Dipeptide boronic acid inhibitors of trypsin-like enzymes
First Claim
Patent Images
1. A compound of formula (I) ##STR54## or a pharmaceutically acceptale salt wherein:
- R1 isa) --(C1 -C12 alkyl )--X, or ##STR55## X is a) halogenb) --CN,c) --NO2,d) --CF3,e) --NH2f) --NHC(═
NH)H,g) --NHC(═
NH)NHOH,h) --NHC(═
NH)NHCN,i) --NHC(═
NH)NHR2,j) --NHC(═
NH)NHC(═
O)R2,k) --C(═
NH)NHR2,l) --C(═
NH)NHC(═
O)R2,m) --C(═
O)NHR2,n) --CO2 R2,o) --OR2,p) --OCF3,q) --SR2, orr) --SC(═
NH)NHR2 ;
R2 isa) hydrogen,b) C1 -C4 alkyl,c) aryl,d) --(C1 -C4 alkyl)-aryl;
R3 isa) --C(═
O)CR6 R7 -aryl,b) --C(═
O)--(C2 -C5 alkenyl)-aryl,c) --C(═
O)CR6 R7 (CH2)r --W--(CR6 R7)r -aryl,d) --C(═
O)CR6 R7 (CH2)r CR8 R9 -aryl,e) --C(═
O)CR6 R7 (CH2)r CR8 R9 -heteroaryl,,f) --C(═
O)CR6 R7 (CH2)r CR8 R9 -heterocycle,g) --C(═
O)-aryl,,h) --C(═
O)-heteroaryl,i) --C(═
O)-heterocycle,j) --C(═
O)O(CH2)t -adamantyl,k) --C(═
O)CH2)t --(C5 -C7 cycloalkyl),l) --C(═
O)(CH2)t --W--(C5 -C7 cycloalkyl), ##STR56## wherein aryl is limited to phenyl, ##STR57## wherein aryl is limited to phenyl, ##STR58## R4 and R5 are independently selected at each occurrence from the group consisting of;
a) hydrogen,b) C1 -C4 alkyl,c) --(C1 -C4 alkyl )-aryl, ord) --C5 -C7 cycloalkyl;
R6, R7, R8 and R9 are independently selected at each occurrence from the group consisting of;
a) hydrogen,b) C1 -C4 alkyl,c) C1 -C4 alkoxy,d) aryl,e) --(C1 -C4 alkyl)-aryl,f) --O--aryl, org) --(CH2)p --CO2 R4 ;
R10 is phenyl, where phenyl is optionally substituted with one to three substituents selected from the group consisting of;
halogen, C1 -C4 alkyl, C1 -C4 alkoxy, methylenedioxy, --NO2, --CF3, --S(O)r --(C1-C4-alkyl), --OH, --NH2, --NH(C1 -C4 alkyl), --N(C1 -C4 alkyl)2, --NHC(═
O)R4, NHCO2 R4, --(CH2)p --CO2 R4 ;
R12 is;
a) hydrogen,b) C1 -C4 alkyl,c) aryl,c) --(C1 -C4 alkyl)-aryl, ord) C5 -C7 cycloalkyl;
A isa) --BY1 Y2,b) --C(═
O)CF3,c) --PO3 H2, ord) --CO2 H;
W isa) --O--,b) --S(O)r --,c) --NR4 --,d) --NC(═
O)R4 --, ore) --NCO2 R4 --;
Y1 and Y2 area) --OH,b) --F,c) --NR4 R5,d) C1 -C8 alkoxy, or when taken together Y1 and Y2 form ae) cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O,f) cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O,g) cyclic boron amide-ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O;
n is independently selected at each occurrence from 0 or 1;
p is independently selected at each occurrence from 0 to 3;
q is independently selected at each occurrence from 0 to 4;
r is independently selected at each occurrence from 0 to 2;
t is independently selected at each occurrence from 1 to 3.
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Abstract
The present invention relates to the discovery of new C-terminal boronic acid dipeptide inhibitors of trypsin-like enzymes such as thrombin and pharmaceutical compositions thereof.
25 Citations
12 Claims
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1. A compound of formula (I) ##STR54## or a pharmaceutically acceptale salt wherein:
- R1 is
a) --(C1 -C12 alkyl )--X, or ##STR55## X is a) halogen b) --CN, c) --NO2, d) --CF3, e) --NH2 f) --NHC(═
NH)H,g) --NHC(═
NH)NHOH,h) --NHC(═
NH)NHCN,i) --NHC(═
NH)NHR2,j) --NHC(═
NH)NHC(═
O)R2,k) --C(═
NH)NHR2,l) --C(═
NH)NHC(═
O)R2,m) --C(═
O)NHR2,n) --CO2 R2, o) --OR2, p) --OCF3, q) --SR2, or r) --SC(═
NH)NHR2 ;R2 is a) hydrogen, b) C1 -C4 alkyl, c) aryl, d) --(C1 -C4 alkyl)-aryl; R3 is a) --C(═
O)CR6 R7 -aryl,b) --C(═
O)--(C2 -C5 alkenyl)-aryl,c) --C(═
O)CR6 R7 (CH2)r --W--(CR6 R7)r -aryl,d) --C(═
O)CR6 R7 (CH2)r CR8 R9 -aryl,e) --C(═
O)CR6 R7 (CH2)r CR8 R9 -heteroaryl,,f) --C(═
O)CR6 R7 (CH2)r CR8 R9 -heterocycle,g) --C(═
O)-aryl,,h) --C(═
O)-heteroaryl,i) --C(═
O)-heterocycle,j) --C(═
O)O(CH2)t -adamantyl,k) --C(═
O)CH2)t --(C5 -C7 cycloalkyl),l) --C(═
O)(CH2)t --W--(C5 -C7 cycloalkyl), ##STR56## wherein aryl is limited to phenyl, ##STR57## wherein aryl is limited to phenyl, ##STR58## R4 and R5 are independently selected at each occurrence from the group consisting of;a) hydrogen, b) C1 -C4 alkyl, c) --(C1 -C4 alkyl )-aryl, or d) --C5 -C7 cycloalkyl; R6, R7, R8 and R9 are independently selected at each occurrence from the group consisting of; a) hydrogen, b) C1 -C4 alkyl, c) C1 -C4 alkoxy, d) aryl, e) --(C1 -C4 alkyl)-aryl, f) --O--aryl, or g) --(CH2)p --CO2 R4 ; R10 is phenyl, where phenyl is optionally substituted with one to three substituents selected from the group consisting of;
halogen, C1 -C4 alkyl, C1 -C4 alkoxy, methylenedioxy, --NO2, --CF3, --S(O)r --(C1-C4-alkyl), --OH, --NH2, --NH(C1 -C4 alkyl), --N(C1 -C4 alkyl)2, --NHC(═
O)R4, NHCO2 R4, --(CH2)p --CO2 R4 ;R12 is; a) hydrogen, b) C1 -C4 alkyl, c) aryl, c) --(C1 -C4 alkyl)-aryl, or d) C5 -C7 cycloalkyl; A is a) --BY1 Y2, b) --C(═
O)CF3,c) --PO3 H2, or d) --CO2 H; W is a) --O--, b) --S(O)r --, c) --NR4 --, d) --NC(═
O)R4 --, ore) --NCO2 R4 --; Y1 and Y2 are a) --OH, b) --F, c) --NR4 R5, d) C1 -C8 alkoxy, or when taken together Y1 and Y2 form a e) cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O, f) cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O, g) cyclic boron amide-ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O; n is independently selected at each occurrence from 0 or 1; p is independently selected at each occurrence from 0 to 3; q is independently selected at each occurrence from 0 to 4; r is independently selected at each occurrence from 0 to 2; t is independently selected at each occurrence from 1 to 3. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12)
- R1 is
Specification
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Current AssigneeBristol-Myers Squibb Pharma Company (Bristol-Myers Squibb Company)
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Original AssigneeDu Pont De Nemours (Belgium) Bvba (DuPont de Nemours, Inc.)
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InventorsCacciola, Joseph, Pacofsky, Gregory J., Kettner, Charles A., Fevig, John M., Wang, Chia-Lin, Amparo, Eugene C., Abelman, Matthew M.
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Primary Examiner(s)McKane, Joseph K.
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Application NumberUS08/139,444Time in Patent Office741 DaysField of Search548/405, 548/413, 548/110, 514/423, 514/422, 514/414, 514/375, 514/387, 514/314, 514/343, 514/183, 514/213, 546/15, 540/452, 540/485, 540/487US Class Current514/64CPC Class CodesA61K 38/00 Medicinal preparations cont...C07D 207/16 Carbon atoms having three b...C07F 5/025 Boronic and borinic acid co...C07F 9/572 Five-membered ringsC07K 5/06191 containing heteroatoms diff...
