Compounds are provided having the following formula: ##STR1## wherein R, R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are defined in the specification, which have matrix metalloproteinase inhibiting activity.

FIELD OF INVENTION 
This invention relates to 
4-(4-substituted-benzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepin 
e-3-hydroxyamic acids which act as matrix metalloproteinase inhibitors. The 
compounds of the present invention are useful in disease conditions 
mediated by matrix metalloproteinases, such as tumor growth. 
osteoarthritis. rheumatoid arthritis and degenerative cartilage loss. 
BACKGROUND OF THE INVENTION 
Matrix metalloproteinases (MMPs) are a group of enzymes that have been 
implicated in the pathological destruction of connective tissue and 
basement membranes. These zinc-containing endopeptidases consist of 
several subsets of enzymes, including collagenases, stromelysins and 
gelatinases. Of these, the gelatinases have been shown to be the MMPs most 
intimately involved with the growth and spread of tumors. 
For example, it is known that the level of expression of gelatinase is 
elevated in malignancies, and that gelatinase can degrade the basement 
membrane which leads to tumor metastasis. Angiogenesis, required for the 
growth of solid tumors, has also recently been shown to have a gelatinase 
component to its pathology as reported in "Matrix Metalloproteinases, 
Novel Targets for Directed Cancer Therapy", Drugs and Aging, 11:229-244 
(1997). 
Other conditions mediated by MMPs include restenosis, MMP-mediated 
osteopenias, inflammatory diseases of the central nervous system, skin 
aging, osteoarthritis, rheumatoid arthritis, septic arthritis, corneal 
ulceration, abnormal wound healing, bone disease, proteinuria. aneurysmal 
aortic disease, degenerative cartilage loss following traumatic joint 
injury. demyelinating diseases of the nervous system, cirrhosis of the 
liver, glomerular disease of the kidney, premature rupture of fetal 
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/ neo-vascularization and corneal graft rejection. Studies 
relating to these conditions are set forth, e.g., in "Recent Advances in 
Matrix Metalloproteinase Inhibitor Research", R. P. Beckett et al., 
Research Focus, 1:16-26, (1996); Curr. Opin. Ther. Patents, 4(1): 7-16, 
(1994); Curr. Medicinal Chem., 2: 743-762, (1995); Exp. Opin. Ther. 
Patents, 5(2): 1087-110, (1995); Exp. Opin. Ther. Patents, 5(12): 
1287-1196, (1995); "Inhibition of Matrix Metallo-proteinases: Structure 
Based Design", Current Pharmaceutical Design, 2:524-661. (1996). "Matrix 
Metalloproteinase Inhibitor Drugs", Emerging Drugs, 2:205-230 (1997). 
TNF-.alpha. converting enzyme (TACE) catalyzes the formation of TNF-.alpha. 
from membrane bound TNF-.alpha. precursor protein. TNF-.alpha. is a 
pro-inflammatory cytokine that is believed to have a role in rheumatoid 
arthritis, septic shock, graft rejection, cachexia, anorexia, 
inflammation, congestive heart failure, inflammatory disease of the 
central nervous system, inflammatory bowel disease, insulin resistance and 
HIV infection, in addition to its well-documented antitumor properties. 
Research with anti-TNF-.alpha. antibodies in transgenic animals has 
demonstrated that blocking the formation of TNF-.alpha. inhibits the 
progression of arthritis. This observation has recently been extended to 
humans as described in "TNF-.alpha. in Human Diseases", Current 
Pharmaceutical Design, 2:662-667 (1996). 
It is expected that small molecule inhibitors of MMPs and TACE would have 
the potential for treating a variety of disease states. Although a variety 
of MMP and TACE inhibitors are known, many of these molecules are peptidic 
and peptide-like which demonstrate bioavailability and pharmacokinetic 
problems. Long acting, orally bioavailable non-peptide inhibitors of MMPs 
and/or TACE would thus be highly desirable for the treatment of the 
disease states discussed above. 
U.S. Pat. No. 5,455,258 discloses 2-substituted-2-(arylsulfonylamino) 
hydroxyamic acids and their use as MMP inhibitors. WO 97/18194, discloses 
N-(arylsulfonyl)tetrahydroisoquinolone-hydroxyamic acids and related 
bicyclic derivatives thereof and their use as MMP inhibitors. WO 97/20824 
discloses 1-(arylsulfonyl)-4-(substituted)piperazine-2-hydroxyamic acids, 
4-(arylsulfonyl) morpholine-3-hydroxyamic acids, 
4-(arylsulfonyl)-tetrahydro-2H,1,4-thiazine-3-hydroxyamic acids, 
3-(substituted-1-(arylsulfonyl)hexahydro-2-hydroxyamic acids and related 
compounds as useful MMP inhibitors. 
SUMMARY OF THE INVENTION 
This invention relates to novel derivatives of substituted 
2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid hydroxyamide 
which exhibit inhibitory activity against MMPs. The compounds of the 
present invention are represented by the following formula 1 
##STR2## 
wherein 
R is selected from hydrogen, (C.sub.1 -C.sub.3) alkyl, --CN, --OR', --SR', 
--CF.sub.3, --OCF.sub.3, Cl, F, NH.sub.2, NH(C.sub.1 -C.sub.3)alkyl, 
--N(R')CO(C.sub.1 -C.sub.3)alkyl, --N(R')(R'), NO.sub.2, --CONH.sub.2, 
--SO.sub.2 NH.sub.2, --SO.sub.2 N(R')(R'), or --N(R')COCH.sub.2 O-(C.sub.1 
-C.sub.3)alkyl, wherein R' is (C.sub.1 -C.sub.3) alkyl or hydrogen: 
R.sub.4 is (C.sub.1 -C.sub.6)alkyl-O--, (C.sub.1 -C.sub.6)alkyl-S--, 
##STR3## 
wherein R" is hydrogen, halogen, cyano, methyl or --OCH.sub.3 ; 
R.sub.1 and R.sub.2 are each, independently, hydrogen or CH.sub.3 ; 
R.sub.3 is (C.sub.1 -C.sub.8)alkyl. NH.sub.2 CH.sub.2 CO--, (C.sub.1 
-C.sub.6)alkylNHCH.sub.2 CO--, HO(CH.sub.2).sub.m CO--, HCO--. 
Aryl(CH.sub.2).sub.n CO--, Heteroaryl(CH.sub.2).sub.n CO--, (C.sub.1 
-C.sub.3)alkyl-O-(CH.sub.2).sub.n CO--, (C.sub.1 -C.sub.3)alkylCO--, 
(C.sub.1 -C.sub.3)alkylCO--NHCH.sub.2 CO--, (C.sub.3 
-C.sub.7)cycloalkylCO--, (C.sub.1 -C.sub.3)alkylSO.sub.2 --, 
Aryl(CH.sub.2).sub.n SO.sub.2 --, Heteroaryl(CH.sub.2).sub.n SO.sub.2 --, 
(C.sub.1 -C.sub.3)alkyl-O-(CH.sub.2).sub.m --SO.sub.2 --, (C.sub.1 
-C.sub.3)alkyl-O-(CH.sub.2).sub.m, (C.sub.1 -C.sub.3)alkyl-O-(C.sub.1 
-C.sub.3)alkyl-O-(C.sub.1 -C.sub.3)alkyl, HO--(C.sub.1 
-C.sub.3)alkyl-O-(C.sub.1 -C.sub.3)alkyl, Aryl-O--CH.sub.2 CO--, 
Heteroaryl-O--CH.sub.2 CO--, ArylCH.dbd.CHCO--, HeteroarylCH.dbd.CHCO--, 
(C.sub.1 -C.sub.3)alkylCH.dbd.CHCO--, 
##STR4## 
Aryl(C.sub.1 -C.sub.3)alkyl, Heteroaryl(C.sub.1 -C.sub.3)alkyl, 
ArylCH.dbd.CHCH.sub.2 --, HeteroarylCH.dbd.CHCH.sub.2 --, (C.sub.1 
-C.sub.6)alkylCH.dbd.CHCH.sub.2 --, 
##STR5## 
R'OCH.sub.2 CH(OR')CO--, (R'OCH.sub.2).sub.2 C(R')CO--. 
##STR6## 
[(C.sub.1 -C.sub.6)alkyl].sub.2 --N--(C.sub.1 -C.sub.6)alkyl CO--, or 
(C.sub.1 -C.sub.6)alkyl-NH--(C.sub.1 -C.sub.6)alkylCO--; 
wherein 
m=1 to 3; n=0 to 3; 
Aryl is 
##STR7## 
and 
Heteroaryl is 
##STR8## 
wherein X is hydrogen, halogen, (C.sub.1 -C.sub.3)alkyl or --OCH.sub.3 and 
R and R' are as defined above; 
L is hydrogen, (C.sub.1 -C.sub.3)alkyl, --CN, --OR', --SR', --CF.sub.3, 
--OCF.sub.3, Cl, F, NH.sub.2, --NH--(C.sub.1 -C.sub.3)alkyl, 
--N(R')CO(C.sub.1 -C.sub.3)alkyl. N(R')(R'), --NO.sub.2, --CONH.sub.2, 
--SO.sub.2 NH.sub.2, --SO.sub.2 N(R')(R'), --N(R')COCH.sub.2 O--(C.sub.1 
-C.sub.3)alkyl, 
##STR9## 
M is 
##STR10## 
or N(R')(R') where R' is as defined above; 
W is O, S, NH or N(C.sub.1 -C.sub.3)alkyl; 
Y is hydrogen, F, Cl, CF.sub.3 or OCH.sub.3 ; and X' is halogen, hydrogen, 
(C.sub.1 -C.sub.3)alkyl, O-(C.sub.1 -C.sub.3)alkyl, or --CH.sub.2 OH; and 
pharmaceutically acceptable salts thereof. 
DETAILED DESCRIPTION OF THE INVENTION 
Preferably, the compounds of the present invention are those of formula 1 
wherein R is hydrogen, (C.sub.1 -C.sub.3)alkyl, --CN, --OR', --SR', 
--CF.sub.3, --OCF.sub.3, Cl, F, NH.sub.2, NH(C.sub.1 -C.sub.3)alkyl, 
--N(R')CO(C.sub.1 -C.sub.3)alkyl, --N(R')(R'), NO.sub.2, --CONH.sub.2, 
--SO.sub.2 NH.sub.2, --SO.sub.2 N(R')(R'), or --N(R')COCH.sub.2 O-(C.sub.1 
-C.sub.3)alkyl, wherein R' is (C.sub.1 -C.sub.3)alkyl or hydrogen; 
R.sub.4 is (C.sub.1 -C.sub.6)alkyl-O--, (C.sub.1 -C.sub.6)alkyl-S--, 
##STR11## 
wherein R" is hydrogen, halogen, cyano, methyl or --OCH.sub.3 ; 
R.sub.1 and R.sub.2 are each, independently, hydrogen or CH.sub.3 ; 
R.sub.3 is (C.sub.1 -C.sub.8)alkyl, NH.sub.2 CH.sub.2 CO--, (C.sub.1 
-C.sub.6)alkylNHCH.sub.2 CO--, HO(CH.sub.2).sub.m CO--, HCO--, 
Aryl(CH.sub.2).sub.n CO--, Heteroaryl(CH.sub.2).sub.n CO--, (C.sub.1 
-C.sub.3)alkyl-O-(CH.sub.2).sub.n CO--, (C.sub.1 -C.sub.3)alkylCO--, 
(C.sub.1 -C.sub.3)alkylCO--NHCH.sub.2 CO--, (C.sub.3 
-C.sub.7)cycloalkylCO--, Aryl-O--CH.sub.2 CO--, HeteroarylOCH.sub.2 CO--, 
ArylCH.dbd.CHCO--, HeteroarylCH.dbd.CHCO--, (C.sub.1 
-C.sub.3)alkylCH.dbd.CHCO--, 
##STR12## 
wherein 
m=1 to 3; n=0 to 3; 
Aryl is 
##STR13## 
and 
Heteroaryl is 
##STR14## 
wherein X is hydrogen, halogen, (C.sub.1 -C.sub.3)alkyl or --OCH.sub.3 
wherein R and R' are as defined above; and pharmaceutically acceptable 
salts thereof. 
More preferably, the compounds of the present invention are those of 
formula 1 wherein R is hydrogen, (C.sub.1 -C.sub.3)alkyl, --CN, --OR', 
--SR', --CF.sub.3, --OCF.sub.3, Cl, F, NH.sub.2, NH(C.sub.1 
-C.sub.3)alkyl, --N(R')CO(C.sub.1 -C.sub.3)alkyl, --N(R')(R'), NO.sub.2, 
--CONH.sub.2, --SO.sub.2 NH.sub.2, --SO.sub.2 N(R')(R'), --N(R')COCH.sub.2 
O-(C.sub.1 -C.sub.3)alkyl, wherein R' is (C.sub.1 -C.sub.3)alkyl or 
hydrogen; 
R.sub.4 is (C.sub.1 -C.sub.6)alkyl-O--, (C.sub.1 -C.sub.6)alkyl-S--, 
##STR15## 
wherein R" is hydrogen, halogen, cyano, methyl or --OCH.sub.3 ; 
R.sub.1 and R.sub.2 are each, independently, hydrogen or CH.sub.3 ; 
R.sub.3 is 
##STR16## 
[(C.sub.1 -C.sub.6)alkyl].sub.2 --N--(C.sub.1 -C.sub.6)alkyl CO--, or 
(C.sub.1 -C.sub.6)alkyl-NH--(C.sub.1 -C.sub.6)alkylCO--, wherein R' is 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, (C.sub.1 -C.sub.3)alkyl, --CN, 
--OR', --SR', --CF.sub.3, --OCF.sub.3, Cl, F, NH.sub.2, NH(C.sub.1 
-C.sub.3)alkyl. --N(R')CO(C.sub.1 -C.sub.3)alkyl, --N(R')(R'), NO.sub.2, 
--CONH.sub.2, --SO.sub.2 NH.sub.2, --SO.sub.2 N(R')(R'), or 
--N(R')COCH.sub.2 O-(C.sub.1 -C.sub.3)alkyl, wherein R' is (C.sub.1 
-C.sub.3)alkyl or hydrogen; 
R.sub.4 is (C.sub.1 -C.sub.6)alkyl-O--, (C.sub.1 -C.sub.6)alkyl-S--, 
##STR17## 
wherein R" is hydrogen, halogen, cyano, methyl or --OCH.sub.3 ; 
R.sub.1 and R.sub.2 are each, independently hydrogen or CH.sub.3 ; 
R.sub.3 is (C.sub.1 -C.sub.3)alkylSO.sub.2 --, Aryl(CH.sub.2).sub.n 
SO.sub.2 --, Heteroaryl(CH.sub.2).sub.n SO.sub.2 --, or (C.sub.1 
-C.sub.3)alkyl-O-(CH.sub.2).sub.m --SO.sub.2, 
wherein 
m=1 to3; n=0 to 3; 
Aryl is 
##STR18## 
and 
Heteroaryl is 
##STR19## 
wherein X is hydrogen, halogen, (C.sub.1 -C.sub.3)alkyl or --OCH.sub.3 and 
R and R' are as defined above, and pharmaceutically acceptable salts 
thereof. 
A further, more preferred embodiment of the present invention includes 
compounds represented by formula 1 wherein 
R is selected from hydrogen, (C.sub.1 -C.sub.3)alkyl, --CN, --OR', --SR', 
--CF.sub.3, --OCF.sub.3, Cl, F, NH.sub.2, NH(C.sub.1 -C.sub.3)alkyl, 
--N(R')CO(C.sub.1 -C.sub.3)alkyl, --N(R')(R'), NO.sub.2, --CONH.sub.2, 
--SO.sub.2 NH.sub.2, --SO.sub.2 N(R')(R'), or --N(R')COCH.sub.2 O-(C.sub.1 
-C.sub.3)alkyl, wherein R' is (C.sub.1 -C.sub.3)alkyl or hydrogen; 
R.sub.4 is (C.sub.1 -C.sub.6)alkyl-O--, (C.sub.1 -C.sub.6)alkyl-S--, 
##STR20## 
wherein R" is hydrogen, halogen, cyano, methyl or --OCH.sub.3 ; 
R.sub.1 and R.sub.2 are each, independently hydrogen or CH.sub.3 ; 
R.sub.3 is (C.sub.1 -C.sub.8)alkyl, Aryl(C.sub.1 -C.sub.3)alkyl, 
Heteroaryl(C.sub.1 -C.sub.3)alkyl, ArylCH.dbd.CHCH.sub.2, 
HeteroarylCH.dbd.CHCH.sub.2 --, or (C.sub.1 
-C.sub.6)alkylCH.dbd.CHCH.sub.2 --, 
wherein 
Aryl is 
##STR21## 
and 
Heteroaryl is 
##STR22## 
wherein X is hydrogen, halogen, (C.sub.1 -C.sub.3)alkyl or --OCH.sub.3 and 
R and R' are as defined above; and pharmaceutically acceptable salts 
thereof. 
Additionally preferred compounds of the present invention include those of 
formula 1 wherein R is hydrogen, (C.sub.1 -C.sub.3)alkyl, --CN, --OR', 
--SR', --CF.sub.3, --OCF.sub.3, Cl, F, NH.sub.2, NH(C.sub.1 
-C.sub.3)alkyl, --N(R')CO(C.sub.1 -C.sub.3)alkyl, --N(R')(R'), NO.sub.2, 
--CONH.sub.2, --SO.sub.2 NH.sub.2, --SO.sub.2 N(R')(R'), or 
--N(R')COCH.sub.2 O-(C.sub.1 -C.sub.3)alkyl, wherein R' is (C.sub.1 
-C.sub.3) alkyl or hydrogen, 
R.sub.4 is (C.sub.1 -C.sub.6)alkyl-O--, (C.sub.1 -C.sub.6)alkyl-S--. 
##STR23## 
wherein R" is hydrogen, halogen, cyano, methyl or --OCH.sub.3 ; 
R.sub.1 and R.sub.2 are each. independently hydrogen or CH.sub.3, 
R.sub.3 is 
##STR24## 
wherein 
m=1 to 3; n=0 to 3; 
L is hydrogen, (C.sub.1 -C.sub.3)alkyl, --CN, --OR', --SR', --CF.sub.3, 
--OCF.sub.3, Cl, F, NH.sub.2, --NH--(C.sub.1 -C.sub.3)alkyl, 
--N(R')CO(C.sub.1 -C.sub.3)alkyl, N(R')(R'), --NO.sub.2, --CONH.sub.2, 
--SO.sub.2 NH.sub.2, --SO.sub.2 N(R')(R'), --N(R')COCH.sub.2 O-(C.sub.1 
-C.sub.3)alkyl, 
##STR25## 
M is 
##STR26## 
or N(R')(R') where R' is as defined above; 
W is O, S, NH or N(C.sub.1 -C.sub.3)alkyl; 
Y is hydrogen, F, Cl, CF.sub.3 or OCH.sub.3 ; and X' is halogen, hydrogen, 
(C.sub.1 -C.sub.3)alkyl, O-(C.sub.1 -C.sub.3)alkyl, or --CH.sub.2 OH; and 
pharmaceutically acceptable salts thereof. 
The compounds of formula 1 may be advantageously prepared according to 
Reaction Schemes 1 to 7. Variations in these schemes may be made to 
improve productivity without negatively impacting the amount and nature of 
the product, by means that will be recognized by those skilled in the art. 
For example, reactive groups may be blocked with suitable blocking 
moieties which may then be deblocked under standard conditions (for 
instance, hydroxy groups may be protected with trimethylsilyl or 
t-butyl-dimethylsilyl moieties which are then removed in a later reaction 
step). 
In general, the compounds of Formula 1 are synthesized from an alkyl ester 
(such as methyl, ethyl, t-butyl and the like) of serine, threonine, or 
3,3-dimethyl-3-hydroxypropionic acids. One reaction pathway is shown in 
Reaction Scheme 1. It is noted that methyl esters are shown in all of the 
Reaction Schemes, however, it is to be understood that the use of methyl 
esters is for purposes of illustration only, and other suitable alkyl 
esters or benzyl esters may similarly be used. 
In Reaction Scheme 1, serine, threonine, beta-hydroxyvaline and related 
derivatives are converted to the corresponding 
N-(4-substituted-benzenesulfonyl) derivatives 3 and alkylated with 
suitable substituted or unsubstituted 2-nitrobenzyl bromides or 
2-nitrobenzyl chlorides to provide the corresponding nitro derivatives 5. 
Reduction under conventional reducing conditions, such as catalytic 
hydrogeneration (with Pd/C) or chemical reduction (e.g., with SnCl.sub.2 
or FeCl.sub.3) results in amino derivatives 6. Reaction of the 
N-(2-aminobenzyl) derivatives 6 with alkanoyl chlorides, alkylsulfonyl 
chlorides, aroyl chlorides, heteroaroyl chlorides, aryl sulfonyl 
chlorides, heteroarylsulfonyl chlorides and the like, in the presence of 
trialkylamines or pyridene, provides the dihydroalanine derivatives 7. 
Ring closure to the [1,4]benzodiazepine compounds 9 is carried out by 
reaction with a mild base such as sodium or potassium bicarbonate in an 
alcohol solvent such as methanol or ethanol. Standard conditions which 
involve hydrolysis of the ester (NaOH), acid chloride formation and 
reaction of the acid chloride with hydroxylamine are then used to convert 
the ester derivatives 8 to the hydroxamic acids 9. Ester derivatives 8 
(where the ester function is a t-butyl ester) are converted to the acid 
with trifluoroacetic acid under standard conditions. 
As illustrated in Reaction Scheme 2, derivatives 10, which contain a 
blocked hydroxyl group, are alkylated with 2-nitro or 2-amino benzyl 
alcohol derivatives 11 by application of the Mitsunobu reaction to give 
intermediates 12. Reduction of the 2-nitro group and removal of the 
hydroxy blocking group with derivatives 12, where the R.sub.4 group is a 
protected amino moiety with simultaneous deblocking of the amino and 
hydroxyl functions, gives intermediate compounds 13. The intermediate 13 
may then be reacted with benzyloxycarbonyl chloride to give the closed 
ring [1,4]benzodiazepine 14. Reaction of this compound with acyl 
chlorides, aroyl chlorides, heteroaroyl chlorides, alkysulfonyl chlorides, 
arylsulfonyl chlorides and heteroarylsulfonyl chlorides and the like 
results in the intermediates 15. 
##STR27## 
wherein 
n=0 to 3; 
m=1 to 3; 
R.sub.1 =(C.sub.1 -C.sub.3)alkyl; R=Hydrogen; halogen; OCH.sub.3 ; NO.sub.2 
; NH.sub.2 ; CF.sub.3 ; NHCOCH.sub.3 ; NHCOCH.sub.2 OCH.sub.3 ; CONH.sub.2 
; --N(R')(R'), --N(R')CO(C.sub.1 -C.sub.3)alkyl; (C.sub.1 -C.sub.3)alkyl; 
R.sub.3 =Ar(CH.sub.2).sub.n CO--; Heteroaryl(CH.sub.2).sub.n CO--, 
Ar(CH.sub.2).sub.n SO.sub.2 --; Heteroaryl(CH.sub.2).sub.n SO.sub.2 --; 
Alkyl-O--CH.sub.2).sub.n CO--; Alkyl-O-(CH.sub.2).sub.m SO.sub.2 --; 
AlkylCO--; AlkylSO.sub.2 --; AlkylCO--NHCH.sub.2 CO--; and 
cycloalkyl(C.sub.3 -C.sub.7)CO--; and 
R.sub.4 is as defined herein. 
##STR28## 
wherein 
n=0 to 3; 
m=1 to 3; 
.O slashed.=phenyl; 
DEAD=diethylazodicarboxylate; 
R.sub.6 =Ar(CH.sub.2).sub.n --; Alkyl-; Heteroaryl(CH.sub.2).sub.n --; 
Alkyl-O-(CH.sub.2).sub.n --; Cycloalkyl(C.sub.3 -C.sub.7); 
R.sub.7 =Ar(CH.sub.2).sub.n --; Alkyl-; Heteroaryl(CH.sub.2).sub.n --; 
Alkyl-O-(CH.sub.2).sub.m --; 
R.sub.8 =Ar(CH.sub.2).sub.n CO--; Ar(CH.sub.2).sub.n SO.sub.2 --; 
AlkylCO--; AlkylSO.sub.2 --; Heteroaryl(CH.sub.2).sub.n CO--; 
Heteroaryl(CH.sub.2).sub.n SO.sub.2 --; Alkyl-O-(CH.sub.2).sub.n CO--; 
Alkyl-O-(CH.sub.2).sub.m SO.sub.2 --. 
1-substituted arylmethyl-2,3,4,5-tetrahydro-1H [1,4]-benzodiazepines may be 
prepared in the manner illustrated in Reaction Schemes 3 and 4. In 
Reaction Scheme 3, the methyl 
3-hydroxy-2-[4-methoxybenzenesulfonyl)-(2-aminobenzyl)amino]-propionates 6 
are subjected to reductive alkylation with arylcarboxaldehydes and 
heteroarylcarboxaldehydes to provide intermediates 17. Standard reaction 
conditions such as reactions with triphenylphosphine and diethyl 
azodicarboxylate (DEAD) or triplenylphosphine with either carbon 
tetrachloride or carbon tetrabromide, results in the "dehydroalanine" 
derivatives 18 which are then ring closed to the [1,4]benzodiazepines 20. 
In an alternative route to the 3-hydroxamic acid derivatives 21(Scheme 4), 
N-aroyl derivatives 22 are reduced with reducing agents such as borane or 
lithium aluminum hydride to reduce both the ester and amide functions. The 
3-(hydroxymethyl)-1-(arylmethyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine 
23 are oxidized with stardard reagents known to convert a hydroxymethyl 
group to a carboxylic acid:reagents such as NaIO.sub.4 with catalyst 
RuO.sub.2 (e.g., see J. Org. Chem., 46:3936 (1981); Synlett, p. 143, 
(1996)). Coupling the acids (via the acid chlorides) to hydroxylamine then 
gives products 21. Certain intermediates as exemplified by formula 25 may 
be reduced with borane under mild conditions to give derivatives 25a in 
which the amide carbonyl is selectively reduced. These intermediates 25a 
are then converted to hydroxamic acid derivatives via hydrolysis of the 
ester to the acid and coupling the acid chloride with hydroxylamine. 
##STR29## 
wherein 
##STR30## 
and R.sub.9 and R.sub.10 are: Cl, Br, F, OCH.sub.3, OEt, SCH.sub.3, 
##STR31## 
wherein 
##STR32## 
and R.sub.9 and R.sub.10 are hydrogen, Cl, Br, F, OCH.sub.3, OEt, 
SCH.sub.3, 
##STR33## 
CF.sub.3, OCF.sub.3, or Me.sub.2 N--. 
##STR34## 
wherein R.sub.8 =alkyl, arylalkyl, aryloxyalkyl, heterocyclicalkyl, or 
alkyloxyalkyloxyalkyl. 
Other, preferred compounds of the present invention are those with basic 
moieties in the 1-(substituted carbonyl) group which may be prepared in 
the manner shown in Reaction Scheme 5. Reaction of the 
2,3,4,5-tetrahydro-1H-[1,4]-benzodiazepines 14 (without a substituent at 
the 1-position) with carbonyl chloride derivatives in the manner depicted 
in Reaction Scheme 5, results in intermediates 25 which are then converted 
to acid 26 and hydroxamic acids 27. The intermediates 25 may also be 
synthesized by reaction of methyl 
2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionates 6 
with acid chlorides to live "dehydroalanine" derivatives 28. As previously 
described, mild bases such as NaHCO.sub.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 7-membered 
2,3,4,5-tetrahydro-1H-[1,4]diazepines 25. 
##STR35## 
As illustrated in Reaction Scheme 6, aryl-arylcarbonyl, 
heteroaryl-arylcarbonyl, aryl-heteroarylcarbonyl, 
heteroaryl-heteroarylcarbonyl derivatives 30 may be synthesized by 
standard palladium catalysed coupling of bromoaroyl or bromheteroaroyl 
derivatives 29 with appropriate arylstannanes, heteroarylstannanes, 
arylboronic acids, heteroarylboronic acids, aryl triflates, heteroaryl 
triflates and the like, under known conditions. For example, see 
Synthesis, 563-566 (1997); J. Org. Chem., 62:3405-3406, (1997); 
Tetrahedron Lett., 36:5247-5250, (1995); Heterocycles, 45:467, (1997); 
Tetrahedron Lett., 38:1118-1182, (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, aryl-aryl, heteroaryl-aryl, 
aryl-heteroaryl and heteroaryl-heteroaryl carboxylic ester derivatives can 
be prepared and these derivatives converted to carboxylic acid 
intermediates. The acids are then converted to acid chlorides which are 
reacted with esters of 
2-[(2-aminobenzyl)-(4-substituted-benzenesulfonyl)amino]-3-hydroxypropiona 
te as illustrated for conversion of derivatives 6 to intermediates 31. The 
following references describe procedures for the synthesis of methyl 
3-arylpyrrole-4-carboxylates as in J. Org. Chem., 62:2649-2651, (1997); 
methyl (2-methylphenyl)benzoates as in J. Org. Chem., 62:3405-3406, 
(1997); and methyl benzoates substitued with heterocyclic moieties such as 
furanyl, thienyl or pyridinyl groups as in Tetrahedron Lett., 
27:4407-4410, (1986). 
##STR36## 
where 
##STR37## 
Y is H, F, Cl, CF.sub.3, CH.sub.3, or OCH.sub.3 ; 
X is halogen, hydrogen, or (C.sub.1 -C.sub.3)alkyl; 
R and R' are as defined herein; and 
R.sub.4 is as defined herein. 
The intermediates 2,4,5,6-tetrahydro-1H-[1,4]benzodiazepines 39 and 38 may 
be prepared from glycine esters in the manner exemplified in Reaction 
Scheme 7. In this synthetic route, N-(4-substituted-benzenesulfonyl) 
derivatives of glycine ethyl ester, glycine t-butyl ester or glycine 
methyl ester 33 are alkylated with a substituted (R) or unsubstituted 
(R=H) 2-nitrobenzyl bromide in N,N-dimethylformamide or 
1-methyl-2-pyrrolidinone in the presence of potassium carbonate to give 
intermediates 34. Alternatively, the esters of 
N-(4-substituted-benzenesulfonyl) glycines, such as the methyl ester 33. 
are first reacted with sodium hydride in N,N-dimethylformamide or 
1-methyl-2-pyrrolidinone and the resulting anion reacted with substituted 
or unsubstituted 2-nitrobenzylbromides to provide compounds 34. Reaction 
of derivates 34 with N,N-dimethyl(methylene)ammonium chloride or the 
iodide salts under standard reaction conditions (e.g., as set forth in 
Fieser and Fieser, 10:160-161; 8:194 affords the dimethylaminomethyl 
(Mannich type) compounds as intermediates for elimination to the 
"dehydroalanine" derivatives 37 or direct ring closure of 36 to 39 via an 
elimination-addition reaction. Ring closure of compounds 37 provides 
intermediates 38 for conversion to hydroxamic acids. Variations of the 
reactions conditions for conversion of 36 to 39 involve heating in the 
presence of Lewis acids, such as BF.sub.3 or heating an acid salt of 36 to 
effect the elimination-addition reaction. 
##STR38## 
The intermediate carboxylic acids for conversion to the 
tetrahydro[1,4]benzodiazepine-3-carboxylic acid, hydroxyamides may be 
synthesized via different routes as shown in Schemes 1-8. For the 
synthesis of some of the desired products of Formula 1, alternate routes 
may be preferred as shown in Scheme 8. Under these conditions, 
intermediate carboxylate esters of Intermediate 41 or acids of 
Intermediate 44 wherein the R.sub.4 substituent is an OH group are 
prepared. Intermediates with R.sub.4 an OH group may be prepared from 
derivatives wherein the OH group is protected by a croup which can be 
selectively removed. Derivatives 40 wherein R.sub.4 is an OCH.sub.3 moiety 
are suitable precursors to the desired phenolic compounds 41 and 44 
through cleavage of the oxygen methyl bond. As shown in Scheme 8, the 
anion of the phenolic OH group may be prepared in situ and then alkylated. 
Suitable bases are alkaline metal carbonates, hydrides, alkoxides and 
organic bases. Reaction with an alkylating moiety represented by the 
Formula (C.sub.1 -C.sub.6)alkyl-X wherein X is a reactive leaving group 
such as a chloride, bromide, iodide, O-mesylate of an O-tosylate gives the 
derivatives 42 and 45. 
The alkylation reaction may be carried out with caboxylate esters such as 
41 or with the carboxylic acids such as 44. Alternatively, the phenolic 
compounds 41 and 44 may be reacted under Mitsunobe Reaction conditions to 
afford the O-alkylated derivatives 42 and 45. Standard Mitsunobe Reaction 
conditions, such as those described in the following literature 
references, may be used in the coupling reactions: J. Heterocyclic Chem. 
34:349 (1997); Tetrahedron Lett. 37:6439 (1996); J. Org. Chem., 56:7173 
(1991); Tetrahedron Lett. 5709 (1989); Synthesis 1:28 (1981). 
##STR39## 
The compounds of the present invention which have a basic moiety may be 
used in the form of salts derived from pharmaceutically or physiologically 
acceptable acids. These salts include, but are not limited to, salts with 
inorganic acids (such as hydrochloric acid, sulfuric acid, nitric acid, 
phosphoric acid) or organic acids (such as acetic acid, oxalic acid, 
succinic acid, and maleic acid). Other salts of compounds with an acidic 
moiety include those with alkali metals or alkaline earth metals (such as 
sodium, potassium, calcium, and magnesium) or organic bases. 
When the present compounds are utilized in pharmaceutical compositions, 
they may be combined with one or more pharmaceutically acceptable 
carriers, e.g., solvents, diluents and the like. Such compositions 
containing the present compounds may be administered orally, in the form 
of tablets, capsules, dispersible powders, granules, suspensions, syrups 
or elixirs; parentally, in the form of a sterile injectable solution or 
suspension; or topically, in the form of creams, lotions, ointments, etc. 
Such pharmaceutical compositions may contain from about 1 to about 100 mg 
of active ingredient in combination with the carrier. 
The effective dosage of the present compounds utilized to treat a specific 
condition will vary depending upon the particular compound employed, the 
mode of administration and the type and severity of the condition being 
treated. However, in general, satisfactory results are obtained when the 
present compounds are administered at a dosage of about 0.001 to 1000 
mg/kg of body weight. 
As noted above, the compounds of the present invention may be administered 
orally, as well as by intravenous. intramuscular, subcutaneous or topical 
routes. Solid carriers useful for preparing tablets, capsules, etc., 
include starch, lactose, dicalcium phosphate, microcrystalline cellulose, 
sucrose and kaolin. Liquid carriers useful for preparing compositions of 
the present compounds include sterile water, polyethylene, glycols, 
non-ionic surfactants, and edible oils such as corn, sesame, and peanut 
oils. Adjuvants conventionally used in the preparation of pharmaceutical 
compositions may also be included, such as flavoring agents, coloring 
agents, preservatives and antioxidants. 
The compounds of the present invention were tested for biological activity 
according to the following procedures. 
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 calorimetrically with DTNB 
((5,5'-dithio-bis(2-nitro-benzoic acid)). This assay is disclosed in 
Weingarten et al., "Spectrophotometric Assay for Vertebrate Collegenase", 
Anal. Biochem., 147:437-440, (1985). The enzyme activity is measured by 
the rate of the color increase. 
The thiopeptide substrate was made up fresh as a 20 mM stock in 100% DMSO 
and the DTNB was dissolved in 100% DMSO as a 100 mM stock and stored in 
the dark at room temperature. The substrate and the DTNB were diluted 
together to 1 mM with substrate buffer (50 mM HEPES, pH 7.5, 5 mM 
CaCl.sub.2) before use. The stock of human neutrophil gelatinase B was 
diluted with assay buffer (50 mM HEPES, pH 7.5, 5 mM CaCl.sub.2, 0.02% 
Brij) to a final concentration of 0.15 nM. 
The assay buffer, enzyme. DTNB/substrate (500 .mu.M final concentration) 
and vehicle or inhibitor were added to a 96 well plate (total reaction 
volume of 200 .mu.l) and the increase in color was monitored 
spectrophotometrically for 5 minutes at 405 nm on a plate reader. 
The increase in OD.sub.405 was plotted and the slope of the line was 
calculated. The slope represents the reaction rate. The linearity of the 
reaction rate was confirmed (r.sup.2 &gt;0.85) and the mean (x.+-.sem) of the 
control rate was calculated and compared for statistical significance 
(p&lt;0.05) with drug-treated rates using Dunnett's multiple comparison test. 
Dose-response relationships were generated using multiple doses of drug 
and IC.sub.50 values with 95% CI were estimated using linear regression 
(IPRED, HTB). 
In Vitro Collagenase Assay 
This assay was based on the cleavage of a peptide substrate 
((Dnp-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMa)-NH.sub.2), available from 
Peptide International, Inc.) by collagenase releasing the fluorescent NMa 
group which was quantitated on the fluorometer as disclosed in Bickett et 
al., "A High Throughput Fluorogenic Substrate for Interstitial Collagenase 
(MMP-1) and Gelatinase (MMP-9)", Anal. Biochem., 212:58-64, (1993). Dnp 
quenches the NMa fluorescence in the intact substrate. 
The assay was run in HCBC assay buffer (50 mM HEPES, pH 7.0, 5 mM 
Ca.sup.+2, 0.02% Brij, 0.5% Cysteine), with human recombinant fibroblast 
collagenase (truncated, mw=18,828. from Wyeth-Ayerst Research, Radnor, 
Pa.). The substrate was dissolved in methanol and stored frozen in 1 mM 
aliquots. Collagenase was stored frozen in buffer in 25 .mu.M aliquots. In 
conducting the assay, the substrate was dissolved in HCBC buffer to a 
final concentration of 10 .mu.M and collagenase to a final concentration 
of 5 nM. The compounds being examined were dissolved in methanol, DMSO, or 
HCBC. The methanol and DMSO were diluted in HCBC to &lt;1.0%. The compounds 
were added to a 96 well plate containing enzyme and the reaction was 
started by the addition of substrate. 
The reaction was read (excitation 340 nm, emission 444 nm) for 10 min. and 
the increase in fluorescence over time was plotted as a linear line. The 
slope of the line was calculated representing the reaction rate. The 
linearity of the reaction rate was confirmed (r.sup.2 &gt;0.85). The mean 
(x.+-.sem) of the control rate was calculated and compared for statistical 
significance (p&lt;0.05) with drug-treated rates using Dunnett's multiple 
comparison test. Dose-response relationships were generated using multiple 
doses of drug and IC.sub.50 values with 95% CI were estimated using linear 
regression. 
Procedure for Measuring TACE Inhibition 
In a 96-well black microtiter plate, each well received a solution composed 
of 10 .mu.L TACE (available from Immunex) at a final concentration of 1 
.mu.g/mL, 70 .mu.L Tris buffer, have a pH of 7.4 and containing 10% 
glycerol (final concentration 10 mM), and 10 .mu.L of test compound 
solution in DMSO (final concentration 1 .mu.M, DMSO concentration&lt;1%). The 
plates were incubated for 10 minutes at room temperature. The reaction was 
initiated by addition of a fluorescent peptidyl substrate (final 
concentration 100 .mu.M) to each well with shaking on a shaker for 5 sec. 
The reaction was read (excitation 340 nm, emission 420 nm) for 10 min. and 
the increase in fluorescence over time was plotted as a linear line. The 
slope of the line was calculated and this represents the reaction rate. 
The linearity of the reaction rate was confirmed (r.sup.2 &gt;0.85). The mean 
(x.+-.sem) of the control rate was calculated and compared for statistical 
significance (p&lt;0.05) with drug-treated rates using Dunnett's multiple 
comparison test. Dose-response relationships were generated using multiple 
doses of drug and IC.sub.50 values with 95% CI were estimated using linear 
regression. 
The results obtained following these standard experimental test procedures 
are presented in Table 1. 
TABLE 1 
__________________________________________________________________________ 
#STR40## 
- Compound IC.sub.50 (nM) 
R.sub.3 of Example 
R R.sub.1 
R.sub.2 
R.sub.4 
MMP-1 
MMP-9 
MMP-13 
TACE 
__________________________________________________________________________ 
#STR41## 
2 H H H 
--OCH.sub.3 -- 
14.1 5.1 391 
.+-. 12 
- --SO.sub.2 CH.sub.3 3 H H H --OCH.sub.3 156.5 7.9 3.0 104 .+-. 8 
--SO.sub.2 
CH.sub.2 
CH.sub.2 
CH.sub.3 10 H H 
H --OCH.sub.3 
183 7.0 2.8 
91 .+-. 10 
- 
4 H H H 
--OCH.sub.3 
224.1 12.2 4.3 
101 .+-. 3 
- --COCH.sub.3 
6 H H H 
--OCH.sub.3 18.4 
1.4 1.0 103 .+-. 
7 
- 
5 H H H 
--OCH.sub.3 15.8 
(23) 0.56 
(1.7) 0.4 (1.1) 
95 .+-. 10 
- 
7 H H H 
--OCH.sub.3 20.4 
(34) 0.6 (1.9) 
0.4 (1.3) 77.7 
.+-. 7 
- 
8 H H H 
--OCH.sub.3 19.7 
1.1 1.1 12.8 
.+-. 1.2 
- 
13 H H H 
--OCH.sub.3 54.9 
9.8 2.0 154 .+-. 
27 
- COCH.sub.2 OCH.sub.3 9 H H H --OCH.sub.3 34.1 1.34 1.19 95.2 
.+-. 14.8 
- 
12 H H H 
--OCH.sub.3 523 
17.9 25.7 207 
.+-. 21 
- 
1 H H H 
--OCH.sub.3 96.2 
5.1 3.7 352 .+-. 
34 
- 
11 H H H 
--OCH.sub.3 55.4 
3.9 2.3 271 .+-. 
20 
- 
15 H H H 
--OCH.sub.3 52.7 
0.7 0.4 199 .+-. 
19 
- 
14 H H H 
--OCH.sub.3 542 
12.6 3.7 45% 
(1 uM) 
- 
55 H H H 
--OCH.sub.3 171 
4.0 3.3 68.5 
.+-. 7.2 
- 
57 H H H 
--OCH.sub.3 465 
12.7 7.2 318 
.+-. 27 
- 
31 H H H 
--OCH.sub.3 75.5 
3.0 2.6 36% (1 
uM) 
- 
40 H H H 
--OCH.sub.3 16.6 
1.4 1.2 28.5 
.+-. 6.6 
- 
58 H H H 
--OCH.sub.3 65.5 
4.4 2.9 154 .+-. 
20 
- --COCH.sub.2 OCH.sub.3 59 7-CH.sub.3 H H --OCH.sub.3 105 2.6 1.8 
125 .+-. 6 
- 
60 7-CH.sub.3 
H H --OCH.sub.3 
22.7 1.4 1.3 143 
.+-. 4 
- 
61 8-Cl H H 
--OCH.sub.3 239 
(265) 1.3 
(3.9) 0.4 (4.3) 
1248 .+-. 69 
- --CH.sub.2 
CH.sub.2 
OCH.sub.3 62 H H 
H --OCH.sub.3 
1000 100 
100 51 (1 
.mu.M) 
- 
63 7-CH.sub.3 
H H --OCH.sub.3 
130 5.6 3.1 
446 .+-. 48 
- 
64 8-Cl H H 
--OCH.sub.3 157 
6.1 3.4 384 
.+-. 8 
- 
65 H H H 
--OCH.sub.3 23.5 
1.5 1.5 157 .+-. 
13 
- 
66 H H H 
--OCH.sub.3 83.4 
3.4 2.6 148 .+-. 
14 
- 
67 H H H 
--OCH.sub.3 1323 
50.8 73.9 
551 .+-. 29 
- 
71 H H H 
--OCH.sub.3 41.3 
2.4 1.3 136 .+-. 
15 
- 
72 H H H 
--OCH.sub.3 4982 
187 317 
808 .+-. 
__________________________________________________________________________ 
90

The present invention will now be illustrated with reference to the 
following, non-limiting examples. 
REFERENCE EXAMPLE 1 
(L) N-(Benzyloxycarbonyl)-O-benzylserine, t-butyl ester 
Into a solution of 25 g (0.076 mol) of N-(benzyloxycarbonyl)-O-benzylserine 
in 600 ml of CH.sub.2 Cl.sub.2 cooled to -6.degree. C. in an ice-salt bath 
was bubbled isobutylene, while 4.1 ml of concentrated sulfuric acid was 
added dropwise thereto. The mixture was stirred for 4 hours and worked up 
as described in Synthetic Commun., 26:2723 (1996) to give 29.24 g of 
product as a yellow oil. 
REFERENCE EXAMPLE 2 
L-Serine, t-butyl ester 
A mixture of 29.24 g (0.076 mol) of (L) 
N-(benzyloxycarbonyl)-O-benzylserine, t-butyl ester from Reference Example 
1, 24.1 g (0.38 mol) of ammonium formate and 38.3 g of 10% palladium on 
carbon in 600 ml of methanol was heated at 65.degree. C. for 20 hours and 
stirred at room temperature overnight. The mixture was filtered through 
diatomaceous earth and the filter pad was washed with methanol. The 
filtrate was concentrated to give 12.18 g (99.6%) of product as described 
in Synthetic Commun., 26:2723 (1996). 
REFERENCE EXAMPLE 3 
N-(4-Methoxybenzenesulfonyl)-L-serine, t-butyl ester 
(3-hydroxy-2-(4-methoxybenzenesulfonylamino)propionic acid, tert-butyl 
ester) 
To a solution of 12.18 g (0.0756 mol) of L-serine, t-butyl ester, 26.52 ml 
of triethylamine in 160 ml of CH.sub.2 Cl.sub.2 (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.degree. 
C. for 0.5 hours and at room temperature overnight. The mixture was washed 
with H.sub.2 O, 2N citric acid, brine and dried with Na.sub.2 SO.sub.4. 
The solvent was removed under vacuum to give 25.34 g of solid which was 
triturated with hexane. The solid was recrystallized from 120 ml of 
toluene to give 12.18 g (48.7%) of product as a white solid. The filtrate 
was concentrated and the residue chromatographed on silica gel with 
hexane-ethyl acetate (7:3) as eluent to give 5.71 g (22.8%) of white 
solid. m.p. 70-75.degree. C. Anal. for C.sub.14 H.sub.21 NO.sub.6 S: 
Calc'd: 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 
3-hydroxy-2-(4-methoxybenzenesulfonylamino)-propionic acid tert-butyl 
ester in 50 ml of N,N-dimethylformamide, cooled in an ice bath, was added 
0.781 g (19.5 mmol) of sodium hydride. After gas evolution ceased, a 
solution of 4.02 g (18.6 mmol) of 2-nitrobenzylbromide in 18 ml of 
N,N-dimethylformamide was added dropwise. The mixture was stirred under 
nitrogen at room temperature for 4 hours and 1.0 g of 2-nitrobenzyl 
bromide was added. The mixture was stirred at room temperature overnight 
and the solvent removed under vacuum. The residue was diluted with water 
and extracted with CH.sub.2 Cl.sub.2. The organic extract was washed with 
H.sub.2 O, brine and dried with Na.sub.2 SO.sub.4. The solvent was removed 
to give 11.2 g of solid which was chromatographed on silica gel with 
hexane-ethyl acetate (1:1) as eluent followed by hexane-ethyl acetate 
(35:65) as eluent. The fractions containing product were combined and the 
solvent was then removed to gave 7.7 g (89%) of solid. A sample from a 3 
mmol run gave a gum. Anal. for C.sub.21 H.sub.26 N.sub.2 O.sub.8 S: 
Calc'd: 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 ester 
A 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 SnCl.sub.2.2H.sub.2 O in 
20 ml of methanol was heated in an oil bath at 90.degree. C. for 2 hours. 
The solvent was removed under vacuum and ethyl acetate added to the 
residue. The mixture was neutralized with saturated sodium bicarbonate 
solution and filtered through diatomaceous earth. The ethyl acetate layer 
was separated and washed with H.sub.2 O, brine and dried with Na.sub.2 
SO.sub.4. The solvent was removed under vacuum to give 0.30 g (53%) of a 
gum. Anal. for C.sub.21 H.sub.28 N.sub.2 O.sub.6 S: Calc'd: C, 57.8; 
H,6.5; N,6.4; Found: C, 57.8; H,7.0; N,6.2. 
REFERENCE EXAMPLE 6 
2-[(2-Aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionic acid 
A solution of 0.75 g (1.72 mmol) of 
2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionic 
acid, tert-butyl ester and 6 ml of trifluoroacetic acid in 6 ml of 
CH.sub.2 Cl.sub.2 was stirred at room temperature for 3 hours and then 
concentrated to dryness under vacuum. To the residue was added H.sub.2 O, 
CH.sub.2 Cl.sub.2 and 1N NaOH until the aqueous layer reached pH 8. The 
aqueous layer was then separated, acidified with 2 N citric acid and 
extracted with ethyl acetate. The extract was washed with H.sub.2 O, brine 
and dried Na.sub.2 SO.sub.4. The solvent was removed under vacuum to give 
0.35 g (54%) of a solid. Anal. for C.sub.17 H.sub.20 N.sub.2 O.sub.6 S: 
Calc'd: C, 53.7; H,5.3; N,7.4; Found: C, 53.0; H,5.3; N,6.9. 
REFERENCE EXAMPLE 7 
2-{(2-[3-(Trifluoromethylbenzoyl)aminobenzyl]-(4-methoxybenzenesulfonyl)ami 
no}acrylic acid, tert-butyl ester 
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 CH.sub.2 Cl.sub.2 was stirred at 
room temperature for 3.5 hours. The mixture was poured into H.sub.2 O and 
extracted with CH.sub.2 Cl.sub.2. The extract was washed with H.sub.2 O, 2 
N citric acid, H.sub.2 O, 1 N NaHCO.sub.3, brine and dried with Na.sub.2 
SO.sub.4. The solvent was removed to give 0.72 g of solid. The solid was 
dissolved in 2 ml of tetrahydrofuran and 1.5 ml of triethylamine was added 
thereto. The solution was heated at 65.degree. C. overnight and 
concentrated to dryness under vacuum. The residue was extracted with 
CH.sub.2 Cl.sub.2 and the extract washed with H.sub.2 O and dried with 
Na.sub.2 SO.sub.4. The solvent was removed under vacuum to give 0.55 g of 
product as a solid. From a similar run the product was chromatographed on 
silica gel with hexane-ethyl acetate to give a solid, m.p. 65-72.degree. 
C. Anal. for C.sub.29 H.sub.29 F.sub.3 N.sub.2 O.sub.6 S: Calc'd: C, 59.0; 
H,5.0; N,4.7; Found: C, 59.2; H,5.2, N,4.4. 
REFERENCE EXAMPLE 8 
4-(4-Methoxybenzenesulfonyl)-1-(3-trifluoromethylbenzoyl)-2,3,4,5-tetrahydr 
o-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]-aminobenzoyl]-(4-methoxybenzenesulfonyl 
)amino}acrylic acid, tert-butyl ester and 0.102 g (1.21 mmol) of 
NaHCO.sub.3 in 4 ml of methanol was stirred at room temperature overnight 
and the solvent removed. The residue was extracted with CH.sub.2 Cl.sub.2 
and the extract washed with H.sub.2 O, brine and dried with Na.sub.2 
SO.sub.4. 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.degree. C. Anal. for C.sub.29 H.sub.29 F.sub.3 N.sub.2 O.sub.6 S: 
Calc'd: 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-tetrahydr 
o-1H-[1,4]benzodiazepine-3-carboxylic acid 
A mixture of 0.36 g (0.61 mmol) of 
4-(4-methoxybenzenesulfonyl)-1-(3-trifluoromethylbenzoyl)-2,3,4,5-tetrahyd 
ro-1H-[1,4]benzodiazepine-3-carboxylic acid, tert-butyl ester and 3 ml of 
trifluoroacetic acid in 3 ml of CH.sub.2 Cl.sub.2 was stirred at room 
temperature for 3 hours. The mixture was concentrated to dryness under 
vacuum and the residue extracted with CH.sub.2 Cl.sub.2. The CH.sub.2 
Cl.sub.2 was washed with 1 N NaHCO.sub.3 and the aqueous layer (pH 8) was 
acidified with 2 N citric acid and extracted with ethyl acetate. The 
extract was dried (Na.sub.2 SO.sub.4). The original CH.sub.2 Cl.sub.2 
extract was washed with 2 N citric acid, H.sub.2 O, brine and dried with 
Na.sub.2 SO.sub.4. The CH.sub.2 Cl.sub.2 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.degree. C. Anal. for C.sub.25 H.sub.21 F.sub.3 
N.sub.2 O.sub.6 S: Calc'd: C,56.2; H,4.0; N,5.2; Found: C,55.1; H,3.7; 
N,5.0. 
REFERENCE EXAMPLE 10 
Methyl 
1-([1,1'-Biphenyl]-2-carbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrah 
ydro-1H-[1,4]benzodiazepine-3-carboxylate 
To a mixture of 1.5 g (3.8 mmol) of methyl 
2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate 
and 2.65 ml of triethylamine in 12 ml of CH.sub.2 Cl.sub.2 chilled at 
0.degree. C. was added a solution of [1,1'-biphenyl]-2-carbonyl chloride 
in 6 ml of CH.sub.2 Cl.sub.2. The mixture was stirred at room temperature 
overnight and diluted with CH.sub.2 Cl.sub.2 and H.sub.2 O. The organic 
layer was separated and washed with 2 N citric acid, brine and dried-with 
Na.sub.2 SO.sub.4. The solvent was removed under vacuum to give 2.2 g of a 
white foam. Anal. for C.sub.31 H.sub.28 N.sub.2 O.sub.6 S: Calc'd: C,66.9; 
H,5.1; N,5.0; Found: C,67.3; H,5.2; N,4.7. 
REFERENCE EXAMPLE 11 
Methyl 
4-(4-Methoxybenzenesulfonyl)-1-(2-methyl-5-fluorobenzoyl)-2,3,4,5-tetrahyd 
ro-1H-[1,4]benzodiazepine-3-carboxylate 
To a mixture of 1.5 g (3.80 mmol) of methyl 
2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate 
and 2.64 ml (18.97 mmol) of triethylamine in 15 ml of CH.sub.2 Cl.sub.2, 
chilled to 0.degree. C., was added 1.36 g (11.4 mmol) of 
2-methyl-5-fluorobenzoyl chloride. The mixture was stirred at room 
temperature overnight. The solution was then diluted with CH.sub.2 
Cl.sub.2 and water and the organic layer separated. The organic layer was 
washed with 2 N citric acid, brine and dried with Na.sub.2 SO.sub.4. The 
solvent was removed under vacuum to give 2.2 g of a white foam. Anal. for 
C.sub.26 H.sub.25 FN.sub.2 O.sub.6 S: Calc'd: C,60.9; H,4.9; N,5.5; Found: 
C,60.9; H,5.0; N,5.0; Mass spectrum (ES) 513.4 (M+H). 
REFERENCE EXAMPLE 12 
Methyl 
4-(4-Methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-c 
arboxylate 
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 CH.sub.2 Cl.sub.2 
chilled to 0.degree. C. was added 9.05 ml (63.4 mmol) of benzyl 
chloroformate. The mixture was stirred overnight and then cooled to 
0.degree. C. and 0.8 ml of triethylamine and 9.05 ml (63.4 mmol) of benzyl 
chloroformate were added thereto. The mixture was stirred overnight and 
then washed with H.sub.2 O, 2 N citric acid, brine and dried with Na.sub.2 
SO.sub.4. 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 product as a viscous yellow oil. From a similar 0.5 
g run, there was obtained 0.178 g of an oil. Anal. for C.sub.18 H.sub.20 
N.sub.2 O.sub.5 S: Calc'd: C,57.4; H,5.4; N,7.4; S,8.5; Found: C,57.9; 
H,5.4; N,6.7; S,7.9; Mass spectrum (ES) 377.2 (M+H). 
REFERENCE EXAMPLE 13 
Methyl 3-Hydroxy-2-(4-methoxybenzenesulfonylamino)propionate 
To a mixture of 5.0 g (32.14 mmol) of D,L-serine, methyl ester and 15.7 ml 
(0.012 mol) of triethylamine in 100 ml of CH.sub.2 Cl.sub.2, cooled to 
0.degree. C., was added portionwise 6.64 g (32.14 mmol) of 
4-methoxybenzenesulfonyl chloride. The mixture was then stirred under 
argon at room temperature for 2 days. The mixture was diluted with 100 ml 
of CH.sub.2 Cl.sub.2 and then washed with 60 ml each of H.sub.2 O, 2 N 
citric acid, brine and dried with Na.sub.2 SO.sub.4. 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.degree. C. Anal. for 
C.sub.11 H.sub.15 NO.sub.6 S: Calc'd: C,45.7; H,5.2; N,4.8; S,11.1; Found: 
C,45.6; H,5.2; N,4.8; S,1.11. 
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, was added portionwise 2.29 g 
(57.03 mmol) of NaH (60% in oil). The mixture was stirred at 0.degree. C. 
for 20 minutes and then a solution of 12.32 g (57.03 mmol) of 
2-nitrobenzyl bromide in 25 ml of dry N,N-dimethylformamide was added 
dropwise. The solution was stirred at room temperature for 48 hours and 
diluted with 500 ml of ethyl acetate and water. The organic layer was 
separated and the aqueous layer extracted with 250 ml of ethyl acetate. 
The combined organic layer and extract was washed with 200 ml each of 
H.sub.2 O, 1 N NaHCO.sub.3, brine and dried with Na.sub.2 SO.sub.4. The 
solvent was removed and the residual solid was triturated with ethyl 
acetate, cooled and filtered to give 13.5 g (61%) of white crystals, 
having a m.p. 127-129.degree. C. From a small scale run (3.0 g) there was 
obtained 2.32 g of white crystals, having a m.p. 127-129.degree. C. Anal. 
for C.sub.18 H.sub.20 N.sub.2 O.sub.8 S: Calc'd: C.50.9; H,4.8; N,6.6; 
Found: C,50.9; H,4.8; N,6.5. 
REFERENCE EXAMPLE 15 
Methyl 
2-[(2-Aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate 
To a mixture under nitrogen of 1.5 g (3.53 mmol) of methyl 
3-hydroxy-2-[(4-methoxybenzenesulfonyl)-(2-nitrobenzyl)amino]propionate in 
5 ml of dry ethanol was added 1.12 g (17.69 mmol) of ammonium formate 
followed by the addition of 0.50 g of 10% palladium on carbon. The mixture 
was stirred overnight at room temperature and heated at 80.degree. C. for 
2 hours. The mixture was filtered through diatomaceous earth and the 
filtrate concentrated to dryness under vacuum to give a semisolid. 
Trituration with ethyl acetate gave 0.65 g (47%) of white crystals, m.p. 
138-140.degree. C.; Anal. for C.sub.18 H.sub.22 N.sub.2 O.sub.6 S: Calc'd: 
C,54.8; H,5.6; N,7.1; Found: C,53.0; H,5.6; N,6.8. 
REFERENCE EXAMPLE 16 
Methyl 
3-Hydroxy-2-{(4-methoxybenzenesulfonyl)-[2-(2,2,2-trifluoroacetylamino)ben 
zyl]amino}propionate 
To a solution of 0.50 g (1.27 mmol) of methyl 
2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate in 
5 ml of CH.sub.2 Cl.sub.2 was added 1.8 ml (12.7 mmol) of trifluoroacetic 
anhydride. The solution was stirred for 1 hour and concentrated to dryness 
under vacuum. Methanol was added to the residue and the solvent was 
removed under vacuum. The addition of methanol and concentration to 
dryness was repeated twice. The residue was chromatographed on silica gel 
thick layer plates with hexane-ethyl acetate (1:1) to give 0.50 g of a 
colorless glass. Anal. for C.sub.20 H.sub.21 F.sub.3 N.sub.2 O.sub.7 S: 
Calc'd: C,49.0; H,4.3; N,5.7; Found: C.49.0; H,4.5; N,5.4. 
REFERENCE EXAMPLE 17 
Methyl 2-[(4-Methoxybenzenesulfonyl)-(2-nitrobenzyl)amino]acrylate 
To a solution of 1.0 g (2.356 mmol) of methyl 
3-hydroxy-2-[(4-methoxybenzenesulfonyl)-(2-nitrobenzyl)amino]propionate in 
2 ml of pyridine, cooled to -10.degree. C. was added 0.539 g (2.83 mmol) 
of 4-methylbenzeuesulfonyl chloride. The solution was chilled overnight 
and 4 ml of pyridine and 0.539 g (2.83 mmol) of 4-methylbenzene-sulfonyl 
chloride were added. The mixture was stirred and chilled at -10.degree. C. 
for 24 hours and diluted with H.sub.2 O. The mixture was extracted with 
ethyl acetate and the extract washed with H.sub.2 O, 2 N citric acid, and 
brine and then dried (Na.sub.2 SO.sub.4). 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 H.sub.2 
O. The mixture was extracted with ethyl acetate and the extract was washed 
with H.sub.2 O, 2 N citric acid, and brine and then dried with Na.sub.2 
SO.sub.4. 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.degree. C. 
Anal. for C.sub.18 H.sub.18 N.sub.2 O.sub.7 S: Calc'd: C,53.2; H,4.5; 
N,6.9; Found: C,53.7; H,4.5; N,7.2. 
REFERENCE EXAMPLE 18 
Methyl 2-{(4-Methoxybenzenesulfonyl)-[2-(4-pyridinylcarbonyl) 
aminobenzyl]amino}acrylate 
To a mixture of 1.5 g (3.80 mmol) of methyl 
2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate 
and 3.0 ml (21.6 mmol) of triethylamine in 15 ml of CH.sub.2 Cl.sub.2 
cooled to 0.degree. C. was added 1.7 g (9.5 mmol) ml of 4-pyridinecarbonyl 
chloride (isonicotinoyl chloride). The mixture was stirred at room 
temperature overnight and diluted with CH.sub.2 Cl.sub.2. The mixture was 
washed with H.sub.2 O, 2 N citric acid, and brine and then dried with 
Na.sub.2 SO.sub.4. The solvent was removed to give 1.8 g of a light tan 
solid; Anal. for C.sub.24 H.sub.23 N.sub.3 O.sub.6 S: Calc'd: 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). 
Utilizing the procedure described in Reference Example 18. the following 
intermediate compounds can be prepared from the appropriately 
unsubstituted methyl 
2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate or 
the appropriately substituted methyl 
2-[(substituted-2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxyp 
ropionate. 
REFERENCE EXAMPLE 19 
Methyl 
2-{(4-Methoxybenzenesulfonyl)-[2-(2,2,2-trifluoroacetylamino)benzyl]amino} 
acrylate 
white crystals, m.p. 120-121.degree. C. Anal. for C.sub.20 H.sub.19 F.sub.3 
N.sub.2 O.sub.6 S: Calc'd: C.50.9; H,4.1; N,5.9; Found: C,50.8; H,4.2; 
N,5.6. 
REFERENCE EXAMPLE 20 
Methyl 2-[(2-Benzoylaminobenzyl)-(4-methoxybenzenesulfonyl) amino]acrylate 
yellow oil. Anal. for C.sub.25 H.sub.24 N.sub.2 O.sub.6 S: Calc'd: C,62.5; 
H,5.0; N,5.8; Found: C,62.7; H,5.3; N,5.0. 
REFERENCE EXAMPLE 21 
Methyl 2-[(2-Acetylaminobenzyl)-(4-methoxybenzenesulfonyl) amino]acrylate 
REFERENCE EXAMPLE 22 
Methyl 
2-((4-Methoxybenzenesulfonyl)-{2-[(3-pyridinylcarbonyl)amino]benzyl}amino) 
acrylate 
off-white solid. Anal. for C.sub.24 H.sub.23 N.sub.3 O.sub.6 S: Calc'd: 
C,59.9; H,4.8; N,8.7; S,6.6; Found: C,58.9; H,4.8; N,8.4; S,6.4; Mass 
spectrum (ES) 482.8(M+H). 
EXAMPLE 23 
Methyl 
2-((4-Methoxybenzenesulfonyl)-{[(2-thienylcarbonyl)amino]benzyl}amino)acry 
late 
tan solid. Anal. for C.sub.23 H.sub.22 N.sub.2 O.sub.6 S.sub.2 : Calc'd: 
C.56.8; H,4.6; N,5.8; Found: C,55.7; H,4.4; N,4.9. 
REFERENCE EXAMPLE 24 
Methyl 
2-{[2-(-Methoxyacetylamino)benzyl]-(4-methoxybenzenesulfonyl)amino}acrylat 
yellow oil. Anal. for C.sub.21 H.sub.24 N.sub.2 O.sub.7 S: Calc'd: C,56.2; 
H,5.4; N,6.3; Found: C,55.3; H,5.6; N,5.8. 
REFERENCE EXAMPLE 25 
Methyl 
2-{(4-Methoxybenzenesulfonyl)-[2-(n-propylsulfonylamino)benzyl]amino}acryl 
ate 
light brown oil. Anal. for C.sub.21 H.sub.2.sub.6 N.sub.2 O.sub.7 S.sub.2 : 
Calc'd: C,52.3; H,5.4; N,5.8; Found: C,51.9; H,5.4; N,5.7. 
REFERENCE EXAMPLE 26 
Methyl 
2-{[2-(3-Phenylpropionyl)aminobenzyl]-(4-methoxybenzenesulfonyl)amino}acry 
late 
light brown oil. Anal. for C.sub.27 H.sub.28 N.sub.2 O.sub.6 S: Calc'd: 
C,63.8; H,5.6; N,5.5; Found: C,66.7; H,5.8; N,4.1. 
REFERENCE EXAMPLE 27 
tert-Butyl 
2-{[2-(3-Trifluoromethylbenzoyl)aminobenzyl]-(4-methoxybenzenesulfonyl)ami 
no}acrylate 
yellow solid; m.p. 65-72.degree. C. 
REFERENCE EXAMPLE 28 
Methyl 
2-{[2-(4-Biphenylcarbonyl)aminobenzyl]-(4-methoxybenzenesulfonyl)amino}acr 
ylate 
white solid. Anal for C.sub.31 H.sub.28 N.sub.2 O.sub.6 S: Calc'd: C,66.9; 
H,5.1; N,5.0; Found: C,66.1; H,5.0; N,5.1. 
REFERENCE EXAMPLE 29 
Methyl 
2-{[2-(Cyclopropylcarbonyl)aminobenzyl]-(4-methoxybenzenesulfonyl)amino}ac 
rylate 
yellow oil. Anal. for C.sub.22 H.sub.24 N.sub.2 O.sub.6 S: Calc'd: 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 
Methyl 
2-{[2-(Cyclohexylcarbonyl)aminobenzyl]-(4-methoxybenzenesulfonyl)amino}acr 
ylate 
white foam. Anal. for C.sub.25 H.sub.30 N.sub.2 O.sub.6 S: Calc'd: 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 
Methyl 
2-{[2-(3-Fluorobenzoyl)aminobenzyl]-(4-methoxybenzenesulfonyl)amino}acryla 
te 
REFERENCE EXAMPLE 32 
Methyl 
2-{[2-(3-Chlorobenzoyl)aminobenzyl]-(4-methoxybenzenesulfonyl)amino}acryla 
te 
REFERENCE EXAMPLE 33 
Methyl 
2-{[2-(2,4-Dichlorobenzoyl)aminobenzyl]-(4-methoxybenzenesulfonyl)amino}ac 
rylate 
REFERENCE EXAMPLE 34 
Methyl 
2-{[2-(2,3-Difluorobenzoyl)aminobenzyl]-(4-methoxybenzenesulfonyl)amino}ac 
rylate 
REFERENCE EXAMPLE 35 
Methyl 
2-{[2-(2-Chloro-4-fluorobenzoyl)aminobenzyl]-(4-methoxybenzenesulfonyl)ami 
no}acrylate 
REFERENCE EXAMPLE 36 
Methyl 
2-{[2-(2-Furanylcarbonyl)aminobenzyl]-(4-methoxybenzenesulfonyl)amino}acry 
late 
off-white solid. Anal. for C.sub.23 H.sub.22 N.sub.2 O.sub.7 S. Calc'd: 
C,58.7; H,4.7; N,6.0; Found: Ca58.0; H,4.1; N,3.8; Mass Spectrum (ES) 
470.9 (M+H). 
REFERENCE EXAMPLE 37 
Methyl 
2-((4-Methoxybenzenesulfonyl)-{2-[(3-thienylcarbonyl)amino]benzyl}amino)ac 
rylate 
REFERENCE EXAMPLE 38 
Methyl 
2-{[2-(2-Acetylaminoacetyl)aminobenzyl]-(4-methoxybenzenesulfonyl)amino}ac 
rylate 
REFERENCE EXAMPLE 39 
Methyl 
2-{[2-(2-Dimethylacetyl)aminobenzyl]-(4-methoxybenzenesulfonyl)amino}acryl 
ate 
REFERENCE EXAMPLE 40 
Methyl 
2-{[2-(Cyclobutylcarbonyl)aminobenzyl]-(4-methoxybenzenesulfonyl)amino}acr 
ylate 
REFERENCE EXAMPLE 41 
Methyl 
1-Methoxyacetyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]be 
nzodiazepine-3-carboxylate 
To a mixture of 0.449 g (1 mmol) of methyl 
2-[[2-(2-methoxyacetamido)benzyl]-(4-methoxybenzene-sulfonyl]amino]acrylat 
e 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 removed under vacuum. To the residue was added ethyl 
acetate and water. The organic layer was separated and washed with H.sub.2 
O and brine and then dried with Na.sub.2 SO.sub.4. The solvent was removed 
to give 0.41 g of solid. The solid was crystallized from ethyl acetate to 
give 0.28 g of white crystals, m.p. 160-163.degree. C. Anal. for C.sub.21 
H.sub.24 N.sub.2 O.sub.7 S: Calc'd: 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). 
Utilizing the procedure in Reference Example 41, the following intermediate 
compounds can be prepared from the appropriate methyl 
2-{(4-methoxybenzenesulfonyl)-[2-(substituted 
amino)benzyl]amino}acrylates. 
REFERENCE EXAMPLE 42 
Methyl 
4-(4-Methoxybenzenesulfonyl)-1-(4-methylphenylsulfonyl)-2,3,4,5-tetrahydro 
-1H-[1,4]benzodiazepine-3-carboxylate 
white foam. Anal. for C.sub.25 H.sub.26 N.sub.2 O.sub.7 S.sub.2 : Calc'd: 
C,56.6; H,4.9; N,5.3 Found: C,56.2; H,5.2; N,5.2. 
REFERENCE EXAMPLE 43 
Methyl 
1,4-Bis-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepi 
ne-3-carboxylate 
white solid. Anal. for C.sub.25 H.sub.26 N.sub.2 O.sub.8 S.sub.2 : Calc'd: 
C,54.9; H,4.8; N,5.1; Found: C,54.8; H,4.9; N,5.1. 
REFERENCE EXAMPLE 44 
Methyl 
1-Methanesulfonyl-4-(4-methoxybenzeuesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4] 
benzodiazepine-3-carboxylate 
white crystals, m.p. 136-137.degree. C. Anal. for C.sub.19 H.sub.22 N.sub.2 
O.sub.7 S.sub.2 : Calc'd: C,50.2; H,4.9; N,6.2; Found: C,50.1; H,4.9; 
N,6.4. 
REFERENCE EXAMPLE 45 
Methyl 
1-Benzoyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodia 
zepine-3-carboxylate 
tan solid. Anal. for C.sub.25 H.sub.24 N.sub.2 O.sub.2 S: Calc'd: C,62.2; 
H,5.4; N,5.8; Found: C,62.3; H,5.2; N,5.6. 
REFERENCE EXAMPLE 46 
Methyl 
1-Acetyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiaz 
epine-3-carboxylate 
white crystals, m.p. 150-155.degree. C. Anal. for C.sub.20 H.sub.22 N.sub.2 
O.sub.6 S: Calc'd: C,57.4; H,5.3; N,6.7; Found: C,56.6; H, 5.2; N,6.5. 
REFERENCE EXAMPLE 47 
Methyl 
4-(4-Methoxybenzenesulfonyl)-1-(3-pyridinylcarbonyl)-2,3,4,5-tetrahydro-1H 
-[1,4]benzodiazepine-3-carboxylate 
off-white solid; Anal. for C.sub.24 H.sub.23 N.sub.3 O.sub.6 S: Calc'd: 
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 
Methyl 
4-(4-Methoxybenzenesulfonyl)-1-(2-thienylcarbonyl)-2,3,4,5-tetrahydro-1H-[ 
1,4]benzodiazepine-3-carboxylate 
off-white solid. Anal. for C.sub.23 H.sub.22 N.sub.2 O.sub.6 S.sub.2 : 
Calc'd: C,56.8; H,4.6; N,5.8; Found: C,56.0; H,4.6; N,5.2. 
REFERENCE EXAMPLE 49 
Methyl 
4-(4-Methoxybenzenesulfonyl)-1-(4-pyridinylcarbonyl)-2,3,4,5-tetrahydro-1H 
-[1,4]benzodiazepine-3-carboxylate 
off-white crystals, m.p. 162-164.degree. C. Anal. for C.sub.24 H.sub.23 
N.sub.3 O.sub.6 S: Calc'd: C.59.9; H,4.8; N,8.7; Found: C,59.9; H,4.8; 
N,8.7. 
REFERENCE EXAMPLE 50 
Methyl 
1-(4-Biphenylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H- 
[1,4]benzodiazepine-3-carboxylate 
white solid; Anal. for C.sub.31 H.sub.28 N.sub.2 O.sub.6 S: Calcd: 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 
Methyl 
4-(4-Methoxybenzenesulfonyl)-1-(propane-1-sulfonyl)-2,3,4,5-tetrahydro-1H- 
[1,4]benzodiazepine-3-carboxylate 
yellow oil. Anal. for C.sub.21 H.sub.26 N.sub.2 O.sub.7 S.sub.2 : Calc'd: 
C,52.3; H,5.4; N,5.8; Found: C.51.8; H,5.4; N,5.6. 
REFERENCE EXAMPLE 52 
Methyl 
1-([1,1'-Biphenyl]-2-carbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrah 
ydro-1H-[1,4]benzodiazepine-3-carboxylate 
white foam. Anal. for C.sub.31 H.sub.28 N.sub.2 O.sub.6 S: Calc'd: 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 
Methyl 
1-(3-Fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1, 
4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 54 
Methyl 
4-(4-Methoxybenzenesulfonyl)-1-(2-methyl-5-fluorobenzoyl)-2,3,4,5-tetrahyd 
ro-1H-[1,4]benzodiazepine-3-carboxylate 
white solid; Anal. for C.sub.26 H.sub.25 FN.sub.2 O.sub.6 S: Calc'd: 
C,60.9; H,4.9; N,5.5; Found: C,60.9; H,5.0; N,5.0. 
REFERENCE EXAMPLE 55 
Methyl 
4-(4-Methoxybenzenesulfonyl)-1-(2-methyl-3-fluorobenzoyl)-2,3,4,5-tetrahyd 
ro-1H-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 56 
Methyl 
4-(4-Methoxybenzenesulfonyl)-1-(3-phenylpropionyl)-2,3,4,5-tetrahydro-1H-[ 
1,4]benzodiazepine-3-carboxylate 
white solid; Anal. for C.sub.27 H.sub.28 N.sub.2 O.sub.6 S: Calc'd: 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 
Methyl 
4-(4-Methoxybenzenesulfonyl)-1-(2-trifluoromethylbenzoyl)-2,3,4,5-tetrahyd 
ro-1H-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 58 
Methyl 
1-(2-Chloro-6-trifluoromethylbenzoyl)-4(4-methoxybenzenesulfonyl)-2,3,4,5- 
tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 59 
Methyl 
1-(4-Fluoro-2-trifluoromethylbenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 
-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 60 
Methyl 
1-(2-Fluoro-6-trifluoromethylbenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 
-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 61 
Methyl 
4-(4-Methoxybenzenesulfonyl)-1-(2-methylbenzoyl)-2,3,4,5-tetrahydro-1H-[1, 
4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 62 
Methyl 
4-(4-Methoxybenzenesulfonyl)-1-(2-methyl-6-chlorobenzoyl)-2,3,4,5-tetrahyd 
ro-1H-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 63 
Methyl 
1-(2,4-Dimethylbenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H 
-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 64 
Methyl 
1-(2,5-Dimethylbenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H 
-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 65 
Methyl 
1-(2-Chloro-4-fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahyd 
ro-1H-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 66 
Methyl 
1-(2-Chlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1, 
4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 67 
Methyl 
1-(2-Fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1, 
4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 68 
Methyl 
1-(2-Chloro-6-fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahyd 
ro-1H-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 69 
Methyl 
1-(2,3-Difluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H 
-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 70 
Methyl 
1-(2,4-Dichlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H 
-[1,4]benzodiazepine-3-carboxylate 
Prepared according to the procedure set forth in Reference Example 10; 
white solid. Anal. for C.sub.25 H.sub.22 Cl.sub.2 N.sub.2 O.sub.6 S: 
Calc'd: 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 
Methyl 
1-(2,3-Dichlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H 
-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 72 
Methyl 
1-(2,5-Dichlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H 
-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 73 
Methyl 
1-(2-Methoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1 
,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 74 
Methyl 
1-(4-Chloro-2-methoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahy 
dro-1H-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 75 
Methyl 
4-(4-Methoxybenzenesulfonyl)-1-(2-methylthiobenzoyl)-2,3,4,5-tetrahydro-1H 
-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 76 
Methyl 
4-(4-Methoxybenzenesulfonyl)-1-(3-methyl-2-thienylcarbonyl)-2,3,4,5-tetrah 
ydro-1H-[1.4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 77 
Methyl 
4-(4-Methoxybenzenesulfonyl)-1-(4-methyl-2-thienylcarbonyl)-2,3,4,5-tetrah 
ydro-1H-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 78 
Methyl 
1-(3-Chloro-2-thienylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrah 
ydro-1H-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 79 
Methyl 
1-(2-Furanylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[ 
1,4]benzodiazepine-3-carboxylate 
off-white solid, m.p. 165-167.degree. C. Anal. for C.sub.23 H.sub.22 
N.sub.2 O.sub.7 S: Calc'd: 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 
Methyl 
4-(4-Methoxybenzenesulfonyl)-1-(3-methyl-2-furanylcarbonyl)-2,3,4,5-tetrah 
ydro-1H-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 81 
Methyl 
4-(4-Methoxybenzenesulfonyl)-1-(4-methyl-2-furanylcarbonyl)-2,3,4,5-tetrah 
ydro-1H-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 82 
Methyl 
1-(5-Chloro-2-furanylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrah 
ydro-1H-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 83 
Methyl 
1-(5-Chloro-2-thienylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrah 
ydro-1H-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 84 
Methyl 
1-Propionyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzod 
iazepine-3-carboxylate 
REFERENCE EXAMPLE 85 
Methyl 
1-Hexanoyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodi 
azepine-3-carboxylate 
REFERENCE EXAMPLE 86 
Methyl 
1-(3-Methoxypropionyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H- 
[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 87 
Methyl 
4-(4-Methoxybenzenesulfonyl)-1-(3-thienylcarbonyl)-2,3,4,5-tetrahydro-1H-[ 
1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 88 
Methyl 
1-(3-Furanylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[ 
1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 89 
Methyl 
1-(trans-Crotonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4 
]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 90 
Methyl 
1-(Methacryloyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]b 
enzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 91 
Methyl 
1-(Chloroacetyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]b 
enzodiazepine-3-carboxylate 
Following the method described for Reference Example 18. 3.0 g (7.61 mmol) 
of methyl 
2-[2-aminobenzyl)-(4-methoxy-benzenesulfonyl)-amino]-3-hydroxypropionate 
was reacted with 1.82 ml (22.8 mmol) of chloroacetylchloride to give 4.0 g 
of solid. Chromatography on silica gel with ethyl acetate-hexane (1:1) as 
a solvent gave 1.5 g of methyl 
2-[(2-chloroacetylaminobenzyl)-(4-methoxybenzenesulfonyl)-amino]acrylate. 
A 1.3 g sample of the preceding compound was reacted with 0.312 g of 
anhydrous NaHCO.sub.3 in 10 ml of anhydrous methanol at room temperature 
overnight and the mixture was then heated at 80.degree. C. for 5 hours. 
The solvent was removed and the residue partitioned between H.sub.2 O and 
ethyl acetate. The ethyl acetate extract was washed with brine, dried with 
Na.sub.2 SO.sub.4 and the solvent removed. The residue was triturated with 
hexane-ethyl acetate, chilled and filtered to give the product; Mass 
spectrum (ES) 453.1 (M+H). 
REFERENCE EXAMPLE 92 
Methyl 
1-(Acetylaminoacetyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[ 
1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 93 
Methyl 
1-(N,N-Dimethylaminoacetyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydr 
o-1H-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 94 
Methyl 
1-(Cyclopropylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H 
-[1,4]benzodiazepine-3-carboxylate 
white crystals, m.p. 98-100.degree. C. Anal. for C.sub.22 H.sub.24 N.sub.2 
O.sub.6 S: Calc'd: 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 
Methyl 
1-(Cyclobutylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H- 
[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 96 
Methyl 
4-(4-Methoxybenzenesulfonyl)-1-(trifluoroacetyl)-2,3,4,5-tetrahydro-1H-[1, 
4]benzodiazepine-3-carboxylate 
To a solution of 1.0 g (2.54 mmol) of methyl 
3-hydroxy-2-{(4-methoxybenzenesulfonyl)-[2-(2,2,2-trifluoroacetylamino)ben 
zyl]amino}propionate in 10 ml of CH.sub.2 Cl.sub.2 was added 1.8 ml (12.7 
mmol) of trifluoroacetic anhydride. After 1 hour at room temperature, the 
solvent was removed. Dichloromethane was added several times and the 
solvent removed under vacuum after each addition. Methanol was then added 
2 times and the solvent removed under vacuum to give methyl 
2-{(4-methoxybenzenesulfonyl)-[2-(2,2,2-trifluoroacetylamino)benzyl]-amino 
}acrylate as a glass. The glass was dissolved in methanol and 0.213 g of 
anhydrous NaHCO.sub.3 was added. The mixture was stirred at room 
temperature overnight and concentrated under vacuum to dryness. To the 
residue was added ethyl acetate and water. The organic layer was 
separated, washed with H.sub.2 O, brine and dried with Na.sub.2 SO.sub.4. 
The solvent was removed and the residue (1.0 g) was chromatographed on 
silica gel thick layer plates with hexane-ethyl acetate (1:1) as solvent 
to give 0.365 g of product as a glass. Anal. for C.sub.20 H.sub.19 F.sub.3 
N.sub.2 O.sub.6 S: Calc'd: 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 
Methyl 
4-(4-Methoxybenzenesulfonyl)-1-(4-methylphenylsulfonyl)-2,3,4,5-tetrahydro 
-1H-[1,4]benzodiazepine-3-carboxylate 
To 0.50 g (1.26 mmol) of 
2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate in 
5 ml of pyridine cooled to 0.degree. C. was added 0.284 g (2.59 mmol) of 
tosyl chloride. The mixture was stirred at 0.degree. C. for 2 hours and 
then concentrated to remove the solvent. To the residue was added 8 ml of 
anhydrous ethanol and the mixture refluxed for 2 days. The mixture was 
concentrated to dryness and ethyl acetate added. The mixture was washed 
with H.sub.2 O, 2 N citric acid, brine and dried with Na.sub.2 SO.sub.4. 
The filtrate was filtered through a thin pad of hydrous magnesium silicate 
and the filter pad washed with ethyl acetate. The filtrate was 
concentrated to dryness to give 0.60 g of a foam. Anal. for C.sub.25 
H.sub.26 N.sub.2 O.sub.7 S.sub.2 : Calc'd: 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 
Methyl 
2-[(4-Methoxybenzenesulfonyl)-(2-methylsulfonylaminobenzyl)amino]acrylate 
To a solution of 1.0 g (2.54 mmol) of methyl 
[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate in 
10 ml of pyridine cooled to -5.degree. C. was added 0.432 ml (5.58 mmol) 
of methanesulfonyl chloride. The mixture was stirred at 0.degree. C. for 
48 hours. To the mixture was added ice and H.sub.2 O and the mixture was 
extracted with ethyl acetate. The extract was washed with H.sub.2 O, 2 N 
citric acid, brine and dried with Na.sub.2 SO.sub.4. The solvent was 
removed under vacuum and the residue triturated with ethyl acetate-hexane 
to give 0.90 g of a solid, 128-142.degree. C. Anal. for C.sub.19 H.sub.22 
N.sub.2 O.sub.7 S.sub.2 : Calc'd: 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 
Methyl 
1,4-Bis-(4-Methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepi 
ne-3-carboxylate 
To a solution of 1.0 g (2.34 mmol) of methyl 
2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate in 
6 ml of pyridine cooled to 0.degree. C. to -5.degree. C. was added 1.07 
(5.18 mmol) of 4-methoxybenzenesulfonyl chloride. After 2 hours, the 
mixture was concentrated to dryness under vacuum. To the residue was added 
12 ml of ethanol and the mixture refluxed overnight. The solvent was 
removed under vacuum and the residue chromatographed on silica gel thick 
layer plates with ethyl acetate-hexane (1:1) as solvent to give 0.83 g 
(60%) of product as a white foam; Anal. calc'd for C.sub.25 H.sub.26 
N.sub.2 O.sub.8 S.sub.2 : 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) methyl 
2-{[2-(4-methoxybenzenesulfonyl)aminobenzyl]-(4-methoxybenzenesulfonyl)ami 
no}-3-hydroxypropionate. Anal. for C.sub.25 H.sub.28 N.sub.2 O.sub.9 
S.sub.2 : Calc'd: 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 
Methyl 
1-Acetyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiaz 
epine-3-carboxylate 
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 anhydrous sodium 
bicarbonate. The mixture was stirred at room temperature overnight and the 
solvent removed under vacuum. To the residue was added ethyl acetate and 
H.sub.2 O. The organic layer was separated, washed with brine and dried 
with Na.sub.2 SO.sub.4. The solvent was removed and the residue dried 
under vacuum to give 0.59 g of white crystals, m.p. 150-155.degree. C. 
Anal. for C.sub.20 H.sub.22 N.sub.2 O.sub.6 S: Calc'd: 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 
Methyl 
3-Acetoxy-2-[(2-diacetylaminobenzyl)-(4-methoxybenzenesulfonyl)amino]propi 
onate 
A mixture of 1.0 g (2.54 mmol) of methyl 
2-[(2-aminobenzyl)-(4-ethoxybenzenesulfonyl)amino]-3-hydroxypropionate and 
1.3 ml of acetic anhydride in 8 ml of toluene was heated at 100.degree. C. 
for 2 hours. The mixture was concentrated and 3 ml of acetic anhydride 
added thereto. The mixture was heated at 100.degree. C. overnight and 
concentrated to dryness under high vacuum to give an oil. The oil was 
dried at 75.degree. C. under vacuum for 48 hours to give 1.2 g of a yellow 
oil. Anal. for C.sub.24 H.sub.28 N.sub.2 O.sub.9 S: Calc'd: 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 
Methyl 2-[(2-Diacetylaminobenzyl)-(4-methoxybenzenesulfonyl)amino]acrylate 
A mixture of 1.0 g (1.97 mmol) of methyl 
3-acetoxy-2-[(2-diacetylaminobenzyl)-(4-methoxybenzenesulfonyl)amino]propi 
onate and 0.826 ml (5.92 mmol) of triethylamine in 5 ml of CH.sub.2 
Cl.sub.2 was stirred at room temperature overnight. The solution was 
diluted with 30 ml of CH.sub.2 Cl.sub.2 and washed with 20 ml each of 
H.sub.2 O, 2 N citric acid, brine and dried with Na.sub.2 SO.sub.4. The 
solvent was removed under vacuum to give a brown oil. Anal. for C.sub.22 
H.sub.24 N.sub.2 O.sub.7 S: Calc'd: 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 
Methyl 
2-{(4-Methoxybenzenesulfonyl)-[2-(2,2,2-trifluoroacetylamino)benzyl]amino} 
acrylate 
To a suspension of 1.0 g (2.54 mmol) of methyl 
2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate in 
10 ml of toluene was added 1.8 ml (12.7 mmol) of trifluoroacetic anhydride 
(solid dissolves). The solution was stirred for 2 hours at room 
temperature and heated at 100.degree. C. overnight. The mixture was then 
concentrated to dryness under vacuum. To the residue was added 0.9 ml of 
trifluoroacetic anhydride and the solution stirred at room temperature for 
1.5 hours and concentrated to dryness. To the residue was added 10 ml of 
toluene and the mixture refluxed for 2 hours. The solution was cooled to 
room temperature and 2.5 ml of triethylamine added and the mixture stirred 
at room temperature overnight. The solution was concentrated to dryness 
and the residue dissolved in ethyl acetate. The ethyl acetate was washed 
with H.sub.2 O, brine and dried (Na.sub.2 SO.sub.4). 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.degree. C. Anal. for C.sub.20 H.sub.19 F.sub.3 N.sub.2 O.sub.6 S: 
Calc'd: 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-tetrahydr 
o-1H-[1,4]benzodiazepine-3-carboxylic Acid 
To a mixture of 1.9 g (3.71 mmol) of methyl 
4-(4-methoxybenzenesulfonyl)-1-(2-methyl-5-fluorobenzoyl)-2,3,4,5-tetrahyd 
ro-1H-[1,4]benzodiazepine-3-carboxylate in 10 ml of tetrahydrofuran was 
added 5 ml (4.82 mmol) of 1 N NaOH. The mixture was stirred at room 
temperature for 1.5 hours and the solvent removed under vacuum. To the 
residue was added ethyl acetate and the mixture neutralized with 1 N HCl. 
The organic layer was separated, washed with brine and dried with Na.sub.2 
SO.sub.4. The solvent was removed under vacuum to give 1.41 g of white 
solid. Anal. for C.sub.25 H.sub.23 FN.sub.2 O.sub.6 S: Calc'd: C,60.2; 
H,4.7; N,5.6; Found: C,60.2; H,4.8; N,5.4 S,6.4; F,3.6; Mass spectrum (ES) 
497.5 (M-H). 
Utilizing the method described in Reference Example 104, the following 
benzodiazepine-3-carboxylic acids can be prepared. 
REFERENCE EXAMPLE 105 
4-(4-Methoxybenzenesulfonyl)-1-(4-methylphenylsulfonyl)-2,3,4,5-tetrahydro- 
1H-[1,4]benzodiazepine-3-carboxylic acid 
white foam. Anal. for C.sub.24 H.sub.24 N.sub.2 O.sub.7 S.sub.2 : Calc'd: 
C,55.8; H,4.7; N,5.4; Found: C,53.9; H,5.1; N,4.8; Mass spectrum (ES) 
512.2 (M+H). 
REFERENCE EXAMPLE 106 
1,4-Bis-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepin 
e-3-carboxylic acid 
off-white solid. Anal. for C.sub.24 H.sub.24 N.sub.2 O.sub.8 S.sub.2 : 
Calc'd: 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 
1-Methanesulfonyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]b 
enzodiazepine-3-carboxylic acid 
white solid. Anal. for C.sub.18 H.sub.20 N.sub.2 O.sub.7 S.sub.2 : Calc'd: 
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 
1-Benzoyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiaz 
epine-3-carboxylic acid 
white foam. Anal. for C.sub.24 H.sub.22 N.sub.2 O.sub.6 S: Calc'd 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 
1-Acetyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiaze 
pine-3-carboxylic acid 
white solid; Anal. for C.sub.19 H.sub.22 N.sub.2 O.sub.6 S: Calc'd: C,56.4; 
H,5.0; N,6.9; Found: C,55.2; H,4.9; N,6.6; S,7.8; Mass spectrum (ES) 404.9 
(M+H). 
REFERENCE EXAMPLE 110 
4-(4-Methoxybenzenesulfonyl)-1-(3-pyridinylcarbonyl)-2,3,4,5-tetrahydro-1H- 
[1,4]benzodiazepine-3-carboxylic acid 
white solid; m.p. 250-255. Anal. for C.sub.23 H.sub.21 N.sub.3 O.sub.6 S: 
Calc'd: 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 C.sub.22 H.sub.20 N.sub.2 O.sub.6 S.sub.2 : Calc'd: 
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 
1-Methoxyacetyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]ben 
zodiazepine-3-carboxylic acid 
white crystals, m.p. 193-194.degree. C. Anal. for C.sub.20 H.sub.22 N.sub.2 
O.sub.7 S: Calc'd: 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.degree. C. Anal. for C.sub.23 H.sub.21 N.sub.3 
O.sub.6 S: Calc'd: 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. Anal. for C.sub.30 H.sub.26 N.sub.2 O.sub.6 S: Calc'd: 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-(propane-1-sulfonyl)-2,3,4,5-tetrahydro-1H-[ 
1,4]benzodiazepine-3-carboxylic acid 
white foam. Anal. for C.sub.20 H.sub.24 N.sub.2 O.sub.7 S.sub.2 : Calc'd: 
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 
1-([1,1'-Biphenyl]-2-carbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahy 
dro-1H-[1,4]benzodiazepine-3-carboxylic acid 
white foam; m.p. 106-145.degree. C. Anal. for C.sub.30 H.sub.26 N.sub.2 
O.sub.6 S: Calc'd: C,66.4; H,4.8; N,5.2; Found: C,65.7; H,5.0; N,4.8; Mass 
spectrum (ES) 541.1 (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-tetrahydr 
o-1H-[1,4]benzodiazepine-3-carboxylic acid 
REFERENCE EXAMPLE 119 
4-(4-Methoxybenzenesulfonyl)-1-(3-phenylpropionyl)-2,3,4,5-tetrahydro-1H-[1 
,4]benzodiazepine-3-carboxylic acid 
white solid. Anal. for C.sub.26 H.sub.26 N.sub.2 O.sub.6 S: Calc'd: 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-tetrahydr 
o-1H-[1,4]benzodiazepine-3-carboxylic acid 
REFERENCE EXAMPLE 121 
1-(2-Chloro-6-trifluoromethylbenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5- 
tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid 
REFERENCE EXAMPLE 122 
1-(4-Fluoro-2-trifluoromethylbenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5- 
tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid 
REFERENCE EXAMPLE 123 
1-(2-Fluoro-6-trifluoromethylbenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5- 
tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid 
REFERENCE EXAMPLE 124 
4-(4-Methoxybenzenesulfonyl)-1-(2-methylbenzoyl)-2,3,4,5-tetrahydro-1H-[1,4 
]benzodiazepine-3-carboxylic acid 
REFERENCE EXAMPLE 125 
4-(4-Methoxybenzenesulfonyl)-1-(2-methyl-6-chlorobenzoyl)-2,3,4,5-tetrahydr 
o-1H-[1,4]benzodiazepine-3-carboxylic acid 
REFERENCE EXAMPLE 126 
1-(2,4-Dimethylbenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H- 
[1,4]benzodiazepine-3-carboxylic acid 
REFERENCE EXAMPLE 127 
1-(2,5-Dimethylbenzoyl)-4-(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-tetrahydr 
o-1H-[1,4]benzodiazepine-3-carboxylic acid 
REFERENCE EXAMPLE 129 
1-(2-Chlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4 
]benzodiazepine-3-carboxylic acid 
REFERENCE EXAMPLE 130 
1-(2-Fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4 
]benzodiazepine-3-carboxylic acid 
REFERENCE EXAMPLE 131 
1-(2-Chloro-6-fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydr 
o-1H-[1,4]benzodiazepine-3-carboxylic acid 
REFERENCE EXAMPLE 132 
1-(2,3-Difluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H- 
[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. Anal. for C.sub.24 H.sub.20 Cl.sub.2 N.sub.2 O.sub.6 S: 
Calc'd: C,53.8; H,3.8; N,5.2; Found: C,52.8; H,3.9; N,4.9; Mass spectrum 
(ES) 533 (M-H). 
REFERENCE EXAMPLE 134 
1-(2,3-Dichlorobenzoyl)-4-(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-1H- 
[1,4]benzodiazepine-3-carboxylic acid 
REFERENCE EXAMPLE 136 
1-(2-Methoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1, 
4]benzodiazepine-3-carboxylic acid 
REFERENCE EXAMPLE 137 
1-(4-Chloro-2-methoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahyd 
ro-1H-[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-car 
boxylic acid 
REFERENCE EXAMPLE 140 
4-(4-Methoxybenzenesulfonyl)-1-(4-methyl-2-thienylcarbonyl)-2,3,4,5-tetrahy 
dro-1H-[1,4]benzodiazepine-3-carboxylic acid 
REFERENCE EXAMPLE 141 
1-(3-Chloro-2-thienylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahy 
dro-1H-[1,4]benzodiazepine-3-carboxylic acid 
REFERENCE EXAMPLE 142 
1-(2-Furanylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1 
,4]benzodiazepine-3-carboxylic acid 
white solid. Anal. for C.sub.22 H.sub.20 N.sub.2 O.sub.7 S: Calc'd: C, 
57.9; H, 4.4; N, 6.1; Found: C, 56.5; H, 4.5; N, 5.7; Mass spectrum (ES) 
455.1 (M-H). 
REFERENCE EXAMPLE 143 
4-(4-Methoxybenzenesulfonyl)-1-(3-methyl-2-furanylcarbonyl)-2,3,4,5-tetrahy 
dro-1H-[1,4]benzodiazepine-3-carboxylic acid 
REFERENCE EXAMPLE 144 
4-(4-Methoxybenzenesulfonyl)-1-(4-methyl-2-furanylcarbonyl)-2,3,4,5-tetrahy 
dro-1H-[1,4]benzodiazepine-3-carboxylic acid 
REFERENCE EXAMPLE 145 
1-(5-Chloro-2-furanylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahy 
dro-1H-[1,4]benzodiazepine-3-carboxylic acid 
REFERENCE EXAMPLE 146 
1-(5-Chloro-2-thienylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahy 
dro-1H-[1,4]benzodiazepine-3-carboxylic acid 
REFERENCE EXAMPLE 147 
1-Propionyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodi 
azepine-3-carboxylic acid 
REFERENCE EXAMPLE 148 
1-Hexanoyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodia 
zepine-3-carboxylic acid 
REFERENCE EXAMPLE 149 
1-(3-Methoxypropionyl)-4-(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-1H-[1 
,4]benzodiazepine-3-carboxylic acid 
REFERENCE EXAMPLE 152 
1-(trans-Crotonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4] 
benzodiazepine-3-carboxylic acid 
REFERENCE EXAMPLE 153 
1-(Methacryloyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]be 
nzodiazepine-3-carboxylic acid 
REFERENCE EXAMPLE 154 
1-(Pyrrolidinoacetyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1 
,4]benzodiazepine-3-carboxylic acid 
REFERENCE EXAMPLE 155 
1-(Acetylaminoacetyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1 
,4]benzodiazepine-3-carboxylic acid 
REFERENCE EXAMPLE 156 
1-(Cyclopropylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H- 
[1,4]benzodiazepine-3-carboxylic acid 
white crystals, m.p. 131-135.degree. C. Anal. for C.sub.21 H.sub.22 N.sub.2 
O.sub.6 S: Calc'd: 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)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[ 
1,4]benzodiazepine-3-carboxylic acid 
white solid. Anal. for C.sub.24 H.sub.28 N.sub.2 O.sub.6 S: Calc'd: C,61.0; 
H,6.0; N,5.9; Found: C,57.0; H,5.7; N,5.4; Mass spectrum (ES) 471.5 (M-H). 
REFERENCE EXAMPLE 159 
(D,L)N-(4-Methoxybenzenesulfonyl)-O-(2-tetrahydropyranyl)serine, Methyl 
ester 
A mixture of 1.44 g (5 mmol) of N-(4-methoxybenzenesulfonyl)serine, methyl 
ester; 1.05 g (12.5 mmol) of 3,4-dihydro-2H-pyran and 9.5 mg of 
4-methylbenzenesulfonic acid monohydrate in 5 ml of tetrahydrofuran was 
refluxed overnight and the mixture was concentrated to dryness under 
vaccum. The residue was extracted with CH.sub.2 Cl.sub.2 and the extract 
washed with 2 N NaHCO.sub.3, brine and dried with Na.sub.2 SO.sub.4. The 
solution was filtered through a thin pad of hydrous magnesium silicate and 
the filter pad washed with CH.sub.2 Cl.sub.2. The filtrate was 
concentrated to dryness and the residue (2.3 g) was extracted with three 
50 ml portions of hot hexane to give 1.92 g of product as a yellow oil; 
Mass spectrum (ES) 374.4 (MH.sup.+). 
REFERENCE EXAMPLE 160 
Methyl 
3-Hydroxy-2-{[4-methoxybenzenesulfonyl]-[2-(4-morpholinocarbonylamino)benz 
yl]amino}propionate 
To a mixture of 1.0 g (2.54 mmol) of methyl 
2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate in 
8 ml of pyridine chilled at 0.degree. to -10.degree. C. was added 740 
.mu.L (6.34 mmol) of morpholinocarbonyl chloride. The mixture was kept at 
0.degree. to 5.degree. C. overnight. The mixture was concentrated under 
vacuum and diluted with ethyl acetate. The solution was washed with 
H.sub.2 O, 2 N citric acid, and brine and dried with Na.sub.2 SO.sub.4. 
The solvent was removed under vacuum to give 1.61 g of solid 
(yellow-orange foam). The solid was chromatographed on thick layer silica 
gel plates with hexane-ethyl acetate (1:3) as solvent to give 0.86 g of 
solid. Anal. for C.sub.23 H.sub.29 N.sub.3 O.sub.8 S: Calc'd: 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 
Methyl 
2-{(4-Methoxybenzenesulfonyl)-[2-(4-morpholinocarbonylamino)benzyl]amino 
acrylate 
To a solution of 0.70 g (1.38 mmol) of methyl 
3-hydroxy-2-{[4-methoxybenzenesulfonyl]-[2-(4-morpholinocarbonylamino)benz 
yl]amino}propionate and 769 .mu.L (5.54 mmol) of triethylamine in 8 ml of 
CH.sub.2 Cl.sub.2, cooled to 0.degree. 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 CH.sub.2 
Cl.sub.2. The extract was washed with 2 N citric acid, brine and dried 
with Na.sub.2 SO.sub.4. The solvent was removed to give 0.67 g of a yellow 
oil. Anal. for C.sub.23 H.sub.27 N.sub.3 O.sub.7 S: Calc'd: 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 
Methyl 
4-(4-Methoxybenzenesulfonyl)-1-(4-morpholinocarbonyl)-2,3,4,5-tetrahydro-1 
H-[1,4]-benzodiazepine-3-carboxylate 
A mixture of 0.50 g (1.02 mmol) of methyl 
2-{(4-methoxybenzenesulfonyl)-[2-(4-morpholinocarbonyl-amino)benzyl]amino} 
acrylate and 0.111 g (1.32 mmol) of anhydrous NaHCO.sub.3 in 5 ml of 
anhydrous methanol was stirred at room temperature for 16 hours. An 
additional 55 mg of NaHCO.sub.3 was added and the mixture stirred at room 
temperature for 2 hours. The solvent was removed under vacuum and the 
residue diluted with H.sub.2 O and extracted with ethyl acetate. The 
extract was washed with brine and dried with Na.sub.2 SO.sub.4. The 
solvent was removed and the residue triturated with hexane-ethyl acetate 
to give 0.36 g of a yellow solid, Anal. calc'd for C.sub.23 H.sub.27 
N.sub.3 O.sub.7 S: 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-morpholinocarbonyl)-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-1 
H-[1,4]benzodiazepine-3-carboxylate and 1 ml (0.95 mmol) of 1 N NaOH in 5 
ml of tetrahydrofuran was stirred at room temperature for 1 hour. The 
mixture was concentrated under vacuum and the acidified with 1 N HCl and 
cooled. The mixture was filtered and the solid washed with water to give 
0.26 g of white solid. Anal. for C.sub.22 H.sub.25 N.sub.3 O.sub.7 S: 
Calc'd: 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-[(2-Tetrahydropyranyl)oxy]-2-[(4-methoxybenzenesulfonyl)-(2-nitro-4-chlo 
robenzyl)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-nitrobenzyl alcohol and 1.16 g (4.4 mmol) 
of triphenylphosphine in 4.5 ml of tetrahydrofuran was added dropwise a 
solution of 0.766 g (4.4 mmol) of diethyl azodicarboxylate in 1 ml of 
tetrahydrofuran. The mixture was stirred at room temperature overnight and 
the solvent removed under vacuum. The residue was triturated with diethyl 
ether, filtered and the filtrate passed through a thin pad of hydrous 
magnesium silicate. The pad was washed with ethyl acetate and the total 
filtrate concentrated to dryness under vacuum to give 4.54 g of solid. The 
solid was chromatographed on silica gel with hexane-ethyl acetate (55:45) 
as solvent. The fractions containing product were combined and the solvent 
removed to give 0.55 g of oily solid; Mass spectrum (ES) 543.1 (M+H). 
REFERENCE EXAMPLE 165 
Methyl 
2-{[2-(4-Pyridinylmethyleneamino)benzyl]-[4-methoxybenzenesulfonyl]amino}- 
3-hydroxypropionate 
A mixture of 0.50 g (1.268 mmol) of methyl 
2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)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 concentrated under vacuum to 
dryness. To the residue was added H.sub.2 O and ethyl acetate. The ethyl 
acetate layer was separated and concentrated to dryness under vacuum. The 
solid was purified by thick layer chromatography on silica gel with 
hexane-ethyl acetate as solvent to give 0.40 g of solid product (plus a 
small amount of starting material). Anal. for C.sub.24 H.sub.25 N.sub.3 
O.sub.6 S: Calc'd: 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 
Methyl 
1-(Cyclohexylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H- 
[1,4]benzodiazepine-3-carboxylate 
To a solution of 0.80 g (1.64 mmol) of methyl 
2-{[2-(cyclohexylcarbonyl)-aminobenzyl]-(4-methoxybenzenesulfonyl)amino}ac 
rylate 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.sub.3 added. The mixture was stirred overnight 
and the solvent removed under vacuum. To the residue was added H.sub.2 O 
and ethyl acetate and the organic layer separated. The ethyl acetate 
extract was washed with brine, dried with Na.sub.2 SO.sub.4 and the 
solvent removed under vacuum to give 0.83 g of the product as a yellow 
oil. Anal. for C.sub.25 H.sub.30 N.sub.2 O.sub.6 S: Calc'd: 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]prop 
ionate 
To a solution of 0.289 g (1 mmol) of methyl 
3-hydroxy-2-(4-methoxybenzenesulfonylamino)propionate in 4 ml of 
N,N-dimethylformamide cooled in an ice bath was added 40 mg of NaH (60% in 
oil) (1 mmol). After the gas evolution ceased, 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 extracted with 
CH.sub.2 Cl.sub.2. The extract was washed with H.sub.2 O, brine and dried 
with Na.sub.2 SO.sub.4. The solvent was removed to give 0.53 g of solid 
which was chromatographed on thick layer silica gel plates with 
hexane-ethyl acetate (2:1) as solvent to give 0.143 g (31%) of product, as 
crystals, m.p. 112.degree.-114.degree. C. Anal. for C.sub.18 H.sub.19 
ClN.sub.2 O.sub.8 S: Calc'd: 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]prop 
ionate 
A mixture of 0.454 g (1 mmol) of methyl 
3-hydroxy-2-[(4-methoxybenzenesulfonyl)-(4-chloro-2-nitrobenzyl)amino]prop 
ionate and 0.451 g (2 mmol) of SnCl.sub.2.2H.sub.2 O in 12 ml of methanol 
was refluxed for 2 hours. An additional 0.451 g (2 mmol) of 
SnCl.sub.2.2H.sub.2 O was added and the mixture refluxed for 2 hours. 
The solvent was removed and ethyl acetate added. The mixture was 
neutralized with 1 N NaHCO.sub.3 and then stirred for 1 hour and filtered. 
The ethyl acetate layer was separated and washed with H.sub.2 O, brine and 
dried with Na.sub.2 SO.sub.4. The solvent was removed to give 0.42 g of 
solid which was chromatographed on thick layer silica gel plates with 
hexane-ethyl acetate (45:55) as solvent to give 60 mg of product (R.sub.F 
0.66) as a glass. m.p. 99.degree.-112.degree. C. Anal. for C.sub.18 
H.sub.21 ClN.sub.2 O.sub.6 S: Calc'd: 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]prop 
ionate 
To a solution of 0.458 g (1 mmol) of methyl 
3-hydroxy-2-[(4-methoxybenzenesulfonyl)-(4-chloro-2-nitrobenzyl)amino]prop 
ionate in 25 ml of ethanol and 25 ml of ethyl acetate was added 0.045 g of 
10% Pd/C (wet--50% H.sub.2 O). 
The mixture was shaken in a Parr hydrogenator under 35 pounds per square 
inch of hydrogen for 3 hours. The mixture was filtered through 
diatomaceous earth and the filtrate was concentrated to dryness under 
vacuum to give 0.47 g of the product as a solid (approximately 90% pure). 
Thin layer chromatography on silica gel, NMR and Mass spectrum (ES) 429.1 
(M+H) 395.1 (M+H) indicated approximately 10% of deschloro derivative. 
A mixture of 4.74 g of methyl 
3-hydroxy-2-[(4-methoxybenzenesulfonyl)-(4-chloro-2-aminobenzyl)amino}prop 
ionate, and 0.470 g of 10% Pd/C (wet--50% H.sub.2 O) in 200 ml of ethyl 
acetate-ethanol (1:1) was shaken in a Parr hydrogenator under 35 psi of 
hydrogen for 4 hours. The mixture was filtered through diatomaceous earth 
and the solvent removed to give 4.5 g of solid. The solid was 
chromatographed by HPLC on a Waters Prep machine with a 4.times.30 cm 
silica gel column with a step gradient of hexane-ethyl acetate (9:1 to 6:4 
to 1:1 to 0:100) to give 1.56 g of a class, m.p. 110.degree.-123.degree. 
C. Anal. for C.sub.18 H.sub.21 ClN.sub.2 O.sub.6 S: Calc'd: C, 50.4; H, 
4.9; N, 6.5; Cl, 8.3; Found: C, 50.3; H, 4.8; N, 6.5; Cl, 7.8. 
REFERENCE EXAMPLE 170 
N-(4-Methoxybenzenesulfonyl)-glycine, Methyl Ester 
To a mixture of 12.5 g (0.1 mol) of glycine, methyl ester hydrochloride in 
120 ml of CH.sub.2 Cl.sub.2, 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-methoxybenzenesulfonyl chloride in 40 ml of 
CH.sub.2 Cl.sub.2. The mixture was stirred at room temperature overnight 
and poured into water. The organic layer was separated and washed with 2 N 
citric acid, H.sub.2 O, 1 N NaHCO.sub.3, brine and dried with Na.sub.2 
SO.sub.4. The solvent was removed under vacuum to give 24.6 g of residue 
which was triturated with ethyl acetate to give 19.9 g of crystals, m.p. 
59.degree.-61.degree. C. Anal. for C.sub.10 H.sub.13 NSO.sub.5 : Calc'd: 
C,46.3; H,5.1; N,5.4; Found: C,46.2; H,5.0; N,5.2. 
REFERENCE EXAMPLE 171 
Methyl 2-[(4-methoxybenzenesulfonyl)-(2-nitrobenzyl)amino]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-(4-methoxybenzenesulfonyl)-lycine, methyl ester in 40 ml of 
N,N-dimethylformamide. After gas evolution ceased, a solution of 6.80 g, 
(32 mmol) of 2-nitrobenzyl bromide in 40 ml of N,N-dimethylformamide was 
added dropwise to the mixture. The mixture was then stirred at room 
temperature overnight under nitrogen and the solvent removed under vacuum. 
The residue was extracted with CH.sub.2 Cl.sub.2 and the extract washed 
with H.sub.2 O, 2 N citric acid, H.sub.2 O, 1 N NaHCO.sub.3. brine and 
dried with Na.sub.2 SO.sub.4. The solution was filtered through a thin pad 
of hydrous magnesium silicate and the filter pad washed with CH.sub.2 
Cl.sub.2. The filtrate was concentrated under vacuum to give 11.79 g of 
solid. Trituration with ethyl acetate gave 2.64 (22%) of crystals, m.p. 
114.degree.-116.degree. C. Anal. for C.sub.17 H.sub.18 N.sub.2 O.sub.7 S: 
Calc'd: 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 product as crystals 
was obtained by chilling at 0.degree. C. and filtering the mother liquors. 
REFERENCE EXAMPLE 172 
Methyl 2-[(2-Aminobenzyl)-(4-methoxybenzenesulfonyl)amino]acetate 
(A) To a mixture of 2.15 g (5.45 mmol) of 
methyl-2-[(4-methoxybenzenesulfonyl)-(2-nitrobenzyl)amino]acetate and 1.57 
g (25 mmol) of ammonium formate in 10 ml of anhydrous methanol was added 
0.42 g of 10% palladium on carbon. The mixture was stirred at room 
temperature for 1.5 hours and then filtered through diatomaceous earth. 
The filtrate was concentrated to dryness under vacuum and the residue 
diluted with H.sub.2 O (25 ml) and extracted with CH.sub.2 Cl.sub.2 (75 
ml). The extract was washed with brine, dried with Na.sub.2 SO.sub.4 and 
the solvent removed to give 0.45 g of solid. Crystallization from ethyl 
acetate gave 0.124 g of white crystals, m.p. 100.degree.-102.degree. C. 
Anal. for C.sub.17 H.sub.20 N.sub.2 O.sub.5 S: Calc'd: 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 (wet--50% 
H.sub.2 O) and the mixture shaken in a Parr hydrogenator under 35 pounds 
per square inch of hydrogen for 4.5 hours at room temperature. The mixture 
was filtered through diatomaceous earth and the filtrate concentrated to 
dryness under vacuum to give 4.0 g of crystals. m.p. 
100.degree.-102.degree. 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 10 N NaOH and the 
mixture refluxed for 2 hours. The solvent was removed under vacuum and the 
residue partitioned between water and ether. The water layer was separated 
and acidified with 2 N citric acid. The solid was filtered, washed with 
H.sub.2 O and dried in a vacuum oven at room temperature to give 4.45 g 
(91%) of crystals, m.p. 145.degree.-147.degree. C. Anal. for C.sub.16 
H.sub.18 N.sub.2 O.sub.5 S: Calc'd: 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-1H-[1,4] 
benzodiazepine-3-carboxylate 
To a cooled (0.degree. C.) mixture 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 CH.sub.2 Cl.sub.2 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 
H.sub.2 O, 2 N citric acid, and brine and dried with Na.sub.2 SO.sub.4. 
The solvent was removed to give 2.4 g of crude methyl 
2-{(4-methoxybenzenesulfonyl)-[2-(phenoxyacetylamino)benzyl]amino}acrylate 
as an oil. Anal. for C.sub.26 H.sub.26 N.sub.2 O.sub.7 S: Calc'd: 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 2.0 g (3.92 mmol) sample of the preceding compound in 15 ml of 
methanol was added 0.494 g of anhydrous NaHCO.sub.3 and the mixture 
stirred for 5 hours. The mixture was concentrated under vacuum and ethyl 
acetate and H.sub.2 O were added to the residue. The mixture was filtered 
and the organic layer of the filtrate separated, washed with brine and 
dried with Na.sub.2 SO.sub.4. The solvent was removed to give 0.36 g of 
product as off-white crystals, m.p. 151.degree.-153.degree. C. Anal. for 
C.sub.26 H.sub.26 N.sub.2 O.sub.7 S: Calc'd: 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-1H-[1,4]benzodiazepine 
A mixture of 0.100 g (0.208 mmol) of methyl 
4-(4-methoxybenzenesulfonyl)-1-(3-pyridinylcarbonyl)-2,3,4,5-tetrahydro-1H 
-[1,4]benzodiazepine-3-carboxylate and 3 ml of borane-tetrahydroforan 
complex in tetrahydrofuran (1.0 M) was refluxed overnight. The solution 
was cooled to room temperature, diluted with methanol and the solvent 
removed. Methanol was added several times and, after each addition. the 
solvent was removed. To the residue was added 1N NaHCO.sub.3. The mixture 
was stirred for 45 minutes and then extracted with ethyl acetate. The 
extract was concentrated and then washed with H.sub.2 O, brine and dried 
with Na.sub.2 SO.sub.4. The solvent was removed under vacuum and the 
residue chromatographed on thick layer silica gel plates with 10% methanol 
in ethyl acetate as solvent to give 60 mg of solid (R.sub.F 0.26). 
Crystallization from ethyl acetate gave 30 mg of white crystals. Anal. for 
C.sub.23 H.sub.25 N.sub.3 O.sub.4 S: Calc'd: C,62.8; H,5.7; N,9.6; S,7.3; 
Found: C,61.1; H,5.6; N,9.2; S,7.3; Mass spectrum (ES) 440.2 (M+H). 
REFERENCE EXAMPLE 176 
Methyl 
4-(4-Methoxybenzenesulfonyl)-1-(2-methoxypyridinyl-3-carbonyl)-2,3,4,5-tet 
rahydro-1H-[1,4]benzodiazepine-3-carboxylate 
To a cooled (0.degree. C.) mixture of 1.0 g (2.54 mmol) of methyl 
2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate 
and 1.8 ml (12.68 mmol) of triethylamine in 10 ml of CH.sub.2 Cl.sub.2 was 
added 0.957 g (5.58 mmol) of 2-methoxypyridine-3-carbonyl chloride in 4 ml 
of CH.sub.2 Cl.sub.2. The solution was stirred at room temperature 
overnight, diluted with H.sub.2 O and CH.sub.2 Cl.sub.2 and the organic 
layer separated. The organic layer was washed with H.sub.2 O, 2N citric 
acid, and brine and dried with Na.sub.2 SO.sub.4. The solvent was removed 
under vacuum to give 1.2 g of solid. The solid was chromatographed on 
thick layer silica gel plates with ethyl acetate-hexane (3:1) as solvent 
to give 0.27 g of yellow foam. Anal. for C.sub.25 H.sub.25 N.sub.3 O.sub.7 
S: Calc'd: 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 (ice-water bath) mixture of 30% HBr in acetic acid (3 ml) was 
added 2.5 g 5-methyl-2-nitrobenzyl alcohol and the chilled solution 
stirred for 2 hours. The mixture was poured into ice-water and extracted 
with diethyl ether. The extract was washed with H.sub.2 O, brine and the 
solvent removed under vacuum to give a mixture of product (50%) and 
starting material (50%). 
REFERENCE EXAMPLE 178 
Methyl 
3-Hydroxy-2-[(4-methoxybenzenesulfonyl)-(5-methyl-2-nitrobenzyl)amino]prop 
ionate 
A solution of 23.14 g (0.08 mol) of methyl 
3-hydroxy-2-(4-methoxybenzenesulfonylamino)propionate in 120 ml of dry 
N,N-dimethylformamide was added dropwise to a stirred suspension of 3.2 g 
(0.08 mol) of sodium hydride (57% in oil) in 120 ml of 
N,N-dimethylformide. When gas evolution ceased, the mixture was chilled in 
an ice bath and a solution of 16.4 g (0.084 mol) of 5-methyl-2-nitrobenzyl 
chloride in 100 ml of N N-dimethylformamide was added. To the mixture was 
added 12.6 g (0.084 mol) of anhydrous sodium iodide and the mixture was 
chilled in an ice bath and stirred for 20 minutes. The mixture was allowed 
to warm to room temperature and was stirred overnight. The solvent was 
removed under vacuum and the residue diluted with 200 ml of H.sub.2 O 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 H.sub.2 O, brine and dried with Na.sub.2 SO.sub.4. The solvent 
was removed to give 41.18 g of crude product. The product was 
chromatographed on silica gel with hexane-ethyl acetate (1:1) as solvent 
to give 8.14 g (R.sub.F 0.38) of product as a yellow semi-solid. From a 
small scale run (1 mmol) the product was chromatographed twice on thick 
silica gel plates with hexane-ethyl acetate (1:1) to give 0.12 g of a 
yellow semi-solid. Anal. for C.sub.19 H.sub.22 N.sub.2 SO.sub.8 : Calc'd: 
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]prop 
ionate 
To a solution of 3.4 g of methyl 
3-hydroxy-2-[(4-methoxybenzenesulfonyl)-(5-methyl-2-nitrobenzyl)-amino]pro 
pionate in 200 ml of ethanol-ethyl acetate (1:1) was added 0.34 g of 10% 
palladium on carbon (wet -50% H.sub.2 O). The mixture was then shaken in a 
Parr hydrogenator under 35 psi of hydrogen for 2.5 hours. The mixture was 
filtered through diatomaceous earth and the filtrate concentrated under 
vacuum to give 2.86 a of a brown oil. Anal. for Cl.sub.19 H.sub.4 N.sub.2 
O.sub.6 S: Calc'd: 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 
Methyl 
3-[(2-Tetrahydropyranyl)oxy]-2-[(-4-methoxybenzenesulfonyl)-(5-methyl-2-ni 
trobenzyl)amino]propionate 
To a mixture of 1.75 g (4.68 mmol) of 
(D,L)N-(4-methoxybenzenesulfonyl)-O-(2-tetrahydropyranyl) serine, methyl 
ester, 0.790 g (4.68 mmol) of 5-methyl-2-nitrobenzyl alcohol and 1.23 g 
(4.68 mmol) of triphenylphosphine in 4.5 ml of anhydrous tetrahydrofuran 
was added dropwise (over 15 minutes) a solution of 0.815 g (4.68 mmol) of 
diethyl azodicarboxylate (DEAD) in 1 ml of tetrahydrofuran. The mixture 
was stirred at room temperature overnight and the solvent removed under 
vacuum. The residue was triturated with diethyl ether and the solid 
filtered off. The filtrate was concentrated to dryness under vacuum to 
give 4.67 g of solid. The solid was chromatographed on silica gel with 
hexane-ethyl acetate (1:1) to give 0.56 g of product (R.sub.F 0.48). 
REFERENCE EXAMPLE 181 
Methyl 
1-Methoxyacetyl-4-(4-methoxybenzenesulfonyl)-7-methyl-2,3,4,5-tetrahydro-1 
H-[1,4]benzodiazepine-3-carboxylate 
To a cooled (0.degree. C.) mixture of 1.598 g (3.91 mmol) of methyl 
3-hydroxy-2-[(4-methoxybenzenesulfonyl)-(2-amino-5-methylbenzyl)amino]prop 
ionate 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 
CH.sub.2 Cl.sub.2 and washed with H.sub.2 O, 2N citric acid, H.sub.2 O, 
brine and dried with Na.sub.2 SO.sub.4. The solution was filtered through 
a thin pad of hydrous magnesium silicate and the filtrate concentrated to 
give 1.94 g of crude methyl 
2-{[2-(methoxyacetylamino)-5-methylbenzyl]-(4-methoxy-benzenesulfonyl)-ami 
no}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.sub.3 
and the mixture was stirred overnight at room temperature. The solvent was 
removed under vacuum and the residue partitioned between 100 ml of ethyl 
acetate and 20 ml of water. The ethyl acetate layer was separated and 
washed with H.sub.2 O, brine and dried with Na.sub.2 SO.sub.4. The 
solution was filtered through a thin pad of hydrous magnesium silicate and 
the filtrate concentrated under vacuum to give a yellow oil. Trituration 
with ethyl acetate-hexane gave 1.26 g (78%) of tan crystals, m.p. 
122-124.degree. C. Anal. for C.sub.22 H.sub.26 N.sub.2 O.sub.7 S: Calc'd: 
C.57.1; H,5.7: N,6.1; Found: C,57.4; H,5.7; N,6.0. 
REFERENCE EXAMPLE 182 
Methyl 
1-Benzoyl-4-(4-methoxybenzenesulfonyl)-7-methyl-2,3,4,5-tetrahydro-1H-[1,4 
]benzodiazeprine-3-carboxylate 
To a cooled (0.degree. C.) mixture of 1.465 g (3.586 mmol) of methyl 
3-hydroxy-2-[4-methoxybenzenesulfonyl)-(2-amino-5-methylbenzyl)amino]propi 
onate and 2.49 ml (17.93 mmol) of triethylamine in 20 ml of CH.sub.2 
Cl.sub.2 was added 0.915 ml (7.89 mmol) of benzoyl chloride. The mixture 
was stored at room temperature overnight, diluted with CH.sub.2 Cl.sub.2 
and washed with H.sub.2 O, 2N citric acid, H.sub.2 O, brine and dried with 
Na.sub.2 SO.sub.4. The solution was filtered through a thin pad of hydrous 
magnesium silicate and the filtrate concentrated under vacuum to give 1.8 
g of crude methyl 
2-[(2-benzoylamino-5-methylbenzyl)-(4-methoxybenzenesulfonyl)amino]acrylat 
e as a brown oil. Anal. for C.sub.26 H.sub.26 N.sub.2 O.sub.6 S: Calc'd: 
C,63.1; H,5.3; N,5.7; Found: C,63.9; H,5.2; N,5.2. 
As described for Reference Example 181, 1.825 g (3.68 mmol) of the 
preceding compound was stirred with 0.402 g (4.78 mmol) of NaHCO.sub.3 in 
1.5 ml of methanol to give an oil. Trituration with hexane (plus several 
drops of ethyl acetate) gave crystals, m.p. 58.degree.-62.degree. C. 
REFERENCE EXAMPLE 183 
Methyl 
1-(trans-Crotonyl)-4-(4-methoxybenzenesulfonyl)-7-methyl-2,3,4,5-tetrahydr 
o-1H-[1,4]benzadiazepine-3-carboxylate 
As described for Reference Examples 181 and 182, a mixture of 1.41 g (3.455 
mmol) of methyl 
3-hydroxy-2-[-(4-methoxybenzenesulfonyl)-(2-amino-5-methylbenzyl)amino]pro 
pionate, 1.75 g (17.3 mmol) of triethylamine and 0.809 ml of trans-crotonyl 
chloride in 15 ml of CH.sub.2 Cl.sub.2 was stirred overnight to give 1.52 
g of methyl 
2-{[2-(trans-crotonylamino)-5-methylbenzyl]-(4-methoxybenzenesulfonyl) 
amino}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.sub.3 in 15 ml of 
methanol at room temperature overnight. To the mixture was added 0.056 g 
of NaHCO.sub.3 and the mixture was heated at 80.degree. C. for 3 hours and 
worked up as for Reference Example 181 to give a 1.05 g of a yellow glass. 
m. p. 75.degree.-84.degree. C. Mass spectrum (ES) 459.4 (M+H). 
REFERENCE EXAMPLE 184 
1-(trans-Crotonyl)-4-(4-methoxybenzenesulfonyl)-7-methyl-2,3,4,5-tetrahydro 
-1H-[1,4]benzodiazepene-3-carboxylic acid 
A mixture of 1.26 g (2.72 mmol) of methyl 
1-(trans-crotonyl)-4-(4-methoxybenzenesulfonyl)-7-methyl-2,3,4.5-tetrahydr 
o-1H-[1,4]benzodiazepine-3-carboxylate and 3.53 ml (3.53 mmol) of 1N NaOH 
in 10 ml of tetrahydrofuran was stirred at room temperature for 3 hours. 
The solvent was removed under vacuum and the residue dissolved in H.sub.2 
O and the solution extracted with ethyl acetate. The aqueous layer was 
acidified with 1N HCl (pH 2) and extracted with CH.sub.2 Cl.sub.2. The 
CH.sub.2 Cl.sub.2 extract was dried with Na.sub.2 SO.sub.4 and the solvent 
removed to give 1.06 g (after drying under vacuum) of solid, m.p. 
101.degree.-105.degree. C. 
REFERENCE EXAMPLE 185 
1-(Benzoyl)-4-(4-methoxybenzenesulfonyl)-7-methyl-2,3-4,5-tetrahydro-1H[1,4 
]benzodiazepine-3-carboxylic acid 
A mixture of 1.18 g, (2.38 mmol) of methyl 
1-(benzoyl)-4-(4-methoxybenzenesulfonyl)-7-methyl-2,3,4.5-tetrahydro-1H-[1 
,4]benzodiazepine-3-carboxylate and 3.09 ml (3.09 mmol) of 1N NaOH in 10 ml 
of tetrahydrofuran was stored at room temperature overnight and the 
solvent removed under vacuum. The residue was diluted with H.sub.2 O, 
extracted with ethyl acetate and the aqueous layer acidified with 2N 
citric acid. The mixture was extracted with CH.sub.2 Cl, and the CH.sub.2 
Cl.sub.2 extracts were washed with H.sub.2 O, brine and dried with 
Na.sub.2 SO.sub.4. The solvent was removed to give 0.82 g of a light 
yellow glass, m.p. 95.degree.-100.degree. C.; Mass spectrum (ES) 481.4 
(M+H). 
REFERENCE EXAMPLE 186 
Methyl 
4-(4-Methoxybenzenesulfonyl)-1-(2-methoxyethyl)-2,3,4,5-tetrahydro-1H-[1,4 
]benzodiazepine-3-carboxylate 
A mixture of 1.6 g (3.57 mmol) of methyl 
1-(methoxyacetyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4] 
benzodiazepine-3-carboxylate and 32 ml of borane in tetrahydrofuran (1.0M) 
was refluxed under nitrogen overnight. Methanol was added and the solvent 
removed. To the residue was added 25 ml of CH.sub.2 Cl.sub.2 and 25 ml of 
2N HCl and the mixture stirred at room temperature for 1 hour. The organic 
layer was separated and washed with H.sub.2 O and concentrated to dryness. 
The residue was triturated with ethyl acetate-hexane, cooled and filtered 
to give 1.2 g of white crystals, m.p. 86.degree.-90.degree. C.; Mass 
spectrum (ES) 435.4 (M+H). Anal. for C.sub.21 H.sub.26 N.sub.2 O.sub.6 S: 
Calc'd: 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)-2,3,4,5-tetrahydro-1H[1,4]b 
enzodiazepine-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 1N NaOH in 10 ml of 
tetrahydrofuran was stirred at room temperature for 2 hours and the 
solvent removed. To the residue was added water and the mixture acidified 
with 1N HCl. The mixture was extracted with ethyl acetate and the extract 
was washed with brine and dried with Na.sub.2 SO.sub.4. The solvent was 
removed and the residue triturated with ethyl acetate-hexane, cooled and 
filtered to give 0.65 g of white crystals, m.p. 164.degree.-165.degree. 
C.,; Mass spectrum (ES) 421.4 (M+H). Anal. for C.sub.20 H.sub.24 N.sub.2 
O.sub.6 S: Calc'd: C,57.1; H,5.8; N,6.7; Found: C,57.3; H,5.7; N,6.4. 
REFERENCE EXAMPLE 188 
Methyl 
1-(Benzyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodi 
azepine-3-carboxylate 
A mixture of 0.20 g (0.416 mmol) of methyl 
1-(benzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzod 
iazepine-3 -carboxylate and 4 ml of borane in tetrahydrofuran (1.0M) was 
refluxed overnight and the solvent removed. To the residue was added 5 ml 
of CH.sub.2 Cl.sub.2 and 5 ml of 2N HCl and the mixture stirred for 1 
hour. The organic layer was separated and concentrated to dryness. The 
residue was chromatographed on thick layer silica gel plates with 
hexane-ethyl acetate (2:1) as solvent to give 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-hydroxyprop 
ionate was reacted with 4-(trifluoromethoxy)benzoyl chloride to give 2.59 g 
of methyl 2-{2-[4-(trifluoromethoxy) 
benzoyl]amino-4-chlorobenzyl]amino}acrylate as a yellow oil; Mass spectrum 
(ES) 599.3 (M+H). The preceding compound was stirred with 0.445 g (5.29 
mmol) of anhydrous NaHCO.sub.3 in 15 ml of methanol at room temperature 
for 16 hours and then was heated at 80.degree. C. for 2 hours. The solvent 
was removed and the residue extracted with ethyl acetate. The extract was 
washed with H.sub.2 O. brine, and dried (Na.sub.2 SO.sub.4). The solvent 
was removed and the residue crystallized from ethyl acetate-hexane to give 
methyl 
4-(4-methoxybenzenesulfonyl)-1-[4-(trifluoromethoxy)benzoyl}-8-chloro-2,3, 
4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate as yellow crystals, 
m.p. 149.degree.-151.degree. C. Anal. for C.sub.26 H.sub.22 ClF.sub.3 
O.sub.7 S: Calc'd: 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 preceding compound was stirred with 3.43 ml of 1N 
NaOH in 10 ml of tetrahydrofuran at room temperature for 2 hours and 
worked up as for Reference Example 104 to give 1.52 g of product. 
Crystallization from ethyl acetate-hexane gave 1.2 g of white crystals, 
m.p. 184.degree.-186.degree. C. 
REFERENCE EXAMPLE 190 
Methyl 
4-(4-Methoxybenzenesulfonyl)-1-(4-morpholinoacetyl)-2,3,4,5-tetrahydro-1H[ 
1,4]benzodiazepine-3-carboxylate 
A mixture of 0.10 g (0.22 mmol) of methyl 
1-(chloroacetyl)4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]be 
nzodiazepine-3-carboxylate, 21.2 .mu.l of morpholine and 125.4 .mu.l of 
N,N-diisopropylethylamine in 3 ml of CH.sub.2 Cl.sub.2 was stirred 
overnight at room temperature. An additional 2.2 .mu.l of morpholine was 
added and the solution stirred for 2 days at room temperature. The mixture 
was diluted with CH.sub.2 Cl.sub.2 and washed with H.sub.2 O, brine and 
dried with Na.sub.2 SO.sub.4. The solvent was removed to give the product 
as a solid, Mass spectrum (ES) 504.3 (M+H). Anal. for C.sub.24 H.sub.29 
N.sub.3 O.sub.7 S: Calc'd: C,57.2; H,5.8: N,8.3; Found: C,56.5; H,5.6: 
N,8.1. 
REFERENCE EXAMPLE 191 
Methyl 
4-(4-Methoxybenzenesulfonyl)-1-[2-(1-pyrazolyl)phenylcarbonyl]-7-methyl-2, 
3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate 
As described for the general reaction of ethyl 2-fluorobenzoate with amines 
set forth in Tetrahedron, 53:7557-7576 (1997), ethyl 2-fluorobenzoate was 
reacted with pyrazole by refluxing N,N-dimethylformamide to give ethyl 
2-(1-pyrazolyl)benzoate, as a thick yellow oil. Anal. Calc'd: for C.sub.12 
H.sub.12 N.sub.2 O.sub.2 : 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 hrs and the solvent removed. The residue was made 
acidic (pH6) with 2N citric acid and the precipated solid was filtered to 
obtain 3.7 g of product. The pH of the filtrate was adjusted to 4.5 and 
extracted with ethyl acetate. The extract was concentrated to dryness to 
give 1.5 g of product. The two crops were combined to give 5.2 g of 
2-(1-pyrazolyl)benzoic acid, mp 140-142.degree. C. To the preceding 
compound (2.07 g) in 5 ml CH.sub.2 Cl.sub.2 (chilled in an ice bath) was 
added 11.1 ml of a 2 Molar solution of oxalyl chloride in CH.sub.2 
Cl.sub.2 and 0.085 ml of N,N-dimethylformamide. The mixture was allowed to 
warm to room temperature and stirred for 4 hours. The solvent was removed 
and 25 ml of toluene added (twice) and removed under vacuum to give 
2-(1-pyrazolyl)benzoyl chloride as a yellow solid. 
A 2.3 g sample of the preceding compound was reacted with 1.5 g of the 
compound of Reference Example 179 in 15 ml of CH.sub.2 Cl.sub.2 and 5.12 
ml of triethylamine in the manner described for Reference Example 181 to 
give methyl 
2-[(4-methoxybenzenesulfonyl)-{2-[2-(1-pyrazolyl)phenylcarbonyl]amino-5-me 
thylbenzyl}amino]acrylate. This compound was cyclized with NaHCO.sub.3 in 
methanol in the manner described in Reference Example 181 to give methyl 
4-(4-methoxybenzenesulfonyl)-1-[2-(1-pyrazolyl)phenylcarbonyl]-7-methyl-2, 
3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate (m.p. 240-242.degree. 
C.). 
A 1.16 sample of the preceding compound was hydrolysed with 2.69 ml of 1N 
NaOH in 10 ml of tetrahydrofuran in the manner described for Reference 
Example 104 to give 0.71 g of 
4-(4-methoxybenzenesulfonyl)-1-[2-(1-pyrazolyl)phenylcarbonyl)-7-methyl-2, 
3,4,5-tetrahydro-1H[1,4]benzodiazepine-3-carboxylic acid (mp 
149-151.degree. C.). 
REFERENCE EXAMPLE 192 
Methyl 
4-(4-Methoxybenzenesulfonyl)-1-[2-(4-morpholino)phenylcarbonyl]-8-chloro-2 
,3,4,5-tetrahydro-1H-3,4)benzodiazepine-3-carboxylate 
Ethyl 2-morpholinobenzoate prepared in the manner described in Tetrahedron, 
53:7557, (1997) was refluxed with 10N NaOH in tetrahydrofuran-ethanol 
(8:2) for 1.5 hrs to give 2-morpholinobenzoic acid, mp 156-157.degree. C. 
A 1.8 g, sample of this compound in 5 ml of CH.sub.2 Cl.sub.2 (chilled) 
was added to a solution of 7.9 ml of oxalyl chloride in CH.sub.2 Cl.sub.2 
(2M) followed by the addition of 0.058 ml of N,N-dimethylformanide. The 
solution was stirred at room temperature for 6 hrs and the solvent 
removed. Toluene was added (2 times) and removed to give 
2-(4-morpholino)benzoyl chloride as a yellow solid. 
The preceding 2-(4-morpholino)benzoyl chloride was reacted with methyl 2-in 
the manner described in Reference Examples 181 and 189, and the product 
was stirred with NaHCO.sub.3 in methanol to give methyl 
4-(4-methoxybenzenesulfonyl)-1-[2-(4-morpholino)phenylcarbonyl]-8-chloro-2 
,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate, as a white solid 
having a mp 100-105.degree. C. 
To 0.90 g of this compound in 10 ml of tetrahydrofuran was added 1.95 ml of 
1N NaOH and the solution was stirred at room temperature overnight. 
Acidification with 2N citric acid gave 0.82 g of 
4-(4-methoxybenzenesulfonyl)-1-[2-(4-morpholino)phenylcarbonyl]-8-chloro-2 
,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid (mp 
136-143.degree. C.). 
REFERENCE EXAMPLE 193 
Methyl 
1-(4-Ethoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1, 
4]benzodiazepine-3-carboxylate 
A mixture of 0.270 g of methyl 
4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-c 
arboxylate of Reference Example 12, 0.291 g of 4-ethoxybenzoyl chloride and 
500 .mu.l of triethylamine in 5 ml of CH.sub.2 Cl.sub.2 was stirred at 
room temperature overnight. The mixture was diluted with CH.sub.2 Cl.sub.2 
and H.sub.2 O and the CH.sub.2 Cl.sub.2 layer was separated and 
concentrated to dryness. The residue was triturated with ethyl acetate to 
give 0.276 g of methyl 
1-(4-ethoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5tetrahydro-1H-[1,4 
]benzodiazepine-3-carboxylate as white crystals, (mp 187-190.degree. C.). 
A 0.47 g sample of this compound was hydrolyzed with 1.2 ml of 1N NaOH in 4 
ml of tetrahydrofuran. Dilution with H.sub.2 O and acidification with 1N 
HCl gave 0.40 g of the acid as a white solid, mp 144-152.degree. C. 
REFERENCE EXAMPLE 194 
Methyl 
4-(4-Methoxybenzenesulfonyl)-1-[2-chloro-4-(3-methyl-1-pyrazolyl)phenylcar 
bonyl}-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate 
As described in Example 65, methyl 
4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-c 
arboxylate was reacted with 4-(3-methyl-1-pyrazolyl)-2-chlorobenzoyl 
chloride to give methyl 
4-(4-methoxybenzenesulfonyl)-1-[2-chloro-4-(3-methyl-1-pyrazolyl)phenylcar 
bonyl]-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate as a white 
solid. Anal. for C.sub.29 H.sub.27 ClN.sub.4 O.sub.6 S: Calc'd: C, 58.3; 
H, 4.6; N, 9.4. Found: C,58.2; H, 4.9; N, 8.9. 
This compound was hydrolysed with 1N NaOH in tetrahydrofuran as described 
in Reference Example 185 to give the benzodiazepine-3-carboxylic acid 
derivative as a white solid. 
REFERENCE EXAMPLE 195 
1-Benzyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiaze 
pine-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 CH.sub.3 OH, CH.sub.2 
Cl.sub.2 (40 ml) and 30 ml of 2N HCl and the mixture stirred at room 
temperature for 1.5 hr. The organic layer was separated, washed with 
brine, dried with Na.sub.2 SO.sub.4 and the solvent removed. The residue 
was crystallized from ethanol-hexane to give 1.15 g of methyl 
1-benzyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiaz 
epine-3-carboxylate as white crystals, mp 120-122.degree. C. A sample (1.0 
g) of this compound was hydrolysed with 2.8 ml of 1N NaOH in 7 ml of 
tetrahydrofuran as described in Reference Example 104 to give 0.64 g of 
the 2,3,4,5- tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid 
derivative as white crystals (mp 183-185.degree. C.). 
REFERENCE EXAMPLE 196 
Methyl 
1-(2,4-Dimethoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1 
H-[1,4]benzodiazepine-3-carboxylate 
To a cooled (0.degree. C.) solution of 1.0 g (2.66 mmol) of 
4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-c 
arboxylate from Reference Example 12 and 1.85 ml (13.3 mmol) of 
triethylarnine in 8 ml of CH.sub.2 Cl.sub.2 was added 1.17 g (6.65 mmol) 
of 2,4-dimethoxybenzoyl chloride. The mixture was stirred at room 
temperature overnight, diluted with CH.sub.2 Cl.sub.2 and washed with 2N 
citric acid. The organic layer was washed with H.sub.2 O, 1N Na.sub.2 
CO.sub.3, brine and dried over Na.sub.2 SO.sub.4. The solvent was removed 
and the residue was chromatographed on thick layer silica gel plates with 
ethyl acetate-hexane (1:1) as an eluent to give 1.0 g of methyl 
1-(2,4-dimethoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1 
H-[1,4]benzodiazepine-3-carboxylate as a white foam. Anal. for C.sub.27 
H.sub.28 H.sub.2 O.sub.8 S: Calc'd: 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 0.80 g (1.48 mmol) sample of the preceding compound and 1.92 ml (1.92 
mmol) of 1N NaOH in 5 ml of tetrahydrofuran was stirred at room 
temperature for 1.5 hours. The solvent was removed and the residue diluted 
with water. The solution was acidified with 1N HCl, chilled and filtered 
to give 0.70 g of 
1-(2,4-dimethoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1 
H-[1,4]benzodiazepine-3-carboxylic acid as a white solid. Anal. for 
C.sub.26 H.sub.26 N.sub.2 O.sub.8 S: Calc'd: 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 
Methyl 
4-(4-Methoxybenzenesulfonyl)-1-[2-(4-methylpiperazin-1-yl)acetyl]-2,3,4,5- 
tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate 
To a mixture of 2.5 g (6.64 mmol) of methyl 
4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-c 
arboxylate (Reference Example 12) and 4.63 ml (33.2 mmol) of triethylamine 
in 40 ml of CH.sub.9 Cl.sub.2 cooled to 0.degree. C. was added to 1.65 g 
(14.63 mmol) of chloroacetyl chloride. The solution was stirred at room 
temperature for 2 days, chilled to 0.degree. C. and 926 .mu.l of 
triethylamine and 750 mg of chloroacetyl chloride were added thereto. The 
mixture was stirred at room temperature overnight, diluted with CH.sub.2 
Cl.sub.2 and H.sub.2 O. The insoluble solid was filtered off. The organic 
layer of the filtrate was separated, washed with brine, dried with 
Na.sub.2 SO.sub.4 and filtered through diatomaceous earth. The solvent was 
removed and the residue triturated with ethyl acetate and a trace of 
ethanol. Chilling and filtering gave 0.75 g of methyl 
1-(chloroacetyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]b 
enzo-diazepine-3-carboxylate (Reference Example 91). Anal. for C.sub.20 
H.sub.21 ClN.sub.2 O.sub.6 S: Calc'd: 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 
CH.sub.2 Cl.sub.2 cooled to 0.degree. C. was added 1.2 ml (6.79 mmol) of 
N,N-diisopropylethylamine followed by the addition of 753.2 .mu.l (6.79 
mmol) of 1-methylpiperazine. The mixture was stirred at room temperature 
overnight, diluted with CH.sub.2 Cl.sub.2, and washed with 2N citric acid, 
H.sub.2 O, 1M NaHCO.sub.3, brine and dried (Na.sub.2 SO.sub.4). The citric 
acid wash was made basic with saturated NaHCO.sub.3 and then extracted 
with CH.sub.2 Cl.sub.2. The extract was dried over Na.sub.2 SO.sub.4 and 
the solvent removed under vacuum to give 1.10 g of methyl 
4-(4-methoxybenzenesulfonyl)-1-[2-(4-methylpiperazin-1-yl)acetyl]-2,3,4,5- 
tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate as a white glass. 
A mixture of 1.0 g (1.94 mmol) of the preceding compound and 2.3 ml (2.3 
mmol) of 1N KOH in 5 ml of methanol was stirred at room temperature for 2 
hours. The solvent was removed under vacuum. To the residue was added 
toluene (2 times) and the solvent removed under vacuum after each 
addition. The solid was dried at 65.degree. C. under vacuum for 6 hours to 
give 1.1 g of potassium 
4-(4-methoxybenzenesulfonyl)-1-[2-(4-methylpiperazin-1-yl)acetyl]-2,3,4,5- 
tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate as a white solid. 
REFERENCE EXAMPLE 198 
Methyl 
1-Acetyl-4-(4-hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiaz 
epine-3-carboxylate 
To a cooled (0.degree.) solution of 2.0 g (4.78 mmol) of methyl 
1-acetyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiaz 
epine-3-carboxylate in 14 ml of CH.sub.2 Cl.sub.2 was added dropwise 143.3 
ml (14.3 mmol) of a 1.0 molar solution of BBr.sub.3 in CH.sub.2 Cl.sub.2 
The mixture was stirred at room temperature for 1.5 hours. Ice and H.sub.2 
O were added to the reaction mixture and the insolubles filtered off. The 
filtrate was diluted with CH.sub.2 Cl.sub.2 and H.sub.2 O and the CH.sub.2 
Cl.sub.2 layer separated, washed with brine and dried (Na.sub.2 SO.sub.4) 
The solvent was removed under vacuum to give 1.5 g of a white foam. The 
solid was chromatographed on silica gel with hexane-ethyl acetate (1:1) as 
solvent to give a foam which was dried under vacuum to give 0.52 g of 
product as a white foam; Anal. Calc'd for C.sub.19 H.sub.20 N.sub.2 
O.sub.6 S: C, 56 4:H, 5.0; N, 6.9 Found: C 55.1; H, 4.7: N, 6.5. 
REFERENCE EXAMPLE 199 
Methyl 
4-(4-Hydroxybenzenesulfonyl)-1-(2-thienylcarbonyl)-2,3,4,5-tetrahydro-1H-[ 
1,4]benzodiazepine-3-carboxylate 
To a solution of 4.0 g (8.22 mmol) of methyl 
4-(4-methoxybenzenesulfonyl)-1-(2-thienylcarbonyl)-2,3,4,5-tetrahydro-1H-[ 
1,4]benzodiazepine-3-carboxylate in 17 ml of CH.sub.2 Cl.sub.2 chilled to 
0.degree. C., was added slowly 16.4 ml (16.44 mmol) of 1.0 molar solution 
of boron tribromide in CH.sub.2 Cl.sub.2. The mixture was stirred at room 
temperature overnight and diluted with CH.sub.2 Cl.sub.2. The mixture was 
filtered and the solid washed with CH.sub.2 Cl.sub.2. and H.sub.2 O. The 
filtrate was diluted with H.sub.2 O and the organic layer separated. The 
solvent was removed under vacuum and the solid chromatographed on silica 
gel with hexane-ethyl acetate (1:1) as solvent to give 0.80 g of off white 
foam; Mass Spectrum (ES) 473.5 (M+H); Anal. Calc'd for C.sub.22 H.sub.20 
N.sub.2 O.sub.6 S.sub.2 : C, 55.9; H, 4.3; N, 5.9. Found: C, 54.5; H, 4.4; 
N, 5.5. 
REFERENCE EXAMPLE 200 
Methyl 
1-Benzoyl-4-(4-hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodia 
zepine-3-carboxylate 
To a solution of 9.8 g (20.39 mmol) of methyl 
1-benzoyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetraydro-1H-[1,4]benzodiaz 
epine in 50 ml of CH.sub.2 Cl.sub.2 cooled to 0.degree., was added slowly 
40.8 ml (40.8 mmol) of a 1.0 molar solution of BBr.sub.3 in CH.sub.2 
Cl.sub.2. The mixture was stirred under nitrogen at room temperature 
overnight. Ice and H.sub.2 O were added and the mixture diluted with 
CH.sub.2 Cl.sub.2. The organic layer was separated and the aqueous layer 
extracted with ethyl acetate. The combined organic extracts (CH.sub.2 
Cl.sub.2 +ethyl acetate) were concentrated under vacuum and the residue 
dissolved in ethyl acetate. The solution was washed with H.sub.2 O, brine 
and dried (Na.sub.2 SO.sub.4). The solution was filtered through a thin 
pad of hydrous magnesium silicate and the filtrate concentrated to 
dryness. The residue was chromatographed on silica gel with hexane-ethyl 
acetate as solvent to give 8 g of product as an off-white foam; Mass 
Spectrum (ES) 467 (M+H); Anal Calc'd for C.sub.24 H.sub.22 N.sub.2 O.sub.6 
S: C, 61.8; H, 4.8; N, 6.0. Found: C, 61.3; H, 4.6; N, 5.8. 
Utilizing the method described in Reference Examples 198-200, the following 
methyl-1-substituted-4-hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4] 
benzodiazepine-3-carboxylates can be prepared. 
REFERENCE EXAMPLE 201 
Methyl 
4-(4-Hydroxybenzenesulfonyl)-1-(4-methylphenylsulfonyl)-2,3,4,5-tetrahydro 
-1H-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 202 
Methyl 
1-Methanesulfonyl-4-(4-hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4] 
benzodiazepinef-3-carboxylate 
6.0 g (13.2 mmol) of Reference Example 44 and 22.6 ml (22.6 mmol) of 
BBr.sub.3 in CH.sub.2 Cl.sub.2 (solution) gave, after chromatography on 
silica with ethyl acetate-hexane (1:1), 0.82 g of a white foam; Mass 
spectrum (ES) 440.9 (M+H). 
REFERENCE EXAMPLE 203 
Methyl 
4-(4-Hydroxybenzenesulfonyl)-1-(3-pyridinylcarbonyl)-2,3,4,5-tetrahydro-1H 
-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 204 
Methyl 
4-(4-Hydroxybenzenesulfonyl)-1-(4-pyridinylcarbonyl-2,3,4,5-tetrahydro-1H- 
[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 205 
Methyl 
1-(4-Biphenylcarbonl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[ 
1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 206 
Methyl 
4-(4-Hydroxybenzenesulfonyl)-1-(propane-1-sulfonyl)-2,3,4,5-tetrahydro-1H- 
[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 207 
Methyl 
1-([1,1'-Biphenyl]-2-carbonyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5-tetrah 
ydro-1H-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 208 
Methyl 
1-(3-Fluorobenzoyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1, 
4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 209 
Methyl 
4-(4-Hydroxybenzenesulfonyl)-1-(2-methyl-5-fluorobenzoyl)-2,3,4,5-tetrahyd 
ro-1H-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 210 
Methyl 
4-(4-Hydroxybenzenesulfonyl)-1-(2-methyl-3-fluorobenzoyl)-2,3,4,5-tetrahyd 
ro-1H-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 211 
Methyl 
4-(4-Hydroxybenzenesulfonyl)-1-(3-phenylpropionyl)-2,3,4,5-tetrahydro-1H-[ 
1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 212 
Methyl 
4-(4-Hydroxybenzenesulfonyl)-1-(2-trifluoromethylbenzoyl)-2,3,4,5-tetrahyd 
ro-1H-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 213 
Methyl 
1-(2-Chloro-6-trifluoromethylbenzoyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5 
-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 214 
Methyl 
1-(4-Fluoro-2-trifluoromethylbenzoyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5 
-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 215 
Methyl 
1-(2-Fluoro-6-trifluoromethybenzoyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5- 
tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 216 
Methyl 
4-(4-Hydroxybenzenesulfonyl)-1-(2methylbenzoyl)-2,3,4,5-tetrahydro-1H-[1,4 
]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 217 
Methyl 
4-(4-Hydroxybenzenesulfonyl)-1-(2-methyl-6-chlorobenzoyl)-2,3,4,5-tetrahyd 
ro-1H-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 218 
Methyl 
1-(2,4-Dimethylbenzoyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H 
-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 219 
Methyl 
1-(2,5-Dimethylbenzoyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H 
-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 220 
Methyl 
1-(2-Chloro-4-fluorobenzoyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5-tetrahyd 
ro-1H-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 221 
Methyl 
1-(2-Chlorobenzoyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1, 
4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 222 
Methyl 
1-(2-Fluorobenzoyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1, 
4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 223 
Methyl 
1-(2-Chloro-6-fluorobenzoyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5-tetrahyd 
ro-1H-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 224 
Methyl 
1-(2,3-Difluorobenzoyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H 
-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 225 
Methyl 
1-(2,4-Dichlorobenzoyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H 
-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 226 
Methyl 
1-(2,3-Dichlorobenzoyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H 
-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 227 
Methyl-1-(2,5-Dichlorobenzoyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5-tetrahy 
dro-1H-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 228 
Methyl 
4-(4-Hydroxybenzenesulfonyl)-1-(2-methylthiobenzoyl)-2,3,4,5-tetrahydro-1H 
-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 229 
Methyl 
4-(4-Hydroxybenzenesulfonyl)-1-(3-methyl-2-thienylcarbonyl)-2,3,4,5-tetrah 
ydro-1H-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 230 
Methyl 
4-(4-Hydroxybenzenesulfonyl)-1-(4-methyl-2-thienylcarbonyl)-2,3,4,5-tetrah 
ydro-1H-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 231 
Methyl 
1-(3-Chloro-2-thienylcarbonyl)-4-(hydroxybenzenesulfonyl)-2,3,4,5-tetrahyd 
ro-1H-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 232 
Methyl 
1-(2-Furanylcarbonyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[ 
1,4]benzodiazepine-3-carboxylate 
To a solution of 3.0 g (6.38 mmol) of methyl 
1-(2-furanylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[ 
1,4]benzodiazepine-3-carboxylate in., 15 ml of CH.sub.2 Cl.sub.2 (cooled to 
0.degree. C.) was added dropwise 12.8 ml (2.8 mmol) of BBr.sub.3 in 
CH.sub.2 Cl.sub.2 (1.0M in CH.sub.2 Cl.sub.2). The mixture was stirred at 
room temperature for 3 days, diluted with CH.sub.2 Cl.sub.2 and then ice 
was added. The organic layer was separated, washed with H.sub.2 O, brine 
and dried (Na.sub.2 SO.sub.4). The solvent was removed and the residue 
chromatographed on silica gel (flash column) with ethyl acetate-hexane 
(1:1) as solvent. The fractions containing product were combined, the 
solvent removed and the residue triturated with ethyl acetate. Chilling 
and filtering gave 0.72 g of methyl 
1-(2-furanylcarbonyl)-4-hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4 
]benzodiazepine-3-carboxylate as a white solid, mp 204-206.degree. C.; Anal 
Cal'd for C.sub.22 H.sub.20 N.sub.2 O.sub.7 S: C, 57.9; H, 4.2; N, 6.1. 
Found: C,57.2; H,4.3; N, 6.0.;Mass spectrum (ES) 457.1 (M+H). 
REFERENCE EXAMPLE 233 
Methyl 
4-(4-Hydroxybenzenesulfonyl)-1-(3-methyl-2-furanylcarbonyl)-2,3,4,5-tetrah 
ydro-1H-[-1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 234 
Methyl 
4-(4-Hydroxybenzenesulfonyl)-1-(4-methyl-2-furanylcarbonyl)-2,3,4,5-tetrah 
ydro-1H-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 235 
Methyl 
1-(5-Chloro-2-furanylcarbonyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5-tetrah 
ydro-1H-[1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 236 
Methyl 
1-(5-Chloro-2-thienylcarbonyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5-tetrah 
ydro-1H-[1,4]benzodeiazepine-3-carboxylate 
REFERENCE EXAMPLE 237 
Methyl 
1-Propionyl-4-(4-hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzod 
eiazepine-3-carboxylate 
REFERENCE EXAMPLE 238 
Methyl 
1-Hexanoyl-4-(4-hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodi 
azepine-3-carboxylate 
REFERENCE EXAMPLE 239 
Methyl 
4-(4-Hydroxybenzenesulfonyl)-1-(3-thienylcarbonyl)-2,3,4,5-tetrahydro-1H-[ 
1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 240 
Methyl 
1-(3-Furanylcarbonyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[ 
1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 241 
Methyl 
1-(Acetylaminoacetyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[ 
1,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 242 
Methyl 1-(N,N 
Dimethylaminoacetyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1 
,4]benzodiazepine-3-carboxylate 
REFERENCE EXAMPLE 243 
Methyl 
1-(Cyclopropylcarbonyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H 
-[1,4]benzodiazepine 
To a solution of 4.44 g (10 mmol) of methyl 
1-cyclopropylcarbonyl-4-(4-methoxybenzenefulfonyl)-2,3,4-tetrahydro-1H-[1, 
4]benzodiaxepine-3-carboxylate in 25 ml of CH.sub.2 Cl.sub.2 chilled to 
0.degree. C. was added dropwise 22 ml (22 mmol) of BBr.sub.3 in CH.sub.2 
Cl.sub.2 (1.0 molar solution). The mixture was stirred overnight, cooled 
and diluted with ice and H.sub.2 O. Dichloromethane was added and the 
organic layer separated and washed with H.sub.2 O, brine and dried 
(Na.sub.2 SO.sub.4). The solvent was removed under vacuum to give a solid 
which was chromatographed on silica gel with the solvent ethyl 
acetate-hexane (1:1) to give 1.0 g of methyl 
1-cyclopropylcarbonyl-4-(4-hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[ 
1,4]benzodiazepine-3-carboxylate as a foam; Mass spectrum (ES) 431.3 (M+H). 
REFERENCE EXAMPLE 244 
Methyl 
4-(4-Hydroxybenzenesulfonyl)-1-(trifluoroacetyl)-2,3,4,5-tetrahydro-1H-[1, 
4]benzodiazepine 
EXAMPLE 1 
4-(4-Methoxybenzenesulfonyl)-1-(3-trifluoromethylbenzoyl)-2,3,4,5-tetrahydr 
o-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
To a solution of 0.297 g (0.556 mmol) of 
4-(4-methoxybenzenesulfonyl)-1-(3-trifluoromethylbenzoyl)-2,3,4,5-tetrahyd 
ro-1H-[1,4]benzodiazepine-3-carboxylic acid from Reference Example 9 in 5 
ml of CH.sub.2 Cl.sub.2, was added 0.556 ml (1.11 mmol) of 2.0M oxalyl 
chloride in CH.sub.2 Cl.sub.2 and 0.044 ml of N,N-dimethylformamide. The 
mixture was stirred under nitrogen at room temperature for 1.5 hours and 
cooled in an ice bath. To this solution was added a chilled mixture of 
0.156 g (2.24 mmol) of hydroxylamine hydrochloride and 4.68 ml (3.36 mmol) 
of triethylamine in 1.39 ml of tetrahydrofuran and 0.33 ml of H.sub.2 O. 
The mixture was stirred at room temperature overnight and diluted with 
CH.sub.2 Cl.sub.2. The mixture was washed with 2N citric acid, H.sub.2 O, 
1N NaHCO.sub.3, brine and dried with Na.sub.2 SO.sub.4. The solvent was 
removed under vacuum to give 0.29 g of solid. Chromatography on thick 
layer silica gel plates with ethyl acetate-methanol (9:1) gave 60 mg of 
solid, m.p. 128-130.degree. C. Anal. for C.sub.25 H.sub.22 F.sub.3 N.sub.3 
O.sub.6 S: Calc'd: C,54.6; H,4.0; N,7.7; Found: C.54.1; H,4.2; N,7.3. 
Utilizing the procedure described in Example 1, the following compounds are 
prepared from the appropriately 
1-substituted-4(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzo 
diazepine-3-carboxylic acids. 
EXAMPLE 2 
4-(4-Metboxybenzenesulfonyl)-1-(4-methylphenylsulfonyl)-2,3,4,5-tetrahydro- 
1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
Solid. Anal. for C.sub.24 H.sub.25 N.sub.3 O.sub.7 S.sub.2 : Calc'd: 
C,54.2; H,4.7; N,7.9: Found: C,53.5; H,5.2; N,7.3. 
EXAMPLE 3 
1-Methanesulfonyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]b 
enzodiazepine-3-carboxylic acid, Hydroxyamide 
Solid. Anal. for C.sub.18 H.sub.21 N.sub.3 O.sub.7 S.sub.2 : Calc'd: 
C.47.5; H,4.7; N.9.2; Found: C,46.8; H,4.8: N,8.5. 
EXAMPLE 4 
1,4-Bis-(4-Methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepin 
e-3-carboxylic acid, Hydroxyamide 
Solid. Anal. for C.sub.24 H.sub.25 N.sub.3 O.sub.8 S.sub.2 : Calc'd: 
C,52.6; H,4.6; N,7.7; Found: C,52.2; H,4.8; N,7.3. 
EXAMPLE 5 
1-Benzoyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiaz 
epine-3-carboxylic acid, Hydroxyamide 
White solid. Anal. for C.sub.24 H.sub.23 N.sub.3 O.sub.6 S: Calc'd: C,59.9; 
H,4.8; N,8.7.; Found: C,59.2; H,4.6; N,8.6; S, 6.4; Mass spectrum (ES) 
482.3 (M+H). 
EXAMPLE 6 
1-Acetyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiaze 
pine-3-carboxylic acid, Hydroxyamide 
White crystals. m.p. 195-197.degree. C. Anal. for C.sub.19 H.sub.21 N.sub.3 
O.sub.6 S: Calc'd: C,54.4; H,5.1; N,10.0; Found: C,52.6; H,4.9; N,9.4. 
EXAMPLE 7 
4-(4-Methoxybenzenesulfonyl)-1-(3-pyridinylcarbonyl)-2,3,4,5-tetrahydro-1H- 
[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
White crystals, m.p. 167-169.degree. C. Anal. for C.sub.23 H.sub.22 N.sub.4 
O.sub.6 S: Calc'd: C,57.3; H,4.6; N, 11.6; Found: 55.3; H,4.6; N,10.6. 
EXAMPLE 8 
4-(4-Methoxybenzenesulfonyl)-1-(2-thienylcarbonyl)-2,3,4,5-tetrahydro-1H-[1 
,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
White solid. Anal. for C.sub.22 H.sub.21 N.sub.3 O.sub.6 S): Calc'd: 
C,54.2; H,4.3; N,8.6; Found: C.53.7; H,4.4; N,8.1. 
EXAMPLE 9 
1-Methoxyacetyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]ben 
zodiazepine-3-carboxylic acid, Hydroxyamide 
White crystals, m.p. 143-145.degree. C. Anal. for C.sub.20 H.sub.23 N.sub.3 
O.sub.7 S: Calc'd: C,53.4; H,5.2; N,9.4; Found: C,53.9; H,5.6; N,8.5. 
EXAMPLE 10 
4-(4-Methoxybenzenesulfonyl)-1-(propane-1-sulfonyl)-2,3,4,5-tetrahydro-1H-[ 
1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
Off-white solid. Anal. for C.sub.20 H.sub.25 N.sub.3 O.sub.7 S.sub.2 : 
Calc'd: C,49.7; H,5.2; N,8.7; Found: C,48.9; H,5.3; N,8.4. 
EXAMPLE 11 
4-(4-Methoxybenzenesulfonyl)-1-(2-methyl-5-fluorobenzoyl)-2,3,4,5-tetrahydr 
o-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
Off-white solid. Anal. for C.sub.25 H.sub.24 FN.sub.3 O.sub.6 S: Calc'd: 
C,58.5; H.4.7; N,8.2; Found: C,57.1; H,4.8; N.7.6. 
EXAMPLE 12 
4-(4-Methoxybenzenesulfonyl)-1-(3-phenylpropionyl)-2,3,4,5-tetrahydro-1H-[1 
,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
Solid. Anal. for C.sub.26 H.sub.27 N.sub.3 O.sub.6 S: Calc'd: C,61.3; 
H.5.3; N,8.3; Found: C.59.8; H,5.3; N,7.5. 
EXAMPLE 13 
4-(4-Methoxybenzenesulfonyl)-1-(4-pyridinylcarbonyl)-2,3,4,5-tetrahydro-1H- 
[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
White crystals, m.p. 155-165.degree. C. Anal. for C.sub.23 H.sub.22 N.sub.4 
O.sub.6 S: Calc'd: C,57.3; H,4.6; N,11.6; Found: C.56.8; H.4.9; N,10.9. 
EXAMPLE 14 
1-([1,1'-Biphenyl]-2-carbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahy 
dro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
Purified by chromatography on silica gel thick layer plates with 
hexane-ethyl acetate as solvent to give a white solid; m.p. 
176-178.degree. C. Anal. for C.sub.30 H.sub.27 N.sub.3 O.sub.6 S: Calc'd: 
C,64.6; H,4.9; N,7.5: Found: C,63.7; H,4.6; N,7.1. 
EXAMPLE 15 
1-(4-Biphenylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[ 
1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
Purified by chromatography on silica gel thick layer plates with 
hexane-ethyl acetate (1:1) as solvent to give a white solid, m.p. 
160-168.degree. C. Anal. for C.sub.30 H.sub.27 N.sub.3 O.sub.6 S: Calc'd: 
C,64.6; H,4.9; N,7.5; Found: C,61.2. H,4.9; N,7.0; Mass spectrum (ES) 
558.1 (M+H). 
EXAMPLE 16 
1-(3-Fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4 
]benzodiazepine-3-carboxylic acid, Hydroxyamide 
EXAMPLE 17 
4-(4-Methoxybenzenesulfonyl)-1-(2-methyl-3-fluorobenzoyl)-2,3,4,5-tetrahydr 
o-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
EXAMPLE 18 
4-(4-Methoxybenzenesulfonyl)-1 
-(2-methyl-3-trifluoromethylbenzoyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiaze 
pine-3-carboxylic acid, Hydroxyamide 
EXAMPLE 19 
1-(2-Chloro-6-trifluoromethylbenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5- 
tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
EXAMPLE 20 
1-(4-Fluoro-2-trifluoromethylbenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5- 
tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
EXAMPLE 21 
1-(2-Fluoro-6-trifluoromethylbenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5- 
tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
EXAMPLE 22 
4-(4-Methoxybenzenesulfonyl)-1-(2-methylbenzoyl)-2,3,4,5-tetrahydro-1H-[1,4 
]benzodiazepine-3-carboxylic acid, Hydroxyamide 
EXAMPLE 23 
4-(4-Methoxybenzenesulfonyl)-1-(2-methyl-6-chlorobenzoyl)-2,3,4,5-tetrahydr 
o-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
EXAMPLE 24 
1-(2,4-Dimethylbenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H- 
[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
EXAMPLE 25 
1-(2,5-Dimethylbenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H- 
[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
EXAMPLE 26 
1-(2-Chloro-4-fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydr 
o-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
EXAMPLE 27 
1-(2-Chlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4 
]benzodiazepine-3-carboxylic acid, Hydroxyamide 
EXAMPLE 28 
1-(2-Fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4 
]benzodiazepine-3-carboxylic acid, Hydroxyamide 
EXAMPLE 29 
1-(2-Chloro-6-fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydr 
o-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
EXAMPLE 30 
1-(2,3-Difluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H- 
[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
EXAMPLE 31 
1-(2,4-Dichlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H- 
[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
white crystals, m.p. 158-162.degree. C. Anal. for C.sub.24 H.sub.21 
Cl.sub.2 N.sub.3 O.sub.6 S: Calc'd: C,52.4: H.3.9; N,7.6; Found: C,52. 1; 
H,3.8; N,7.5; Mass spectrum (ES) 549.9 (M+H); 552.0 (M+H). 
EXAMPLE 32 
1-(2,3-Dichlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H- 
[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
EXAMPLE 33 
1-(2,5-Dichlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H- 
[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
EXAMPLE 34 
1-(2- 
Methoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]be 
nzodiazepine-3-carboxylic acid, Hydroxyamide 
EXAMPLE 35 
1-(4-Chloro-2-methoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahyd 
ro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide 
EXAMPLE 36 
4-(4-Methoxybenzenesulfonyl)-1-(2-methylthiobenzoyl)-2,3,4,5-tetrahydro-1H- 
[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
EXAMPLE 37 
4-(4-Methoxybenzenesulfonyl)-1 
-(3-methyl-2-thienylcarbonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3- 
carboxylic acid, Hydroxyamide 
EXAMPLE 38 
4-(4-(Methoxybenzenesulfonyl)-1-(4-methyl-2-thienylcarbonyl)-2,3,4,5-tetrah 
ydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
EXAMPLE 39 
1-(3-Chloro-2-thienylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahy 
dro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
EXAMPLE 40 
1-(2-Furanylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1 
,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
white solid. Anal. for C.sub.22 H.sub.21 N.sub.3 O.sub.7 S: Calc'd: C, 
56.0; H, 4.5; N, 8.9; Found: C, 55.6; H, 4.8; N, 8.3; Mass spectrum (ES) 
472.0 (M+H). 
EXAMPLE 41 
4-(4-Methoxybenzenesulfonyl)-1-(3-methyl-2-furanylcarbonyl)-2,3,4,5-tetrahy 
dro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
EXAMPLE 42 
4-(4-Methoxybenzenesulfonyl)-1-(4-methyl-2-furanylcarbonyl)-2,3,4,5-tetrahy 
dro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
EXAMPLE 43 
1(5-Chloro-2-furanylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahyd 
ro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
EXAMPLE 44 
1-(5-Chloro-2-thienylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahy 
dro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
EXAMPLE 45 
1-Propionyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodi 
azepine-3-carboxylic acid, Hydroxyamide 
EXAMPLE 46 
1-Hexanoyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodia 
zepine-3-carboxylic acid, Hydroxyamide 
EXAMPLE 47 
1-(3-Methoxypropionyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[ 
1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
EXAMPLE 48 
4-(4-Methoxybenzenesulfonyl)-1-(3-thienylcarbonyl)-2,3,4,5-tetrahydro-1H-[1 
,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
EXAMPLE 49 
1-(3-Furanylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1 
,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
EXAMPLE 50 
1-(trans-Crotonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4] 
benzodiazepine-3-carboxylic acid, Hydroxyamide 
EXAMPLE 51 
1-(Methacryloyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]be 
nzodiazepine-3-carboxylic acid, Hydroxyamide 
EXAMPLE 52 
1-(Acetylaminoacetyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1 
,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
EXAMPLE 53 
1-(Aminoacetyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]ben 
zodiazepine-3-carboxylic acid, Hydroxyamide 
EXAMPLE 54 
1-(N,N-Dimethylaminoacetyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro 
-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
EXAMPLE 55 
1-(Cyclopropylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H- 
[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
off-white solid. Anal. for C.sub.21 H.sub.23 N.sub.3 O.sub.6 S: Calc'd: 
C,56.6; H,5.2; N,9.4; Found: C,55.1; H,5.2; N,8.8; Mass spectrum (ES) 
446.5 (M+H). 
EXAMPLE 56 
1-(Cyclobutylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[ 
1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
EXAMPLE 57 
1-(Cyclohexylcarbonyl)-4-(4-methoxybenzenesufonyl)-2,3,4,5-tetrahydro-1H-[1 
,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
off-white solid. Anal. for C.sub.24 H.sub.29 N.sub.3 O.sub.6 S: Calc'd: 
C,59.1; H,6.0; N,8.6; Found: C,58.0; H,6.0; N,8.1; Mass spectrum (ES) 
488.6 (M+H). 
EXAMPLE 58 
4-(4-Methoxybenzenesulfonyl)-1-(phenoxyacetyl)-2,3,4,5-tetrahydro-1H-[1,4]b 
enzodiazepine-3-carboxylic acid, Hydroxamide 
A mixture of 0.70 g (1.37 mmol) of methyl 
4-(4-methoxybenzenesulfonyl)-1-(phenoxyacetyl)-2,3,4-5-tetrahydro-1H[1,4]b 
enzodiazepine-3-carboxylate and 1.8 ml (1.78 mmol) of 1N NaOH in 3 ml of 
tetrahydrofuran was stirred at room temperature for 2 hours. The mixture 
was diluted with 3 ml of H.sub.2 O and acidified with 1N HCl to give a 
gummy solid. Ethyl acetate was added thereto and the mixture was chilled 
overnight. Filtration gave 
4-(4-methoxybenzenesulfonyl)-1-(phenoxyacetyl)-2,3,4,5-tetrahydro-1H-[1,4] 
benzodiazepine-3-carboxylic acid as crystals. m.p. 188.degree.-191.degree. 
C. 
To a 0.496 g (1 mmol) sample of the preceeding compound in 5 ml of CH.sub.2 
Cl.sub.2 cooled to 0.degree. C., was added 1 ml (2 mmol) of oxalyl 
chloride followed by the addition of 77.4 .mu.l (1 mmol) of 
N,N-dimethylformamide. The mixture was stirred at room temperature under 
nitrogen for 1 hour (referred to as solution A). In a separate flask was 
added 0.278 g (4 mmol) of hydroxyamine hydrochloride, 0.5 ml of H.sub.2 O 
and 836.3 .mu.l (5 mmol) of triethylamine. The mixture was stirred for 20 
minutes and then cooled to 0.degree. C. (referred to as solution B). The 
cooled solution B was added to the cooled (0.degree. C.) and stirred 
solution A and then this mixture was allowed to warm to room temperature 
and was stirred overnight. The mixture was concentrated under vacuum, 
diluted with CH.sub.2 Cl.sub.2 and washed with H.sub.2 O, 2N citric acid, 
1N NaHCO.sub.3, and brine and dried with Na.sub.2 SO.sub.4. The solvent 
was removed and the residue crystallized from hexane-ethyl acetate (3:97) 
to give 0.396 g of white crystals, m.p. 159.degree.-163.degree. C. Anal. 
for C.sub.25 H.sub.25 N.sub.3 O.sub.7 S; Calc'd: C,58.7; H,4.9, N.8.2; 
Found: C,58.4; H,5. 1; N,7.8; Mass spectrum (ES) 512 (M+H). 
EXAMPLE 59 
1-Methoxyacetyl-4-(4-methoxybenzenesulfonyl)-7-methyl-2,3-4,5-tetrahydro-1H 
-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamine 
A mixture of 1.26 g (2.72 mmol) of methyl 
1-metboxyacetyl4-(4-methoxybenzenesulfonyl)-7-methyl-2,3,4,5-tetrahydro-1H 
-[1,4]benzodiazepine-3-carboxylate from Reference Example 181, 3.53 ml of 
1N NaOH and 10 ml of tetrahydrofuran was stirred at room temperature for 3 
hours. The solvent was then removed under vacuum and the residue dissolved 
in H.sub.2 O and extracted with ethyl acetate. The aqueuous layer was 
acidified with 1N HCl and then extracted with CH.sub.2 Cl.sub.2. The 
CH.sub.2 Cl.sub.2 layer was dried over Na.sub.2 SO.sub.4 and the solvent 
removed to provide a solid. This material was dried in a vacuum oven and 
given 1.06 of solid, m.p. 101-105.degree. C. 
A 1.02 g (2.27 mmol) sample of 
1-methoxyacetyl-4-(4-methoxybenzenesulfonyl)-7-methyl-2,3-4,5-tetrahydro-1 
H-[1,4]benzodiazepine-3-carboxylic acid prepared above was dissolved in 
2.57 ml of 1N KOH. Toluene was added several times and the solvent was 
removed after each addition. The residue was dried in a vacuum oven to 
give 1.1 g of potassium salt. A mixture of 2.26 ml (4.52 mmol) of oxalyl 
chloride in 20 ml of CH.sub.2 Cl.sub.2 was cooled at 0.degree. C. and 
0.351 ml (4.52 mmol) of N,N-dimethylformamide (DMF) was added dropwise. 
The mixture was stirred for 5 minutes and the potassium salt (1.1 g) was 
added. The mixture was allowed to warm to room temperature and was stirred 
for 2 hours under nitrogen. The mixture was cooled (0.degree. C.) and this 
mixture was added to a cooled (0.degree. C.) mixture of 0.628 g (9.04 
mmol) of hydroxylamine hydrochloride, 1.89 ml (13.56 mmol) of 
triethylamine in 1 ml of tetrahydrofuran-water (8:2). The mixture was 
stirred and chilled at 0.degree. C. for 10 minutes and then stirred at 
room temperature overnight. The solvent was removed under vacuum and the 
residue diluted with CH.sub.2 Cl.sub.2 --H.sub.2 O and acidified with 2N 
citric acid (pH 4). The CH.sub.2 Cl.sub.2 layer was separated and washed 
with H.sub.2 O, 1N NaHCO.sub.3, H.sub.2 O, and brine and dried with 
Na.sub.2 SO.sub.4. The solution was filtered through a thin pad of hydrous 
magnesium silicate and the solvent removed under vacuum to give 0.73 g of 
solid. Crystallization from ethyl acetate gave 0.32 g of crystals, m.p. 
146.degree.-148.degree. C. 
EXAMPLE 60 
1-Benzoyl-4-(4-methoxybenzenesulfonyl)-7-methyl-2,3,4,5-tetrahydro-1H[1,4]b 
enzodianzepine-3-carboxylic acid, Hydroxyamide 
In the manner described in Example 59, 0.83 g (1.71 mmol) of 
1-benzoyl-4-(4-methoxybenzene-sulfonyl)-7-methyl-2,3,4,5-tetrahydro-1H[1,4 
]benzodianzepine-3-carboxylic acid from Reference Example 185 was converted 
to the potassium salt with 1.87 ml of 1N KOH and the salt reacted with 
oxalyl chloride-DMF to give the acid chloride which was reacted with 
hydroxylamine. The solid from the reaction gave from CH.sub.2 Cl.sub.2 
0.20 g, of yellow solid, m.p. 137.degree.-139.degree. C. 
EXAMPLE 61 
4-(4-Methoxybenzenesulfonyl)-1-[4-(trifluoromethoxy)benzoyl]-8-chloro-2,3,4 
,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
In the manner described for Example 59, the potassium salt was prepared 
from 1.20 g of 
4-(4-methoxybenzenesulfonyl)-1-[4-(trifluoromethoxy)benzoyl)-8-chloro-2,3, 
4.5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid from Reference 
Example 189, m.p. 184.degree.-186.degree. C. and reacted with oxalyl 
chloride-DMF and the acid chloride reacted with hydroxylamine to give 1.20 
g of solid. Chromatography on thick layer silica gel plates with ethyl 
acetate-methanol (95:5) gave 0.58 g of solid m.p. 134.degree. dec; Mass 
spectrum (ES) 601 (M+H). 
EXAMPLE 62 
4-(4-Methoxybenzenesulfonyl)-1-(2-methoxyetbyl)-2,3,4,5-tetrahydro-1H-[1,4] 
benzodiazepine-3-carboxylic acid, Hydroxyamide 
In the manner described for Example 1, 0.55 g of 
4-(4-methoxybenzenesulfonyl)-1-(2-methoxyethyl)-2,3,4,5-tetrahydro-1H-[1,4 
]-benzodiazepine-3-carboxylic acid from Reference Example 187 was reacted 
with oxalyl chloride and the resulting acid chloride reacted with 
hydroxylamine to 0.40 g of solid. Chromatography on thick layer silica gel 
plates with ethyl acetate-methanol (7:3) gave 0.150 g of product as an 
off-white foam; Mass spectrum (ES) 434.3 (M-H) Anal. for C.sub.20 H.sub.25 
N.sub.3 O.sub.6 S: Calc'd: C,55.2; H,5.8; N,9.7; Found: C,54.0; H,5.8; 
N,9.3. 
EXAMPLE 63 
4-(4-Methoxybenzenesulfonyl)-1-[2-(1-pyrazolyl)phenylcarbonyl]2,3,4,5-tetra 
hydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
As described for the general reaction of ethyl 2-fluorobenzoate with amines 
set forth in Tetrahedron, 53, 7557-7576 (1997), ethyl 2-fluorobenzoate was 
reacted with pyrazole by refluxing N, N-dimethylformamide to give ethyl 
2-(1-pyrazolyl)benzoate, as a thick yellow oil. Anal. Calc'd: for C.sub.12 
H.sub.12 N.sub.2 O.sub.2 : 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 hrs and the solvent removed. The residue was made 
acidic (pH6) with 2N citric acid and the precipated solid was filtered to 
obtain 3.7g of product. The pH of the filtrate was adjusted to 4:5 and 
extracted with ethyl acetate The extract was concentrated to dryness to 
give 1.5 g of product. The two crops were combined to give 5.2 g of 
2-(1-pyrazolyl)benzoic acid, mp 140-142.degree. C. To the preceding 
compound (2.07 g) in 5 ml CH.sub.2 Cl.sub.2 (chilled in an ice bath )was 
added 11.1 ml of a 2 Molar solution of oxalyl chloride in CH.sub.2 
Cl.sub.2 and 0.085 ml of N,N-dimethylformamide. The mixture was allowed to 
warm to room temperature and stirred for 4 hours. The solvent was removed 
and 25 ml of toluene added (twice) and removed under vacuum to give 
2-(1-pyrazolyl)benzoyl chloride as a yellow solid. 
A 2.3 g sample of the preceding compound was reacted with 1.5 g of the 
compound of Reference Example 179 in 15 ml of CH.sub.2 Cl.sub.2 and 5.12 
ml of triethylamine in the manner described for Reference Example 181 to 
give methyl 
2-[(4-methoxybenzenesulfonyl)-{2-[2-(1-pyrazolyl)phenylcarbonyl]amino-5-me 
thylbenzyl}amino]acrylate. This compound was cyclized with NaHCO.sub.3 in 
methanol in the manner described in Reference Example 181 to give methyl 
4-(4-methoxybenzenesulfonyl)-1-[2-(1-pyrazolyl)phenylcarbonyl]-7-methyl-2, 
3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate, m.p. 240-242.degree. 
C. 
A 1.16 g sample of the preceding compound was hydrolysed with 2.69 ml of 1N 
NaOH in 10 ml of tetrahydrofuran in the manner described for Reference 
Example 104 to give 0.71 g of 
4-(4-methoxybenzenesulfonyl)-1-[2-(1-pyrazolyl)phenylcarbonyl)-7-methyl-2, 
3,4,5-tetrahydro-1H[1,4]benzodiazepine-3-carboxylic acid, mp 
149-151.degree. C. 
In the manner described in Example 59, 1.1 g of the preceding compound was 
converted to the potassium salt and reacted with oxalyl chloride and then 
hydroxylamine to give the above-identified product as white crystals, mp 
194-196.degree. C. 
EXAMPLE 64 
4-(4-Methoxybenzenesulfonyl)-1-[2-(4-morpholino)phenylcarbonyl}-8-chloro-2, 
3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
Ethyl 2-morpholinobenzoate prepared in the manner described in Tetrahedron, 
53:7557, (1997) was refluxed with 10N NaOH in tetrahydrofuran-ethanol 
(8:2) for 1.5 hrs to give 2-morpholinobenzoic acid, mp 156-157.degree. C. 
A 1.8 g sample of this compound in 5 ml of CH.sub.2 Cl.sub.2 (chilled) was 
added a solution of 7.9 ml of oxalyl chloride in CH.sub.2 Cl.sub.2 (2M) 
followed by the addition of 0.058 ml of N,N-dimethylformamide. The 
solution was stirred at room temperature for 6 hrs and the solvent 
removed. Toluene was added (2 times) and removed to give 
2-(4-morpholino)benzoyl chloride as a yellow solid. 
In the manner described in Reference Examples 181 and 189, the preceding 
2-(4-morpholino)benzoyl chloride was reacted with methyl 
2-[(2-amino-4-chlorobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxyprop 
ionate and the product was stirred with NaHCO.sub.3 in methanol to give 
methyl 
4-(4-methoxybenzenesulfonyl)-1-[2-(4-morpholino)phenylcarbonyl]-8-chloro-2 
,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate, as a white solid 
having a mp 100-105.degree. C. 
To 0.90 g of this compound in 10 ml of tetrahydrofuran was added 1.95 ml of 
1N NaOH and the solution was stirred at room temperature overnight. 
Acidification with 2N citric acid gave 0.82 g of solid, mp 136-143.degree. 
C. This compound, 
4-(4-methoxybenzenesulfonyl)-1-[2-(4-morpholino)phenylcarbonyl]-8-chloro-2 
,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid (0.78 g) was 
converted to the potassium salt and reacted first with oxalyl chloride and 
then with hydroxylamine as described in Example 63 to give 0.276 g of 
product as a light yellow solid, mp 132.degree. C. 
EXAMPLE 65 
1-(4-Ethoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4 
]benzodiazepine-3-carboxylic acid, Hydroxyamide 
A mixture of 0.270 g of methyl 
4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-c 
arboxylate of Reference Example 12, 0.291 g of 4-ethoxybenzoyl chloride and 
500 .mu.l of triethylamine in 5 ml of CH.sub.2 Cl.sub.2 was stirred at 
room temperature overnight. The mixture was diluted with CH.sub.2 Cl.sub.2 
and H.sub.2 O and the CH.sub.2 Cl.sub.2 layer was separated and 
concentrated to dryness. The residue was triturated with ethyl acetate to 
give 0.276 g of methyl 
1-(4-ethoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5tetrahydro-1H-[1,4 
]benzodiazepine-3-carboxylate as white crystals, mp 187-190.degree. C. 
A 0.47 g sample of this compound was hydrolyzed with 1.2 ml of 1N NaOH in 4 
ml of tetrahydrofuran. Dilution with H.sub.2 O and acidification with 1N 
HCl gave 0.40 g of the acid as a white solid, mp 144-152.degree. C. The 
preceding compound (0.35 g) was converted to the above-titled compound in 
the manner described in Example 1 to provide 0.195 g of solid, mp 
136-142.degree. C. 
EXAMPLE 66 
4-(4-Methoxybenzenesulfonyl)-1-[2-chloro-4-(3-methyl-1-pyrazolyl)phenylcarb 
onyl}-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, 
Hydroxyamide 
As described in Example 65, methyl 
4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-c 
arboxylate was reacted with 4-(3-methyl-1-25 pyrazolyl)-2-chlorobenzoyl 
chloride to give methyl 
4-(4-methoxybenzenesulfonyl)-1-[2-chloro-4-(3-methyl-1-pyrazolyl)phenylcar 
bonyl]-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate as a white 
solid. Anal. for C.sub.29 H.sub.27 C.sub.1 N.sub.4 O.sub.6 S: Calc'd: C, 
58.3; H, 4.6; N, 9.4. Found: C,58.2; H, 4.9; N, 8.9. 
This compound was hydrolysed with 1N NaOH in tetrahydrofuran as described 
in Reference Example 185 to give the benzodiazepine-3-carboxylic acid 
derivative as a white solid. This compound was reacted with oxalyl 
chloride and then reacted with hydroxylamine as described in Example 1 to 
give the product as white crystals, mp 189-191.degree. C. 
EXAMPLE 67 
1-Benzyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiaze 
pine-3-carboxylic acid, Hydroxylamide 
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 CH.sub.3 OH, CH.sub.2 
Cl.sub.2 (40 ml) and 30 ml of 2N HCl and the mixture stirred at room 
temperature for 1.5 hr. The organic layer was separated, washed with 
brine, dried with Na.sub.2 SO.sub.4 and the solvent removed. The residue 
was crystallized from ethanol-hexane to give 1.15 g of methyl 
1-benzyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiaz 
epine-3-carboxylate as white crystals, mp 120-122.degree. C. A sample (1.0 
g) of this compound was hydrolysed with 2.8 ml of 1N NaOH in 7 ml of 
tetrahydrofuran as described in Reference Example 104 to give 0.64 g of 
the 2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid derivative 
as white crystals, mp 183-185.degree. C. 
A 0.55 g sample of this compound was converted to the acid chloride which 
was reacted with hydroxylamine as described in Example 1 to give the 
product as a light brown foam; Mass spectrum (ES) 468.1 (M+H). 
Utilizing the procedure described in Example 65 above, the following 
compounds may be prepared. 
EXAMPLE 68 
4-(4-Methoxybenzenesulfonyl)-1-(4-(2-thienyl)phenyl-carbonyl)-2,3,4,5-tetra 
hydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
EXAMPLE 69 
4-(4-Methoxybenzenesulfonyl)-1-(4-(3-thienyl)phenyl-carbonyl)-2,3,4,5-tetra 
hydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
EXAMPLE 70 
4-(4-Methoxybenzenesulfonyl)-1-[2-(3-pyrazol)phenyl-carbonyl]-2,3,4,5-tetra 
hydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
EXAMPLE 71 
1-(2,4-Dimethoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H 
-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
To a cooled (0.degree. C.) solution of 1.0 g (2.66 mmol) of 
4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-c 
arboxylate from Reference Example 12 and 1.85 ml (13.3 mmol) of 
triethylamine in 8 ml of CH.sub.2 Cl.sub.2 was added 1.17 g, (6.65 mmol) 
of 2,4-dimethoxybenzoyl chloride. The mixture was stirred at room 
temperature overnight, diluted with CH.sub.2 Cl.sub.2 and washed with 2N 
citric acid. The organic layer was washed with H.sub.2 O, 1N Na.sub.2 
CO.sub.3, brine and dried over Na.sub.2 SO.sub.4. The solvent was removed 
and the residue was chromatographed on thick layer silica gel plates with 
ethyl acetate-hexane (1:1) as an eluent to give 1.0 g of methyl 
1-(2,4-dimethoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1 
H-[1,4]benzodiazepine-3-carboxylate as a white foam. Anal. for C.sub.27 
H.sub.28 H.sub.2 O.sub.8 S: Calc'd: 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 0.80 g (1.48 mmol) sample of the preceding compound and 1.92 ml (1.92 
mmol) of 1N NaOH in 5 ml of tetrahydrofuran was stirred at room 
temperature for 1.5 hours. The solvent was removed and the residue diluted 
with water. The solution was acidified with 1N HCl, chilled and filtered 
to give 0.70 g of 
1-(2,4-dimethoxy-benzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 
1H-[1,4]benzodiazepine-3-carboxylic acid as a white solid. Anal. for 
C.sub.26 H.sub.26 N.sub.2 O.sub.8 S: Calc'd: 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). 
A 0.80 g (1.52 mmol) sample of the preceding compound in 10 ml of CH.sub.2 
Cl.sub.2 (chilled to 0.degree. C.) was added to 1.52 ml (3.04 mmol) of 
oxalyl cholride (2.0M solution in CH.sub.2 Cl.sub.2). To the solution was 
added 118 .mu.l (1.52 mmol) of N,N-dimethylformamide and the solution 
stirred at 0.degree. C. for 1.5 hours (Mixture A). A mixture of 0.422 g 
(6.08 mmol) of hydroxylamine hydrochloride, 1.27 ml (9.14 mmol) of 
triethylamine, 5 ml of N,N-dimethylformamide and 0.5 ml of water was 
prepared in a separate flask, stirred for 20 minutes at room temperature 
and then cooled to 0.degree. C. in an ice bath (Mixture B). The cooled 
solution of Mixture A was added to the cooled Mixture B and then stirred 
at room temperature overnight. The mixture was diluted with CH.sub.2 
Cl.sub.2 and 2N citric acid added. The organic layer was separated, washed 
with H.sub.2 O, brine and dried with Na.sub.2 SO.sub.4. The solvent was 
removed and the residue crystalized from ethanol to give 0.40 g of product 
as white crystals, mp 189-191.degree. C. Anal. for C.sub.26 H.sub.27 
N.sub.3 O.sub.8 S: Calc'd: C,57.7; H,5.0; N,7.7; Found: C,57.6; H,4.9; 
N,7.7; Mass Spectrum (ES): 542.2 (M+H). 
EXAMPLE 72 
4-(4-Methoxybenzenesulfonyl)-1-[2-(4-methylpiperazin-1-yl)acetyl]-2,3,4,5-t 
etrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
To a mixture of 2.5 g (6.64 mmol) of methyl 
4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-c 
arboxylate (Reference Example 12) and 4.63 ml (33.2 mmol) of triethylamine 
in 40 ml of CH.sub.2 Cl.sub.2 cooled to 0.degree. C. was added to 1.65 g 
(14.63 mmol) of chloroacetyl chloride. The solution was stirred at room 
temperature for 2 days, chilled to 0.degree. C. and 926 .mu.l of 
triethylamine and 750 mg of chloroacetyl chloride were added thereto. The 
mixture was stirred at room temperature overnight, diluted with CH.sub.2 
Cl.sub.2 and H.sub.2 O. The insoluble solid was filtered off. The organic 
layer of the filtrate was separated , washed with brine, dried with 
Na.sub.2 SO.sub.4 and filtered through diatomaceous earth. The solvent was 
removed and the residue triturated with ethyl acetate and a trace of 
ethanol. Chilling and filtering gave 0.75 g of methyl 
1-(chloroacetyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]b 
enzo-diazepine-3-carboxylate (Reference Example 91). Anal. for C.sub.2 
OH.sub.21 ClN.sub.2 O.sub.6 S: Calc'd: 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 
CH.sub.2 Cl.sub.2 cooled to 0.degree. C. was added 1.2 ml (6.79 mmol) of 
N,N-diisopropylethylamine followed by the addition of 753.2 .mu.l (6.79 
mmol) of 1-methylpiperazine. The mixture was stirred at room temperature 
overnight, diluted with CH.sub.2 Cl.sub.2, and washed with 2N citric acid, 
H.sub.2 O, 1M NaHCO.sub.3, brine and dried (Na.sub.2 SO.sub.4). The citric 
acid wash was made basic with saturated NaHCO.sub.3 and then extracted 
with CH.sub.2 Cl.sub.2. The extract was dried over Na.sub.2 SO.sub.4 and 
the solvent removed under vacuum to give 1.10 g of methyl 
4-(4-methoxybenzenesulfonyl)-1-[2-(4-methylpiperazin-1-yl)acetyl]-2,3,4,5- 
tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate as a white glass. 
A mixture of 1.0 g (1.94 mmol) of the preceding compound and 2.3 ml (2.3 
mmol) of 1N KOH in 5 ml of methanol was stirred at room temperature for 2 
hours. The solvent was removed under vacuum. To the residue was added 
toluene (2 times) and the solvent removed under vacuum after each 
addition. The solid was dried at 65.degree. C. under vacuum for 6 hours to 
give 1.1 g of potassium 
4-(4-methoxybenzenesulfonyl)-1-[2-(4-methylpiperazin-1-yl)acetyl]-2,3,4,5- 
tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate as a white solid. 
To 1.85 ml (3.69 mmol) of a 2.0 molar solution of oxalyl chloride in 
CH.sub.2 C1.sub.2, cooled to 0C, was added slowly 286 .mu.l (3.69 mmol) of 
N,N-dimethylformamide (precipitate formed). To this stirred mixture was 
1.0 g (1.85 mmol) of the preceding compound in 5 ml of CH.sub.2 Cl.sub.2. 
The mixture was stirred under nitrogen for two hours (Mixture A). 
In a separate flask, a mixture of 0.514 g (7.4 mmol) of hydroxylamine 
hydrochloride, 1.55 ml (11.1 mmol) of triethylamine in 
tetrahydrofuran-water (4:1) was stirred at room temperature and then 
cooled to 0.degree. C. and stirred for 5 minutes. To this mixture was 
added the cooled (0.degree. C.) Mixture A and then the resulting solution 
stirred at room temperature overnight. The mixture was concentrated under 
vacuum and CH.sub.2 Cl.sub.2 added. The organic layer was separated and 
concentrated to dryness to give 1.4 g of product. The product was 
chromatographed on thick layer silica gel plates with CH.sub.2 Cl.sub.2 
--CH.sub.3 OH--NH.sub.4 OH(45:6:1) as a solvent to give 65 mg of brown 
solid: 
Mass Spectrum (ES): 518.3 (M+H). 
EXAMPLE 73 
4-[4-(4-Chlorophenyloxy)benzenesulfonyl]-1-(methoxyacetyl)-2,3,4,5-tetrahyd 
ro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
A. N-[4-(4-Chlorophenyloxybenzenesulfonyl)serine methyl ester 
(methyl-3-hydroxy-2-[4-(4-chlorophenoxy)benzenesulonylamino]propionate). 
To a mixture of 3.42 g (22 mmol) of serine, methyl ester, hydrochloride 
and 10.7 ml (77.0 mmol) of triethylamine in 60 ml of CH.sub.2 Cl.sub.2, 
chilled to 0.degree. C., was added 6.063 g (20 mmol) of 
4-(4-chlorophenyloxy)benzenesulfonyl chloride. The mixture was stirred at 
room temperature overnight, diluted with CH.sub.2 Cl.sub.2 and washed with 
2N citric acid, H.sub.2 O, 1N NaHCO.sub.3, brine and dried with Na.sub.2 
SO.sub.4. The solvent was removed to give an oil which was dried under 
vacuum at 68.degree. C. to give a solid. Trituration with hexane-ethyl 
acetate gave 5.85 g of off-white crystals, mp 90-94.degree. C. Anal. for 
C.sub.16 H.sub.16 ClNO.sub.6 S: Calc'd: C,49.8; H,4.2; N,3.6; Found: 
C,50.l; H,4.1; N,3.8; Mass Spectrum (ES): 385.9 (M+H). 
B. Methyl 
3-hydroxy-2-{[4-(4-chlorophenyloxy)benzene-sulfonyl]-(2-nitrobenzyl)amino} 
proprionate. To a cooled (0.degree. C.) solution of 5.5 g (14.76 mmol) of 
compound from part A in 60 ml of dry N,N-dimethylformamide was added 
(portionwise), 0.682 g (17 mmol) of sodium hydride (60% in oil). After gas 
evolution ceased, 3.7 g (17 mmol) of 2-nitrobenzylbromide in 15 ml of 
N,N-dimethylformamide was added slowly. The mixture was stirred at room 
temperature overnight and diluted with 200 ml of ethyl acetate and 150 ml 
of water. The organic layer was separated and washed with H.sub.2 O, brine 
and dried with Na.sub.2 SO.sub.4. The solvent was removed under vacuum and 
the residue chromatographed on a silica gel column with hexane-ethyl 
acetate (2:1) as an eluent to give 4.7 g of a brown oil. Anal. for 
C.sub.23 H.sub.21 ClN.sub.2 O.sub.8 S: Calc'd: C,53.0; H,4.1; N,5.4; 
Found: C,53.2; H,4.2; N,5.1; Mass Spectrum (ES): 521.2 (M+H). 
C. Methyl 
2-{(2-aminobenzyl)-[4-(4-chlorophenyloxy)benzene-sulfonyl]amino}-3-hydroxy 
propionate. A mixture of 3.0 g (5.77 mmol) of the compound from part B and 
0.300 g of 10% wet palladium on carbon (50% in H.sub.2 O) in 300 ml of 
ethyl acetate-ethanol (1:1) was shaken in a Parr hydrogenator under 35 psi 
of hydrogen for 4 hours. The mixture was filtered through diatomaceous 
earth and the solvent removed under vacuum. The residue was dried at 
65.degree. C. under vacuum to give 2.63 g of an off-white solid. Anal. for 
C.sub.23 H.sub.23 ClN.sub.2 O.sub.6 S: Calc'd: C,56.3; H,4.7; N,5.7; 
Found: C,56.6; H,4.6; N,5.6; Mass Spectrum (ES): 491.1 (M+H). 
D. Methyl 
2-{[4-(4-chlorophenyloxy)benzenesulfonyl]-[2-(methoxyacetylamino)benzyl]am 
ino}acrylate. To a mixture of 0.80 g (1.63 mmol) of the compound from Part 
C and 1.14 ml (8.15 mmol) of triethylaniine in 8 ml of CH.sub.2 Cl.sub.2, 
cooled to 0.degree. C., was added 328 .mu.l (3.58 mmol) of methoxyacetyl 
chloride. The mixture was stirred at room temperature overnight, diluted 
with CH.sub.2 Cl.sub.2 and washed with H.sub.2 O, 2N citric acid, brine 
and dried (Na.sub.2 SO.sub.4). The solvent was removed under vacuum and 
the residue chromatographed on thick layer silica gel plates with 
hexane-ethylacetate (2: 1) as a solvent to give 0.48 g of a white foam. 
Anal. for C.sub.26 H.sub.25 ClN.sub.2 O.sub.7 S: Calc'd: C,57.3; H,4.6; 
N,5.1; Found: C,56.7; H,4.7; N,5.0; Mass Spectrum (ES): 545.2 (M+H). 
E. Methyl 
4-[4-(4-chlorophenyloxy)benzenesulfonyl]-1-(methoxyacetyl)-2,3,4,5-tetrahy 
dro-1H-[1.4]benzodiazepine-3-carboxylate. A mixture of 0.45 g (0.827 mmol) 
of the compound from part D and 0.09 g of anhydrous NaHCO.sub.3 in 5 ml of 
dry methanol was stirred at room temperature overnight. The solvent was 
removed, ethyl acetate added and the mixture washed with H.sub.2 O, brine 
and dried with Na.sub.2 SO.sub.4. The solvent was removed to give 0.43 g 
of an off-white solid. Anal. for C.sub.26 H.sub.25 ClN.sub.2 O.sub.7 S: 
Calc'd: C,57.3; H,4.6; N,5.1; Found: C,57.6; H,4.6; N,5.0; Mass Spectrum 
(ES): 545.2 (M+H). 
F. 
4-[(4-Chlorophenyloxybenzenesulfonyl]-1-(methoxyacetyl)-2,3,4,5-tetrahydro 
-1H-[1,4]benzodiazepine-3-carboxylic acid. A mixture of 0.52 g (0.956 mmol) 
of the compound from Part F and 1.2 ml (1.2 mmol) of 1N KOH in 8 ml of 
methanol was stirred at room temperature for 2 hours. An additional 0.6 ml 
of 1N KOH was added and the mixture was stirred at room temperature 
overnight. The mixture was concentrated, diluted with H.sub.2 O and 
extracted with ethyl acetate. The extract was washed with brine and dried 
over Na.sub.2 SO.sub.4. The solvent was removed and the product dried at 
65.degree. C. under vacuum to give 0.49 g of off-white foam. Anal. for 
C.sub.25 H.sub.23 ClN.sub.2 O.sub.7 S: Calc'd: C,56.6; H,4.4; N,5.3; 
Found: C,56.6; H,4.3; N,5.0; Mass Spectrum (ES): 531.2 (M+H). 
To a solution of 0.45 g (0.848 mmol) of the compound from Part F in 4 ml of 
CH.sub.2 Cl.sub.2 cooled to 0.degree. C. was added 850 .mu.l (1.69 mmol) 
of oxalyl chloride (2.0 molar solution in CH.sub.2 Cl.sub.2) and then 50.2 
.mu.l (0.848 mmol) of N,N-dimethylflormamide. This mixture was stirred 
under nitrogen for 2 hours (Solution A). In a separate flask a mixture of 
2.12 g (5.0 mmol) of hydroxylamine hydrochloride, 1.07 ml (7.65 mmol) of 
triethyl amine, 4 ml of tetrahydroforan and 0.4 ml of H.sub.2 O was 
stirred for 15 minutes and cooled to 0.degree. C. To this mixture was 
added the cooled (0.degree. C.) Solution A and the mixture was stirred at 
room temperature overnight. The mixture was concentrated under vacuum, 
diluted with ethyl acetate and washed with H.sub.2 O, 1N NaHCO.sub.3 2N 
citric acid, brine and dried over Na.sub.2 SO.sub.4. The solvent was 
removed under vacuum and the residue chromatographed on thick layer silica 
gel plates with 2% methanol in ethyl acetate to give 0.20 g of the product 
of the Example as a brown solid. Anal. for C.sub.25 H.sub.24 ClN.sub.3 
O.sub.7 S: Calc'd: C,55.0; H,4.4; N,7.7; Found: C,53.1; H,5.0; N,6.7; Mass 
Spectrum (ES): 546.3 (M+H). 
EXAMPLE 74 
4-[4-(4-Chlorophenyloxy)benzenesulfonyl]-1-(2-thienylcarbonyl)-2,3,4,5-tetr 
ahydro-1H[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
The following reactions were carried out in the manner described for 
Example 73, Parts D, E, and F. A 1.4 g (2.85 mmol) sample of methyl 
2-{(2-aminobenzyl)-[4-(4-chlorophenyloxy)benzenesulfonyl]amino}-3-hydroxyp 
ropionate (the compound of Part C of Example 73) was reacted with 1.25 g 
(8.55 mmol) of 2-thiophenecarbonyl chloride to give 1.7 g of methyl 
2-{[4-(4-chlorophenyloxy)benzyenesulfonyl]-[2-(2-thienylcarbonyl-amino)ben 
zyl]amino}acrylate as a yellow oil. Mass Spectrum (ES): 583.1 (M+H). 
The reaction of 1.5 g of the preceding compound with 0.251 g of NaHCO.sub.3 
in 8 ml methanol gave 1.6 g of methyl 
4-[4-(4-chlorophenyloxy)benzenesulfonyl)-1-(2-thienylcarbonyl)-2,3,4,5-tet 
rahydro-1H-[1,4]benzodiazepine-3-carboxylate as a yellow oil. Mass Spectrum 
(ES): 583.1 (M+H). 
The hydrolysis of 1.5 g of the preceding compound with 3.3 ml of 1N NaOH in 
6 ml of tetrahydroforan gave 1.2 g of 
4-[4-(4-chlorophenyloxy)benzenesulfonyl]-1-(2-thienylcarbonyl)-2,3,4,5-tet 
rahydro-1H-[1,4]benzodiazepine-3-carboxylic acid as an off-white foam. As 
described for Example 73, 1.0 g of the preceding 
benzodiazepine-3-carboxylic acid was reacted with oxalyl chloride and then 
with hydroxylamine to give the product of the Example as a solid 
(off-white foam). Mass Spectrum (ES): 584.2 (M+H). 
EXAMPLE 75 
4-[4-(4-Chlorophenyloxy)benzenesulfonyl]-1-(benzoyl)-2,3,4,5-tetrahydro-1H[ 
1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
The following reactions were carried out in the manner described for 
Example 73, Parts D, E, and F. A 1.0 g (2.04 mmol) sample compound C of 
Example 73 was reacted with 710 .mu.l (6.10 mmol) of benzoyl chloride to 
give 1.25 g of methyl 
2-{[4-(4-chlorophenyloxy)benzenesulfonyl]-[2-(benzoylamino)benzyl]amino}ac 
rylate as a brown oil. Mass Spectrum (ES): 577.2 (M+H). 
The reaction of 1.1 g (1.9 mmol) of the preceding compound with 0.208 g 
(2.48 mmol) of NaHCO.sub.3 in 8 ml of methanol gave 1.1 g of methyl 
4-[4-(4-chlorophenyloxy)benzenesulfonyl]-1-(benzoyl)-2,3,4,5-tetrahydro-1H 
-[1,4]benzodiazepine-3-carboxylate as a brown oil. Mass Spectrum (ES): 
577.1 (M+H). 
A 1.0 g (1.73 mmol) sample of the preceding compound was hydrolysed with 
2.3 ml (2.75 mmol) of 1N NaOH in 5 ml of tetrahydrofuran to give 0.50 g of 
4-[4-(4-chlorophenyloxy)benzenesulfonyl]-1-(benzoyl)-2,3,4,5-tetrahydro-1H 
-[1,4]benzodiazepine-3-carboxylic acid as a white foam. As described for 
Example 73, 0.460 g (0.817 mmol) of the preceding 
benzodiazepine-3-carboxylic acid was reacted with oxalyl chloride and then 
with hydroxylamine to give 0.04 g of the product of the Example as a light 
brown solid. Mass Spectrum (ES): 578.2 (M+H). 
EXAMPLE 76 
4-[4-(4-Pyridinyloxy)benzenesulfonyl]-1-(methoxyacetyl)-2,3,4,5-tetrahydro- 
1H[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 
A. To a cooled mixture of 6.84 g (44 mmol) of D, L-serine, methyl ester 
hydrochloride and 21.4 (144 mmol) of triethylamine in 90 ml of CH.sub.2 
Cl.sub.2 was added a solution of 10.78 g (40 mmol) of 
4-(4-pyridinyloxy)benzenesulfonyl chloride in 50 ml of CH.sub.2 Cl.sub.2. 
The mixture was stirred at room temperature overnight, diluted with 50 ml 
of CH.sub.2 Cl.sub.2 and the solution washed with H.sub.2 O, 1N 
NaHCO.sub.3, 2N citric acid, brine and dried (with Na.sub.2 SO.sub.4). The 
solvent was removed under vacuum to give a solid. The aqueous 2N citric 
acid wash was made basic with saturated NaHCO.sub.3 and then extracted 
with CH.sub.2 Cl.sub.2. The solvent was removed to give a solid. The two 
crops of solid were combined, washed with H.sub.2 O and then hexane. The 
solid was dried at 80.degree. C. to give 10.95 g of methyl 
3-hydroxy-2-[4-(4-pyridinyloxy)-benzenesulfonylamino]propionate as white 
crystals, mp. 137-139.degree. C. 
B. To a solution of 4.5 g (12,.78 mmol) of the product from Part A in 35 ml 
of dry N,N-dimethylformanide cooled to 0.degree. C. was added 
(portionwise) 0.662 g (16.61 mmol) of NaHCO.sub.3 (60% in oil). The 
mixture was stirred 15 minutes and 3.59 g (16.61 mmol) of 
2-nitrobenzylbromide in 15 ml of N,N-dimethylformamide was added hereto. 
The mixture was stirred at room temperature overnight, diluted with ethyl 
acetate (200 ml) and H.sub.2 O (100 ml). The organic layer was separated 
and washed with H.sub.2 O, brine and dried (with Na.sub.2 SO.sub.4). The 
solvent was removed to give 5.9 g of solid. Column chromatography on 
silica gel with ethyl acetate-hexane (10:1) as an eluant gave 1.4 g of 
methyl 2-{(2-nitrobenzyl)-[4-(4-pyridinyloxy) 
benzenesulfonyl]amino}-3-hydroxypropionate as an off-white solid. Mass 
Spectrum (ES): 488.1 (M+H). 
The compound from Part B was converted to the product of the Example in the 
manner described for Example 73 in Parts D, E, and F. 
EXAMPLE 77 
1-(Benzoyl)-4-(4-pentyloxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]-benz 
odiazepine-3-carboxylic Acid, Hydroxyamide 
To a stirred solution of 1.24 g (4.82 mmol) of triphenylphosphine in 12 ml 
of toluene and 3 ml of N,N-dimethylformamide was added 524 .mu.L (4.82 
mmol) of 1-pentanol and 1.5 g (3.22 mmol) of methyl 
1-(benzoyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzod 
iazepine-3-carboxylate. To this stirred mixture was added 259 .mu.l (4.82 
mmol) of diethyl azodicarboxylate and the mixture was stirred overnight. 
The solvent was removed and the residue chromatographed on silica gel with 
ethyl acetate-hexane (1:3) as solvent. Concentration of the fractions 
containing product gave 1.59 g of a white solid; mp 170-172.degree. C; 
Anal. Calcd for C.sub.29 H.sub.32 N.sub.2 O.sub.6 : C, 64.9; H, 6.0; N, 
5.2. Found: C, 64.7; H, 6.0; H, 5.4. 
A mixture of a 1.4 g (2.61 mmol) sample of the preceding compound and 3.4 
ml (3.4 mmol) of 1N KOH in 7 ml of tetrahydrofuran was stirred at room 
temperature for 2 hrs and the solvent removed under vacuum. To the residue 
was added toluene and the solvent removed (repeated two times). The 
residue was dried at 85.degree. C. under vacuum overnight to give 1.5 g of 
1-(benzoyl)-4-(4-pentyloxybenzenesulfonyl)-2,3,4,5- 
tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid as the potassium salt. 
To 10 ml of CH.sub.2 Cl.sub.2 was added 4.8 ml (9.6 mmol) of oxalyl 
chloride in CH.sub.2 Cl.sub.2 (2.0 molar) and the solution chilled to 
0.degree. C. To the chilled solution was added 740 .mu.L (9.56 mmol) of 
N,N-dimethylformamide and 1.34 g (2.39 mmol) of the preceding potassuim 
salt in 5 ml of dry N,N-dimethylformamide. The mixture was stirred at room 
temperature for 1.5 hr, cooled to 0.degree. C., and added to a chilled 
(0.degree. C.) solution of 2.2 ml (35.9 mmol) of 50% aqueous hydroxylamine 
in 10 ml of tetrahydrofuran. The mixture was stirred at room temperature 
overnight and diluted with CH.sub.2 Cl.sub.2. The CH.sub.2 C1.sub.2 layer 
was separated, washed with H.sub.2 O and concentrated to dryness under 
vacuum. The residue was chromatographed on silica gel with ethyl 
acetate-hexane (1:1) as solvent. Fraction containing product was 
concentrated to dryness and the residue dissolved in ethyl acetate. The 
solution was washed with three times with H.sub.2 O and once with brine 
and dried (Na.sub.2 SO.sub.4). The solvent was removed and the residue 
dried at 85.degree. C. under vacuum overnight to give 0.96 g of product as 
a white foam; Mass spectrum (ES) 538.0 (M+H). 
EXAMPLE 78 
1-Acetyl-4-(4-Hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiaze 
pine-3-carboxylic acid, Hydroxyamide 
To a crude mixture of 
1-acetyl-4-(4-hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiaz 
epine-3-carboxylic acid (0.55 g) and N-hydroxybenzotriazole (0.414 g) in 5 
ml of N,N-dimethylformamide was added 0.684 g of 
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride. The mixture 
was stirred at room temperature for 1 hr and then 750 .mu.L of 
hydroxylamine in water (50%) was added and the mixture stirred at room 
temperature overnight. The mixture was diluted with ethyl acetate and then 
washed with H.sub.2 O, 2N citric acid, brine and dried (Na.sub.2 
SO.sub.4). The solvent was removed under vacuum to give a solid. 
Chromatography on silica gel with 10% methanol in ethyl acetate as solvent 
gave a solid which was dried at 78.degree. C under vacuum overnight to 
give an off-white foam; Mass spectrum (ES) 406.1 (M+H); Anal. Calcd. For 
C.sub.18 H.sub.19 N.sub.3 O.sub.6 S; C, 53.3; H, 4.7; N, 10.4. Found: C, 
52.6; H, 5.2; N, 10.4. 
The present invention may be embodied in other specific forms without 
departing from the spirit or essential attributes thereof and, 
accordingly, reference should be made to the appended claims, rather than 
to the foregoing specification, as indicating the scope of the invention.