Imidazole containing aminoboronic acids
First Claim
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1. A compound of the formula (IA) ##STR19## or a pharmaceutically acceptable salt thereof, wherein:
- R1 isa) --C(═
O)--CH[(CH2)n R4 ]--NR5 R6b) --C(═
O)--CR8 R9 --(CH2)p --R4, orc) --C(═
O)--CR8 R9 --W--(CH2)r --R4 ;
R2 isa) --CH2 C(R12)2 -aryl, or ##STR20## R3 is a) hydrogen, orb) R2 and R3 can be taken together to form;
##STR21## R4 is a) aryl, orb) C3 -C8 cycloalkyl;
R5 isa) hydrogen, orb) --(C1 -C4 alkyl)-aryl;
R6 isa) --C(═
O)--R7,b) --C(═
O)--OR7,c) --C(═
O)--NR5 R7,d) --S(O)2 --R7, ore) --S(O)2 --NR5 R7 ;
R7 isa) C1 -C4 alkyl, orb) --(C1 -C4 alkyl)-aryl;
R8 and R9 are independently;
a) hydrogen,b) C1 -C4 alkyl,d) aryl, ore) --(C1 -C4 alkyl)-aryl;
R8 and R9 can be taken together to form a (C3 -C7)cycloalkyl;
R12 isa) --(C1-C5)alkyl, orb) --(C1-C5)fluoroalkyl;
aryl as used hereinabove is phenyl or phenyl optionally substituted with from one to three groups selected independently from;
F, Cl, Br, I, C1 -C4 alkyl, C1 -C4 alkoxy, methylenedioxy, --NO2, --CF3, --S(O)r --(C1 -C4 alkyl), CN, --OH, --NH2, --NH(C1 -C4 alkyl), --N(C1 -C4 alkyl)2, --NHC(═
O) (C1 -C4 alkyl), --(CH2)p --CO2 (C1 -C4 alkyl), or phenyl;
T is --NH2 ;
Y1 and Y2 area) --OH, or when taken together Y1 and Y2 form with B;
b) a cyclic boron ester derived from a diol selected from pinanediol, pinacol, 1,2-ethanediol, 1,3,-propanediol, 1,2-propanediol, 2,3-butanediol, 1,2-diisopropylethanediol, 5,6-decanediol and 1,2-dicyclohexylethanediol;
n is 0 or 1;
p is 0 to 3;
r is 0 to 2;
s is 1 to 4; and
t is 1 to 3.
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Abstract
The present invention relates generally to α-aminoboronic acids and corresponding peptide analogs of the formula (I): ##STR1## in which the α-carbon is substituted with an optionally functionalized imidazole containing alkyl group. These compounds are useful as inhibitors of trypsin-like serine protease enzymes, especially thrombin, Factor X and Factor VII.
48 Citations
3 Claims
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1. A compound of the formula (IA) ##STR19## or a pharmaceutically acceptable salt thereof, wherein:
- R1 is
a) --C(═
O)--CH[(CH2)n R4 ]--NR5 R6b) --C(═
O)--CR8 R9 --(CH2)p --R4, orc) --C(═
O)--CR8 R9 --W--(CH2)r --R4 ;R2 is a) --CH2 C(R12)2 -aryl, or ##STR20## R3 is a) hydrogen, or b) R2 and R3 can be taken together to form;
##STR21## R4 is a) aryl, orb) C3 -C8 cycloalkyl; R5 is a) hydrogen, or b) --(C1 -C4 alkyl)-aryl; R6 is a) --C(═
O)--R7,b) --C(═
O)--OR7,c) --C(═
O)--NR5 R7,d) --S(O)2 --R7, or e) --S(O)2 --NR5 R7 ; R7 is a) C1 -C4 alkyl, or b) --(C1 -C4 alkyl)-aryl; R8 and R9 are independently; a) hydrogen, b) C1 -C4 alkyl, d) aryl, or e) --(C1 -C4 alkyl)-aryl; R8 and R9 can be taken together to form a (C3 -C7)cycloalkyl; R12 is a) --(C1-C5)alkyl, or b) --(C1-C5)fluoroalkyl; aryl as used hereinabove is phenyl or phenyl optionally substituted with from one to three groups selected independently from; F, Cl, Br, I, C1 -C4 alkyl, C1 -C4 alkoxy, methylenedioxy, --NO2, --CF3, --S(O)r --(C1 -C4 alkyl), CN, --OH, --NH2, --NH(C1 -C4 alkyl), --N(C1 -C4 alkyl)2, --NHC(═
O) (C1 -C4 alkyl), --(CH2)p --CO2 (C1 -C4 alkyl), or phenyl;T is --NH2 ; Y1 and Y2 are a) --OH, or when taken together Y1 and Y2 form with B; b) a cyclic boron ester derived from a diol selected from pinanediol, pinacol, 1,2-ethanediol, 1,3,-propanediol, 1,2-propanediol, 2,3-butanediol, 1,2-diisopropylethanediol, 5,6-decanediol and 1,2-dicyclohexylethanediol; n is 0 or 1; p is 0 to 3; r is 0 to 2; s is 1 to 4; and t is 1 to 3. - View Dependent Claims (2, 3)
- R1 is
Specification
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Current AssigneeBristol-Myers Squibb Pharma Company (Bristol-Myers Squibb Company)
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Original AssigneeThe Dupont Merck Pharmaceutical Company
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InventorsCacciola, Joseph, Dominguez, Celia, Fevig, John Matthew
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Primary Examiner(s)BERNHARDT, EMILY A
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Application NumberUS08/409,573Time in Patent Office816 DaysField of Search548/110, 544/60, 544/69, 544/229, 546/13, 514/64, 514/18, 514/19, 530/331US Class Current514/64CPC Class CodesA61K 38/00 Medicinal preparations cont...C07F 5/025 Boronic and borinic acid co...C07K 5/06191 containing heteroatoms diff...
