CA2317546A1 - 2,3,4,5-tetrahydro-1h-¬1,4|-benzodiazepine-3-hydroxamic acids as matrix metalloproteinase inhibitors - Google Patents
2,3,4,5-tetrahydro-1h-¬1,4|-benzodiazepine-3-hydroxamic acids as matrix metalloproteinase inhibitors Download PDFInfo
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- CA2317546A1 CA2317546A1 CA002317546A CA2317546A CA2317546A1 CA 2317546 A1 CA2317546 A1 CA 2317546A1 CA 002317546 A CA002317546 A CA 002317546A CA 2317546 A CA2317546 A CA 2317546A CA 2317546 A1 CA2317546 A1 CA 2317546A1
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Abstract
Compounds are provided having formula (I), wherein R, R1, R2, R3 and R4 are defined in the specification, which have matrix metalloproteinase inhibiting activity.
Description
2,3,4,5-TETRAHYDRO-1H-[1,4]-BENZODIAZEPIN&-3-HYDROXAMIC ACIDS AS MATRIX
METALLOPROTEINASE
INHIBITORS
S
FIELD OF INVENTION
This invention relates to 4-(4-substituted-benzenesulfonyl)-2,3,4,5-tetrahydro-1 H-[ 1,4]benzodiazepine-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 gelatinises. Of these, the gelatinises 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 gelatinise is elevated in malignancies, and that gelatinise 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 gelatinise component to its pathology as reported in "Matrix Metalloproteinases, Novel Targets for Directed Cancer Therapy", pigs and AQinQ, 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, 5 ( 1996); Curr. Opin. Ther. Patents. 4( 1 ): 7-16, ( 1994); Curr. Medicinal Chem., 2: 743 762, (1995); Ex~. Opin. Ther. Patents, 5(2): 1087-110, (1995); Exp. Opin.
Ther.
n s 5( 12): 1287-1196, ( 1995); "Inhibition of Matrix Metallo-proteinases:
Structure Based Design", Current Pharmaceutical Design. 2:524-661, (1996). "Matrix Metalloproteinase Inhibitor Drugs", Emerg ng Drugs, 2:205-230 ( 1997).
TNF-a convening enzyme (TACE) catalyzes the formation of TNF-a from membrane bound TNF-a precursor protein. TNF-a 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-a antibodies in transgenic animals has demonstrated that blocking the formation of TNF-a inhibits the progression of arthritis. This observation has recently been extended to humans as described in "TNF-a in Human Diseases", Current Pharmaceutical Design, 2:662-667 ( 1996).
It is expected that small molecule inhibitors of MMPs and TACK would have the potential for treating a variety of disease states. Although a variety of MMP
and TACE
inhibitors are known, many of these molecules are peptidic and peptide-like which demonstrate bioavailability and pharmacokinetic problems. Long acting, orally bioavailable non-peptide inhibitors of MMPs and/or TACE would thus be highly desirable for the treatment of the disease states discussed above.
U.S. Patent No, 5,455,258 discloses 2-substituted-2-(arylsulfonylamino) hydroxyamic acids and their use as MMP inhibitors. WO 97/18194, discloses N-(arylsulfonyl)tetrahydroisoquinolone-hydroxyamic acids and related bicyclic derivatives thereof and their use as MMP inhibitors. WO 97/20824 discloses 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-[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 HOHN R N
wherein R is selected from hydrogen, (C1 - C3) alkyl, -CN, -OR', -SR', -CF3, -OCFg, Cl, F, NH2, NH(C1 - C3)alkyl, -N(R')CO(C~ - C3)alkyl, -N(R')(R'), N02, -CONH2, -S02NH2, -S02N(R')(R'), or -N(R')COCH20-(C~ - C3)alkyl, wherein R' is (C1 -C3) alkyl or hydrogen;
R4 is (C~ - C6) alkyl-O-, (C~ - C6) alkyl-S-, R
R> > ~S~ > >
~~R1 ~~RI ~~R~
NON , - D ' , ~ - S fl' ~ ' N N
R~ , -S ~ ~ R~ , or R, wherein R ~ is hydrogen, halogen, cyano, methyl or -OCH3;
IS
R1 and R2 are each, independently, hydrogen or CH3;
R3 is (C~ - Cg)alkyl, NH2CH2C0-, (C~ - C6)alkylNHCH2C0-, HO(CH2)r,,CO-, HCO-, Aryl(CH2)"CO-, Heteroaryl(CH2)nC0-, (C 1 - Cg)alkyl-O-(CHZ)"CO-, (C1 - C3)alkylCO-, (C1 - C3)alkylCO-NHCH2C0-, (C3 - C~)cycloalkylCO-, (C) - C;)alkylSO,-. Aryl(CH2)~SO,-. Heteroaryl(CH,)"S02-, (C~ - C3)alkyl-O-(CH~)m-SO,-. (C~ - C3)alkyl-O-(CHZ)m, (C~ - C3)alkyl-O-(C~ - C3)alkyl-O-(C~ -C3)alkyl. HO-(C i - C3)alkyl-O-(C1 - C3)alkyl. Aryl-O-CH,CO-. Heteroaryl-O-CH~CO-, AryICH=CHCO-. HeteroarylCH=CNCO-. (C1 - C31a1kylCH=CHCO-, O / ~ O
CH.,OC- , or ' i~ CH.,OC-NHCH.,CO- ;
S
Aryl(C1 - C3)alkyl, Heteroaryl(C) - C3)alkyl, AryICH=CHCH2-, HeteroarylCH=CHCH2-. (C ~ - C6)alkylCH=CHCH2-, Y
~ Co- , Y~~~~
Co- ~ ~ co-M N
M \~CO- /
Y r~~ CO-\ ~y ~ W
CO-/ \ M
~ CO- y ~' '~ CO-\ / ~ 'J
s R'OCHZ CH(OR')CO-, (R'OCH2)2C(R')CO-, CH3- ~N(C~ - C3)alkylCH=CH-CO- , ~N-(Ci - C6)alkylCO-N-(C~ - C6)alkylCO- , (C~ - C3)alkyICONHCO-, \N-(C~-C~alkylCO- , N-(Ci - C6)aIkyICO- , N-(Ci-C6)alkylCO- . ~N-(C~-C6)alkylCO- , ~ N N= I
~1 CH3-~N(C~ - C6)alkylCO- , t-Boc- ~N-(C~ - C~alkylCO- .
R. CO- p EtOC~N(C1 - C6)alkylCO- , R~ ~,~/O
METALLOPROTEINASE
INHIBITORS
S
FIELD OF INVENTION
This invention relates to 4-(4-substituted-benzenesulfonyl)-2,3,4,5-tetrahydro-1 H-[ 1,4]benzodiazepine-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 gelatinises. Of these, the gelatinises 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 gelatinise is elevated in malignancies, and that gelatinise 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 gelatinise component to its pathology as reported in "Matrix Metalloproteinases, Novel Targets for Directed Cancer Therapy", pigs and AQinQ, 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, 5 ( 1996); Curr. Opin. Ther. Patents. 4( 1 ): 7-16, ( 1994); Curr. Medicinal Chem., 2: 743 762, (1995); Ex~. Opin. Ther. Patents, 5(2): 1087-110, (1995); Exp. Opin.
Ther.
n s 5( 12): 1287-1196, ( 1995); "Inhibition of Matrix Metallo-proteinases:
Structure Based Design", Current Pharmaceutical Design. 2:524-661, (1996). "Matrix Metalloproteinase Inhibitor Drugs", Emerg ng Drugs, 2:205-230 ( 1997).
TNF-a convening enzyme (TACE) catalyzes the formation of TNF-a from membrane bound TNF-a precursor protein. TNF-a 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-a antibodies in transgenic animals has demonstrated that blocking the formation of TNF-a inhibits the progression of arthritis. This observation has recently been extended to humans as described in "TNF-a in Human Diseases", Current Pharmaceutical Design, 2:662-667 ( 1996).
It is expected that small molecule inhibitors of MMPs and TACK would have the potential for treating a variety of disease states. Although a variety of MMP
and TACE
inhibitors are known, many of these molecules are peptidic and peptide-like which demonstrate bioavailability and pharmacokinetic problems. Long acting, orally bioavailable non-peptide inhibitors of MMPs and/or TACE would thus be highly desirable for the treatment of the disease states discussed above.
U.S. Patent No, 5,455,258 discloses 2-substituted-2-(arylsulfonylamino) hydroxyamic acids and their use as MMP inhibitors. WO 97/18194, discloses N-(arylsulfonyl)tetrahydroisoquinolone-hydroxyamic acids and related bicyclic derivatives thereof and their use as MMP inhibitors. WO 97/20824 discloses 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-[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 HOHN R N
wherein R is selected from hydrogen, (C1 - C3) alkyl, -CN, -OR', -SR', -CF3, -OCFg, Cl, F, NH2, NH(C1 - C3)alkyl, -N(R')CO(C~ - C3)alkyl, -N(R')(R'), N02, -CONH2, -S02NH2, -S02N(R')(R'), or -N(R')COCH20-(C~ - C3)alkyl, wherein R' is (C1 -C3) alkyl or hydrogen;
R4 is (C~ - C6) alkyl-O-, (C~ - C6) alkyl-S-, R
R> > ~S~ > >
~~R1 ~~RI ~~R~
NON , - D ' , ~ - S fl' ~ ' N N
R~ , -S ~ ~ R~ , or R, wherein R ~ is hydrogen, halogen, cyano, methyl or -OCH3;
IS
R1 and R2 are each, independently, hydrogen or CH3;
R3 is (C~ - Cg)alkyl, NH2CH2C0-, (C~ - C6)alkylNHCH2C0-, HO(CH2)r,,CO-, HCO-, Aryl(CH2)"CO-, Heteroaryl(CH2)nC0-, (C 1 - Cg)alkyl-O-(CHZ)"CO-, (C1 - C3)alkylCO-, (C1 - C3)alkylCO-NHCH2C0-, (C3 - C~)cycloalkylCO-, (C) - C;)alkylSO,-. Aryl(CH2)~SO,-. Heteroaryl(CH,)"S02-, (C~ - C3)alkyl-O-(CH~)m-SO,-. (C~ - C3)alkyl-O-(CHZ)m, (C~ - C3)alkyl-O-(C~ - C3)alkyl-O-(C~ -C3)alkyl. HO-(C i - C3)alkyl-O-(C1 - C3)alkyl. Aryl-O-CH,CO-. Heteroaryl-O-CH~CO-, AryICH=CHCO-. HeteroarylCH=CNCO-. (C1 - C31a1kylCH=CHCO-, O / ~ O
CH.,OC- , or ' i~ CH.,OC-NHCH.,CO- ;
S
Aryl(C1 - C3)alkyl, Heteroaryl(C) - C3)alkyl, AryICH=CHCH2-, HeteroarylCH=CHCH2-. (C ~ - C6)alkylCH=CHCH2-, Y
~ Co- , Y~~~~
Co- ~ ~ co-M N
M \~CO- /
Y r~~ CO-\ ~y ~ W
CO-/ \ M
~ CO- y ~' '~ CO-\ / ~ 'J
s R'OCHZ CH(OR')CO-, (R'OCH2)2C(R')CO-, CH3- ~N(C~ - C3)alkylCH=CH-CO- , ~N-(Ci - C6)alkylCO-N-(C~ - C6)alkylCO- , (C~ - C3)alkyICONHCO-, \N-(C~-C~alkylCO- , N-(Ci - C6)aIkyICO- , N-(Ci-C6)alkylCO- . ~N-(C~-C6)alkylCO- , ~ N N= I
~1 CH3-~N(C~ - C6)alkylCO- , t-Boc- ~N-(C~ - C~alkylCO- .
R. CO- p EtOC~N(C1 - C6)alkylCO- , R~ ~,~/O
-S-O R' N- (C ~ - C6)alkylCO-R' O CO-[(C~ - C6)alkyl]Z-N-(C1 - C6)alkyl CO-. or (C~ - C6)alkyl-NH-(C1 - C6)alkylCO-;
wherein m=lto3;n=Oto3;
Aryl is /X
~~, and R
Heteroaryl is ~~.,~X ~~~X
J X ~ \~ ~ \~ ~ , N O
~'r~~\X \r- N ~r,- N
<N~ ° < ~ ~ < ~
R' ~r-.~X ~r-rr X
~N ° ~ ~N ~ °r O N N
R, R, wherein X is hydrogen, halogen, (C 1 - C3) alkyl or -OCH3 and R and R' are as defined above;
L is hydrogen, (C1-C3)alkyl, -CN, -OR', -SR', -CFg, -OCF3, C1, F, NH2, -NH-(C~
-C3)alkyl, -N(R')CO(C1 - C3)alkyl, N(R')(R'), -N02, -CONH2, -S02NH2, -SOZN(R')(R'), -N(R')COCH20-(C~ - C3)alkyl, CONH- y~~~CONH- y~~/CONH-<' ,or < ~ ;
S O
wherein m=lto3;n=Oto3;
Aryl is /X
~~, and R
Heteroaryl is ~~.,~X ~~~X
J X ~ \~ ~ \~ ~ , N O
~'r~~\X \r- N ~r,- N
<N~ ° < ~ ~ < ~
R' ~r-.~X ~r-rr X
~N ° ~ ~N ~ °r O N N
R, R, wherein X is hydrogen, halogen, (C 1 - C3) alkyl or -OCH3 and R and R' are as defined above;
L is hydrogen, (C1-C3)alkyl, -CN, -OR', -SR', -CFg, -OCF3, C1, F, NH2, -NH-(C~
-C3)alkyl, -N(R')CO(C1 - C3)alkyl, N(R')(R'), -N02, -CONH2, -S02NH2, -SOZN(R')(R'), -N(R')COCH20-(C~ - C3)alkyl, CONH- y~~~CONH- y~~/CONH-<' ,or < ~ ;
S O
M is n ~'-,/
' Y~ J ' N
<N~ N ~O.N , R' \ '~ ~ ~'-,~ Y
< ~ ' <'7 ' « ' N N N
R'' ~ - , ~ ~~ OCO- ~ ~ N-tBoc - N- . p - , N- , U
~N- , or N(R')(R') where R' is as defined above;
W is O, S, NH or N(CI - C3)alkyl;
Y is hydrogen, F, Cl, CF3 or OCHg; and X' is halogen, hydrogen, (CI -C3)alkyl, O-(C1 - C3)alkyl, or -CHZOH; and pharmaceutically acceptable salts thereof.
When used herein the term C1-C3 alkyl covers methyl, ethyl, n-propyl and i-propyl groups. When used herein the term C1-C( alkyl covers, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl and pentyl groups. When used herein the term C3-C~ cycloalkyl covers saturated and unsaturated cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-cyclopropenyl, 2-cyclopropenyl, 1-cyclobutenyl and 2-cyclobutenyl.
R is suitably hydrogen, halogen or (C1-C3)alkyl, for example hydrogen, chloro or methyl. R1 is suitably hydrogen. R2 is suitably hydrogen. R4 is suitably (C
alkyl)-O-, for example methoxy. R3 is suitably selected from the group: (C 1-C3)alkyl-S02_, aryl(CH2)nS02_, (C1-C3)alkyl-CO-, aryl(CH2)nC0-, heteroaryl(CH2)nC0-, (C1-C3)alkyl-O-(CH2)nC0-, (C3-C~)cycloalkyl-CO-, (Cl-C3)alkyl-O-(CH2)m- or aryl(C1-C3)alkyl-~ for example methylsulphonyl, n-propylsulphonyl, 4-methyl-phenylsulphonyl, 4-methoxyphenylsulponyl, methylcarbonyl, 3-trifluormethylcarbonyl, 2-phenylethylcarbonyl, methoxymethylcarbonyl, cyclopropylcarbonyl, cyclohexylcarbonyl, 2-methoxyethyl, phenylcarbonyl, 2-methyl-5-fluorophenylcarbonyl, 4-biphenylcarbonyl, 2-biphenylcarbonyl, 2,4-dichlorophenylcarbonyl, phenoxymethylcarbonyl, phenylcarbonyl, 4-trifluoromethylphenylcarbonyl, 2-imidazol-1-yl-phenylcarbonyl, 2-morpholin-4-yl-phenylcarbonyl, 4-ethoxyphenylcarbonyl, 4-(4-methyl-imidazol-1-yl)-2-choloro-phenylcarbonyl, 2,4-dimethoxyphenylcarbonyl, 4-methyl-piperazin-I-ylmethylcarbonyl, 3-pyridinylcarbonyl, 2-thienylcarbonyl, 4-pyridinylcarbonyl, furanylcarbonyl or benzyl.
Preferably, the compounds of the present invention are those of formula 1 wherein R is hydrogen, (C~ - C3) alkyl, -CN, -OR', -SR', -CF3, -OCF3, CI, F, NH2, NH(C1 - C3)alkyl, -N(R')CO(C1 - C3)alkyl, -N(R')(R'), N02, -CONHZ, -S02NH2, -S02N(R')(R'), or -N(R')COCHZO-(C~ - C3)alkyl, wherein R' is (C ~ - C3) alkyl or hydrogen;
R4 is (C1 - C6) alkyl-O-, (C1 - C6) alkyl-S-, R
O RI , ~S~ > >
~~R' ~~R~ ~~R~
NON ~ -o-': ~ ~ -S f'~
N N
R~ , -S ~ ~ R~ , or R, wherein R~~ is hydrogen, halogen, cyano, methyl or -OCH3;
R1 and R2 are each, independently, hydrogen or CH3;
R3 is (C ~ - Cg)alkyl, NH2CH2C0-, (C ~ - C6)alkylNHCH2C0-, HO(CH2)I,,CO-, HCO-, Aryl(CH2)nC0-, Heteroaryl(CH2)nC0-, (C1 - C3)alkyl-O-(CH2)"CO-, (C~ - C3)alkylCO-, (C~ - C3)alkylCO-NHCH2C0-, (Cg - C~)cycloallcylCO-, Aryl-O-CH2C0-, HeteroarylOCH2C0-, AryICH=CHCO-, HeteroarylCH=CHCO-, (C~ - C3)alkyICH=CHCO-, _8_ i ~ i Q
~ CH20C- , ' i~ CH20C-NHCHzCO- , wherein m=lto3;n=Oto3;
Aryl is X
I ~ and R' Heteroaryl is ~r-,~X ~r~~X
J X ~ ~ > ' < ~ ' N S O
X
I j ~'-v > > ~> >
\N O S
i R' 'rr ~,~X ~~N
,N , <N,N . or <N J X , O
R, R, wherein X is hydrogen, halogen, (C I - C3) alkyl or -OCHg 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, (Ct - C3) alkyl, -CN. -OR', -SR', -CFg, -OCF3, Cl, F, NH2, NH(C1 - C3)alkyl, -N(R')CO(Ct - C3)alkyl, -N(R')(R'), N02, -CONH2, -S02NH2, -S02N(R')(R'), -N(R')COCH20-(C~ - C3)alkyl, wherein R' is (C~ - C3) alkyl or hydrogen;
R4 is (C~ - C6) alkyl-O-, (C~ - C6) alkyl-S-, I ~ ~ I
R~ , ~S~ R~ , I ~ ~~R' ~~R~ ~~R~
N~%N ' - D ' ~ ' - S f'' ~ ' N N
I ~ R ~ , - S I ~ R~~ , or "
R, wherein R~~ is hydrogen, halogen, cyano, methyl or -OCH3;
Rt and R2 are each, independently, hydrogen or CH3;
R3 is CH3- N(C~ - C3)alkylCH=CH-CO- , N-(C1- C6)alkylCO- , N-(C -C alk 1C0-N-(C~ - C~alkylCO- , (C~ - C~alkylCONHCO-, ' i ~ Y
N-(Ci - C6)alkylCO- , N-(C~-C6)alkylCO- , ~N-(Ci-C6)alkylCO- , ~N N
CH3- N(C1- C6)alkylCO- , t-Boc-NN~N-(C1 - C~alkylCO-U
' CO- O ~
EtOC~N(CI - C~alkylCO- , R~ ~/O
' O R' N- (C ~ - C6)alkylCO-R' O CO-[(C1 - C6)alkyl]2-N-(C1 - C6)alkyl CO-, or (C1 - C6)alkyl-NH-(C1 - C6)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, (Ct - C3) alkyl, -CN, -OR', -SR', -CF3, -OCF3, C1, F, NH2, NH(C1 - C3)alkyl, -N(R')CO(C~ - C3)alkyl, -N(R')(R'), N02, -CONH2, -S02NH2, -S02N(R')(R'), or -N(R')COCH20-(Ct - C3)alkyl, wherein R' is (Ct -C3) alkyl or hydrogen;
R4 is (Ct - C6) alkyl-O-, (Ct - C6) alkyl-S-, R
Rt . ~S~ t ~~Rt ~~Rt ~~Rt N~N ~ - p ' , - S f'' N N
R~ , -S ~ ~ R~ , or R, wherein R~~ is hydrogen, halogen, cyano, methyl or -OCH3;
R1 and R2 are each, independently hydrogen or CH3;
R3 is (Ct - C3)alky1S02-, Aryl(CH2)nS02-, Heteroaryl(CH2)nS02-, or (Ct -C3)alkyl-O-(CH2)m-SO2, wherein m=lto3;n=Oto3;
Aryl is /X
I ~] and R' Heteroaryl is ~~,/X ~~/X
, ~ , X \< ' N O
X
< <~
N O
R' ~r,.--'~/X ~r- N
~N , < ,N , or < J X
O N N
R. R, wherein X is hydrogen, halogen, (Ct - C3) alkyl or -OCH3 and R and R' are as defined above; and pharmaceutically acceptable salts thereof.
A further, more preferred embodiment of the present invention includes compounds represented by formula 1 wherein R is selected from hydrogen, (C~ - C3) alkyl, -CN, -OR', -SR', -CF3, -OCFg, Cl, F, NH2, NH(Ct - Cg)alkyl, -N(R')CO(C~ - C3)alkyl, -N(R')(R'), N02, -CONH2, -S02NH2, -S02N(R')(R'), or -N(R')COCH20-(Ct - Cg)alkyl, wherein R' is (C1 - Cg) alkyl or hydrogen;
R4 is (Ct - C6) alkyl-O-, (C~ - C6) alkyl-S-, R
Rt , ~S~ t , ~~Rt ~~Rt ~~Rt NON , - ~ ~ ~ - S f'' N N
R~ , -S ~ ~ R~ , or R, wherein R~~ is hydrogen, halogen, cyano, methyl or -OCH3;
R~ and R2 are each, independently hydrogen or CH3;
R3 is (C1 - Cg)alkyl, Aryl(C~ - Cg)alkyl, Heteroaryl(Ct - C3)alkyl, AryICH=CHCH2, HeteroarylCH=CHCH2-, or (C~ - C6)alkylCH=CHCH2-, wherein Aryl is Heteroaryl is X
./
and R' ~~,~X ~r,-,~X
J X ' ~/> ° < ~ ' N S O
X
~,-N
<N ' < ~ ' o S
R' ~~ ~~N ~l- N X
<OiN . <N~ ~ or <N~
I I
R, R, wherein X is hydrogen, halogen, (C~ - C3) alkyl or -OCH3 and R and R' are as defined above; and pharmaceutically acceptable salts thereof.
Additionally preferred compounds of the present invention include those of formula 1 wherein R is hydrogen, (C~ - C3) alkyl, -CN, -OR', -SR', -CF3, -OCF3, C1, F, NH2, NH(C1 - C3)alkyl, -N(R')CO(C1 - C3)alkyl, -N(R')(R'), N02, -CONH2, -S02NH2, -S02N(R')(R'), or -N(R')COCH20-(C1 - C3)alkyl, wherein R' is (C~ - Cg) alkyl or hydrogen;
R4 is (C~ - C6) alkyl-O-, (C1 - C6) alkyl-S-, R
R~ , ~S~ 1 , - I ~ ~~R1 ~~R1 ~~R~
N~%N ' - ~l ~ . - s f'~ ~ ' N N
R~ , -S ~ ~ R~ , or R, wherein R ~ is hydrogen, halogen, cyano, methyl or -OCH3;
R~ and R2 are each, independently hydrogen or CH3;
R3 is Y
~ Co- Y~~~~ _ co- , ~ ~ Co , L N
M
M NCO- /
Y f"~ ;~ CO- /
J , yv , / w co-/ ~ M
~ CO- ~ or y rl~ CO_ w / ~SJ
wherein m=1 to3;n=Oto3;
L is hydrogen, (C1 - Cg)alkyl, -CN, -OR', -SR', -CF3, -OCP3, C1, F, NH2, -NH-(C~ - C3)alkyl, -N(R')CO(C1 - C3)alkyl, N(R')(R'), -N02, -CONH2, -S02NH2, -S02N(R')(R'), -N(R')COCH20-(C1 - Cg)alkyl, Y r--,, CONH- y ~ CONH-CONH- ~ ~ ~ , or S O
M is w ~''-,/
y ~N J
<O/ ' <N~ <N~ ~O~N
R' ~'-~% Y
< ~ ' <~ ' « .
N N N
R- N- , I \ OCO-N~ N , Ice- , / ~/
tB oc - ~ ~ ~N- , N- , ~l~- , or N(R')(R') where R' is as defined above;
W is O, S, NH or N(C~ - C3)alkyl;
Y is hydrogen, F, Cl, CF3 or OCH3; and X' is halogen, hydrogen, (C~ -C3)alkyl, O-(C1 - C3)alkyl, or -CH20H; and pharmaceutically acceptable salts thereof.
The compounds of the invention may be prepared by reacting an appropriate acid halide such as the acid chloride or bromide with hydroxylamine. The acid halide may be prepared by reacting the con esponding acid or a metal salt thereof with an activating agent such as oxalyl chloride, oxalyl bromide, thionyl chloride, thionyl bromide, (chloromethylene)dimethylammoniumchloride or (bromomethylene)dimethyl ammonium bromide. The subsequent reaction of the acid halide with hydroxylamine may suitably be performed in situ.
Metal salts may be prepared by reacting a ester of formula Ia Ra R2~i N
R~
R
la wherein R21 is (C1-6)alkyl, benzyl or arylalkyl and all other groups are as defined above, with a base such as lithium hydroxide, potassium hydroxide, sodium hydroxide or barium hydroxide. This may suitably be performed in a solvent such as a (C1-Cg) alcohol, tetrahydrofuran, N,N-dimethylformide or p-dioxane in the presence or absence of water. The resulting metal salt may be directly converted to the desired product or it may first be converted to the acid, e.g. by treating it with aqueous hydrochloric acid or acetic acid. Alternatively the ester of formula la may be converted to its acid by treatment with an aqueous mineral acid such as hydrochloric acid, hydrobromic acid or trifluoroacetic acid and the acid converted to the desired product as described above.
The compounds of formula 1 may be advantageously prepared according to Reaction Schemes 1 to 7. Variations in these schemes may be made to improve productivity without negatively impacting the amount and nature of the product, by 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 vitro derivatives 5 .
Reduction under conventional reducing conditions, such as catalytic hydrogeneration (with Pd/C) or chemical reduction (e.g., with SnCl2 or FeCl3) 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-vitro or 2-amino benzyl alcohol derivatives 11 by application of the Mitsunobu reaction to give intermediates 12. Reduction of the 2-vitro group and removal of the hydroxy blocking group with derivatives 12. where the 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 [1,4J
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.
Scheme 1 O
II
CHgO C NH2 / \ O SO 2 ~ ~ Ra ~R~ C1S02~ Ra --~ CH 30 C NH
HO ~ + Y
R2 2 ~R~ N02 1 HO ~z ~ CH2Br O S0 2 ~ ~ Ra 3 R I
II
/ v R O SO -~~ \- Ra HO ~,, Hz ~ 1I
~z 6 HO ~~ R ~ / NO 2 Ar(CH 2 ~COCI Heteroaryl(CH 2 ~COCI zR ~J
Ar(CH2)nS02Cl Heteroaryl(CH2)~ 02C1 5 Alkyl-O-CH2~COC1 Alkyl-O-(CH2)m02C1 ~ S02 ~ / Ra AlkyICOCI AlkylS02C1 CH 30 C
Cycloalkyl( C3to C~)CO Rt~ / ~ R
Rz I ~ a g tl (1) OH-R~ Rz HN / (2) C1COCOC1 R (3) NH20H
p II ~02 ~ / Ra HOHN'C
Rt~ I %R
Rz N
wherein n=Oto3;
m=lto3;
R1 = (Cl - C3)alkyl; R = Hydrogen; halogen; OCH3; NO2; NH2; CF3; NHCOCH3;
NHCOCH20CH3; CONH2; -N(R')(R'), -N(R')CO(C1 - C3)alkyl; (C1 - Cg)alkyl;
R3 = Ar(CH2)"CO-; Heteroaryl(CHZ)"CO-, Ar(CH2)"S02-; Heteroaryl(CH2)nS02-;
Alkyl-O-CH2)nC0-; Alkyl-O-(CH2)mS02-: AlkylCO-; Alky1S02-; AlkylCO-NHCHZCO-; and cycloalkyl(C3 - C~)CO-; and R4 is as defined herein.
Scheme 2 SO ~ ~ g~ O SO 2 ~ ~ Ra O
I ~ H+ CH3 O C NH
R~ + ~~O ' ~ \ CH 20H
HO 2 0 + ~
3 10 ' R
RS = -NOZ
t-BocNH- ~ 3 P + DEAD
~CH 20CONH-O SO 2 ~ ~ Ri R g = NO2 O S02 R4 CH3 0 C N ( I ) H 2+ Pd/C CH30 C N
R~ (2.a-) H R~ \
N \ .
HO H2 R 5 = t-BocNH- ~ : I
I J
(1)H+ ;TFA
R RS= f~CH20CONH- 12 (I) H+
fO CH 20COCI
R6 COCI 2 ~
SO 2 ~ ~ R4 O SO Ra O or II
CH301C N R~S02C1 CH30C
R, I R~~ . R
R~\NH I % R R6COC1 RZ ~N ~ v 2 _ or R 8 14 R~SO 2CI 15 wherein n=Oto3;
m=lto3;
~ = phenyl;
DEAD = diethylazodicarboxylate;
R~, = Ar(CH2)~ ; Alkyl-; Heteroaryl(CH2)n ;Alkyl-O-(CH2)n ; Cycloalkyl(Cg -C~);
R~ = Ar(CH2)"; Alkyl-; Heteroaryl(CH2)n-; Alkyl-O-(CH2)m ;
Rg = Ar(CH2)nC0-; Ar(CH2)"S02-; AIkylCO-; AIkylS02-; Heteroaryl(CH2)nC0-;
Heteroaryl(CH2)"S02-; Alkyl-O-(CH2)"CO-; Alkyl-O-(CH2)t,,S02-.
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 NaI04 with catalyst Ru02 (e.g., see J. Org.
Chem., 46:3936 ( 1981 ); Synlett, p. 143, ( 199b)). 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.
Scheme 3 SO2~ ~ Ra R S02~ / Ra R
CH OC
CH 30 C N Ar CHO
_--i R i % R
HO R2 ~H I ~ R OH Ho R2 N
~s II
CHI
6 16 Ar NaCNBH 3 _ HOAc R S~ 2 ~ I ~
CH30C ~ N (C6H5 ) P Il S02 ~ ~ Ra R J ~ / / R ~ 3 CH 30 CAN
t ' H I - DEAD I Rt ~ / R
CH2Ar L.IO~ HN
i8 ~ _ CH2Ar CH 30C ~ iN~ ~( C6 H 5 )3 P
CCI
C1~R~HN / ~R 4 I
CH2Ar S02~ ~ R4 ~ 19 _ CH 30C N O SO 2 ~ / Ra Rt~ I ~ R H0. tt R~~N
z ( R~ I % R
CHZAr R2 wherein 21 CHZAr Rto .R9 ~ ~ Rto R9 Ar= ~ / , ~ '/~ ~ ~~~ , ~ 1 , ~~~R9 ~~~R9 ~~~ Rto CN ,, / ~.i C ~ , ~ ~ ~ , or N R9 S p ~~~ R to ; and R 9 and R 1 Q are: C1, Br, F, OCH , OEt , SCH 3 , ~ pCH
p Q O
COEt , CF3 , pCF3 ICNH 2 , -NHCOCH 3 , or Me2N-.
Scheme 4 SO 2 ~ / ~ SO 2 ~ / Ra I
Rt~ ~ R BHP R~~ / ~~ R
R~ N /_ R2 N
Q ~ ~Ar CH2Ar O SO R4 ~ SO 2 ~ / Ra II I 2 ~ / HO~ N
HOC N N
RtY / '/ R H Rt?'N / ,' R
_ 2 R2 CH CH ZAr wherein Rto ~ Rto R9 Ar= ~ \ I ~~ ~ ~ ~ ~ ~% R9 /~% R~ ~~~Rto J N /.. S O
Rto , and R9 and Rto are hydrogen ,CI, Br, F, OCH3 , OEt , q SCH 3 , COCH 3 , COEt , CF3 , OCF3 , or Me2N-.
I 02 ~ / Ra q S02 ~ /
I
CH HOC N CH30C~ N
Rt]I' / %R B~ Rt?I I %rt R2 N _.. ~ R2 O'C~ Rs CH2R8 wherein R8 = 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- I H-[ 1,4]-benzodiazepines 14 (without a substituent at the I-position) with carbonyl chloride derivatives in the manner depicted in Reaction Scheme S, results in intermediates 25 which are then converted to acid 26 and hydroxamic acids 27. The intermediates may also be synthesized by reaction of methyl 2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl) amino]-3-hydroxypropionates 6 with acid chlorides to give "dehydroalanine" derivatives 28. As previously described, mild bases such as NaHC03 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-1 H-[ 1,4] diazepines 25.
Scheme 5 SO 2 ~ / ~ ~ SO 2 ~ / R4 CH OC ~ CH 30C
R COCI Y
R>>~ I %R 8 Rt]i I ~ R
2 H Et 3 N or pyridine O ~ Re Wherein R8 = O N-(CH ) 25 2 n ~-(CH2)~
S~ -(CH2)~ ~ .(CH2)n OH-N
n CH3~-(CH2)n ~ ~ N-(CH2)n -(CH2) ~ ( CH3( CH2~ 12~(CH2 )n n t-B~ -(CH2) n EtOC~ ~ .(CH2 ) n O
~CH2pC_ CH 3 CONIC
and n = 0 to 3 SO 2 R4 ~ SO 2 ~ / R4 i N HOC N
HO /~ RY I / R
R~ ~ R i >' R2 w N I ~ R2 \
O ~' Rs-~ O ~ Ra R4 p SO 2 ~ / Ra CH30C N CH O~~/N
HO R2 I ~R R BCOCI R JLR2H / ~ R
--Et 3 N O ~~ R8 NaHC03 CH OH
SO 2 ~ / R4 Rt'I I %R
RZ N' _.
O 'R8 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 sis, 563-566 {1997); J.
em , 62:3405-3406, ( 1997); Tetrahedron l..ett., 36:5247-5250, ( 1995);
Heteroc,~, 45:467, ( 1997); Tetrahedron Lett., 38:1118-1182, ( 1997);
Heterocycles, 42:189-I 94, ( 1996); Tetrahedron L_ett., 5005-5006, ( 1993); Synthesis, 843, ( 1987);
Heterocycles, 2711-2716, ( 1987); and Tetrahedron Lett., 4407-4410, ( 1986).
By coupling with such palladium catalysts, aryl-aryl, heteroaryl-aryl, aryl-heteroaryl and heteroaryl-heteroaryl carboxylic ester derivatives can be prepared and these derivatives converted to carboxylic acid intermediates. The acids are then converted to acid chlorides which are reacted with esters of 2- [(2-aminobenzyl)-(4-substituted-benzenesulfonyl)amino]-3-hydroxypropionate as illustrated for conversion of derivatives 6 to intenmediates 31. The following references describe procedures for the synthesis of methyl 3-arylpyrrole-4-carboxylates as in J. Ore. Chem., 62:2649-2651, (1997); methyl (2-methylphenyl) benzoates as in J. Ors;. Chem.. 62:3405-3406, ( 1997); and methyl benzoates substitued with heterocycIic moieties such as furanyl, thienyl or pyridinyl groups as in Tetrahedron Lett., 27:4407-4410, ( 1986).
Scheme 6 O SO ~ ~ R4 W
CH O C N 2 y ~~ W W
3 ' R y/ ~ W ; ~, ; Y '~~ ~°ry~\ etc R~~ ~ / S~ Co~ ;
RZ ~ ~- W = B(OH)2 ; SnMe3 ; Sn(n-butyl)3 ;
O ~ Ar~ O-Triflate; ZnCI ; or ZnBr;
Y\~~ B~~~l ~~1 Y\~~~
Ar'= ~~~ ~ CNl , ~S j ~ or <O~ CH OC S02 ~ ~ Ra Br 3 Pd(PPh3)4 or Pd(PPh3)2C12 H ~ . /R
or Ri R2 H2 equivalent Pd catalyst _ _ 6 CI
Y
o so ~ ~ R4 o so 2~ R4 of 2~ CH 1 Y;~ R +
R~~N ~ ~ R ~ / % R Et3N L or R2 I V 2 ... Cl O~ Ai' ~ p~Ar" ~
30 31 O ~ Ar M y M M
where Ar" _ ~~~ ~ ~ ~ , ~~~~~ ~ Y ' \ j ~ oY <,r ~ j ,J J N
L
X Y
L is Y ~~ CONH- . ~~ ~ CONH- ~ or y~ O~ CONH- ' S
Y
M is ~ 1'n/ y~~%
y~ ~ ' ~J ' ~Sj , ~OJ , N
Y \ N Y\r'_' 'N , N. , < ~ N , or 'N, ;
O I
R' R' Y is H, F, Cl, CFg, CHg, or OCH3;
X is halogen, hydrogen, or (C1 - C3)alkyl;
R and R' are as defined herein; and R4 is as defined herein.
The intermediates 2.4,5.6-tetrahydro-I H-[ 1.4]benzodiazepines 39 and 38 may be prepared from glycine esters in the manner e~cemplified 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) ?-nitrobenzyl bromide in N.N-dimethylformamide or 1-methyl-2-pyrrolidinone in the presence of potassium carbonate to give intermediates 34.
Alternatively, the ester 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 us BF3, or heating an acid salt of 36 to effect the elimination-addition reaction.
Scheme 7 CH30CCH2NH2 + C1S0 ~ ~ R4 ~ CH30CCH2NHS ~ ~ R4 33 CH2Br O
il R
CH30CCH2~ S02 ~ ~ R4 NH2 H2 CH30CCH2 N-S02 ~ ~ R4 I .' R Ps-~---- H
~ 2 N02 35 +
CH2 = N(CH3)2C1- R
or +
CH2 = N(CH3)2I-O _ S / ~ R
CH30CCI~N-S02 ~ ~ R4 CH~~ ~ 4 (CH3)2I~ CH 2 CH2 H
/,R
NH2 ~ ,~ ~t3 ~
O S02 ~ ~ R4 ~ SO ~ ~ R4 C OC l~t CH30C 1~T H3 / /R ~ / %R
39 3g 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,~ substituent is an OH group are prepared.
Intermediates with R4 an OH group may be prepared from derivatives wherein the OH group is protected by a group which can be selectively removed. Derivatives 40 wherein R4 is an OCH~ 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,-C6)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.
Ors.
Chem., 56:7173 ( 1991 ); Tetrahedron Lett. 5709 ( 1989); S n he is 1:28 ( 1981 ).
Scheme 8 / H3 O $Oz \ / H
CH30 R BBr3 N R
R / ~ CH 30 I Rt N
Rz R3 Rz R3 40 (C t-C6)alkyl-X
1 ) OH B~ (C t-Ce)alkylOH
2) BBr3 or (C6Hs)~P
DEAD
O ~~ \ / H O ~pz \ / O-alkyl(C,-C6) N R
R, N /
Rz R3 ._ RtRz R
(C6EIs~P 42 or Base DEAD (Ct~6~1ky1pH
(C t-C6~1kY1_X
OH
O ~Oz \ / O-alkyl(Ct-Cs) p SOz \ / O-alkyl(Ct-C6) N '~R OH HO N
(C,-C6)alkYl /
Rt I Rt N /
Rz R3 - Rz R3 (C,-C6)alkyl-X
X = halogen, OTs, OMs 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 malefic 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 Garners, 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 Garner.
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.
Adjuvant.c 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 colorimetrically with DTNB ((5,5'-dithio-bis(2-nitro-benzoic acid)). This assay is disclosed in Weingarten et al., "Spectrophotometric Assay for Vertebrate Collegenase", Anal. Biochem., 147:437-440, ( 1985). The enzyme activity is measured by the rate of the color increase.
The thiopeptide substrate was made up fresh as a 20 mM stock in 100% DMSO
and the DTNB was dissolved in 100% DMSO as a 100 mM stock and stored in the dark at room temperature. The substrate and the DTNB were diluted together to 1 mM
with substrate buffer (50 mM HEPES, pH 7.5, 5 mM CaCl2) before use. The stock of human neutrophil gelatinase B was diluted with assay buffer (SO mM HEPES, pH
7.5, 5 mM CaCl2, 0.02% Brij) to a final concentration of 0.15 nM.
The assay buffer, enzyme, DTNB/substrate (500 ErM final concentration) and vehicle or inhibitor were added to a 96 well plate (total reaction volume of 200p1) and the increase in color was monitored spectrophotometrically for 5 minutes at 405 nm on a plate reader.
The increase in OD405 was plotted and the slope of the line was calculated.
The slope represents the reaction rate. The linearity of the reaction rate was confirmed (r2 >0.85) and the mean (x t sem) of the control rate was calculated and compared for statistical significance (p <0.05 j with drug-treated rates using Dunnett's multiple comparison test. Dose-response relationships were generated using multiple doses of drug and ICSp values with 95% CI were estimated using linear regression (IPRED, HTB).
In Vitro CollaEenase Assay This assay was based on the cleavage of a peptide substrate ((Dnp-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMa)-NH2), available from Peptide International, Inc.) by collagenase releasing the fluorescent NMa group which was quantitated on the fluorometer as disclosed in Bickett et al., "A High Throughput Fluorogenic Substrate WO 99!37625 PCT/US99/01325 for Interstitial Collagenase (MMP-1 ) and Gelatinase (MMP-9)", Anal. Biochem., 212:58-64, ( 1993). Dnp quenches the NMa t7uorescence in the intact substrate.
The assay was inn in HCBC assay buffer (50 n>Ni HEPES, pH 7.0, 5 mM
Ca+2, 0.02% Brij, 0.5% Cysteine), with human recombinant fibroblast collagenase (truncated, mw=18,828, from Wyeth-Ayerst Research, Radnor, PA). The substrate was dissolved in methanol and stored frozen in 1 mM aliquots. Collagenase was stored frozen in buffer in 25 pNl aliquots. In conducting the assay, the substrate was dissolved in HCBC buffer to a final concentration of 10 E.~M and collagenase to a final concentration of 5 nM. The compounds being examined were dissolved in methanol, DMSO, or HCBC. The methanol and DMSO were diluted in HCBC to < 1.0%. The compounds were added to a 96 well plate containing enzyme and the reaction was started by the addition of substrate.
The reaction was read (excitation 340 nm, emission 444 nm) for 10 min. and the increase in fluorescence over time was plotted as a linear line. The slope of the line was calculated representing the reaction rate. The linearity of the reaction rate was confirmed (r2 >0.85). The mean (x t sem) of the control rate was calculated and compared for statistical significance (p <0.05) with drug-treated rates using Dunnett's multiple comparison test. Dose-response relationships were generated using multiple doses of drug and IC50 values with 95% CI were estimated using linear regression.
Procedure for Measuring TACE Inhibition In a 96-well black microtiter plate, each well received a solution composed of pI. TACE (available from Immunex) at a final concentration of 111g/mL, 701rL.
Tris buffer, have a pH of 7.4 and containing 10% glycerol (final concentration 10 mM), and 10 pL of test compound solution in DMSO (final concentration 1 pM, DMSO
concentration < 1 %). The plates were incubated for 10 minutes at room temperature.
The reaction was initiated by addition of a fluorescent peptidyl substrate (final concentration 100 ECM) 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 (r2 >0.85). The mean (xtsem) of the control rate was calculated and compared for statistical significance (p<0.05) with drug-treated rates using Dunnett's WO 99/37625 PC'f/US99/01325 multiple comparison test. Dose-response relationships were generated using multiple doses of dmg and ICSp values with 95% CI were estimated using linear regression.
The results obtained following these standard experimental test procedures are presented in Table 1.
Table I
O $O~~R4 N
HORN
Rt N / i R
RZ
Compound of R3 Example R R~RZ R4 ICs o (nM) _ - - - - MMP-1 MMP-9MMP- I TALE
-SO ~ ~ 2 H H H -OCH3_ 14.1 5.1 391 -SOiCH3 3 H H H -OCH3156.5 7.9 3.0 104 -SOZC H2CH2CH H H H -OCH.~183 7.0 2.8 91 -SO~OCH3 4 H H H -OCH~2~.1 12.2 4.3 101 t -COCH 6 H H H -OCH318.4 1.4 10 103 -CO / ~ 5 H H H -OCH315.8 0.56 95 (23) (1.7) 10 0.4 (1.1) Compound of R3 R R~ RZ R4 ICs Example (nM) -CO- 7 H H H -OCH~20.4 0.6 0.4 77.7 I (34) ( ( 1.3) + 7 ~ 1.9) -CO-~ 8 H H H -OCH319.7 1.1 1.1 12.8 1.2 -CO- 13 H H H -OCH354.9 9.8 2.0 154 +_ I , 27 ~
~N
COCH20CH3 9 H H H -OCH334.1 1.34 1.19 95,2 14.8 -CO(CH~ 12 H H H -OCH 523 17.9 25 ~ 3 7 /
. 207 +
-CO 1 H H H -OCH 96.2 5.1 3.7 352 ~ ~ 34 /
-CO
/ 11 H H H -OCH 55.4 3.9 2.3 271 +
F
-C 15 H H H -OCH352.7 0.7 0.4 199 -CO
/
14 H H H -OCH 542 12.6 3.7 4596 3 ( 1 uM) 55 H H H -OCH3171 4.0 3.3 6g,5 -CO~ 7.2 -CO~ 57 H H H -OCH3465 12.7 7.2 318 -CO-~CI 31 H H H -OCH375.5 3.0 2 . 367o(luM) -C 40 H H H -OCH316.6 1.4 1.2 28.5 /~ 6.6 O
-C~H 58 H H H -OCH365.5 4.4 2.9 154 2o- 20 Compound of R~ Example R Ri R, R.~ lCso (nM) -COCH.,OCH~ 59 -CH3 H H -OCH~105 2.6 1.8 12516 C / \ 60 7-CH3 H H -OCH~22.7 1.4 1.3 143+4 -C ~ ~ OCF3 61 g-CI H H -OCH~239 1.3 0.4 1248 (265) (3.9) (4.3) t 69 -CHzCH,OCH; 62 H H H -OCH;1000 100 100 51 ( 1pM) CN
\
63 7-CH; H H -OCH3130 5.6 3.1 aa6 t as -C / \
64 8-Cl H H -OCH3l57 6.1 3.4 384 -CO ~ t 8 -C ~ ~ OCZHS 65 H H H -pCH323.5 1.5 1.5 157 t 13 -C0~1,~CH3 66 H H H -OCH~g3.4 3.4 2.6 148 t 14 -CH2-~ 67 H H H -OCH31323 50.8 73.9 551 f 29 -C
71 H H H -OCH~41.3 2.4 1.3 136 t 15 OCH
n -CO-CH~I~N-CH372 H H H -OCH34982 187 317 808 t 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 moI) of N-(benzyloxycarbonyl)-O-benzylserine in 600 ml of CH2C12 cooled to -6°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.
WO 99/37625 PC'T/US99/01325 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°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 S, nty hetic 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 CH2Cl2 (cooled in an ice bath) was added, in small portions, 16.1 g (0.0771 mol) of 4-methoxybenzene-sulfonyl chloride. The mixture was stirred at 0°C for 0.5 hours and at room temperature overnight. The mixture was washed with H20, 2N citric acid, brine and dried with Na2S04. The solvent was removed under vacuum to give 25.34 g of solid which was triturated with hexane. The solid was recrystallized from 120 ml of toluene to give 12.18 g (48:7%) of product as a white solid. The filtrate was concentrated and the residue chromatographed on silica gel with hexane-ethyl acetate (7:3) as eluent to give 5.71 g (22.8%) of white solid.
m.p. 70-75°C. Anal. for C14H21N06S:
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 ~-butyl ester in 50 ml of N,~1-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,~1-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 CH2Cl2. The organic extract was washed with H20, brine and dried with Na2S04. 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 C21H26N208S:
Calc'd: C,54.1; H,5.6; N,6.0;
Found: C,54.0; H,5.7; N,6Ø
Reference Example 5 2-[(2-Aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3 hydroxypropionic acid, tert-butyl ester A mixture of 0.60 g ( 1.28 mmol) of 3-hydroxy-2-[(4-methoxybenzene sulfonyl)-(2-nitrobenzyl)amino] propionic acid, tit-butyl ester and 1.45 g (6.45 mmol) of SnCl2~2H20 in 20 ml of methanol was heated in an oil bath at 90°C
for 2 hours.
The solvent was removed under vacuum and ethyl acetate added to the residue.
The mixture was neutralized with saturated sodium bicarbonate solution and filtered through diatomaceous earth. The ethyl acetate layer was separated and washed with H20, brine and dried with Na2S04. The solvent was removed under vacuum to give 0.30 g (53%) of a gum. Anal. for C21 H28N206S:
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-methoxybenzene-sulfonyl)amino]-3-hydroxypropionic acid, tent-butyl ester and 6 ml of trifluoroacetic acid in 6 ml of CH2C12 was stirred at room temperature for 3 hours and then concentrated to dryness under vacuum. To the residue was added H20, CH2Cl2 and 1N NaOH until the aqueous layer 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 H20, brine and dried Na2S04. The solvent was removed under vacuum to give 0.35 g (54%) of a solid. Anal. for C17H2pN206S:
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)amino}acrylic acid, tert-butyl ester A mixture of 0.431 g (1 mmol) of 2-[(2-amino-benzyl)-(4-methoxybenzene-S sulfonyl)amino]-3-hydroxy-propionic acid, tert-butyl ester, 0.474 g (2.2 mmol) of 3-(trifluoromethyl)benzoyl chloride and 1 ml of pyridine in 2 ml of CH2C12 was stirred at room temperature for 3.5 hours. The mixture was poured into H20 and extracted with CH2C12. The extract was washed with H20, 2 N citric acid, H20, 1 N NaHC03, brine and dried with Na2S04. 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°C overnight and concentrated to dryness under vacuum. The residue was extracted with CH2C12 and the extract washed with H20 and dried with Na2S04. The solvent was removed under vacuum to give 0.55 g of product as a solid. From a similar run the product was chromatographed on silica gel with hexane-ethyl acetate to give a solid, m.p. 65-72°C. Anal. for C29H29F3N2O6S:
Calc'd: C, 59.0; H,5.0; N,4.7;
Found: C, 59.2; H,5.2; N,4.4.
Reference Example 8 20 4-(4-Methoxybenzenesulfonyl)-I-(3-trifluoromethylbenzoyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, tert-butyl ester A mixture of 0.55 g (0.932 mmol) of 2-{(2-[3-(trifluoromethyl)benzoyl) aminobenzoyl]-(4-methoxybenzenesulfonyl)amino } acrylic acid, tert-butyl ester and O.I02 g (1.21 mmol) of NaHC03 in 4 ml of methanol was stirred at room temperature overnight and the solvent removed. The residue was extracted with CH2C12 and the extract washed with H20, brine and dried with Na2S04. The solvent was removed to give 0.57 g of solid. The solid was chromatographed on thick layer silica gel plates with hexane-ethyl acetate (1:1) as solvent to give 0.30 g of a light yellow solid, m.p.
57-60°C. Anal. for C29H29F3N2O6S:
Calc'd: C,59.0; H,5.0; N,4.7;
Found: C,58.8; N,5.0; N,4.6.
Reference Example 9 4-(4-Methoxybenzenesulfonyl)-1-(3-trifluoromethylbenzoyl)-2,3,4,5 tetrahydro-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-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, ten-butyl ester and 3 ml of trifluoroacetic acid in 3 ml of CH2Cl2 was stirred at room temperature for 3 hours. The mixture was concentrated to dryness under vacuum and the residue extracted with CH2Cl2. The CH2Cl2 was washed with 1 N NaHC03 and the aqueous layer (pH 8) was acidified with 2 N citric acid and extracted with ethyl acetate. The extract was dried (Na2S04}. The original CH2C12 extract was washed with 2 N citric acid, H20, brine and dried with Na2S04. The CH2C12 extract and the ethyl acetate extract were combined and the solvent removed under vacuum to give 0.31 g of solid, m.p: 105-110°C. Anal. for C25H21F3N206S:
Calc'd: C,56.2; H,4.0; N,5.2;
Found: C,55.1; H,3.7; N,5Ø
Reference Example 10 Methyl 1-([l,1'-Biphenyl]-2-carbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-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 CH2C12 chilled at 0°C was added a solution of [ 1,1'-biphenyl]-2-carbonyl chloride in 6 ml of CH2Cl2. The mixture was stirred at room temperature overnight and diluted with CH2Cl2 and H20. The organic layer was separated and washed with 2 ~1 citric acid, brine and dried with Na2S04, The solvent was removed under vacuum to give 2.2 g of a white foam. Anal. for C31 H28N206S:
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-tetrahydro-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 CH2Cl2, chilled to 0°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 CH2Cl2 and water and the organic layer separated. The organic layer was washed with 2 N citric acid. brine and dried with Na2S04, The solvent was removed under vacuum to give 2.2 g of a white foam.
Anal. for C~6H25FN~06S:
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-carboxylate To a mixture of 5.0 g (12.68 mmol) of methyl 2-[(2-aminobenzylj-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate and 17.7 ml (26.8 mmol) of triethylamine in 50 ml of CH2Cl2 chilled to 0°C was added 9.05 ml (63.4 mmol) of benzyl chloroformate. The mixture was stirred overnight and then cooled to 0°C and .8 ml of triethylamine and 9.05 ml (63.4 mmol) of benzyl chloroformate were added thereto. The mixture was stirred overnight and then washed with H20, 2 N
citric acid, brine and dried with Na2S04, 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 1 gH2pN205S:
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 CH2Cl2, cooled to 0°C, was added portionwise 6.64 g (32.14 mmol) of 4-methoxybenzenesulfonyl chloride. The mixture was then stirred under argon at room temperature for 2 days. The mixture was diluted with 100 ml of CH2CI2 and then washed with 60 ml each of H20, 2 N citric acid, brine and dried with Na2S04, The solvent was removed under vacuum to give a solid.
Crystallization from ethyl acetate gave 5.0 g (54%) of white crystals, m.p. 92-94°C.
Anal. for C 11 H 1 SN06S:
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,11.1.
Reference Example 14 Methyl 3-Hydroxy-2-[(4-methoxybenzenesulfonyl)-(2-nitrobenzyl) amino]propionate To a solution of 15.0 g (51.85 mmol) of methyl 3-hydroxy-2-(4-methoxybenzenesulfonylamino)propionate in 125 ml of N,N-dimethylfolmamide, 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°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 H20, 1 N NaHC03, brine and dried with Na2S04, The solvent was removed and the residual solid was triturated with ethyl acetate, cooled and filtered to give 13.5 g (61 %) of white crystals, having a m.p. 127-129°C. From a small scale run (3.0 g) there was obtained 2.32 g of white crystals, having a m.p. 127-129°C. Anal. for C18H2pN2O8S:
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 fonnate followed by the addition of 0.50 g of 10% palladium on carbon. The mixture was stirred overnight at room temperature and heated at 80°C for 2 hours. The mixture was filtered through diatomaceous earth and the filtrate concentrated to dryness under vacuum to give a semisolid.
Trituration with ethyl acetate gave 0.65 g (47%) of white crystals, m.p. 138-140°C;
Anal, for C 18H22N206S:
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)benzyl]amino}propionate To a solution of 0.50 g ( 1.27 mmol) of methyl 2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate in 5 ml of CH2Cl2 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 C20H21F3N207S:
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°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 methylbenzene-sulfonyl chloride were added. The mixture was stirred and chilled at -10°C for 24 hours and diluted with H20. The mixture was extracted with ethyl acetate and the extract washed with H20, 2 N citric acid, and brine and then dried (Na2S04).
The solvent was removed under vacuum to give 1.2 g of an oil. The oil was dissolved in 6 ml of pyridine and 1.08 g of 4-methylbenzenesulfonyl chloride was added thereto.
The mixture was stirred at room temperature overnight and diluted with H20.
The mixture was extracted with ethyl acetate and the extract was washed with H20, citric acid, and brine and then dried with Na2S04, The solvent was removed to give 1.0 g of brown oil. The oil was crystallized from ethanol to give white crystals, m.p. 65-67°C. Anal. for C18H18N20~7S:
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 CH2C12, cooled to 0°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 CH2Cl2. The mixture was washed with H20, 2 N citric acid, and brine and them dried with Na2S04, The solvent was removed to give 1.8 g of a tight tan solid; Anal. for C24H23N306S~
Calc'd: C,59.9; H,4.8; N,8.7; 5,6.6;
Found: C,59.0; H,4.8; N,8.5; S,6.9;
Mass spectrum (ES) 482.6(M+H).
Utilizing the procedure described in Reference Example 18, the following intermediate compounds can be prepared from the appropriately unsubstituted methyl 2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate or the appropriately substituted methyl 2-[(substituted-2-aminobenzyl)-(4-methoxybenzene-sulfonyl)amino]-3-hydroxypropionate.
Reference Example 19 Methyl 2-{ (4-Methoxybenzenesulfonyl)-[2-(2,2,2-trifluoroacetylamino)benzyl]amino}acrylate white crystals, m.p. 120-121 °C. Anal. for C2pH 19F3N206S:
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-Benzoylamlnobenzyl)-(4-methoxybenzenesulfonyl) amino]acrylate yellow oil. Anal. for C25H24N206S:
Calc'd: C,62.5; H,5.0; N,5.8;
Found: C,62.7; H,5.3; N,5Ø
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 C24H23N306S:
Calc'd: C,59.9: H,4.8; N,8.7; S,6.6;
Found: C,58.9: H,4.8; N,8.4; S,6.4;
Mass spectrum (ES) 482.8(M+H).
Example 23 Methyl 2-((4-Methoxybenzenesulfonyl)-{ [(2 thienylcarbonyl)amino]benzyl}amino)acrylate tan solid. Anal. for C23H22N2~6S2:
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}acrylate yellow oil. Anal. for C21 H24N20'7S:
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}acrylate light brown oil. Anal. for C21H26N2~7S2:
Calc'd: C,52.3; H,5.4; N,5.8;
Found: C,51.9; H,5.4; N,5.7.
Reference Example 26 Methyl 2-{ [2-(3-Phenylpropionyl)aminobenzyl]-(4 methoxybenzenesulfonyl)amino}acrylate light brown oil. Anal. for C27H28N206S:
Calc'd: C,63.8; H,5.6; N,5.5;
Found: C,66.7; H,5.8; N,4.1.
_4ø_ Reference Example 27 tert-Butyl 2-{[2-(3-Trifluoromethylbenzoyl)aminobenzyl]-(4-methoxybenzenesulfonyl)amino}acrylate yellow solid; m.p. 65-72°C.
Reference Example 28 Methyl 2-{ [2-(4~Biphenylcarbonyl)aminobenzyl]-(4 methoxybenzenesulfonyl)amino}acrylate white solid. Anal for C31H28N206S:
Calc'd: C,66.9; H,S.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}acrylate yellow oil. Anal. for C22H24N2~6s:
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}acrylate white foam. Anal. for C25H30N206S:
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}acrylate Reference Example 32 Methyl 2-{[2-(3-Chlorobenzoyl)aminobenzyl]-(4-methoxybenzenesulfonyl)amino}acrylate Reference Example 33 Methyl 2-{[2-(2,4-Dichlorobenzoyl)aminobenzyl]-(4 methoxybenzenesulfonyl)amino}acrylate Reference Example 34 Methyl 2-{ [2-(2,3-Difluorobenzoyl)aminobenzyl]-(4 methoxybenzenesulfonyl)amino}acrylate Reference Example 35 Methyl 2-{ [2-(2-Chloro-4-fluorobenzoyl)aminobenzyl]-(4-methoxybenzenesulfonyl)amino}acrylate Reference Example 36 Methyl 2-{ [2-(2-Furanylcarbonyl)aminobenzyl]-(4-methoxybenzenesulfonyl)amino}acrylate off-white solid. Anal. for C23H22N2~7S.
Calc'd: C,58.7; H,4.7; N,6.0;
Found: C,58.0; H,4.1; N,3.8;
Mass Spectrum (ES) 470.9 (M+H).
Reference Example 37 Methyl 2-((4-Methoxybenzenesulfonyl)-{2-((3-thienylcarbonyl)amino]benzyl}amino)acrylate Reference Example 38 Methyl 2-{ [2-(2-Acetylaminoacetyl)aminobenzyl]-(4 methoxybenzenesulfonyl)amino}acrylate Reference Example 39 Methyl 2-{ [2-(2-Dimethylacetyl)aminobenzyl]-(4-methoxybenzenesulfonyl)amino}acrylate Reference Example 40 Methyl 2-{ [2-(Cyclobutylcarbonyl)aminobenzyl]-(4-methoxybenzenesulfonyl)amino}acrylate Reference Example 41 Methyl 1-Methoxyacetyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate To a mixture of 0.449g ( 1 mmol) of methyl 2-[[2-(2-methoxyacetamido)-benzyl]-(4-methoxybenzene-sulfonyl]amino]acrylate in S ml of anhydrous methanol was added 0.109 g ( 1.3 mmol) of anhydrous sodium bicar-bonate. The mixture was stirred at room temperature overnight and the solvent removed under vacuum. To the residue was added ethyl acetate and water. The organic layer was separated and washed with H20 and brine and then dried with Na2S04, 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°C. Anal. for C21H24N207S:
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-methoxybenzene-sulfonyl)-[2-(substituted amino)benzyl]amino)acrylates.
Reference Example 42 Methyl 4-(4-Methoxybenzenesulfonyl)-1-(4-methylphenylsulfonyl) 2,3,4,5-tetrahydro-1 H-( 1,4]benzodiazepine-3-carboxylate white foam. Anal. for C25H26N207S2:
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 I,4-Bis-(4-methoxybenzenesu)fonyl)-2,3,4,5-tetrahydro-1H-(1,4]benzodiazepine-3-carboxylate white solid. Anal. for C25H26N208S2:
Calc'd: C,54.9; H,4.8; N,5.1;
Found: C,54.8; H,4.9; N,5.1.
_ 47 _ Reference Example 44 Methyl 1-Methanesulfonyl-4-(4-methoxybenzeuesulfonyl)-2,3,4,5-tetrahydro-1H-[l,4Jbenzodiazepine-3-carboxylate white crystals, m.p. 136-137°C. Anal. for C19H22N207S2:
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]benzodiazepine-3-carboxylate tan solid. Anal. for C25H24N2~2S:
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-1 H-[1,4]benzodiazepine-3-carboxylate white crystals, m.p. 150-155°C. Anal. for C2pH22N2~6S:
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-1 H-[ 1,4J benzodiazepine-3-carboxylate off white solid; Anal. for C24H23N3~6S:
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-[l,4Jbenzodiazepine-3-carboxylate off white solid. Anal. for C23H22N2~6S2:
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°C. Anal. for C24H23N3~6S:
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-1.H-[1,4]benzodiazepine-3-carboxylate white solid; Anal, for C31H28N206S:
Calc'd: C,66.9; H,5.1; N,S.O;
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-sulfonyt)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate yellow oil. Anal. for C21H26N2~7S2:
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-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate white foam. Anal. for C31H28N206S:
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-tetrahydro-1H-[ 1,4]benzodiazepine-3-carboxylate white solid; Anal. for C26H25FN206S:
Calc'd: C,60.9; H,4.9; N,5.5;
Found: C,60.9; H,5.0; N,5Ø
Reference Example 55 Methyl 4-(4-Methoxybenzenesulfonyl)-1-(2-methyl-3-fluorobenzoyl)-2,3,4,5-tetrahydro-1 H-[ 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 C27H28N206S:
Calc'd: C,63.8; H,5.6; N,5.5;
Found: C,64.0; H,5.7; N,5.3: 5,6.5.
Reference Example 57 Methyl 4-(4-Methoxybenzenesulfonyl)-1-(2-trifluoromethylbenzoyl)-2,3,4,5-tetrahydro-1H-[ 1,4] benzodiazepine-3-carboxylate Reference Example 5$
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-tetrahydro-1 H-[ 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-tetrahydro-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-tetrahydro-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 C25H22C12N206S:
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-tetrahydro-1 H-[ l,4Jbenzodiazepine-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-tetrahydro-1H-[1.4]benzodiazepine-3-carboxylate Reference Example 77 Methyl 4-(4-Methoxybenzenesulfonyl)-1-(4-methyl-2-thienylcarbonyl)-2,3,4,5-tetrahydro-1H-[ 1,4]benzodiazepine-3-carboxylate Reference Example 7$
Methyl 1-(3-Chloro-2-thienylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-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°C. Anal. for C23H22N207S:
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-tetrahydro-1H-[ 1,4)benzodiazepine-3-carboxylate Reference Example 81 Methyl 4-(4-Methoxybenzenesulfonyl)-1-(4-methyl-2-furanylcarbonyl) 2,3,4,5-tetrahydro-1H-[ 1,4]benzodiazepine-3-carboxylate Reference Example 82 Methyl 1-(5-Chloro-2-furanylcarbonyl)-4-(4-methoxybenzenesulfonyl) 2,3,4,5-tetrahydro-IH-[1,4]benzodiazepine-3-carboxylate Reference Example 83 Methyl 1-(5-Chloro-2-thienylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate Reference Example 84 Methyl 1-Propionyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate Reference Examprle 85 Methyl 1-Hexanoyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate Reference Example 86 Methyl 1-(3-Methoxypropionyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[ I,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]benzodiazepine-3-carboxylate Reference Example 91 Methyl 1-(Chloroacetyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate Following the method described for Reference Example 18, 3.0 g (7.61 mmol) of methyl 2-[2-aminobenzyl)-(4-methoxy-benzenesulfonyl)-amino]-3-hydroxy-propionate was reacted with 1.82 ml (22.8 mmol) of chloroacetylchloride to give 4.0 g of solid. Chromatography on silica gel with ethyl acetate-hexane ( 1:1 ) as a solvent gave 1.5 g of methyl 2-[(2-chloroacetylaminobenzyl)-(4-methoxybenzenesulfonyl)-amino]-acrylate. A 1.3 g sample of the preceding compound was reacted with 0.312 g of anhydrous NaHC03 in 10 ml of anhydrous methanol at room temperature overnight and the mixture was then heated at 80°C for 5 hours. The solvent was removed and the residue partitioned between H20 and ethyl acetate. The ethyl ~etate extract was washed with brine, dried with Na2S04 ~d the solvent removed. The residue was trittlrated with hexane-ethyl acetate, chilled and filtered to give the product; Mass sp~~um (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-tetrahydro-1 H-[ 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°C. Anal. for C22H24N206S:
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 tetrahyd ro-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)benzyl]amino}propionate in 10 ml of CH2C12 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 NaHC03 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 H20, brine and dried with Na2S04. 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 C2pH 19F3N2O6S:
Calc'd: C,50.9; H,4.1; N,5.9; F,12.1; 5,6.7;
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)-I-(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-methoxybenzene-sulfonyl)amino]-3-hydroxypropionate in 5 ml of pyridine cooled to 0°C
was added 0.284 g (2.59 mmol) of tosyl chloride. The mixture was stirred at 0°C
for 2 hours and then concentrated to remove the solvent. To the residue 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 H20, 2 N citric acid, brine and dried with Na2S04. 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 C25H26N207S2:
Calc'd: C,56.6; H,4.9; N,5.3; 5,12.1;
Found: C,56.2; H,5.2; N,5.2; 5,11.4;
Mass spectrum (ES) 531.6 (M+H).
Reference Example 98 Methyl 2-[(4-Methoxybeozenesulfonyl)-(2-methylsulfonylaminobenzyl)amino]acrylate To a solution of 1.0 g (2.54 mmol) of methyl [(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate in 10 ml of pyridine cooled to -5°C was added 0.432 ml (5.58 mmol) of methanesulfonyl chloride. The mixture was stirred at 0°C for 48 hours. To the mixture was added ice and H20 and the mixture was extracted with ethyl acetate. The extract was washed with H20, 2 N citric acid, brine and dried with Na2S04, The solvent was removed under vacuum and the residue triturated with ethyl acetate-hexane to give 0.90 g of a solid, 128-142°C. Anal. for C 19H22N207S2:
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-1 H-[1,4]benzodiazepine-3-carboxylate To a solution of 1.0 g (2.34 mmot) of methyl ?-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate in 6 ml of pyridine cooled to 0°C to -5°C was added 1.07 (5.18 mmol) of 4-methoxybenzenesulfonyl chloride. After 2 hours, the mixture was concentrated to dryness under vacuum. To the residue was added 12 ml of ethanol and the mixture refluxed overnight. The solvent was removed under vacuum and the residue chromatographed on silica gel thick layer plates with ethyl acetate-hexane ( I :1 ) as solvent to give 0.83 g (60%) of product as a white foam;
Anal. calc'd for C25H2(~N2O8S2: C,54.9; H,4.8; N,5.1; S,11.7. Found: C,54.8;
H,4.9; N,5.0; 5,11.5; Mats spectrum (ES) 547.1 (M+H); and a second component (0.38 g) methyl 2-{ [2-(4-methoxybenzenesulfonyl)aminobenzyl]-(4-methoxybenzene-sulfonyl)amino}-3-hydroxypropionate. Anal. for C25H28N2O9S2:
Calc'd: C,53.2; H,5.0; N,5.0; S,11.4;
Found: C,51.8; H,S.1; N,4.7; S,1 I .3;
Mass spectrum (ES) 565.2 (M+H).
Reference Example 100 Methyl 1-Acetyl-4-(4'-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1 H-[ 1,4] benzodiazepine-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 H20. The organic layer was separated, washed with brine and dried with Na2S04, The solvent was removed and the residue dried under vacuum to give 0.59 g of white crystals, m.p. 150-155°C. Anal. for C2pH22N2O6S:
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]propionate A mixture of 1.0 g (2.54 mmol) of methyl 2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate and 1.3 ml of acetic anhydride WO 99/37625 PC'T/US99/o1325 in 8 ml of toluene was heated at 100°C for 2 hours. The mixture was concentrated and 3 ml of acetic anhydride added thereto. The mixture was heated at 100°C
overnight and concentrated to dryness under high vacuum to give an oil. The oil was dried at 75°C
under vacuum for 48 hours to give 1.2 g of a yellow oil. Anal. for C24H28N2O9S:
Calc'd: C,54.5; H,5.2; N,5.5; S,6.2;
Found: C,54.6; H,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-diacetyl-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]propionate and 0.826 ml (5.92 mmol) of triethylamine in 5 ml of CH2C12 was stirred at room temperature overnight.
The solution was diluted with 30 ml of CH2Cl2 and washed with 20 ml each of H20, 2 ~I citric acid, brine and dried with Na2S04, The solvent was removed under vacuum to give a brown oil. Anal. for C22H24N207S:
Calc'd: C,57.4; H,5.3; N,6. I ; 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°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 H20, brine and dried (Na2S04). The solvent was removed under vacuum to give 1.0 g of colorless oil. Crystallization from ethyl acetate -hexane gave 0.625 g of colorless crystals, m.p. 120-121 °C.
Anal. for C2pH 19F3N206S:
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;
S Mass spectrum (ES) 473.1 (M+H).
Reference Example 104 4-(4-Methoxybenzenesulfonyl)-1-(2-methyl-5-fluorobenzoyl)-2,3,4,5 tetrahydro-1H-[1,4~]benzodiazepine-3-carboxylic Acid To a mixture of 1.9 g (3.71 mmol) of methyl 4-(4-methoxybenzenesulfonyl)-1-(2-methyl-5-fluorobenzoyl)-2,3,4,5-tetrahydro-1H-[ 1,4]benzodiazepine-3-carboxylate in 10 ml of tetrahydrofuran wac 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
HCI. The 15 organic layer was separated, washed with brine and dried with Na2S04. The solvent waa removed under vacuum to give 1.41 g of white solid. Anal. for C25H23~2065:
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 C24H24N20'752:
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-1 H
[1,4]benzodiazepine-3-carboxylic acid off white solid. Anal. for C24H?4N208S2:
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]benzodiazepine-3-carboxylic acid white solid. Anal. for C ~ gH2pN207S2:
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]benzodiazepine-3-carboxylic acid white foam. Anal. for C24H22N206S:
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-1 H
[1,4]benzodiazepine-3-carboxylic acid white solid; Anal. for C19H22N206S:
Calc'd: C,56.4; H,5.0; N,6.9;
Found: C,55.2; H,4.9; N,6.6; 5,7.8;
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 C23H? 1 N306S:
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 C22H20N2~6S2:
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]benzodiazepine-3-carboxylic acid white crystals, m.p. 193-194°C. Anal. for C2pH22N2~7S:
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 °C. Anal. for C23H21 N306S:
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 C3pH26N206S:
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 C2pH24N2~7S2:
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 tetrahydro-1H-(1,4]benzodiazepine-3-carboxylic acid white foam; m.p. 106-145°C. Anal. for C3pH26N2~6S:
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-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid WO 99/3'I625 PCT/US99/01315 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 C26H26N206S:
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-tetrahydro-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-Methoxybenzenesulfooyl)-1-(2-methyl-6-chlorobenzoyl)-2,3,4,5-tetrahydro-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 S Reference Example 128 1-(2-Chloro-4-fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid Reference Example 129 1-(2-Chlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-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 tetrahydro-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 C24H20CI2N2~6S:
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 WO 99/37625 PCT/US99l01325 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-IH-[1,4]benzodiazepine-3-carboxylic acid Reference Example 137 1-(4-Chloro-2-methoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-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-carboxylic acid Reference Example 140 4-(4-Methoxybenzenesulfonyl)-1-(4-methyl-2-thienylcarbonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid Reference Example 141 1-(3-Chloro-2-thienylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-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 C22H2pN2~7S:
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 tetrahydro-1H-[1,4)benzodiazepine-3-carboxylic acid Reference Example 144 4-(4-Methoxybenzenesulfonyl)-1-(4-methyl-2-furanylcarbonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid Reference Example 145 1-(5-Chloro-2-furanylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid Reference Example 146 1-(5-Chloro-2-thienylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid Reference Example 147 1-Propionyl-4-(4-methoxybenzenesulfonyl}-2,3,4,5-tetrahydro-1H
[1,4)benzodiazepine-3-carboxylic acid Reference Example 148 1-Hexanoyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H
[1,4]benzodiazepine-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 WO 99/37625 PCT/US99/Oi325 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]benzodiazepine-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°C. Anal. for C21H22N2~6S:
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 C24H28N206S:
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-methyl benzenesulfonic acid monohydrate in 5 ml of tetrahydrofuran was refluxed overnight and the mixture was concentrated to dryness under vaccum. The residue was extracted with CH2Cl2 and the extract washed with 2 N NaHC03, . brine and dried with Na2S04, The solution was filtered through a thin pad of hydrous magnesium silicate and the filter pad washed with CH2C12. The filtrate was concentrated to dryness and the residue (2.3 g) was extracted with three SO ml portions of hot hexane to give 1.92 g of product as a yellow oil; Mass spectrum (ES) 374.4 (MH+).
Reference Example 160 Methyl 3-Hydroxy-2-{ [4-methoxybenzenesulfonyl]-[2-(4-morpholinocarbonylamino)benzyl]amino}propionate To a mixture of 1.0 g (2.54 mmol) of methyl 2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate in 8 ml of pyridine chilled at OP
to -10°C was added 740 pL, (6.34 mmol) of morpholinocarbonyl chloride.
The mixture was kept at OP to 5°C overnight. The mixture was concentrated under vacuum and diluted with ethyl acetate. The solution was washed with H20, 2 N citric acid, and brine and dried with Na2S04, 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 C23H29N308S:
Calc'd: C,54.4; H,5.8; N,8.3;
Found: C,53.9; H,5.7; N,B.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-methoxy-benzenesulfonyl]-[2-(4-morpholinocarbonylamino)benzyl]amino }propionate and lli, (5.54 mmol) of triethylamine in 8 ml of CH2C12, cooled to 0°C, was added 0.386 g (2.03 mmol) of 4-methylbenzenesulfonyl chloride. The mixture was stirred at room temperature for 2 hours, diluted with water and extracted with CH2C12. The extract was washed with 2 N citric acid, brine and dried with Na2S04, The solvent was removed to give 0.67 g of a yellow oil. Anal. for C23H27N307S:
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 NaHC03 in 5 ml of anhydrous methanol was stirred at room temperature for 16 hours. An additional 55 mg of NaHC03 was added and the mixture stirred at room temperature for 2 hours. The solvent was removed under vacuum and the residue diluted with H20 and extracted with ethyl acetate. The extract was washed with brine and dried with Na2S04. 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 C23H27N30~7S:
C,56.4; H,5.6; N,8.6; 5,6.6. 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-1H-[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 HCI and cooled. The mixture was filtered and the solid washed with water to give 0.26 g of white solid. Anal. for C22H25N307S:
Calc'd: C,55.6; H,5.3; hI,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-vitro-4-chlorobenzyl)amino]propionate To a mixture of 1.67 g (4.4 mmol) of (D,L) N-(4-methoxybenzenesulfonyl)-O-(2-tetrahydropyranyl) serine, methyl ester, 0.825 g (4.4 mol) of 4-chloro-2-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 H20 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 C24H25N306S:
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 } acrylate in 10 ml of methanol was added 0.207 g (2.46 mmol) of anhydrous sodium bicarbonate. The mixture was stirred for 2 days and then an additional 0.207 g of NaHC03 added. The mixture was stirred overnight and the solvent removed under vacuum. To the residue was added H20 and ethyl acetate and the organic layer separated. The ethyl acetate extract was washed with brine, dried with Na2S04 and the solvent removed under vacuum to give 0.83 g of the product as a yellow oil. Anal. for C25H3pN206S: 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]propionate To a solution of 0.289 g ( 1 mmol) of methyl 3-hydroxy-2-(4-methoxybenzenesulfonylamino)propionate in 4 ml of N,N-dirnethylformamide 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 CH2Cl2.
The extract was washed with H20, brine and dried with Na2S04. 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°-114°C. Anal. for C 18H 19C1N2O8S:
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]propionate A mixture of 0.454 g ( 1 mmol) of methyl 3-hydroxy-2-[(4-methoxy-benzenesulfonyl)-(4-chloro-2-nitrobenzyl)amino]propionate and 0.451 g (2 mmol) of SnCl2~2H20 in 12 ml of methanol was refluxed for 2 hours. An additional 0.451 g (2 mmol) of SnCl2~2H20 was added and the mixture refluxed for 2 hours. The solvent was removed and ethyl acetate added. The mixture was neutralized with 1 N
NaHC03 and then stirred for 1 hour and filtered. The ethyl acetate layer was separated and washed with H20, brine and dried with Na2S04. 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 (RF 0.66) as a glass, m.p.
99°- I I 2°C. Anal. for C I8H21 C1N206S:
Calc'd: C,50.4; H,4.9: N,6.5;
Found: C,49.7; H,4.9; N,6.4:
Mass specwm (ES) 429.1 (M+H).
Reference Example 169 Methyl 3-Hydroxy-2-[(4-methoxybenzenesulfonyl)-(4-chloro-2-aminobenzyl)amino]propionate To a solution of 0.458 g ( 1 mmol) of methyl 3-hydroxy-2-[(4-methoxybenzenesulfonyl)-(4-chloro-2-nitrobenzyl)amino]propionate in 25 ml of ethanol and 25 ml of ethyl acetate was added 0.045 g of 10% Pd/C (wet - 50%
H20).
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 } propionate, and 0.470 g of 10% Pd/C (wet-50% H20) in 200 ml of ethyl acetate-ethanol ( I :1 ) was shaken in a Parr hydrogenator under 35 psi of hydrogen for 4 hours. The mixture was filtered through diatomaceous earth and the solvent removed to give 4.5 g of solid. The solid was chromatographed by HPLC
on a Waters Prep machine with a 4 x 30 cm silica gel column with a step gradient of hexane-ethyl acetate (9:1 to 6:4 to 1:1 to 0:100) to give 1.56 g of a glass, m.p.
110°-123°C.
Anal. for CI8H21CIN206S:
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 CH2Cl2, cooled in an ice bath was added 41.7 ml (0.3 mol) of triethylamine, followed by the dropwise addition of a solution of 20.65 g (0.1 mol) of 4 methoxybenzenesulfonyl chloride in 40 ml of CH2Cl2. The mixture was stirred at room temperature overnight and poured into water. The organic layer was separated and washed with 2 N citric acid, H20, 1 N NaHC03, brine and dried with Na2S04, The solvent was removed under vacuum to give 24.6 g of residue which was triturated with ethyl acetate to give 19.9 g of crystals, m.p. 59°-61°C.
Anal. for C1pH13NS05:
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 ~T,N-dimethylformamide was added dropwise a solution of 7.78 g (30 mmol) of N-(4-methoxybenzenesulfonyl)glycine, methyl ester in 40 ml of N,N-dimethyl-formamide. After gas evolution ceased, a solution of 6.80 g (32 mmol) of 2-nitrobenzyl bromide in 40 ml of N,N-dimethylformamide was added dropwise to the mixture. The mixture was then stirred at room temperature overnight under nitrogen and the solvent removed under vacuum. The residue was extracted with CH2Cl2 and the extract washed with H20, 2 N citric acid, H20, 1 N NaHC03, brine and dried with Na2S04, The solution was filtered through a thin pad of hydrous magnesium silicate and the filter pad washed with CH2Cl2. The filtrate was concentrated under vacuum to give 11.79 g of solid. Trituration with ethyl acetate gave 2.64 g (22%) of crystals, m.p. 114°C-116°C. Anal. for C17H18N20~7S:
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%j of product as crystals was obtained by chilling at 0°C and filtering the mother liquors.
Reference Example 172 Methyl 2-[(2-Aminobenzyl)-(4-methoxybenzenesulfonyl)amino]acetate (A) To a mixture of 2.15 g (5.45 mmol) of methyl-2-[(4-methoxy-benzenesulfonyl)-(2-nitrobenzyl)amino]acetate and 1.57 g (25 mmol) of ammonium formate in 10 ml of anhydrous methanol was added 0.42 g of 10% palladium on carbon. The mixture was stirred at room temperature for 1.5 hours and then filtered through diatomaceous earth. The filtrate was concentrated to dryness under vacuum and the residue diluted with H20 (25 ml) and extracted with CH2C12 (75 ml).
The extract was washed with brine, dried with Na2S04 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°-102°C. Anal. for C 17H2pN2O5S:
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% H20) and the mixture shaken in a Purr hydrogenator under 35 pounds per square inch of hydrogen for 4.5 hours at room temperature.
The mixture was filtered through diatomaceous earth and the filtrate concentrated to dryness under vacuum to give 4.0 g of crystals, m.p. 100°-102°C.
Reference Example 173 2-[(2-Aminobenzyl)-(4-methoxybenzenesulfonyl)amino]acetic Acid To a solution of 5.14 g ( 14.1 mmol) of methyl 2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino] acetate in 50 ml of methanol-tetrahydrofuran ( 1:1 ) was i 5 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 H20 and dried in a vacuum oven at room temperature to give 4.45 g (91 %) of crystals, m.p. 145°-147°C. Anal. for C16H18N205S:
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°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 CH2Cl2 was added 1.58 g ( 1 l .4 mol) of phenoxyacetyl chloride. The mixture was stirred at room temperature overnight and filtered.
The filtrate was washed with H20, 2 N citric acid, and brine and dried with Na2S04, The solvent was removed to give 2.4 g of crude methyl 2-{(4-methoxybenzenesulfonyl)-[2-(phenoxyacetylamino)benzyl]amino~acrylate av an oil. Anal. for C26H26N207S:
Calc'd: C,61.2; H,5.1; N,5.5;
Found: C,62.6; H,5.1; N,4.0;
Mass spectrum (ES) S I 1 (M+H).
To a 2.0 g (3.92 mmol) sample of the preceding compound in 1 S ml of methanol was added 0.494 g of anhydrous NaHC03 and the mixture stirred for 5 hours. The mixture was concentrated under vacuum and ethyl acetate and H20 were added to the residue. The mixture was filtered and the organic layer of the filtrate separated, washed with brine and dried with Na2S04, The solvent was removed to give 0.36 g of product as off white crystals, m.p. I51°-153°C.
Anal. for C26H26N20?S:
Calc'd: C,61.2; H,5.1; N,5.5;
Found: C,61.1; H,S.1; N,5.4;
Mass spectrum (ES) 511 (M+H).
Reference Example 175 3-hydroxymethyi-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-1 H-[ 1,4]benzodiazepine-3-carboxylate and 3 ml of borane-tetrahydroforan complex in tetrahydrofuran ( 1.0 M) was refluxed overnight. The solution was cooled to room temperature, diluted with methanol and the solvent removed. Methanol was added several times and, after each addition, the solvent was removed. To the residue was added 1 N NaHC03. The mixture was stirred for 45 minutes and then extracted with ethyl acetate. The extract was concentrated and then washed with H20, brine and dried with Na2S04, 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 (RF 0.26).
Crystallization from ethyl acetate gave 30 mg of white crystals. Anal. for C23H25N304S:
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-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate To a cooled (0°C) mixture of 1.0 g (2.54 mmol) of methyl 2-[(2-aminobenzyl}-(4-methoxybenzenesulfonyl) amino]-3-hydroxypropionate and 1.8 ml ( 12.68 mmol) of triethylamine in 10 ml of CH2C12 was added 0.957 g (5.58 mmol) of 2-methoxypyridine-3-carbonyl chloride in 4 ml of CH2C12. The solution was stirred at WO 99/37625 PC'f/US99/01325 room temperature overnight. diluted with H20 and CH2Cl2 and the organic layer separated. The organic Layer was washed with H20, 2 N citric acid, and brine and dried with Na2S04, 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 C25H25N307S:
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 H20, brine and the solvent removed under vacuum to give a mixture of product (50%) and starting material (50%).
Reference Example 178 Methyl 3-Hydroxy-2-[(4-methoxybenzenesulfonyl)-(5-methyl-2-nitrobenzyl)amino]propionate A solution of 23.14 g (0.08 mol) of methyl 3-hydroxy-2-(4-methoxybenzenesulfonylamino)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 S-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 H20 and extracted with S00 ml of ethyl acetate. The aqueous layer was extracted with an additional 200 ml of ethyl acetate. The combined extract was washed with H20, brine and dried with Na2S04, 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 (RF 0.38) of product as a yellow semi-solid. From a small scale run ( 1 mmol) the product was chromatographed twice on thick silica gel plates with hexane-ethyl acetate ( 1:1 ) to give 0.12 g of a yellow semi-solid. Anal. for C 19H22N2SOg:
Calc'd: C,52.0: H,5.1; N,6.4;
Found: C,51.7; H,S.1; N,6Ø
Reference Example 179 Methyl 3-Hydroxy-2-[(4-methoxybenzenesulfonyl)-(2-amino-5-methylbenzyl)amino]propionate To a solution of 3.4 g of methyl 3-hydroxy-2-[(4-methoxybenzenesulfonyl)-(5-methyl-2-nitrobenzyl)-amino]propionate in 200 ml of ethanol-ethyl acetate ( 1:1 ) was added 0.34 g of 10% palladium on carbon (wet - 50% H20). The mixture was then shaken in a Parr hydrogenator under 35 psi of hydrogen for 2.5 hours. The mixture was filtered through diatomaceous earth and the filtrate concentrated under vacuum to give 2.86 g of a brown oil. Anal. for C 19H24N206S:
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-nitrobenzyl)amino]propionate To a mixture of 1.75 g (4.68 mmol) of (D,L)~l-(4-methoxybenzenesulfonyl)-O-(2-tetrahydropyranyl) serine, methyl ester, 0.790 g (4.68 mmol) of 5-methyl-2-nitrobenzyl alcohol and 1.23 g (4.68 mmol) of triphenylphosphine -in 4.5 ml of anhydrous tetrahydrofuran was added dropwise (over 15 minutes) a solution of 0.815 g (4.68 mmol) of diethyl azodicarboxylate (DEAD) in 1 ml of tetrahydrofuran. The mixture was stirred at room temperature overnight and the solvent removed under vacuum. The residue was triturated with diethyl ether and the solid filtered off. The filtrate was concentrated to dryness under vacuum to give 4.67 g of solid. The solid was chromatographed on silica gel with hexane-ethyl acetate ( 1:1 ) to give 0.56 g of product (RF 0.48).
Reference Example 181 Methyl 1-Methoxyacetyl-4-(4-methoxybenzenesulfonyl) 7-methyl-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate To a cooled (0°C) mixture of 1.598 g (3.91 mmol) of methyl 3-hydroxy-2-[(4 methoxybenzenesulfonyl)-(2-amino-5-methylbenzyl)amino]propionate and 1.97 g (19.5) mmol) of triethylamine in 15 ml of dichloromethane was added 0.787 ml (8.60 mmol) of methoxyacetylchloride. The mixture was stirred at room temperature _77_ overnight. The mixture was then diluted with CH2Cl2 and washed with H20. 2 N
citric acid, H20. brine and dried with Na2S04. The solution was filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to give 1.94 g of crude methyl 2-{ [2-(methoxyacetylamino)-5-methylbenzyl]-(4-methoxy-benzene-sulfonyl)-amino}acrylate as a brown oil. Mass spectrum (ES) 463.4 (M+H).
To a solution of 1.62 g (3.5 mmol) of the preceding compound in 15 lnl of anhydrous methanol was added 0.382 g (4.50 mmol) of anhydrous NaHC03 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 H20, brine and dried with Na2S04. 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°10) of tan crystals, m. p. 122°-124°C. Anal. for C22H26N207S:
Calc'd: C,57.1; H,5.7; N,6.1;
Found: C,57.4; H,5.7; N,6Ø
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°C) mixture of 1.465 g (3.586 mmol) of methyl 3-hydroxy-2-[4-methoxybenzenesulfonyl)-(2-amino-5-methylbenzyl)amino]propionate and 2.49 ml (17.93 mmol) of triethylamine in 20 ml of CH2Cl2 was added 0.915 ml (7.89 mmol) of benzoyl chloride. The mixture was stored at room temperature overnight, diluted with CH2C12 and washed with H20, 2 N citric acid, H20, brine and dried with Na2S04, The solution was filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated under vacuum to give 1.8 g of crude methyl 2-[(2 benzoylamino-5-methylbenzyl)-(4-methoxybenzenesulfonyl)amino]acrylate as a brown oil. Anal. for C26H26N206S:
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 NaHC03 in 1.5 ml of .methanol to give an oil. Trituration with hexane (plus several drops of ethyl acetate) gave crystals, m. p. 58°-62°C.
_78_ Reference Example 183 Methyl 1-(traps-Crotonyl)-4-(4-methoxybenzenesulfonyl)-7-methyl 2,3,4,5-tetrahydro-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-methyl-benzyl)amino]propionate, 1.75 g ( 17.3 mmol) of triethylamine and 0.809 ml of trans-crotonyl chloride in 15 ml of CH2Cl2 was stirred overnight to give 1.52 g of methyl 2-{ [2-(traps-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 mlnol) of NaHC03 in 15 ml of methanol at room - temperature overnight. To the mixture was added 0.056 g of NaHC03 and the mixture was heated at 80°C for 3 hours and worked up as for Reference Example 181 to give a I .OS g of a yellow glass, m. p. 75°-84°C. Mass spectrum (ES) 459.4 (M+H).
Reference Example 184 1-(traps-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-(traps-crotonyl)-4-(4-methoxybenzenesulfonyl)-7-methyl-2,3,4,5-tetrahydro-1 H-( 1,4]benzodiazepine-3-carboxylate and 3.53 ml (3.53 mmol) of 1 N NaOH in 10 ml of tetrahydrofuran was stirred at room temperature for 3 hours. The solvent was removed under vacuum and the residue dissolved in H20 and the solution extracted with ethyl acetate.
The aqueous layer was acidified with 1N HCl (pH 2) and extracted with CH2C12. The CH2Cl2 extract was dried with Na2S04 and the solvent removed to give 1.06 g (after drying under vacuum) of solid, m. p. 101°-105° 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 1.18g (2.38 mml) of methyl 1-(benzoyl)-4-(4-methoxy-benzenesulfonyl)-7-methyl-2,3,4,5-tetrahydro- I H-( 1,4]benzodiazepine-3-carboxylate and 3.09 ml (3.09 mmol) of 1N NaOH in 10 ml of tetrahydrofuran was stored at mom temperature overnight and the solvent removed under vacuum. The residue was diluted with H20, extracted with ethyl acetate and the aqueous layer acidified with 2N
citric acid. The mixture was extracted with CH2Cl2 and the CH2Cl2 extracts were washed with H20, brine and dried with Na2S04, The solvent was removed to give 0.828 of a light yellow glass, m.p. 95°-100°C; Mass spectrum (ES) 481.4 (M+H).
Reference Example 186 Methyl 4-(4-Methoxybenzenesulfonyl)-1-(2-methoxyethyl)-2,3,4,5 tetrahydro-1 H-[ 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-I H-[ 1,4]benzodiazepine-3-carboxylate and 32 ml of borane in tetrahydrofuran ( I .0 M) was refluxed under nitrogen overnight.
Methanol was added and the solvent removed. To the residue was added 25 ml of CH2Cl2 and 25 ml of 2 N HCl and the mixture stirred at room temperature for I
hour.
The organic layer was separated and washed with H20 and concentrated to dryness.
The residue was triturated with ethyl acetate-hexane, cooled and filtered to give 1.2 g of white crystals, m.p. 86°-90°C; Mass spectrum (ES) 435.4 (M+H).
Anal. for C21 H26N206S:
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-IH[1,4]benzodiazepine-3-carboxylic acid A mixture of 1.0 g (2.3 mmol) of methyl 4-(4-methoxybenzenesulfonyl)-1-(2 methoxyethyl)-2,3,4,5-tetrahydro-IH-[1,4]benzodiazepine-3-carboxylate and 3.0 ml of 1 N NaOH in 10 ml of tetrahydrofuran was stirred at room temperature for 2 hours and the solvent removed. To the residue was added water and the mixture acidified with 1 N HCI. The mixture was extracted with ethyl acetate and the extract was washed with brine and dried with Na2S04, The solvent was removed and the residue triturated with ethyl acetate-hexane, cooled and filtered to give 0.65 g of white crystals, m.p. 164°-165°C; Mass spectrum (ES) 421.4 (M+H). Anal. for C2pH24N2O6S:
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]benzodiazepine-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]benzodiazepine-3-carboxylate and 4 ml of borane in tetrahydrofuran ( 1.0 M) was refluxed overnight and the solvent removed. To the residue was added 5 ml of CH2C12 and 5 ml of 2N HCI 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-hydroxypropionate 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 NaHC03 in 15 ml of methanol at room temperature for 16 hours and then was heated at 80°C for 2 hours. The solvent was removed and the residue extracted with ethyl acetate. The extract was washed with H20, brine, and dried (Na2S04). 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°-151°C. Anal. for C26H22C~307S:
Calc'd: C,52.1; H,3.7; N,4.7; C1,6.0; F,9.5;
Found: C,51.8; H,3.6; N,4.7; C1,5.9: F,9.4.
1.58g (2.64 mmol) of the preceding compound was stirred with 3.43 ml of 1 N
NaOH in 10 ml of tetrahydrofuran at room temperature for 2 hours and worked up as for Reference Example 104 to give 1.52 g of product. Crystallization from ethyl acetate-hexane gave 1.2 g of white crystals, m.p. 184°-186°C.
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- 1 H-[ 1,4]benzodiazepine-3-carboxylate, 21.2 ~1 of morpholine and 125.4 El of N,N-diisopropylethylamine in 3 ml of CH2Cl2 was stirred overnight at room temperature. An additional 2.2 El of morpholine was added and the solution stirred for 2 days at room temperature. The mixture was diluted with CH2C12 and washed with H20, brine and dried with Na2S04, The solvent was removed to give the product as a solid, Mass spectrum (ES) 504.3 (M+H). Anal.
for C24H29N30'7S:
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
[l,4Jbenzodiazepine-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,2 H,2 N2O2: C, 66.7; H, 5.6; N
13.0: Found:
C, 66.5: H, 5.4: N, 12.9; Mass spectrum (ES) 217.2 (M+H). A sample (7.02g) of this compound and 8.42 ml of SN 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 l.Sg of product. The two crops were combined to give 5.2g of 2-(1-pyrazolyl)benzoic acid, mp 140-142°C. To the preceding compound (2.07 g) in 5 ml CH2Cl2 (chilled in an ice bath )was added 11.1 ml of a 2 Molar solution of oxalyl chloride in CH2CI2 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 l.Sg of the compound of Reference Example 179 in 15 ml of CH2CI2 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-methylbenzyl }-amino]acrylate. This compound was cyclized with NaHC03 in methanol in the manner described in Reference Example 181 to give methyl 4-(4-methoxybenzenesulfonyl)-[2-(1-pyrazolyl)phenylcarbonyl]-7-methyl-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate (m.p. 240-242° 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)phenyl-carbonyl)-7-methyl-2,3,4,5-tetrahydro-1H[1,4]benzodiazepine-3- carboxylic acid (mp 149-151°C).
Reference Example 192 Methyl 4-(4-Methoxybenzenesulfonyl)-1-[2-(4-morpholino)phenylcarbonyl}-8-chloro-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate Ethyl 2-morpholinobenzoate prepared in the manner described in Tetrahedron, 53:7557, ( 1997) was refluxed with 10 N NaOH in tetrahydrofuran-ethanol (8:2) for 1.5 hrs to give 2-morpholinobenzoic acid, mp 156-157°C. A 1.8 g sample of this compound in 5 ml of CH2Cl2 (chilled) was added to a solution of 7.9 ml of oxalyl chloride in CH2C12 (2M) followed by the addition of 0.058 ml of N,N-.
dimethylformamide. The solution was stirred at room temperature for 6 hrs and the solvent removed. Toluene was added (2 times) and removed to give 2-(4-morpholino)benzoyl chloride as a yellow solid.
The preceding 2-(4-morpholino)benzoyl chloride was reacted with methyl 2-[(2-amino-4-chlorobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate in the manner described in Reference Examples 181 and 189, and the product was stirred with NaHC03 in methanol to give methyl 4-(4-methoxybenzenesulfonyl)-1-[2-(4-morpholino)phenylcarbonyl]-8-chloro-2,3,4,5-tetrahydro-1 H-[
1,4]benzodiazepine-3-carboxylate, as a white solid having a mp 100-105°C.
To 0.90g of this compound in 10 ml of tetrahydrofuran was added 1.95 ml of 1 N NaOH and the solution was stirred at room temperature overnight.
Acidification with 2N citric acid gave 0.82 g of 4-(4-methoxybenzenesulfonyl)-1-[2-(4-moiphalino)-phenylcarbonyl]-8-chloro-2,3,4,5-tetrahydro- I H-[ 1,4]benzodiazepine-3-carboxylic acid (mp 136-143 °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-carboxylate of Reference Example 12, 0.291 g of 4-ethoxybenzoyl chloride and 500 E,~l of triethylamine in 5 ml of CH2Cl2 was stirred at room temperature overnight. The mixture was diluted with CH=C12 and H20 and the CH2CI2 layer was separated and concentrated to dryness. The residue was triturated with ethyl acetate to give 0.276g of methyl 1-(4-ethoxybenzoyl)-4-(4-methoxy-benzenesulfonyl)-2,3,4,5tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate as white crystals, (mp 187-190°C).
A 0.47 g sample of this compound was hydrolyzed with 1.2 ml of 1~T NaOH in 4 ml of tetrahydrofuran. Dilution with H20 and acidification with 1 N HCl gave 0.40 g of the acid as a white solid, mp 144-152°C.
Reference Example 194 Methyl 4-(4-Methoxybenzenesulfonyl) -1-[2-chloro-4-(3-methyl-1-pyrazolyl)phenylcarbonyl}-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-lH-[1,4]benzodiazepine-3-carboxylate was reacted with 4-{3-methyl-1-pyrazolyl)-2-chlorobenzoyl chloride to give methyl 4-(4-methoxybenzenesulfonyl)-I-[2-chloro-4-(3-methyl- I-pyrazolyl)phenylcarbonyl]-2,3,4,5-tetrahydro- I H-[
1,4]benzo-diazepine-3-carboxylate as a white solid. Anal. for C29H27CIN4O6S:
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 1~1 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]benzodiazepine-3-carboxylic acid A mixture of 1.7 g of the compound of Reference Example 45 and 25 ml of borane in tetrahydrofuran ( 1.0 Molar) was refluxed under nitrogen overnight.
To the solution was added 5 ml of CH30H, CH2Cl2 (40 ml) and 30 ml of 2~1 HCl and the mixture stirred at room temperature for 1.5 hr. The organic layer was separated, washed with brine, dried with Na2S04 and the solvent removed. The residue was crystallized from ethanol-hexane to give 1.15g of methyl 1-benzyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-(1,4]benzodiazepine-3-carboxylate as white crystals, mp 120-122°C. A sample (1.0 g) of this compound was hydrolysed with 2.8 ml of 1 ~I 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°C).
Reference Example 196 Methyl 1-(2,4-Dimethoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate To a cooled (0°C) solution of 1.0 g (2.66 mmol) of 4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate from Reference Example 12 and 1.85 ml ( 13.3 mmol) of triethylamine in 8 ml of CH2C12 was added 1.17 g (6.65 mmol) of 2,4-dimethoxybenzoyl chloride. The mixture was stirred at room temperature overnight, diluted with CH2Cl2 and washed with 2 ~T citric acid. The organic layer was washed with H20, 1 ~1 Na2C03, brine and dried over Na2S04. 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-1H-[1,4]benzodiazepine-3-carboxylate as a white foam. Anal. for C27H28H208S:
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 1 ~l NaOH in 5 ml of tetrahydrofuran was stirred at room temperature for 1.5 hours. The solvent was removed and the residue diluted with water. The solution was acidified with 1 N HCI, chilled and filtered to give 0.70 g of 1-(2,4-dimethoxy-benzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1 H-( 1,4]benzodiazepine-3-carboxylic acid as a white solid. Anal. for C26H26N208S:
Calc'd: C,59.3; H,5.0; N,5.3;
Found: C,56.1; H,4.8; N,S.O;
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-carboxylate (Reference Example 12) and 4.63 ml (33.2 mmol) of triethylamine in 40 ml of CH2Cl2 cooled to 0°C
was added to 1.65 g ( 14.63 mmol) of chloroacetyl chloride. The solution was stirred at room temperature for 2 days, chilled to 0°C and 926 lil of triethylamine and 750 mg of chloroacetyl chloride were added thereto. The mixture was stirred at room temperature overnight, diluted with CH2C12 and H20. The insoluble solid was filtered off.
The organic layer of the filtrate was separated , washed with brine, dried with Na2S04 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]benzo-diazepine-3-carboxylate (Reference Example 91 ). Anal. for C20H21 C1N206S:
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 CH2C12 cooled to 0°C was added 1.2 ml (6.79 mmol) of N,N-diisopropylethylamine followed by the addition of 753.2 pl (6.79 mmol) of 1-methylpiperazine. The mixture was stirred at room temperature overnight, diluted with CH2Cl2, and washed with 2 ~T
citric acid, H20, 1 M NaHC03, brine and dried (Na2S04). The citric acid wash was made basic with saturated NaHC03 and then extracted with CH2Cl2. The extract was dried over Na2S04 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-IH-[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 1 N KOH in 5 ml of methanol was stirred at room temperature for 2 hours.
The solvent was removed under vacuum. To the residue was added toluene (2 times) and the solvent removed under vacuum after each addition. The solid was dried at 65°C
under vacuum for 6 hours to give 1.1 g of potassium 4-(4-methoxybenzenesulfonyl)-1 [2-(4-methylpiperazin-1-yl)acetyl]-2,3,4,5-tetrahydro-1H-[ 1,4]benzodiazepine-carboxylate as a white solid.
Reference Example 198 Methyl 1-Acetyl-4-(4-hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4] benzodiazepine-3-carboxylate To a cooled (0°) solution of 2.Og (4.78 mmol) of methyl 1-acetyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate in 14 ml of CH2 C12 was added dropwise 143.3m1 ( 14.3mmo1) of a 1.0 molar solution of BBr3 in CH2 C12 . The mixture was stirred at room temperature for 1.5 hours.
Ice and H20 were added to the reaction mixture and the insolubles filtered off. The filtrate was diluted with CH2C12 and H20 and the CH2Cl2 layer separated, washed with brine and dried (Na2 S04). 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,9H2oN2O6S: 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 CH2CI2 chilled to 0°C, was added slowly 16.4 ml ( 16.44 mmol) of 1.0 molar solution of boron tribromide in CH2C12. The mixture was stirred at room temperature overnight and diluted with CH2Cl2. The mixture was filtered and the solid washed with CH2Cl2. and H20. The filtrate was diluted with H20 and the organic layer separated.
The solvent was removed under vacuum and the solid chromatographed on silica gel with hexane-ethyl acetate ( 1:1 ) as solvent to give 0.80 g of off white foam;
Mass Spectrum (ES) 473.5 (M+H); Anal. Calc'd for C22 H2o N206 S2: C, 55.9; H, 4.3;
N, 5.9. Found: C, 54.5; H, 4.4; N, 5.5.
_87_ Reference Example 200 Methyl 1-Benzoyl-4-(4-hydroxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-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]benzodiazepine in 50 ml of CH2C12 cooled to 0°, was added slowly 40.8 ml (40.8 mmol) of a 1.0 molar solution of BBr3 in CH2C12, The mixture was stirred under nitrogen at room temperature overnight. Ice and H20 were added and the mixture diluted with CH2C12. The organic layer was separated and the aqueous layer extracted with ethyl acetate. The combined organic extracts {CH2CI2+ethyl acetate) were concentrated under vacuum and the residue dissolved in ethyl acetate. The solution was washed with H20, brine and dried (Na2S04). 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 C24H22N206S~ C, 61.8; H, 4.8; N, 6Ø
Found: C, 61.3; H, 4.6; N, 5.8.
Utilizing the method described in Reference Examples 191-193, the following methyl-1-substituted-4-hydroxybenzenesulfonyl}-2,3,4,5-tetrahydro-1 H-[ 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 BBr3 in CH2C12 (solution) gave, after chromatography on silica with ethyl acetate-hexane (1:1), 0.82g of a white foam; Mass spectrum (ES) 440.9 (M + H).
Reference Example 203 Methyl 4-(4-Hydroxybenzenesu~fonyl)-1-(3-pyridinylcarbonyl) 2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate _88_ 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-tetrahydro-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-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate Reference Example 210 Methyl 4-(4-Hydroxybenzenesulfonyl)-1-(2-methyl-3-fiuorobenzoyl)-2,3,4,5-tetrahydro-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 WO 99/37625 PCT/US99/o1325 Reference Example 212 Methyl 4-(4-Hydroxybenzenesulfonyl)-1-(2-trifluoromethylbenzoyl) 2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate Reference Example 213 Methyl 1-(2-Chloro-6-trifluoromethylbenzoyl)-4-(4 hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1 H-[ 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-(2 methylbenzoyl)-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-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylateReference 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-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate Reference Example 221 Methyl 1-(2-Chlorobenzoyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5 tetrahydro-1 H-[ 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-tetrahydro-1 H-[ 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 I-(2,3-Dichiorobenzoyl)-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-tetrahydro-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-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate Reference Example 230 Methyl 4-(4-Hydroxybenzenesulfonyl)-1-(4-methyl-2-thienylcarbonyl) 2,3,4,5- tetrahydro-1H-[1,4)benzodiazepine-3-carboxylate Reference Example 231 Methyl 1-(3-Chloro-2-thienylcarbonyl)-4-( hydroxybenzenesulfonyl)-2,3,4,5- tetrahydro-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.Og (6.38 mmol) of methyl 1-(2 furanylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1 H-[ 1,4]benzodiazepine-3-carboxylate in., 15 ml of CH2C12 (cooled to 0°C ) was added dropwise 12.8m1 (2.8 mmol) of BBr3 in CH2C12 (1.0 M in CH2C12).The mixture was stirred at room temperature for 3 days, diluted with CH2C12 and then ice was added. The organic layer was separated, washed with H20, brine 'and dried (Na~S04). 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 0.72g of methyl 1-(2- furanyl-carbonyl)-4-hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4)benzodiazepine-carboxylate as a white solid, mp 204-206°C; Anal Cal'd for C22H2oN207S:
C, 57.9; H, 4.2; N, 6.1. Found: C,57.2; H,4.3; N, 6.O.;Mass spectrum (ES) 457.1 (M+H).
Reference Example 233 Methyl 4-(4-Hydroxybenzenesulfonyl)-1-(3-methyl-2-furanylcarbonyl)-2,3,4,5- tetrahydro-1H-[-1,4]benzodiazepine-3-carboxylate Reference Example 234 Methyl 4-(4-Hydroxybenzenesulfonyl)-1-(4-methyl-2-furanylcarbonyl)-2,3,4,5-tetrahydro-1H-(1,4]benzodiazepine-3-carboxylate Reference Example 235 Methyl 1-(5-Chloro-2-furanylcarbonyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5- tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate Reference Example 236 Methyl 1-(5-Chloro-2-thienylcarbonyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodeiazepine-3-carboxylate Reference Example 237 Methyl 1- Propionyl-4-(4-hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodeiazepine-3-carboxylate Reference Example 238 Methyl 1-Hexanoyl-4-(4-hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-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 24 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-hydroxybenzenesulfonyi)- 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..44g( 10 mmol) of methyl 1-cyclopropylcarbonyl-4-(4-methoxybenzenefulfonyl)-2,3,4-tetrahydro-1H-[1,4]benzodiaxepine -3-carboxylate in 25 ml of CH2C12 chilled to 0~~ C was added dropwise 22 ml (22 mmol) of BBr3 in CH2Cl2 ( 1.0 molar solution). The mixture was stirred overnight, cooled and diluted with ice and H20. Dichloromethane was added and the organic layer separated and washed with H20, brine and dried (Na2S04). 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-hydroxybenzene-sulfonyl)-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-tetrahydro-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-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid from Reference Example 9 in 5 ml of CH2C12, was added 0.556 ml ( 1. I 1 mmol) of 2.0 M oxalyl chloride in CH2Cl2 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 H20. The mixture was stirred at room temperature overnight and diluted with CH2Cl2. The mixture was washed with 2 N citric acid, H20, 1 N NaHC03, brine and dried with Na2S04. The solvent was removed under vacuum to give 0.29 g of solid. Chromatography on thick layer silica gel plates with WO 99/3?625 PCT/US99/01325 ethyl acetate-methanol (9:1) gave 60 mg of solid, m.p. 128-130°C. Anal.
for C25H22F3N306S:
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- I H-[ 1,4]benzodiazepine-3-carboxylic acids.
Example 2 4-(4-Methoxybenzenesulfonyl)-1-(4-methylphenylsulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Solid. Anal. for C24H2gN307S2:
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]benzodiazepine-3-carboxylic acid, Hydroxyamide Solid. Anal. for C 18H21 N307S2:
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-[l,4Jbenzodiazepine-3-carboxylic acid, Hydroxyamide Solid. Anal. for C24H25N3~8S2:
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]benzodiazepine-3-carboxylic acid, Hydroxyamide White solid. Anal. for C24H23N3~6S:
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]benzodiazepine-3-carboxylic acid, Hydroxyamide White crystals. m.p. 195-197°C. Anal. for C19H21N306S:
Calc'd: C,54.4; H,S.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°C. Anal. for C23H22N4O6S:
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-lH-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide White solid. Anal. for C22H21 N306S2:
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]benzodiazepine-3-carboxylic acid, Hydroxyamide White crystals, m.p. 143-145°C. Anal. for C2pH23N3O7S:
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 C2pH25N30'752:
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-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Off white solid. Anal. for C25H24FN306S:
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 C26H27N306S:
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°C. Anal. for C23H22N406S:
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-tetrahydro-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°C. Anal. for C3pH27N306S:
Calc'd: C,64.6; H,4.9; N,7.5;
Found: C,63.7; H,4.6; N,7.1.
WO 99/37625 PC'T/US99/01325 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°C. Anal.
for C30H27N306S:
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-[l,4Jbenzodiazepine-3-carboxylic acid, Hydroxyamide Example 17 4-(4-Methoxybenzenesulfonyl)-1-(2-methyl-3-fluorobenzoyl)-2,3,4,5-tetrahydro-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]benzodiazepine-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-tetrahydro-tH-[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-tetrahydro-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-tetrahydro-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°C. Anal. for C24H21C12N306S:
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 IO 1-(2,3-Dichlorobenzoyl)-4-(4-methoxybenzenesulfon~yi)-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]benzodiazepine-3-carboxylic acid, Hydroxyamide Example 35 1-(4-Chloro-2-methoxybenzoyl)-4-(4-methoxybenzenesutfonyl)-2,3,4,5 tetrahydro-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-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Example 39 1-(3-Chloro-2-thienylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-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 C22H21N3~7s:
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 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Example 42 4-(4-Methoxybenzenesulfonyl)-1-(4-methyl-2-furanylcarbonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Example 43 1-(5-Chloro-2-furanylcarbonyl)-4-(4-methoxybenzenesulfonyt)-2,3;4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Example 44 1-(5-Chloro-2-thienylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Example 45 1-Propionyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Example 46 1-Hexanoyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-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-(traps-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-1 H
[1,4)benzodiazepine-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-1 H
[1,4]benzodiazepine-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 C21 H23N306S:
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-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide off white solid. Anal. for C24H29N3O6S:
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]benzodiazepine-3-carboxylic acid, Hydroxamide A mixture of 0.70 g (1.37mmol) of methyl 4-(4-methoxybenzenesulfonyl)-1 (phenoxyacetyl)-2,3,4-S-tetrahydro-1H[1,4]benzodiazepine-3-carboxylate and 1.8 ml ( 1.78 mmol) of 1 N NaOH in 3 ml of tetrahydrofuran was stirred at room temperature for 2 hours. The mixture was diluted with 3 ml of H20 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°-191°C.
To a 0.496 g (1 mmol) sample of the preceeding compound in 5 ml of CH2C12 cooled to 0°C, was added 1 ml (2 mmol) of oxalyl chloride followed by the addition of 77.4 pl ( 1 mmol) of ~1,~T-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 H20 and 836.3 pl (5 mmol) of triethylamine. The mixture was stirred for 20 minutes and then cooled to 0°C (referred to as solution B}. The cooled solution B was added to the cooled (0°C) and stirred solution A and then this mixture was allowed to warm to room temperature and was stirred overnight. The mixture was concentrated under vacuum, diluted with CH2C12 and washed with H20, 2N citric acid, 1 N NaHC03, and brine and dried with Na2S04, The solvent was removed and the residue crystallized from hexane-ethyl acetate (3:97) to give 0.396 g of white crystals, m.p.
I59°-163°C. Anal.
for C25H25N30'7S:
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-methoxyacetyl-4-(4-methoxybenzenesulfonyl)-7-methyl-2,3,4,5-tetrahydro-I H-[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 H20 and extracted with ethyl acetate. The aqueuous layer was acidified with IN HCl and then extracted with CH2C12. The CH2C12 layer was dried over Na2S04 and the solvent removed to provide a solid. This material was dried in a vacuum oven and given 1.06 of solid, m.p. 101-105°C.
A 1.02 g (2.27 mmol) sample of 1-methoxyacetyl-4.-(4-methoxy-benzenesulfonyl)-7-methyl-2,3-4,5-tetrahydro-1H-[ 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 CH2Cl2 was cooled at 0°C and 0.351 ml (4.52 mmol) of N,N-dimethylformamide (DMF) was added dropwise. The mixture was stirred for 5 minutes and the potassium salt ( 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°C) and this mixture was added to a cooled (0°C) mixture of 0.628 g (9.04 mmol) of hydroxylamine hydrochloride, 1.89 ml ( 13.56 mmol) of triethylamine in 1 ml of tetrahydrofuran-water (8:2). The mixture was stirred and chilled at 0°C for 10 minutes and then stirred at room temperature overnight. The solvent was removed under vacuum and the residue diluted with CH2C12-H20 and acidified with 2 N
citric acid (pH 4). The CH2C12 layer was separated and washed with H20. 1N NaHC03.
H20, and brine and dried with Na2S04, The solution was filtered through a thin pad of hydrous magnesium silicate and the solvent removed under vacuum to give 0.73 g of solid. Crystallization from ethyl acetate gave 0.32 g of crystals, m.p.
146°-148°C.
Example 60 1-Benzoyl-4-(4-methoxybenzenesulfonyl)-7-methyl-2,3,4,5-tetrahydro 1H[1,4]benzodianzepine-3-carboxylic acid, Hydroxyamide In the manner described in Example 59, 0.83 g ( 1.71 mmol) of 1-benzoyl-4-(4-methoxybenzene-sulfonyl)-7-methyl-2,3,4,5-tetrahydro-1 H[ 1,4]benzodianzepine-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 CH2C12 0.20 g. of yellow solid, m.p. 137°-139°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°-186°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° dec;
Mass spectrum (ES) 601 (M+H).
Example 62 4-(4-Methoxybenzenesulfonyl)-1-(2-methoxyethyl)-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-methoxy-benzenesulfonyl )-1-(2-methoxyethyl)-2,3,4,5-tetrahydro-1 H-[ 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 C2pH25N3O6S:
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-tetrahydro-1 H-[ 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,2 H,2 N2O2: C, 66.7; H, 5.6; N
13:0: Found:
C, 66.5: H, 5.4: N, 12.9; Mass spectrum (ES) 217.2 (M+H). A sample (7.02g) of this compound and 8.42 ml of SN 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 l.Sg of product. The two crops were combined to give 5.2g of 2-(1-pyrazolyl)benzoic acid, mp 140-142°C. To the preceding compound (2.07 g) in 5 ml CH2C12 (chilled in an ice bath )was added 11.1 ml of a 2 Molar solution of oxalyl chloride in CHZCh 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 l.Sg of the compound of Reference Example 179 in 15 ml of CH2Cl2 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-methylbenzyl}-amino]acrylate. This compound was cyclized with NaHC03 in methanol in the manner described in Reference Example 181 to give methyl 4-(4-methoxybenzenesulfonyl)-[2-( 1-pyrazolyl)phenylcarbonyl]-7-methyl-2, 3,4,5-tetrahydro-1 H-[
1,4]benzodiazepine-3-carboxylate, m.p. 240-242° 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)phenyl-carbonyl)-7-methyl-2,3,4,5-tetrahydro-1H(1,4]benzodiazepine-3- carboxylic acid, mp 149-151 °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°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 10 N NaOH in tetrahydrofuran-ethanol (8:2) for 1.5 hrs to give 2-morpholinobenzoic acid, mp 156-157°C. A 1.8 g sample of this compound in S ml of CH2C12 (chilled) was added a solution of 7.9 ml of oxalyl chloride in CH2Cl2 (2M) followed by the addition of 0.058 ml of N, N-dimethylformamide.
The solution was stirred at room temperature for 6 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-hydroxypropionate and the product was stinred with NaHCOg in methanol to give methyl 4-(4-methoxybenzenesulfonyl)-1-[2-(4-morpholino)phenylcarbonyl]-8-chloro-2,3,4,5-tetrahydro-1H-[ 1,4]benzodiazepine-carboxylate, as a white solid having a mp 100-105°C.
To 0.90g of this compound in 10 ml of tetrahydrofuran was added 1.95 ml of 1 ~1 NaOH and the solution was stirred at room temperature overnight.
Acidification with 2~T citric acid gave 0.82 g of solid, mp 136-143°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 (0.78g) was converted to the potassium salt and reacted first with oxalyl chloride and then with hydroxylamine as described in Example 63 to give 0.276g of product as a light yellow solid, mp 132° C.
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- I H-( 1,4] benzodiazepine-3-carboxylate of Reference Example 12, 0.291 g of 4-ethoxybenzoyl chloride and 500 E.11 of triethylamine in 5 ml of CH2Ch was stirred at room temperature overnight. The mixture was diluted with CH~Ch and H20 and the CH2Cl2 layer was separated and concentrated to dryness. The residue was triturated with ethyl acetate to give 0.2768 of methyl 1-(4-ethoxybenzoyl)-4-(4-methoxybenzene-sulfonyl)-2,3,4,Stetrahydro-1H-[1,4]benzodiazepine-3-carboxylate as white crystals, mp 187-190°C.
A 0.47 g sample of this compound was hydrolyzed with 1.2 ml of IN NaOH in 4 ml of tetrahydrofuran. Dilution with H20 and acidification with 1N HCl gave 0.40 g of the acid as a white solid, mp 144-152°C. The preceding compound (0.358) was converted to the above-titled compound in the manner described in Example 1 to provide 0.1958 of solid, mp 136-142°C.
Example 66 4-(4-Methoxybenzenesulfonyl) -1-[2-chloro-4-(3-methyl-1-pyrazolyl)phenylcarbonyl}-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-lH-[1,4]benzodiazepine-3-carboxylate 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)phenylcarbonyl]-2,3,4,5-tetrahydro-1 H-[
1,4Jbenzo-diazepine-3-carboxylate as a white solid. Anal. for C29H27C1N4O6S:
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 1 N 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 I to give the product as white crystals, mp 189-191°C.
Example 67 1-Benzyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H
[1,4]benzodiazepine-3-carboxylic acid, Hydroxylamide A mixture of 1.7 g of the compound of Reference Example 45 and 25 ml of S borane in tetrahydrofuran ( 1.0 Molar) was refluxed under nitrogen overnight. To the solution was added 5 ml of CH30H, CH2Cl2 (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 Na2S04 and the solvent removed. The residue was crystallized from ethanol-hexane to give 1.15g of methyl 1-benzyl-4-(4 methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1 H-[ 1,4]benzodiazepine-3-carboxylate as white crystals, mp 120-122°C. A sample ( 1.0 g) of this compound was hydrolysed with 2.8 ml of 1 N NaOH in 7 ml of tetrahydrofuran as described in Reference Example 104 to give 0.64 g of the 2,3,4,5- tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid derivative as white crystals, mp 183-185°C.
A 0.55 g sample of this compound was converted to the acid chloride which was reacted with hydroxylamine as described in Example 1 to give the product as a light brown foam; Mass spectrum (ES) 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-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Example 69 4-(4-Methoxybenzenesulfonyl)-1-(4-(3-thienyl)phenyl-carbonyl) 2,3,4,5-tetrahydro-1H-[1,4)benzodiazepine-3-carboxylic acid, Hydroxyamide Example 70 4-(4-Methoxybenzenesulfonyl)-1-[2-(3-pyrazol)phenyl-carbonylJ
2,3,4,5-tetrahydro-1H-[l,4Jbenzodiazepine-3-carboxylic acid, Hydroxyamide Example 71 1-(2,4-Dimethoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[l,4Jbenzodiazepine-3-carboxylic acid, Hydroxyamide To a cooled (0°C) solution of 1.0 g (2.66 mmol) of 4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1 H-[ 1,4]benzodiazepine-3-carboxylate from Reference Example 12 and 1.85 ml ( 13.3 mmol) of triethylamine in 8 ml of CH2Cl2 was added 1.17 g (6.65 mmol) of 2,4-dimethoxybenzoyl chloride. The mixture was stirred at room temperature overnight, diluted with CH2CI2 and washed with 2 N citric acid. The organic layer was washed with H20, 1 N Na2C03, brine and dried over Na2S04. 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-1H-[l,4Jbenzodiazepine-3-carboxylate as a white foam. Anal. for C2~H2gH20gS:
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 1 N NaOH in 5 ml of tetrahydrofuran was stirred at room temperature for 1.5 hours. The solvent was removed and the residue diluted with water. The solution was acidified with 1 N HCI, chilled and filtered to give 0.70 g of 1-(2,4-dimethoxy-benzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1 H-[
1,4]benzodiazepine-3-carboxylic acid as a white solid. Anal. for C26H26N208S:
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 CH2Cl2 (chilled to 0°C) was added to 1.52 ml (3.04 mmol) of oxalyl cholride (2.0 M solution in CH2Cl2). To the solution was added 118 pl ( 1.52 mmol) of N,N-dimethylformamide and the solution stirred at 0°C for 1.5 hours (Mixture A). A mixture of 0.422 g (6.08 mmol) of hydroxylamine hydrochloride, 1.27 ml (9.14 mmol) of triethylamine, 5 ml of N,N-dimethyformamide and 0.5 ml of water was prepared in a separate flask, stirred for 20 minutes at room temperature and then cooled to 0°C in an ice bath (Mixture B).
S 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 CH2C12 and 2 N citric acid added. The organic layer was separated, washed with H20, brine and dried with NaZS04. The solvent was removed and the residue crystalized from ethanol to give 0.40 g of product as white crystals, mp 189-191°C. Anal. for C26H2~N30gS:
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-tetrahydro-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-carboxylate (Reference Example 12) and 4.63 ml (33.2 mmol) of triethylamine in 40 ml of CH2C12 cooled to 0°C
was added to 1.65 g ( 14.63 mmol) of chloroacetyl chloride. The solution was stirred at room temperature for 2 days, chilled to 0°C and 926 ~.~1 of triethylamine and 750 mg of chloroacetyl chloride were added thereto. The mixture was stirred at room temperature overnight, diluted with CH2C12 and H20. The insoluble solid was filtered off.
The organic layer of the filtrate was separated , washed with brine, dried with Na2S04 and filtered through diatomaceous earth. The solvent was removed and the residue triturated with ethyl acetate and a trace of ethanol. Chilling and filtering gave 0.75 g of methyl 1-(chloroacetyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1 H-[
1,4J-benzodiazepine-3-carboxylate (Reference Example 91 ). Anal. for CZpH2 i CIN206S:
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 CH2C12 cooled to 0°C was added 1.2 ml (6.79 mmol) of N,N-diisopropylethylamine followed by the addition of 753.2 Irl (6.79 mmol) of 1-methylpiperazine. The mixture was stinted at room temperature overnight, diluted with CH2Cl2, and washed with 2 N
citric acid, H20, 1 M NaHC03, brine and dried (Na2S04). The citric acid wash was made basic with saturated NaHC03 and then extracted with CH2C12. The extract was dried over Na2S04 and the solvent removed under vacuum to give 1.10 g of methyl 4-(4-methoxybenzenesulfonyl)-I-[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 1 N KOH in 5 ml of methanol was stirred at room temperature for 2 hours.
The solvent was removed under vacuum. To the residue was added toluene (2 times) and the solvent removed under vacuum after each addition. The solid was dried at 65°C
under vacuum for 6 hours to give 1.1 g of potassium 4-(4-methoxybenzenesulfonyl)-1-[2-(4-methylpiperazin- I -yl)acetyl]-2,3,4, 5-tetrahydro-1 H-[
1,4]benzodiazepine-3-carboxylate as a white solid.
To 1.85 mI (3.69 mmol) of a 2.0 molar solution of oxalyl chloride in CH2C12, cooled to 0°C, was added slowly 286 Erl (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 CH2C12. The mixture was stirred under nitrogen for two hours (Mixture A).
In a separate flask, a mixture of 0.514 g (7.4 mmol) of hydroxylamine hydrochloride, 1.55 ml ( 11.1 mmol) of triethylamine in tetrahydrofuran-water (4:1 ) was stirred at room temperature and then cooled to 0°C and stirred for 5 minutes. To this mixture was added the cooled (0°C) Mixture A and then the resulting solution stirred at room temperature overnight. The mixture was concentrated under vacuum and CH2Cl2 added. The organic layer was separated and concentrated to dryness to give 1.4 g of product. The product was chromatographed on thick layer silica gel plates with CH2C12-CH30H-NH40H(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 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide A. N-f4-(4-Chlorophenyloxvbenzenesulfonvl)serine. methyl ester (methyl-3-hydroxy-2-f4-(4-chloro hp enoxv)benzenesulonylaminolpro in onate~. 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 CH2C12, chilled to 0°C, was added 6.063 g (20 mmol) of 4-(4-chlorophenyloxy)benzenesulfonyl chloride. The mixture was stirred at room temperature overnight, diluted with CH2C12 and washed with 2 N citric acid, H20, 1 N
NaHC03, brine and dried with Na2S04. The solvent was removed to give an oil which was dried under vacuum at 68°C to give a solid. Trituration with hexane-ethyl acetate gave 5.85 g of off white crystals, mp 90-94°C. Anal. for C16H16C1N06S:
Calc'd: C,49.8; H,4.2; N,3.6;
Found: C,50.1; H,4.1; N,3.8;
Mass Spectrum (ES): 385.9 (M+H).
B. Met yl 3-hyd, roxy-2-f f4-(4-chloronhen~y)benzene-sulfony1112-nitrobenzrLl)amino}rro nn 'ovate. To a cooled (0°C) solution of 5.5 g (14.76 mmol) of compound from part A in 60 ml of dry N,N-dimethylformamide was added (portionwise), 0.682 g ( 17 mmol) of sodium hydride (60% in oil). After gas evolution ceased, 3.7 g ( I 7 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 H20, brine and dried with Na2S04. 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 C23H21C1NZOgS:
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. Mme'~,Y12-{,(2-aminobenzyly-[4-(4-chlorQphenyloxy)benzene-~ulfon lv laming-3-~,ydro~ynropionate. 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 H20) 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°C under vacuum to give 2.63 g of an off white solid. Anal. for C23H23C1N206S:
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. yl 2-(f4-(4-chloropheny c~ylbenzenesulfon y.~[2-(metho~~
ace lamino)benzyllamino )~ acrvlate. To a mixture of 0.80 g ( 1.63 mmol) of the compound from Part C and 1.14 ml (8.15 mmol) of triethylamine in 8 ml of CH2C12, cooled to 0°C, was added 328 lrl (3.58 mmol) of methoxyacetyl chloride.
The mixture was stirred at room temperature overnight, diluted with CH2CI2 and washed with H20, 2 N citric acid, brine and dried (Na2S04). 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 C26H25C1N20~S:
Calc'd: C,57.3; H,4.6; N,5.1;
Found: C,56.?; H,4.7; N,5.0;
Mass Spectrum (ES): 545.2 (M+H).
E. Methyl 4-f4-(4-chlorophen loxy)benzenesulfonvll-1-(methox3r~ce~rl)-2.3.4.5-tetrah~rdro-1H-[1.41benzodiazenine-3-carboxylate. A mixture of 0.45 g (0.827 mmol) of the compound from part D and 0.09 g of anhydrous NaHC03 in 5 ml of dry methanol was stirred at room temperature overnight. The solvent was removed, ethyl acetate added and the mixture washed with H20, brine and dried with Na2S04.
The solvent was removed to give 0.43 g of an off white solid. Anal. for C26H25C1N20~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-f(4-Chlorophenyloxy)benzenesulfon l~methoxvacetyl)-2 3 4 5-~ydro-1H-f 1.4]benzodiaz~ine-3-carboxylic acid. A mixture of 0.52g (0.956 mmol) of the compound from Part F and 1.2 ml ( 1.2 mmol) of 1 N 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 H20 and extracted with ethyl acetate.
The extract was washed with brine and dried over Na2S04. The solvent was removed and the product dried at 65°C under vacuum to give 0.49 g of off white foam. Anal. for C25H23C1N20~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 CH2C12 cooled to 0°C was added 850 Nl ( 1.69 mmol) of oxalyl chloride (2.0 molar solution in CH2Cl2) and then 50.2 pl (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 triethylamine, 4 ml of tetrahydroforan and 0.4 ml of H20 was stirred for 15 minutes and cooled to 0°C. To this mixture was added the cooled (0°C) Solution A and the mixture was stirred at room temperature overnight. The mixture was concentrated under vacuum, diluted with ethyl acetate and washed with H20, 1N NaHC03 2 N
citric acid, brine and dried over Na2S04. 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 C25H24C1N30~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)benzenesulfonylJ-1-(2-thienylcarbonyl) 2,3,4,5-tetrahydro-1H[l,4Jbenzodiazepine-3-carboxylic acid, Hydroxyamide The following reactions were carried out in the manner described for Example 73, Parts D, E, and F. A 1.4 g (2.85 mmol) sample of methyl 2-{(2-aminobenzyl)-[4-(4-chlorophenyloxy)benzenesulfonyl]amino}-3-hydroxypropionate (the compound of Part C of Example 73) was reacted with 1.25 g (8.55 mmol) of 2-thiophenecarbonyl chloride to give 1.7 g of methyl 2-{ [4-(4-chlorophenyloxy)benzyenesulfonyl]-[2-(2-thienylcarbonyl-amino)benzyl]amino } acrylate as a yellow oil.
Mass Spectrum (ES): 583.1 (M+H).
The reaction of 1.5 g of the preceding compound with 0.251 g of NaHC03 in 8 ml methanol gave 1.6 g of methyl 4-[4-(4-chlorophenyloxy)benzenesulfonyl)-1-(2-thienylcarbonyl)-2,3,4,5-tetrahydro-lH-[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 1 N NaOH
in 6 ml of tetrahydroforan gave 1.2 g of 4-[4-(4-chlorophenyloxy)benzenesulfonyl]-I-(2-thienylcarbonyl)-2,3,4,5-tetrahydro-IH-[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 Nl (6.10 mmol) of benzoyl chloride to give I.25 g of methyl 2-{[4-(4-chlorophenyloxy)benzenesulfonyl]-[2-(benzoylamino)benzyl]amino}acrylate as a brown oil.
Mass Spectrum (ES): 577.2 (M+H).
The reaction of 1. I g ( 1.9 mmol) of the preceding compound with 0.208 g (2.48 mmol) of NaHC03 in 8 ml of methanol gave 1.1 g of methyl 4-[4-(4-chlorophenyloxy)benzenesulfonyl]-1-(benzoyl)-2,3,4,5-tetrahydro-1 H-[I,4]benzodiazepine-3-carboxylate as a brown oil.
Mass Spectrum (ES): 577.1 (M+H).
A 1.0 g ( 1.73 mmol) sample of the preceding compound was hydrolysed with 2.3 ml (2.75 mmol) of 1 N NaOH in 5 ml of tetrahydrofuran to give 0.50 g of 4-[4-(4-chlorophenyloxy)benzenesulfonyl]-1-(benzoyl)-2,3,4,5-tetrahydro-IH-[1,4]benzodiazepine-3-carboxylic acid as a white foam. As described for Example 73, 0.460 g (0.817 mural) 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 CH2C12 was added a solution of 10.78 g (40 mmol) of 4-(4-pyridinyloxy)benzenesulfonyl chloride in 50 ml of CH2C12. The mixture was stirred at room temperature overnight, diluted with 50 ml of CH2CI2 and the solution washed with H20, 1N NaHC03, 2 N citric acid, brine and dried (with Na2S04). The solvent was removed under vacuum to give a solid. The aqueous 2 N citric acid wash was made basic with saturated NaHC03 and then extracted with CH2Cl2. The solvent was removed to give a solid. The two crops of solid were combined, washed with H20 and then hexane. The solid was dried at 80°C
to give 10.95 g of methyl 3-hydroxy-2-[4-(4-pyridinyloxy)-benzenesulfonylamino]
propionate as white crystals, mp. 137-139°C.
B . To a solution of 4.5 g ( 12,.78 mmol) of the product from Part A in 35 ml of dry N,N-dimethylformanude cooled to 0°C was added (portionwise) 0.662 g (16.61 mmol) of NaHCOg (60% in oil). The mixture was stirred 15 minutes and 3.59 g ( 16.61 mmol) of 2-nitrobenzylbromide in 1 S ml of N,N-dimethylfonmamide was added hereto. The mixture was stirred at room temperature overnight, diluted with ethyl acetate (200 ml) and H20 (100 ml). The organic layer was separated and washed with H20, brine and dried (with Na2S04). 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.
WO 99/37625 PCTIUS99/Ot3Z5 Example 77 1-(Benzoyl)-4-(4-pentyloxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H
[1,4]-benzodiazepine-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 ~tL (4.82 mmol) of I-pentanol and 1.5 g (3.22 mmol) of methyl I-(benzoyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate. To this stinred mixture was added 259 l,tL (4.82 mmol) of diethyl azodicarboxylate and the mixture was stirred overnight. The solvent was removed and the residue chromatographed on silica gel with ethyl acetate-hexane ( 1:3) as solvent. Concentration of the fractions containing product gave 1.59 g of a white solid; mp 170-172°C; Anal. Calcd for C29H32N2O6: 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°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 CH2Cl2 was added 4.8 ml (9.6 mmol) of oxalyl chloride in CH2CI2 (2.0 molar) and the solution chilled to 0°C. To the chilled solution was added 740 N.L, (9.56 mmol) of N,N-dimethylformamide and 1.34g (2.39 mmol) of the preceding potassuim salt in 5 ml of dry N,N-dimethylformamide. The mixture was stirred at room temperature for 1.5 hr, cooled to 0°C ,and added to a chilled (0°C) solution of 2.2 ml (35.9 mmol) of 50% aqueous hydroxylamine in 10 ml of tetrahydrofuran. The mixture was stirred at room temperature overnight and diluted with CH2Cl2. The CH2Cl2 layer was separated, washed with H20 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 H20 and once with brine and dried (Na2S04). The solvent was removed and the residue dried at 85°C under vacuum overnight to give 0.96 g of product as a white foam; Mass spectrum (ES) 538.0 (M+H).
Example 78 1-Acetyl-4-(4-Hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide To a crude mixture of 1-acetyl-4-(4-hydroxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid (O.SSg) ~ and N-hydroxy benzotriazole (0.414g) 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 ~,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 H20, 2N citric acid, brine and dried (Na~S04).
The solvent was removed under vacuum to give a solid. Chromatography on silica gel with 10% methanol in ethyl acetate as solvent gave a solid which was dried at 78°C
under vacuum overnight to give an off white foam; Mass spectrum (ES) 406.1 (M+H);
Anal. Calcd. For C,gH,9N306S; 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.
' Y~ J ' N
<N~ N ~O.N , R' \ '~ ~ ~'-,~ Y
< ~ ' <'7 ' « ' N N N
R'' ~ - , ~ ~~ OCO- ~ ~ N-tBoc - N- . p - , N- , U
~N- , or N(R')(R') where R' is as defined above;
W is O, S, NH or N(CI - C3)alkyl;
Y is hydrogen, F, Cl, CF3 or OCHg; and X' is halogen, hydrogen, (CI -C3)alkyl, O-(C1 - C3)alkyl, or -CHZOH; and pharmaceutically acceptable salts thereof.
When used herein the term C1-C3 alkyl covers methyl, ethyl, n-propyl and i-propyl groups. When used herein the term C1-C( alkyl covers, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl and pentyl groups. When used herein the term C3-C~ cycloalkyl covers saturated and unsaturated cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-cyclopropenyl, 2-cyclopropenyl, 1-cyclobutenyl and 2-cyclobutenyl.
R is suitably hydrogen, halogen or (C1-C3)alkyl, for example hydrogen, chloro or methyl. R1 is suitably hydrogen. R2 is suitably hydrogen. R4 is suitably (C
alkyl)-O-, for example methoxy. R3 is suitably selected from the group: (C 1-C3)alkyl-S02_, aryl(CH2)nS02_, (C1-C3)alkyl-CO-, aryl(CH2)nC0-, heteroaryl(CH2)nC0-, (C1-C3)alkyl-O-(CH2)nC0-, (C3-C~)cycloalkyl-CO-, (Cl-C3)alkyl-O-(CH2)m- or aryl(C1-C3)alkyl-~ for example methylsulphonyl, n-propylsulphonyl, 4-methyl-phenylsulphonyl, 4-methoxyphenylsulponyl, methylcarbonyl, 3-trifluormethylcarbonyl, 2-phenylethylcarbonyl, methoxymethylcarbonyl, cyclopropylcarbonyl, cyclohexylcarbonyl, 2-methoxyethyl, phenylcarbonyl, 2-methyl-5-fluorophenylcarbonyl, 4-biphenylcarbonyl, 2-biphenylcarbonyl, 2,4-dichlorophenylcarbonyl, phenoxymethylcarbonyl, phenylcarbonyl, 4-trifluoromethylphenylcarbonyl, 2-imidazol-1-yl-phenylcarbonyl, 2-morpholin-4-yl-phenylcarbonyl, 4-ethoxyphenylcarbonyl, 4-(4-methyl-imidazol-1-yl)-2-choloro-phenylcarbonyl, 2,4-dimethoxyphenylcarbonyl, 4-methyl-piperazin-I-ylmethylcarbonyl, 3-pyridinylcarbonyl, 2-thienylcarbonyl, 4-pyridinylcarbonyl, furanylcarbonyl or benzyl.
Preferably, the compounds of the present invention are those of formula 1 wherein R is hydrogen, (C~ - C3) alkyl, -CN, -OR', -SR', -CF3, -OCF3, CI, F, NH2, NH(C1 - C3)alkyl, -N(R')CO(C1 - C3)alkyl, -N(R')(R'), N02, -CONHZ, -S02NH2, -S02N(R')(R'), or -N(R')COCHZO-(C~ - C3)alkyl, wherein R' is (C ~ - C3) alkyl or hydrogen;
R4 is (C1 - C6) alkyl-O-, (C1 - C6) alkyl-S-, R
O RI , ~S~ > >
~~R' ~~R~ ~~R~
NON ~ -o-': ~ ~ -S f'~
N N
R~ , -S ~ ~ R~ , or R, wherein R~~ is hydrogen, halogen, cyano, methyl or -OCH3;
R1 and R2 are each, independently, hydrogen or CH3;
R3 is (C ~ - Cg)alkyl, NH2CH2C0-, (C ~ - C6)alkylNHCH2C0-, HO(CH2)I,,CO-, HCO-, Aryl(CH2)nC0-, Heteroaryl(CH2)nC0-, (C1 - C3)alkyl-O-(CH2)"CO-, (C~ - C3)alkylCO-, (C~ - C3)alkylCO-NHCH2C0-, (Cg - C~)cycloallcylCO-, Aryl-O-CH2C0-, HeteroarylOCH2C0-, AryICH=CHCO-, HeteroarylCH=CHCO-, (C~ - C3)alkyICH=CHCO-, _8_ i ~ i Q
~ CH20C- , ' i~ CH20C-NHCHzCO- , wherein m=lto3;n=Oto3;
Aryl is X
I ~ and R' Heteroaryl is ~r-,~X ~r~~X
J X ~ ~ > ' < ~ ' N S O
X
I j ~'-v > > ~> >
\N O S
i R' 'rr ~,~X ~~N
,N , <N,N . or <N J X , O
R, R, wherein X is hydrogen, halogen, (C I - C3) alkyl or -OCHg 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, (Ct - C3) alkyl, -CN. -OR', -SR', -CFg, -OCF3, Cl, F, NH2, NH(C1 - C3)alkyl, -N(R')CO(Ct - C3)alkyl, -N(R')(R'), N02, -CONH2, -S02NH2, -S02N(R')(R'), -N(R')COCH20-(C~ - C3)alkyl, wherein R' is (C~ - C3) alkyl or hydrogen;
R4 is (C~ - C6) alkyl-O-, (C~ - C6) alkyl-S-, I ~ ~ I
R~ , ~S~ R~ , I ~ ~~R' ~~R~ ~~R~
N~%N ' - D ' ~ ' - S f'' ~ ' N N
I ~ R ~ , - S I ~ R~~ , or "
R, wherein R~~ is hydrogen, halogen, cyano, methyl or -OCH3;
Rt and R2 are each, independently, hydrogen or CH3;
R3 is CH3- N(C~ - C3)alkylCH=CH-CO- , N-(C1- C6)alkylCO- , N-(C -C alk 1C0-N-(C~ - C~alkylCO- , (C~ - C~alkylCONHCO-, ' i ~ Y
N-(Ci - C6)alkylCO- , N-(C~-C6)alkylCO- , ~N-(Ci-C6)alkylCO- , ~N N
CH3- N(C1- C6)alkylCO- , t-Boc-NN~N-(C1 - C~alkylCO-U
' CO- O ~
EtOC~N(CI - C~alkylCO- , R~ ~/O
' O R' N- (C ~ - C6)alkylCO-R' O CO-[(C1 - C6)alkyl]2-N-(C1 - C6)alkyl CO-, or (C1 - C6)alkyl-NH-(C1 - C6)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, (Ct - C3) alkyl, -CN, -OR', -SR', -CF3, -OCF3, C1, F, NH2, NH(C1 - C3)alkyl, -N(R')CO(C~ - C3)alkyl, -N(R')(R'), N02, -CONH2, -S02NH2, -S02N(R')(R'), or -N(R')COCH20-(Ct - C3)alkyl, wherein R' is (Ct -C3) alkyl or hydrogen;
R4 is (Ct - C6) alkyl-O-, (Ct - C6) alkyl-S-, R
Rt . ~S~ t ~~Rt ~~Rt ~~Rt N~N ~ - p ' , - S f'' N N
R~ , -S ~ ~ R~ , or R, wherein R~~ is hydrogen, halogen, cyano, methyl or -OCH3;
R1 and R2 are each, independently hydrogen or CH3;
R3 is (Ct - C3)alky1S02-, Aryl(CH2)nS02-, Heteroaryl(CH2)nS02-, or (Ct -C3)alkyl-O-(CH2)m-SO2, wherein m=lto3;n=Oto3;
Aryl is /X
I ~] and R' Heteroaryl is ~~,/X ~~/X
, ~ , X \< ' N O
X
< <~
N O
R' ~r,.--'~/X ~r- N
~N , < ,N , or < J X
O N N
R. R, wherein X is hydrogen, halogen, (Ct - C3) alkyl or -OCH3 and R and R' are as defined above; and pharmaceutically acceptable salts thereof.
A further, more preferred embodiment of the present invention includes compounds represented by formula 1 wherein R is selected from hydrogen, (C~ - C3) alkyl, -CN, -OR', -SR', -CF3, -OCFg, Cl, F, NH2, NH(Ct - Cg)alkyl, -N(R')CO(C~ - C3)alkyl, -N(R')(R'), N02, -CONH2, -S02NH2, -S02N(R')(R'), or -N(R')COCH20-(Ct - Cg)alkyl, wherein R' is (C1 - Cg) alkyl or hydrogen;
R4 is (Ct - C6) alkyl-O-, (C~ - C6) alkyl-S-, R
Rt , ~S~ t , ~~Rt ~~Rt ~~Rt NON , - ~ ~ ~ - S f'' N N
R~ , -S ~ ~ R~ , or R, wherein R~~ is hydrogen, halogen, cyano, methyl or -OCH3;
R~ and R2 are each, independently hydrogen or CH3;
R3 is (C1 - Cg)alkyl, Aryl(C~ - Cg)alkyl, Heteroaryl(Ct - C3)alkyl, AryICH=CHCH2, HeteroarylCH=CHCH2-, or (C~ - C6)alkylCH=CHCH2-, wherein Aryl is Heteroaryl is X
./
and R' ~~,~X ~r,-,~X
J X ' ~/> ° < ~ ' N S O
X
~,-N
<N ' < ~ ' o S
R' ~~ ~~N ~l- N X
<OiN . <N~ ~ or <N~
I I
R, R, wherein X is hydrogen, halogen, (C~ - C3) alkyl or -OCH3 and R and R' are as defined above; and pharmaceutically acceptable salts thereof.
Additionally preferred compounds of the present invention include those of formula 1 wherein R is hydrogen, (C~ - C3) alkyl, -CN, -OR', -SR', -CF3, -OCF3, C1, F, NH2, NH(C1 - C3)alkyl, -N(R')CO(C1 - C3)alkyl, -N(R')(R'), N02, -CONH2, -S02NH2, -S02N(R')(R'), or -N(R')COCH20-(C1 - C3)alkyl, wherein R' is (C~ - Cg) alkyl or hydrogen;
R4 is (C~ - C6) alkyl-O-, (C1 - C6) alkyl-S-, R
R~ , ~S~ 1 , - I ~ ~~R1 ~~R1 ~~R~
N~%N ' - ~l ~ . - s f'~ ~ ' N N
R~ , -S ~ ~ R~ , or R, wherein R ~ is hydrogen, halogen, cyano, methyl or -OCH3;
R~ and R2 are each, independently hydrogen or CH3;
R3 is Y
~ Co- Y~~~~ _ co- , ~ ~ Co , L N
M
M NCO- /
Y f"~ ;~ CO- /
J , yv , / w co-/ ~ M
~ CO- ~ or y rl~ CO_ w / ~SJ
wherein m=1 to3;n=Oto3;
L is hydrogen, (C1 - Cg)alkyl, -CN, -OR', -SR', -CF3, -OCP3, C1, F, NH2, -NH-(C~ - C3)alkyl, -N(R')CO(C1 - C3)alkyl, N(R')(R'), -N02, -CONH2, -S02NH2, -S02N(R')(R'), -N(R')COCH20-(C1 - Cg)alkyl, Y r--,, CONH- y ~ CONH-CONH- ~ ~ ~ , or S O
M is w ~''-,/
y ~N J
<O/ ' <N~ <N~ ~O~N
R' ~'-~% Y
< ~ ' <~ ' « .
N N N
R- N- , I \ OCO-N~ N , Ice- , / ~/
tB oc - ~ ~ ~N- , N- , ~l~- , or N(R')(R') where R' is as defined above;
W is O, S, NH or N(C~ - C3)alkyl;
Y is hydrogen, F, Cl, CF3 or OCH3; and X' is halogen, hydrogen, (C~ -C3)alkyl, O-(C1 - C3)alkyl, or -CH20H; and pharmaceutically acceptable salts thereof.
The compounds of the invention may be prepared by reacting an appropriate acid halide such as the acid chloride or bromide with hydroxylamine. The acid halide may be prepared by reacting the con esponding acid or a metal salt thereof with an activating agent such as oxalyl chloride, oxalyl bromide, thionyl chloride, thionyl bromide, (chloromethylene)dimethylammoniumchloride or (bromomethylene)dimethyl ammonium bromide. The subsequent reaction of the acid halide with hydroxylamine may suitably be performed in situ.
Metal salts may be prepared by reacting a ester of formula Ia Ra R2~i N
R~
R
la wherein R21 is (C1-6)alkyl, benzyl or arylalkyl and all other groups are as defined above, with a base such as lithium hydroxide, potassium hydroxide, sodium hydroxide or barium hydroxide. This may suitably be performed in a solvent such as a (C1-Cg) alcohol, tetrahydrofuran, N,N-dimethylformide or p-dioxane in the presence or absence of water. The resulting metal salt may be directly converted to the desired product or it may first be converted to the acid, e.g. by treating it with aqueous hydrochloric acid or acetic acid. Alternatively the ester of formula la may be converted to its acid by treatment with an aqueous mineral acid such as hydrochloric acid, hydrobromic acid or trifluoroacetic acid and the acid converted to the desired product as described above.
The compounds of formula 1 may be advantageously prepared according to Reaction Schemes 1 to 7. Variations in these schemes may be made to improve productivity without negatively impacting the amount and nature of the product, by 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 vitro derivatives 5 .
Reduction under conventional reducing conditions, such as catalytic hydrogeneration (with Pd/C) or chemical reduction (e.g., with SnCl2 or FeCl3) 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-vitro or 2-amino benzyl alcohol derivatives 11 by application of the Mitsunobu reaction to give intermediates 12. Reduction of the 2-vitro group and removal of the hydroxy blocking group with derivatives 12. where the 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 [1,4J
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.
Scheme 1 O
II
CHgO C NH2 / \ O SO 2 ~ ~ Ra ~R~ C1S02~ Ra --~ CH 30 C NH
HO ~ + Y
R2 2 ~R~ N02 1 HO ~z ~ CH2Br O S0 2 ~ ~ Ra 3 R I
II
/ v R O SO -~~ \- Ra HO ~,, Hz ~ 1I
~z 6 HO ~~ R ~ / NO 2 Ar(CH 2 ~COCI Heteroaryl(CH 2 ~COCI zR ~J
Ar(CH2)nS02Cl Heteroaryl(CH2)~ 02C1 5 Alkyl-O-CH2~COC1 Alkyl-O-(CH2)m02C1 ~ S02 ~ / Ra AlkyICOCI AlkylS02C1 CH 30 C
Cycloalkyl( C3to C~)CO Rt~ / ~ R
Rz I ~ a g tl (1) OH-R~ Rz HN / (2) C1COCOC1 R (3) NH20H
p II ~02 ~ / Ra HOHN'C
Rt~ I %R
Rz N
wherein n=Oto3;
m=lto3;
R1 = (Cl - C3)alkyl; R = Hydrogen; halogen; OCH3; NO2; NH2; CF3; NHCOCH3;
NHCOCH20CH3; CONH2; -N(R')(R'), -N(R')CO(C1 - C3)alkyl; (C1 - Cg)alkyl;
R3 = Ar(CH2)"CO-; Heteroaryl(CHZ)"CO-, Ar(CH2)"S02-; Heteroaryl(CH2)nS02-;
Alkyl-O-CH2)nC0-; Alkyl-O-(CH2)mS02-: AlkylCO-; Alky1S02-; AlkylCO-NHCHZCO-; and cycloalkyl(C3 - C~)CO-; and R4 is as defined herein.
Scheme 2 SO ~ ~ g~ O SO 2 ~ ~ Ra O
I ~ H+ CH3 O C NH
R~ + ~~O ' ~ \ CH 20H
HO 2 0 + ~
3 10 ' R
RS = -NOZ
t-BocNH- ~ 3 P + DEAD
~CH 20CONH-O SO 2 ~ ~ Ri R g = NO2 O S02 R4 CH3 0 C N ( I ) H 2+ Pd/C CH30 C N
R~ (2.a-) H R~ \
N \ .
HO H2 R 5 = t-BocNH- ~ : I
I J
(1)H+ ;TFA
R RS= f~CH20CONH- 12 (I) H+
fO CH 20COCI
R6 COCI 2 ~
SO 2 ~ ~ R4 O SO Ra O or II
CH301C N R~S02C1 CH30C
R, I R~~ . R
R~\NH I % R R6COC1 RZ ~N ~ v 2 _ or R 8 14 R~SO 2CI 15 wherein n=Oto3;
m=lto3;
~ = phenyl;
DEAD = diethylazodicarboxylate;
R~, = Ar(CH2)~ ; Alkyl-; Heteroaryl(CH2)n ;Alkyl-O-(CH2)n ; Cycloalkyl(Cg -C~);
R~ = Ar(CH2)"; Alkyl-; Heteroaryl(CH2)n-; Alkyl-O-(CH2)m ;
Rg = Ar(CH2)nC0-; Ar(CH2)"S02-; AIkylCO-; AIkylS02-; Heteroaryl(CH2)nC0-;
Heteroaryl(CH2)"S02-; Alkyl-O-(CH2)"CO-; Alkyl-O-(CH2)t,,S02-.
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 NaI04 with catalyst Ru02 (e.g., see J. Org.
Chem., 46:3936 ( 1981 ); Synlett, p. 143, ( 199b)). 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.
Scheme 3 SO2~ ~ Ra R S02~ / Ra R
CH OC
CH 30 C N Ar CHO
_--i R i % R
HO R2 ~H I ~ R OH Ho R2 N
~s II
CHI
6 16 Ar NaCNBH 3 _ HOAc R S~ 2 ~ I ~
CH30C ~ N (C6H5 ) P Il S02 ~ ~ Ra R J ~ / / R ~ 3 CH 30 CAN
t ' H I - DEAD I Rt ~ / R
CH2Ar L.IO~ HN
i8 ~ _ CH2Ar CH 30C ~ iN~ ~( C6 H 5 )3 P
CCI
C1~R~HN / ~R 4 I
CH2Ar S02~ ~ R4 ~ 19 _ CH 30C N O SO 2 ~ / Ra Rt~ I ~ R H0. tt R~~N
z ( R~ I % R
CHZAr R2 wherein 21 CHZAr Rto .R9 ~ ~ Rto R9 Ar= ~ / , ~ '/~ ~ ~~~ , ~ 1 , ~~~R9 ~~~R9 ~~~ Rto CN ,, / ~.i C ~ , ~ ~ ~ , or N R9 S p ~~~ R to ; and R 9 and R 1 Q are: C1, Br, F, OCH , OEt , SCH 3 , ~ pCH
p Q O
COEt , CF3 , pCF3 ICNH 2 , -NHCOCH 3 , or Me2N-.
Scheme 4 SO 2 ~ / ~ SO 2 ~ / Ra I
Rt~ ~ R BHP R~~ / ~~ R
R~ N /_ R2 N
Q ~ ~Ar CH2Ar O SO R4 ~ SO 2 ~ / Ra II I 2 ~ / HO~ N
HOC N N
RtY / '/ R H Rt?'N / ,' R
_ 2 R2 CH CH ZAr wherein Rto ~ Rto R9 Ar= ~ \ I ~~ ~ ~ ~ ~ ~% R9 /~% R~ ~~~Rto J N /.. S O
Rto , and R9 and Rto are hydrogen ,CI, Br, F, OCH3 , OEt , q SCH 3 , COCH 3 , COEt , CF3 , OCF3 , or Me2N-.
I 02 ~ / Ra q S02 ~ /
I
CH HOC N CH30C~ N
Rt]I' / %R B~ Rt?I I %rt R2 N _.. ~ R2 O'C~ Rs CH2R8 wherein R8 = 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- I H-[ 1,4]-benzodiazepines 14 (without a substituent at the I-position) with carbonyl chloride derivatives in the manner depicted in Reaction Scheme S, results in intermediates 25 which are then converted to acid 26 and hydroxamic acids 27. The intermediates may also be synthesized by reaction of methyl 2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl) amino]-3-hydroxypropionates 6 with acid chlorides to give "dehydroalanine" derivatives 28. As previously described, mild bases such as NaHC03 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-1 H-[ 1,4] diazepines 25.
Scheme 5 SO 2 ~ / ~ ~ SO 2 ~ / R4 CH OC ~ CH 30C
R COCI Y
R>>~ I %R 8 Rt]i I ~ R
2 H Et 3 N or pyridine O ~ Re Wherein R8 = O N-(CH ) 25 2 n ~-(CH2)~
S~ -(CH2)~ ~ .(CH2)n OH-N
n CH3~-(CH2)n ~ ~ N-(CH2)n -(CH2) ~ ( CH3( CH2~ 12~(CH2 )n n t-B~ -(CH2) n EtOC~ ~ .(CH2 ) n O
~CH2pC_ CH 3 CONIC
and n = 0 to 3 SO 2 R4 ~ SO 2 ~ / R4 i N HOC N
HO /~ RY I / R
R~ ~ R i >' R2 w N I ~ R2 \
O ~' Rs-~ O ~ Ra R4 p SO 2 ~ / Ra CH30C N CH O~~/N
HO R2 I ~R R BCOCI R JLR2H / ~ R
--Et 3 N O ~~ R8 NaHC03 CH OH
SO 2 ~ / R4 Rt'I I %R
RZ N' _.
O 'R8 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 sis, 563-566 {1997); J.
em , 62:3405-3406, ( 1997); Tetrahedron l..ett., 36:5247-5250, ( 1995);
Heteroc,~, 45:467, ( 1997); Tetrahedron Lett., 38:1118-1182, ( 1997);
Heterocycles, 42:189-I 94, ( 1996); Tetrahedron L_ett., 5005-5006, ( 1993); Synthesis, 843, ( 1987);
Heterocycles, 2711-2716, ( 1987); and Tetrahedron Lett., 4407-4410, ( 1986).
By coupling with such palladium catalysts, aryl-aryl, heteroaryl-aryl, aryl-heteroaryl and heteroaryl-heteroaryl carboxylic ester derivatives can be prepared and these derivatives converted to carboxylic acid intermediates. The acids are then converted to acid chlorides which are reacted with esters of 2- [(2-aminobenzyl)-(4-substituted-benzenesulfonyl)amino]-3-hydroxypropionate as illustrated for conversion of derivatives 6 to intenmediates 31. The following references describe procedures for the synthesis of methyl 3-arylpyrrole-4-carboxylates as in J. Ore. Chem., 62:2649-2651, (1997); methyl (2-methylphenyl) benzoates as in J. Ors;. Chem.. 62:3405-3406, ( 1997); and methyl benzoates substitued with heterocycIic moieties such as furanyl, thienyl or pyridinyl groups as in Tetrahedron Lett., 27:4407-4410, ( 1986).
Scheme 6 O SO ~ ~ R4 W
CH O C N 2 y ~~ W W
3 ' R y/ ~ W ; ~, ; Y '~~ ~°ry~\ etc R~~ ~ / S~ Co~ ;
RZ ~ ~- W = B(OH)2 ; SnMe3 ; Sn(n-butyl)3 ;
O ~ Ar~ O-Triflate; ZnCI ; or ZnBr;
Y\~~ B~~~l ~~1 Y\~~~
Ar'= ~~~ ~ CNl , ~S j ~ or <O~ CH OC S02 ~ ~ Ra Br 3 Pd(PPh3)4 or Pd(PPh3)2C12 H ~ . /R
or Ri R2 H2 equivalent Pd catalyst _ _ 6 CI
Y
o so ~ ~ R4 o so 2~ R4 of 2~ CH 1 Y;~ R +
R~~N ~ ~ R ~ / % R Et3N L or R2 I V 2 ... Cl O~ Ai' ~ p~Ar" ~
30 31 O ~ Ar M y M M
where Ar" _ ~~~ ~ ~ ~ , ~~~~~ ~ Y ' \ j ~ oY <,r ~ j ,J J N
L
X Y
L is Y ~~ CONH- . ~~ ~ CONH- ~ or y~ O~ CONH- ' S
Y
M is ~ 1'n/ y~~%
y~ ~ ' ~J ' ~Sj , ~OJ , N
Y \ N Y\r'_' 'N , N. , < ~ N , or 'N, ;
O I
R' R' Y is H, F, Cl, CFg, CHg, or OCH3;
X is halogen, hydrogen, or (C1 - C3)alkyl;
R and R' are as defined herein; and R4 is as defined herein.
The intermediates 2.4,5.6-tetrahydro-I H-[ 1.4]benzodiazepines 39 and 38 may be prepared from glycine esters in the manner e~cemplified 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) ?-nitrobenzyl bromide in N.N-dimethylformamide or 1-methyl-2-pyrrolidinone in the presence of potassium carbonate to give intermediates 34.
Alternatively, the ester 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 us BF3, or heating an acid salt of 36 to effect the elimination-addition reaction.
Scheme 7 CH30CCH2NH2 + C1S0 ~ ~ R4 ~ CH30CCH2NHS ~ ~ R4 33 CH2Br O
il R
CH30CCH2~ S02 ~ ~ R4 NH2 H2 CH30CCH2 N-S02 ~ ~ R4 I .' R Ps-~---- H
~ 2 N02 35 +
CH2 = N(CH3)2C1- R
or +
CH2 = N(CH3)2I-O _ S / ~ R
CH30CCI~N-S02 ~ ~ R4 CH~~ ~ 4 (CH3)2I~ CH 2 CH2 H
/,R
NH2 ~ ,~ ~t3 ~
O S02 ~ ~ R4 ~ SO ~ ~ R4 C OC l~t CH30C 1~T H3 / /R ~ / %R
39 3g 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,~ substituent is an OH group are prepared.
Intermediates with R4 an OH group may be prepared from derivatives wherein the OH group is protected by a group which can be selectively removed. Derivatives 40 wherein R4 is an OCH~ 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,-C6)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.
Ors.
Chem., 56:7173 ( 1991 ); Tetrahedron Lett. 5709 ( 1989); S n he is 1:28 ( 1981 ).
Scheme 8 / H3 O $Oz \ / H
CH30 R BBr3 N R
R / ~ CH 30 I Rt N
Rz R3 Rz R3 40 (C t-C6)alkyl-X
1 ) OH B~ (C t-Ce)alkylOH
2) BBr3 or (C6Hs)~P
DEAD
O ~~ \ / H O ~pz \ / O-alkyl(C,-C6) N R
R, N /
Rz R3 ._ RtRz R
(C6EIs~P 42 or Base DEAD (Ct~6~1ky1pH
(C t-C6~1kY1_X
OH
O ~Oz \ / O-alkyl(Ct-Cs) p SOz \ / O-alkyl(Ct-C6) N '~R OH HO N
(C,-C6)alkYl /
Rt I Rt N /
Rz R3 - Rz R3 (C,-C6)alkyl-X
X = halogen, OTs, OMs 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 malefic 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 Garners, 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 Garner.
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.
Adjuvant.c 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 colorimetrically with DTNB ((5,5'-dithio-bis(2-nitro-benzoic acid)). This assay is disclosed in Weingarten et al., "Spectrophotometric Assay for Vertebrate Collegenase", Anal. Biochem., 147:437-440, ( 1985). The enzyme activity is measured by the rate of the color increase.
The thiopeptide substrate was made up fresh as a 20 mM stock in 100% DMSO
and the DTNB was dissolved in 100% DMSO as a 100 mM stock and stored in the dark at room temperature. The substrate and the DTNB were diluted together to 1 mM
with substrate buffer (50 mM HEPES, pH 7.5, 5 mM CaCl2) before use. The stock of human neutrophil gelatinase B was diluted with assay buffer (SO mM HEPES, pH
7.5, 5 mM CaCl2, 0.02% Brij) to a final concentration of 0.15 nM.
The assay buffer, enzyme, DTNB/substrate (500 ErM final concentration) and vehicle or inhibitor were added to a 96 well plate (total reaction volume of 200p1) and the increase in color was monitored spectrophotometrically for 5 minutes at 405 nm on a plate reader.
The increase in OD405 was plotted and the slope of the line was calculated.
The slope represents the reaction rate. The linearity of the reaction rate was confirmed (r2 >0.85) and the mean (x t sem) of the control rate was calculated and compared for statistical significance (p <0.05 j with drug-treated rates using Dunnett's multiple comparison test. Dose-response relationships were generated using multiple doses of drug and ICSp values with 95% CI were estimated using linear regression (IPRED, HTB).
In Vitro CollaEenase Assay This assay was based on the cleavage of a peptide substrate ((Dnp-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMa)-NH2), available from Peptide International, Inc.) by collagenase releasing the fluorescent NMa group which was quantitated on the fluorometer as disclosed in Bickett et al., "A High Throughput Fluorogenic Substrate WO 99!37625 PCT/US99/01325 for Interstitial Collagenase (MMP-1 ) and Gelatinase (MMP-9)", Anal. Biochem., 212:58-64, ( 1993). Dnp quenches the NMa t7uorescence in the intact substrate.
The assay was inn in HCBC assay buffer (50 n>Ni HEPES, pH 7.0, 5 mM
Ca+2, 0.02% Brij, 0.5% Cysteine), with human recombinant fibroblast collagenase (truncated, mw=18,828, from Wyeth-Ayerst Research, Radnor, PA). The substrate was dissolved in methanol and stored frozen in 1 mM aliquots. Collagenase was stored frozen in buffer in 25 pNl aliquots. In conducting the assay, the substrate was dissolved in HCBC buffer to a final concentration of 10 E.~M and collagenase to a final concentration of 5 nM. The compounds being examined were dissolved in methanol, DMSO, or HCBC. The methanol and DMSO were diluted in HCBC to < 1.0%. The compounds were added to a 96 well plate containing enzyme and the reaction was started by the addition of substrate.
The reaction was read (excitation 340 nm, emission 444 nm) for 10 min. and the increase in fluorescence over time was plotted as a linear line. The slope of the line was calculated representing the reaction rate. The linearity of the reaction rate was confirmed (r2 >0.85). The mean (x t sem) of the control rate was calculated and compared for statistical significance (p <0.05) with drug-treated rates using Dunnett's multiple comparison test. Dose-response relationships were generated using multiple doses of drug and IC50 values with 95% CI were estimated using linear regression.
Procedure for Measuring TACE Inhibition In a 96-well black microtiter plate, each well received a solution composed of pI. TACE (available from Immunex) at a final concentration of 111g/mL, 701rL.
Tris buffer, have a pH of 7.4 and containing 10% glycerol (final concentration 10 mM), and 10 pL of test compound solution in DMSO (final concentration 1 pM, DMSO
concentration < 1 %). The plates were incubated for 10 minutes at room temperature.
The reaction was initiated by addition of a fluorescent peptidyl substrate (final concentration 100 ECM) 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 (r2 >0.85). The mean (xtsem) of the control rate was calculated and compared for statistical significance (p<0.05) with drug-treated rates using Dunnett's WO 99/37625 PC'f/US99/01325 multiple comparison test. Dose-response relationships were generated using multiple doses of dmg and ICSp values with 95% CI were estimated using linear regression.
The results obtained following these standard experimental test procedures are presented in Table 1.
Table I
O $O~~R4 N
HORN
Rt N / i R
RZ
Compound of R3 Example R R~RZ R4 ICs o (nM) _ - - - - MMP-1 MMP-9MMP- I TALE
-SO ~ ~ 2 H H H -OCH3_ 14.1 5.1 391 -SOiCH3 3 H H H -OCH3156.5 7.9 3.0 104 -SOZC H2CH2CH H H H -OCH.~183 7.0 2.8 91 -SO~OCH3 4 H H H -OCH~2~.1 12.2 4.3 101 t -COCH 6 H H H -OCH318.4 1.4 10 103 -CO / ~ 5 H H H -OCH315.8 0.56 95 (23) (1.7) 10 0.4 (1.1) Compound of R3 R R~ RZ R4 ICs Example (nM) -CO- 7 H H H -OCH~20.4 0.6 0.4 77.7 I (34) ( ( 1.3) + 7 ~ 1.9) -CO-~ 8 H H H -OCH319.7 1.1 1.1 12.8 1.2 -CO- 13 H H H -OCH354.9 9.8 2.0 154 +_ I , 27 ~
~N
COCH20CH3 9 H H H -OCH334.1 1.34 1.19 95,2 14.8 -CO(CH~ 12 H H H -OCH 523 17.9 25 ~ 3 7 /
. 207 +
-CO 1 H H H -OCH 96.2 5.1 3.7 352 ~ ~ 34 /
-CO
/ 11 H H H -OCH 55.4 3.9 2.3 271 +
F
-C 15 H H H -OCH352.7 0.7 0.4 199 -CO
/
14 H H H -OCH 542 12.6 3.7 4596 3 ( 1 uM) 55 H H H -OCH3171 4.0 3.3 6g,5 -CO~ 7.2 -CO~ 57 H H H -OCH3465 12.7 7.2 318 -CO-~CI 31 H H H -OCH375.5 3.0 2 . 367o(luM) -C 40 H H H -OCH316.6 1.4 1.2 28.5 /~ 6.6 O
-C~H 58 H H H -OCH365.5 4.4 2.9 154 2o- 20 Compound of R~ Example R Ri R, R.~ lCso (nM) -COCH.,OCH~ 59 -CH3 H H -OCH~105 2.6 1.8 12516 C / \ 60 7-CH3 H H -OCH~22.7 1.4 1.3 143+4 -C ~ ~ OCF3 61 g-CI H H -OCH~239 1.3 0.4 1248 (265) (3.9) (4.3) t 69 -CHzCH,OCH; 62 H H H -OCH;1000 100 100 51 ( 1pM) CN
\
63 7-CH; H H -OCH3130 5.6 3.1 aa6 t as -C / \
64 8-Cl H H -OCH3l57 6.1 3.4 384 -CO ~ t 8 -C ~ ~ OCZHS 65 H H H -pCH323.5 1.5 1.5 157 t 13 -C0~1,~CH3 66 H H H -OCH~g3.4 3.4 2.6 148 t 14 -CH2-~ 67 H H H -OCH31323 50.8 73.9 551 f 29 -C
71 H H H -OCH~41.3 2.4 1.3 136 t 15 OCH
n -CO-CH~I~N-CH372 H H H -OCH34982 187 317 808 t 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 moI) of N-(benzyloxycarbonyl)-O-benzylserine in 600 ml of CH2C12 cooled to -6°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.
WO 99/37625 PC'T/US99/01325 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°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 S, nty hetic 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 CH2Cl2 (cooled in an ice bath) was added, in small portions, 16.1 g (0.0771 mol) of 4-methoxybenzene-sulfonyl chloride. The mixture was stirred at 0°C for 0.5 hours and at room temperature overnight. The mixture was washed with H20, 2N citric acid, brine and dried with Na2S04. The solvent was removed under vacuum to give 25.34 g of solid which was triturated with hexane. The solid was recrystallized from 120 ml of toluene to give 12.18 g (48:7%) of product as a white solid. The filtrate was concentrated and the residue chromatographed on silica gel with hexane-ethyl acetate (7:3) as eluent to give 5.71 g (22.8%) of white solid.
m.p. 70-75°C. Anal. for C14H21N06S:
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 ~-butyl ester in 50 ml of N,~1-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,~1-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 CH2Cl2. The organic extract was washed with H20, brine and dried with Na2S04. 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 C21H26N208S:
Calc'd: C,54.1; H,5.6; N,6.0;
Found: C,54.0; H,5.7; N,6Ø
Reference Example 5 2-[(2-Aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3 hydroxypropionic acid, tert-butyl ester A mixture of 0.60 g ( 1.28 mmol) of 3-hydroxy-2-[(4-methoxybenzene sulfonyl)-(2-nitrobenzyl)amino] propionic acid, tit-butyl ester and 1.45 g (6.45 mmol) of SnCl2~2H20 in 20 ml of methanol was heated in an oil bath at 90°C
for 2 hours.
The solvent was removed under vacuum and ethyl acetate added to the residue.
The mixture was neutralized with saturated sodium bicarbonate solution and filtered through diatomaceous earth. The ethyl acetate layer was separated and washed with H20, brine and dried with Na2S04. The solvent was removed under vacuum to give 0.30 g (53%) of a gum. Anal. for C21 H28N206S:
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-methoxybenzene-sulfonyl)amino]-3-hydroxypropionic acid, tent-butyl ester and 6 ml of trifluoroacetic acid in 6 ml of CH2C12 was stirred at room temperature for 3 hours and then concentrated to dryness under vacuum. To the residue was added H20, CH2Cl2 and 1N NaOH until the aqueous layer 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 H20, brine and dried Na2S04. The solvent was removed under vacuum to give 0.35 g (54%) of a solid. Anal. for C17H2pN206S:
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)amino}acrylic acid, tert-butyl ester A mixture of 0.431 g (1 mmol) of 2-[(2-amino-benzyl)-(4-methoxybenzene-S sulfonyl)amino]-3-hydroxy-propionic acid, tert-butyl ester, 0.474 g (2.2 mmol) of 3-(trifluoromethyl)benzoyl chloride and 1 ml of pyridine in 2 ml of CH2C12 was stirred at room temperature for 3.5 hours. The mixture was poured into H20 and extracted with CH2C12. The extract was washed with H20, 2 N citric acid, H20, 1 N NaHC03, brine and dried with Na2S04. 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°C overnight and concentrated to dryness under vacuum. The residue was extracted with CH2C12 and the extract washed with H20 and dried with Na2S04. The solvent was removed under vacuum to give 0.55 g of product as a solid. From a similar run the product was chromatographed on silica gel with hexane-ethyl acetate to give a solid, m.p. 65-72°C. Anal. for C29H29F3N2O6S:
Calc'd: C, 59.0; H,5.0; N,4.7;
Found: C, 59.2; H,5.2; N,4.4.
Reference Example 8 20 4-(4-Methoxybenzenesulfonyl)-I-(3-trifluoromethylbenzoyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, tert-butyl ester A mixture of 0.55 g (0.932 mmol) of 2-{(2-[3-(trifluoromethyl)benzoyl) aminobenzoyl]-(4-methoxybenzenesulfonyl)amino } acrylic acid, tert-butyl ester and O.I02 g (1.21 mmol) of NaHC03 in 4 ml of methanol was stirred at room temperature overnight and the solvent removed. The residue was extracted with CH2C12 and the extract washed with H20, brine and dried with Na2S04. The solvent was removed to give 0.57 g of solid. The solid was chromatographed on thick layer silica gel plates with hexane-ethyl acetate (1:1) as solvent to give 0.30 g of a light yellow solid, m.p.
57-60°C. Anal. for C29H29F3N2O6S:
Calc'd: C,59.0; H,5.0; N,4.7;
Found: C,58.8; N,5.0; N,4.6.
Reference Example 9 4-(4-Methoxybenzenesulfonyl)-1-(3-trifluoromethylbenzoyl)-2,3,4,5 tetrahydro-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-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, ten-butyl ester and 3 ml of trifluoroacetic acid in 3 ml of CH2Cl2 was stirred at room temperature for 3 hours. The mixture was concentrated to dryness under vacuum and the residue extracted with CH2Cl2. The CH2Cl2 was washed with 1 N NaHC03 and the aqueous layer (pH 8) was acidified with 2 N citric acid and extracted with ethyl acetate. The extract was dried (Na2S04}. The original CH2C12 extract was washed with 2 N citric acid, H20, brine and dried with Na2S04. The CH2C12 extract and the ethyl acetate extract were combined and the solvent removed under vacuum to give 0.31 g of solid, m.p: 105-110°C. Anal. for C25H21F3N206S:
Calc'd: C,56.2; H,4.0; N,5.2;
Found: C,55.1; H,3.7; N,5Ø
Reference Example 10 Methyl 1-([l,1'-Biphenyl]-2-carbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-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 CH2C12 chilled at 0°C was added a solution of [ 1,1'-biphenyl]-2-carbonyl chloride in 6 ml of CH2Cl2. The mixture was stirred at room temperature overnight and diluted with CH2Cl2 and H20. The organic layer was separated and washed with 2 ~1 citric acid, brine and dried with Na2S04, The solvent was removed under vacuum to give 2.2 g of a white foam. Anal. for C31 H28N206S:
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-tetrahydro-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 CH2Cl2, chilled to 0°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 CH2Cl2 and water and the organic layer separated. The organic layer was washed with 2 N citric acid. brine and dried with Na2S04, The solvent was removed under vacuum to give 2.2 g of a white foam.
Anal. for C~6H25FN~06S:
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-carboxylate To a mixture of 5.0 g (12.68 mmol) of methyl 2-[(2-aminobenzylj-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate and 17.7 ml (26.8 mmol) of triethylamine in 50 ml of CH2Cl2 chilled to 0°C was added 9.05 ml (63.4 mmol) of benzyl chloroformate. The mixture was stirred overnight and then cooled to 0°C and .8 ml of triethylamine and 9.05 ml (63.4 mmol) of benzyl chloroformate were added thereto. The mixture was stirred overnight and then washed with H20, 2 N
citric acid, brine and dried with Na2S04, 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 1 gH2pN205S:
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 CH2Cl2, cooled to 0°C, was added portionwise 6.64 g (32.14 mmol) of 4-methoxybenzenesulfonyl chloride. The mixture was then stirred under argon at room temperature for 2 days. The mixture was diluted with 100 ml of CH2CI2 and then washed with 60 ml each of H20, 2 N citric acid, brine and dried with Na2S04, The solvent was removed under vacuum to give a solid.
Crystallization from ethyl acetate gave 5.0 g (54%) of white crystals, m.p. 92-94°C.
Anal. for C 11 H 1 SN06S:
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,11.1.
Reference Example 14 Methyl 3-Hydroxy-2-[(4-methoxybenzenesulfonyl)-(2-nitrobenzyl) amino]propionate To a solution of 15.0 g (51.85 mmol) of methyl 3-hydroxy-2-(4-methoxybenzenesulfonylamino)propionate in 125 ml of N,N-dimethylfolmamide, 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°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 H20, 1 N NaHC03, brine and dried with Na2S04, The solvent was removed and the residual solid was triturated with ethyl acetate, cooled and filtered to give 13.5 g (61 %) of white crystals, having a m.p. 127-129°C. From a small scale run (3.0 g) there was obtained 2.32 g of white crystals, having a m.p. 127-129°C. Anal. for C18H2pN2O8S:
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 fonnate followed by the addition of 0.50 g of 10% palladium on carbon. The mixture was stirred overnight at room temperature and heated at 80°C for 2 hours. The mixture was filtered through diatomaceous earth and the filtrate concentrated to dryness under vacuum to give a semisolid.
Trituration with ethyl acetate gave 0.65 g (47%) of white crystals, m.p. 138-140°C;
Anal, for C 18H22N206S:
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)benzyl]amino}propionate To a solution of 0.50 g ( 1.27 mmol) of methyl 2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate in 5 ml of CH2Cl2 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 C20H21F3N207S:
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°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 methylbenzene-sulfonyl chloride were added. The mixture was stirred and chilled at -10°C for 24 hours and diluted with H20. The mixture was extracted with ethyl acetate and the extract washed with H20, 2 N citric acid, and brine and then dried (Na2S04).
The solvent was removed under vacuum to give 1.2 g of an oil. The oil was dissolved in 6 ml of pyridine and 1.08 g of 4-methylbenzenesulfonyl chloride was added thereto.
The mixture was stirred at room temperature overnight and diluted with H20.
The mixture was extracted with ethyl acetate and the extract was washed with H20, citric acid, and brine and then dried with Na2S04, The solvent was removed to give 1.0 g of brown oil. The oil was crystallized from ethanol to give white crystals, m.p. 65-67°C. Anal. for C18H18N20~7S:
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 CH2C12, cooled to 0°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 CH2Cl2. The mixture was washed with H20, 2 N citric acid, and brine and them dried with Na2S04, The solvent was removed to give 1.8 g of a tight tan solid; Anal. for C24H23N306S~
Calc'd: C,59.9; H,4.8; N,8.7; 5,6.6;
Found: C,59.0; H,4.8; N,8.5; S,6.9;
Mass spectrum (ES) 482.6(M+H).
Utilizing the procedure described in Reference Example 18, the following intermediate compounds can be prepared from the appropriately unsubstituted methyl 2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate or the appropriately substituted methyl 2-[(substituted-2-aminobenzyl)-(4-methoxybenzene-sulfonyl)amino]-3-hydroxypropionate.
Reference Example 19 Methyl 2-{ (4-Methoxybenzenesulfonyl)-[2-(2,2,2-trifluoroacetylamino)benzyl]amino}acrylate white crystals, m.p. 120-121 °C. Anal. for C2pH 19F3N206S:
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-Benzoylamlnobenzyl)-(4-methoxybenzenesulfonyl) amino]acrylate yellow oil. Anal. for C25H24N206S:
Calc'd: C,62.5; H,5.0; N,5.8;
Found: C,62.7; H,5.3; N,5Ø
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 C24H23N306S:
Calc'd: C,59.9: H,4.8; N,8.7; S,6.6;
Found: C,58.9: H,4.8; N,8.4; S,6.4;
Mass spectrum (ES) 482.8(M+H).
Example 23 Methyl 2-((4-Methoxybenzenesulfonyl)-{ [(2 thienylcarbonyl)amino]benzyl}amino)acrylate tan solid. Anal. for C23H22N2~6S2:
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}acrylate yellow oil. Anal. for C21 H24N20'7S:
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}acrylate light brown oil. Anal. for C21H26N2~7S2:
Calc'd: C,52.3; H,5.4; N,5.8;
Found: C,51.9; H,5.4; N,5.7.
Reference Example 26 Methyl 2-{ [2-(3-Phenylpropionyl)aminobenzyl]-(4 methoxybenzenesulfonyl)amino}acrylate light brown oil. Anal. for C27H28N206S:
Calc'd: C,63.8; H,5.6; N,5.5;
Found: C,66.7; H,5.8; N,4.1.
_4ø_ Reference Example 27 tert-Butyl 2-{[2-(3-Trifluoromethylbenzoyl)aminobenzyl]-(4-methoxybenzenesulfonyl)amino}acrylate yellow solid; m.p. 65-72°C.
Reference Example 28 Methyl 2-{ [2-(4~Biphenylcarbonyl)aminobenzyl]-(4 methoxybenzenesulfonyl)amino}acrylate white solid. Anal for C31H28N206S:
Calc'd: C,66.9; H,S.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}acrylate yellow oil. Anal. for C22H24N2~6s:
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}acrylate white foam. Anal. for C25H30N206S:
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}acrylate Reference Example 32 Methyl 2-{[2-(3-Chlorobenzoyl)aminobenzyl]-(4-methoxybenzenesulfonyl)amino}acrylate Reference Example 33 Methyl 2-{[2-(2,4-Dichlorobenzoyl)aminobenzyl]-(4 methoxybenzenesulfonyl)amino}acrylate Reference Example 34 Methyl 2-{ [2-(2,3-Difluorobenzoyl)aminobenzyl]-(4 methoxybenzenesulfonyl)amino}acrylate Reference Example 35 Methyl 2-{ [2-(2-Chloro-4-fluorobenzoyl)aminobenzyl]-(4-methoxybenzenesulfonyl)amino}acrylate Reference Example 36 Methyl 2-{ [2-(2-Furanylcarbonyl)aminobenzyl]-(4-methoxybenzenesulfonyl)amino}acrylate off-white solid. Anal. for C23H22N2~7S.
Calc'd: C,58.7; H,4.7; N,6.0;
Found: C,58.0; H,4.1; N,3.8;
Mass Spectrum (ES) 470.9 (M+H).
Reference Example 37 Methyl 2-((4-Methoxybenzenesulfonyl)-{2-((3-thienylcarbonyl)amino]benzyl}amino)acrylate Reference Example 38 Methyl 2-{ [2-(2-Acetylaminoacetyl)aminobenzyl]-(4 methoxybenzenesulfonyl)amino}acrylate Reference Example 39 Methyl 2-{ [2-(2-Dimethylacetyl)aminobenzyl]-(4-methoxybenzenesulfonyl)amino}acrylate Reference Example 40 Methyl 2-{ [2-(Cyclobutylcarbonyl)aminobenzyl]-(4-methoxybenzenesulfonyl)amino}acrylate Reference Example 41 Methyl 1-Methoxyacetyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate To a mixture of 0.449g ( 1 mmol) of methyl 2-[[2-(2-methoxyacetamido)-benzyl]-(4-methoxybenzene-sulfonyl]amino]acrylate in S ml of anhydrous methanol was added 0.109 g ( 1.3 mmol) of anhydrous sodium bicar-bonate. The mixture was stirred at room temperature overnight and the solvent removed under vacuum. To the residue was added ethyl acetate and water. The organic layer was separated and washed with H20 and brine and then dried with Na2S04, 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°C. Anal. for C21H24N207S:
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-methoxybenzene-sulfonyl)-[2-(substituted amino)benzyl]amino)acrylates.
Reference Example 42 Methyl 4-(4-Methoxybenzenesulfonyl)-1-(4-methylphenylsulfonyl) 2,3,4,5-tetrahydro-1 H-( 1,4]benzodiazepine-3-carboxylate white foam. Anal. for C25H26N207S2:
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 I,4-Bis-(4-methoxybenzenesu)fonyl)-2,3,4,5-tetrahydro-1H-(1,4]benzodiazepine-3-carboxylate white solid. Anal. for C25H26N208S2:
Calc'd: C,54.9; H,4.8; N,5.1;
Found: C,54.8; H,4.9; N,5.1.
_ 47 _ Reference Example 44 Methyl 1-Methanesulfonyl-4-(4-methoxybenzeuesulfonyl)-2,3,4,5-tetrahydro-1H-[l,4Jbenzodiazepine-3-carboxylate white crystals, m.p. 136-137°C. Anal. for C19H22N207S2:
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]benzodiazepine-3-carboxylate tan solid. Anal. for C25H24N2~2S:
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-1 H-[1,4]benzodiazepine-3-carboxylate white crystals, m.p. 150-155°C. Anal. for C2pH22N2~6S:
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-1 H-[ 1,4J benzodiazepine-3-carboxylate off white solid; Anal. for C24H23N3~6S:
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-[l,4Jbenzodiazepine-3-carboxylate off white solid. Anal. for C23H22N2~6S2:
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°C. Anal. for C24H23N3~6S:
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-1.H-[1,4]benzodiazepine-3-carboxylate white solid; Anal, for C31H28N206S:
Calc'd: C,66.9; H,5.1; N,S.O;
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-sulfonyt)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate yellow oil. Anal. for C21H26N2~7S2:
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-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate white foam. Anal. for C31H28N206S:
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-tetrahydro-1H-[ 1,4]benzodiazepine-3-carboxylate white solid; Anal. for C26H25FN206S:
Calc'd: C,60.9; H,4.9; N,5.5;
Found: C,60.9; H,5.0; N,5Ø
Reference Example 55 Methyl 4-(4-Methoxybenzenesulfonyl)-1-(2-methyl-3-fluorobenzoyl)-2,3,4,5-tetrahydro-1 H-[ 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 C27H28N206S:
Calc'd: C,63.8; H,5.6; N,5.5;
Found: C,64.0; H,5.7; N,5.3: 5,6.5.
Reference Example 57 Methyl 4-(4-Methoxybenzenesulfonyl)-1-(2-trifluoromethylbenzoyl)-2,3,4,5-tetrahydro-1H-[ 1,4] benzodiazepine-3-carboxylate Reference Example 5$
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-tetrahydro-1 H-[ 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-tetrahydro-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-tetrahydro-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 C25H22C12N206S:
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-tetrahydro-1 H-[ l,4Jbenzodiazepine-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-tetrahydro-1H-[1.4]benzodiazepine-3-carboxylate Reference Example 77 Methyl 4-(4-Methoxybenzenesulfonyl)-1-(4-methyl-2-thienylcarbonyl)-2,3,4,5-tetrahydro-1H-[ 1,4]benzodiazepine-3-carboxylate Reference Example 7$
Methyl 1-(3-Chloro-2-thienylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-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°C. Anal. for C23H22N207S:
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-tetrahydro-1H-[ 1,4)benzodiazepine-3-carboxylate Reference Example 81 Methyl 4-(4-Methoxybenzenesulfonyl)-1-(4-methyl-2-furanylcarbonyl) 2,3,4,5-tetrahydro-1H-[ 1,4]benzodiazepine-3-carboxylate Reference Example 82 Methyl 1-(5-Chloro-2-furanylcarbonyl)-4-(4-methoxybenzenesulfonyl) 2,3,4,5-tetrahydro-IH-[1,4]benzodiazepine-3-carboxylate Reference Example 83 Methyl 1-(5-Chloro-2-thienylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate Reference Example 84 Methyl 1-Propionyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate Reference Examprle 85 Methyl 1-Hexanoyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate Reference Example 86 Methyl 1-(3-Methoxypropionyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[ I,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]benzodiazepine-3-carboxylate Reference Example 91 Methyl 1-(Chloroacetyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate Following the method described for Reference Example 18, 3.0 g (7.61 mmol) of methyl 2-[2-aminobenzyl)-(4-methoxy-benzenesulfonyl)-amino]-3-hydroxy-propionate was reacted with 1.82 ml (22.8 mmol) of chloroacetylchloride to give 4.0 g of solid. Chromatography on silica gel with ethyl acetate-hexane ( 1:1 ) as a solvent gave 1.5 g of methyl 2-[(2-chloroacetylaminobenzyl)-(4-methoxybenzenesulfonyl)-amino]-acrylate. A 1.3 g sample of the preceding compound was reacted with 0.312 g of anhydrous NaHC03 in 10 ml of anhydrous methanol at room temperature overnight and the mixture was then heated at 80°C for 5 hours. The solvent was removed and the residue partitioned between H20 and ethyl acetate. The ethyl ~etate extract was washed with brine, dried with Na2S04 ~d the solvent removed. The residue was trittlrated with hexane-ethyl acetate, chilled and filtered to give the product; Mass sp~~um (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-tetrahydro-1 H-[ 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°C. Anal. for C22H24N206S:
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 tetrahyd ro-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)benzyl]amino}propionate in 10 ml of CH2C12 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 NaHC03 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 H20, brine and dried with Na2S04. 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 C2pH 19F3N2O6S:
Calc'd: C,50.9; H,4.1; N,5.9; F,12.1; 5,6.7;
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)-I-(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-methoxybenzene-sulfonyl)amino]-3-hydroxypropionate in 5 ml of pyridine cooled to 0°C
was added 0.284 g (2.59 mmol) of tosyl chloride. The mixture was stirred at 0°C
for 2 hours and then concentrated to remove the solvent. To the residue 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 H20, 2 N citric acid, brine and dried with Na2S04. 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 C25H26N207S2:
Calc'd: C,56.6; H,4.9; N,5.3; 5,12.1;
Found: C,56.2; H,5.2; N,5.2; 5,11.4;
Mass spectrum (ES) 531.6 (M+H).
Reference Example 98 Methyl 2-[(4-Methoxybeozenesulfonyl)-(2-methylsulfonylaminobenzyl)amino]acrylate To a solution of 1.0 g (2.54 mmol) of methyl [(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate in 10 ml of pyridine cooled to -5°C was added 0.432 ml (5.58 mmol) of methanesulfonyl chloride. The mixture was stirred at 0°C for 48 hours. To the mixture was added ice and H20 and the mixture was extracted with ethyl acetate. The extract was washed with H20, 2 N citric acid, brine and dried with Na2S04, The solvent was removed under vacuum and the residue triturated with ethyl acetate-hexane to give 0.90 g of a solid, 128-142°C. Anal. for C 19H22N207S2:
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-1 H-[1,4]benzodiazepine-3-carboxylate To a solution of 1.0 g (2.34 mmot) of methyl ?-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate in 6 ml of pyridine cooled to 0°C to -5°C was added 1.07 (5.18 mmol) of 4-methoxybenzenesulfonyl chloride. After 2 hours, the mixture was concentrated to dryness under vacuum. To the residue was added 12 ml of ethanol and the mixture refluxed overnight. The solvent was removed under vacuum and the residue chromatographed on silica gel thick layer plates with ethyl acetate-hexane ( I :1 ) as solvent to give 0.83 g (60%) of product as a white foam;
Anal. calc'd for C25H2(~N2O8S2: C,54.9; H,4.8; N,5.1; S,11.7. Found: C,54.8;
H,4.9; N,5.0; 5,11.5; Mats spectrum (ES) 547.1 (M+H); and a second component (0.38 g) methyl 2-{ [2-(4-methoxybenzenesulfonyl)aminobenzyl]-(4-methoxybenzene-sulfonyl)amino}-3-hydroxypropionate. Anal. for C25H28N2O9S2:
Calc'd: C,53.2; H,5.0; N,5.0; S,11.4;
Found: C,51.8; H,S.1; N,4.7; S,1 I .3;
Mass spectrum (ES) 565.2 (M+H).
Reference Example 100 Methyl 1-Acetyl-4-(4'-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1 H-[ 1,4] benzodiazepine-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 H20. The organic layer was separated, washed with brine and dried with Na2S04, The solvent was removed and the residue dried under vacuum to give 0.59 g of white crystals, m.p. 150-155°C. Anal. for C2pH22N2O6S:
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]propionate A mixture of 1.0 g (2.54 mmol) of methyl 2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate and 1.3 ml of acetic anhydride WO 99/37625 PC'T/US99/o1325 in 8 ml of toluene was heated at 100°C for 2 hours. The mixture was concentrated and 3 ml of acetic anhydride added thereto. The mixture was heated at 100°C
overnight and concentrated to dryness under high vacuum to give an oil. The oil was dried at 75°C
under vacuum for 48 hours to give 1.2 g of a yellow oil. Anal. for C24H28N2O9S:
Calc'd: C,54.5; H,5.2; N,5.5; S,6.2;
Found: C,54.6; H,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-diacetyl-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]propionate and 0.826 ml (5.92 mmol) of triethylamine in 5 ml of CH2C12 was stirred at room temperature overnight.
The solution was diluted with 30 ml of CH2Cl2 and washed with 20 ml each of H20, 2 ~I citric acid, brine and dried with Na2S04, The solvent was removed under vacuum to give a brown oil. Anal. for C22H24N207S:
Calc'd: C,57.4; H,5.3; N,6. I ; 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°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 H20, brine and dried (Na2S04). The solvent was removed under vacuum to give 1.0 g of colorless oil. Crystallization from ethyl acetate -hexane gave 0.625 g of colorless crystals, m.p. 120-121 °C.
Anal. for C2pH 19F3N206S:
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;
S Mass spectrum (ES) 473.1 (M+H).
Reference Example 104 4-(4-Methoxybenzenesulfonyl)-1-(2-methyl-5-fluorobenzoyl)-2,3,4,5 tetrahydro-1H-[1,4~]benzodiazepine-3-carboxylic Acid To a mixture of 1.9 g (3.71 mmol) of methyl 4-(4-methoxybenzenesulfonyl)-1-(2-methyl-5-fluorobenzoyl)-2,3,4,5-tetrahydro-1H-[ 1,4]benzodiazepine-3-carboxylate in 10 ml of tetrahydrofuran wac 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
HCI. The 15 organic layer was separated, washed with brine and dried with Na2S04. The solvent waa removed under vacuum to give 1.41 g of white solid. Anal. for C25H23~2065:
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 C24H24N20'752:
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-1 H
[1,4]benzodiazepine-3-carboxylic acid off white solid. Anal. for C24H?4N208S2:
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]benzodiazepine-3-carboxylic acid white solid. Anal. for C ~ gH2pN207S2:
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]benzodiazepine-3-carboxylic acid white foam. Anal. for C24H22N206S:
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-1 H
[1,4]benzodiazepine-3-carboxylic acid white solid; Anal. for C19H22N206S:
Calc'd: C,56.4; H,5.0; N,6.9;
Found: C,55.2; H,4.9; N,6.6; 5,7.8;
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 C23H? 1 N306S:
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 C22H20N2~6S2:
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]benzodiazepine-3-carboxylic acid white crystals, m.p. 193-194°C. Anal. for C2pH22N2~7S:
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 °C. Anal. for C23H21 N306S:
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 C3pH26N206S:
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 C2pH24N2~7S2:
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 tetrahydro-1H-(1,4]benzodiazepine-3-carboxylic acid white foam; m.p. 106-145°C. Anal. for C3pH26N2~6S:
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-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid WO 99/3'I625 PCT/US99/01315 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 C26H26N206S:
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-tetrahydro-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-Methoxybenzenesulfooyl)-1-(2-methyl-6-chlorobenzoyl)-2,3,4,5-tetrahydro-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 S Reference Example 128 1-(2-Chloro-4-fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid Reference Example 129 1-(2-Chlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-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 tetrahydro-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 C24H20CI2N2~6S:
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 WO 99/37625 PCT/US99l01325 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-IH-[1,4]benzodiazepine-3-carboxylic acid Reference Example 137 1-(4-Chloro-2-methoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-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-carboxylic acid Reference Example 140 4-(4-Methoxybenzenesulfonyl)-1-(4-methyl-2-thienylcarbonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid Reference Example 141 1-(3-Chloro-2-thienylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-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 C22H2pN2~7S:
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 tetrahydro-1H-[1,4)benzodiazepine-3-carboxylic acid Reference Example 144 4-(4-Methoxybenzenesulfonyl)-1-(4-methyl-2-furanylcarbonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid Reference Example 145 1-(5-Chloro-2-furanylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid Reference Example 146 1-(5-Chloro-2-thienylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid Reference Example 147 1-Propionyl-4-(4-methoxybenzenesulfonyl}-2,3,4,5-tetrahydro-1H
[1,4)benzodiazepine-3-carboxylic acid Reference Example 148 1-Hexanoyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H
[1,4]benzodiazepine-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 WO 99/37625 PCT/US99/Oi325 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]benzodiazepine-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°C. Anal. for C21H22N2~6S:
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 C24H28N206S:
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-methyl benzenesulfonic acid monohydrate in 5 ml of tetrahydrofuran was refluxed overnight and the mixture was concentrated to dryness under vaccum. The residue was extracted with CH2Cl2 and the extract washed with 2 N NaHC03, . brine and dried with Na2S04, The solution was filtered through a thin pad of hydrous magnesium silicate and the filter pad washed with CH2C12. The filtrate was concentrated to dryness and the residue (2.3 g) was extracted with three SO ml portions of hot hexane to give 1.92 g of product as a yellow oil; Mass spectrum (ES) 374.4 (MH+).
Reference Example 160 Methyl 3-Hydroxy-2-{ [4-methoxybenzenesulfonyl]-[2-(4-morpholinocarbonylamino)benzyl]amino}propionate To a mixture of 1.0 g (2.54 mmol) of methyl 2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate in 8 ml of pyridine chilled at OP
to -10°C was added 740 pL, (6.34 mmol) of morpholinocarbonyl chloride.
The mixture was kept at OP to 5°C overnight. The mixture was concentrated under vacuum and diluted with ethyl acetate. The solution was washed with H20, 2 N citric acid, and brine and dried with Na2S04, 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 C23H29N308S:
Calc'd: C,54.4; H,5.8; N,8.3;
Found: C,53.9; H,5.7; N,B.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-methoxy-benzenesulfonyl]-[2-(4-morpholinocarbonylamino)benzyl]amino }propionate and lli, (5.54 mmol) of triethylamine in 8 ml of CH2C12, cooled to 0°C, was added 0.386 g (2.03 mmol) of 4-methylbenzenesulfonyl chloride. The mixture was stirred at room temperature for 2 hours, diluted with water and extracted with CH2C12. The extract was washed with 2 N citric acid, brine and dried with Na2S04, The solvent was removed to give 0.67 g of a yellow oil. Anal. for C23H27N307S:
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 NaHC03 in 5 ml of anhydrous methanol was stirred at room temperature for 16 hours. An additional 55 mg of NaHC03 was added and the mixture stirred at room temperature for 2 hours. The solvent was removed under vacuum and the residue diluted with H20 and extracted with ethyl acetate. The extract was washed with brine and dried with Na2S04. 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 C23H27N30~7S:
C,56.4; H,5.6; N,8.6; 5,6.6. 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-1H-[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 HCI and cooled. The mixture was filtered and the solid washed with water to give 0.26 g of white solid. Anal. for C22H25N307S:
Calc'd: C,55.6; H,5.3; hI,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-vitro-4-chlorobenzyl)amino]propionate To a mixture of 1.67 g (4.4 mmol) of (D,L) N-(4-methoxybenzenesulfonyl)-O-(2-tetrahydropyranyl) serine, methyl ester, 0.825 g (4.4 mol) of 4-chloro-2-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 H20 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 C24H25N306S:
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 } acrylate in 10 ml of methanol was added 0.207 g (2.46 mmol) of anhydrous sodium bicarbonate. The mixture was stirred for 2 days and then an additional 0.207 g of NaHC03 added. The mixture was stirred overnight and the solvent removed under vacuum. To the residue was added H20 and ethyl acetate and the organic layer separated. The ethyl acetate extract was washed with brine, dried with Na2S04 and the solvent removed under vacuum to give 0.83 g of the product as a yellow oil. Anal. for C25H3pN206S: 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]propionate To a solution of 0.289 g ( 1 mmol) of methyl 3-hydroxy-2-(4-methoxybenzenesulfonylamino)propionate in 4 ml of N,N-dirnethylformamide 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 CH2Cl2.
The extract was washed with H20, brine and dried with Na2S04. 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°-114°C. Anal. for C 18H 19C1N2O8S:
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]propionate A mixture of 0.454 g ( 1 mmol) of methyl 3-hydroxy-2-[(4-methoxy-benzenesulfonyl)-(4-chloro-2-nitrobenzyl)amino]propionate and 0.451 g (2 mmol) of SnCl2~2H20 in 12 ml of methanol was refluxed for 2 hours. An additional 0.451 g (2 mmol) of SnCl2~2H20 was added and the mixture refluxed for 2 hours. The solvent was removed and ethyl acetate added. The mixture was neutralized with 1 N
NaHC03 and then stirred for 1 hour and filtered. The ethyl acetate layer was separated and washed with H20, brine and dried with Na2S04. 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 (RF 0.66) as a glass, m.p.
99°- I I 2°C. Anal. for C I8H21 C1N206S:
Calc'd: C,50.4; H,4.9: N,6.5;
Found: C,49.7; H,4.9; N,6.4:
Mass specwm (ES) 429.1 (M+H).
Reference Example 169 Methyl 3-Hydroxy-2-[(4-methoxybenzenesulfonyl)-(4-chloro-2-aminobenzyl)amino]propionate To a solution of 0.458 g ( 1 mmol) of methyl 3-hydroxy-2-[(4-methoxybenzenesulfonyl)-(4-chloro-2-nitrobenzyl)amino]propionate in 25 ml of ethanol and 25 ml of ethyl acetate was added 0.045 g of 10% Pd/C (wet - 50%
H20).
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 } propionate, and 0.470 g of 10% Pd/C (wet-50% H20) in 200 ml of ethyl acetate-ethanol ( I :1 ) was shaken in a Parr hydrogenator under 35 psi of hydrogen for 4 hours. The mixture was filtered through diatomaceous earth and the solvent removed to give 4.5 g of solid. The solid was chromatographed by HPLC
on a Waters Prep machine with a 4 x 30 cm silica gel column with a step gradient of hexane-ethyl acetate (9:1 to 6:4 to 1:1 to 0:100) to give 1.56 g of a glass, m.p.
110°-123°C.
Anal. for CI8H21CIN206S:
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 CH2Cl2, cooled in an ice bath was added 41.7 ml (0.3 mol) of triethylamine, followed by the dropwise addition of a solution of 20.65 g (0.1 mol) of 4 methoxybenzenesulfonyl chloride in 40 ml of CH2Cl2. The mixture was stirred at room temperature overnight and poured into water. The organic layer was separated and washed with 2 N citric acid, H20, 1 N NaHC03, brine and dried with Na2S04, The solvent was removed under vacuum to give 24.6 g of residue which was triturated with ethyl acetate to give 19.9 g of crystals, m.p. 59°-61°C.
Anal. for C1pH13NS05:
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 ~T,N-dimethylformamide was added dropwise a solution of 7.78 g (30 mmol) of N-(4-methoxybenzenesulfonyl)glycine, methyl ester in 40 ml of N,N-dimethyl-formamide. After gas evolution ceased, a solution of 6.80 g (32 mmol) of 2-nitrobenzyl bromide in 40 ml of N,N-dimethylformamide was added dropwise to the mixture. The mixture was then stirred at room temperature overnight under nitrogen and the solvent removed under vacuum. The residue was extracted with CH2Cl2 and the extract washed with H20, 2 N citric acid, H20, 1 N NaHC03, brine and dried with Na2S04, The solution was filtered through a thin pad of hydrous magnesium silicate and the filter pad washed with CH2Cl2. The filtrate was concentrated under vacuum to give 11.79 g of solid. Trituration with ethyl acetate gave 2.64 g (22%) of crystals, m.p. 114°C-116°C. Anal. for C17H18N20~7S:
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%j of product as crystals was obtained by chilling at 0°C and filtering the mother liquors.
Reference Example 172 Methyl 2-[(2-Aminobenzyl)-(4-methoxybenzenesulfonyl)amino]acetate (A) To a mixture of 2.15 g (5.45 mmol) of methyl-2-[(4-methoxy-benzenesulfonyl)-(2-nitrobenzyl)amino]acetate and 1.57 g (25 mmol) of ammonium formate in 10 ml of anhydrous methanol was added 0.42 g of 10% palladium on carbon. The mixture was stirred at room temperature for 1.5 hours and then filtered through diatomaceous earth. The filtrate was concentrated to dryness under vacuum and the residue diluted with H20 (25 ml) and extracted with CH2C12 (75 ml).
The extract was washed with brine, dried with Na2S04 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°-102°C. Anal. for C 17H2pN2O5S:
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% H20) and the mixture shaken in a Purr hydrogenator under 35 pounds per square inch of hydrogen for 4.5 hours at room temperature.
The mixture was filtered through diatomaceous earth and the filtrate concentrated to dryness under vacuum to give 4.0 g of crystals, m.p. 100°-102°C.
Reference Example 173 2-[(2-Aminobenzyl)-(4-methoxybenzenesulfonyl)amino]acetic Acid To a solution of 5.14 g ( 14.1 mmol) of methyl 2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino] acetate in 50 ml of methanol-tetrahydrofuran ( 1:1 ) was i 5 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 H20 and dried in a vacuum oven at room temperature to give 4.45 g (91 %) of crystals, m.p. 145°-147°C. Anal. for C16H18N205S:
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°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 CH2Cl2 was added 1.58 g ( 1 l .4 mol) of phenoxyacetyl chloride. The mixture was stirred at room temperature overnight and filtered.
The filtrate was washed with H20, 2 N citric acid, and brine and dried with Na2S04, The solvent was removed to give 2.4 g of crude methyl 2-{(4-methoxybenzenesulfonyl)-[2-(phenoxyacetylamino)benzyl]amino~acrylate av an oil. Anal. for C26H26N207S:
Calc'd: C,61.2; H,5.1; N,5.5;
Found: C,62.6; H,5.1; N,4.0;
Mass spectrum (ES) S I 1 (M+H).
To a 2.0 g (3.92 mmol) sample of the preceding compound in 1 S ml of methanol was added 0.494 g of anhydrous NaHC03 and the mixture stirred for 5 hours. The mixture was concentrated under vacuum and ethyl acetate and H20 were added to the residue. The mixture was filtered and the organic layer of the filtrate separated, washed with brine and dried with Na2S04, The solvent was removed to give 0.36 g of product as off white crystals, m.p. I51°-153°C.
Anal. for C26H26N20?S:
Calc'd: C,61.2; H,5.1; N,5.5;
Found: C,61.1; H,S.1; N,5.4;
Mass spectrum (ES) 511 (M+H).
Reference Example 175 3-hydroxymethyi-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-1 H-[ 1,4]benzodiazepine-3-carboxylate and 3 ml of borane-tetrahydroforan complex in tetrahydrofuran ( 1.0 M) was refluxed overnight. The solution was cooled to room temperature, diluted with methanol and the solvent removed. Methanol was added several times and, after each addition, the solvent was removed. To the residue was added 1 N NaHC03. The mixture was stirred for 45 minutes and then extracted with ethyl acetate. The extract was concentrated and then washed with H20, brine and dried with Na2S04, 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 (RF 0.26).
Crystallization from ethyl acetate gave 30 mg of white crystals. Anal. for C23H25N304S:
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-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate To a cooled (0°C) mixture of 1.0 g (2.54 mmol) of methyl 2-[(2-aminobenzyl}-(4-methoxybenzenesulfonyl) amino]-3-hydroxypropionate and 1.8 ml ( 12.68 mmol) of triethylamine in 10 ml of CH2C12 was added 0.957 g (5.58 mmol) of 2-methoxypyridine-3-carbonyl chloride in 4 ml of CH2C12. The solution was stirred at WO 99/37625 PC'f/US99/01325 room temperature overnight. diluted with H20 and CH2Cl2 and the organic layer separated. The organic Layer was washed with H20, 2 N citric acid, and brine and dried with Na2S04, 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 C25H25N307S:
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 H20, brine and the solvent removed under vacuum to give a mixture of product (50%) and starting material (50%).
Reference Example 178 Methyl 3-Hydroxy-2-[(4-methoxybenzenesulfonyl)-(5-methyl-2-nitrobenzyl)amino]propionate A solution of 23.14 g (0.08 mol) of methyl 3-hydroxy-2-(4-methoxybenzenesulfonylamino)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 S-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 H20 and extracted with S00 ml of ethyl acetate. The aqueous layer was extracted with an additional 200 ml of ethyl acetate. The combined extract was washed with H20, brine and dried with Na2S04, 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 (RF 0.38) of product as a yellow semi-solid. From a small scale run ( 1 mmol) the product was chromatographed twice on thick silica gel plates with hexane-ethyl acetate ( 1:1 ) to give 0.12 g of a yellow semi-solid. Anal. for C 19H22N2SOg:
Calc'd: C,52.0: H,5.1; N,6.4;
Found: C,51.7; H,S.1; N,6Ø
Reference Example 179 Methyl 3-Hydroxy-2-[(4-methoxybenzenesulfonyl)-(2-amino-5-methylbenzyl)amino]propionate To a solution of 3.4 g of methyl 3-hydroxy-2-[(4-methoxybenzenesulfonyl)-(5-methyl-2-nitrobenzyl)-amino]propionate in 200 ml of ethanol-ethyl acetate ( 1:1 ) was added 0.34 g of 10% palladium on carbon (wet - 50% H20). The mixture was then shaken in a Parr hydrogenator under 35 psi of hydrogen for 2.5 hours. The mixture was filtered through diatomaceous earth and the filtrate concentrated under vacuum to give 2.86 g of a brown oil. Anal. for C 19H24N206S:
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-nitrobenzyl)amino]propionate To a mixture of 1.75 g (4.68 mmol) of (D,L)~l-(4-methoxybenzenesulfonyl)-O-(2-tetrahydropyranyl) serine, methyl ester, 0.790 g (4.68 mmol) of 5-methyl-2-nitrobenzyl alcohol and 1.23 g (4.68 mmol) of triphenylphosphine -in 4.5 ml of anhydrous tetrahydrofuran was added dropwise (over 15 minutes) a solution of 0.815 g (4.68 mmol) of diethyl azodicarboxylate (DEAD) in 1 ml of tetrahydrofuran. The mixture was stirred at room temperature overnight and the solvent removed under vacuum. The residue was triturated with diethyl ether and the solid filtered off. The filtrate was concentrated to dryness under vacuum to give 4.67 g of solid. The solid was chromatographed on silica gel with hexane-ethyl acetate ( 1:1 ) to give 0.56 g of product (RF 0.48).
Reference Example 181 Methyl 1-Methoxyacetyl-4-(4-methoxybenzenesulfonyl) 7-methyl-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate To a cooled (0°C) mixture of 1.598 g (3.91 mmol) of methyl 3-hydroxy-2-[(4 methoxybenzenesulfonyl)-(2-amino-5-methylbenzyl)amino]propionate and 1.97 g (19.5) mmol) of triethylamine in 15 ml of dichloromethane was added 0.787 ml (8.60 mmol) of methoxyacetylchloride. The mixture was stirred at room temperature _77_ overnight. The mixture was then diluted with CH2Cl2 and washed with H20. 2 N
citric acid, H20. brine and dried with Na2S04. The solution was filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to give 1.94 g of crude methyl 2-{ [2-(methoxyacetylamino)-5-methylbenzyl]-(4-methoxy-benzene-sulfonyl)-amino}acrylate as a brown oil. Mass spectrum (ES) 463.4 (M+H).
To a solution of 1.62 g (3.5 mmol) of the preceding compound in 15 lnl of anhydrous methanol was added 0.382 g (4.50 mmol) of anhydrous NaHC03 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 H20, brine and dried with Na2S04. 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°10) of tan crystals, m. p. 122°-124°C. Anal. for C22H26N207S:
Calc'd: C,57.1; H,5.7; N,6.1;
Found: C,57.4; H,5.7; N,6Ø
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°C) mixture of 1.465 g (3.586 mmol) of methyl 3-hydroxy-2-[4-methoxybenzenesulfonyl)-(2-amino-5-methylbenzyl)amino]propionate and 2.49 ml (17.93 mmol) of triethylamine in 20 ml of CH2Cl2 was added 0.915 ml (7.89 mmol) of benzoyl chloride. The mixture was stored at room temperature overnight, diluted with CH2C12 and washed with H20, 2 N citric acid, H20, brine and dried with Na2S04, The solution was filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated under vacuum to give 1.8 g of crude methyl 2-[(2 benzoylamino-5-methylbenzyl)-(4-methoxybenzenesulfonyl)amino]acrylate as a brown oil. Anal. for C26H26N206S:
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 NaHC03 in 1.5 ml of .methanol to give an oil. Trituration with hexane (plus several drops of ethyl acetate) gave crystals, m. p. 58°-62°C.
_78_ Reference Example 183 Methyl 1-(traps-Crotonyl)-4-(4-methoxybenzenesulfonyl)-7-methyl 2,3,4,5-tetrahydro-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-methyl-benzyl)amino]propionate, 1.75 g ( 17.3 mmol) of triethylamine and 0.809 ml of trans-crotonyl chloride in 15 ml of CH2Cl2 was stirred overnight to give 1.52 g of methyl 2-{ [2-(traps-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 mlnol) of NaHC03 in 15 ml of methanol at room - temperature overnight. To the mixture was added 0.056 g of NaHC03 and the mixture was heated at 80°C for 3 hours and worked up as for Reference Example 181 to give a I .OS g of a yellow glass, m. p. 75°-84°C. Mass spectrum (ES) 459.4 (M+H).
Reference Example 184 1-(traps-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-(traps-crotonyl)-4-(4-methoxybenzenesulfonyl)-7-methyl-2,3,4,5-tetrahydro-1 H-( 1,4]benzodiazepine-3-carboxylate and 3.53 ml (3.53 mmol) of 1 N NaOH in 10 ml of tetrahydrofuran was stirred at room temperature for 3 hours. The solvent was removed under vacuum and the residue dissolved in H20 and the solution extracted with ethyl acetate.
The aqueous layer was acidified with 1N HCl (pH 2) and extracted with CH2C12. The CH2Cl2 extract was dried with Na2S04 and the solvent removed to give 1.06 g (after drying under vacuum) of solid, m. p. 101°-105° 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 1.18g (2.38 mml) of methyl 1-(benzoyl)-4-(4-methoxy-benzenesulfonyl)-7-methyl-2,3,4,5-tetrahydro- I H-( 1,4]benzodiazepine-3-carboxylate and 3.09 ml (3.09 mmol) of 1N NaOH in 10 ml of tetrahydrofuran was stored at mom temperature overnight and the solvent removed under vacuum. The residue was diluted with H20, extracted with ethyl acetate and the aqueous layer acidified with 2N
citric acid. The mixture was extracted with CH2Cl2 and the CH2Cl2 extracts were washed with H20, brine and dried with Na2S04, The solvent was removed to give 0.828 of a light yellow glass, m.p. 95°-100°C; Mass spectrum (ES) 481.4 (M+H).
Reference Example 186 Methyl 4-(4-Methoxybenzenesulfonyl)-1-(2-methoxyethyl)-2,3,4,5 tetrahydro-1 H-[ 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-I H-[ 1,4]benzodiazepine-3-carboxylate and 32 ml of borane in tetrahydrofuran ( I .0 M) was refluxed under nitrogen overnight.
Methanol was added and the solvent removed. To the residue was added 25 ml of CH2Cl2 and 25 ml of 2 N HCl and the mixture stirred at room temperature for I
hour.
The organic layer was separated and washed with H20 and concentrated to dryness.
The residue was triturated with ethyl acetate-hexane, cooled and filtered to give 1.2 g of white crystals, m.p. 86°-90°C; Mass spectrum (ES) 435.4 (M+H).
Anal. for C21 H26N206S:
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-IH[1,4]benzodiazepine-3-carboxylic acid A mixture of 1.0 g (2.3 mmol) of methyl 4-(4-methoxybenzenesulfonyl)-1-(2 methoxyethyl)-2,3,4,5-tetrahydro-IH-[1,4]benzodiazepine-3-carboxylate and 3.0 ml of 1 N NaOH in 10 ml of tetrahydrofuran was stirred at room temperature for 2 hours and the solvent removed. To the residue was added water and the mixture acidified with 1 N HCI. The mixture was extracted with ethyl acetate and the extract was washed with brine and dried with Na2S04, The solvent was removed and the residue triturated with ethyl acetate-hexane, cooled and filtered to give 0.65 g of white crystals, m.p. 164°-165°C; Mass spectrum (ES) 421.4 (M+H). Anal. for C2pH24N2O6S:
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]benzodiazepine-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]benzodiazepine-3-carboxylate and 4 ml of borane in tetrahydrofuran ( 1.0 M) was refluxed overnight and the solvent removed. To the residue was added 5 ml of CH2C12 and 5 ml of 2N HCI 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-hydroxypropionate 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 NaHC03 in 15 ml of methanol at room temperature for 16 hours and then was heated at 80°C for 2 hours. The solvent was removed and the residue extracted with ethyl acetate. The extract was washed with H20, brine, and dried (Na2S04). 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°-151°C. Anal. for C26H22C~307S:
Calc'd: C,52.1; H,3.7; N,4.7; C1,6.0; F,9.5;
Found: C,51.8; H,3.6; N,4.7; C1,5.9: F,9.4.
1.58g (2.64 mmol) of the preceding compound was stirred with 3.43 ml of 1 N
NaOH in 10 ml of tetrahydrofuran at room temperature for 2 hours and worked up as for Reference Example 104 to give 1.52 g of product. Crystallization from ethyl acetate-hexane gave 1.2 g of white crystals, m.p. 184°-186°C.
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- 1 H-[ 1,4]benzodiazepine-3-carboxylate, 21.2 ~1 of morpholine and 125.4 El of N,N-diisopropylethylamine in 3 ml of CH2Cl2 was stirred overnight at room temperature. An additional 2.2 El of morpholine was added and the solution stirred for 2 days at room temperature. The mixture was diluted with CH2C12 and washed with H20, brine and dried with Na2S04, The solvent was removed to give the product as a solid, Mass spectrum (ES) 504.3 (M+H). Anal.
for C24H29N30'7S:
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
[l,4Jbenzodiazepine-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,2 H,2 N2O2: C, 66.7; H, 5.6; N
13.0: Found:
C, 66.5: H, 5.4: N, 12.9; Mass spectrum (ES) 217.2 (M+H). A sample (7.02g) of this compound and 8.42 ml of SN 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 l.Sg of product. The two crops were combined to give 5.2g of 2-(1-pyrazolyl)benzoic acid, mp 140-142°C. To the preceding compound (2.07 g) in 5 ml CH2Cl2 (chilled in an ice bath )was added 11.1 ml of a 2 Molar solution of oxalyl chloride in CH2CI2 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 l.Sg of the compound of Reference Example 179 in 15 ml of CH2CI2 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-methylbenzyl }-amino]acrylate. This compound was cyclized with NaHC03 in methanol in the manner described in Reference Example 181 to give methyl 4-(4-methoxybenzenesulfonyl)-[2-(1-pyrazolyl)phenylcarbonyl]-7-methyl-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate (m.p. 240-242° 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)phenyl-carbonyl)-7-methyl-2,3,4,5-tetrahydro-1H[1,4]benzodiazepine-3- carboxylic acid (mp 149-151°C).
Reference Example 192 Methyl 4-(4-Methoxybenzenesulfonyl)-1-[2-(4-morpholino)phenylcarbonyl}-8-chloro-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate Ethyl 2-morpholinobenzoate prepared in the manner described in Tetrahedron, 53:7557, ( 1997) was refluxed with 10 N NaOH in tetrahydrofuran-ethanol (8:2) for 1.5 hrs to give 2-morpholinobenzoic acid, mp 156-157°C. A 1.8 g sample of this compound in 5 ml of CH2Cl2 (chilled) was added to a solution of 7.9 ml of oxalyl chloride in CH2C12 (2M) followed by the addition of 0.058 ml of N,N-.
dimethylformamide. The solution was stirred at room temperature for 6 hrs and the solvent removed. Toluene was added (2 times) and removed to give 2-(4-morpholino)benzoyl chloride as a yellow solid.
The preceding 2-(4-morpholino)benzoyl chloride was reacted with methyl 2-[(2-amino-4-chlorobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate in the manner described in Reference Examples 181 and 189, and the product was stirred with NaHC03 in methanol to give methyl 4-(4-methoxybenzenesulfonyl)-1-[2-(4-morpholino)phenylcarbonyl]-8-chloro-2,3,4,5-tetrahydro-1 H-[
1,4]benzodiazepine-3-carboxylate, as a white solid having a mp 100-105°C.
To 0.90g of this compound in 10 ml of tetrahydrofuran was added 1.95 ml of 1 N NaOH and the solution was stirred at room temperature overnight.
Acidification with 2N citric acid gave 0.82 g of 4-(4-methoxybenzenesulfonyl)-1-[2-(4-moiphalino)-phenylcarbonyl]-8-chloro-2,3,4,5-tetrahydro- I H-[ 1,4]benzodiazepine-3-carboxylic acid (mp 136-143 °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-carboxylate of Reference Example 12, 0.291 g of 4-ethoxybenzoyl chloride and 500 E,~l of triethylamine in 5 ml of CH2Cl2 was stirred at room temperature overnight. The mixture was diluted with CH=C12 and H20 and the CH2CI2 layer was separated and concentrated to dryness. The residue was triturated with ethyl acetate to give 0.276g of methyl 1-(4-ethoxybenzoyl)-4-(4-methoxy-benzenesulfonyl)-2,3,4,5tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate as white crystals, (mp 187-190°C).
A 0.47 g sample of this compound was hydrolyzed with 1.2 ml of 1~T NaOH in 4 ml of tetrahydrofuran. Dilution with H20 and acidification with 1 N HCl gave 0.40 g of the acid as a white solid, mp 144-152°C.
Reference Example 194 Methyl 4-(4-Methoxybenzenesulfonyl) -1-[2-chloro-4-(3-methyl-1-pyrazolyl)phenylcarbonyl}-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-lH-[1,4]benzodiazepine-3-carboxylate was reacted with 4-{3-methyl-1-pyrazolyl)-2-chlorobenzoyl chloride to give methyl 4-(4-methoxybenzenesulfonyl)-I-[2-chloro-4-(3-methyl- I-pyrazolyl)phenylcarbonyl]-2,3,4,5-tetrahydro- I H-[
1,4]benzo-diazepine-3-carboxylate as a white solid. Anal. for C29H27CIN4O6S:
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 1~1 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]benzodiazepine-3-carboxylic acid A mixture of 1.7 g of the compound of Reference Example 45 and 25 ml of borane in tetrahydrofuran ( 1.0 Molar) was refluxed under nitrogen overnight.
To the solution was added 5 ml of CH30H, CH2Cl2 (40 ml) and 30 ml of 2~1 HCl and the mixture stirred at room temperature for 1.5 hr. The organic layer was separated, washed with brine, dried with Na2S04 and the solvent removed. The residue was crystallized from ethanol-hexane to give 1.15g of methyl 1-benzyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-(1,4]benzodiazepine-3-carboxylate as white crystals, mp 120-122°C. A sample (1.0 g) of this compound was hydrolysed with 2.8 ml of 1 ~I 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°C).
Reference Example 196 Methyl 1-(2,4-Dimethoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate To a cooled (0°C) solution of 1.0 g (2.66 mmol) of 4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate from Reference Example 12 and 1.85 ml ( 13.3 mmol) of triethylamine in 8 ml of CH2C12 was added 1.17 g (6.65 mmol) of 2,4-dimethoxybenzoyl chloride. The mixture was stirred at room temperature overnight, diluted with CH2Cl2 and washed with 2 ~T citric acid. The organic layer was washed with H20, 1 ~1 Na2C03, brine and dried over Na2S04. 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-1H-[1,4]benzodiazepine-3-carboxylate as a white foam. Anal. for C27H28H208S:
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 1 ~l NaOH in 5 ml of tetrahydrofuran was stirred at room temperature for 1.5 hours. The solvent was removed and the residue diluted with water. The solution was acidified with 1 N HCI, chilled and filtered to give 0.70 g of 1-(2,4-dimethoxy-benzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1 H-( 1,4]benzodiazepine-3-carboxylic acid as a white solid. Anal. for C26H26N208S:
Calc'd: C,59.3; H,5.0; N,5.3;
Found: C,56.1; H,4.8; N,S.O;
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-carboxylate (Reference Example 12) and 4.63 ml (33.2 mmol) of triethylamine in 40 ml of CH2Cl2 cooled to 0°C
was added to 1.65 g ( 14.63 mmol) of chloroacetyl chloride. The solution was stirred at room temperature for 2 days, chilled to 0°C and 926 lil of triethylamine and 750 mg of chloroacetyl chloride were added thereto. The mixture was stirred at room temperature overnight, diluted with CH2C12 and H20. The insoluble solid was filtered off.
The organic layer of the filtrate was separated , washed with brine, dried with Na2S04 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]benzo-diazepine-3-carboxylate (Reference Example 91 ). Anal. for C20H21 C1N206S:
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 CH2C12 cooled to 0°C was added 1.2 ml (6.79 mmol) of N,N-diisopropylethylamine followed by the addition of 753.2 pl (6.79 mmol) of 1-methylpiperazine. The mixture was stirred at room temperature overnight, diluted with CH2Cl2, and washed with 2 ~T
citric acid, H20, 1 M NaHC03, brine and dried (Na2S04). The citric acid wash was made basic with saturated NaHC03 and then extracted with CH2Cl2. The extract was dried over Na2S04 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-IH-[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 1 N KOH in 5 ml of methanol was stirred at room temperature for 2 hours.
The solvent was removed under vacuum. To the residue was added toluene (2 times) and the solvent removed under vacuum after each addition. The solid was dried at 65°C
under vacuum for 6 hours to give 1.1 g of potassium 4-(4-methoxybenzenesulfonyl)-1 [2-(4-methylpiperazin-1-yl)acetyl]-2,3,4,5-tetrahydro-1H-[ 1,4]benzodiazepine-carboxylate as a white solid.
Reference Example 198 Methyl 1-Acetyl-4-(4-hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4] benzodiazepine-3-carboxylate To a cooled (0°) solution of 2.Og (4.78 mmol) of methyl 1-acetyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate in 14 ml of CH2 C12 was added dropwise 143.3m1 ( 14.3mmo1) of a 1.0 molar solution of BBr3 in CH2 C12 . The mixture was stirred at room temperature for 1.5 hours.
Ice and H20 were added to the reaction mixture and the insolubles filtered off. The filtrate was diluted with CH2C12 and H20 and the CH2Cl2 layer separated, washed with brine and dried (Na2 S04). 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,9H2oN2O6S: 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 CH2CI2 chilled to 0°C, was added slowly 16.4 ml ( 16.44 mmol) of 1.0 molar solution of boron tribromide in CH2C12. The mixture was stirred at room temperature overnight and diluted with CH2Cl2. The mixture was filtered and the solid washed with CH2Cl2. and H20. The filtrate was diluted with H20 and the organic layer separated.
The solvent was removed under vacuum and the solid chromatographed on silica gel with hexane-ethyl acetate ( 1:1 ) as solvent to give 0.80 g of off white foam;
Mass Spectrum (ES) 473.5 (M+H); Anal. Calc'd for C22 H2o N206 S2: C, 55.9; H, 4.3;
N, 5.9. Found: C, 54.5; H, 4.4; N, 5.5.
_87_ Reference Example 200 Methyl 1-Benzoyl-4-(4-hydroxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-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]benzodiazepine in 50 ml of CH2C12 cooled to 0°, was added slowly 40.8 ml (40.8 mmol) of a 1.0 molar solution of BBr3 in CH2C12, The mixture was stirred under nitrogen at room temperature overnight. Ice and H20 were added and the mixture diluted with CH2C12. The organic layer was separated and the aqueous layer extracted with ethyl acetate. The combined organic extracts {CH2CI2+ethyl acetate) were concentrated under vacuum and the residue dissolved in ethyl acetate. The solution was washed with H20, brine and dried (Na2S04). 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 C24H22N206S~ C, 61.8; H, 4.8; N, 6Ø
Found: C, 61.3; H, 4.6; N, 5.8.
Utilizing the method described in Reference Examples 191-193, the following methyl-1-substituted-4-hydroxybenzenesulfonyl}-2,3,4,5-tetrahydro-1 H-[ 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 BBr3 in CH2C12 (solution) gave, after chromatography on silica with ethyl acetate-hexane (1:1), 0.82g of a white foam; Mass spectrum (ES) 440.9 (M + H).
Reference Example 203 Methyl 4-(4-Hydroxybenzenesu~fonyl)-1-(3-pyridinylcarbonyl) 2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate _88_ 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-tetrahydro-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-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate Reference Example 210 Methyl 4-(4-Hydroxybenzenesulfonyl)-1-(2-methyl-3-fiuorobenzoyl)-2,3,4,5-tetrahydro-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 WO 99/37625 PCT/US99/o1325 Reference Example 212 Methyl 4-(4-Hydroxybenzenesulfonyl)-1-(2-trifluoromethylbenzoyl) 2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate Reference Example 213 Methyl 1-(2-Chloro-6-trifluoromethylbenzoyl)-4-(4 hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1 H-[ 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-(2 methylbenzoyl)-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-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylateReference 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-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate Reference Example 221 Methyl 1-(2-Chlorobenzoyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5 tetrahydro-1 H-[ 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-tetrahydro-1 H-[ 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 I-(2,3-Dichiorobenzoyl)-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-tetrahydro-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-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate Reference Example 230 Methyl 4-(4-Hydroxybenzenesulfonyl)-1-(4-methyl-2-thienylcarbonyl) 2,3,4,5- tetrahydro-1H-[1,4)benzodiazepine-3-carboxylate Reference Example 231 Methyl 1-(3-Chloro-2-thienylcarbonyl)-4-( hydroxybenzenesulfonyl)-2,3,4,5- tetrahydro-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.Og (6.38 mmol) of methyl 1-(2 furanylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1 H-[ 1,4]benzodiazepine-3-carboxylate in., 15 ml of CH2C12 (cooled to 0°C ) was added dropwise 12.8m1 (2.8 mmol) of BBr3 in CH2C12 (1.0 M in CH2C12).The mixture was stirred at room temperature for 3 days, diluted with CH2C12 and then ice was added. The organic layer was separated, washed with H20, brine 'and dried (Na~S04). 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 0.72g of methyl 1-(2- furanyl-carbonyl)-4-hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4)benzodiazepine-carboxylate as a white solid, mp 204-206°C; Anal Cal'd for C22H2oN207S:
C, 57.9; H, 4.2; N, 6.1. Found: C,57.2; H,4.3; N, 6.O.;Mass spectrum (ES) 457.1 (M+H).
Reference Example 233 Methyl 4-(4-Hydroxybenzenesulfonyl)-1-(3-methyl-2-furanylcarbonyl)-2,3,4,5- tetrahydro-1H-[-1,4]benzodiazepine-3-carboxylate Reference Example 234 Methyl 4-(4-Hydroxybenzenesulfonyl)-1-(4-methyl-2-furanylcarbonyl)-2,3,4,5-tetrahydro-1H-(1,4]benzodiazepine-3-carboxylate Reference Example 235 Methyl 1-(5-Chloro-2-furanylcarbonyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5- tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate Reference Example 236 Methyl 1-(5-Chloro-2-thienylcarbonyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodeiazepine-3-carboxylate Reference Example 237 Methyl 1- Propionyl-4-(4-hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodeiazepine-3-carboxylate Reference Example 238 Methyl 1-Hexanoyl-4-(4-hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-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 24 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-hydroxybenzenesulfonyi)- 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..44g( 10 mmol) of methyl 1-cyclopropylcarbonyl-4-(4-methoxybenzenefulfonyl)-2,3,4-tetrahydro-1H-[1,4]benzodiaxepine -3-carboxylate in 25 ml of CH2C12 chilled to 0~~ C was added dropwise 22 ml (22 mmol) of BBr3 in CH2Cl2 ( 1.0 molar solution). The mixture was stirred overnight, cooled and diluted with ice and H20. Dichloromethane was added and the organic layer separated and washed with H20, brine and dried (Na2S04). 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-hydroxybenzene-sulfonyl)-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-tetrahydro-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-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid from Reference Example 9 in 5 ml of CH2C12, was added 0.556 ml ( 1. I 1 mmol) of 2.0 M oxalyl chloride in CH2Cl2 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 H20. The mixture was stirred at room temperature overnight and diluted with CH2Cl2. The mixture was washed with 2 N citric acid, H20, 1 N NaHC03, brine and dried with Na2S04. The solvent was removed under vacuum to give 0.29 g of solid. Chromatography on thick layer silica gel plates with WO 99/3?625 PCT/US99/01325 ethyl acetate-methanol (9:1) gave 60 mg of solid, m.p. 128-130°C. Anal.
for C25H22F3N306S:
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- I H-[ 1,4]benzodiazepine-3-carboxylic acids.
Example 2 4-(4-Methoxybenzenesulfonyl)-1-(4-methylphenylsulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Solid. Anal. for C24H2gN307S2:
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]benzodiazepine-3-carboxylic acid, Hydroxyamide Solid. Anal. for C 18H21 N307S2:
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-[l,4Jbenzodiazepine-3-carboxylic acid, Hydroxyamide Solid. Anal. for C24H25N3~8S2:
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]benzodiazepine-3-carboxylic acid, Hydroxyamide White solid. Anal. for C24H23N3~6S:
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]benzodiazepine-3-carboxylic acid, Hydroxyamide White crystals. m.p. 195-197°C. Anal. for C19H21N306S:
Calc'd: C,54.4; H,S.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°C. Anal. for C23H22N4O6S:
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-lH-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide White solid. Anal. for C22H21 N306S2:
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]benzodiazepine-3-carboxylic acid, Hydroxyamide White crystals, m.p. 143-145°C. Anal. for C2pH23N3O7S:
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 C2pH25N30'752:
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-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Off white solid. Anal. for C25H24FN306S:
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 C26H27N306S:
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°C. Anal. for C23H22N406S:
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-tetrahydro-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°C. Anal. for C3pH27N306S:
Calc'd: C,64.6; H,4.9; N,7.5;
Found: C,63.7; H,4.6; N,7.1.
WO 99/37625 PC'T/US99/01325 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°C. Anal.
for C30H27N306S:
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-[l,4Jbenzodiazepine-3-carboxylic acid, Hydroxyamide Example 17 4-(4-Methoxybenzenesulfonyl)-1-(2-methyl-3-fluorobenzoyl)-2,3,4,5-tetrahydro-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]benzodiazepine-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-tetrahydro-tH-[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-tetrahydro-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-tetrahydro-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°C. Anal. for C24H21C12N306S:
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 IO 1-(2,3-Dichlorobenzoyl)-4-(4-methoxybenzenesulfon~yi)-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]benzodiazepine-3-carboxylic acid, Hydroxyamide Example 35 1-(4-Chloro-2-methoxybenzoyl)-4-(4-methoxybenzenesutfonyl)-2,3,4,5 tetrahydro-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-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Example 39 1-(3-Chloro-2-thienylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-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 C22H21N3~7s:
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 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Example 42 4-(4-Methoxybenzenesulfonyl)-1-(4-methyl-2-furanylcarbonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Example 43 1-(5-Chloro-2-furanylcarbonyl)-4-(4-methoxybenzenesulfonyt)-2,3;4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Example 44 1-(5-Chloro-2-thienylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Example 45 1-Propionyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Example 46 1-Hexanoyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-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-(traps-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-1 H
[1,4)benzodiazepine-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-1 H
[1,4]benzodiazepine-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 C21 H23N306S:
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-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide off white solid. Anal. for C24H29N3O6S:
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]benzodiazepine-3-carboxylic acid, Hydroxamide A mixture of 0.70 g (1.37mmol) of methyl 4-(4-methoxybenzenesulfonyl)-1 (phenoxyacetyl)-2,3,4-S-tetrahydro-1H[1,4]benzodiazepine-3-carboxylate and 1.8 ml ( 1.78 mmol) of 1 N NaOH in 3 ml of tetrahydrofuran was stirred at room temperature for 2 hours. The mixture was diluted with 3 ml of H20 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°-191°C.
To a 0.496 g (1 mmol) sample of the preceeding compound in 5 ml of CH2C12 cooled to 0°C, was added 1 ml (2 mmol) of oxalyl chloride followed by the addition of 77.4 pl ( 1 mmol) of ~1,~T-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 H20 and 836.3 pl (5 mmol) of triethylamine. The mixture was stirred for 20 minutes and then cooled to 0°C (referred to as solution B}. The cooled solution B was added to the cooled (0°C) and stirred solution A and then this mixture was allowed to warm to room temperature and was stirred overnight. The mixture was concentrated under vacuum, diluted with CH2C12 and washed with H20, 2N citric acid, 1 N NaHC03, and brine and dried with Na2S04, The solvent was removed and the residue crystallized from hexane-ethyl acetate (3:97) to give 0.396 g of white crystals, m.p.
I59°-163°C. Anal.
for C25H25N30'7S:
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-methoxyacetyl-4-(4-methoxybenzenesulfonyl)-7-methyl-2,3,4,5-tetrahydro-I H-[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 H20 and extracted with ethyl acetate. The aqueuous layer was acidified with IN HCl and then extracted with CH2C12. The CH2C12 layer was dried over Na2S04 and the solvent removed to provide a solid. This material was dried in a vacuum oven and given 1.06 of solid, m.p. 101-105°C.
A 1.02 g (2.27 mmol) sample of 1-methoxyacetyl-4.-(4-methoxy-benzenesulfonyl)-7-methyl-2,3-4,5-tetrahydro-1H-[ 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 CH2Cl2 was cooled at 0°C and 0.351 ml (4.52 mmol) of N,N-dimethylformamide (DMF) was added dropwise. The mixture was stirred for 5 minutes and the potassium salt ( 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°C) and this mixture was added to a cooled (0°C) mixture of 0.628 g (9.04 mmol) of hydroxylamine hydrochloride, 1.89 ml ( 13.56 mmol) of triethylamine in 1 ml of tetrahydrofuran-water (8:2). The mixture was stirred and chilled at 0°C for 10 minutes and then stirred at room temperature overnight. The solvent was removed under vacuum and the residue diluted with CH2C12-H20 and acidified with 2 N
citric acid (pH 4). The CH2C12 layer was separated and washed with H20. 1N NaHC03.
H20, and brine and dried with Na2S04, The solution was filtered through a thin pad of hydrous magnesium silicate and the solvent removed under vacuum to give 0.73 g of solid. Crystallization from ethyl acetate gave 0.32 g of crystals, m.p.
146°-148°C.
Example 60 1-Benzoyl-4-(4-methoxybenzenesulfonyl)-7-methyl-2,3,4,5-tetrahydro 1H[1,4]benzodianzepine-3-carboxylic acid, Hydroxyamide In the manner described in Example 59, 0.83 g ( 1.71 mmol) of 1-benzoyl-4-(4-methoxybenzene-sulfonyl)-7-methyl-2,3,4,5-tetrahydro-1 H[ 1,4]benzodianzepine-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 CH2C12 0.20 g. of yellow solid, m.p. 137°-139°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°-186°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° dec;
Mass spectrum (ES) 601 (M+H).
Example 62 4-(4-Methoxybenzenesulfonyl)-1-(2-methoxyethyl)-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-methoxy-benzenesulfonyl )-1-(2-methoxyethyl)-2,3,4,5-tetrahydro-1 H-[ 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 C2pH25N3O6S:
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-tetrahydro-1 H-[ 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,2 H,2 N2O2: C, 66.7; H, 5.6; N
13:0: Found:
C, 66.5: H, 5.4: N, 12.9; Mass spectrum (ES) 217.2 (M+H). A sample (7.02g) of this compound and 8.42 ml of SN 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 l.Sg of product. The two crops were combined to give 5.2g of 2-(1-pyrazolyl)benzoic acid, mp 140-142°C. To the preceding compound (2.07 g) in 5 ml CH2C12 (chilled in an ice bath )was added 11.1 ml of a 2 Molar solution of oxalyl chloride in CHZCh 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 l.Sg of the compound of Reference Example 179 in 15 ml of CH2Cl2 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-methylbenzyl}-amino]acrylate. This compound was cyclized with NaHC03 in methanol in the manner described in Reference Example 181 to give methyl 4-(4-methoxybenzenesulfonyl)-[2-( 1-pyrazolyl)phenylcarbonyl]-7-methyl-2, 3,4,5-tetrahydro-1 H-[
1,4]benzodiazepine-3-carboxylate, m.p. 240-242° 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)phenyl-carbonyl)-7-methyl-2,3,4,5-tetrahydro-1H(1,4]benzodiazepine-3- carboxylic acid, mp 149-151 °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°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 10 N NaOH in tetrahydrofuran-ethanol (8:2) for 1.5 hrs to give 2-morpholinobenzoic acid, mp 156-157°C. A 1.8 g sample of this compound in S ml of CH2C12 (chilled) was added a solution of 7.9 ml of oxalyl chloride in CH2Cl2 (2M) followed by the addition of 0.058 ml of N, N-dimethylformamide.
The solution was stirred at room temperature for 6 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-hydroxypropionate and the product was stinred with NaHCOg in methanol to give methyl 4-(4-methoxybenzenesulfonyl)-1-[2-(4-morpholino)phenylcarbonyl]-8-chloro-2,3,4,5-tetrahydro-1H-[ 1,4]benzodiazepine-carboxylate, as a white solid having a mp 100-105°C.
To 0.90g of this compound in 10 ml of tetrahydrofuran was added 1.95 ml of 1 ~1 NaOH and the solution was stirred at room temperature overnight.
Acidification with 2~T citric acid gave 0.82 g of solid, mp 136-143°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 (0.78g) was converted to the potassium salt and reacted first with oxalyl chloride and then with hydroxylamine as described in Example 63 to give 0.276g of product as a light yellow solid, mp 132° C.
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- I H-( 1,4] benzodiazepine-3-carboxylate of Reference Example 12, 0.291 g of 4-ethoxybenzoyl chloride and 500 E.11 of triethylamine in 5 ml of CH2Ch was stirred at room temperature overnight. The mixture was diluted with CH~Ch and H20 and the CH2Cl2 layer was separated and concentrated to dryness. The residue was triturated with ethyl acetate to give 0.2768 of methyl 1-(4-ethoxybenzoyl)-4-(4-methoxybenzene-sulfonyl)-2,3,4,Stetrahydro-1H-[1,4]benzodiazepine-3-carboxylate as white crystals, mp 187-190°C.
A 0.47 g sample of this compound was hydrolyzed with 1.2 ml of IN NaOH in 4 ml of tetrahydrofuran. Dilution with H20 and acidification with 1N HCl gave 0.40 g of the acid as a white solid, mp 144-152°C. The preceding compound (0.358) was converted to the above-titled compound in the manner described in Example 1 to provide 0.1958 of solid, mp 136-142°C.
Example 66 4-(4-Methoxybenzenesulfonyl) -1-[2-chloro-4-(3-methyl-1-pyrazolyl)phenylcarbonyl}-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-lH-[1,4]benzodiazepine-3-carboxylate 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)phenylcarbonyl]-2,3,4,5-tetrahydro-1 H-[
1,4Jbenzo-diazepine-3-carboxylate as a white solid. Anal. for C29H27C1N4O6S:
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 1 N 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 I to give the product as white crystals, mp 189-191°C.
Example 67 1-Benzyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H
[1,4]benzodiazepine-3-carboxylic acid, Hydroxylamide A mixture of 1.7 g of the compound of Reference Example 45 and 25 ml of S borane in tetrahydrofuran ( 1.0 Molar) was refluxed under nitrogen overnight. To the solution was added 5 ml of CH30H, CH2Cl2 (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 Na2S04 and the solvent removed. The residue was crystallized from ethanol-hexane to give 1.15g of methyl 1-benzyl-4-(4 methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1 H-[ 1,4]benzodiazepine-3-carboxylate as white crystals, mp 120-122°C. A sample ( 1.0 g) of this compound was hydrolysed with 2.8 ml of 1 N NaOH in 7 ml of tetrahydrofuran as described in Reference Example 104 to give 0.64 g of the 2,3,4,5- tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid derivative as white crystals, mp 183-185°C.
A 0.55 g sample of this compound was converted to the acid chloride which was reacted with hydroxylamine as described in Example 1 to give the product as a light brown foam; Mass spectrum (ES) 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-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Example 69 4-(4-Methoxybenzenesulfonyl)-1-(4-(3-thienyl)phenyl-carbonyl) 2,3,4,5-tetrahydro-1H-[1,4)benzodiazepine-3-carboxylic acid, Hydroxyamide Example 70 4-(4-Methoxybenzenesulfonyl)-1-[2-(3-pyrazol)phenyl-carbonylJ
2,3,4,5-tetrahydro-1H-[l,4Jbenzodiazepine-3-carboxylic acid, Hydroxyamide Example 71 1-(2,4-Dimethoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[l,4Jbenzodiazepine-3-carboxylic acid, Hydroxyamide To a cooled (0°C) solution of 1.0 g (2.66 mmol) of 4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1 H-[ 1,4]benzodiazepine-3-carboxylate from Reference Example 12 and 1.85 ml ( 13.3 mmol) of triethylamine in 8 ml of CH2Cl2 was added 1.17 g (6.65 mmol) of 2,4-dimethoxybenzoyl chloride. The mixture was stirred at room temperature overnight, diluted with CH2CI2 and washed with 2 N citric acid. The organic layer was washed with H20, 1 N Na2C03, brine and dried over Na2S04. 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-1H-[l,4Jbenzodiazepine-3-carboxylate as a white foam. Anal. for C2~H2gH20gS:
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 1 N NaOH in 5 ml of tetrahydrofuran was stirred at room temperature for 1.5 hours. The solvent was removed and the residue diluted with water. The solution was acidified with 1 N HCI, chilled and filtered to give 0.70 g of 1-(2,4-dimethoxy-benzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1 H-[
1,4]benzodiazepine-3-carboxylic acid as a white solid. Anal. for C26H26N208S:
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 CH2Cl2 (chilled to 0°C) was added to 1.52 ml (3.04 mmol) of oxalyl cholride (2.0 M solution in CH2Cl2). To the solution was added 118 pl ( 1.52 mmol) of N,N-dimethylformamide and the solution stirred at 0°C for 1.5 hours (Mixture A). A mixture of 0.422 g (6.08 mmol) of hydroxylamine hydrochloride, 1.27 ml (9.14 mmol) of triethylamine, 5 ml of N,N-dimethyformamide and 0.5 ml of water was prepared in a separate flask, stirred for 20 minutes at room temperature and then cooled to 0°C in an ice bath (Mixture B).
S 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 CH2C12 and 2 N citric acid added. The organic layer was separated, washed with H20, brine and dried with NaZS04. The solvent was removed and the residue crystalized from ethanol to give 0.40 g of product as white crystals, mp 189-191°C. Anal. for C26H2~N30gS:
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-tetrahydro-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-carboxylate (Reference Example 12) and 4.63 ml (33.2 mmol) of triethylamine in 40 ml of CH2C12 cooled to 0°C
was added to 1.65 g ( 14.63 mmol) of chloroacetyl chloride. The solution was stirred at room temperature for 2 days, chilled to 0°C and 926 ~.~1 of triethylamine and 750 mg of chloroacetyl chloride were added thereto. The mixture was stirred at room temperature overnight, diluted with CH2C12 and H20. The insoluble solid was filtered off.
The organic layer of the filtrate was separated , washed with brine, dried with Na2S04 and filtered through diatomaceous earth. The solvent was removed and the residue triturated with ethyl acetate and a trace of ethanol. Chilling and filtering gave 0.75 g of methyl 1-(chloroacetyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1 H-[
1,4J-benzodiazepine-3-carboxylate (Reference Example 91 ). Anal. for CZpH2 i CIN206S:
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 CH2C12 cooled to 0°C was added 1.2 ml (6.79 mmol) of N,N-diisopropylethylamine followed by the addition of 753.2 Irl (6.79 mmol) of 1-methylpiperazine. The mixture was stinted at room temperature overnight, diluted with CH2Cl2, and washed with 2 N
citric acid, H20, 1 M NaHC03, brine and dried (Na2S04). The citric acid wash was made basic with saturated NaHC03 and then extracted with CH2C12. The extract was dried over Na2S04 and the solvent removed under vacuum to give 1.10 g of methyl 4-(4-methoxybenzenesulfonyl)-I-[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 1 N KOH in 5 ml of methanol was stirred at room temperature for 2 hours.
The solvent was removed under vacuum. To the residue was added toluene (2 times) and the solvent removed under vacuum after each addition. The solid was dried at 65°C
under vacuum for 6 hours to give 1.1 g of potassium 4-(4-methoxybenzenesulfonyl)-1-[2-(4-methylpiperazin- I -yl)acetyl]-2,3,4, 5-tetrahydro-1 H-[
1,4]benzodiazepine-3-carboxylate as a white solid.
To 1.85 mI (3.69 mmol) of a 2.0 molar solution of oxalyl chloride in CH2C12, cooled to 0°C, was added slowly 286 Erl (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 CH2C12. The mixture was stirred under nitrogen for two hours (Mixture A).
In a separate flask, a mixture of 0.514 g (7.4 mmol) of hydroxylamine hydrochloride, 1.55 ml ( 11.1 mmol) of triethylamine in tetrahydrofuran-water (4:1 ) was stirred at room temperature and then cooled to 0°C and stirred for 5 minutes. To this mixture was added the cooled (0°C) Mixture A and then the resulting solution stirred at room temperature overnight. The mixture was concentrated under vacuum and CH2Cl2 added. The organic layer was separated and concentrated to dryness to give 1.4 g of product. The product was chromatographed on thick layer silica gel plates with CH2C12-CH30H-NH40H(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 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide A. N-f4-(4-Chlorophenyloxvbenzenesulfonvl)serine. methyl ester (methyl-3-hydroxy-2-f4-(4-chloro hp enoxv)benzenesulonylaminolpro in onate~. 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 CH2C12, chilled to 0°C, was added 6.063 g (20 mmol) of 4-(4-chlorophenyloxy)benzenesulfonyl chloride. The mixture was stirred at room temperature overnight, diluted with CH2C12 and washed with 2 N citric acid, H20, 1 N
NaHC03, brine and dried with Na2S04. The solvent was removed to give an oil which was dried under vacuum at 68°C to give a solid. Trituration with hexane-ethyl acetate gave 5.85 g of off white crystals, mp 90-94°C. Anal. for C16H16C1N06S:
Calc'd: C,49.8; H,4.2; N,3.6;
Found: C,50.1; H,4.1; N,3.8;
Mass Spectrum (ES): 385.9 (M+H).
B. Met yl 3-hyd, roxy-2-f f4-(4-chloronhen~y)benzene-sulfony1112-nitrobenzrLl)amino}rro nn 'ovate. To a cooled (0°C) solution of 5.5 g (14.76 mmol) of compound from part A in 60 ml of dry N,N-dimethylformamide was added (portionwise), 0.682 g ( 17 mmol) of sodium hydride (60% in oil). After gas evolution ceased, 3.7 g ( I 7 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 H20, brine and dried with Na2S04. 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 C23H21C1NZOgS:
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. Mme'~,Y12-{,(2-aminobenzyly-[4-(4-chlorQphenyloxy)benzene-~ulfon lv laming-3-~,ydro~ynropionate. 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 H20) 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°C under vacuum to give 2.63 g of an off white solid. Anal. for C23H23C1N206S:
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. yl 2-(f4-(4-chloropheny c~ylbenzenesulfon y.~[2-(metho~~
ace lamino)benzyllamino )~ acrvlate. To a mixture of 0.80 g ( 1.63 mmol) of the compound from Part C and 1.14 ml (8.15 mmol) of triethylamine in 8 ml of CH2C12, cooled to 0°C, was added 328 lrl (3.58 mmol) of methoxyacetyl chloride.
The mixture was stirred at room temperature overnight, diluted with CH2CI2 and washed with H20, 2 N citric acid, brine and dried (Na2S04). 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 C26H25C1N20~S:
Calc'd: C,57.3; H,4.6; N,5.1;
Found: C,56.?; H,4.7; N,5.0;
Mass Spectrum (ES): 545.2 (M+H).
E. Methyl 4-f4-(4-chlorophen loxy)benzenesulfonvll-1-(methox3r~ce~rl)-2.3.4.5-tetrah~rdro-1H-[1.41benzodiazenine-3-carboxylate. A mixture of 0.45 g (0.827 mmol) of the compound from part D and 0.09 g of anhydrous NaHC03 in 5 ml of dry methanol was stirred at room temperature overnight. The solvent was removed, ethyl acetate added and the mixture washed with H20, brine and dried with Na2S04.
The solvent was removed to give 0.43 g of an off white solid. Anal. for C26H25C1N20~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-f(4-Chlorophenyloxy)benzenesulfon l~methoxvacetyl)-2 3 4 5-~ydro-1H-f 1.4]benzodiaz~ine-3-carboxylic acid. A mixture of 0.52g (0.956 mmol) of the compound from Part F and 1.2 ml ( 1.2 mmol) of 1 N 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 H20 and extracted with ethyl acetate.
The extract was washed with brine and dried over Na2S04. The solvent was removed and the product dried at 65°C under vacuum to give 0.49 g of off white foam. Anal. for C25H23C1N20~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 CH2C12 cooled to 0°C was added 850 Nl ( 1.69 mmol) of oxalyl chloride (2.0 molar solution in CH2Cl2) and then 50.2 pl (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 triethylamine, 4 ml of tetrahydroforan and 0.4 ml of H20 was stirred for 15 minutes and cooled to 0°C. To this mixture was added the cooled (0°C) Solution A and the mixture was stirred at room temperature overnight. The mixture was concentrated under vacuum, diluted with ethyl acetate and washed with H20, 1N NaHC03 2 N
citric acid, brine and dried over Na2S04. 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 C25H24C1N30~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)benzenesulfonylJ-1-(2-thienylcarbonyl) 2,3,4,5-tetrahydro-1H[l,4Jbenzodiazepine-3-carboxylic acid, Hydroxyamide The following reactions were carried out in the manner described for Example 73, Parts D, E, and F. A 1.4 g (2.85 mmol) sample of methyl 2-{(2-aminobenzyl)-[4-(4-chlorophenyloxy)benzenesulfonyl]amino}-3-hydroxypropionate (the compound of Part C of Example 73) was reacted with 1.25 g (8.55 mmol) of 2-thiophenecarbonyl chloride to give 1.7 g of methyl 2-{ [4-(4-chlorophenyloxy)benzyenesulfonyl]-[2-(2-thienylcarbonyl-amino)benzyl]amino } acrylate as a yellow oil.
Mass Spectrum (ES): 583.1 (M+H).
The reaction of 1.5 g of the preceding compound with 0.251 g of NaHC03 in 8 ml methanol gave 1.6 g of methyl 4-[4-(4-chlorophenyloxy)benzenesulfonyl)-1-(2-thienylcarbonyl)-2,3,4,5-tetrahydro-lH-[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 1 N NaOH
in 6 ml of tetrahydroforan gave 1.2 g of 4-[4-(4-chlorophenyloxy)benzenesulfonyl]-I-(2-thienylcarbonyl)-2,3,4,5-tetrahydro-IH-[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 Nl (6.10 mmol) of benzoyl chloride to give I.25 g of methyl 2-{[4-(4-chlorophenyloxy)benzenesulfonyl]-[2-(benzoylamino)benzyl]amino}acrylate as a brown oil.
Mass Spectrum (ES): 577.2 (M+H).
The reaction of 1. I g ( 1.9 mmol) of the preceding compound with 0.208 g (2.48 mmol) of NaHC03 in 8 ml of methanol gave 1.1 g of methyl 4-[4-(4-chlorophenyloxy)benzenesulfonyl]-1-(benzoyl)-2,3,4,5-tetrahydro-1 H-[I,4]benzodiazepine-3-carboxylate as a brown oil.
Mass Spectrum (ES): 577.1 (M+H).
A 1.0 g ( 1.73 mmol) sample of the preceding compound was hydrolysed with 2.3 ml (2.75 mmol) of 1 N NaOH in 5 ml of tetrahydrofuran to give 0.50 g of 4-[4-(4-chlorophenyloxy)benzenesulfonyl]-1-(benzoyl)-2,3,4,5-tetrahydro-IH-[1,4]benzodiazepine-3-carboxylic acid as a white foam. As described for Example 73, 0.460 g (0.817 mural) 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 CH2C12 was added a solution of 10.78 g (40 mmol) of 4-(4-pyridinyloxy)benzenesulfonyl chloride in 50 ml of CH2C12. The mixture was stirred at room temperature overnight, diluted with 50 ml of CH2CI2 and the solution washed with H20, 1N NaHC03, 2 N citric acid, brine and dried (with Na2S04). The solvent was removed under vacuum to give a solid. The aqueous 2 N citric acid wash was made basic with saturated NaHC03 and then extracted with CH2Cl2. The solvent was removed to give a solid. The two crops of solid were combined, washed with H20 and then hexane. The solid was dried at 80°C
to give 10.95 g of methyl 3-hydroxy-2-[4-(4-pyridinyloxy)-benzenesulfonylamino]
propionate as white crystals, mp. 137-139°C.
B . To a solution of 4.5 g ( 12,.78 mmol) of the product from Part A in 35 ml of dry N,N-dimethylformanude cooled to 0°C was added (portionwise) 0.662 g (16.61 mmol) of NaHCOg (60% in oil). The mixture was stirred 15 minutes and 3.59 g ( 16.61 mmol) of 2-nitrobenzylbromide in 1 S ml of N,N-dimethylfonmamide was added hereto. The mixture was stirred at room temperature overnight, diluted with ethyl acetate (200 ml) and H20 (100 ml). The organic layer was separated and washed with H20, brine and dried (with Na2S04). 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.
WO 99/37625 PCTIUS99/Ot3Z5 Example 77 1-(Benzoyl)-4-(4-pentyloxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H
[1,4]-benzodiazepine-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 ~tL (4.82 mmol) of I-pentanol and 1.5 g (3.22 mmol) of methyl I-(benzoyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate. To this stinred mixture was added 259 l,tL (4.82 mmol) of diethyl azodicarboxylate and the mixture was stirred overnight. The solvent was removed and the residue chromatographed on silica gel with ethyl acetate-hexane ( 1:3) as solvent. Concentration of the fractions containing product gave 1.59 g of a white solid; mp 170-172°C; Anal. Calcd for C29H32N2O6: 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°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 CH2Cl2 was added 4.8 ml (9.6 mmol) of oxalyl chloride in CH2CI2 (2.0 molar) and the solution chilled to 0°C. To the chilled solution was added 740 N.L, (9.56 mmol) of N,N-dimethylformamide and 1.34g (2.39 mmol) of the preceding potassuim salt in 5 ml of dry N,N-dimethylformamide. The mixture was stirred at room temperature for 1.5 hr, cooled to 0°C ,and added to a chilled (0°C) solution of 2.2 ml (35.9 mmol) of 50% aqueous hydroxylamine in 10 ml of tetrahydrofuran. The mixture was stirred at room temperature overnight and diluted with CH2Cl2. The CH2Cl2 layer was separated, washed with H20 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 H20 and once with brine and dried (Na2S04). The solvent was removed and the residue dried at 85°C under vacuum overnight to give 0.96 g of product as a white foam; Mass spectrum (ES) 538.0 (M+H).
Example 78 1-Acetyl-4-(4-Hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide To a crude mixture of 1-acetyl-4-(4-hydroxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid (O.SSg) ~ and N-hydroxy benzotriazole (0.414g) 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 ~,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 H20, 2N citric acid, brine and dried (Na~S04).
The solvent was removed under vacuum to give a solid. Chromatography on silica gel with 10% methanol in ethyl acetate as solvent gave a solid which was dried at 78°C
under vacuum overnight to give an off white foam; Mass spectrum (ES) 406.1 (M+H);
Anal. Calcd. For C,gH,9N306S; C, 53.3; H, 4.7; N, 10.4. Found: C, 52.6; H, 5.2; N, 10.4.
The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof and, accordingly, reference should be made to the appended claims, rather than to the foregoing specification, as indicating the scope of the invention.
Claims (12)
1. A compound of Formula 1:
wherein R is selected from hydrogen, (C1 - C3) alkyl, -CN, -OR', -SR', -CF3, -OCF3, Cl, F, NH2, NH(C1 - C3)alkyl, -N(R')CO(C1 - C3)alkyl, -N(R')(R'), NO2, -CONH2, -SO2NH2, -SO2N(R')(R'), -N(R')COCH2O-(C1 - C3)alkyl, wherein R' is (C1 - C3)alkyl or hydrogen;
R4 is hydroxy, (C1 - C6)alkyl-O-, (C1 - C6)alkyl-S-, wherein R" is hydrogen, halogen, cyano, methyl or -OCH3;
R1 and R2 are each, independently, hydrogen or CH3;
R3 is (C1 - C8)alkyl, NH2CH2CO-, (C1 - C6)alkylNHCH2CO-, HO(CH2)m CO-, HCO-, Aryl(CH2)n CO-, Heteroaryl(CH2)n CO-, (C1 - C3)alkyl-O-(CH2)n CO-, (C1 - C3)alkylCO-, (C1 - C3)alkylCO-NHCH2CO-, (C3 - C7)cycloalkylCO-, (C1 - C3)alkylSO2-, Aryl(CH2)n SO2-, Heteroaryl(CH2)n SO2-, (C1 - C3)alkyl-O-(CH2)m-SO2-, (C1 - C3)alkyl-O-(CH2)m, (C1 - C3)alkyl-O-(C1 - C3)alkyl-O-(C1 -C3)-alkyl, HO-(C1-C3)alkyl-O-(C1-C3)alkyl, Aryl-O-CH2CO-, Heteroaryl-O-CH2CO-, ArylCH=CHCO-, HeteroarylCH=CHCO-, (C1-C3)alkylCH=CHCO-, Aryl(C1-C3)alkyl, Heteroaryl(C1-C3)alkyl, ArylCH=CHCH2-, HeteroarylCH=CHCH2-, (C1-C6)alkylCH=CHCH2-, R'OCH2 CH(OR')CO-, (R'OCH2)2C(R')CO-, [(C1 - C6)alkyl]2-N-(C1 - C6)alkyl CO-, or (C1 - C6)alkyl-NH-(C1 - C6)alkylCO-;
wherein m = 1 to 3; n = 0 to 3;
Aryl is and Heteroaryl is wherein X is hydrogen, halogen, (C1 - C3) alkyl or -OCH3, and R and R' are as defined above;
L is hydrogen, (C1-C3)alkyl, -CN, -OR', -SR', -CF3, -OCF3, Cl, F, NH2, -NH-(C1-C3)alkyl, -N(R')CO(C1 - C3)alkyl, N(R')(R'), -NO2, -CONH2, -SO2NH2, -SO2N(R')(R'), -N(R')COCH2O-(C1 - C3)alkyl, M is , or N(R')(R') where R' is as defined above;
W is O, S, NH or N(C1 - C3)alkyl;
Y is hydrogen, F, Cl, CF3 or OCH3; and X' is halogen, hydrogen, (C1 -C3)alkyl, O-(C1 - C3)alkyl, or -CH2OH; and pharmaceutically acceptable salts thereof.
wherein R is selected from hydrogen, (C1 - C3) alkyl, -CN, -OR', -SR', -CF3, -OCF3, Cl, F, NH2, NH(C1 - C3)alkyl, -N(R')CO(C1 - C3)alkyl, -N(R')(R'), NO2, -CONH2, -SO2NH2, -SO2N(R')(R'), -N(R')COCH2O-(C1 - C3)alkyl, wherein R' is (C1 - C3)alkyl or hydrogen;
R4 is hydroxy, (C1 - C6)alkyl-O-, (C1 - C6)alkyl-S-, wherein R" is hydrogen, halogen, cyano, methyl or -OCH3;
R1 and R2 are each, independently, hydrogen or CH3;
R3 is (C1 - C8)alkyl, NH2CH2CO-, (C1 - C6)alkylNHCH2CO-, HO(CH2)m CO-, HCO-, Aryl(CH2)n CO-, Heteroaryl(CH2)n CO-, (C1 - C3)alkyl-O-(CH2)n CO-, (C1 - C3)alkylCO-, (C1 - C3)alkylCO-NHCH2CO-, (C3 - C7)cycloalkylCO-, (C1 - C3)alkylSO2-, Aryl(CH2)n SO2-, Heteroaryl(CH2)n SO2-, (C1 - C3)alkyl-O-(CH2)m-SO2-, (C1 - C3)alkyl-O-(CH2)m, (C1 - C3)alkyl-O-(C1 - C3)alkyl-O-(C1 -C3)-alkyl, HO-(C1-C3)alkyl-O-(C1-C3)alkyl, Aryl-O-CH2CO-, Heteroaryl-O-CH2CO-, ArylCH=CHCO-, HeteroarylCH=CHCO-, (C1-C3)alkylCH=CHCO-, Aryl(C1-C3)alkyl, Heteroaryl(C1-C3)alkyl, ArylCH=CHCH2-, HeteroarylCH=CHCH2-, (C1-C6)alkylCH=CHCH2-, R'OCH2 CH(OR')CO-, (R'OCH2)2C(R')CO-, [(C1 - C6)alkyl]2-N-(C1 - C6)alkyl CO-, or (C1 - C6)alkyl-NH-(C1 - C6)alkylCO-;
wherein m = 1 to 3; n = 0 to 3;
Aryl is and Heteroaryl is wherein X is hydrogen, halogen, (C1 - C3) alkyl or -OCH3, and R and R' are as defined above;
L is hydrogen, (C1-C3)alkyl, -CN, -OR', -SR', -CF3, -OCF3, Cl, F, NH2, -NH-(C1-C3)alkyl, -N(R')CO(C1 - C3)alkyl, N(R')(R'), -NO2, -CONH2, -SO2NH2, -SO2N(R')(R'), -N(R')COCH2O-(C1 - C3)alkyl, M is , or N(R')(R') where R' is as defined above;
W is O, S, NH or N(C1 - C3)alkyl;
Y is hydrogen, F, Cl, CF3 or OCH3; and X' is halogen, hydrogen, (C1 -C3)alkyl, O-(C1 - C3)alkyl, or -CH2OH; and pharmaceutically acceptable salts thereof.
2. A compound according to claim 1, wherein R is hydrogen, (C1 - C3) alkyl, -CN, -OR', -SR', -CF3, -OCF3, Cl, F, NH2, NH(C1 - C3)alkyl, -N(R')CO(C1 - C3)alkyl, -N(R')(R'), NO2, -CONH2, -SO2NH2, -SO2N(R')(R'), or -N(R')COCH2O-(C1 - C3)alkyl, wherein R' is (C1 - C3) alkyl or hydrogen;
R4 is (C1 - C6) alkyl-O-, (C1 - C6) alkyl-S-, , wherein R" is hydrogen, halogen, cyano, methyl or -OCH3;
R1 and R2 are each, independently, hydrogen or CH3;
R3 is (C1 - C8)alkyl, NH2CH2CO-, (C1 - C6)alkylNHCH2CO-, HO(CH2)m CO-, HCO-, Aryl(CH2)n CO-, Heteroaryl(CH2)n CO-, (C1 - C3)alkyl-O-(CH2)n CO-, (C1 - C3)alkylCO-, (C1 - C3)alkylCO-NHCH2CO-, (C3 - C7)cycloalkylCO-, Aryl-O-CH2CO-, HeteroarylOCH2CO-, ArylCH=CHCO-, HeteroarylCH=CHCO-, (C1 - C3)alkylCH=CHCO-, wherein m = 1 to 3; n = 0 to 3;
Aryl is and Heteroaryl is wherein X is hydrogen, halogen, (C1 - C3) alkyl or -OCH3 wherein R and R' are as defined above; and pharmaceutically acceptable salts thereof.
R4 is (C1 - C6) alkyl-O-, (C1 - C6) alkyl-S-, , wherein R" is hydrogen, halogen, cyano, methyl or -OCH3;
R1 and R2 are each, independently, hydrogen or CH3;
R3 is (C1 - C8)alkyl, NH2CH2CO-, (C1 - C6)alkylNHCH2CO-, HO(CH2)m CO-, HCO-, Aryl(CH2)n CO-, Heteroaryl(CH2)n CO-, (C1 - C3)alkyl-O-(CH2)n CO-, (C1 - C3)alkylCO-, (C1 - C3)alkylCO-NHCH2CO-, (C3 - C7)cycloalkylCO-, Aryl-O-CH2CO-, HeteroarylOCH2CO-, ArylCH=CHCO-, HeteroarylCH=CHCO-, (C1 - C3)alkylCH=CHCO-, wherein m = 1 to 3; n = 0 to 3;
Aryl is and Heteroaryl is wherein X is hydrogen, halogen, (C1 - C3) alkyl or -OCH3 wherein R and R' are as defined above; and pharmaceutically acceptable salts thereof.
3. A compound according to claim 1, wherein R is hydrogen, (C1 - C3) alkyl, -CN, -OR', -SR', -CF3, -OCF3, Cl, F, NH2, NH(C1 - C3)alkyl, -N(R')CO(C1 - C3)alkyl, -N(R')(R'), NO2, -CONH2, -SO2NH2, -SO2N(R')(R'), -N(R')COCH2O-(C1 - C3)alkyl, wherein R' is (C1 - C3) alkyl or hydrogen;
R4 is (C1 - C6) alkyl-O-, (C1 - C6) alkyl-S-, , wherein R" is hydrogen, halogen, cyano, methyl or -OCH3;
R1 and R2 are each, independently, hydrogen or CH3;
R3 is [(C1 - C6)alkyl)2-N-(C1 - C6)alkyl CO-, or (C1 - C6)alkyl-NH-(C1 - C6)alkylCO-, where R' is as defined above;
and pharmaceutically acceptable salts thereof.
R4 is (C1 - C6) alkyl-O-, (C1 - C6) alkyl-S-, , wherein R" is hydrogen, halogen, cyano, methyl or -OCH3;
R1 and R2 are each, independently, hydrogen or CH3;
R3 is [(C1 - C6)alkyl)2-N-(C1 - C6)alkyl CO-, or (C1 - C6)alkyl-NH-(C1 - C6)alkylCO-, where R' is as defined above;
and pharmaceutically acceptable salts thereof.
4. A compound according to claim 1, wherein R is hydrogen, (C1 - C3) alkyl, -CN, -OR', -SR', -CF3, -OCF3, Cl, F, NH2, NH(C1 - C3)alkyl, -N(R')CO(C1 - C3)alkyl, -N(R')(R'), NO2, -CONH2, -SO2NH2, -SO2N(R')(R'), -N(R')COCH2O-(C1 - C3)alkyl, wherein R' is (C1 - C3) alkyl or hydrogen;
R4 is (C1 - C6) alkyl-O-, (C1 - C6) alkyl-S-.
wherein R" is hydrogen, halogen, cyano, methyl or -OCH3;
R1 and R2 are each, independently, hydrogen or CH3;
R3 is (C1 - C3)alkylSO2-, Aryl(CH2)n SO2-, Heteroaryl(CH2)n SO2-, or (C1 -C3)alkyl-O-(CH2)m-SO2, wherein m = 1 to 3; n = 0 to 3;
Aryl is and Heteroaryl is wherein X is hydrogen, halogen, (C1 - C3) alkyl or -OCH3 and R and R' are as defined above; and pharmaceutically acceptable salts thereof.
R4 is (C1 - C6) alkyl-O-, (C1 - C6) alkyl-S-.
wherein R" is hydrogen, halogen, cyano, methyl or -OCH3;
R1 and R2 are each, independently, hydrogen or CH3;
R3 is (C1 - C3)alkylSO2-, Aryl(CH2)n SO2-, Heteroaryl(CH2)n SO2-, or (C1 -C3)alkyl-O-(CH2)m-SO2, wherein m = 1 to 3; n = 0 to 3;
Aryl is and Heteroaryl is wherein X is hydrogen, halogen, (C1 - C3) alkyl or -OCH3 and R and R' are as defined above; and pharmaceutically acceptable salts thereof.
5. A compound according to claim 1, wherein R is hydrogen, (C1 - C3) alkyl, -CN, -OR', -SR', -CF3, -OCF3, Cl, F. NH2, NH(C1 - C3)alkyl, -N(R')CO(C1 - C3)alkyl, -N(R')(R'), NO2, -CONH2, -SO2NH2, -SO2N(R')(R'), or -N(R')COCH2O-(C1 - C3)alkyl, wherein R' is (C1 - C3) alkyl or hydrogen;
R4 is (C1 - C6) alkyl-O-, (C1 - C6) alkyl-S-, wherein R" is hydrogen, halogen, cyano, methyl or -OCH3;
R1 and R2 are each, independently, hydrogen or CH3;
R3 is (C1 - C3)alkyl, Aryl(C1 - C3)alkyl, Heteroaryl(C1 - C3)alkyl, ArylCH=CHCH2, HeteroarylCH=CHCH2-, or (C1 - C6)alkylCH=CHCH2-, wherein Aryl is and Heteroaryl is wherein X is hydrogen, halogen, (C1 - C3) alkyl or -OCH3 and R and R' are is as defined above;
and pharmaceutically acceptable salts thereof.
R4 is (C1 - C6) alkyl-O-, (C1 - C6) alkyl-S-, wherein R" is hydrogen, halogen, cyano, methyl or -OCH3;
R1 and R2 are each, independently, hydrogen or CH3;
R3 is (C1 - C3)alkyl, Aryl(C1 - C3)alkyl, Heteroaryl(C1 - C3)alkyl, ArylCH=CHCH2, HeteroarylCH=CHCH2-, or (C1 - C6)alkylCH=CHCH2-, wherein Aryl is and Heteroaryl is wherein X is hydrogen, halogen, (C1 - C3) alkyl or -OCH3 and R and R' are is as defined above;
and pharmaceutically acceptable salts thereof.
6. A compound according to claim 1, wherein R is hydrogen, (C1 - C3) alkyl, -CN, -OR', -SR', -CF3, -OCF3, Cl, F, NH2, NH(C1 - C3)alkyl, -N(R')CO(C1 - C3)alkyl, -N(R')(R'), NO2, -CONH2, -SO2NH2, -SO2N(R')(R'), or -N(R')COCH2O-(C1 - C3)alkyl, wherein R' is (C1 - C3) alkyl or hydrogen;
R4 is (C1 - C6) alkyl-O-, (C1 - C6) alkyl-S-, wherein R" is hydrogen, halogen, cyano, methyl or -OCH3:
R1 and R2 are each, independently, hydrogen or CH3;
R3 is wherein m = 1 to 3; n = 0 to 3;
L is hydrogen, (C1 - C3)alkyl, -CN, -OR', -SR', -CF3, -OCF3, Cl, F, NH2, -NH-(C1 - C3)alkyl, -N(R')CO(C1 - C3)alkyl, N(R')(R'), -NO2, -CONH2, -SO2NH2, -SO2N(R')(R'), -N(R')COCH2O-(C1 - C3)alkyl, M is , or N(R')(R') where R' is as defined above;
W is O, S, NH or N(C1 - C3)alkyl;
Y is hydrogen, F, Cl, CF3 or OCH3; and X' is halogen, hydrogen, (C1 -C3)alkyl, O-(C1 - C3)alkyl, or -CH2OH: and pharmaceutically acceptable salts thereof.
R4 is (C1 - C6) alkyl-O-, (C1 - C6) alkyl-S-, wherein R" is hydrogen, halogen, cyano, methyl or -OCH3:
R1 and R2 are each, independently, hydrogen or CH3;
R3 is wherein m = 1 to 3; n = 0 to 3;
L is hydrogen, (C1 - C3)alkyl, -CN, -OR', -SR', -CF3, -OCF3, Cl, F, NH2, -NH-(C1 - C3)alkyl, -N(R')CO(C1 - C3)alkyl, N(R')(R'), -NO2, -CONH2, -SO2NH2, -SO2N(R')(R'), -N(R')COCH2O-(C1 - C3)alkyl, M is , or N(R')(R') where R' is as defined above;
W is O, S, NH or N(C1 - C3)alkyl;
Y is hydrogen, F, Cl, CF3 or OCH3; and X' is halogen, hydrogen, (C1 -C3)alkyl, O-(C1 - C3)alkyl, or -CH2OH: and pharmaceutically acceptable salts thereof.
7. A compound as claimed in any one of Claims 1 to 6 which is selected from 4-(4-Methoxybenzenesulfonyl)-1-(3-trifluoromethylbenzoyl)-2,3,4,5-tetrahydro-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)-1-(4-methylphenylsulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(Methanesulfonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1,4-Bis-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4] benzodiazepine-carboxylic acid, hydroxyamide, 1-Benzoyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-Acetyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)-1-(3-pyridinylcarbonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)-1-(2-thienylcarbonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-Methoxyacetyl-4-(4-methoxybenzenesulfonyl)-2,3.4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)-1-(propane-1-sulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)-1-(2-methyl-5-fluorobenzoyl)-2,3,4,5-tetrahydro-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)-1-(4-pyridinylcarbonyl)-2,3.4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)-1-(3-phenylpropionyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-([1,1'-Biphenyl]-2-carbonyl)-4-(4-methoxybenzene-sulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(4-Biphenylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(3-Fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)-1-(2-methyl-3-fluorobenzoyl)-2,3,4,5-tetrahydro-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)-1-(2-methyl-3-trifluoromethylbenzoyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(2-Chloro-6-trifluoromethylbenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(4-Fluoro-2-trifluoromethylbenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(2-Fluoro-6-trifluoromethylbenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide.
4-(4-Methoxybenzenesulfonyl)-1-(2-methylbenzoyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)-1-(2-methyl-6-chlorobenzoyl)-2,3,4,5-tetrahydro-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(2,4-Dimethylbenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(2,5-Dimethylbenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(2-Chloro-4-fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(2-Chlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(2-Fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(2-Chloro-6-fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(2,3-Difluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(2,4-Dichlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(2,3-Dichlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(2,5-Dichlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(2-Methoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(4-Chloro-2-methoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)-1-(2-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)-1-(3-methyl-2-thienylcarbonyl)-2,3,4,5-tetrahydro-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)-1-(4-methyl-2-thienylcarbonyl)-2,3,4,5-tetrahydro-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(3-Chloro-2-thienylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(2-Furanylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)-1-(3-methyl-2-furanylcarbonyl)-2,3,4,5-tetrahydro-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)-1-(4-methyl-2-furanylcarbonyl)-2,3,4,5-tetrahydro-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(5-Chloro-2-furanylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(5-Chloro-2-thienylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2.3,4,5-tetrahydro-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-Propionyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-Hexanoyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1 H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(3-Methoxypropionyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)-1-(3-thienylcarbonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(3-Furanylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(trans-Crotonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(Methacryloyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(Acetylaminoacetyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(Aminoacetyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(N,N-Dimethylaminoacetyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(Cyclopropylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)-1-(4-(2-thienyl)phenyl-carbonyl)-2.3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)-1-(4-(3-thienyl)phenylcarbonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)-1-[2-(1-pyrazolyl)phenylcarbonyl]-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)-1-[2-(3-pyrazolyl)phenylcarbonyl]-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(Cycloyhexylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]-benzodiazepine-3-carboxylic acid, hydroxyamide, 1-Methoxyacetyl-4-(4-methoxybenzenesulfonyl)-7-methyl-2,3,4,5-tetrahydro-1H-[1,4]-benzodiazepine-3-carboxylic acid, hydroxyamide, 1-Benzoyl-4-(4-methoxybenzenesulfonyl)-7-methyl-2,3,4,5-tetrahydro-1H-[1,4]-benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)-1-[(4-trifluoromethoxy)benzoyl]-8-chloro-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-methoxybenzenesulfonyl)-1-[2-chloro-4-(3-methyl-1-pyrazolyl)phenylcarbonyl]-2,3,4,5-tetrahydro-1H[1,4]-benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)-1-[2-(1-pyrazolyl)phenylcarbonyl]-7-methyl-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepene-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)-1-[2-(4-morpholino)phenylcarbonyl]-8-chloro-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(4-Ethoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(Cyclobutylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4.5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)-1-(phenoxyacetyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)-1-(2-methoxyethyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-Benzyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(2.4-Dimethoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)-1-[2-(4-methylpiperazin-1-yl)acetyl]-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-[4-(4-Chlorophenyloxy)benzenesulfonyl]-1-(methoxyacetal)-2,3,4,5-tetrahydro-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-[4-(4-Chlorophenyloxy)benzenesulfonyl]-1-(2-thienylcarbonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-[4-(4-Chlorophenyloxy)benzenesulfonyl]-1-(benzoyl-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide and 4-[4-(4-Pyridinyloxy)benzenesulfonyl]-1-(methoxyacetyl)-2,3,4,5-tetrahydro-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide.
4-(4-Methoxybenzenesulfonyl)-1-(2-methylbenzoyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)-1-(2-methyl-6-chlorobenzoyl)-2,3,4,5-tetrahydro-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(2,4-Dimethylbenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(2,5-Dimethylbenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(2-Chloro-4-fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(2-Chlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(2-Fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(2-Chloro-6-fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(2,3-Difluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(2,4-Dichlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(2,3-Dichlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(2,5-Dichlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(2-Methoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(4-Chloro-2-methoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)-1-(2-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)-1-(3-methyl-2-thienylcarbonyl)-2,3,4,5-tetrahydro-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)-1-(4-methyl-2-thienylcarbonyl)-2,3,4,5-tetrahydro-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(3-Chloro-2-thienylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(2-Furanylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)-1-(3-methyl-2-furanylcarbonyl)-2,3,4,5-tetrahydro-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)-1-(4-methyl-2-furanylcarbonyl)-2,3,4,5-tetrahydro-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(5-Chloro-2-furanylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(5-Chloro-2-thienylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2.3,4,5-tetrahydro-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-Propionyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-Hexanoyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1 H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(3-Methoxypropionyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)-1-(3-thienylcarbonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(3-Furanylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(trans-Crotonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(Methacryloyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(Acetylaminoacetyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(Aminoacetyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(N,N-Dimethylaminoacetyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(Cyclopropylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)-1-(4-(2-thienyl)phenyl-carbonyl)-2.3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)-1-(4-(3-thienyl)phenylcarbonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)-1-[2-(1-pyrazolyl)phenylcarbonyl]-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)-1-[2-(3-pyrazolyl)phenylcarbonyl]-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(Cycloyhexylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]-benzodiazepine-3-carboxylic acid, hydroxyamide, 1-Methoxyacetyl-4-(4-methoxybenzenesulfonyl)-7-methyl-2,3,4,5-tetrahydro-1H-[1,4]-benzodiazepine-3-carboxylic acid, hydroxyamide, 1-Benzoyl-4-(4-methoxybenzenesulfonyl)-7-methyl-2,3,4,5-tetrahydro-1H-[1,4]-benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)-1-[(4-trifluoromethoxy)benzoyl]-8-chloro-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-methoxybenzenesulfonyl)-1-[2-chloro-4-(3-methyl-1-pyrazolyl)phenylcarbonyl]-2,3,4,5-tetrahydro-1H[1,4]-benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)-1-[2-(1-pyrazolyl)phenylcarbonyl]-7-methyl-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepene-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)-1-[2-(4-morpholino)phenylcarbonyl]-8-chloro-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(4-Ethoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(Cyclobutylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4.5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)-1-(phenoxyacetyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)-1-(2-methoxyethyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-Benzyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(2.4-Dimethoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)-1-[2-(4-methylpiperazin-1-yl)acetyl]-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-[4-(4-Chlorophenyloxy)benzenesulfonyl]-1-(methoxyacetal)-2,3,4,5-tetrahydro-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-[4-(4-Chlorophenyloxy)benzenesulfonyl]-1-(2-thienylcarbonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-[4-(4-Chlorophenyloxy)benzenesulfonyl]-1-(benzoyl-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide and 4-[4-(4-Pyridinyloxy)benzenesulfonyl]-1-(methoxyacetyl)-2,3,4,5-tetrahydro-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide.
8. A pharmaceutical composition comprising a compound of Formula 1 wherein R is selected from hydrogen, (C1 - C3) alkyl, -CN, -OR', -SR', -CF3, -OCF3, Cl, F, NH2, NH(C1 - C3)alkyl, -N(R')CO(C1 - C3)alkyl, -N(R')(R'), NO2, -CONH2, -SO2NH2, -SO2N(R')(R'), -N(R')COCH2O-(C1 - C3)alkyl, wherein R' is (C1 - C3) alkyl or hydrogen:
R4 is hydroxy (C1 - C6) alkyl-O-, (C1 - C6) alkyl-S-, , wherein R" is hydrogen, halogen, cyano, methyl or -OCH3;
R1 and R2 are each, independently, hydrogen or CH3;
R3 is (C1 - C8)alkyl, NH2CH2CO-, (C1 - C6)alkylNHCH2CO-, HO(CH2)m CO-, HCO-, Aryl(CH2)n CO-, Heteroaryl(CH2)n CO-, (C1 - C3)alkyl-O-(CH2)n CO-, (C1 - C3)alkylCO-, (C1 - C3)alkylCO-NHCH2CO-, (C3 - C7)cycloalkylCO-, (C1 - C3)alkylSO2-, Aryl(CH2)n SO2-, Heteroaryl(CH2)n SO2-, (C1 - C3)alkyl-O-(CH2)m-SO2-, (C1 - C3)alkyl-O-(CH2)m, (C1-C3)alkyl-O-(C1-C3)alkyl-O-(C1-C3)-alkyl, HO-(C1 - C3)alkyl-O-(C1 - C3)alkyl, Aryl-O-CH2CO-, Heteroaryl-O-CH2CO-, ArylCH=CHCO-, HeteroarylCH=CHCO-, (C1 - C3)alkylCH=CHCO-, Aryl(C1 - C3)alkyl, Heteroaryl(C1 - C3)alkyl, ArylCH=CHCH2-, HeteroarylCH=CHCH2-, (C1 - C6)alkylCH=CHCH2-, R'OCH2 CH(OR')CO-, (R'OCH2)2C(R')CO-, [(C1 - C6)alkyl]2-N-(C1 - C6)alkyl CO-, or (C1 - C6)alkyl-NH-(C1 - C6)alkylCO-;
wherein m=1 to 3; n = 0 to 3;
Aryl is and Heteroaryl is wherein X is hydrogen, halogen, (C1 - C3) alkyl or -OCH3, and R and R' are as defined above;
L is hydrogen, (C1-C3)alkyl, -CN, -OR', -SR', -CF3, -OCF3, Cl, F, NH2, -NH-(C1-C3)alkyl, -N(R')CO(C1 - C3)alkyl, N(R')(R'), -NO2, -CONH2, -SO2NH2,-SO2N(R')(R'), -N(R')COCH2O-(C1 - C3)alkyl, M is , or N(R')(R') where R' is as defined above;
W is O, S, NH or N(C1 - C3)alkyl;
Y is hydrogen, F, Cl, CF3 or OCH3; and X' is halogen, hydrogen, (C1 -C3)alkyl, O-(C1 - C3)alkyl, or -CH2OH; and pharmaceutically acceptable salts thereof.
R4 is hydroxy (C1 - C6) alkyl-O-, (C1 - C6) alkyl-S-, , wherein R" is hydrogen, halogen, cyano, methyl or -OCH3;
R1 and R2 are each, independently, hydrogen or CH3;
R3 is (C1 - C8)alkyl, NH2CH2CO-, (C1 - C6)alkylNHCH2CO-, HO(CH2)m CO-, HCO-, Aryl(CH2)n CO-, Heteroaryl(CH2)n CO-, (C1 - C3)alkyl-O-(CH2)n CO-, (C1 - C3)alkylCO-, (C1 - C3)alkylCO-NHCH2CO-, (C3 - C7)cycloalkylCO-, (C1 - C3)alkylSO2-, Aryl(CH2)n SO2-, Heteroaryl(CH2)n SO2-, (C1 - C3)alkyl-O-(CH2)m-SO2-, (C1 - C3)alkyl-O-(CH2)m, (C1-C3)alkyl-O-(C1-C3)alkyl-O-(C1-C3)-alkyl, HO-(C1 - C3)alkyl-O-(C1 - C3)alkyl, Aryl-O-CH2CO-, Heteroaryl-O-CH2CO-, ArylCH=CHCO-, HeteroarylCH=CHCO-, (C1 - C3)alkylCH=CHCO-, Aryl(C1 - C3)alkyl, Heteroaryl(C1 - C3)alkyl, ArylCH=CHCH2-, HeteroarylCH=CHCH2-, (C1 - C6)alkylCH=CHCH2-, R'OCH2 CH(OR')CO-, (R'OCH2)2C(R')CO-, [(C1 - C6)alkyl]2-N-(C1 - C6)alkyl CO-, or (C1 - C6)alkyl-NH-(C1 - C6)alkylCO-;
wherein m=1 to 3; n = 0 to 3;
Aryl is and Heteroaryl is wherein X is hydrogen, halogen, (C1 - C3) alkyl or -OCH3, and R and R' are as defined above;
L is hydrogen, (C1-C3)alkyl, -CN, -OR', -SR', -CF3, -OCF3, Cl, F, NH2, -NH-(C1-C3)alkyl, -N(R')CO(C1 - C3)alkyl, N(R')(R'), -NO2, -CONH2, -SO2NH2,-SO2N(R')(R'), -N(R')COCH2O-(C1 - C3)alkyl, M is , or N(R')(R') where R' is as defined above;
W is O, S, NH or N(C1 - C3)alkyl;
Y is hydrogen, F, Cl, CF3 or OCH3; and X' is halogen, hydrogen, (C1 -C3)alkyl, O-(C1 - C3)alkyl, or -CH2OH; and pharmaceutically acceptable salts thereof.
9. A method of treating disease conditions mediated by matrix metalloproteinase in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula 1 wherein R is selected from hydrogen, (C1 - C3) alkyl, -CN, -OR', -SR', -CF3, -OCF3, Cl, F, NH2, NH(C1 - C3)alkyl, -N(R')CO(C1 - C3)alkyl, -N(R')(R'), NO2, -CONH2, -SO2NH2, -SO2N(R')(R'), -N(R')COCH2O-(C1 - C3)alkyl, wherein R' is (C1 - C3) alkyl or hydrogen;
R4 is hydroxy. (C1 - C6) alkyl-O-, (C1 - C6) alkyl-S-, , wherein R" is hydrogen, halogen, cyano, methyl or -OCH3;
R2 and R2 are each, independently, hydrogen or CH3;
R3 is (C1 - C8)alkyl, NH2CH2CO-, (C1 - C6)alkylNHCH2CO-, HO(CH2)m CO-, HCO-, Aryl(CH2)n CO-, Heteroaryl(CH2)n CO-, (C1 - C3)alkyl-O-(CH2)n CO-, (C1 - C3)alkylCO-, (C1 - C3)alkylCO-NHCH2CO-, (C3 - C7)cycloalkylCO-, (C1 - C3)alkylSO2-, Aryl(CH2)n SO2-, Heteroaryl(CH2)n SO2-, (C1 - C3)alkyl-O-(CH2)m-SO2-, (C1 - C3)alkyl-O-(CH2)m, (C1 - C3)alkyl-O-(C1 - C3)alkyl-O-(C1 - C3)alkyl, HO-(C1 - C3)alkyl-O-(C1 - C3)alkyl, Aryl-O-CH2CO-, Heteroaryl-O-CH2CO-, ArylCH=CHCO-, HeteroarylCH=CHCO-, (C1 - C3)alkylCH=CHCO-, ~
, Aryl(C1 - C3)alkyl, Heteroaryl(C1 - C3)alkyl, ArylCH=CHCH2-, HeteroarylCH=CHCH2-, (C1 - C6)alkylCH=CHCH2-, R'OCH2 CH(OR')CO, (R'OCH2)2C9(R')CO, [(C1 - C6)alkyl]2-N-(C1 - C6)alkyl CO-, or (C1 - C6)alkyl-NH-(C1 - C6)alkylCO-;
wherein m = 1 to 3; n = 0 to 3;
Aryl is and Heteroaryl is wherein X is hydrogen, halogen, (C1 - C3) alkyl or -OCH3, and R and R' are as defined above;
L is hydrogen, (C1-C3)alkyl, -CN, -OR', -SR', -CF3, -OCF3, Cl, F, NH2, -NH-(C1-C3)alkyl, -N(R')CO(C1 - C3)alkyl, N(R')(R'), -NO2, -CONH2, -SO2NH2, -SO2N(R')(R'), -N(R')COCH2O-(C1 - C3)alkyl, M is , or N(R')(R') where R' is as defined above;
W is O, S, NH or N(C1 - C3)alkyl;
Y is hydrogen, F, Cl, CF3 or OCH3; and X' is halogen, hydrogen, (C1 -C3)alkyl, O-(C1 - C3)alkyl, or -CH2OH; and pharmaceutically acceptable salts thereof.
R4 is hydroxy. (C1 - C6) alkyl-O-, (C1 - C6) alkyl-S-, , wherein R" is hydrogen, halogen, cyano, methyl or -OCH3;
R2 and R2 are each, independently, hydrogen or CH3;
R3 is (C1 - C8)alkyl, NH2CH2CO-, (C1 - C6)alkylNHCH2CO-, HO(CH2)m CO-, HCO-, Aryl(CH2)n CO-, Heteroaryl(CH2)n CO-, (C1 - C3)alkyl-O-(CH2)n CO-, (C1 - C3)alkylCO-, (C1 - C3)alkylCO-NHCH2CO-, (C3 - C7)cycloalkylCO-, (C1 - C3)alkylSO2-, Aryl(CH2)n SO2-, Heteroaryl(CH2)n SO2-, (C1 - C3)alkyl-O-(CH2)m-SO2-, (C1 - C3)alkyl-O-(CH2)m, (C1 - C3)alkyl-O-(C1 - C3)alkyl-O-(C1 - C3)alkyl, HO-(C1 - C3)alkyl-O-(C1 - C3)alkyl, Aryl-O-CH2CO-, Heteroaryl-O-CH2CO-, ArylCH=CHCO-, HeteroarylCH=CHCO-, (C1 - C3)alkylCH=CHCO-, ~
, Aryl(C1 - C3)alkyl, Heteroaryl(C1 - C3)alkyl, ArylCH=CHCH2-, HeteroarylCH=CHCH2-, (C1 - C6)alkylCH=CHCH2-, R'OCH2 CH(OR')CO, (R'OCH2)2C9(R')CO, [(C1 - C6)alkyl]2-N-(C1 - C6)alkyl CO-, or (C1 - C6)alkyl-NH-(C1 - C6)alkylCO-;
wherein m = 1 to 3; n = 0 to 3;
Aryl is and Heteroaryl is wherein X is hydrogen, halogen, (C1 - C3) alkyl or -OCH3, and R and R' are as defined above;
L is hydrogen, (C1-C3)alkyl, -CN, -OR', -SR', -CF3, -OCF3, Cl, F, NH2, -NH-(C1-C3)alkyl, -N(R')CO(C1 - C3)alkyl, N(R')(R'), -NO2, -CONH2, -SO2NH2, -SO2N(R')(R'), -N(R')COCH2O-(C1 - C3)alkyl, M is , or N(R')(R') where R' is as defined above;
W is O, S, NH or N(C1 - C3)alkyl;
Y is hydrogen, F, Cl, CF3 or OCH3; and X' is halogen, hydrogen, (C1 -C3)alkyl, O-(C1 - C3)alkyl, or -CH2OH; and pharmaceutically acceptable salts thereof.
10. A compound as claimed in any one of Claims 1 to 7 for use as a medicament.
11. Use of a compound ac claimed in any one of Claims 1 to 7 in the preparation of a medicament for the treatment of a disease condition mediated by matrix metalloproteinases.
12. A process for the preparation of a compound of Formula 1 as claimed in any one of Claims 1 to 7 which comprises reacting the corresponding acid halide with hydroxylamine.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US1437498A | 1998-01-27 | 1998-01-27 | |
| US09/014,374 | 1998-01-27 | ||
| PCT/US1999/001325 WO1999037625A1 (en) | 1998-01-27 | 1999-01-22 | 2,3,4,5-tetrahydro-1h-[1,4]-benzodiazepine-3-hydroxamic acids as matrix metalloproteinase inhibitors |
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| Publication Number | Publication Date |
|---|---|
| CA2317546A1 true CA2317546A1 (en) | 1999-07-29 |
Family
ID=21765097
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002317546A Abandoned CA2317546A1 (en) | 1998-01-27 | 1999-01-22 | 2,3,4,5-tetrahydro-1h-¬1,4|-benzodiazepine-3-hydroxamic acids as matrix metalloproteinase inhibitors |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP1051407A1 (en) |
| JP (1) | JP2002501056A (en) |
| KR (1) | KR20010034406A (en) |
| CN (1) | CN1293663A (en) |
| AR (1) | AR017230A1 (en) |
| AU (1) | AU2240299A (en) |
| BR (1) | BR9907746A (en) |
| CA (1) | CA2317546A1 (en) |
| HU (1) | HUP0100277A3 (en) |
| IL (1) | IL137162A0 (en) |
| NO (1) | NO20003828L (en) |
| PL (1) | PL342045A1 (en) |
| WO (1) | WO1999037625A1 (en) |
| ZA (1) | ZA99569B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US6458783B1 (en) | 1997-09-29 | 2002-10-01 | Bristol-Myers Squibb Company | Non-imidazole benzodiazepine inhibitors of farnesyl protein transferase |
| AR022423A1 (en) * | 1999-01-27 | 2002-09-04 | American Cyanamid Co | COMPOUNDS DERIVED FROM ACIDS 2,3,4,5-TETRAHIDRO-1H- [1,4] BENZODIAZEPINA-3-HYDROXAMICS, PHARMACEUTICAL COMPOSITION THAT INCLUDES THEM, AND THE USE OF THEM FOR THE MANUFACTURE OF A MEDICINAL PRODUCT |
| US6544984B1 (en) | 1999-01-27 | 2003-04-08 | American Cyanamid Company | 2,3,4,5-tetrahydro-1H-(1,4)benzodiazepine-3-hydroxamic acids |
| US6808902B1 (en) | 1999-11-12 | 2004-10-26 | Amgen Inc. | Process for correction of a disulfide misfold in IL-1Ra Fc fusion molecules |
| US20030051728A1 (en) | 2001-06-05 | 2003-03-20 | Lloyd Peter M. | Method and device for delivering a physiologically active compound |
| US20070122353A1 (en) | 2001-05-24 | 2007-05-31 | Hale Ron L | Drug condensation aerosols and kits |
| EP2087908B1 (en) | 2001-06-26 | 2018-05-30 | Amgen Inc. | Antibodies to opgl |
| ES2594867T3 (en) | 2007-03-09 | 2016-12-23 | Alexza Pharmaceuticals, Inc. | Heating unit for use in a drug delivery device |
| FR2950057B1 (en) | 2009-09-17 | 2011-08-26 | Galderma Res & Dev | NOVEL BENZENE CARBOXYLAMIDE COMPOUNDS, PROCESS FOR THEIR SYNTHESIS AND THEIR USE IN MEDICINE AND COSMETICS |
| FR2950056B1 (en) | 2009-09-17 | 2011-08-26 | Galderma Res & Dev | NOVEL BENZENE CARBOXYLAMIDE COMPOUNDS, PROCESS FOR THEIR SYNTHESIS AND THEIR USE IN MEDICINE AND COSMETICS |
| CA3115038A1 (en) | 2018-10-04 | 2020-04-09 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Egfr inhibitors for treating keratodermas |
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| DE59608740D1 (en) * | 1995-11-13 | 2002-03-21 | Hoechst Ag | CYCLIC AND HETEROCYCLIC N-SUBSTITUTED ALPHA-IMINOHYDROXAMIC AND CARBONIC ACIDS |
| ATE283264T1 (en) * | 1995-12-08 | 2004-12-15 | Agouron Pharma | INTERMEDIATE PRODUCTS FOR THE PRODUCTION OF METALPROTEINASE INHIBITORS |
-
1999
- 1999-01-22 CA CA002317546A patent/CA2317546A1/en not_active Abandoned
- 1999-01-22 BR BR9907746-9A patent/BR9907746A/en not_active Application Discontinuation
- 1999-01-22 WO PCT/US1999/001325 patent/WO1999037625A1/en not_active Application Discontinuation
- 1999-01-22 AU AU22402/99A patent/AU2240299A/en not_active Abandoned
- 1999-01-22 HU HU0100277A patent/HUP0100277A3/en unknown
- 1999-01-22 PL PL99342045A patent/PL342045A1/en unknown
- 1999-01-22 CN CN99804237A patent/CN1293663A/en active Pending
- 1999-01-22 EP EP99902417A patent/EP1051407A1/en not_active Withdrawn
- 1999-01-22 IL IL13716299A patent/IL137162A0/en unknown
- 1999-01-22 KR KR1020007008171A patent/KR20010034406A/en not_active Application Discontinuation
- 1999-01-22 JP JP2000528549A patent/JP2002501056A/en active Pending
- 1999-01-26 AR ARP990100299A patent/AR017230A1/en unknown
- 1999-01-26 ZA ZA9900569A patent/ZA99569B/en unknown
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2000
- 2000-07-26 NO NO20003828A patent/NO20003828L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| HUP0100277A3 (en) | 2002-03-28 |
| CN1293663A (en) | 2001-05-02 |
| EP1051407A1 (en) | 2000-11-15 |
| BR9907746A (en) | 2000-10-17 |
| KR20010034406A (en) | 2001-04-25 |
| NO20003828L (en) | 2000-09-26 |
| PL342045A1 (en) | 2001-05-21 |
| AU2240299A (en) | 1999-08-09 |
| NO20003828D0 (en) | 2000-07-26 |
| AR017230A1 (en) | 2001-08-22 |
| HUP0100277A2 (en) | 2002-02-28 |
| IL137162A0 (en) | 2001-07-24 |
| JP2002501056A (en) | 2002-01-15 |
| ZA99569B (en) | 2000-07-26 |
| WO1999037625A1 (en) | 1999-07-29 |
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