butyl ester in 50 ml of N, N-dimethylformamide, cooled in an ice bath, 0.781 g (19.5 g) were added. mmol) of sodium hydride. After the gas emission ceased, a solution of 4.02 g (18.6 mmol) of 2-nitrobenzylbromide in 18 ml of N, N-dimethylformamide was added by dripping. 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 was removed under vacuum. The residue was diluted with water and extracted with CH2C12. The organic extract was washed with H20, 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 the product were combined and the solvent was then stirred to give 7.7 g (89%) of solid. A sample of a 3 mmol test gave a gum. Anal, for C2iH26N208S: Cale: C, 54.1; H, 5.6; N, 6.0; Found: C, 54.0; H, 5.7; N. 6.0.
Reference Example 5 2- [(2-Aminobenzyl) - (4-methoxybenzenesulfonyl) amino] -3-hydroxypropionic acid tert-butyl esterA mixture of 0.60 g (1.28 mmol) of 3-hydroxy-2- [(4-methoxybenzenesulfonyl) - (2-nitrobenzyl) amino] propionic acid tert-butyl ester and 1.45 g (6.45 mmol) of SnCl2 »2H20 in 20 ml of methanol, it was heated in an oil bath at 90 ° C for 2 hours. The solvent was removed under vacuum and ethyl acetate was 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 H20, brine and dried with Na2SO4. The solvent was removed under vacuum to give 0.30 g (53%) of a gum. Anal, for C2? H28N206S: Calculated: 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-methoxybenzenesulfonyl) amino] -3-hydroxypropionic acid A solution of 0.75 g (1.72 mmol) of 2- [(2-aminobenzyl) - (4-aminobenzyl) tert-butyl ester -methoxybenzenesulfonyl) amino] -3-hydroxypropionic acid and 6 ml of trifluoroacetic acid in 6 ml of CH2C12, stirred at room temperature for 3 hours and then concentrated to dryness under vacuum. To the residue was added H20, CH2Cl2 and 1N NaOH until the aqueous layer reaches pH 8. The aqueous layer was then separated, acidified with 2N citric acid and extracted with ethyl acetate. The extract was washed with H2O, brine and Na2SO4 was dried. The solvent was removed under vacuum to give 0.35 g (54%) of a solid. Analysis for C? H2oN206S: Calculated: C, 53.7; H, 5.3; N, 7.4; Found: C, 53.0; H, 5.3; N, 6.9.
Reference Example 7 2- Tertiary butyl ester. { (2- [3- (trifluoromethylbenzoyl) aminobenzyl] - (4-methoxybenzenesulfonyl) amino} acrylic A mixture of 0.431 g (1 mmol) of 2- [(2-amino-benzyl) - (4-methoxybenzenesulfonyl) 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 CH2Cl2 was stirred at room temperature for 3.5 hours. The mixture was poured into H20 and extracted with CH2C12. The extract was washed with H20, 2 N citric acid, H20, 1 N NaHC03, brine and dried with Na2SO4. The solvent was removed to give 0.72 g of the solid. The solid was dissolved in 2 ml of tetrahydrofuran and 1.5 ml of triethylamine was added thereto. The solution was heated to 65 ° C overnight and concentrated to dryness under vacuum. The residue was extracted with CHC12 and the extract was washed with H20 and dried with Na2SO4. The solvent was removed under vacuum to give 0.55 g of the product as a solid. From a similar process the product was chromatographed on silica gel with hexane-ethyl acetate to give a solid, m.p. 65-72 ° C. Anal, for C29H29F3N206S: Calculated: 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) -1- (3-trifluoromethylbenzoyl) -2,3,4,5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylic acid tert-butyl ester A mixture of 0.55 g (0.932 mmol) of 2- [(2- [3- (trifluoromethyl) benzoyl] -amino-benzoyl] - (4-methoxybenzenesulfonyl) amino) tert-butyl ester and 0.102 g (1.21 mmol) of NaHC03 in 4 ml of methanol was stirred at room temperature overnight and the solvent was removed. The residue was extracted with CH2Cl2 and the extract was 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 C29H29F3N206S: Calculated: C, 59.0; H, 5.0; N, 4.7; Found: C, 58.8; N, 5.0; N, 4.6.
Reference Example 9 4- (4-Methoxybenzenesulfonyl) -1- (3-trifluoromethylbenzoyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] enzodiazepine-3-carboxylic acid A mixture of 0.36 g (0.61 mmol) of 4- (4-methoxybenzenesulfonyl) -1- (3-trifluoromethylbenzoyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine tert-butyl ester -3-carboxylic acid and 3 ml of trifluoroacetic acid in 3 ml of CH2C12, was stirred at room temperature for 3 hours. The mixture was concentrated to dryness under vacuum and the residue was extracted with CH2C12. The CH2C12 was washed with NaHCO3 IN and the aqueous layer (pH 8) was acidified with 2N citric acid and extracted with ethyl acetate. The extract was dried (Na2SO4). The original CH2C12 extract was washed with 2N citric acid, H20, brine and dried with Na2SO4. The CHC1 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 C25H2? F3 206S: Calculated: C, 56.2; H, 4.0; N, 5.2; Found: C, 55.1; H, 3.7; N, 5.0.
Reference Example 10 1- ([1,1 '-biphenyl] -2-carbonyl) -A- (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3- methyl 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 CH2C12 cooled to 0 ° C, added a solution of [1, 1 '-biphenyl] -2-carbonyl chloride in 6 ml of CH2C12. The mixture was stirred at room temperature overnight and diluted with CH2C1 and H20. The organic layer was separated and washed with 2 N citric acid, brine and dried with Na 2 SO 4. The solvent was removed under vacuum to give 2.2 g of a white foam. Anal, for C3iH28N206S: Calculated: C, 66.9; H, 5.1; N, 5.0; Found: C, 67.3; H, 5.2; N, 4.7.
Reference Example 11 A - (4-Methoxybenzenesulfonyl) -1- (2-methyl-5-fluorobenzoyl) -2,3,4,5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylic acid methyl ester 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 CH2Cl2, cooled to 0 ° C, 1.36 g (11.4 mmol) of 2-methyl-5-fluorobenzoyl chloride was added. The mixture was stirred at room temperature overnight. The solution was then diluted with CH2C12 and water and the organic layer was separated. The organic layer was washed with 2 N citric acid, brine and dried with Na 2 SO 4. The solvent was removed under vacuum to give 2.2 g of a white foam. Anal, for C26H25 N206S: Calculated: 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 4- (4-Methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl 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 CH2C1 cooled to 0 ° C, was added to 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 H20, 2N citric acid, brine and dried with Na2SO4 was washed. 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 2.7 g of the product as a yellow viscous oil. From a batch of 0.5 g similar, 0.178 g of an oil was obtained. Anal, for C? 8H2oN2? 5S: Calculated: 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 15.7 ml (0.012 mol) of triethylamine in 100 ml of CHC12, cooled to 0 ° C, 6.64 g was added dropwise. (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 CH2C12 and then washed with 60 ml each of H20, 2N 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 CnH? 5N06S: Calculated: C, 45.7; H, 5.2; N, 4.8; S, 11.1; Found: C, 45.6; H, 5.2; N, 4.8; S, 11.1.
Reference Example 14 Methyl 3-hydroxy-2- [(4-methoxybenzenesulfonyl) - (2-nitrobenzyl) amino] propionate 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, 2.29 g portions were added in portions. (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 N was added dropwise., Dry N-dimethylformamide. 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 was extracted with 250 ml of ethyl acetate. The combined organic layer and the extract were washed with 200 ml each of H20, 1N NaHC03, 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, which have a m.p. 127-129 ° C. From a small scale batch (3.0 g), 2.32 g of white crystals were obtained, which have a m.p. 127-129 ° C. Anal, for C? 8H20N2O8S: Calculated: C, 50.9; H, 4.8; N, 6.6; Found: C, 50.9; H, 4.8; N, 6.5.
Reference Example 15 2- [(2-Aminobenzyl) - (4-methoxybenzenesulfonyl) amino] -3-hydroxypropionate methyl To a mixture under nitrogen of 1.5 g (3.53 mmol) of methyl 3-hydroxy-2- [(4-methoxybenzenesulfonyl) - (2-nitrobenzyl) amino] propionate in 5 ml of dry ethanol, 1.12 g (17.69 mmcl) were added. ) of ammonium format 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 was concentrated to dryness under vacuum to give a semi-solid. Trituration with ethyl acetate gave 0.65 g (47%) of white crystals, m.p. 138-140 ° C; Anal, for C? 8H22N206S: Calculated: C, 54.8; H, 5.6; N, 7.1; Found: C, 53.0; H, 5.6; N, 6.8.
Reference Example 16 3-Hydroxy-2-. { (4-methoxybenzenesulfonyl) - [2- (2, 2, 2-trifluoroacetylamino) benzyl] amino} methyl 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 CH2Cl2, 1.8 ml (12.7 mmol) of trifluoroacetic anhydride are added. . 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 methanol addition and the concentration to dryness was repeated twice. The residue was chromatographed on thick gel plates with hexane-ethyl acetate (1: 1) to give 0.50 g of a colorless crystal. Anal, for C20H2? F3N2O7S: Calculated: C, 49.0; H, 4.3; N, 5.7; Found: C, 49.0; H, 4.5; N, 5.4.
Reference Example 17 2- [(4-Methoxybenzenesulfonyl) - (2-nitrobenzyl) amino] methyl acrylate To a solution of 1.0 g (2.356 mmol) of methyl 3-hydroxy-2- [(4-methoxy-benzenesulfonyl) - (2-nitrobenzyl) amino] propionate in 2 ml of pyridine, cooled to -10 ° C, they added 0.539 g (2.83 mmol) of 4-methylbenzenesulfonyl chloride. The solution was refrigerated overnight and 4 ml of pyridine and 0.539 g (2.83 mmol) of 4-methylbenzenesulfonyl chloride were added. The mixture was stirred and cooled to -10 ° C for 24 hours and diluted with H20. The mixture was extracted with ethyl acetate and the extract was washed with H20, 2N 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 H20. The mixture was extracted with ethyl acetate and the extract was washed with H20, 2N 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 C? 8H? 8N207S: Calculated: C, 53.2; H, 4.5; N, 6.9; Found: C, 53.7; H, 4.5; N, 7.2.
Reference Example 18 2-. { (4-Methoxybenzenesulfonyl) - [2- (4-pyridinylcarbonyl) aminobenzyl] amino} methyl 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 CH2C12, cooled to 0 ° C, 1.7 g (9.5 mmol) ml of 4-pyridinecarbonyl chloride (isonicotinoyl chloride) were added. The mixture was stirred at room temperature overnight and was diluted with CH2C12. The mixture was washed with H20, 2N 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 C24H23N306S: Calculated: C, 59.9; H, 4.8; N, 8.7; S, 6.6; Found: C, 59.0; H, 4.8; N, 8.5; S, 6.9; Mass spectrum (ES) 482.6 (M + H; Using the procedure described in Reference Example 18, the following intermediates can be prepared from suitably unsubstituted 2- [(2-aminobenzyl) - (4-methoxybenzenesulfonyl) amino] -3-hydroxypropionate or appropriately substituted (substituted-2-aminobenzyl) - (4-methoxybenzenesulfonyl) amino] -3-hydroxypropionate.
Reference Example 19 2-. { (4-Methoxybenzenesulfonyl) - [2- (2, 2, 2-trifluoroacetylamino) benzyl] amino} Methyl acrylate White crystals, m.p. 120-121 ° C. Anal, for C20H19F3N2O6S: Calculated: C, 50.9; H, 4.1; N, 5.9; Found: C, 50.8; H, 4.2; N, 5.6.
Reference Example 20 2- [(2-Benzoylaminobenzyl) - (4-methoxybenzenesulfonyl) amino] methyl acrylate Yellow oil. Anal, for C25H24N206S: Calculated: C, 62.5; H, 5.0; N, 5.8; Found: C, 62.7; H, 5.3; N, 5.0.
Reference Example 21 2- [(2-Acetylaminobenzyl) - (4-methoxybenzenesulfonyl) amino] methyl acrylate Reference Example 22 2- ((4-Methoxybenzenesulfonyl) -. {- 2- [(3-pyridinylcarbonyl) amino] benzyl} amino) methyl acrylate Whitish solid. Anal, for C 24 H 23 N 3 O 6 S: Calculated: 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).
Reference Example 23 2- ((4-Methoxybenzenesulfonyl) -. {- [(2-thienylcarbonyl) amino] benzyl} amino) methyl acrylate solid cinnamon color. Anal, for C23H22 2O6S2: Calculated: C, 56.8; H, 4.6; N, 5.8; Found: C, 55.7; H, 4.4; N, 4.9.
Reference Example 24 2-. { [2- (- Methoxyacetylamino) benzyl] - (4-methoxybenzenesulfonyl) amino} methyl acrylate yellow oil. Anal, for C2iH24N2? 7S: Calculated: C, 56.2; H, 5.4; N, 6.3; Found: C, 55.3; H, 5.6; N, 5.8.
Reference Example 25 2-. { (4-Methoxybenzenesulfonyl) - [2- (n-propylsulfonylamino) benzyl] amino} methyl acrylate light brown oil. Anal, for C2? H26N2? 7S2: Calculated: C, 52.3; H, 5.4; N, 5.8; Found: C, 51.9; H, 5.4; N, 5.7.
Reference Example 26 2-. { [2- (3-phenylpropionyl) aminobenzyl] - (4-methoxybenzenesulfonyl) amino} methyl acrylate light brown oil. Anal, for C2H28N2? 6S: Calculated: C, 63.8; H, 5.6; N, 5.5; Found: C, 66.7; H, 5.8; N, 4.1.
Reference Example 27 2-. { [2- (3-trifluoromethylbenzoyl) aminobenzyl] - (4-methoxybenzenesulfonyl) amino} yellow solid tert-butyl acrylate, m.p. 65-72 ° C.
Reference Example 28 2-. { [2- (4-biphenylcarbonyl) aminobenzyl] - (4-methoxybenzenesulfonyl) amino} white solid methyl acrylate. Anal, for C3? H28N206S: Calculated: C, 66.9; H, 5.1; N, 5.0; Found: C, 66.1; H, 5.0; N, 5.1.
Reference Example 29 2-. { [2- (Cyclopropylcarbonyl) aminobenzyl] - (4-methoxybenzenesulfonyl) amino} methyl acrylate yellow oil. Anal, for C22H24N206S: Calculated: C, 59.5; H, 5.4; N, 6.3; Found: C, 60.0; H, 5.7; N, 6.0; Mass spectrum (ES) 445.5 (M + H), Reference Example 30 2-. { [2- (Cyclohexylcarbonyl) aminobenzyl] - (4-methoxybenzenesulfonyl) amino} Methyl acrylate white foam. Anal, for C25H30N2O6S: Calculated: C, 61.7; H, 6.2; N, 5.8; Found: C, 59.1; H, 6.0; N, 5.4; Mass spectrum (ES) 487.5 (M + H).
Reference Example 31 2-. { [2- (3-Fluorobenzoyl) aminobenzyl] - (4-methoxybenzenesulfonyl) amino} methyl acrylate Reference Example 32 2-. { [2- (3-Chlorobenzoyl) aminobenzyl] - (4-methoxybenzenesulfonyl) amino} methyl acrylate Reference Example 33 2-. { [2- (2, -Dichlorobenzoyl) aminobenzyl] - (4-methoxybenzenesulfonyl) methyl amino-acrylate Reference Example 34 2-. { [2- (2, 3-Difluorobenzoyl) aminobenzyl] - (4-methoxybenzenesulfonyl) amino} methyl acrylate Reference Example 35 2-. { [2- (2-Chloro-4-fluorobenzoyl) aminobenzyl] - (4-ethoxybenzenesulfonyl) amino} methyl acrylate Reference Example 36 2-. { [2- (2-Furanylcarbonyl) aminobenzyl] - (4-methoxybenzenesulfonyl) amino} solid whitish methyl acrylate. Anal, for C23H22N2O-7S. Calculated: C, 58.7; H, 4.7; N, 6.0; Found: C, 58.0; H, 4.1; N, 3.8; Mass Spectrum (ES) 470.9 (M + H).
Reference Example 37 2- ((4-Methoxybenzenesulfonyl) -. {- 2- [(3-thienylcarbonyl) amino] benzyl} amino) methyl acrylate Reference Example 38 2-. { [2- (2-Acetylaminoacetyl) aminobenzyl] - (4-methoxybenzenesulfonyl) amino} methyl acrylate Reference Example 39 2-. { [2- (2-Dimethylacetyl) aminobenzyl] - (4-methoxybenzenesulfonyl) amino} methyl acrylate Reference Example 40 2-. { [2- (Cyclobutylcarbonyl) aminobenzyl] - (4-methoxybenzenesulfonyl) amino} methyl acrylate Reference Example 41 Methyl l-methoxyacetyl-4- (4-methoxybenzenesulfonyl) -2, 3,4,5-tetrahydro-lH- [1,] benzodiazepine-3-carboxylate To a mixture of 0.449 g (1 mmol) of Methyl 2 - [[2- (2-methoxy-acetamido) -benzyl] - (4-methoxybenzenesulfonyl] amino] acrylate in 5 ml of anhydrous methanol was added 0.109 g (1.3 mmol) of anhydrous sodium bicarbonate. The mixture was stirred at room temperature overnight and the solvent was removed under vacuum.To the residue was added ethyl acetate and water.The organic layer was separated and washed with H20 and brine and then dried with Na2SO4. The solid was crystallized from ethyl acetate to give 0.41 g of solid. 0. 28 g of white crystals, m.p. 160-163 ° C. Anal, for C2? H24N207S: Calculated: C, 56.2; H, 5.4; N, 6.3; Found: C, 56.1; H, 5.3; N, 6.3; S, 6.9; Mass spectrum (ES) 449.1 (M + H).
Using the procedure in the Example of Reference 41, the following intermediates can be prepared from 2-. { Suitable methyl (4-methoxy-benzenesulfonyl) - [2- (amino-substituted) -benzyl] amino-acrylates.
Reference Example 42 4- (4-Methoxybenzenesulfonyl) -1- (4-methylphenylsulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylate methyl white foam. Anal, for C25H26N207S2: Calculated: C, 56.6; H, 4.9; "N, 5.3 Found: C, 56.2; H, 5.2; N, 5.2.
Reference Example 43 1,4-Bis- (4-methoxybenzenesulfonyl) -2,3,4,5,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylate methyl solid white. Anal, for C25H26N208S2: Calculated: C, 54.9; H, 4.8; N, 5.1; Found: C, 54.8; H, 4.9; N, 5.1.
Reference Example 44 l-Methanesulfonyl-4- (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylate methyl white crystals, m.p. 136-137 ° C. Anal, for C? 9H22N207S2: Calculated: C, 50.2; H, 4.9; N, 6.2; Found: C, 50.1; H, 4.9; N, 6.4.
Reference Example 45 l-Benzoyl-4- (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl cinnamon. Anal, for C25H24N202S: Calculated: C, 62.2; H, 5.4; N, 5.8; Found: C, 62.3; H, 5.2; N, 5.6.
Reference Example 46 l-Acetyl-4- (4-methoxybenzenesulfonyl) -2, 3,, 5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylate methyl white crystals, m.p. 150-155 ° C. Anal, for C20H22N2O6S: Calculated: C, 57.4; H, 5.3; N, 6.7; Found: C, 56.6; H, 5.2; N, 6.5.
Reference Example 47 4- (4-Methoxybenzenesulfonyl) -1- (3-pyridinylcarbonyl) -2, 3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylate methyl whitish solid. Anal, for C24H23N3? 6S: Calculated: C, 59.9; H, 4.8; N, 8.7; Found: C, 59.2; H, 4.8; N, 8.3; Mass Spectrum (ES) 482.2 (M + H).
Reference Example 48 4- (methyl-methyl-methyl-benzenesulfonyl) -1- (2-thienylcarbonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl ester. Anal, for C23H22 2O6S2: Calculated: C, 56.8; H, 4.6; N, 5.8; Found: C, 56.0; H, 4.6; N, 5.2.
Reference Example 49 4- (4-Methoxybenzenesulfonyl) -1- (4-pyridinylcarbonyl) -2, 3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylate methyl whitish crystals, m.p. 162-164 ° C. Anal, for C24H23N306S: Calculated: C, 59.9; H, 4.8; N, 8.7; Found: C, 59.9; H, 4.8; N, 8.7.
Reference Example 50 1- (4-Biphenylcarbonyl) -4- (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid methyl ester white. Anal, for C3? H28N2? 6S: Calculated: C, 66.9; H, 5.1; N, 5.0; Found: C, 65.8; H, 5.2; N, 5.0. Mass spectrum (ES) 557.6 (M + H).
Reference Example 51 4- (4-Methoxybenzenesulfonyl) -1- (propan-1-sulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl yellow oil. Anal, for C21H26 2O-7S2: Calculated: C, 52.6; H, 5.4; N, 5.8; Found: C, 51.8; H, 5.4; N, 5.6.
Reference Example 52 1- ([1,1'-Biphenyl] -2-carbonyl) -A- (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3- Methyl carboxylate white foam. Anal, for C31H28N2? 6S: Calculated: C, 66.9; H, 5.1; N, 5.0; Found: C, 67.3; H, 5.2; N, 4.7; Mass spectrum (ES) 557.6 (M + H).
Reference Example 53 1- (3-Fluorobenzoyl) -A- (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,] benzodiazepine-3-carboxylic acid methyl ester Reference Example 54 4- (4-Methoxybenzenesulfonyl) -1- (2-methyl-5-fluorobenzoyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylate methyl solid white; Anal, for C26H25FN206S: Calculated: C, 60.9; H, 4.9; N, 5.5; Found: C, 60.9; H, 5.0; N, 5.0.
Reference Example 55 4- (4-Methoxybenzenesulfonyl) -1- (2-methyl-3-fluorobenzoyl) -2,3,4,5-tetrahydro-lH- [1,] benzodiazepine-3-carboxylic acid methyl ester Reference Example 56 4- (4-Methoxybenzenesulfonyl) -1- (3-phenylpropionyl) -2, 3, 4, 5-tetrahydro-1H- [1,4] benzodiazepin-3-carboxylic acid methyl ester white; Anal, for C2H28 2? 6S: Calculated: C, 63.8; H, 5.6; N, 5.5; Found: C, 64.0; H, 5.7; N, 5.3; S, 6.5.
Reference Example 57 4- (4-Methoxybenzenesulfonyl) -1- (2-trifluoromethylbenzoyl) -, 3,4, 5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl Reference Example 58 1- (2-Chloro-6-trifluoromethylbenzoyl) -A - (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylic acid methyl ester Reference Example 59 1- (4-Fluoro-2-trifluoromethylbenzoyl) -A- (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylic acid methyl ester Reference Example 60 1- (2-Fluoro-6-trifluoromethylbenzoyl) -A - (A-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid methyl Reference Example 61 4- (4-Methoxybenzenesulfonyl) -1- (2-methylbenzoyl) -2, 3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid Example Reference 62 4- (4-Methoxybenzenesulfonyl) -1- (2-methyl-6-chlorobenzoyl) -, 3,4, 5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl Reference Example 63 - (2, -Dimethylbenzoyl) -A - (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl Reference Example 64 - (2,5-Dimethylbenzoyl) -A - (4-methoxybenzenesulfonyl) -2, 3,4,5-tetrahydro-lH- [1,] benzodiazepine-3-carboxylic acid methyl Reference Example 65 1- (2-Chloro-4-fluorobenzoyl) -4- (4-methoxybenzenesulfonyl) -, 3,4, 5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl Reference Example 66 1- (2-Chlorobenzoyl) -4- (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid Example Reference 67 1- (2-Fluorobenzoyl) -A - (4-methoxybenzenesulfonyl) -2, 3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl Reference Example 68 1- (2-Chloro-6-fluorobenzoyl) -4- (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl ester Reference Example 69 1- (2,3-Difluorobenzoyl) -4- (4-methoxybenzenesulfonyl) -2, 3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl Reference Example 70 Methyl 1- (2, -Dichlorobenzoyl) -A - (-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylate Prepared according to the procedure described in Reference Example 10; solid white. Anal, for C25H22C12N206S: Calculated: C, 54.7; H, 4.0; N, 5.1; Found: C, 54.4; H, 3.8; N, 4.9; Mass spectrum (548.9) (M + H); 550.9 (M + H).
Reference Example 71 - (2,3-Dichlorobenzoyl) -A - (4-methoxybenzenesulfonyl) -2, 3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl Reference Example 72 - (2, 5-Dichlorobenzoyl) -4- (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl Reference Example 73 1- (2-Methoxybenzoyl) -4- (4-methoxybenzenesulfonyl) -2, 3,4,5-tetrahydro-lH- [1,] benzodiazepin-3-carboxylic acid methyl Reference Example 74 1- (4-Chloro-2-methoxybenzoyl) -A - (4-methoxybenzenesulfonyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl Reference Example 75 4- (4-methoxybenzenesulfonyl) -1- (2-methylthiobenzoyl) -2,3,4,5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylic acid Example Reference 76 4- (4-Methoxybenzenesulfonyl) -1- (3-methyl-2-thienylcarbonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl Reference Example 77 4- (4-Methoxybenzenesulfonyl) -1- (4-methyl-2-thienylcarbonyl) -2,3,4,5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylic acid methyl ester Reference Example 78 1- (3-Chloro-2-thienylcarbonyl) -4- (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid methyl ester Reference Example 79 1- (O-2-Furanylcarbonyl) -A - (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,] benzodiazepin-3-carboxylate methyl whitish solid. p.f. 165-167 ° C. Anal. for C23H22N2? 7S: Calculated: C, 58.7; H, 4.7; N, 6.0; Found: C, 58.4; H, 4.6; N, 5.7; Mass spectrum (ES) 470.9 (M + H).
Reference Example 80 4- (4-Methoxybenzenesulfonyl) -1- (3-methyl-2-furanylcarbonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl ester Reference Example 81 4- (4-Methoxybenzenesulfonyl) -l- (4-methyl-2-furanylcarbonyl) -2,3,4,5-tetrahydro-lH- [1,] benzodiazepine-3-carboxylic acid methyl ester Reference Example 82 1- (5-Chloro-2-furanylcarbonyl) -A - (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid methyl ester Reference Example 83 1- (5-Chloro-2-thienylcarbonyl) -4- (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] enzyodiazepine-3-carboxylic acid methyl ester Reference Example 84 l-Propionyl-4- (-methoxybenzenesulfonyl) -2,3,4, 5-tetrahydro-1H- [1,] benzodiazepin-3-carboxylic acid methyl Example Reference 85 l-Hexanoyl-4- (4 -methoxybenzenesulfonyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl Reference Example 86 1- (3-Methoxypropionyl) -A- (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] methyl-enzodiazepin-3-carboxylate Reference Example 87 4- (4-Methoxybenzenesulfonyl) -1- (3-thienylcarbonyl) -2,3,4,5-tetrahydro-lH- [1,] benzodiazepin-3-carboxylic acid methyl ester Reference Example 88 1- (3-Furanylcarbonyl) -A - (4-methoxybenzenesulfonyl) -2, 3,4,5-tetrahydro-lH- [1,] benzodiazepine-3-carboxylic acid methyl Reference Example 89 1- (trans-Crotonyl) -4- (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl Reference Example 90 1- (Methacryloyl) -A - (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid methyl ester Reference Example 91 1- (Chloroacetyl ) -4- (4-methoxybenzenesulfonyl) -2, 3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl ester Following the method described by Reference Example 18, 3.0 g (7.61 mmol) ) of methyl 2- [2-aminobenzyl] - (4-methoxy-benzenesulfonyl) -amino] -3-hydroxy-propionate was reacted with 1.82 ml (22.8 mmol) of chloroacetyl chloride 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 2- [(2-chloroacetylaminobenzyl) - (4-methoxybenzenesulfonyl) -amino] acrylate. A 1.3 g sample of the above compound was reacted with 0.312 g of anhydrous NaHCO 3 in 10 ml 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 was partitioned between H20 and ethyl acetate. The ethyl acetate extract was washed with brine, dried with Na 2 SO 4 and the solvent was removed. The residue was triturated with hexane-ethyl acetate, cooled and filtered to give the product; Mass spectrum (ES) 453.1 (M + H).
Reference Example 92 1- (Acetylaminoacetyl) -4- (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid methyl Reference Example 93 1- (N, N-Dimethylaminoacetyl) -A - (4-methoxybenzenesulfonyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl Reference Example 94 - (Cyclopropylcarbonyl) -A - (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylate methyl white crystals, m.p. 98-100 ° C. Anal, for C22H24N2O6S: Calculated: C, 59.5; H, 5.4; N, 6.3; Found: C, 59.3; H, 5.6; N, 6.2; Mass spectrum (ES) 445.1 (M + H).
Reference Example 95 - (Cyclobutylcarbonyl) -4- (4-methoxybenzenesulfonyl) -2, 3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl Reference Example 96 4- (4-Methoxybenzenesulfonyl) -1- (trifluoroacetyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-methylcarboxylate To a solution of 1.0 g (2.54 mmol) of 3-hydroxy-2-i (4-methoxy-benzenesulfonyl) - [2- (2,2,2-trifluoroacetylamino) benzyl] amino} Methyl propionate in 10 ml of CH 2 C 12 was added 1.8 ml (12.7 mmol) of trifluoroacetic anhydride. After 1 hour at room temperature, the solvent was removed. The dichloromethane was added several times and the solvent was removed under vacuum after each addition. The methanol was then added 2 times and the solvent was removed under vacuum to give 2-. { (4-methoxybenzenesulfonyl) - [2- (2,2,2-trifluoroacetylamino) benzyl] -amino} Methyl acrylate as a crystal. The crystal was dissolved in methanol and 0.213 g of anhydrous NaHCO 3 was added. The mixture was stirred at room temperature overnight and concentrated in vacuo to dryness. To the residue were added ethyl acetate and water. The organic layer was separated, washed with H2O, brine and dried with Na2S? . The solvent was removed and the residue (1.0 g) was chromatographed on thick silica gel plates with hexane-ethyl acetate (1: 1) as solvent to give 0.365 g of the product as a crystal. Anal, for C2oHi9F3N206S: Calculated: C, 50.9; H, 4.1; N, 5.9; F, 12.1; S, 6.7; Found: C, 50.8; H, 4.4; N, 5.5; F, 11.7; S, 6.7; Mass spectrum (ES) 473.1 (M + H).
Reference Example 97 4- (4-Methoxybenzenesulfonyl) -1- (4-methylphenylsulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl ester To 0.50 g (1.26 mmol) of 2 [(2-aminobenzyl) - (4-methoxybenzenesulfonyl) -amino] -3-hydroxypropionate in 5 ml of pyridine cooled to 0 ° C, 0.284 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 were added 8 ml of anhydrous ethanol and the mixture was refluxed for 2 days. The mixture was concentrated to dryness and ethyl acetate was added. The mixture was washed with H20, 2N citric acid, brine and dried with Na2SO4. The filtrate was filtered through a thin pad of aqueous magnesium silicate and the filter pad was washed with ethyl acetate. The filtrate was concentrated to dryness to give 0.60 g of a foam. Anal, for C25H26 2? 7S2: Calculated: C, 56.6; H, 4.9; N, 5.3; S, 12.1; Found: C, 56.2; H, 5.2; N, 5.2; S, 11.4; Mass spectrum (ES) 531.6 (M + H).
Reference Example 98 2- [(4-Methoxybenzenesulfonyl) - (2-methylsulfonylaminobenzyl) amino] methyl 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, 0.432 ml (5.58 mmol) was added. ) of methanesulfonyl chloride. The mixture was stirred at 0 ° C for 48 hours. Ice and H20 were added to the mixture and the mixture was extracted with ethyl acetate. The extract was washed with H2O, 2N citric acid, brine and dried with Na2SO4. The solvent was removed under vacuum and the residue was triturated with ethyl acetate-hexane to give 0.90 g of a solid. 128-142 ° C. Anal. for C19H22N2O7S2: Calculated: C, 50.2; H, 4.9; N, 6.2; S, 14.1; Found: C, 49.6; H, 5.0; N, 6.9; S, 14.0; Mass spectrum (ES) 455.5 (M + H).
Reference Example 99 1, 4-Bis- (4-methoxybenzenesulfonyl) -2,3,4, 5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl 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, 1.07 (5.18 mmol) of sodium chloride was added. -methoxybenzenesulfonyl. After 2 hours, the mixture was concentrated to dryness under vacuum. To the residue was added 12 ml of ethanol and the mixture was refluxed overnight. The solvent was removed under vacuum and the residue chromatographed on thick silica gel plates with ethyl acetate-hexane (1: 1) as solvent to give 0.83 g (60%) of the product as a white foam. Anal, calculated for C25H26N208S2: C, 54.9; H, 4.8; N, 5.1; S, 11.7; Found: C, 54.8; H, 4.9; N, 5.0; S, 11.5; Mass spectrum (ES) 547.1 (M + H); and a second component (0.38 g) of 2-. { [2- (4-methoxybenzenesulfonyl) aminobenzyl] - (4-methoxy-benzenesulfonyl) amino} -3-hydroxypropionate methyl. Anal. for C25H28N2O9S2: Calculated: C, 53.2; H, 5.0; N, 5.0; S, 11.4; Found: C, 51.8; H, 5.1; N, 4.7; S, 11.3; Mass spectrum (ES) 565.2 (M + H).
Reference Example 100 l-Acetyl-4- (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl To a solution of 0.70 g (1.52 mmol) of methyl 2 - [(2-diacetylaminobenzyl) - (4-methoxybenzenesulfonyl) amino] acrylate in 5 ml of anhydrous methanol was added 0.332 g (3.95 mmol) of sodium bicarbonate. anhydrous. The mixture was stirred at room temperature overnight and the solvent was removed under vacuum. To the residue was added ethyl acetate and H0. The organic layer was separated, washed with brine and dried with Na 2 SO 4. The solvent was removed and the residue was dried under vacuum to give 0.59 g of white crystals, m.p. 150-155 ° C. Anal, for C20H22N2O6S: Calculated: C, 57.4; H, 5.3; N, 6.7; S, 7.7; Found: C, 56.6; H, 5.2; N, 6.5; S, 7.5; Mass spectrum (ES) 419.9 (M + H).
Reference Example 101 3-Acetoxy-2- [(2-diacetylaminobenzyl) - (4-methoxybenzenesulfonyl) amino] propionate methyl A mixture of 1.0 g (2.54 mmol) of 2 - [(2-aminobenzyl) - (4-methoxybenzenesulfonyl Methyl] -3-hydroxypropionate and 1.3 ml of acetic anhydride in 8 ml of toluene, was heated at 100 ° C for 2 hours. The mixture was concentrated and 3 ml of acetic anhydride were 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 1.2 g of a yellow oil. Anal, for C24H28N2? 9S: Calculated for C, 54.5; H, 5.2; N, 5.5; S, 6.2; Found: C, 54.6; H, 5.1; N, 5.4; S, 6.4; Mass spectrum (ES) 520.8 (M + H).
Reference Example 102 2- [(2-Diacetylaminobenzyl) - (4-methoxybenzenesulfonyl) amino] methyl 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 CH2C12 was stirred at room temperature overnight. The solution was diluted with 30 ml of CH2C12 and washed with 20 ml each of H20, 2N citric acid, brine and dried with Na2SO4. The solvent was removed under vacuum to give a brown oil. Anal, for C22H24N207S: Calculated: C, 57.4; H, 5.3; N, 6.1; S, 7.0; Found: C, 56.2; H, 5.5; N, 5.6; S, 7.2.
Reference Example 103 2-. { (4-Methoxybenzenesulfonyl) - [2- (2,2,2-trifluoroacetylamino) benzyl] amino} methyl 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, 1.8 ml (12.7 mmol) of trifluoroacetic anhydride was added. (dissolved solid). The solution was stirred for 2 hours at room temperature and heated at 100 ° C overnight. Then the mixture was concentrated to dryness under vacuum. To the residue was added 0.9 ml of trifluoroacetic anhydride and the solution was stirred at room temperature for 1.5 hours and concentrated to dryness. To the residue was added 10 ml of toluene and the mixture was refluxed for 2 hours. The solution was cooled to room temperature and 2.5 ml of triethylamine were added and the mixture was stirred at room temperature overnight. The solution was concentrated to dryness and the residue was dissolved in ethyl acetate. The ethyl acetate was washed with H20, brine and dried (Na2SO4). The solvent was removed under vacuum to give 1.0 g of colorless oil. Crystallization from ethyl acetate-hexane gave 0.625 g of colorless crystals, m.p. 120-121 ° C. Anal, for C2oHi9F3N2? 6S: Calculated: C, 50.9; H, 4.1; N, 5.9; S, 6.7; F, 12.1; Found: C, 50.8; H, 4.2; N, 5.6; S, 6.8; F, 11.9; Mass spectrum (ES) 473.1 (M + H).
Reference Example 104 4- (4-Methoxybenzenesulfonyl) -1- (2-methyl-5-fluorobenzoyl) -2,3,4,5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylic acid To a mixture of 1.9 g (3.71 mmol) of 4- (4-methoxybenzenesulfonyl) -1- (2-methyl-5-fluorobenzoyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin- 3-methyl carboxylate in 10 ml of tetrahydrofuran, 5 ml (4.82 mmol) of IN NaOH were added. The mixture was stirred at room temperature for 1.5 hours and the solvent was removed under vacuum. To the residue was added ethyl acetate and the mixture was neutralized with IN HCl. The organic layer was separated, washed with brine and dried with Na 2 SO 4. The solvent was removed under vacuum to give 1.41 g of white solid. Anal, for C25H23FN206S: Calculated: 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). Using the method described in Reference Example 104, the following benzodiazepine-3-carboxylic acids can be prepared.
Reference Example 105 4- (4-Methoxybenzenesulfonyl) -1- (4-methylphenylsulfonyl) • 2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid White foam. Anal, for C24H24N07S2: Calculated: 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).
Reference Example 106 1,4-Bis- (4-methoxybenzenesulfonyl) -2,4,4,5,5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylic acid Whitish solid. Anal, for C2H24N208S2: Calculated: C, 54.1; H, 4.5; N, 5.3; Found: C, 52.4; H, 4.8; N, 4.7; Mass spectrum (ES) 533.1 (M + H).
Reference Example 107 L-methanesulfonyl-4- (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid White solid. Anal, for C? 8H2o 207S2: Calculated: C, 49.1; H, 4.6; N, 6.3; 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) -2,4,5,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid White foam. Anal, for C24H22N2O6S: Calculated: C, 61.5; H, 5.2; N, 6.0; Found: C, 60.8; H, 5.2; N, 5.7; Mass spectrum (ES) 467.9 (M + H).
Reference Example 109 L-Acetyl-4- (4-methoxybenzenesulfonyl) -2,4,5,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid White solid. Anal, for C19H22N206S: Calculated: 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).
Reference Example 110 4- (4-Methoxybenzenesulfonyl) -1- (3-pyridinylcarbonyl) 2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid White solid, m.p. 250-255. Anal, for C23H21N3O6S: Calculated: C, 59.1; H, 4.5; N, 9.0; Found: C, 58.3; H, 4.7; N, 8.3; Mass spectrum (ES); 468.2 (M + H).
Reference Example 111 4- (4-Methoxybenzenesulfonyl) -1- (2-thienylcarbonyl) -2,3,4,5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylic acid White solid. Anal, for C22H20N2O6S2: Calculated: C, 55.9; H, 4.3; N, 5.9; Found: C, 54.9; H, 4.4; N, 5.4; Mass spectrum (ES) 473.1 (M + H).
Reference Example 112 L-Methoxyacetyl-4- (4-methoxybenzenesulfonyl) -2,4,5,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid white crystals, m.p. 193-194 ° C. Anal, for C20H22 2O7S: Calculated: C, 55.3; H, 5.1; N, 6.5; Found: C, 55.1; H, 4.9; N, 6.2; Mass spectrum (ES) 433.1 (M-H).
Reference Example 113 4- (4-Methoxybenzenesulfonyl) -1- (4-pyridinylcarbonyl) -2,3,4,5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylic acid White crystals, m.p. 258-261 ° C. Anal, for C23H2iN306S: Calculated: C, 59.1; H, 4.5; N, 9.0; Found: C, 58.8; H, 4.5; N, 8.8; Mass spectrum (ES) 483.3 (M + H).
Reference Example 114 1- (4-Biphenylcarbonyl) -4- (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylic acid White foam. Analysis for C3ori26 2? 6S: Calculated: C, 66.4; H, 4.8; N, 5.2; Found: C, 64.7; H, 5.2; N, 4.8; Mass Spectrum (ES) 543.6 (M + H).
Reference Example 115 4- (4-Methoxybenzenesulfonyl) -1- (propan-1-sulfonyl) -2,3,4,5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylic acid White foam. Analysis for C20H2N2O-7S2: Calculated: C, 51.3; 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 Acid ([1,1'-biphenyl-2-carbonyl) -4- (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylic foam white p.f. 106-145 ° C. Analysis for C30H26N2O6S: Calculated: C, 66.4; H, 4.8; N, 5.2; Found: C, 65.7; H, 5.0; N, 4.8; Mass Spectrum (ES) 541.1 (M-H).
Reference Example 117 1- (3-Fluorobenzoyl) -4- (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylic acid Reference Example 118 4- (4-Methoxybenzenesulfonyl) -1- (2-methyl-3-fluorobenzoyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid Reference Example 119 4- (4-Methoxybenzenesulfonyl) -1- (3-phenylpropionyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazep n-3-carboxylic acid white solid; Analysis for C 26 H 26 N 2 O 6 S: Calculated: C, 63.1; H, 5.3; 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) -1- (2-trifluoromethylbenzoyl) -2,3,4,5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylic acid Reference Example 121 1- (2-Chloro-6-trifluoromethylbenzoyl) -4- (4-methoxybenzenesulfonyl) -2,4,4,5,5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylic acid Reference Example 122 1- (4-Fluoro-2-trifluoromethylbenzoyl) -4- (4-methoxybenzenesulfonyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid Reference Example 123 1- (2-Fluoro-6-trifluoromethylbenzoyl) -A- (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylic acid Reference Example 12 i 4- (4-Methoxybenzenesulfonyl) -1- (2-methylbenzoyl) -2,3,4,5-tetrahydro-lH- [1,] enzodiazepine-3-carboxylic acid Reference Example 125 4- (4-Methoxybenzenesulfonyl) -1- (2-methyl-6-chlorobenzoyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid Reference Example 126 1- (2,4-Dimethylbenzoyl) -A - (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylic acid Reference Example 127 1- (2,5-Dimethylbenzoyl) -A- (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylic acid Reference Example 128 1- (2-Chloro-4-fluorobenzoyl) -4- (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylic acid Reference Example 129 1- (2-Chlorobenzoyl) -4- (4-methoxybenzenesulfonyl) -2, 3, 4, 5-tetrahydro-lH- [1,] benzodiazepine-3-carboxylic acid Reference Example 130 1- (2-Fluorobenzoyl) -A - (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid Reference Example 131 1- (2-Chloro-6-fluorobenzoyl) -4- (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylic acid Reference Example 132 1- (2,3-difluorobenzoyl) -4- (4-methoxybenzenesulfonyl) 2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid Reference Example 133 1- (2,4-Dichlorobenzoyl) -4- (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylic acid white solid; Analysis for C2H20N2O6S: Calculated: 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 1- (2,3-Dichlorobenzoyl) -A - (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylic acid Reference Example 135 1- (2, 5-Dichlorobenzoyl) -4- (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid Reference Example 136 1- (2-Methoxybenzoyl) -A- (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid Example Reference 137 Acid 1- (4-Chloro-2-methoxybenzoyl) -4- (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid Reference Example 138 4- (4-Methoxybenzenesulfonyl) -1- (2-methylthiobenzoyl) -2,3,4,5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylic acid Reference Example 139 4- (4-Methoxybenzenesulfonyl) -1- (3-methyl-2-thienylcarbonyl) -2,3,4,5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylic acid Reference Example 140 4- (4-Methoxybenzenesulfonyl) -1- (4-methyl-2-thienylcarbonyl) -2,3,4,5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylic acid Reference Example 141 1- (3-Chloro-2-thienylcarbonyl) -4- (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid Reference Example 142 1- (2-furanylcarbonyl) -A - (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylic acid white solid; Analysis for C22H20N2O-7S: Calculated: 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).
Reference Example 143 4- (4-Methoxybenzenesulfonyl) -1- (3-methyl-2-furanylcarbonyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid Reference Example 144 4- (4-Methoxybenzenesulfonyl) -1- (4-methyl-2-furanylcarbonyl) -2,3,4,5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylic acid Reference Example 145 1- (5-Chloro-2-furanylcarbonyl) -4- (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylic acid Example Reference 146 1- (5-Chloro-2-thienylcarbonyl) -4- (4-ethoxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid Reference Example 147 l-Propionyl-4- (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid Reference Example 148 l-Hexanoyl-4- (4-methoxybenzenesulfonyl) -2, 3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid Reference Example 149 1- (3-Methoxypropionyl) -A- (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylic acid Reference Example 150 4- (4-Methoxybenzenesulfonyl) -1- (3-thienylcarbonyl) -2,3,4,5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylic acid Reference Example 151 4- (3-furanylcarbonyl) -4- (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid Reference Example 152 1- (Trans-Crotonyl) -4- (4-methoxybencepsulfonyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid Reference Example 153 1- (Methacryloyl) -A - (4-methoxybenzenesulfonyl) -2, 3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid Reference Example 154 1- (Pyrrolidinacetyl) -4- (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid Reference Example 155 1- (Acetylaminoacetyl) -A - (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid Reference Example 156 1- (Cyclopropylcarbonyl) -A- (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid white crystals; p.f. 131-135 ° C. Analysis for C21H22N2O6S: Calculated: C, 58.6; H, 5.2; N, 6.5; Found: C, 58.1; H, 5.5; N, 5.8; Mass Spectrum (ES) 431.5 (M + H).
Reference Example 157 1- (Cyclobutylcarbonyl) -4- (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylic acid Reference Example 158 1- (Cyclohexylcarbonyl) -A- (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylic acid white solid; Analysis for C24H28N2? 6S: Calculated: 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).
Reference Example 159 Methyl ester of (D, L) N- (4-methoxybenzenesulfonyl) -O- (2-tetrahydropyranyl) serine A sample of 1.44 g (5 mmol) of methyl ester of N- (4-methoxybenzenesulfonyl) serine; 1.05 g (12.5 mmol) of 3,4-dihydro-2H-pyran and 9.5 mg of 4-methylbenzenesulfonic acid monohydrate in 5 ml of tetrahydrofuran was refluxed overnight and the mixture was concentrated to dryness under vacuum. The residue was extracted with CH 2 Cl 2 and the extract was washed with 2 N NaHCO 3, brine and dried with Na2S04. The solution was filtered through a thin pad of aqueous magnesium silicate and the filter pad was 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 yield 1.92 g of the product as a yellow oil; Mass Spectrum (ES) 374. 4 (MH +).
Reference Example 160 3-hydroxy-2-. { [4-methoxybenzenesulfonyl] - [2- (4-morpholinocarbonylamino)) benzyl] amino} methyl propionate To a mixture of 1.0 g (2.54 mmol) of methyl 2 - [(2-aminobenzyl) - (4-methoxy-benzenesulfonyl) amino] -3-hydroxypropionate in 8 ml of cooled pyridine At 0 ° to 10 ° C, 740 μL (6.34 mmol) of morpholinocarbonyl chloride were added. The mixture was kept at 0 ° C to 5 ° C overnight. The mixture was concentrated under vacuum and diluted with ethyl acetate. The solution was washed with H2O, 2N citric acid, and brine and dried with Na2SO4. The solvent was removed under vacuum to yield 1.61 g of the solid (yellow-orange foam). The solid was subjected to chromatography on thick layer silica gel plates with hexane-ethyl acetate (1: 3) as solvent to yield 0.86 g of the solid. Analysis for C23H29N308S: Calculated: C, 54.4; H, 5.8; N, 8.3; Found: C, 53.9; H, 5.7; N, 8.1; Mass Spectrum (ES) 508.4 (M + H).
Reference Example 161 2-. { (4-methoxybenzenesulfonyl) - [2- (4-morpholinocarbonylamino) benzyl] amino} Methyl acrylate To a solution of 0.70 g (1.38 mmol) of 3-hydroxy-2-. { [4-methoxy-benzenesulfonyl] - [2- (4-morpholinocarbonylamino) benzyl] amino} Methyl propionate and 769 μL (5.54 mmol) of triethylamine in 8 ml of CH2C12, 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 CH2C12. The extract was washed with 2N citric acid, brine and dried with Na2SO4. The solvent was removed to yield 0.67 g of a yellow oil. Analysis for C23H2-7N3O7S: Calculated: C, 56.4; 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 4- (4-methoxybenzenesulfonyl) -1- (4-morpholinocarbonyl) -2, 3,4,5-tetrahydro-lH- [1,4] -benzodiazepine-3-carboxylic acid methyl ester A mixture of 0.50 g (1.02 mmol) of 2-. { (4-methoxybenzenesulfonyl) - [2- (4-morpholinocarbonyl-amino) benzyl] amino} Methyl acrylate and 0.111 g (1.32 mmol) of anhydrous NaHCO 3 in 5 ml of anhydrous methanol was stirred at room temperature for 16 hours. An additional 55 mg of NaHCO 3 was added and the mixture was stirred at room temperature for 2 hours. The solvent was removed under vacuum and the residue was diluted with H20 and extracted with ethyl acetate. The extract was washed with brine and dried with Na2SO4. The solvent was removed and the residue was triturated with hexane-ethyl acetate to yield 0.36 g of a yellow solid; Analysis calculated for C23H27N3? 7S: C, 56.4; 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) -1- (4-morpholinecarbonyl) -2,3,4,5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylic acid A mixture of 0.36 g (0.735 mmol) of methyl 4- (4-methoxybenzenesulfonyl) -1- (4-morpholinocarbonyl) -2, 3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylate and 1 ml (0.95 mmol) of IN NaOH in 5 ml of tetrahydrofuran was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum and acidified with IN HCl and cooled. The mixture was filtered and the solid was washed with water to yield 0.26 g of a white solid. Analysis for C22H25N307S: Calculated: C, 55.6; H, 5.3; N, 8.8; Found: C, 53.5; H, 5.6; N, 8.3; Mass spectrum (ES) 474.3 (M-H).
Reference Example 164 methyl 3- [-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) -O- (2-tetrahydropyranyl) serine methyl ester, 0.825 g (4.4 mol) of 4-chloro-2- alcohol Nitrobenzyl and 1.16 g (4.4 mmol) of triphenylphosphine in 4.5 ml of tetrahydrofuran were 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 was removed under vacuum. The residue was triturated with diethyl ether, filtered and the filtrate was passed through a thin pad of aqueous magnesium silicate. The pad was washed with ethyl acetate and the total filtrate was concentrated to dryness under vacuum to yield 4.54 g of the solid. The solid was chromatographed on silica gel with hexane-ethyl acetate (55:45) as solvent. The fractions containing the product were combined and the solvent was removed to yield 0.55 g of oily solid; Mass spectrum (ES) 543.1 (M + H).
Reference Example 165 2-. { [2- (4-pyridinylmethyleneamino) benzyl] - [4-methoxybenzenesulfonyl] amino} Methyl-3-hydroxypropionate A mixture of 0.50 g (1.268 mmol) of methyl 2 - [(2-aminobenzyl) - (4-methoxy-benzenesulfonyl) amino] -3-hydroxypropionate and 1,268 mmol of 4-pyridinecarboxaldehyde in 7 ml of anhydrous ethanol was refluxed for 1.5 hours and the mixture was concentrated in vacuo 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 yield 0.40 g of the solid product (plus a small amount of starting material). Analysis for C24H25N306S: Calculated: C, 59.6; H, 5.2; N, 8.7; Found: C, 57.6; H, 5.7; N, 7.4; Mass spectrum (ES) 484 (M + H) -product; 395.1 (M + H) - starting material.
Reference Example 166 1- (cyclohexylcarbonyl) -4- (4-methoxybenzenesulfonyl) -2, 3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl To a solution of 0.80 g (1.64 mmol) of 2-. { [2- (cyclohexylcarbonyl) -aminobenzyl] - (4-methoxybenzenesulfonyl) amino} Methyl acrylate in 10 ml of methanol was added 0.207 g (2.46 mmol) of anhydrous sodium bicarbonate. The mixture was stirred for 2 days and then an additional 0.207 g of NaHCO 3 was added. The mixture was stirred overnight and the solvent was removed under vacuum. To the residue was added H20 and ethyl acetate and the organic layer was separated. The ethyl acetate extract was washed with brine, dried with Na 2 SO 4 and the solvent was removed under vacuum to yield 0.83 g of the product as a yellow oil. Analysis calculated for C 25 H 30 N 2 O 6 S: Calculated: C, 61.7; H, 6.2; 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 0.289 g (1 mmol) of 3-hydroxy-2- (4 methyl methoxy-benzenesulfonylamino) 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 emission ceased, 0.165 g (1.1 mmol) of sodium iodide was added, followed by the addition of 0.226 g (1.1 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 was extracted with CH2Cl2. The extract was washed with H2O, brine and dried with Na2SO4. The solvent was removed to give 0.53 g of the solid which was subjected to chromatography on thick-layer silica gel plates with hexane-ethyl acetate (2: 1) as solvent to yield 0.143 g (31%) of the product, as crystals, mp 112 ° -114 ° C. Analysis for C? 8H? 9ClN208S: Calculated: C, 47.2; H, 4.2; N, 6.1; Found: C, 47.0; H, 4.1; N, 6.0; Mass spectrum (ES) 459.2 (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 3-hydroxy-2- [(4 -methoxy-benzenesulfonyl) - methyl (4-chloro-2-nitrobenzyl) amino] propionate and 0.451 g (2 mmol) of SnCl2 * 2H20 in 12 ml of methanol was refluxed for 2 hours. An additional 0.451 g (2 mmol) of SnCl2ß2H20 was added and the mixture was refluxed for 2 hours. The solvent was removed and ethyl acetate was added. The mixture was neutralized with INH NaHC03 and then stirred for 1 hour and filtered. The ethyl acetate layer was separated and washed with H20, brine and dried with Na2SO4. The solvent was removed to yield 0.42 g of the solid which was subjected to chromatography on thick-film silica gel plates with hexane-ethyl acetate (45:55) as solvent to yield 60 mg of the product (RF 0.66) as a solvent. crystal, mp 99 ° -112 ° C. Analysis for C? 8H2? Cl 206S: Calculated: C, 50.4; H, 4.9; N, 6.5; Found: C, 49.7; 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-methoxy-benzenesulfonyl) - (4-chloro-2-nitrobenzyl) amino] propionate in 25 ml of ethanol and 25 ml of acetate of ethyl was added 0.045 g of 10% Pd / C (wet - 50% H20). The mixture was shaken in a Parr hydrogenator under 35 psi (24602.37 kg / m2) of hydrogen for 3 hours. The mixture was filtered through diatomaceous earth and the filtrate was concentrated to dryness under vacuum to yield 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) 395.1 (M + H) indicated approximately 10% non-chlorine derivative. A mixture of 4.74 g of 3-hydroxy-2- [(4-methoxybenzenesulfonyl) - (4-chloro-2-aminobenzyl) amino} methyl propionate, and 0.470 g of 10% Pd / C (wet - 50% H20) in 200 ml of ethyl acetate-ethanol (1: 1) was shaken in a Parr hydrogenator under 35 psi (24602.37 kg / m2) of hydrogen per 4 hours. The mixture was filtered through diatomaceous earth and the solvent was removed to yield 4.5 g of the solid. The solid was subjected to HPLC chromatography 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 produce 1.56 g of a crystal, mp 110 ° -123 ° C. Analysis for C? 8H2? ClN205S: Calculated: 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 (0.1 mol) of glycine methyl ester hydrochloride in 120 ml of CH2Cl2, cooled in an ice bath was added 41.7 ml ( 0.3 mol) of triethylamine, followed by the dropwise addition of a solution of 20.65 g (0.1 mol) of 4-methoxy-benzenesulfonyl chloride in 40 ml of CH2Cl2. The mixture was stirred at room temperature overnight and poured into water. The organic layer was separated and washed with 2N citric acid, H20, NaHC03 IN, brine and dried with NaHS04. The solvent was removed under vacuum to yield 24.6 g of the residue which was triturated with ethyl acetate to yield 19.9 g of crystals, m.p. 59 ° -61 ° C. Analysis for C? 0H? 3NSO5: Calculated: C, 46.3; H, 5.1; N, 5.4; Found: C, 46.2; H, 5.0; N, 5.2.
Reference Example 171 2- [(4-methoxybenzenesulfonyl) - (2-nitrobenzyl) amino] methyl acetate To a stirred and cooled mixture of 1.2 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- methyl ester ( 4-methoxybenzenesulfonyl) glycine in 40 ml of N, N-dimethylformamide. After the gas emission 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 was removed under vacuum. The residue was extracted with CH2C12 and the extract was washed with H2O, 2N citric acid, H2O, NaHC03 IN, brine and dried with Na2SO4. The solution was filtered through a thin pad of aqueous magnesium silicate and the filter pad was washed with CH2C12. The filtrate was concentrated under vacuum to yield 11.79 g of the solid. Trituration with ethyl acetate gave 2.64 g (22%) of crystals, m.p., 114 ° C-116 ° C. Analysis for C? H? 8N207S: Calculated: C, 51.8; H, 4.6; N, 7.1; Found: C, 51.7; H, 4.6; N, 7.1. From the mother liquors an additional 6.49 g (55%) of the product as crystals were obtained by cooling to 0 ° C and filtering the mother liquors.
Reference Example 172 2- [(2-aminobenzyl) - (4-methoxybenzenesulfonyl) amino] acetate methyl (A) To a mixture of 2.15 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 was diluted with H20 (25 mL) and extracted with CH2C12 (75 mL). The extract was washed with brine, dried with Na 2 SO 4 and the solvent was removed to yield 0.45 g of the solid. Crystallization from ethyl acetate gave 0.124 g of white crystals, m.p. 100 ° -102 ° C. Analysis for C? 7H2o 2? 5S Calculated: C, 56.0; H, 5.5; N, 7.7; Found: C, 56.1; H, 5.6; N, 7.6.
(B) To a solution of 4.2 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 (humid - 50% H20) and the mixture was shaken in a Parr hydrogenator under 35 psi (24602.37 kg / m2) of hydrogen for 4.5 hours at room temperature. The mixture was filtered through diatomaceous earth and the filtrate was 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 5.14 g (14.1 mmol) of methyl 2 - [(2-aminobenzyl) - (4-methoxybenzenesulfonyl) amino] acetate in 50 ml of methanol-tetrahydrofuran (1: 1) was added 2.86 ml of ION NaOH and the mixture was refluxed for 2 hours. The solvent was removed under vacuum and the residue was partitioned between water and ether. The water layer was separated and acidified with 2N citric acid. The solid was filtered, washed with H20 and dried in a vacuum oven at room temperature to yield 4.45 g (91%) of crystals, m.p. 145 ° -147 ° C. Analysis for C? 6H? 8N2? 5S: Calculated: C, 54.9; H, 5.2; N, 8.0; Found: C, 55.1; H, 5.2; N, 7.9.
Reference Example 174 Methyl 4- (4-methoxybenzenesulfonyl) -1- (phenoxyacetyl) -2,3,4,5-tetrahydro-1- [1,4] benzodiazepine-3-carboxylate To a cooled mixture (0 ° C) ) of 1.5 g (3.8 mmol) of methyl 2- [(2-aminobenzyl) - (4-methoxybenzenesulfonyl) amino] -3-hydroxypropionate and 2.7 ml (19 mmol) of triethylamine in 15 ml of CH2C12 was added 1.58 g ( 11.4 mol) of phenoxyacetyl chloride. The mixture was stirred at room temperature overnight and filtered. The filtrate was washed with H2O, 2N citric acid, and brine and dried with NaSO4. The solvent was removed to yield 2.4 g of 2-. { (4-methoxybenzenesulfonyl) - [2- (phenoxyacetylamino) benzyl] amino} crude methyl acrylate as an oil. Analysis for C 26 H 26 2 O 7 S: Calculated: C, 61.2; H, 5.1; N, 5.5; Found: C, 62.6; H, 5.1; N, 4.0; Mass spectrum (ES) 511 (M + H). To a sample of 20 g (3.92 mmol) of the preceding compound in 15 ml of methanol was added 0.494 g of anhydrous NaHCO 3 and the mixture was stirred for 5 hours. The mixture was concentrated under vacuum and ethyl acetate and H20 were added to the residue. The mixture was filtered and the organic layer of the filtrate was separated, washed with brine and dried with Na2SO4. The solvent was removed to yield 0.36 g of product as off-white crystals, m.p. 151 ° -153 ° C. Analysis for C26H26 207S: Calculated: C, 61.2; H, 5.1; N, 5.5; Found: C, 61.1; H, 5.1; N, 5.4; Mass spectrum (ES) 511 (M + H).
Reference Example 175 3-hydroxymethyl-4- (4-methoxybenzenesulfonyl) -1- (3-pyridinylmethyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine A mixture of 0.100 'g (0.208 mmol) of 4- (4-methoxybenzenesulfonyl) -1- (3-pyridinylcarbonyl) -2,4,5,5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylate of methyl 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 was removed. Methanol was added several times and, after each addition, the solvent was removed. To the residue was added NaHCO3 IN. The mixture was stirred for 45 minutes and then extracted with ethyl acetate. The extract was concentrated and then washed with H20, brine and dried with Na2SO4. The solvent was removed under vacuum and the residue was subjected to chromatography on thick-film silica gel plates with 10% methanol in ethyl acetate as solvent to yield 60 mg of the solid (RF 0.26).
Crystallization from ethyl acetate gave 30 mg of white crystals. Analysis for C23H25N3? 4S: Calculated: C, 62.8; H, 5.7; N, 9.6; S, 7.3; Found: C, 61.1; H, 5.6; N, 9.2; S, 7.3; Mass spectrum (ES) 440.2 (M + H).
Reference Example 176 4- (4-methoxybenzenesulfonyl) -1- (2-methoxypyridinyl-3-carbonyl) -2,3,4,5-tetrahydro-lH- [1,] benzodiazepine-3-carboxylic acid methyl To a cooled (0 ° C) mixture of 1.0 g (2.54 mmol) of methyl 2- [(2-amino-benzyl) - (4-methoxybenzenesulfonyl) amino] -3-hydroxypropionate and 1.8 ml (12.68 mmol) of triethylamine in 10 ml of CH2Cl2 0.957 g (5.58 mmol) of 2-methoxypyridine-3-carbonyl chloride in 4 ml of CH2C12 was added. The solution was stirred at room temperature overnight, diluted with H20 and CH2C12 and the organic layer was separated. The organic layer was washed with H20, 2N citric acid, and brine and dried with Na2SO4. The solvent was removed under vacuum to yield 1.2 g of the solid. The solid was subjected to chromatography on thick-film silica gel plates with ethyl acetate-hexane (3: 1) as solvent to yield 0.27 g of yellow foam. Analysis for C25H25N30S: Calculated: C, 58.7; H, 4.93; N, 8.21; Found: C, 57.8; H, 4.5; N, 8.3; S, 6.2.
Reference Example 177 5-Methyl-2-nitrobenzyl bromide To a cooled mixture (water-ice bath) of 30% HBr in acetic acid (3 ml) was added 2.5 g of 5-methyl-2-nitrobenzyl alcohol and the cooled solution was stirred for 2 hours. The mixture was poured into ice-water and extracted with diethyl ether. The extract was washed with H20, brine and the solvent was removed under vacuum to produce a mixture of the product (50%) and starting material (50%).
Reference Example 173 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-methoxy-benzenesulfonylamino) propionate in 120 ml of dry N, -dimethylformamide was added dropwise to a stirred suspension of 3.2 g (0.08 mol) of sodium hydride (57% in oil) in 20 ml of N, N-dimethylformide. When the gas emission ceased, the mixture was cooled 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 cooled 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 was diluted with 200 ml of H0 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 yield 41.18 g of the crude product. The product was chromatographed on silica gel with hexane-ethyl acetate (1: 1) as solvent to yield 8.14 g (RF 0.38) of the product as a yellow semi-solid. From a small scale test (1 mmol) the product was chromatographed twice on thick silica gel plates with hexane-ethyl acetate (1: 1) to yield 0.12 g of a yellow semi-solid. Analysis for C19H22N2SO8: Calculated: C, 52.0; H, 5.1; N, 6.4; Found: C, 51.7; H, 5.1; 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 charcoal (humid - 50% H20). The mixture was then shaken in a Parr hydrogenator under 35 psi (24602.37 kg / m2) of hydrogen for 2.5 hours. The mixture was filtered through diatomaceous earth and the filtrate was concentrated under vacuum to yield 2.86 g of a brown oil. Analysis for Ci9H24N206S: Calculated: C, 55.9; H, 5.9; N, 6.9; Found: C, 55.6; H, 5.9; N, 6.4; Mass spectrum (ES) 409 (M + H).
Reference Example 180 3- [(2-Tetrahydropyranyl) oxy] -2- [(-4-methoxybenzenesulfonyl) - (5-methyl-2-nitrobenzyl) amino] propionate methyl To a mixture of 1.75 g (4.68 mmol) of methyl ester of (D, L) N- (4-methoxybenzenesulfonyl) -O- (2-tetrahydropyranyl) serine, 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) to 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 solvence was removed under vacuum. The residue was triturated with diethyl ether and the solid was removed by filtration. The filtrate was concentrated to dryness under vacuum to yield 4.67 g of the solid. The solid was chromatographed on silica gel with hexane-ethyl acetate (1: 1) to yield 0.56 g of the product (RF 0.48).
Reference Example 131 l-methoxyacetyl-4- (4-methoxybenzenesulfonyl) -7-methyl-2, 3,4,5-tetrahydro-lH- [1,] benzodiazepine-3-carboxylic acid methyl To a cooled (0 ° C) mixture of 1598 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 methoxyacetylchloride. The mixture was stirred at room temperature overnight. The mixture was then diluted with CHC12 and washed with H20, 2N citric acid, H20, brine and dried with Na2SO4. The solution was filtered through a thin pad of aqueous magnesium silicate and the filtrate was concentrated to yield 1.94 g of 2-. { [2- (methoxyacetylamino) -5-methylbenzyl] - (4-methoxy-benzenesulfonyl) -amino} crude methyl 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 NaHCO 3 and the mixture was stirred overnight at room temperature. The solvent was removed under vacuum and the residue was partitioned between 100 ml of ethyl acetate and 20 ml of water. The ethyl acetate layer was separated and washed with H20, brine and dried with Na2SO4. The solution was filtered through a thin pad of aqueous magnesium silicate and the filtrate was concentrated under vacuum to produce a yellow oil. Trituration with ethyl acetate-hexane gave 1.26 g (78%) of tan crystals, m.p. 122 ° -124 ° C. Analysis for C22H26N07S: Calculated: C, 57.1; H, 5.7; N, 6.1; Found: C, 57.4; H, 5.7; N, 6.0 Reference Example 182 methyl l-benzoyl-4- (4-methoxybenzenesulfonyl) -7-methyl-2, 3,4,5-tetrahydro-lH- [1,4] benzodiazeprin-3-carboxylate To a cooled (0 ° C) mixture of 1465 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 CH2C12 was added 0.915 ml (7.89 mmol) of benzoyl chloride. The mixture was stored at room temperature overnight, diluted with CH2Cl2 and washed with H2O, 2N citric acid, H2O, brine and dried with NaSO4. The solution was filtered through a thin pad of aqueous magnesium silicate and the filtrate was concentrated under vacuum to yield 1.8 g of methyl 2- [(2-benzoylamino-5-methylbenzyl) - (4-methoxybenzenesulfonyl) amino] acrylate raw as a brown oil. Analysis for C26H26N206S: Calculated: C, 63.1; H, 5.3; N, 5.7; Found: C, 63.9; H, 5.2; N, 5.2.
As described for the Reference Example 181, 1825 g (3.68 mmol) of the above compound was stirred with 0.402 g (4.78 mmol) of NaHCO 3 in 1.5 mL of methanol to yield an oil. Trituration with hexane (plus several drops of ethyl acetate) gave crystals, m.p. 58 ° -62 ° C.
Reference Example 183 1- (trans-crotonyl) -A - (4-methoxybenzenesulfonyl) -7-methyl-2,3,4,5-tetrahydro-lH- [1,4] benzadiazepin-3-carboxylic acid methyl ester 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-methylbenzyl) amino] propionate , 1.75 g (17.3 mmol) of triethylamine and 0.809 ml of trans-crotonyl chloride in 15 ml of CH2Cl2 was stirred overnight to yield 1.52 g of 2-. { [2- (trans-crotonylamino) -5-methylbenzyl] - (4-methoxybenzenesulfonyl) amino} methyl acrylate 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 NaHCO 3 in 15 ml of methanol at room temperature overnight. To the mixture was added 0.056 g of NaHCO 3 and the mixture was heated to 80 ° C for 3 hours and worked up as Reference Example 181 to produce about 1.05 g of yellow crystal, m.p. 75 ° -84 ° C. Mass spectrum (ES) 459.4 (M + H).
Reference Example 184 1- (trans-Crotonyl) -A- (4-methoxybenzenesulfonyl) -7-methyl-2,3,4,5-tetrahydro-lH- [1,4] benzodiazepane-3-carboxylic acid A mixture of 1.26 g (2.72 mmol) of l- (trans-crotonyl) -A - (4-methoxybenzenesulfonyl) -7-methyl-2, 3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3 methyl 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 was dissolved in H20 and the solution was extracted with ethyl acetate. The aqueous layer was acidified with IN HCl (pH 2) and extracted with CH2C12. The CH2C12 extract was dried with Na2SO4 and the solvent was removed to yield 1.06 g (after drying under vacuum) of the solid, m.p. 101 ° -105 ° C.
Reference Example 185 1- (Benzoyl) -A- (4-methoxybenzenesulfonyl) -7-methyl-2,3,4,5-tetrahydro-lH [1,4] benzodiazepine-3-carboxylic acid A mixture of 1.18 g (2.38 mmol) of 1- (benzoyl) -4- (4-methoxy-benzenesulfonyl) -7-methyl-2, 3, 4, 5-tetrahydro-lH- [1,4] benzodiazepin-3 Methylcarboxylate and 3.09 ml (3.09 mmol) of IN NaOH in 10 ml of tetrahydrofuran was stored at room temperature overnight and the solvent was removed under vacuum. The residue was diluted with H2O, extracted with acetyl acetate and the aqueous layer was acidified with 2N citric acid. The mixture was extracted with CH2Cl2 and the CH2Cl2 extracts were washed with H2O, brine and dried with Na2SO4. The solvent was removed to yield 0.82 g of a light yellow crystal, m.p. 95 ° -100 ° C; Mass spectrum (ES) 481.4 (M + H).
Reference Example 186 4- (4-methoxybenzenesulfonyl) -1- (2-methoxyethyl) -2, 3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl A mixture of 1.6 g (3.57 mmol) of methyl 1- (methoxyacetyl) -4- (4-methoxy-benzenesulfonyl) -2, 3,4,5-tetrahydro-lH- [1,] benzodiazepine-3-carboxylate and 32 ml of borane in tetrahydrofuran (1.0 M) was refluxed under nitrogen overnight. Methanol was added and the solvent was removed. To the residue was added 25 ml of CH2C12 and 25 ml of 2N HCl and the mixture was stirred at room temperature for 1 hour. The organic layer was separated and washed with H20 and concentrated to dryness. The residue was triturated with ethyl acetate-hexane, cooled and filtered to yield 1.2 g of white crystals, m.p. 86 ° -90 ° C. Mass spectrum (ES) 435.4 (M + H). Analysis for C2? H26N2? 6S: Calculated: C, 58.1; H, 6.0; N, 6.5; Found: C, 58.5; H, 6.0; N, 6.5.
Reference Example 187 4- (4-Methoxybenzenesulfonyl) -1- (2-methoxyethyl) -2,4,5,5-tetrahydro-lH [1,4] benzodiazepine-3-carboxylic acid A mixture of 1.0 g (2.3 mmol) of methyl 4- (4-methoxybenzenesulfonyl) -1- (2-methoxyethyl) -2, 3, 4, 5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylate and 3.0 ml of IN NaOH in 10 ml of tetrahydrofuran was stirred at room temperature for 2 hours and the solvent was removed. To the residue, water was added and the mixture was acidified with IN HCl. The mixture was extracted with ethyl acetate and the extract was washed with brine and dried with Na 2 SO 4. The solvent was removed and the residue was triturated with ethyl acetate-hexane, cooled and filtered to yield 0.65 g of white crystals, m.p. 164 ° -165 ° C; Mass spectrum (ES) 421.4 (M + H). Analysis for C2oH24N206S: Calculated: C, 57.1; H, 5.8; N, 6.7; Found: C, 57.3; H, 5.7; N, 6.4.
Reference Example 183 1- (benzyl) -4- (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid methyl ester A mixture of 0.20 g (0.416 mmol) of 1- (benzoyl) -4- (-methoxy-benzenesulfonyl) -2,3,4,5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylic acid methyl ester and 4 ml of borane in tetrahydrofuran (1.0 M) was refluxed overnight and the solvent was removed. To the residue was added 5 ml of CH2C12 and 5 ml of 2N HCl and the mixture was stirred for 1 hour. The organic layer was separated and concentrated to dryness. The residue was subjected to chromatography on thick-film silica gel plates with hexane-ethyl acetate (2: 1) as solvent to yield 0.140 g of a colorless oil; Mass spectrum (ES) 467.5 (M + H).
Reference Example 189 4- (4-Methoxybenzenesulfonyl) -1- [4- (trifluoromethoxy) benzoyl) -8-chloro-2,3,4,5-tetrahydro-1H [1,4] 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-hydroxypropionate was reacted with sodium chloride. - (trifluoromethoxy) benzoyl to produce 2.59 g of 2-. { 2- [4- (Trifluoromethoxy) benzoyl) amino-4-chlorobenzyl] amino} Methyl acrylate as a yellow oil; Mass spectrum (ES) 599.3 (M + H). The above compound was stirred with 0.445 g (5.29 mmol) of anhydrous NaHCO 3 in 15 ml of methanol at room temperature for 16 hours and then heated at 80 ° C for 2 hours. The solvent was removed and the residue was extracted with ethyl acetate. The extract was washed with H2O, brine, and dried (a2S04). The solvent was removed and the residue was crystallized from ethyl acetate-hexane to yield 4- (4-methoxybenzenesulfonyl) -1- [4- (trifluoromethoxy) benzoyl} -8-chloro-2, 3,4, 5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl as yellow crystals, m.p. 149 ° -151 ° C. Analysis for C26H22C1F307S: Calculated: C, 52.1; H, 3.7; 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. 58 g (2.64 mmol) of the above 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 yield 1.52 g of the product. Crystallization from ethyl acetate-hexane gave 1.2 g of white crystals, m.p. 184 ° -186 ° C.
Reference Example 190 4- (4-methoxybenzenesulfonyl) -1- (4-morpholinecetyl) -2,3,4,5-tetrahydro-lH [1,4] benzodiazepin-3-carboxylic acid methyl ester A mixture of 0.10 g (0.22 mmol) of 1- (chloroacetyl) -A - (4-methoxybenzenesulfonyl) -2, 3, 4, 5-tetrahydro-1H- [1,4] benzodiazepin-3-carboxylic acid methyl ester, 21.2 =) 1 of morpholine and 125.4 ^ 1 of N, N-diisopropylethylamine in 3 ml of CH 2 Cl 2 was stirred overnight at room temperature. A 2.2 = j 1 additional morpholine were added and the solution was stirred for 2 days at room temperature. The mixture was diluted with CH2C12 and washed with H2O, brine and dried with Na2SO4. The solvent was removed to produce the product as a solid. Mass spectrum (ES) 504.3 (M + H). Analysis for C24H29N307S: Calculated: C, 57.2; H, 5.8; N, 8.3; Found: C, 56.5; H, 5.6; N, 8.1.
Reference Example 191 4- (4-methoxybenzenesulfonyl) -1- [2- (1-pyrazolyl) phenylcarbonyl] -7-methyl-2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3 methyl carboxylate • As described for the general reaction of ethyl 2-fluorobenzoate with the amines described in Tetrahedron, 53, 7557-7576 (1997), the ethyl 2-fluorobenzoate was reacted with pyrazole by refluxing N, N-dimethylformamide to produce ethyl 2- (1-pyrazolyl) -benzoate, as a thick yellow oil. Analysis calculated for C12Hi2N202: 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 (7.02 g) of this compound and 8.42 ml of 5N NaOH in 40 ml of ethanol-tetrahydrofuran (2: 1) was refluxed for 2 hours and the solvent was removed. The residue was made acidic (pH 6) with 2N nitric acid and the precipitated solid was filtered to obtain 3.7 g of the product. The pH of the filtrate was adjusted to 4.5 and extracted with ethyl acetate. The extract was concentrated to dryness to yield 1.5 g of the product. The two batches were combined to yield 5.2 g of 2- (1-pyrazolyl) benzoic acid, m.p. 140-142 ° C. To the preceding compound (2.07 g) in 5 ml of CH2C12 (cooled 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 was added (twice) and stirred under vacuum to yield 2- (l-pyrazolyl) benzoyl chloride as a yellow solid. A 2.3 g sample of the above compound was reacted with 1.5 g of the compound of Reference Example 179 in 15 ml of CH2C12 and 5.12 ml of triethylamine in the manner described by Reference Example 181 to produce 2- [(4-methoxybenzenesulfonyl ) -. { 2- [2- (1-pyrazolyl) phenylcarbonyl] amino-5-methyl-benzyl} amino] methyl acrylate. This compound was cyclized with NaHCO 3 in methanol in the manner described in Reference Example 181 to yield 4- (4-methoxybenzenesulfonyl) -1- [2- (1-pyrazolyl) phenylcarbonyl] -7-methyl-2, 3, 4 Methyl 5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylate, mp 240-242 ° C. A sample of 1.16 g of the above compound was hydrolyzed with 2.69 ml of IN NaOH in 10 ml of tetrahydrofuran in the manner described by Reference Example 104 to yield 0.71 g of 4- (4-methoxybenzenesulfonyl) -1- [2- (1-pyrazolyl) -phenyl-carbonyl) -7-methyl-2, 3,4,5-tetrahydro-lH [1,4] benzodiazepine-3-carboxylic acid, mp. 149-151 ° C.
Reference Example 192 4- (4-methoxybenzenesulfonyl) -1- [2- (4-morpholine) phenylcarbonyl} - 8-chloro-2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl Ethyl 2-morpholinbenzoate prepared in the manner described in Tetrahedron, 53: 7557, (1997) was refluxed with 10 N NaOH in tetrahydrofuran-ethanol (8: 2) for 1.5 hours to yield 2-morpholinbenzoic acid, m.p. 156-157 ° C. A sample of 1.8 g of this compound in 5 ml of CHC12 (cooled) was added to a solution of 7.9 ml of oxalyl chloride in CH2Cl2 (2M) followed by the addition of 0.058 ml of N, N-dimethylformamide. The solution was stirred at room temperature for 6 hours and the solvent was removed. Toluene (2 times) was added and stirred to yield 2- (4-morpholine) -benzoyl chloride as a yellow solid. In the manner described in Reference Examples 181 and 189, the above 2- (4-morpholine) benzoyl chloride was reacted with methyl 2- [(2-amino-4-chlorobenzyl) - (4-methoxybenzenesulfonyl) amino] -3-hydroxypropionate and the product was stirred with NaHCO 3 in methanol to yield 4- (4-methoxy-benzenesulfonyl) -1- [2- (4-morpholine) phenylcarbonyl] -8-chloro-2, 3,4,5-tetrahydro-1H- [1,4] benzodiazepin- Methyl 3-carboxylate, as a white solid having a mp 100-105 ° C. To 0.90 g 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 2 N nitric acid gave 0.82 g of the solid, m.p. 136-143 ° C. [compound, 4- (4-methoxybenzenesulfonyl) -1- [2- (4-morpholine) phenylcarbonyl] -8-chloro-2, 3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3- carboxylic] Reference Example 193 1- (4-ethoxybenzoyl) -A - (4-methoxybenzenesulfonyl) -2, 3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl A mixture of 0.270 g of 4- (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid methyl ester of Reference Example 12, 0.291 g of sodium chloride. -ethoxybenzoyl and 500 μl of triethylamine in 5 ml of CH2C12 was stirred at room temperature overnight. The mixture was diluted with CH2Cl2 and H20 and the CH2C12 layer was separated and concentrated to dryness. The residue was triturated with ethyl acetate to yield 0.276 g of 1- (4-ethoxybenzoyl) -4- (4-methoxybenzenesulfonyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] benzodiazepin-3. methyl carboxylate as white crystals, mp 187-190 ° C. A sample of 0.47 g of this compound was hydrolyzed with 1.2 ml of 1 N NaOH in 4 ml of tetrahydrofuran. Dilution with H20 and acidification with HCl 1 N gave 0.40 g of the acid as a white solid, m.p. 144-152 ° C.
Reference Example 194 4- (4-methoxybenzenesulfonyl) -1- [2-chloro-4- (3-methyl-l-pyrazolyl) -phenylcarbonyl} -2, 3, 4, 5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl As described in Example 65, methyl 4- (4-methoxybenzenesulfonyl) -2,3,4,5,5-tetrahydro-lH- [1,] benzodiazepine-3-carboxylate was reacted with 4- (3-) chloride. methyl-l-pyrazolyl) -2-chlorobenzoyl to produce 4- (4-methoxybenzenesulfonyl) -1- [2-chloro-4- (3-methyl-1-pyrazolyl) phenylcarboni-2, 2,3,4,5-tetrahydro- 1 H- [1,4] -benzodiazepin-3-carboxylic acid methyl ester as a white solid. Analysis for C29H27CIN4O6S: Calculated: C, 58.3; H, 4.6; N, 9.4. Found: C, 58.2; H, 4.9; N, 8.9. This compound was hydrolyzed with 1N NaOH in tetrahydrofuran as described in Reference Example 185 to produce the benzodiazepine-3-carboxylic acid derivative as a white solid.
Reference Example 195 l-Benzyl-4- (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-1H- [1,] benzodiazepine-3-carboxylic acid A mixture of 1.7 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 was stirred at room temperature for 1.5 hr. The organic layer was separated, washed with brine, dried with Na 2 SO 4 and the solvent was removed. The residue was crystallized from ethanol-hexane to yield 1.15 g of methyl 1-benzyl-4- (4-methoxybenzenesulfonyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylate as white crystals, mp 120-122 ° C. A sample (1.0 g) of this compound was hydrolyzed with 2.8 ml of 1 N NaOH in 7 ml of tetrahydrofuran as described in Reference Example 104 to yield 0.64 g of the 2, 3, 4, 5, 5-tetrahydroxy derivative lH- [1,4] benzodiazepine-3-carboxylic acid as white crystals, mp 183-185 ° C.
Reference Example 196 1- (2,4-Dimethoxybenzoyl) -A - (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl ester To a cooled (0 ° C) solution of 1.0 g (2.66 mmol) of 4- (4-methoxybenzenesulfonyl) -2,4,4,5,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylate Reference Example 12 and 1.85 ml (13.3 mmol) of triethylamine in 8 ml of CH2C12 was added 1.17 g (6.65 mmol) of 2,4-dimethoxybenzoyl chloride. The mixture was stirred at room temperature overnight, diluted with CH2C12 and washed with 2N citric acid. The organic layer was washed with H20, 1N 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 provide 1.0 g of l- (2,4-dimethoxybenzoyl) -A. Methyl (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] -benzodiazepine-3-carboxylate as a white foam. Analysis for C2H28H08S: Calculated: C, 60.0; H, 5.2; N, 5.2; Found: C, 60.0; H, 5.2; N, 5.1; Mass spectrum (ES): 541.0 (M + H). A sample of 0.80 g (1.48 mmol) 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 was diluted with water. The solution was acidified with 1 N HCl, cooled and filtered to yield 0.70 g of 1- (2,4-dimethoxy-benzoyl) -A- (4-methoxybenzenesulfonyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] benzodiaze acid ? in-3-carboxylic acid as a white solid. Analysis for C26H26N2? 8S: Calculated: C, 59.3; H, 5.0; N, 5.3; Found: C, 56.1; H, 4.8; N, 5.0; Mass spectrum (ES): 527.0 (M + H).
Reference Example 197 4- (4-methoxybenzenesulfonyl) -1- [2- (4-methylpiperazin-1-yl) acetyl] -2,3,4,5-tetrahydro-1H- [1,4] benzodiazepin-3 methyl carboxylate To a mixture of 2.5 g (6.64 mmol) of 4- (4-methoxybenzenesulfonyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl ester (Reference Example 12) and 4.63 ml (33.2 mmsl) 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, cooled 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 CH2C12 and H20. The insoluble acid was removed by filtration. The organic layer of the filtrate was separated, washed with brine, dried with Na2S? and filtered through diatomaceous earth. The solvent was removed and the residue triturated with ethyl acetate and a trail of ethanol. Cooling and filtering gave 0.75 g of methyl 1- (chloroacetyl) -A- (4-methoxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzo-diazepin-3-carboxylate (Example of Reference 91). Analysis for C2oH2iClN206S: Calculated: C, 53.0; H, 4.7; 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 12 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 CH2C12, and washed with 2N nitric acid, H2O, 1 M NaHCO3, brine and dried (Na2SO4). The citric acid wash was made basic with saturated NaHCO 3 and then extracted with CH 2 C 12. The extract was dried over Na2SO4 and the solvent was removed under vacuum to yield 1.10 g of 4- (4-methoxybenzenesulfonyl) -1- [2- (4-methylpiperazin-1-yl) acetyl] -2.3.4, 5 -tetrahydro-lH- [1,4] benzodiazepin-3-carboxylate methyl as a white crystal.
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 was removed under vacuum after each addition. The solid was dried at 65 ° C under vacuum for 6 hours to yield 1.1 g of 4- (4-methoxy-benzenesulfonyl) -1- [2- (4-methylpiperazin-1-yl) acetyl] -2.3.4 , Potassium 5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylate as a white solid.
Reference Example 193 methyl l-acetyl-4- (4-hydroxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylate To a cooled solution (0 ° C) of 2.0 g (4.78 mmol) of l-acetyl-4- (4-methoxybenzenesulfonyl) -2, 3, 4, 5-tetrahydro-1H- [1,4] benzodiazepin-3 Methyl carboxylate in 14 ml of CHC12 was added dropwise to 143.3 ml (14.3 mmol) of a 1.0 molar solution of BBr3 in CH2C12. The mixture was stirred at room temperature for 1.5 hours. Ice and H20 were added to the reaction mixture and the insolubles were removed by filtration. The filtrate was diluted with CH2C12 and H20 and the CH2C12 layer was separated, washed with brine and dried (Na2SO4). The solvent was removed under vacuum to yield 1.5 g of a white foam. The solid was chromatographed on silica gel with hexane-ethyl acetate (1: 1) as solvent to produce a foam which was dried under vacuum to yield 0.52 g of the product as a white foam; Analysis Calculated for C19H20N2O6S: C, 56.4; H, 5.0; N, 6.9; Found: C, 55.1; H, 4.7; N, 6.5.
Reference Example 199 4- (4-hydroxybenzenesulfonyl) -1- (2-thienylcarbonyl) -2, 3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl To a solution of 4.0 g (8.22 mmol) of 4- (4-methoxybenzenesulfonyl) -1- (2-thienylcarbonyl) -2,4,5,5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylate of methyl in 17 ml of CH2Cl2 cooled to 0 ° C, 16.4 ml (16.44 mmol) of 1.0 molar solution of boron tribromide in CH2C1 was slowly added. The mixture was stirred at room temperature overnight and was diluted with CH2C12. The mixture was filtered and the solid was washed with CHC12 and H20. The filtrate was diluted with H20 and the organic layer was separated. The solvent was removed under vacuum and the solid was subjected to chromatography on silica gel with hexane-ethyl acetate (1: 1) as solvent to yield 0.80 g of whitish foam.; Mass spectrum (ES) 473.5 (M + H); Analysis Calculated for C22H2oN206S2: C, 55.9; H, 4.3; N, 5.9. Found: C, 54.5; H, 4.4; N, 5.5.
Reference Example 200 l-benzoyl-4- (4-hydroxybenzenesulfonyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl To a solution of 9.8 g (20.39 mmol) of 1-benzoyl-4- (4-methoxy-benzenesulfonyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] benzodiazepine in 50 ml of CH2C12, cooled at 0o, 40.8 ml (40.8 mmol) of a 1.0 molar solution of BBr3 in CH2C12 was slowly added. The mixture was stirred under nitrogen at room temperature overnight. Ice and H2O were added and the mixture was diluted with CH2Cl2. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts (CH2Cl2 + ethyl acetate) were concentrated under vacuum and the residue was dissolved in ethyl acetate. The solution was washed with H20, brine and dried (Na2S04). The solution was filtered through a thin pad of aqueous magnesium silicate and the filtrate was concentrated to dryness. The residue was chromatographed on silica gel with hexane-ethyl acetate as solvent to yield 8 g of the product as a whitish foam; Mass spectrum (ES) 467 (M + H); Analysis Calculated for C24H22N206S: C, 61.8; H, 4.8; N, 6.0 Found: C, 61.3; H, 4.6; N, 5.8; Using the method described in Reference Examples 198-200, the following methyl-1-substituted-4-hydroxybenzenesulfonyl) -2,4,5,5-tetrahydro-1H- [1,4] benzodiazepin-3 can be prepared carboxylates.
Reference Example 201 4- (4-hydroxybenzenesulfonyl) -1- (4-methylphenylsulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid methyl ester.
Reference Example 202 methyl 1-methanesulfonyl-4- (4-hydroxybenzenesulfonyl) -2, 3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylate Reference Example 203 Methyl 4- (4-hydroxybenzenesulfonyl) -1- (3-pyridinylcarbonyl) 2,3,4,5-tetrahydro-lH- [1,] benzodiazepine-3-carboxylate Reference Example 204 - (4- hydroxybenzenesulfonyl) -1- (4-pyridinylcarbonyl-2, 3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl Reference Example 205 1- (4-biphenylcarbonyl) -4- (4-hydroxybenzenesulfonyl) -2, 3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl Reference Example 206 4- (4-hydroxybenzenesulfonyl) -1- (propan-1-sulfonyl) -2, 3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl Reference Example 207 - ([1,1'-biphenyl] -2-carbonyl) -4- (4-hydroxybenzenesulfonyl) -2, 3,, 5-tetrahydro-lH- [1,4] benzodiazepin-3 methyl carboxylate Reference Example 208 1- (3-Fluorobenzoyl) -A- (4-hydroxybenzenesulfonyl) -2, 3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl Reference Example 209 4- (4-hydroxybenzenesulfonyl) -1- (2-methyl-5-fluorobenzoyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl ester Reference Example 210 4- (4-hydroxybenzenesulfonyl) -1- (2-methyl-3-fluorobenzoyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl ester Reference Example 211 4- (4-hydroxybenzenesulfonyl) -1- (3-phenylpropionyl) -2, 3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl Reference Example 212 4- (4-hydroxybenzenesulfonyl) -1- (2-trifluoromethyl-benzoyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid methyl ester Reference Example 213 1- (2-Chloro-6-trifluoromethylbenzoyl) -A - (4-hydroxybenzenesulfonyl) -2,3,4,5-tetrahydro-1H- [1,4] -enzydiazepin-3-carboxylic acid methyl ester Example of Reference 214 1- (4-Fluoro-2-trifluoromethylbenzoyl) -4- (4-hydroxybenzenesulfonyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl Reference Example 215 1- (2-Fluoro-6-trifluoromethylbenzoyl) -A - (4-hydroxybenzenesulfonyl) -2,3,4,5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylic acid methyl ester Reference Example 216 4- (4-hydroxybenzenesulfonyl) -1- (2-methylbenzoyl) -2, 3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl Reference Example 217 4- (4-hydroxybenzenesulfonyl) -1- (2-methyl-6-chlorobenzoyl) -2,3,4,5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylic acid methyl ester Reference Example 218 - (2,4-dimethylbenzoyl) -4- (4-hydroxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid methyl Example Reference 219 - (2,5-dimethylbenzoyl) -4- (4-hydroxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl Reference Example 220 1- (2-Chloro-4-fluorobenzoyl) -A- (4-hydroxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid methyl Reference Example 221 1- (2-Chlorobenzoyl) -A - (4-hydroxybenzenesulfonyl) -2, 3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl Reference Example 222 1- (2-Fluorobenzoyl) -A - (4-hydroxybenzenesulfonyl) -2, 3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl Reference Example 223 1- (2-chloro-6-fluorobenzoyl) -A - (4-hydroxybenzenesulfonyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl Reference Example 224 - (2,3-difluorobenzoyl) -4- (4-hydroxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl Reference Example 225 1- (2,4-dichlorobenzoyl) -4- (4-hydroxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl Reference Example 226 1- (2,3-dichlorobenzoyl) -A- (4-hydroxybenzenesulfonyl) -2, 3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl Reference Example 227 1- (2, 5-dichlorobenzoyl) -4- (4-hydroxybenzenesulfonyl) -2, 3, 4, 5- tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl Reference Example 228 4- (4-hydroxybenzenesulfonyl) -1- (2-methylthiobenzoyl) -2, 3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl Reference Example 229 - (4-hydroxybenzenesulfonyl) -1- (3-methyl-2-thienylcarbonyl) -, 3,4, 5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl Reference Example 230 - (4-hydroxybenzenesulfonyl) -1- (4-methyl-2-thienylcarbonyl) -, 3,4, 5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl Reference Example 231 - (3-chloro-2-thienylcarbonyl) -A - (4-hydroxybenzenesulfonyl) -, 3,4, 5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl Reference Example 232 - (2-furanylcarbonyl) -4- (4-hydroxybenzenesulfonyl) -2, 3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl Reference Example 233 - methyl (4-hydroxybenzenesulfonyl) -1- (3-methyl-2-furanylcarbonyl) -, 3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylate Reference Example 234 4- (4-hydroxybenzenesulfonyl) -l- (4-methyl-2-furanylcarbonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl Reference Example 235 1- (5-Chloro-2-furanylcarbonyl) -4- (4-hydroxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid methyl ester Reference Example 236 1- (5-Chloro-2-thienylcarbonyl) -4- (4-hydroxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid methyl ester Example of Reference 237 l-propionyl-4- (4-hydroxybenzenesulfonyl) -2, 3, 4, 5-tetrahydro-1H- [1,4] benzodiazepin-3-carboxylic acid methyl Reference Example 238 l-hexanoyl-4- (4-hydroxybenzenesulfonyl) -2,3,4,5-tetrahydro-1H- [1,4] benzodiazepin-3-carboxylic acid methyl Reference Example 239 4- (4-hydroxybenzenesulfonyl) -1- (3-thienylcarbonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl ester Reference Example 240 1- (3-furanylcarbonyl) -A - (4-hydroxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl Reference Example 241 1- (Acetylaminoacetyl) -A - (4-hydroxybenzenesulfonyl) -2, 3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid methyl Reference Example 242 1- (N, N-dimethylaminoacetyl) -A - (4-hydroxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid methyl ester Reference Example 243 - (cyclopropylcarbonyl) -4- (4-hydroxybenzenesulfonyl) -2, 3,4,5-tetrahydro-lH- [1,4] benzodiazepine methyl Reference Example 244 Methyl 4- (4-hydroxybenzenesulfonyl) -1- (trifluoroacetyl) -2, 3,4,5-tetrahydro-lH- [1,4] benzodiazepine Reference Example 245 l-acetyl-4- (4 -but-2-ynyloxybenzenesulfonyl) -2, 3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl To a stirred solution of 3.73 g (14.22 mmol) of triphenylphosphine in 80 ml of toluene-tetrahydrofuran (3: 1) was added 1.06 ml (14.22 mmol) of 2-butyn-1-ol and 5.0 g (12.36 mmol) of -ethyl-4- (4-hydroxybenzenesulfonyl) -2,4,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl ester. To this solution under nitrogen, 2.24 ml (14.22 mmol) of diethyl azodicarboxylate was slowly added dropwise. The mixture was stirred at room temperature overnight and concentrated to dryness under vacuum. To the residue was added ethyl acetate and H20 and the solid was removed by filtration. The filtrate was concentrated under vacuum and extracted with CH2Cl2. The extract was washed with brine, dried (NaS04) and concentrated to dryness under vacuum. The residue was triturated with ethyl acetate-hexane to yield 6.5 g of the solid. This solid was chromatographed on silica gel with ethyl acetate-hexane (1: 1) as solvent to yield 3.9 g of the white solid; Mass spectrum (ES) 4.57.5 (M + H); Analysis Calculated for C23H24 206S: C, 60.5; H, 5.3; N, 6.1. Found: C, 60.2; H, 5.2; N, 6.2.
Reference Example 246 methyl l-benzoyl-4- (4-but-2-ynyloxybenzenesulfonyl) -2, 3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylate To a stirred solution of 1.26 g (4.82 mmol) of triphenylphosphine in 15 ml of toluene-tetrahydrofuran (4: 1) under nitrogen was added 360 μL (4.82 mmol) of 2-butyn-1-ol and 1.5 g of (3.22 mmol). ) of methyl l-benzoyl-4- (4-hydroxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] enzodiazepin-3-carboxylate. To the stirred mixture was slowly added 759 μL of diethyl azodicarboxylate and the clear reddish solution was stirred overnight at room temperature. The solvent was removed under vacuum and CH2C12 was added. The CH2C12 was washed with H20 and brine, dried (Na2SO4) and the solvent was removed. The residue was chromatographed on silica gel with hexane-ethyl acetate (1: 1) to yield 1.65 g of white solid; Mass spectrum (ES) 519 (M + H); Analysis Calculated for C28H26 2? 6S: C, 64.9; H, 5.1; N, 5.4. Found: C, 60.5; H, 5.2; N, 6.9.
Reference Example 247 4- (4-But-2-ynylbenzenesulfonyl) -1- (2-thienylcarbonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl ester To a stirred mixture of 0.475 g (1.81 mmol) of triphenylphosphine, 134.8 μL (1.84 mmol) of 2-butyn-1-ol and 0.74 g of 4- (4-hydroxystenesulfonyl) -1- (2-thienylcarbonyl) -2, 3,4,5-Tetrahydro-lH [1,4] benzodiazepine-2-carboxylic acid methyl ester in 7 ml of toluene and 2 ml of tetrahydrofuran was slowly added 285 μL (1.81 mmol) of diethyl azodicarboxylate. The mixture was stirred overnight at room temperature and 0.475 g of triphenylphosphine, 125 μL of 2-butyn-1-ol and 0.285 of diethyl azodicarboxylate were added to the mixture. The mixture was stirred for 2.5 hours at room temperature and the solvent was removed. CH 2 Cl 2 was added to the residue and the mixture was washed with H 2 O and brine. The CH2C1 layer was dried (Na2SO4) and the solvent was removed to yield 2.0 g of a yellow oil. Chromatography on silica gel with hexane-ethyl acetate (1: 1) gave 1.0 g of whitish foam; Mass spectrum (ES) 525.6 (M + H); Analysis Calculated for C26H2N2? 6S2: C, 59.5; H, 4.6; N, 5.3. Found: C, 56.1; H, 4.9; N, 7.3) Using the method described in Reference Examples 245-247, the following 1-substituted-4- (4-but-2-ynyloxybenzenesulfonyl) -2,3,4,5-tetrahydro-1H- can be prepared [1,4] Methyl benzodiazepine-3-carboxylate and l-substituted-4- (4- [4-substituted-but-2-ynyloxy] -enzylsulfonyl) -2,3,4,5-tetrahydro-lH- [1 , 4] methyl benzodiazepine-3-carboxylates.
Reference Example 248 methyl l-butoxyacetyl-4- (4-but-2-ynyloxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylate Reference Example 249 4- (4-But-2-ynyloxybenzenesulfonyl) -1- (4-methylphenylsulfonyl) -2,4,4,5,5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylic acid methyl ester Reference Example 250 l-Methanesulfonyl-4- (4-but-2-ynyloxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl Reference Example 251 methyl l-benzoyl-4- (4- [4-methoxybut-2-ynyloxy] benzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,] benzodiazepine-3-carboxylate Reference Example 252 l-Acetyl-4- (4- [4-methoxybut-2-ynyloxy] benzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid methyl ester Reference Example 253 4- [4-But-2-ynyloxy] benzenesulfonyl) -1- (3-pyridinylcarbonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid methyl ester Reference Example 254 4- (4-pent-2-ynyloxybenzenesulfonyl) -1- (3-pyridinylcarbonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid methyl ester Reference Example 255 4- (4- [4-methoxybut-2-ynyloxy] benzenesulfonyl) -1- (2-thienylcarbonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3 Methyl carboxylate Reference Example 256 - (4-But-2-ynyloxybenzenesulfonyl) -1- (4-pyridinylcarbonyl) -, 3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid methyl Reference Example 257 1- (4-biphenylcarbonyl) -A- (4-but-2-ynyloxybenzenesulfonyl) -, 3,4, 5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl Reference Example 258 4- (4- [4-methoxybut-2-ynyloxy] enzylsulfonyl) -1- (propan-1-sulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin- 3- methyl carboxylate Reference Example 259 1- ([1,1 '-biphenyl] -2-carbonyl) -4- (4- [4-methoxybut-2-ynyloxy] benzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1, 4] methyl benzod? Azepine-3-carboxylate Reference Example 260 17 1- (3-Fluorobenzoyl) -4- (4-pent-2-ynyloxybenzenesulfonyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl Reference Example 261 4- (4- [4-ethoxybut-2-ynyloxy] benzenesulfonyl) -1- (2-methyl-3-fluorobenzoyl) -2,3,4,5-tetrahydro-1H- [1,4] methyl benzodiazepin-3-carboxylate Reference Example 262 4- (4- [4-dimethylaminobut-2-ynyloxy] benzenesulfonyl) -1- (2-methyl-3-fluorobenzoyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] methyl benzodiazepin-3-carboxylate Reference Example 263 4- (4-But-2-ynyloxybenzenesulfonyl) -1- (2-trifluoromethylbenzoyl) -2,3,4,5-hydroxy-1H- [1,4] benzodiazepine-3-carboxylate Reference Example 264 1- (2-chloro-6-trifluoromethylbenzoyl) -A- (4-pent-2-ynyloxybenzenesulfonyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylate Methyl Reference Example 265 1- (4-Fluoro-2-trifluoromethylbenzoyl) -4- (4- [4-methoxybut-2-ynyloxy] benzenesulfonyl) -2,4,4,5-tetrahydro-lH- [1, 4] methyl benzodiazepin-3-carboxylate Reference Example 266 1- (2-Fluoro-6-trifluoromethylbenzoyl) -4- (4-pent-2-ynyloxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylate of methyl Reference Example 267 4- (4-but-2-ynyloxybenzenesulfonyl) -1- (2-methyl-6-chlorobenzoyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylate of methyl Reference Example 268 1- (2,4-Dimethylbenzoyl) -4- (4- [4-methoxybut-2-ynyloxy] benzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,] benzodiazepin-3 -Methyl carboxylate Reference Example 269 1- (2,5-dimethylbenzoyl) -4- (4- [4-methoxybut-2-ynyloxy] benzenesulfonyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] benzodiazepin- 3-methyl carboxylate Reference Example 270 1- (2-Chloro-4-fluorobenzoyl) -4- (4- [4-methoxybut-2-ynyloxy] benzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] methyl benzodiazepin-3-carboxylate Reference Example 271 1- (2-chlorobenzoyl) -A- (A - [4-methoxybut-2-ynyloxy] benzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3 methyl carboxylate Reference Example 272 1- (2-Chlorobenzoyl) -4- (4-pent-2-ynyloxybenzenesulfonyl) -, 3,4, 5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid methyl Reference Example 273 1- (2-fluorobenzoyl) -A - (A - [4-methoxybut-2-ynyloxy] benzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3 Methyl carboxylate Reference Example 274 1- (2-Chloro-6-fluorobenzoyl) -A- (A - [4-methoxybut-2-ynyloxy] benzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1 , 4] methyl benzodiazepin-3-carboxylate Reference Example 275 1- (2,3-difluorobenzoyl) -4- (4- [4-methoxybut-2-ynyloxy] benzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin- 3-methyl carboxylate Reference Example 276 1- (2, -dichlorobenzoyl) -A- (A- [4-methoxybut-2-ynyloxy] benzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3 -Methyl carboxylate Reference Example 277 - (2,4-dichlorobenzoyl) -4- (4-pent-2-ynyloxybenzenesulfonyl) -, 3,4, 5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl Reference Example 278 1- (2,3-dichlorobenzoyl) -A - (A - [4-methoxybut-2-ynyloxy] benzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin- 3-methyl carboxylate Reference Example 279 1- (2, 5-dichlorobenzoyl) -4- (4- [4-hydroxybut-2-ynyloxy] benzenesulfonyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] methyl benzodiazepin-3-carboxylate Reference Example 280 1- (benzoyl) -4- (4-pent-2-ynyloxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,] benzodiazepin-3-carboxylic acid methyl ester Reference Example 281 4- (4-But-2-ynyloxybenzenesulfonyl) -1- (2-methylthiobenzoyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid methyl ester Reference Example 282 4- (4-But-2-ynyloxybenzenesulfonyl) -1- (3-methyl-2-thienylcarbonyl) -2,3,4,5-tetrahydro-lH- [1,] benzodiazepine-3-carboxylate of methyl Reference Example 283 4- (4- [4-hydroxybut-2-ynyloxy] benzenesulfonyl) -1- (4-methyl-2-thienylcarbonyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] methyl benzodiazepin-3-carboxylate Reference Example 284 1- (3-Chloro-2-thienylcarbonyl) -4- (4- [4-dimethylaminobut-2-ynyloxy] benzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] methyl benzodiazepin-3-carboxylate Reference Example 285 1- (2-furanylcarbonyl) -4- (4- [4-methylaminobut-2-ynyloxy] benzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3 methyl carboxylate Reference Example 236 4- (4-but-2-ynyloxybenzenesulfonyl) -1- (3-methyl-2-furanylcarbonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylate of methyl Reference Example 287 4- (4- [4-but-2-ynyloxybenzenesulfonyl) -1- (-4-methyl-2-furanylcarbonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine -3- Methyl carboxylate Reference Example 288 1- (5-chloro-2-furanylcarbonyl) -4- (4- [4-ethoxybut-2-ynyloxy] benzenesulfonyl) -2,3,4,5-tetrahydro-lH - [1,4] benzodiazepin-3-carboxylic acid methyl Reference Example 289 1- (5-chloro-2-thienylcarbonyl) -A- (A- [4-hydroxybut-2-ynyloxy] benzenesulfonyl) -2,3,4,5-tetrahydro-1H- [1,4] methyl benzodiazepin-3-carboxylate Reference Example 290 l-Propionyl-4- (4- [4-hydroxybut-2-ynyloxy] benzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid methyl ester Reference Example 291 l-hexanoyl-4- (4- [4-methoxybut-2-ynyloxy] enzylsulfonyl) - 2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid methyl ester Reference Example 292 Methyl 4- (4-but-2-ynyloxybenzenesulfonyl) -1- (propionyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylate Reference Example 293 4- (4-But-2-ynyloxybenzenesulfonyl) -1- (3-thienylcarbonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid methyl Reference Example 294 4- (4-But-2-ynyloxybenzenesulfonyl) -1- (3-furanylcarbonyl) -2,3,4,5-tetrahydro-lH- [1,] benzodiazepine-3-carboxylic acid methyl ester Reference Example 295 - (ethoxyacetyl) -A - (A - [4-methoxybut-2-ynyloxy] benzenesulfonyl) 2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid methyl ester Reference Example 295 1- (Acetylaminoacetyl) -4- (4-but-2-ynyloxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,] enkeodiazepine-3-carboxylic acid methyl ester Reference Example 297 1- (N, N-dimethylaminoacetyl) -4- (4- [4-methoxybut-2-ynyloxy] benzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin- 3-methyl carboxylate Reference Example 298 1- (Cyclopropylcarbonyl) -A- (A - [4-methoxybut-2-ynyloxy] benzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylate methyl Reference Example 299 1- (cyclobutylcarbonyl) -4- (4-but-2-ynyloxybenzenesulfonyl) -2,2,4,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid methyl ester Reference Example 300 4- (4-But-2-ynyloxybenzenesulfonyl) -1- (trifluoroacetyl) -2, 3,, 5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl ester Reference Example 301 Sodium 4-but-2-ynyloxybenzenesulfonate To a solution of 52.35 g (0.225 mol) of sodium 4-hydroxybenzenesulfonate salt in 1 L of isopropanol and 225 mL of a 1.0 N solution of sodium hydroxide was added. 59. 96 g (0.45 mol) of l-bromo-2-butine. The resulting mixture was heated at 70 ° for 15 h and then the isopropanol was removed by evaporation in vacuo. The resulting white precipitate was collected by filtration, washed with isopropanol and ether and dried under vacuum to yield 56.0 g (100%) of sodium salt of 4-but-2-ynyloxybenzenesulphonic acid as a white solid.
Reference Example 302 4-But-2-ynyloxybenzenesulfonyl chloride To a 0o solution of 43.8 mL (0.087 mol) of oxalyl chloride in 29 mL of dichloromethane was added 6.77 mL (0.087 mol) of DMF followed by 7.24 g (0.029 mol) of sodium salt of 4-butyl acid. -2-iniloxibencenesulfónico. The reaction mixture was stirred for 10 minutes at 0 ° C then allowed to warm to room temperature and stirred for 2 days. The reaction was then poured onto ice and extracted with 150 mL of hexanes. The organics were washed with water and brine, dried over Na 2 SO 4, filtered and concentrated in vacuo to provide 6.23 g (88%) of the sulfonyl chloride as a yellow solid; p.f. 63-65 ° C; Mass spectrum (El) 243.9 (M +).
Reference Example 303 But-2-inyloxybenzene To a solution of 6.14 g (0.023 mol) of triphenylphosphine dissolved in 100 mL of benzene and 40 mL of THF was added 1.64 g (0.023 mol) of 2-butin-1-ol. After five minutes 2.00 g (0.021 mol) of phenol, dissolved in 10 ml of THF, was added to the reaction followed by 3.69 ml (0.023 mol) of diethyl azodicarboxylate. The resulting reaction mixture was stirred for 18 h at room temperature and then concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate / hexanes (1:10) to provide 2.18 g (70%) of the desired butynyl ether as a clear liquid; Mass spectrum (Electrorocium) 146.0 (MH +) Reference Example 304 4-But-2-ynyloxybenzenesulfonyl chloride To a solution of 0.146 g (1.0 mmol) of but-2-ynyloxybenzene in 0.3 mL of dichloromethane in an acetone / ice bath under N2 was added dropwise a solution of 0.073 mL (1.1 mmol) of chlorosulfonic acid in 0.3 mL of dichloromethane. After the addition was complete, the ice bath was removed and the reaction was stirred at room temperature for 2 hours. To the reaction, 0.113 mL (1.3 mmol) of oxalyl chloride was added dropwise, followed by 0.015 mL of DMF. The reaction was refluxed for 2 h and then diluted with hexane and poured into ice water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo to provide 0.130 mg (53%) of the desired product as a light brown solid. The present invention may be comprised in other specific forms without departing from the spirit or essential attributes thereof and, therefore, reference should be made to the appended claims, rather than to the above specification, as indicating the scope of the invention.
Example 1 l-Acetyl-4- (4-but-2-ynyloxybenzenesulfonyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid hydroxyamide To a mixture of 6.0 g (13.14 mmol) of l-acetyl-4- (4-but-2-ynyloxy-benzenesulfonyl) -2, 3,4, 5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylic acid methyl ester in 66 ml of tetrahydrofuran was added 17.1 (17.1 mmol) of 1 N KOH. The mixture was stored at room temperature for 3 hours and concentrated to dryness. Toluene was added several times and the solvent was removed under vacuum after each addition. The residue was dried under vacuum at 75 ° C for 2 days to yield 6.5 g of the potassium salt of l-acetyl-4- (4-but-2-ynyloxybenzenesulfonyl) -2, 3, 4, 5-tetrahydro- lH- [1,4] benzodiazepine-3-carboxylic; Analysis Calculated for C22H22N6O6SK: C, 55.0; H, 4; N, 5.8. Found C; 52.0, H, 4.5; N, 5.6. The preceding potassium salt was converted to the hydroxamide of 3-carboxylic acid as follows: To a stirred and cooled solution (0o) of 26.1 ml (52.36 mmol) of oxalyl (2.0 M solution in CH2C12) in 80 ml of CH2C12 ) 4.05 ml (52.36 mmol) of N, N-dimethylformamide was slowly added. To this viscous mixture was added a solution of the potassium salt of the above 3-carboxylic acid in 30 ml of N, N-dimethylformamide and the mixture was stirred at room temperature for 1.5 hours and cooled (0o) (solution to). A solution of 11.89 ml (0.194 ml) of hydroxylamine (50% in H20) in 60 ml of tetrahydrofuran was cooled in an ice bath (solution B). Solution A was slowly added to the cold solution B and the mixture was allowed to warm to room temperature and stirred overnight. The mixture was diluted with 200 ml of CH2C12 and washed with 100 ml of H20. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The organic layer and the extract were combined, and the solvent was removed under vacuum. The residue was diluted with 300 ml of ethyl acetate and the solution was washed with 20 ml each of H2O, 2N citric acid, H0 and with 120 ml of NaHCO3 (2 times) and 120 ml of brine. The solution was dried (a2SO4) and the solvent was removed under vacuum to produce a foam. Crystallization from ethyl acetate gave 2.5 g of white crystals, m.p. 167-169 ° C; Analysis Calted for C2H23N306S: C, 57.8; H, 5.1; N, 9.2. Found C; 57.5, H, 5.2; N, 8.9.
Example 2 4- (4-But-2-ynyloxybenzenesulfonyl) -1- (2-thienylcarbonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid hydroxyamide To a mixture of 0.87 g (1.66 mmol) of 4- (4-but-2-ynyloxy-benzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid methyl ester in 4 ml or tetrahydrofuran was added 2.2 ml (2.2 mmol) or 1 N KOH. The solution was stirred at room temperature for 2.5 hours and then concentrated to dryness. Toluene was added repeatedly and the solvent was removed after each addition. The residue was dried at 75 ° C for 60 hours to produce 0.99 of a foam; Analysis Calted for C25H22N2? 6S2K: C, 54.7; H, 3.9; N, 5.1. Found C; 47.8, H, 4.4; N, 6.0 To a cooled (0o) solution of 2.66 ml (5.3 mmol) of oxalyl chloride (2.0 M solution in CH 2 Cl 2) in 8 ml of CH 2 C 12 was slowly added 412 μL of N, N-dimethylformamide. To this solution was added a solution of 0.73 g (1.33 mmol) of the preceding potassium salt in 3 ml of N, N-dimethylformamide (solution A). A solution of 1.22 ml (19.95 mmol) of hydroxylamine (50% in H20) in 6 ml of tetrahydrofuran was cooled to 0 ° (solution B). The cooled solution A was slowly added to the cooled solution B and the mixture was allowed to warm to room temperature and stir overnight. The mixture was diluted with CH2Cl2 and H20 and the organic layer was separated. The aqueous layer was extracted with CH2C1 and the organic layer and extract were combined and concentrated to dryness. The residue was diluted with ethyl acetate and the solution was washed with 2N citric acid, H20, 1 N NaHC03, brine and dried (Na2SO4). The solvent was removed to yield 0.65 g of the solid. The solid was chromatographed on silica gel with hexane-ethyl acetate (1: 1) and then 10% CH30H in ethyl acetate to yield 0.20 g of a white foam: Mass spectrum (ES) 526.4 (M + H ); Analysis Calted for C25H23N302S2: C, 57.1; H, 4.4; N, 8.0. Found C; 56.9, H, 4.3; N, 7.8.
Example 3 l-Benzoyl-4- (4-but-2-ynyloxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] -benzodiazepine-3-carboxylic acid hydroxyamide To a mixture of 1.5 g (2.89 mmol) of l-benzoyl-4- (4-but-2-hydroxy-benzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3 Methyl carboxylate in 7 ml of tetrahydrofuran was added 3.8 ml (3.8 mmol) of 1 N KOH.
The solution was stirred for 2 hours and the mixture was concentrated to dryness. Toluene was added repeatedly and the solvent was removed after each addition to produce a solid. The solid was dried at 75 ° C under vacuum to yield 1.6 g of the potassium salt of l-benzoyl-4- (4-but-2-inylbenzenesulfonyl) -2, 3, 4, 5-tetrahydro-lH- [ 1,4] benzodiazepine-3-carboxylic acid as a white foam; Mass spectrum (ES) 505.2 (M + H): Analysis Calted for C27H24N206SK: C, 61.9; H, 4.5; N, 5.4. Found C; 5.22, H, 4.6; N, 5.9. The preceding potassium salt was converted to the hydroxamide of 3-carboxylic acid as follows: To a stirred and cooled solution (0o) of 4.8 ml (9.6 mmol) of oxalyl chloride (2.0 M solution in CH2C12) in 14 ml of CH2C12) was added 370 μL of N slowly, N-dimethylformamide. To this viscous mixture was added a cooled solution of the potassium salt of the above 3'-carboxylic acid in 5 ml of N, N-dimethylformamide. The mixture was stirred at 0 ° for 1.5 hours (solution A). A solution of 2.2 ml (35.9 mmol) of hydroxylamine (50% in H20) in 10 ml of tetrahydrofuran was cooled in an ice bath (0o) (solution B). The cold solution A was slowly added to the stirred cold solution B. The mixture was allowed to warm to room temperature and stir overnight. The mixture was diluted with CH2C1 and H20 and the organic layer was separated. The organic layer was concentrated and the residue was diluted with ethyl acetate and washed with 1M NaHCO 3, H 2 O, brine and dried (a 2 SO 4). The solvent was removed to yield 2.0 g of a solid. Chromatography on silica gel with 10% CH3OH in ethyl acetate gave 0.96 g of the solid. The solid was dissolved in hexane-ethyl acetate (1: 1) and the solution was filtered through diatomaceous earth and then through gel (500 ml wash). The product was then eluted from silica gel with 10% CH3OH in ethyl acetate to yield 0.593 g of the white solid; Mass spectrum (ES) 520 (M + H); Analysis Calculated for C2-7H25N3O6S: C, 62.4; H, 4.9; N, 8.1. Found C; 61.2, H, 4.9; N, 7.9. Using the method described in Examples 1-3, the following hydroxyamides of 1-substituted-4- (4-but-2-ynyloxybenzenesulfonyl) -2,4,5,5-tetrahydro-lH- [1,4] can be prepared ] benzodiazepine-3-carboxylic acid and hydroxyamides of l-substituted-4- (4- [4-substituted-but-2-ynyl-oxy] benzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1, 4] benzodiazepine-3-carboxylic acid.
Example 4 l-Butoxyacetyl-4- (4-but-2-ynyloxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid hydroxyamide Example 5 Hydroxyamide of 4-acid (4-But-2-ynyloxybenzenesulfonyl) -1- (4-methylphenylsulfonyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid Example 6 4- (4-But-2-ynyloxybenzenesulfonyl) hydroxyamide) -l-methanesulfonyl-2, 3, 4, 5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid Example 7 l-Benzoyl-4- (4- [4-methoxybut-2-ynyloxy] benzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid hydroxyamide Example 8 l-Acetyl-4- (4- [4-methoxybut-2-ynyloxy] benzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid hydroxyamide Example 9 4- [4-But-2-ynyloxy] benzenesulfonyl) -1- (3-pyridinylcarbonyl) -2,4,4,5,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid hydroxyamide Example 10 4- (4-Pent-2-ynyloxy-benzenesulfonyl) -1- (3-pyridinylcarbonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid hydroxyamide Example 11 4- (4- [4-Methoxybut-2-ynyloxy] benzenesulfonyl) -1- (2-thienylcarbonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3 hydroxyamide -carboxylic Example 12 4- (4-But-2-ynyloxybenzenesulfonyl) -1- (4-pyridinylcarbonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid hydroxyamide Example 13 1- (4-Biphenylcarbonyl) -4- (4-but-2-ynyloxybenzenesulfonyl) -2,4,4,5,5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylic acid hydroxyamide Example 14 Hydroxyamide 4- (4- [4-methoxybut-2-ynyloxy] benzenesulfonyl) -1- (propan-1-sulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3- acid carboxylic Example 15 Hydroxyamide of 1- ([1,1'-biphenyl] -2-carbonyl) -4- (4- [4-methoxybut-2-ynyloxy] benzenesulfonyl) -2, 3, 4, 5-tetrahydro-1H hydroxyamide - [1,4] benzodiazepine-3-carboxylic acid Example 16 1- (3-Fluorobenzoyl) -4- (4-pent-2-ynyloxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid hydroxyamide Example 17 4- (4- [4-Ethoxybut-2-ynyloxy] benzenesulfonyl) -1- (2-methyl-3-fluorobenzoyl) -2,3,4,5-tetrahydro-lH- [1,4-Hydroxyamide] ] benzodiazepine-3-carboxylic acid EXAMPLE 18 4- (4- [4-Dimethylaminobut-2-ynyloxy] benzenesulfonyl) -1- (2-methyl-3-fluoro-benzoyl) -2,3,4,5-tetrahydro-1H- [1] Hydroxyamide , 4] benzodiazepine-3-carboxylic acid Example 19 4- (4-But-2-ynyloxybenzenesulfonyl) -1- (2-trifluoromethylbenzoyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid hydroxyamide Example 20 1- (2-Chloro-6-trifluoromethylbenzoyl) -4- (4-pent-2-ynyloxybenzenesulfonyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] benzodiazepin-3- hydroxyamide carboxylic Example 21 1- (4-Fluoro-2-trifluoromethylbenzoyl) 4- (4- [4-methoxybut-2-ynyloxy] benzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] Hydroxyamide benzodiazepine-3-carboxylic acid Example 22 1- (2-Fluoro-6-trifluoromethylbenzoyl) 4- (4-pent-2-ynyloxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid hydroxyamide Example 23 4- (4-But-2-ynyloxybenzenesulfonyl) -1- (2-methyl-6-chlorobenzoyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] benzodiazepin-3-hydroxyamide carboxylic acid 5 Example 24 1- (2, -dimethylbenzoyl) -4- (4- [4-methoxybut-2-ynyloxy] benzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] hydroxyamide benzodiazepine-3-carboxylic acid 10 Example 25 Hydroxyamide of 1- (2,5-dimethylbenzoyl) -4- (4- [4-methoxybut-2-ynyloxy] benzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid '15 Example 26 1- (2-Chloro-4-fluorobenzoyl) -4- (4- [4-methoxybut-2-ynyloxy] benzenesulfonyl) -2,3 hydroxyamide 4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid Example 27 Hydroxyamide 1- (2-chlorobenzoyl) -4- (4- [4-methoxybut-2-ynyloxy] benzenesulfonyl) -2 , 3,4, 5-tetrahydro-lH- [1, 4] benzodiazepine-3-carboxylic acid Example 28 1- (2-Chlorobenzoyl) -4- (4-pent-2-ynyloxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid hydroxyamide Example 29 1- (2-Fluorobenzoyl) -4- (4- [4-methoxybut-2-ynyloxy] benzenesulfonyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] benzodiazepin-3 hydroxyamide -carboxylic Example 30 Hydroxyamide 1- (2-chloro-6-fluorobenzoyl) -4- (4- [4-methoxybut-2-ynyloxy] benzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4 ] benzodiazepine-3-carboxylic acid Example 31 1- (2,3-difluorobenzoyl) -4- (4- [4-methoxybut-2-ynyloxy] benzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine hydroxyamide -3-carboxylic acid Example 32 1- (2,4-Dichlorobenzoyl) -4- (4- [4-methoxybut-2-ynyloxy] benzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1] Hydroxyamide , 4] benzodiazepine-3-carboxylic acid EXAMPLE 33 1- (2,4-Dichlorobenzoyl) -4- (4-pent-2-ynyloxybenzenesulfonyl) -2,3,4,5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylic acid hydroxyamide EXAMPLE 34 1- (2,3-Dichlorobenzoyl) -4- (4- [4-methoxybut-2-ynyloxy] benzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine hydroxyamide -3-carboxylic acid Example 35 Hydroxyamide 1- (2, 5-dichlorobenzoyl) -4- (4- [4-hydroxybut-2-ynyloxy] benzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine -3-carboxylic acid Example 36 1- (Benzoyl) -4- (4-pent-2-ynyloxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid hydroxyamide Example 37 4- (4-But-2-ynyloxybenzenesulfonyl) -1- (2-methylthiobenzoyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid hydroxyamide Example 38 4- (4-But-2-ynyloxybenzenesulfonyl) -1- (3-methyl-2-thienylcarbonyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] benzodiazepin-3-hydroxyamide carboxylic Example 39 4- (4- [4-Hydroxybut-2-ynyloxy] benzenesulfonyl) -1- (4-methy1-2-thienylcarbonyl) -2,3,4,5-tetrahydro-lH- [1,4 acid hydroxyamide ] benzodiazepine-3-carboxylic acid Example 40 1- (3-Chloro-2-thienylcarbonyl) -4- (4- [4-dimethylaminobut 2-ynyloxy] benzenesulfonyl) -2-, 3, 4, 5-tetrahydro-1H- [1,4] hydroxyamide benzodiazepine-3-carboxylic acid Example 41 Hydroxyamide of 1- (2-furanylcarbonyl) -4- (4- [4-methylaminobut-2-ynyloxy] benzenesulfonyl) -2,3,4,5-tetrahydro-1H- [1, 4] benzodiazepine-3-carboxylic acid Example 42 4- (4-But-2-ynyloxybenzenesulfonyl) -1- (3-methyl-2-furanylcarbonyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] benzodiazepin-3-hydroxyamide carboxylic Example 43 4- (4-But-2-ynyloxybenzenesulfonyl) -1- (4-methyl-2-furanylcarbonyl) -2,3,4,5,5-tetrahydro-lH- [1,] benzodiazepine-3-carboxylic acid hydroxyamide Example 44 1- (5-Chloro-2-furanylcarbonyl) -4- (4- [4-ethoxybut-2-ynyloxy] benzenesulfonyl) -2, 3, 4, 5-tetrahydro-lH- [1-4] Hydroxyamide ] benzodiazepine-3-carboxylic acid EXAMPLE 45 1- (5-Chloro-2-thienylcarbonyl) -4- (4- [4-hydroxybut-2-ynyloxy] benzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1-4] Hydroxyamide ] benzodiazepine-3-carboxylic acid Example 46 l-Propionyl-4- (4- [4-hydroxybut-2-ynyloxy] benzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid hydroxyamide Example 47 Hydroxyamide of l-hexanoyl-4- (4- [4-methoxybut-2-ynyloxy] benzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid Example 48 4- (4-But-2-ynyloxybenzenesulfonyl) -1- (propionyl) -2, 3,, 5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid hydroxyamide Example 49 4- (4-But-2-ynyloxybenzenesulfonyl) -1- (3-thienylcarbonyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid hydroxyamide Example 50 Hydroxyamide 4- (4-But-2-ynyloxybenzenesulfonyl) -1- (3-furancarbonyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid Example 51 1- (Ethoxyacetyl) -4- (4- [4-methoxybut-2-ynyloxy] benzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid hydroxyamide Example 52 1- (Acetylaminoacetyl) -4- (4-but-2-ynyloxybenzenesulfonyl) -2,3,4,5,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid hydroxyamide Example 53 1- (N, N-dimethylaminoacetyl) -4- (4- [4-methoxybut-2-ynyloxy] benzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine hydroxyamide -3-carboxylic acid Example 54 1- (Cyclopropylcarbonyl) -4- (4- [4-methoxybut-2-ynyloxy] benzenesulfonyl) -2,3,4,5,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid hydroxyamide Example 55 1- (Cyclobutylcarbonyl) -4- (4-but-2-ynyloxybenzenesulfonyl) -2,3,4,5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylic acid hydroxyamide Example 56 4- (4-But-2-ynyloxybenzenesulfonyl) -1- (trifluoroacetyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid hydroxyamide Example 57 4- (4-But-2-ynyloxybenzenesulfonyl) -1- methoxyacetyl-2,4,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid hydroxyamide Example 58 4- (4- [4-Methoxybut-2-ynyloxy] benzenesulfonyl) -1- (3-pyridinylcarbonyl) -2,4,5,5-tetrahydro-lH- [1,4] benzodiazepin-3 hydroxyamide -carboxylic Example 59 4- (4- [4-Hydroxybut-2-ynyloxy] benzenesulfonyl) -1- (4-pyridinylcarbonyl) -2,4,5,5-tetrahydro-lH- [1,4] benzodiazepine hydroxyamide -3-carboxylic acid Example 60 Hydroxyamide 1- (ethoxyacetyl) -4- (4- [4-ethoxybut-2-ynyloxy] benzenesulfonyl) -2,3,4,5-tetrahydro-1H- [1,4] benzodiazepine-3-carboxylic acid hydroxyamide Example 61 1- (Acetylaminoacetyl) -4- (4- [4-methoxybut-2-ynyloxy] benzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid hydroxyamide Example 62 4- (4- [4-Methoxybut-2-ynyloxy] benzenesulfonyl) -1- (3-methyl-2-thienylcarbonyl) -2,3,4,5-tetrahydro-lH- [1,4] hydroxyamide ] benzodiazepine-3-carboxylic acid Example 63 4- (4-But-2-ynyloxybenzenesulfonyl) -1- (3-methoxypropionyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid hydroxyamide Example 64 4- (4-But-2-ynyloxybenzenesulfonyl) -1- (2-chlorobenzoyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid hydroxyamide Example 65 4- (4-But-2-ynyloxybenzenesulfonyl) -1- (2-fluorobenzoyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid hydroxyamide Example 66 4- (4-But-2-ynyloxybenzenesulfonyl) -1- (3-phenoxyacetyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid hydroxyamide Example 67 4- (4-But-2-ynyloxybenzenesulfonyl) -1- [2- (1-pyrazolyl) phenylcarbonyl] -7-methyl-2,3,4,5-tetrahydro-1H- [1] Hydroxyamide , 4] benzodiazepine-3-carboxylic acid Example 68 Hydroxyamide of 4- (4-but-2-ynyloxybenzenesulfonyl) -1- (5-chloro-2-thienylcarbonyl) -2, 3, 4, 5-tetrahydro-lH- [ 1,4] benzodiazepine-3-carboxylic acid Example 69 4- (4-But-2-ynyloxybenzenesulfonyl) -1- (5-chloro-2-furanylcarbonyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] benzodiazepine- hydroxyamide 3-carboxylic Example 70 4- (4- [4-Methoxybut-2-ynyloxy] -benzenesulfonyl) -1-propionyl-2, 3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid hydroxyamide Example 71 4- (4- [4-Methoxybut-2-ynyloxy] benzenesulfonyl) -1- (3-thienylcarbonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzo-diazepin hydroxyamide -3-carboxylic acid Example 72 1- (Aminoacetyl) -4- (4-but-2-ynyloxybenzenesulfonyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid hydroxyamide Example 73 4- (4-But-2-ynyloxy-benzenesulfonyl) -1- (N, N-dimethylaminoacetyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-hydroxyamide carboxylic Example 74 4- (4-But-2-ynyloxybenzenesulfonyl) -1- (cyclohexylcarbonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid hydroxyamide Example 75 l-Methoxyacetyl-4- (4- [4-methoxybut-2-ynyloxy] benzenesulfonyl) -7-methyl-2-, 3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3 hydroxyamide -carboxylic Example 76 l-Benzoyl-4- (4-but-2-ynyloxybenzenesulfonyl) -7-methyl-2,3,4-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid hydroxyamide Example 77 Hydroxyamide 1- (Benzoyl) -4- (4-but-2-ynyloxybenzenesulfonyl) -8-chloro-2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid Example 78 4- (4-But-2-ynyloxybenzenesulfonyl) -1- (2-furanylcarbonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid hydroxyamide To a solution of 3.0 g (6.38 mmol) of methyl l- (2-furanylcarbonyl) -4- (4-methoxybenzenesulfonyl) -2, 3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylate in 15 ml of CH2C1 (cooled to 0 ° C), 12.8 ml (2.8 mmol) of BBr3 in CH2C12 (1.0 M in CH2C12) was added dropwise. The mixture was stirred at room temperature for 3 days, diluted with CH2C12 and then ice added. The organic layer was separated, washed with H20, 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 the product were combined, the solvent was removed and the residue was triturated with ethyl acetate. Cooling and filtration gave 0.72 g of methyl l- (2-furanylcarbonyl) -4-hydroxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylate as a white solid , pf 204-206 ° C; Analysis Calculated for C 22 H 20 N 2 O 7 S: C, 57.9; H, 4.2; N, 6.1. Found: C, 57.2; H, 4.3; N, 6.0 To 1.26 g (4.82 mmol) of triphenylphosphine in 10 ml of toluene and 2.5 ml of tetrahydrofuran was added 360 μL (4.82 mmol) of 2-butyn-l-ol and 1.48 g (3.2 mmol) of l- (2-furanylcarbonyl) -A- (4-hydroxybenzenesulfonyl) -1H- [1,4] -benzodiazepin-3-carboxylic acid methyl ester. Under nitrogen, 760 μL (4.8 mmol) of diethyl azodicarboxylate was added and the mixture was stirred for 2 days at room temperature. The solvent was removed under vacuum and the residue was chromatographed on silica gel with ethyl acetate-hexane (1: 1) as solvent. The fractions containing the product were combined and the solvent was removed to produce a solid. Trituration with ethyl acetate followed by cooling and filtration gave 2.2 g of the white solid. The solid was recrystallized from ethyl acetate to yield 1.53 g of 1- (2-furanylcarbonyl) -4- (4-but-2-ynyloxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1, 4] Methyl benzodiazepine-3-carboxylate as a solid, mp 119 ° -120 ° C; Mass spectrum (ES) 509.5 (M + H). To 1.8 g (3.54 mmol) of the preceding compound in 10 ml of tetrahydrofuran was added 4.6 ml (4.6 mmol) of 1 N KOH. The mixture was stirred at room temperature for 2.5 hours and diluted with H20 and ethyl acetate. The aqueous layer was separated and acidified with 1 N HCl. The mixture was extracted with ethyl acetate, the extract was washed with brine and dried (Na 2 SO 4). The solvent was removed to yield 1.05 g of 1- (2-furanylcarbonyl) -4- (4-but-2-ynyloxybenzenesulfonyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] benzodiazepin-3 acid. -carboxylic as a white foam: Mass spectrum (ES) 495.5 (M + H): Analysis Calculated for C25H22N207S: C, 60.7; H, 4.5; N, 5.7. Found: C, 57.6; H, 4.8; N, 6.6.
To a solution of 3.4 ml (6.8 mmol) of oxalyl chloride (2.0 M solution in CH2C12) in 8 ml of CH2C12 (0 ° C) was added 527 m or 527 μL of N, N-dimethylformamide. To the solution was added a solution of 0.84 g (1.7 mmol) of the preceding acid in 3 ml of N, N-dimethylformamide. The mixture was stirred at room temperature under nitrogen for 1.5 hours (Solution A). In a separate flask, 1.56 ml (25.5 mmol) of hydroxylamine (50% in H20) was diluted with 6 ml of tetrahydrofuran and the solution was cooled to 0 ° (Solution B). Solution A was added slowly to Solution B and the mixture was stirred overnight at room temperature. The mixture was diluted with CH2C12 and the solution was washed with H20, 2 N citric acid, 1 M NaHCO3, and concentrated to dryness. The solid residue was chromatographed on silica gel (flash column) with ethyl acetate-hexane (1: 1) as a solvent to remove the impurities. The product was eluted with 10% methanol in ethyl acetate. The combined product fractions were concentrated and diluted with ethyl acetate and the solution was dried (Na 2 SO 4). The solvent was removed to yield a solid which was dried 20 hours at 80 ° C under vacuum to yield 0.64 g of the hydroxamic acid product.
Example 79 l-Cyclopropylcarbonyl-4- (4-but-2-ynyloxybenzenesulfonyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid hydroxyamide To a solution of 4.44 g (10 mmol) of methyl 1-cyclopropylcarbonyl-4- (4-methoxybenzenesulfonyl) -2,4,4-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylate in 25 ml of CH2C12 cooled to 0 ° C, 22 ml (22 mmol) of BBr3 in CH2C12 (1.0 molar solution) was added dropwise. The mixture was stirred overnight, cooled and diluted with ice and H2O. Dichloromethane was added and the organic layer was separated and washed with H20, brine and dried (Na2SO). The solvent was removed under vacuum to yield a solid which was chromatographed on silica gel with the solvent ethyl acetate-hexane (1: 1) to yield 1.0 g of 1-cyclopropylcarboni 1-4- (4-hydroxybenzenesulfonyl) ) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid methyl ester as a foam.
As described for Example 57, 0.45 g (1.09 mmol) of the preceding compound and 123 μL (1.64 mmol) of 2-butyn-1-ol were coupled with 0.430 g (1.64 mmol) of triphenylphosphine and 2.59 μL (1.64 mol) of diethyl azodicarboxylate in 3.5 ml of toluene and 1 ml of tet.rahydrofuran as solvent. The product was purified by chromatography on silica gel with ethyl acetate-hexane (1:15) as solvent to yield 0.60 g of 4- (4-but-2-ynyloxybenzenesulfonyl) -1- (cyclopropylcarbonyl) -2,3, 4,5-Tetrahydro-lH- [14] benzodiazepine-3-carboxylic acid methyl ester as a solid. A solution of the preceding compound (0.57 g, 1.18 mmol) in a mixture of 1.5 ml (1.53 mmol) of 1 N KOH and 3 ml of tetrahydrofuran was stirred 3 hours; it was concentrated and extracted with ethyl acetate. The aqueous residue was acidified with 1 N HCl and extracted with ethyl acetate. The extract was washed with brine, dried (Na 2 SO 4) and the solvent was removed to yield 0.23 g of 4- (4-but-2-ynyloxybenzenesulfonyl) -1- (cyclopropylcarbonyl) -2,3,4,5-tetrahydro acid. -lH- [1,4] benzodiazepine-3-carboxylic acid as a whitish solid.
As described for Example 57, 0.20 g (0.427 mmol) of the preceding compound was reacted with 855 μL (1.7 mmol) of N, N-dimethylformamide (DMF) in 3 ml of CH2C12 and 1 ml of DMF followed by the reaction with 393 μL (6.41 mmol) of hydroxylamine (50% in H20) in 2 ml of tetrahydrofuran the product was dried at 80 ° C overnight to yield 0.188 g of a white foam; Mass spectrum (ES) 484.5 (M + H); Analysis Calculated for C 24 H 25 N 3 O 6 S: C, 59.6; H, 5.2; N, 8.7. Found: C, 56.2; H, 5.1; N, 8.6 Example 80 (5-fluoro-2-nitrophenyl) methanol To the 5-fluro-2-nitrobenzoic acid (0.5 g, 2.7 mmol) was added a solution of the borane-tetrahydrofuran complex (5 mL, 1.0 M, 5 mmol) and the resulting solution was heated at 70 ° C for 3 hours. The reaction was then cooled to room temperature and methanol was added. The mixture was concentrated and additional methanol was added two additional times to give 0.48 g (100%) of a white solid, m.p. 82-86 ° C. Analysis Calculated for CH6N303F: C, 49.13; H, 3.52; N, 8.18. Found: C, 48.76; H, 3.56; N, -7.88.
Example 81 2- (Bromomethyl) -4-fluoro-1-nitrobenzene To a solution of (5-fluoro-2-nitrophenyl) ethanol (0.3 g, 1.75 mmol) in methylene chloride (5 mL) was added with triphenylphosphine (0.52 g, 2.01 mmol) and carbon tetrabromide (0.66 g, 2.01 mmol). After 3 hours, the reaction was concentrated and subjected to chromatography using 3:! Hexane: ethyl acetate as eluent to provide 0.38 g (93%) of the desired product as white crystals, m.p. 38-41 ° C. Analysis Calculated for C7H5N302FBr: C, 35.93; H, 2.15; N, 5.99. Found: C, 35.97; H, 2.12; N, 5.91.
EXAMPLE 82 2- ( { [4- (2-Butynyloxy) phenyl] sulfonyl.} Amino) -3-hydroxypropanoate methyl Using the procedure of reference example 170, the glycine methyl ester hydrochloride was converted to the corresponding sulfonamide using 4-But-2-ynyloxybenzenesulfonyl to afford methyl 2- ( { [4- (2-butynyloxy) phenyl] -sulfonyl}. Amino) -3-hydroxypropanoate.
Example 83 2-. { (5-fluoro-2-nitrobenzyl) [(4-methoxyphenyl) sulfonyl] amino} - methyl 3-hydroxypropanoate To a solution of 2- (bromomethyl) -4-fluoro-1-nitrobenzene (1.3 g, 5.56 mmol) at 0 ° C was added tetrabutylammonium todide (2.05 g, 5.56 mmol). The solution was stirred at 0 ° C for 1.5 hours. In a separate flask, methyl 2- ( { [4- (2-butynyloxy) phenyl] sulfonyl}. Amino) -3-hydroxypropanoate (1.73 g, 5.05 mmol) was dissolved in dimethylformamide and cooled to 0 °. C. Sodium hydride (0.21 g, 5.56 mmol, 60% dispersion in oil) was added and the reaction was allowed to stir at 0 ° C for 0.5 hours at this time the bromide solution was added. The reaction was stirred overnight and then cooled rapidly with water. The mixture was extracted twice with ethyl acetate, washed with brine, dried over NaSO4, concentrated in vacuo and chromatographed using 1.5: 1 hexane: ethyl acetate as eluent to give 1.88 g (77%). of the desired product as a white solid, mp 83-88 ° C. Analysis Calculated for C2iH2? N208FS: C, 52.50; H, 4.41; N, 5.83. Found: C, 52.44; H, 4.76; N, 5.56.
EXAMPLE 84 Methyl 2- ((2-amino-5-fluorobenzyl) - {- [4- (2-butynyloxy) phenyl] sulfonyl.] Amino) -3-hydroxypropanoate 2-. { (5-fluoro-2-nitrobenzyl) [(4-methoxyphenyl) sulfonyl] amino} Methyl-3-hydroxypropanoate (1.0 g, 2.08 mmol) was dissolved in ethanol (18 mL). To this was added tin chloride dihydrate (2.35 g, 10.4 mmol) and the reaction was heated at 70 ° C for 2 hours. The reaction was then cooled to room temperature and ice water was added followed by NaHCO 3 to conduct the solution to pH 8. Ethyl acetate was added and the suspension was filtered through celite. The organic layer was separated and washed with brine, dried over Na2SO4, concentrated in vacuo and chromatographed using 1: 1 hexane: ethyl acetate as eluent to give 0.55 g (58%) of desired product as an acetyl. yellow.
Example 85 l-acetyl-4-. { [4- (2-butynyloxy) phenyl] sulfonyl} -7-fluoro-2,3,4,5-tetrahydro-lH-l, 4-benzodiazepin-3-carboxylic acid methyl Methyl-2- ((2-amino-5-fluorobenzyl) - {[[4- (2-butynyloxy) phenyl] -sulfonyl] -amino) -3-hydroxypropanoate methyl (0.48 g, 1.07 mmol) 0.41 g (95%) was converted to the desired product using acetyl chloride as the acylating agent following the procedure outlined in Reference Example 181. Analysis Calculated for C23H23N2O6FS: C, 58.22; H, 4.89; N, 5.90. Found: C, 57.58; H, 4.95; N, 5.60, Example 86 L-acetyl-4- acid. { [4- (2-butynyloxy) phenyl] sulfonyl} -7-fluoro-2,3,4,5-tetrahydro-lH-l, 4-benzodiazepin-3-carboxylic acid l-acetyl-4-. { [4- (2-butynyloxy) phenyl] sulfonyl} -7-fluoro-2, 3, 4, 5-tetrahydro-lH-l, 4-benzodiazepin-3-carboxylic acid methyl ester was hydrolyzed to the carboxylic acid using the procedure of reference example 185 to provide the desired acid as an off-white solid . Analysis Calculated for C22H2iN206FS: C, 57.38; H, 4.6; N, 6.08. Found: C, 56.93; H, 4.71; N, 5.67.
Example 87 l-acetyl-4-. { [4- (2-butynyloxy) phenyl] sulfonyl} -7-fluoro-N-hydroxy-2, 3, 4, 5-tetrahydro-lH-l, 4-benzodiazepin-3-carboxamide Using the procedure of Example 3, 1-acetyl-4- acid. { [4- (2-butynyloxy) phenyl] sulfonyl} -7-fluoro-2, 3, 4, 5-tetrahydro-lH-1,4-benzodiazepine-3-carboxylic acid was converted to hydroxamic acid 45 mg (15%). Mass spectrum (ES) 476.2 (M + H).
It is noted that in relation to this date the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (55)

CLAIMS Having described the invention as above, the contents of the following claims are claimed as property:
1. A compound of Formula I: characterized in that R is selected from hydrogen, (C1-C3) alkyl, -CN, -OR ', -SR', -CF3, -OCF3, Cl, F, NH2, -NH (C1-C3) alkyl, -N ( R ') CO (C? -C3) alkyl, -N (R') (R '), N02, -CONH2, -S02NH2, -S02N (R') (R '), -N (R') COCH2O- (C? -C3) alkyl, wherein R 'is (C? -C3) alkyl or hydrogen; R4 is (C? -C6) alkyl-O- containing a triple bond, wherein R "is hydrogen, -CH2OH, (C? -C6) alkyl, (C? -C6) alkyl-0-CH2-, (C? -C6) alkyl-S-CH2-, (C? -C6) alkyl-NH-CH-, [(C1-C3) alkyl] 2-NCH2-, (C? -C6) cycloalkyl-0-CH2-, [(Ci-C3) alkyl] 2-N- (CH2) 2- 4NHCH2-, . { (Cl-C3 q "") 2 ^ - (CH2) 2-M (CH3) CH2-, -CHrO- ^ ~ \. Ri and R2 are each, independently, hydrogen or CH3; R3 is (Ci-Cß) alkyl, NH2CH2C0-, (C? -C6) alkylNHCH2CO-, H0 (CH2) mC0-, HCO-, Aryl (CH2) nC0-, Heteroaryl (CH2) nC0-, (Ci-C3) alkyl-O- (CH2) nCO-, (C1-C3) alkylCO-, (C1-C3) alkylCO-NHCH2CO-, (C3-C7) cycloalkylCO-, (C1-C3) alkylS02-, Aryl (CH2) nS02- , Heteroaryl (CH2) nS02-, (C1-C3) alkyl-O- (CH2) m-S02-, (C1-C3) alkyl-O- (CH2) mf (C? -C3) alkyl-O- (C1 -C3) alkyl-O- (C1-C3) alkyl, HO- (C1-C3) alkyl-O- (C1-C3) alkyl, Aril-O-CH2CO-, Heteroaryl-0-CH2CO-, ArilCH = CHCO- , HeteroarilCH = CHCO-, (Cx-C3) alkylCH = CHCO-, Aryl (C1-C3) alkyl, Heteroaryl (C? -C3) alkyl, ArilCH = CHCH2-, HeteroarylCH = CHCH2-, (Cx-Ce) alkylCH = CHCH2-, R'OCH2 CH (OR ') CO-. (ROCH2) 2C (R ') CO-, ~ - \ CHrtí N (C, - C3) »? QU? LCH = CH-CO-, O N- (C, -)« iqmiCO-, S N- (C , - Quilkyl CO-, (C? -C3? &?;? U? CONHCO-, - (C? -C6) »iq" «CO-, (N- (C, -C6) ¡» iq «' iCO-. ^ CrQs) »? <?« »C. | JMCi-Cß)« '<! • "' CO- CHj- / - \ NICj-Cfil-iquiiCO-, l-Boc-N r \ ^ - (C, -C?) »Iqui? CO-. . OR [(C? -C6) alkyl] 2-N- (C? -C6) alkyl CO-, or (C? -C6) alkyl-NH- (Cr C6) alkylCO-; where m = 1 to 3; n = 0 to 3; Arilo is Heteroaryl is wherein X is hydrogen, halogen, (C? -C3) alkyl or -0CH3 and R and R 'are as defined above; L is hydrogen, (C? -C3) alkyl, -CN, -OR ', -SR', -CF3, -OCF3, Cl, F, NH2, -NH- (C? -C3) alkyl, -N (R ') CO (C? -C3) alkyl, N (R') (R '), -N02, -CONH2, -S02NH2, -S02N (R') (R '), -N (R') COCH20- ( C? -C3) alkyl, M is 'is as defined above; W is O, S, NH or N (C? -C3) alkyl; And it is hydrogen, F, Cl, CF3 or OCH3; and X 'is halogen, hydrogen, (C? -C3) alkyl, 0- (Cx-C3) alkyl, or -CH20H; and pharmaceutically acceptable salts thereof.
2. A compound according to claim 1, characterized in that: R is hydrogen, (Cx-C3) alkyl, -CN, -OR ', -SR', -CF3, -0CF3, Cl, F, NH2, NH ( C? -C3) alkyl, -N (R ') CO (C? -C3) alkyl, N (R') (R '), N02, -C0NH2, -SO2NH2, -S02N (R') (R ') , or -N (R ') C0CH2-0- (Cx-C3) alkyl, wherein R' is (C? -C3) alkyl or hydrogen; R4 is (Ci-Cd) alkyl-0- containing a triple bond, wherein R "is hydrogen, -CH20H, (C? -C6) alkyl, (Cx-C6) alkyl-0-CH2-, (C-C6) alkyl-S-CH2-, (C? -C6) alkyl- NH-CH2-, [(C? -C3) alkyl] 2-NCH2-, (C-C6) cycloalkyl-0-CH2-, [(C? ~ C3) alkyl] 2-N- (CH2) 2_4NHCH2-, - ((Cl-C3 qup) 2-N- (CH2) 2 -.N (C? 3) CH2-, -CHrO- ^ ~) • Ri and R2 are each, independently, hydrogen or CH3; R3 is (C? -C8) alkyl, NH2CH2CO-, (C-C6) alkylNHCH2C0-, HO (CH2) mCO-, HCO-, Aryl (CH2) nCO-, Heteroaryl (CH2) nC0-, (C ~ C3) alkyl-O- (CH2) nC0-, (C1-C3) alkylCO-, (C? -C3) alkylCO-NHCH2CO-, (C3-C7) cycloalkylC0-, Aryl-0-CH2CO-, Heteroaryl0CH2C0-, where m = 1 to 3; n = 0 to 3; Arilo is Heteroaryl is T3. wherein X is hydrogen, halogen, (C? -C3) alkyl or -0CH3 and R and R 'are as defined above; and pharmaceutically acceptable salts thereof.
3. A compound according to claim 1, characterized in that R is hydrogen, (C1-C3) alkyl, -CN, -OR ', -SR', -CF3, -0CF3, Cl, F, NH2, NH (C ? -C3) alkyl, -N (R ') CO (C? -C3) alkyl, N (R ') (R'), N02, -CONH2, -SO2NH2, -S02N (R ') (R'), -N (R ') C0CH20- (C1-C3) alkyl, wherein R' is ( C1-C3) alkyl or hydrogen; R4 is (C? -C6) alkyl-0- containing a triple bond, wherein R "is hydrogen, -CH2OH, (C? -C6) alkyl," (C? -C6) alkyl-0-CH2-, (C? -C6) alkyl-S-CH2-, (C? -C6) ) alkyl-NH-CH2-, [(C? -C3) alkyl] 2-NCH2-, (C? -C6) cycloalkyl-0-CH2-, [(d-C3) alkyl] 2-N- (CH2) 2-4NHCH2-, < ** > < 2T or *? »* < Y*. xy Ri and R2 are each, independently, hydrogen or CH3; R3 is -), «iquiiCO-, SN ^ C, -C6)» i? Ui? CO -. (C, -C3) »iquuCONHCO-t N- (C, -Cd)» iq "" CO-, i J- (C, -C6)! »'QuMCO-. CHrN KC, C6) alkyl CO-t-Boc-N N- (C, Cf,) alkyl CO- ' [(C? -C6) alkyl] 2-N- (C? -C6) alkyl CO-, or (C? -C6) alkyl-NH- (C C6) alkylCO-, where R 'is as defined above; and pharmaceutically acceptable salts thereof.
4. A compound according to claim 1, characterized in that R is hydrogen, (C? -C3) alkyl, -CN, -0R ', -SR1, -CF3, OCF3, Cl, F, NH2, NH (C? -C3) alkyl, -N (R ') CO (C? -C3) alkyl, N (R ') (R'), N02, -CONH2, -SO2NH2, S02N (R ') (R'), -N (R ') COCH20- (C? -C3) alkyl, where R' is ( C? -C3) alkyl or hydrogen; R4 is (Ci-Ce) alkyl-O- which contains a triple bond, wherein R "is hydrogen, -CH2OH, (C? -C6) alkyl, (C? ~ C6) alkyl-0-CH2-, (C? -C6) alkyl-S-CH2-, (C-C6) alkyl -NH-CH2-, [(C? -C3) alkyl] 2-NCH2-, (C? -C6) cycloalkyl-0-CH2-, [(C? ~ C3) alkyl] 2- (CH2) 2- 4NHCH2-, o- ((C? -C3> iq "'i) 2-N- (CH2> .N (CH3) CH2-, -CHrOY ~ \ Ri and R2 are each, independently, hydrogen or CH3; is (C? -C3) alkylS02-, Aryl (CH2) nS02-, Heteroaryl (CH2) nS02-, or (C? -C3) alkyl-O- (CH2) nS02-, where m = 3; n = 0 to 3, Arilo is Heteroaryl is wherein X is hydrogen, halogen, (C1-C3I alkyl or -0CH3 and R and R 'are as defined above, and pharmaceutically acceptable salts thereof
5. A compound according to claim 1, characterized in that R is hydrogen, (C? -C3) alkyl, -CN, -OR ', -SR', -CF3, -OCF3, Cl, F, NH2, NH (C? -C3) alkyl, -N (R ') CO ( C? -C3) alkyl, N (R ') (R'), N02, -CONH2, -SO2NH2, -S02N (R ') (R'), ON (R ') COCH20- (C1-C3) alkyl, wherein R 'is (C -C3) alkyl or hydrogen, R4 is (C? -C6) alkyl-O- containing a triple bond, -0-CH2-C = CR "wherein R" is hydrogen, -CH2OH, (C? -C6) alkyl, (C? ~ C6) alkyl-0-CH2-, (C? -C6) alkyl-S-CH2-, (C? -C6) alkyl-NH-CH2-, [(C ? -C3) alkyl] 2-NCH2-, (C? -C6) cycloalkyl-0-CH2-, [(C? ~ C3) alkyl] 2-N- (CH2) 2-4 NHCH2-, Ri and R2 are each, independently, hydrogen or CH3; R3 is HCO-, (C-C3) alkylCO-, Aryl (C? -C3) alkylCO-, Heteroaryl (C? -C3) alkylCO-, (C? -C3) alkyl-O- (CH2) nC0-, HO (CH2) mCO-, (C? -C7) cycloalkylCO-, where Aryl is X? f R 'Heteroaryl is wherein X is hydrogen, halogen, (C? -C3) alkyl or -0CH3 and R and R 'are as defined above; and pharmaceutically acceptable salts thereof.
6. A compound according to claim 1, characterized in that R is hydrogen, (C? -C3) alkyl, -CN, -OR ', -SR', -CF3, 0CF3, Cl, F, NH2, NH ( C? -C3) alkyl, -N (R ') CO (C-C3) alkyl, N (R ') (R'), N02, -C0NH2, -SO2NH2, S02N (R ') (R'), or -N (R ') C0CH20- (C? -C3) alkyl, wherein R' is (C? -C3) alkyl or hydrogen; R4 is (C? -C6) alkyl-0- containing a triple bond, -0-CH2-C = CR "wherein R" is hydrogen, -CH2OH, (C? -C6) alkyl, (C? ~ C5) ) alkyl-0-CH2-, (C-C6) alkyl-S-CH2-, (C? -C6) alkyl-NH-CH2-, [(C? -C3) alkyl] 2-NCH2-, (C? -C6) cycloalkyl-0-CH2-, [(Cx-C3) alkyl] 2-N- (CH2) 2-4 NHCH2-,. { (C? -C3 > iq «", -CHrO-r, Rx and R2 are each, independently, hydrogen or CH3; R3 is where m = 1 to 3; n = 0 to 3; L is hydrogen, (C? -C3) alkyl, -CN, -OR ', -SR', -CF3, -OCF3, Cl, F, NH2, -NH- (C? -C3) alkyl, -N (P ') CO (C? -C3) alkyl, N (R') (R '), -N02, -CONH2, -SO2NH2, -S0N (R') (R '), -N (R') COCH20- ( C? -C3) alkyl, and CONH- M is 'is as defined above; W is O, S, NH or N (C? -C3) alkyl; And it 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.
7. The compound according to claim 1, characterized in that it is the hydroxyamide of l-acetyl-4- (4-but-2-ynyloxy-benzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1 , 4] benzodiazepine-3-carboxylic acid.
8. The compound according to claim 1, characterized in that it is the hydroxyamide of 4- (4-but-2-ynyloxy-benzenesulfonyl) -1- (2-thienylcarbonyl) -2,3,4,5-tetrahydro- 1 H- [1,4] benzodiazepine-3-carboxylic acid.
9. The compound according to claim 1, characterized in that it is the hydroxyamide of l-benzoyl-4- (4-but-2-ynyloxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4 ] benzodiazepin-3-carboxylic acid.
10. The compound according to claim 1, characterized in that it is the hydroxyamide of 4- (4-but-2-ynyloxybenzenesulfonyl) -1- (2-furanylcarbonyl) -2,3,4,5-tetrahydro- 1 H- [1,4] benzodiazepine-3-carboxylic acid.
11. The compound according to claim 1, characterized in that it is the hydroxyamide of 4- (4-but-2-ynyloxybenzenesulfonyl) -1- (methanesulfonyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid.
12. The compound according to claim 1, characterized in that it is the hydroxyamide of 4- (4-but-2-ynyloxybenzenesulfonyl) -1-methoxyacetyl-2,3,4,5-tetrahydro-lH- [1 , 4] benzodiazepine-3-carboxylic acid.
13. The compound according to claim 1, characterized in that it is the hydroxyamide of 4- (4-but-2-ynyloxybenzenesulfonyl) -1- (3-pyridinylcarbonyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid.
14. The compound according to claim 1, characterized in that it is the hydroxyamide of 4- (4-but-2-ynyloxybenzenesulfonyl) -1- (4-pyridinylcarbonyl) -2,3,4,5-tetrahydro- 1 H- [1,4] benzodiazepine-3-carboxylic acid.
15. The compound according to claim 1, characterized in that it is the hydroxyamide of l-benzoyl-4- (4- [4-methoxybut-2-ynyloxy] benzenesulfonyl) -2,3,4,5-tetrahydro-lH - [1,4] benzodiazepine-3-carboxylic acid.
16. The compound according to claim 1, characterized in that it is the hydroxyamide of 4- (4- [4-methoxybut-2-ynyloxy] benzenesulfonyl) -1- (3-pyridinylcarbonyl) -2,3,4,5 -tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid.
17. The compound according to claim 1, characterized in that it is the hydroxyamide of 4- (4-pent-2-ynyloxy-benzenesulfonyl) -1- (3-pyridinylcarbonyl) -2,3,4, 5- tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid.
18. The compound according to claim 1, characterized in that it is the hydroxyamide of 4- (4- [4-hydroxybut-2-ynyloxy] benzenesulfonyl) -1- (4-pyridinylcarbonyl) -2,3,4,5 -tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid.
19. The compound according to claim 1, characterized in that it is the hydroxyamide of 4- (4- [4-methoxybut-2-ynyloxy] -benzenesulfonyl) -1- (2-thienylcarbonyl) -2,3,4, 5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid.
20. The compound according to claim 1, characterized in that it is the hydroxyamide of 1- (benzoyl) -A- (4-pent-2-ynyloxy-benzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid.
21. The compound according to claim 1, characterized in that it is the hydroxyamide of l-propionyl-4- (4- [4-hydroxybut-2-ynyloxy] benzenesulfonyl) -2,3,4,5-tetrahydro-lH - [1,4] benzodiazepine-3-carboxylic acid.
22. The compound according to claim 1, characterized in that it is the hydroxyamide of 1- (N, N-dimethylamino-acetyl) -4- (4- [4-methoxybut-2-ynyloxy] bencenesulfonyl) -2 , 3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid.
23. The compound according to claim 1, characterized in that it is the hydroxyamide of 1- (acetylaminoacetyl) -4- (4-but-2-ynyloxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1 , 4] benzodiazepine-3-carboxylic acid.
24. The compound according to claim 1, characterized in that it is the hydroxyamide of 1- (ethoxyacetyl) -4- (4- [4-methoxybut-2-ynyloxy] benzenesulfonyl) -2,3,4,5-tetrahydro -lH- [1,4] benzodiazepine-3-carboxylic acid.
25. The compound according to claim 1, characterized in that it is the hydroxyamide of 4- (4-but-2-ynyloxy-benzenesulfonyl) -1- (3-thienylcarbonyl) -2,3,4,5-tetrahydro- 1 H- [1,4] benzodiazepine-3-carboxylic acid.
26. The compound according to claim 1, characterized in that it is the hydroxyamide of 1- (ethoxyacetyl) -4- (4- [4-ethoxybut-2-ynyloxy] benzenesulfonyl) -2,3,4,5-tetrahydro -lH- [1,4] benzodiazepine-3-carboxylic acid.
27. The compound according to claim 1, characterized in that it is the hydroxyamide of 1- (acetylaminoacetyl) -4- (4- [4-methoxybut-2-ynyloxy] benzenesulfonyl) -2,3,4,5-tetrahydro-lH - [1,4] benzodiazepine-3-carboxylic acid.
28. The compound according to claim 1, characterized in that it is the hydroxyamide of 1- (cyclopropyl-carbonyl) -4- (4- [4-methoxybut-2-ynyloxy] benzenesulfonyl) -2,3,4,5. -tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid.
29. The compound according to claim 1, characterized in that it is the hydroxyamide of 1- (cyclobutylcarbonyl) -4- (4-but-2-ynyloxybenzenesulfonyl) -2, 3, 4, 5-tetrahydro-lH- [1 , 4] benzodiazepine-3-carboxylic acid.
30. The compound according to claim 1, characterized in that it is the hydroxyamide of 4- (4-but-2-ynyl-oxybenzenesulfonyl) -1- (propionyl) -2,3,4,5-tetrahydro- lH- [1,] benzodiazepine-3-carboxylic acid.
31. The compound according to claim 1, characterized in that it is the hydroxyamide of 4- (4- [4-methoxybut-2-ynyloxy] benzenesulfonyl) -1- (3-methyl-2-thienylcarbonyl) -2, 3 , 4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid.
32. The compound according to claim 1, characterized in that it is the hydroxyamide of 4- (4-but-2-ynyloxybenzenesulfonyl) -1- (3-methoxypropionyl) -2,3,4,5-tetrahydro- lH- [1,4] benzodiazepine-3-carboxylic acid.
33. The compound according to claim 1, characterized in that it is the hydroxyamide of 4- (4-but-2-ynyloxybenzenesulfonyl) -1- (2-chlorobenzoyl) -2,3,4,5-tetrahydro- 1 H- [1,4] benzodiazepine-3-carboxylic acid.
34. The compound according to claim 1, characterized in that it is the hydroxyamide of 4- (4-but-2-ynyloxybenzenesulfonyl) -1- (2-fluorobenzoyl) -2,3,4,5-tetrahydro- 1 H- [1,4] benzodiazepine-3-carboxylic acid.
35. The compound according to claim 1, characterized in that it is the hydroxyamide of 4- (4-but-2-ynyloxybenzenesulfonyl) -1- (4-methyl-2-furanylcarbonyl) -2,3,4, 5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid.
36. The compound according to claim 1, characterized in that it is the hydroxyamide of 4- (4-but-2-ynyloxybenzenesulfonyl) -1- (3-furanylcarbonyl) -2,3,4,5,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid.
37. The compound according to claim 1, characterized in that it is the hydroxyamide of 4- (4-but-2-ynyloxybenzenesulfonyl) -1- (phenoxyacetyl) -2,3,4,5-tetrahydro-lH- [1,] benzodiazepine-3-carboxylic acid.
38. The compound according to claim 1, characterized in that it is the hydroxyamide of 4- (4-but-2-ynyloxybenzenesulfonyl) -1- [2- (1-pyrazolyl) phenylcarbonyl] -7-methyl-2 3,4,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid.
39. The compound according to claim 1, characterized in that it is the hydroxyamide of 4- (4-but-2-ynyloxybenzenesulfonyl) -1- (5-chloro-2-thienylcarbonyl) -2,3,4, 5-tetrahydro-lH- [1,] benzodiazepine-3-carboxylic acid.
40. The compound according to claim 1, characterized in that it is the hydroxyamide of 4- (4-but-2-ynyloxybenzenesulfonyl) -1- (5-chloro-2-furanylcarbonyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid.
41. The compound according to claim 1, characterized in that it is the hydroxyamide of 4- (4- [4-methoxybut-2-ynyloxy] -benzenesulfonyl) -1-propionyl-2, 3,4,5-tetrahydro- 1 H- [1,4] benzodiazepine-3-carboxylic acid.
42. The compound according to claim 1, characterized in that it is the hydroxyamide of 4- (4- [4-methoxybut-2-ynyloxy] benzenesulfonyl) -1- (3-thienylcarbonyl) -2,3,4,5 -tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid.
43. The compound according to claim 1, characterized in that it is the hydroxyamide of 1- (aminoacetyl) -4- (4-but-2-ynyloxybenzenesulfonyl) -2,3,4,5-tetrahydro-lH- [1 , 4] benzodiazepine-3-carboxylic acid.
44. The compound according to claim 1, characterized in that it is the hydroxyamide of l-hexanoyl-4- (4- [4-methoxybut-2-ynyloxy] benzenesulfonyl) -2,3,4,5-tetrahydro-1H- [1,4] benzodiazepin-3- carboxylic
45. The compound according to claim 1, characterized in that it is the hydroxyamide of 4- (4-but-2-ynyloxy-benzenesulfonyl) -1- (N, N-dimethylaminoacetyl) -2,3,4, 5- tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid.
46. The compound according to claim 1, characterized in that it is the hydroxyamide of 4- (4-but-2-ynyloxybenzenesulfonyl) -1- (cyclopropylcarbonyl) -2,3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid.
47. The compound according to claim 1, characterized in that it is the hydroxyamide of 4- (4-but-2-ynyloxy-benzenesulfonyl) -1- (cyclohexylcarbonyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid.
48. The compound according to claim 1, characterized in that it is the hydroxyamide of l-methoxyacetyl-4- (4- [4-methoxybut-2-ynyloxy] benzenesulfonyl) -7-methy1-2, 3,4,5 -tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid.
49. The compound according to claim 1, characterized in that it is the hydroxyamide of l-benzoyl-4- (4-but-2-ynyloxybenzenesulfonyl) -7-methyl-2, 3, 4, 5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxylic acid.
50. The compound according to claim 1, characterized in that it is the hydroxyamide of 1- (benzoyl) -A - (4-but-2-ynyloxybenzenesulfonyl) -8-chloro-2, 3,4,5-tetrahydro-lH- [1,4] benzodiazepin-3-carboxylic acid.
51. The compound according to claim 1, characterized in that it is l-acetyl-4-. { [4- (2-butynyloxy) phenyl] sulfonyl} -7-fluoro-N-hydroxy-2, 3,4,5-tetrahydro-lH- [1,4] benzodiazepine-3-carboxamide.
52. A process for the preparation of a compound as claimed in claim 1, characterized in that it comprises one of the following: a) reacting a compound of the formula II: (H) Wherein R, Rlf R2, R3 and R4 are as defined above, and A is COOH or a reactive derivative thereof, with a compound of formula III NH2OH (III) to give a corresponding compound of formula I; b) re-dissolving a mixture (for example racemate) of optically active isomers of a compound of the formula I to isolate a substantially free enantiomer or diastereomer of the other enantiomer or diastereomers; c) acidifying a base compound of formula I with a pharmaceutically acceptable acid to give a pharmaceutically acceptable salt.
53. A pharmaceutical composition characterized in that it comprises a compound of formula 1 wherein R is selected from hydrogen, (C1-C3) alkyl, -CN, -OR ', -SR ', -CF3, -OCF3, Cl, F, NH2, -NH (C? -C3) alkyl, -N (R') CO (C? -C3) alkyl, -N (R ') (R') ), N02, -CONH2, -S02NH2, -S02N (R ') (R'), -N (R ') COCH20- (C-C3) alkyl, wherein R' is (C? -C3) alkyl or hydrogen; R4 is (C? ~ C6) alkyl-O- containing a triple bond, wherein R "is hydrogen, -CH20H, (C? -C6) alkyl, (C? ~ C6) alkyl-0-CH2-, (C? -C6) alkyl-S-CH2-, (C? -C6) alkyl-NH-CH2-, [(C? -C3) alkyl] 2-NCH2-, ( C? -C6) cycloalkyl-0-CH2-, [(C ~ C3) alkyl] 2-N- (CH2) 2-4 NHCH-, . { Rx and R2 are each, independently, hydrogen or CH3; R3 is (C? -C8) alkyl, NH2CH2C0-, (C? -C6) alkylNHCH2CO-, HO (CH2) mCO-, HCO-, Aryl (CH2) nCO-, Heteroaryl (CH2) nC0-, (C? ~ C3) alkyl-0- (CH2) nC0-, (C? -C3) alkylCO-, ( C? -C3) alkylCO-NHCH2CO-, (C3-C7) cycloalkylC0-, (C? -C3) alkylS02-, Aryl (CH2) nS02-, Heteroaryl (CH2) nS02-, (C? -C3) alkyl-O - (CH2) m-S02-, (C? -C3) alkyl-O- (CH2) m-, (C? -C3) alkyl-O- (C? -C3) alkyl-O- (C? -C3) ) alkyl, HO- (C? -C3) alkyl-O- (C? -C3) alkyl, Aryl-0-CH2CO-, Heteroaryl-0-CH2CO-, ArilCH = CHCO-, HeteroarylCH = CHCO-, (C? -C3) alkylCH = CHCO-, Aryl (C1-C3) alkyl, Heteroaryl (C? -C3) alkyl, ArilCH = CHCH2-, HeteroarylCH = CHCH2-, (C? -C6) alkylCH = CHCH2-, R'OCH2 CH. { OR ') CO-. (ROCH2) 2C (R ') CO-, CH3- O / N- (C, -C6) »' q '"' CO- <N- (C? -C6); »iq« i'CO-. ^ - (Cj-Q,) «iui'CO-, |, - (CrC6)« iq "" CO-, CH3-Y (C] -C6) alkyl CO-, 1-B? C-N ^ - (C, - ¡) alkyl CO-. , [(C? -C6) alkyl] 2-N- (C? -C6) alkyl CO-, or (C? -C6) alkyl-NH- (Cr C6) alkylCO-; where m = 1 to 3; n = 0 to 3; Arilo is Heteroaryl is wherein X is hydrogen, halogen, (C? -C3) alkyl or -OCH3 and R and R 'are as defined above; L is hydrogen, (C-C3) alkyl, -CN, -OR ', -SR', -CF3, -OCF3, Cl, F, NH2, -NH- (C? -C3) alkyl, -N (R ') ) CO (C? -C3) alkyl, N (R ') (R'), -N02, -CONH2, -S02NH2, -S02N (R ') (R'), -N (R ') C0CH20- (C ? -C3) alkyl, Month 'or N (R') (R ') where R' is as defined above; W is O, S, NH or N (C-C3) alkyl; And it is hydrogen, F, Cl, CF3 or OCH3; and X 'is halogen, hydrogen, (C? -C3) alkyl, 0- (C-C3) alkyl, or -CH20H; and pharmaceutically acceptable salts thereof.
54. The use of a compound of Formula 1 wherein R is selected from hydrogen, (C? -C3) alkyl, -CN, -OR ', -SR', -CF3, -OCF3, Cl, F, NH2, NH (C3-C3) alkyl, -N ( R ') C0 (C? -C3) alkyl ?, -N (R') (R '), N02, -C0NH2, -S02NH2, -S02N (R') (R '), -N (R') COCH2 -0- (C? -C3) alkyl, wherein R 'is (C? -C3) alkyl or hydrogen; R is (Cx-Ce) alkyl-O- containing a triple bond, wherein R "is hydrogen, -CH20H, (C? -C6) alkyl, (Ci-C6) alkyl-0-CH2-, (C-C6) alkyl-S-CH2-, (C? -C6) alkyl- NH-CH2-, [(C1-C3) alkyl] 2-NCH2-, (C? -C6) cycloalkyl-0-CH2-, [(C ~ C3) alkyl] 2-N- (CH2) 2-4 NHCH2- , Ri and R2 are each, independently, hydrogen or CH3; R3 is (C? -C8) alkyl, NH2CH2CO-, (C? -C6) alk HCH2CO-, HO (CH2) mCO-, HCO-, Aryl (CH2) nCO-, Heteroaryl (CH2) nC0-, (Cx-C3 ) alkyl-0- (CH2) nCO-, (C-C3) alkylCO-, (C? -C3) alkylCO-NHCH2C0-, (C3-C7) cycloalkylCO-, (C-C3) alkylS02-, Aryl (CH2) nS0? -, Heteroaryl (CH2) "S02-, (C-C3) alkyl-0- (CH2) m-S02-, (C? -C3) alkyl-O- (CH2) m, (C? -C3) alkyl-O- (C? -C3) alkyl-O- (C1-C3) alkyl, HO- (C? -C3) alkyl-O- (C1-C3) alkyl, aryl-0-CH2CO-, heteroaryl-0 -CH2CO-, ArilCH = CHCO-, HeteroarylCH = CHCO-, (Cx-C3) alkylCH-CHCO-, Aryl (C-C3) alkyl, Heteroaryl (C? -C3) alkyl, ArilCH = CHCH2-, HeteroarylCH = CHCH2-, (C? -C6) alkylCH = CHCH2-, R OCH2 CH (OR ') CO-, (ROCH2) 2C (R') CO-, CH (d - C6), aq "¡? CO-, CH3-fí (C, -C6) alkylCO-, 1-B? C- N-íC-Cfi) alkyl CO¬ [(C-C6) alkyl] 2-N- (C? -C6) alkyl CO-, or (C-C6) alkyl-NH- (Cr C6) alkylCO-; where m = 1 to 3; n: = 0 to 3; Arilo is Heteroaryl is wherein X is hydrogen, halogen, (C? -C3) alkyl or -OCH3 and R and R 'are as defined above; L is hydrogen, (C? -C3) alkyl, -CN, -OR ', -SR', -CF3, -OCF3, Cl, F, NH2, -NH- (C? -C3) alkyl, -N (R ') CO (C? -C3) alkyl, N (R') (R '), -N02, -CONH2, -S02NH2, -S02N (R') (R '), -N (R') COCH20- ( C? -C3) alkyl, Month 'or N (R') (R1) where R 'is as defined above; W is O, S, NH or N (C? -C3) alkyl; And it is hydrogen, F, Cl, CF3 or OCH3; and X 'is halogen, hydrogen, (C? -C3) alkyl, 0- (C-C3) alkyl, or -CH20H; and pharmaceutically acceptable salts thereof. For the manufacture of a medicament for treating the conditions of the disease mediated by matrix metalloproteinase in a mammal in need thereof.
55. The use of a compound of formula 1 wherein R is selected from hydrogen, (C? -C3) alkyl, -CN, -OR ', -SR', -CF3, -0CF3, Cl, F, NH2, NH (C-C3) alkyl, -N ( R ') CO (C? -C3) alkyl, -N (R') (R '), N02, -C0NH2, -S02NH2, -S02N (R') (R '), -N (R') C0CH2- 0- (C? -C3) alkyl, wherein R 'is (C? -C3) alkyl or hydrogen; R is (C-C6) alkyl-O- containing a triple bond, wherein R "is hydrogen, -CH20H, (C? -C6) alkyl, (C? ~ C6) alkyl-0-CH2-, (C? -C6) alkyl-S-CH2-, (C-C6) alkyl -NH-CH2-, [(C? -C3) alkyl] 2-NCH2-, (C? -C6) cycloalkyl-0-CH2-, [(Cx-C3) alkyl] 2-N- (CH2) 2_4NHCH2- , 5 Rx and R2 are each, independently, hydrogen or CH3; R3 is (C? -Cβ) alkyl, NH2CH2C0-, (C-C6) alkylNHCH2CO-, HO (CH2) raCO-, HCO-, Aryl (CH2) nCO-, Heteroaryl (CH2) nCO-, (C? ~ C3 ) alkyl-O- (CH2) nC0-, (C-C3) alkylCO-, (C? -C3) alkylCO-NHCH2CO-, (C3-C7) cycloalkylCO-, (C? -C3) alkylS02-, Aryl (CH2) ) nS02-, Heteroaryl (CH?) nS02-, (C? -C3) alkyl-O- (CH2) m- S02-, (C? -C3) alkyl-O- (CH2) m, (C? -C3) ) alkyl-O- (C-C3) alkyl-O- (C? -C3) alkyl, HO- (C? -C3) alkyl-O- (C? -C3) alkyl, aryl-0-CH2CO-, heteroaryl -0-CH2CO-, ArilCH = CHCO-, HeteroarilCH = CHCO-, (C? ~ C3) alkylCH = CHCO-, Aryl (C-C3) alkyl, Heteroaryl (C? -C3) alkyl, ArilCH = CHCH2-, HeteroarylCH = CHCH2-, (C? -C6) alkylCH = CHCH2-, R'OCH2 CHOR CO-. (ROCH2) 2C (R) CO-, . - CH and MCj -,) alkyl CO-, 1-B? C-N .N-fC, -C?) Alkyl C? - > (C] - Cß) .alqu, lCO-, [(C? -C6) alkyl] 2-N- (C? -C6) alkyl CO-, or (C? -C6) alkyl-NH- (C6) alkylCO-; where m = 1 to 3; n = 0 to 3; Arilo is Heteroaryl is wherein X is hydrogen, halogen, (C? -C3) alkyl or -OCH3 and R and R 'are as defined above; L is hydrogen, (C1-C3) alkyl, -CN, -OR ', -SR', -CF3, -OCF3, Cl, F, NH2, -NH- (C? -C3) alkyl, -N (Rf) CO (C? -C3) alkyl, N (R ') (R'), -N02, -CONH2, -S02NH2, -S02N (R ') (R'), -N (R ') COCH20- (C1-C3) alkyl, Month --- Í - ^ "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, (C? ~ C3) alkyl, 0- (C? -C3) alkyl, or -CH20H, and pharmaceutically acceptable salts thereof For the manufacture of a medicament for treating a patient who suffers from a condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, degenerative loss of cartilage, and tumor growth.
MXPA/A/2001/007575A 1999-01-27 2001-07-26 2,3,4,5-tetrahydro-1h-[1,4]benzodiazepine-3-hydroxamic acid as matrix metalloproteinase inhibitors MXPA01007575A (en)

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