US5723456A
Expired / Lapsed
US
⏱️ 0.0 years remaining
Therapeutic treatment for cardiovascular diseases
Assignee: Eli Lilly and Co
•
Filing: 1996-06-13
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Granted: 1998-03-03
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Expires: 2016-06-13
Abstract
Abstract A method for treating endothelial cell dysfunction, such as associated with cardiovascular disease are disclosed, particularly using the isozyme selective PKC inhibitor, (S)-3,4-[N,N'-1,1'-((27''-ethoxy)-3'''(O)-4'''-(N,N-dimethylamino)-butane)-bis-(3,3'-indolyl)]-1(H)-pyrrole-2,5-dione hydrochloride salt.
Inventors
- 👤 Michael R. Jirousek
- 👤 William Francis Heath, Jr.
- 👤 Douglas Kirk Ways
- 👤 Lawrence E. Stramm
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-23 13:51
CPC Classifications
C; C07; C07C; C07C43/00; C07C43/02; C07C43/03; C07C43/14; C07C43/17; C07C43/174; C07C43/1745; A; A61; A61K; A61K31/00; A61K31/33; A61K31/395; A61K31/40; A61K31/407; A61P; A61P13/00; A61P3/00; A61P3/06; A61P3/08; A61P3/10; A61P43/00; A61P9/00; A61P9/04; A61P9/10; A61P9/12; C07C43/178; C07C43/1785; C07D; C07D487/00; C07D487/22; C07D498/00; C07D498/22; C07D513/00; C07D513/22; C07F; C07F7/00; C07F7/02; C07F7/08; C07F7/18; C07F7/1804
Claims Analysis
Total Claims: 61
Claim 1
Independent Claim
178 words
A method for treating vascular endothelial cell dysfunction in a mammal comprising administering to a mammal in need of such treatment a cell dysfunction inhibiting amount of a protein kinase C inhibitor, wherein the protein kinase C inhibitor has the following formula: ##STR4## wherein: W is --O--, --S--, --SO--, --SO 2 --, --CO--, C 2 -C 6 alkylene, substituted alkylene, C 2 -C 6 alkenylene, -aryl-, -aryl(CH 2 ) m O--, -heterocycle-, -heterocycle-(CH 2 ) m O--, -fused bicyclic-, -fused bicyclic-(CH 2 ) m O--, --NR 3 --, --NOR 3 --, --CONH--, or --NHCO--; X and Y are independently C 1 -C 4 alkylene, substituted alkylene, or together X, Y, and W combine to form --(CH 2 ) n --AA--; R 1 s are hydrogen or up to four optional substituents independently selected from halo, C 1 -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy, haloalkyl, nitro, NR 4 R 5 , or --NHCO(C 1 -C 4 alkyl); R 2 is hydrogen, CH 3 CO--, NH 2 , or hydroxy; and AA is an amino acid residue.
Claim 2
Independent Claim
178 words
A method for treating vascular endothelial cell dysfunction in a mammal comprising administering to a mammal in need of such treatment a cell dysfunction inhibiting amount of a protein kinase C inhibitor, wherein the protein kinase C inhibitor has the following formula: ##STR4## wherein: W is --O--, --S--, --SO--, --SO 2 --, --CO--, C 2 -C 6 alkylene, substituted alkylene, C 2 -C 6 alkenylene, -aryl-, -aryl(CH 2 ) m O--, -heterocycle-, -heterocycle-(CH 2 ) m O--, -fused bicyclic-, -fused bicyclic-(CH 2 ) m O--, --NR 3 --, --NOR 3 --, --CONH--, or --NHCO--; X and Y are independently C 1 -C 4 alkylene, substituted alkylene, or together X, Y, and W combine to form --(CH 2 ) n --AA--; R 1 s are hydrogen or up to four optional substituents independently selected from halo, C 1 -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy, haloalkyl, nitro, NR 4 R 5 , or --NHCO(C 1 -C 4 alkyl); R 2 is hydrogen, CH 3 CO--, NH 2 , or hydroxy; and AA is an amino acid residue.
Claim 3
Dependent Claim
98 words
The method of claim 1 wherein the protein kinase C inhibitor has the following formula: ##STR5## wherein Z is --(CH 2 ) p -- or --(CH 2 ) p --O--(CH 2 ) p --; R 4 is hydroxy, --SH, C 1 -C 4 alkyl, (CH 2 ) m aryl, --NH(aryl), --N(CH 3 )(CF 3 ), --NH(CF 3 ), or --NR 5 R 6 ; R 5 is hydrogen or C 1 -C 4 alky; R 6 is hydrogen, C 1 -C 4 alkyl or benzyl; p is 0, 1, or 2; and m is independently 2 or 3.
Claim 4
Dependent Claim
69 words
The method of claim 1 wherein the protein kinase C inhibitor has the following formula: ##STR6## wherein Z is --(CH 2 ) p --; R 4 is --NR 5 R 6 , --NH(CF 3 ), or --N(CH 3 ) CF 3 ); R 5 and R 6 are independently H or C 1 -C 4 alkyl; p is 0, 1, or 2; and m is independently 2 or 3.
Claim 5
Dependent Claim
18 words
The method of claim 1, wherein the protein kinase C inhibitor comprises (S)-3,4- N,N'-1,1'-((2"-ethoxy)-3'"(O)-4'"(N,N-dimethylamino)-butane)-bis-(3,3'-indolyl)!-1(H)-pyrrole-2,5-dione or its acid salt.
Claim 6
Dependent Claim
14 words
The method of claim 1 wherein the endothelial cell dysfunction is associated with hyperglycemia.
Claim 7
Dependent Claim
15 words
The method of claim 1 wherein the endothelial cell dysfunction is associated with ischemic-reperfusion injury.
Claim 8
Independent Claim
173 words
A method for treating cardiovascular disease, which comprises administering to a mammal in need of such treatment, a therapeutically effective amount of a protein kinase C inhibitor, wherein the protein kinase C inhibitor has the following formula: ##STR7## wherein: W is --O--, --S--, --SO--, --SO 2 --, --CO--, C 2 -C 6 alkylene, substituted alkylene, C 2 -C 6 alkenylene, -aryl-, -aryl(CH 2 ) m O--, -heterocycle-, -heterocycle-(CH 2 ) m O--, -fused bicyclic-, -fused bicyclic-(CH 2 ) m O--, --NR 3 --, --NOR 3 --, --CONH--, or --NHCO--; X and Y are independently C 1 -C 4 alkylene, substituted alkylene, or together X, Y, and W combine to form --(CH 2 ) n --AA--; R 1 s are hydrogen or up to four optional substituents independently selected from halo, C 1 -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy, haloalkyl, nitro, NR 4 R 5 , or --NHCO(C 1 -C 4 alkyl); R 2 is hydrogen, CH 3 CO--, NH 2 , or hydroxy; and AA is an amino acid residue.
Claim 9
Independent Claim
173 words
A method for treating cardiovascular disease, which comprises administering to a mammal in need of such treatment, a therapeutically effective amount of a protein kinase C inhibitor, wherein the protein kinase C inhibitor has the following formula: ##STR7## wherein: W is --O--, --S--, --SO--, --SO 2 --, --CO--, C 2 -C 6 alkylene, substituted alkylene, C 2 -C 6 alkenylene, -aryl-, -aryl(CH 2 ) m O--, -heterocycle-, -heterocycle-(CH 2 ) m O--, -fused bicyclic-, -fused bicyclic-(CH 2 ) m O--, --NR 3 --, --NOR 3 --, --CONH--, or --NHCO--; X and Y are independently C 1 -C 4 alkylene, substituted alkylene, or together X, Y, and W combine to form --(CH 2 ) n --AA--; R 1 s are hydrogen or up to four optional substituents independently selected from halo, C 1 -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy, haloalkyl, nitro, NR 4 R 5 , or --NHCO(C 1 -C 4 alkyl); R 2 is hydrogen, CH 3 CO--, NH 2 , or hydroxy; and AA is an amino acid residue.
Claim 10
Dependent Claim
98 words
The method of claim 7 wherein the protein kinase C inhibitor has the following formula: ##STR8## wherein Z is --(CH 2 ) p -- or --(CH 2 ) p --O--(CH 2 ) p --; R 4 is hydroxy, --SH, C 1 -C 4 alkyl, (CH 2 ) m aryl, --NH(aryl), --N(CH 3 )(CF 3 ), --NH(CF 3 ), or --NR 3 R 6 ; R 5 is hydrogen or C 1 -C 4 alky; R 6 is hydrogen, C 1 -C 4 alkyl or benzyl; p is 0, 1, or 2; and m is independently 2 or 3.
Claim 11
Dependent Claim
68 words
The method of claim 7 wherein the protein kinase C inhibitor has the following formula: ##STR9## wherein Z is --(CH 2 ) p --; R 4 is --NR 5 R 6 , --NH(CF 3 ), or --N(CH 3 )(CF 3 ); R 5 and R 6 are independently H or C 1 -C 4 alkyl; p is 0, 1, or 2; and m is independently 2 or 3.
Claim 12
Dependent Claim
18 words
The method of claim 7, wherein the protein kinase C inhibitor comprises (S)-3,4- N,N'-1,1'-((2"-ethoxy)-3'"(O)-4'"-(N,N-dimethylamino)-butane)-bis-(3,3'-indolyl)!-1(H)-pyrrole-2,5-dione or its acid salt.
Claim 13
Dependent Claim
31 words
The method of claim 7, wherein the cardiovascular disease is selected from a group consisting of stable angina, unstable angina, variant angina, cardiovascular ischemia, ischemia-reperfusion injury, sudden death, and myocardial infarction.
Claim 14
Dependent Claim
13 words
The method of claim 7, wherein the cardiovascular disease is associated with hyperglycemia.
Claim 15
Independent Claim
170 words
A method for inhibiting onset of cardiovascular disease in a mammal, which comprises administering to a mammal a prophylactically effective amount of a protein kinase C inhibitor, wherein the protein kinase C inhibitor has the following formula: ##STR10## wherein: W is --O--, --S--, --SO--, --SO 2 --, --CO--, C 2 -C 6 alkylene, substituted alkylene, C 2 -C 6 alkenylene, -aryl-, -aryl(CH 2 ) m O--, -heterocycle-, -heterocycle-(CH)Q-- m -fused bicyclic-, -fused bicyclic-(CH 2 ) m O--, --NR 3 --, --NOR 3 --, --CONH--, or --NHCO--; X and Y are independently C 1 -C 4 alkylene, substituted alkylene, or together X, Y, and W combine to form --(CH 2 ) n --AA--; R 1 s are hydrogen or up to four optional substituents independently selected from halo, C 1 -C 4 alkyl, hydroxy, C 4 -C 4 alkoxy, haloalkyl, nitro, NR 4 R 5 , or --NHCO(C 1 -C 4 alkyl); R 2 is hydrogen, CH 3 CO--, NH 2 , or hydroxy; and AA is an amino acid residue.
Claim 16
Independent Claim
170 words
A method for inhibiting onset of cardiovascular disease in a mammal, which comprises administering to a mammal a prophylactically effective amount of a protein kinase C inhibitor, wherein the protein kinase C inhibitor has the following formula: ##STR10## wherein: W is --O--, --S--, --SO--, --SO 2 --, --CO--, C 2 -C 6 alkylene, substituted alkylene, C 2 -C 6 alkenylene, -aryl-, -aryl(CH 2 ) m O--, -heterocycle-, -heterocycle-(CH)Q-- m -fused bicyclic-, -fused bicyclic-(CH 2 ) m O--, --NR 3 --, --NOR 3 --, --CONH--, or --NHCO--; X and Y are independently C 1 -C 4 alkylene, substituted alkylene, or together X, Y, and W combine to form --(CH 2 ) n --AA--; R 1 s are hydrogen or up to four optional substituents independently selected from halo, C 1 -C 4 alkyl, hydroxy, C 4 -C 4 alkoxy, haloalkyl, nitro, NR 4 R 5 , or --NHCO(C 1 -C 4 alkyl); R 2 is hydrogen, CH 3 CO--, NH 2 , or hydroxy; and AA is an amino acid residue.
Claim 17
Dependent Claim
98 words
The method of claim 13 wherein the protein kinase C inhibitor has the following formula: ##STR11## wherein Z is --(CH 2 ) p -- or --(CH 2 ) p --O--(CH 2 ) p --; R 4 is hydroxy, --SH, C 1 -C 4 alkyl, (CH 2 ) m aryl, --NH(aryl), --N(CH 3 )(CF 3 ), --NH(CF 3 ), or --NR 5 R 6 ; R 5 is hydrogen or C 1 -C 4 alky; R 6 is hydrogen, C 1 -C 4 alkyl or benzyl; p is 0, 1, or 2; and m is independently 2 or 3.
Claim 18
Dependent Claim
68 words
The method of claim 13 wherein the protein kinase C inhibitor has the following formula: ##STR12## wherein Z is --(CH 2 ) p --; R 4 is --NR 5 R 6 , --NH(CF 3 ), or --N(CH 3 )(CF 3 ); R 5 and R 6 are independently H or C 1 -C 4 alkyl; p is 0, 1, or 2; and m is independently 2 or 3.
Claim 19
Dependent Claim
18 words
The method of claim 13, wherein the protein kinase C inhibitor comprises (S)-3,4- N,N'-1,1'-((2"-ethoxy)-3'"(O)-4'"-(N,N-dimethylamino)-butane)-bis-(3,3'-indolyl)!-1(H)-pyrrole-2,5-dione or it acid salt.
Claim 20
Independent Claim
172 words
A method for treating microalbuminuria, which comprises administering to a mammal in need of such treatment, a therapeutically effective amount of a protein kinase C inhibitor, wherein the protein kinase C inhibitor has the following formula: ##STR13## wherein: W is --O--, --S--, --SO--, --SO 2 --, --CO--, C 2 -C 6 alkylene, substituted alkylene, C 2 -C 6 alkenylene, -aryl-, -aryl(CH 2 ) m O--, -heterocycle-, -heterocycle-(CH 2 ) m O--, -fused bicyclic-, -fused bicyclic-(CH 2 ) m O--, --NR 3 --, --NOR 3 --, --CONH--, or --NHCO--; X and Y are independently C 1 -C 4 alkylene, substituted alkylene, or together X, Y, and W combine to form --(CH 2 ) m --AA--; R 1 s are hydrogen or up to four optional substituents independently selected from halo, C 1 -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy, haloalkyl, nitro, NR 4 R 5 , or --NHCO(C 1 -C 4 alkyl); R 2 is hydrogen, CH 3 CO--, NH 2 , or hydroxy; and AA is an amino acid residue.
Claim 21
Independent Claim
172 words
A method for treating microalbuminuria, which comprises administering to a mammal in need of such treatment, a therapeutically effective amount of a protein kinase C inhibitor, wherein the protein kinase C inhibitor has the following formula: ##STR13## wherein: W is --O--, --S--, --SO--, --SO 2 --, --CO--, C 2 -C 6 alkylene, substituted alkylene, C 2 -C 6 alkenylene, -aryl-, -aryl(CH 2 ) m O--, -heterocycle-, -heterocycle-(CH 2 ) m O--, -fused bicyclic-, -fused bicyclic-(CH 2 ) m O--, --NR 3 --, --NOR 3 --, --CONH--, or --NHCO--; X and Y are independently C 1 -C 4 alkylene, substituted alkylene, or together X, Y, and W combine to form --(CH 2 ) m --AA--; R 1 s are hydrogen or up to four optional substituents independently selected from halo, C 1 -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy, haloalkyl, nitro, NR 4 R 5 , or --NHCO(C 1 -C 4 alkyl); R 2 is hydrogen, CH 3 CO--, NH 2 , or hydroxy; and AA is an amino acid residue.
Claim 22
Dependent Claim
98 words
The method of claim 17 wherein the protein kinase C inhibitor has the following formula: ##STR14## wherein Z is --(CH 2 ) p -- or --(CH 2 ) p --O--(CH 2 ) p --; R 4 is hydroxy, --SH, C 1 -C 4 alkyl, (CH 2 ) m aryl, --NH(aryl), --N(CH 3 )(CF 3 ), --NH(CF 3 ), or --NR 5 R 6 ; R 5 is hydrogen or C 1 -C 4 alky; R 6 is hydrogen, C 1 -C 4 alkyl or benzyl; p is 0, 1, or 2; and m is independently 2 or 3.
Claim 23
Dependent Claim
68 words
The method of claim 17 wherein the protein kinase C inhibitor has the following formula: ##STR15## wherein Z is --(CH 2 ) p --; R 4 is --NR 5 R 6 , --NH(CF 3 ), or --N(CH 3 )(CF 3 ); R 5 and R 6 are independently H or C 1 -C 4 alkyl; p is 0, 1, or 2; and m is independently 2 or 3.
Claim 24
Dependent Claim
18 words
The method of claim 17, wherein the protein kinase C inhibitor comprises (S)-3,4- N,N'-1,1'-((2"-ethoxy)-3'"(O)-4'"(N,N-dimethylamino)-butane)-bis-(3,3'-indolyl)!-1(H)-pyrrole-2,5-dione or its acid salt.
Claim 25
Dependent Claim
11 words
The method of claim 17, wherein microalbuminuria is associated with diabetes.
Claim 26
Independent Claim
175 words
A method for treating central ischemia brain injury, which comprises administering to a mammal in need of such treatment, a therapeutically effective amount of a protein kinase C inhibitor, wherein the protein kinase C inhibitor has the following formula: ##STR16## wherein: W is --O--, --S--, --SO--, --SO 2 --, --CO--, C 2 -C 6 alkylene, substituted alkylene, C 2 -C 6 alkenylene, -aryl-, -aryl(CH 2 ) m O--, -heterocycle-, -heterocycle-(CH 2 ) m O--, -fused bicyclic-, -fused bicyclic-(CH 2 ) m O--, --NR 3 --, --NOR 3 --, --CONH--, or --NHCO--; X and Y are independently C 1 -C 4 alkylene, substituted alkylene, or together X, Y, and W combine to form --(CH 2 ) n --AA--; R 1 s are hydrogen or up to four optional substituents independently selected from halo, C 1 -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy, haloalkyl, nitro, NR 4 R 5 , or --NHCO(C 1 -C 4 alkyl); R 2 is hydrogen, CH 3 CO--, NH 2 , or hydroxy; and AA is an amino acid residue.
Claim 27
Independent Claim
175 words
A method for treating central ischemia brain injury, which comprises administering to a mammal in need of such treatment, a therapeutically effective amount of a protein kinase C inhibitor, wherein the protein kinase C inhibitor has the following formula: ##STR16## wherein: W is --O--, --S--, --SO--, --SO 2 --, --CO--, C 2 -C 6 alkylene, substituted alkylene, C 2 -C 6 alkenylene, -aryl-, -aryl(CH 2 ) m O--, -heterocycle-, -heterocycle-(CH 2 ) m O--, -fused bicyclic-, -fused bicyclic-(CH 2 ) m O--, --NR 3 --, --NOR 3 --, --CONH--, or --NHCO--; X and Y are independently C 1 -C 4 alkylene, substituted alkylene, or together X, Y, and W combine to form --(CH 2 ) n --AA--; R 1 s are hydrogen or up to four optional substituents independently selected from halo, C 1 -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy, haloalkyl, nitro, NR 4 R 5 , or --NHCO(C 1 -C 4 alkyl); R 2 is hydrogen, CH 3 CO--, NH 2 , or hydroxy; and AA is an amino acid residue.
Claim 28
Dependent Claim
98 words
The method of claim 22 wherein the protein kinase C inhibitor has the following formula: ##STR17## wherein Z is --(CH 2 ) p -- or --(CH 2 ) p --O--(CH 2 ) p --; R 4 is hydroxy, --SH, C 1 -C 4 alkyl, (CH 2 ) m aryl, --NH(aryl), --N(CH 3 )(CF 3 ), --NH(CF 3 ), or --NR 5 R 6 ; R 5 is hydrogen or C 1 -C 4 alky; R 6 is hydrogen, C 1 -C 4 alkyl or benzyl; p is 0, 1, or 2; and m is independently 2 or 3.
Claim 29
Dependent Claim
68 words
The method of claim 22 wherein the protein kinase C inhibitor has the following formula: ##STR18## wherein Z is --(CH 2 ) p --; R 4 is --NR 5 R 6 , --NH(CF 3 ), or --N(CH 3 )(CF 3 ); R 5 and R 6 are independently H or C 1 -C 4 alkyl; p is 0, 1, or 2; and m is independently 2 or 3.
Claim 30
Dependent Claim
18 words
The method of claim 22, wherein the protein kinase C inhibitor comprises (S)-3,4- N,N'-1,1'-((2"-ethoxy)-3'"(O)-4'"-(N,N-dimethylamino)-butane)-bis-(3,3'-indolyl)!-1(H)-pyrrole-2,5-dione or its acid salt.
Claim 31
Independent Claim
172 words
A method for treating restenosis, which comprises administering to a mammal in need of such treatment, a therapeutically effective amount of a protein kinase C inhibitor, wherein the protein kinase C inhibitor has the following formula: ##STR19## wherein: W is --O--, --S--, --SO--, --SO 2 --, --CO--, C 2 -C 6 alkylene, substituted alkylene, C 2 -C 6 alkenylene, -aryl-, -aryl(CH 2 ) m O--, -heterocycle-, -heterocycle-(CH 2 ) m O--, -fused bicyclic-, -fused bicyclic-(CH 2 ) m O--, --NR 3 --, --NOR 3 --, --CONH--, or --NHCO--; X and Y are independently C 1 -C 4 alkylene, substituted alkylene, or together X, Y, and W combine to form --(CH 2 ) n --AA--; R 1 s are hydrogen or up to four optional substituents independently selected from halo, C 1 -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy, haloalkyl, nitro, NR 4 R 5 , or --NHCO(C 1 -C 4 alkyl); R 2 is hydrogen, CH 3 CO--, NH 2 , or hydroxy; and AA is an amino acid residue.
Claim 32
Independent Claim
172 words
A method for treating restenosis, which comprises administering to a mammal in need of such treatment, a therapeutically effective amount of a protein kinase C inhibitor, wherein the protein kinase C inhibitor has the following formula: ##STR19## wherein: W is --O--, --S--, --SO--, --SO 2 --, --CO--, C 2 -C 6 alkylene, substituted alkylene, C 2 -C 6 alkenylene, -aryl-, -aryl(CH 2 ) m O--, -heterocycle-, -heterocycle-(CH 2 ) m O--, -fused bicyclic-, -fused bicyclic-(CH 2 ) m O--, --NR 3 --, --NOR 3 --, --CONH--, or --NHCO--; X and Y are independently C 1 -C 4 alkylene, substituted alkylene, or together X, Y, and W combine to form --(CH 2 ) n --AA--; R 1 s are hydrogen or up to four optional substituents independently selected from halo, C 1 -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy, haloalkyl, nitro, NR 4 R 5 , or --NHCO(C 1 -C 4 alkyl); R 2 is hydrogen, CH 3 CO--, NH 2 , or hydroxy; and AA is an amino acid residue.
Claim 33
Dependent Claim
98 words
The method of claim 26 wherein the protein kinase C inhibitor has the following formula: ##STR20## wherein Z is --(CH 2 ) p -- or --(CH 2 ) p --O--(CH 2 ) p --; R 4 is hydroxy, --SH, C 1 -C 4 alkyl, (CH 2 ) m aryl, --NH(aryl), --N(CH 3 )(CF 3 ), --NH(CF 3 ), or --NR 5 R 6 ; R 5 is hydrogen or C 1 -C 4 alky; R 6 is hydrogen, C 1 -C 4 alkyl or benzyl; p is 0, 1, or 2; and m is independently 2 or 3.
Claim 34
Dependent Claim
68 words
The method of claim 26 wherein the protein kinase C inhibitor has the following formula: ##STR21## wherein Z is --(CH 2 ) p --; R 4 is --NR 5 R 6 , --NH(CF 3 ), or --N(CH 3 )(CF 3 ); R 5 and R 6 are independently H or C 1 -C 4 alkyl; p is 0, 1, or 2; and m is independently 2 or 3.
Claim 35
Dependent Claim
18 words
The method of claim 26, wherein the protein kinase C inhibitor comprises (S)-3,4- N,N'-1,1'-((2"-ethoxy)-3'"(O)-4'"(N,N-dimethylamino)-butane)-bis-(3,3'-indolyl)!-1(H)-pyrrole-2,5-dione or its acid salt.
Claim 36
Independent Claim
174 words
A method for treating atherosclerotic disease state, which comprises administering to a mammal in need of such treatment, a therapeutically effective amount of a protein kinase C inhibitor, wherein the protein kinase C inhibitor has the following formula: ##STR22## wherein: W is --O--, --S--, --SO--, --SO 2 --, --CO--, C 2 -C 6 alkylene, substituted alkylene, C 2 -C 6 alkenylene, -aryl-, -aryl(CH 2 ) m O--, -heterocycle-, -heterocycle-(CH 2 ) m O--, -fused bicyclic-, -fused bicyclic-(CH 2 ) m O--, --NR 3 --, --NOR 3 --, --CONH--, or --NHCO--; X and Y are independently C 1 -C 4 alkylene, substituted alkylene, or together X, Y, and W combine to form --(CH 2 ) n --AA--; R 1 s are hydrogen or up to four optional substituents independently selected from halo, C 1 -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy, haloalkyl, nitro, NR 4 R 5 , or --NHCO(C 1 -C 4 alkyl); R 2 is hydrogen, CH 3 CO--, NH 2 , or hydroxy; and AA is an amino acid residue.
Claim 37
Independent Claim
174 words
A method for treating atherosclerotic disease state, which comprises administering to a mammal in need of such treatment, a therapeutically effective amount of a protein kinase C inhibitor, wherein the protein kinase C inhibitor has the following formula: ##STR22## wherein: W is --O--, --S--, --SO--, --SO 2 --, --CO--, C 2 -C 6 alkylene, substituted alkylene, C 2 -C 6 alkenylene, -aryl-, -aryl(CH 2 ) m O--, -heterocycle-, -heterocycle-(CH 2 ) m O--, -fused bicyclic-, -fused bicyclic-(CH 2 ) m O--, --NR 3 --, --NOR 3 --, --CONH--, or --NHCO--; X and Y are independently C 1 -C 4 alkylene, substituted alkylene, or together X, Y, and W combine to form --(CH 2 ) n --AA--; R 1 s are hydrogen or up to four optional substituents independently selected from halo, C 1 -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy, haloalkyl, nitro, NR 4 R 5 , or --NHCO(C 1 -C 4 alkyl); R 2 is hydrogen, CH 3 CO--, NH 2 , or hydroxy; and AA is an amino acid residue.
Claim 38
Dependent Claim
98 words
The method of claim 30 wherein the protein kinase C inhibitor has the following formula: ##STR23## wherein Z is --(CH 2 ) p -- or --(CH 2 ) p --O--(CH 2 ) p --; R 4 is hydroxy, --SH, C 1 -C 4 alkyl, (CH 2 ) m aryl, --NH(aryl), --N(CH 3 )(CF 3 ), --NH(CF 3 ), or --NR 5 R 6 ; R 5 is hydrogen or C 1 -C 4 alky; R 6 is hydrogen, C 1 -C 4 alkyl or benzyl; p is 0, 1, or 2; and m is independently 2 or 3.
Claim 39
Dependent Claim
68 words
The method of claim 30 wherein the protein kinase C inhibitor has the following formula: ##STR24## wherein Z is --(CH 2 ) p --; R 4 is --NR 5 R 6 , --NH(CF 3 ), or --N(CH 3 )(CF 3 ); R 5 and R 6 are independently H or C 1 -C 4 alkyl; p is 0, 1, or 2; and m is independently 2 or 3.
Claim 40
Dependent Claim
18 words
The method of claim 30, wherein the protein kinase C inhibitor comprises (S)-3,4- N,N'-1,1'-((2"-ethoxy)-3'"(O)-4'"-(N,N-dimethylamino)-butane)-bis-(3,3'-indolyl)!-1(H)-pyrrole-2,5-dione or its acid salt.
Claim 41
Dependent Claim
25 words
The method of claim 30, wherein the atherosclerotic disease state is selected from a group consisting of: cerebrovascular disease, peripheral vascular disease, and cardiovascular disease.
Claim 42
Independent Claim
176 words
A method for treating congestive heart failure in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of a protein kinase C inhibitor, wherein the protein kinase C inhibitor has the following formula: ##STR25## wherein: W is --O--, --S--, --SO--, --SO 2 --, --CO--, C 2 -C 6 alkylene, substituted alkylene, C 2 -C 6 alkenylene, -aryl-, -aryl(CH 2 ) m O--, -heterocycle-, -heterocycle-(CH 2 ) m O--, -fused bicyclic-, -fused bicyclic-(CH 2 ) m O--, --NR 3 --, --NOR 3 --, --CONH--, or --NHCO--; X and Y are independently C 1 -C 4 alkylene, substituted alkylene, or together X, Y, and W combine to form --(CH 2 ) n --AA--; R 1 s are hydrogen or up to four optional substituents independently selected from halo, C 1 -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy, haloalkyl, nitro, NR 4 R 5 , or --NHCO(C 1 -C 4 alkyl); R 2 is hydrogen, CH 3 CO--, NH 2 , or hydroxy; and AA is an amino acid residue.
Claim 43
Independent Claim
176 words
A method for treating congestive heart failure in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of a protein kinase C inhibitor, wherein the protein kinase C inhibitor has the following formula: ##STR25## wherein: W is --O--, --S--, --SO--, --SO 2 --, --CO--, C 2 -C 6 alkylene, substituted alkylene, C 2 -C 6 alkenylene, -aryl-, -aryl(CH 2 ) m O--, -heterocycle-, -heterocycle-(CH 2 ) m O--, -fused bicyclic-, -fused bicyclic-(CH 2 ) m O--, --NR 3 --, --NOR 3 --, --CONH--, or --NHCO--; X and Y are independently C 1 -C 4 alkylene, substituted alkylene, or together X, Y, and W combine to form --(CH 2 ) n --AA--; R 1 s are hydrogen or up to four optional substituents independently selected from halo, C 1 -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy, haloalkyl, nitro, NR 4 R 5 , or --NHCO(C 1 -C 4 alkyl); R 2 is hydrogen, CH 3 CO--, NH 2 , or hydroxy; and AA is an amino acid residue.
Claim 44
Dependent Claim
98 words
The method of claim 35 wherein the protein kinase C inhibitor has the following formula: ##STR26## wherein Z is --(CH 2 ) p -- or --(CH 2 ) p --O--(CH 2 ) p --; R 4 is hydroxy, --SH, C 1 -C 4 alkyl, (CH 2 ) m aryl, --NH(aryl), --N(CH 3 )(CF 3 ), --NH(CF 3 ), or --NR 5 R 6 ; R 5 is hydrogen or C 1 -C 4 alky; R 6 is hydrogen, C 1 -C 4 alkyl or benzyl; p is 0, 1, or 2; and m is independently 2 or 3.
Claim 45
Dependent Claim
68 words
The method of claim 35 wherein the protein kinase C inhibitor has the following formula: ##STR27## wherein Z is --(CH 2 ) p --; R 4 is --NR 5 R 6 , --NH(CF 3 ), or --N(CH 3 )(CF 3 ); R 5 and R 6 are independently H or C 1 -C 4 alkyl; p is 0, 1, or 2; and m is independently 2 or 3.
Claim 46
Dependent Claim
18 words
The method of claim 35, wherein the protein kinase C inhibitor comprises (S)-3,4- N,N'-1,1'-((2"-ethoxy)-3'"(O)-4'"-(N,N-dimethylamino)-butane)-bis-(3,3'-indolyl)!-1(H)-pyrrole-2,5-dione or its acid salt.
Claim 47
Independent Claim
182 words
A method for treating congestive heart failure associated with vascular endothelial cell dysfunction in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of a protein kinase C inhibitor, wherein the protein kinase C inhibitor has the following formula: ##STR28## wherein: W is --O--, --S--, --SO--, --SO 2 --, --CO--, C 2 -C 6 alkylene, substituted alkylene, C 2 -C 6 alkenylene, -aryl-, -aryl(CH 2 ) m O--, -heterocycle-, -heterocycle-(CH 2 ) m O--, -fused bicyclic-, -fused bicyclic-(CH 2 ) m O--, --NR 3 --, --NOR 3 --, --CONH--, or --NHCO--; X and Y are independently C 1 - 4 alkylene, substituted alkylene, or together X, Y, and W combine to form --(CH 2 ) n --AA--; R 1 s are hydrogen or up to four optional substituents independently selected from halo, C 1 -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy, haloalkyl, nitro, NR 4 R 5 , or --NHCO(C 1 -C 4 alkyl); R 2 is hydrogen, CH 3 CO--, NH 2 , or hydroxy; and AA is an amino acid residue.
Claim 48
Independent Claim
182 words
A method for treating congestive heart failure associated with vascular endothelial cell dysfunction in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of a protein kinase C inhibitor, wherein the protein kinase C inhibitor has the following formula: ##STR28## wherein: W is --O--, --S--, --SO--, --SO 2 --, --CO--, C 2 -C 6 alkylene, substituted alkylene, C 2 -C 6 alkenylene, -aryl-, -aryl(CH 2 ) m O--, -heterocycle-, -heterocycle-(CH 2 ) m O--, -fused bicyclic-, -fused bicyclic-(CH 2 ) m O--, --NR 3 --, --NOR 3 --, --CONH--, or --NHCO--; X and Y are independently C 1 - 4 alkylene, substituted alkylene, or together X, Y, and W combine to form --(CH 2 ) n --AA--; R 1 s are hydrogen or up to four optional substituents independently selected from halo, C 1 -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy, haloalkyl, nitro, NR 4 R 5 , or --NHCO(C 1 -C 4 alkyl); R 2 is hydrogen, CH 3 CO--, NH 2 , or hydroxy; and AA is an amino acid residue.
Claim 49
Dependent Claim
98 words
The method of claim 39 where the protein kinase C inhibitor has the following formula: ##STR29## wherein Z is --(CH 2 ) p -- or --(CH 2 ) p --O--(CH 2 ) p --; R 4 is hydroxy, --SH, C 1 -C 4 alkyl, (CH 2 ) m aryl, --NH(aryl), --N(CH 3 )(CF 3 ), --NH(CF 3 ), or --NR 5 R 6 ; R 5 is hydrogen or C 1 -C 4 alky; R 6 is hydrogen, C 1 -C 4 alkyl or benzyl; p is 0, 1, or 2; and m is independently 2 or 3.
Claim 50
Dependent Claim
68 words
The method of claim 39 wherein the protein kinase C inhibitor has the following formula: ##STR30## wherein Z is --(CH 2 ) p --; R 4 is --NR 5 R 6 , --NH(CF 3 ), or --N(CH 3 )(CF 3 ); R 5 and R 6 are independently H or C 1 -C 4 alkyl; p is 0, 1, or 2; and m is independently 2 or 3.
Claim 51
Dependent Claim
18 words
The method of claim 39, wherein the protein kinase C inhibitor comprises (S)-3,4- N,N'-1,1'-((2"-ethoxy)-3'"(O)-4'"-(N,N-dimethylamino)-butane)-bis-(3,3'-indolyl)!-1-(H)-pyrrole-2,5-dione or its acid salt.
Claim 52
Independent Claim
180 words
A method for treating congestive heart failure associated with myocardial injury in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of a protein kinase C inhibitor, wherein the protein kinase C inhibitor has the following formula: ##STR31## wherein: W is --O--, --S--, --SO--, --SO 2 --, --CO--, C 2 -C 6 alkylene, substituted alkenylene, C 2 -C 6 alkenylene, -aryl-, -aryl(CH 2 ) m O--, -heterocycle-, -heterocycle-(CH 2 ) m O--, -fused bicyclic-, -fused bicyclic-(CH 2 ) m O--, --NR 3 --, --NOR 3 , --CONH--, or --NHCO--; X and Y are independently C 1 -C 1 alkylene, substituted alkylene, or together X, Y, and W combine to form --(CH 2 ) n --AA--; R 1 s are hydrogen or up to four optional substituents independently selected from halo, C 1 -C 4 alkyl, hydroxy, C 1 -C 1 -alkoxy, haloalkyl, nitro, NR 4 R 5 , or --NHCO(C 1 -C 4 alkyl); R 2 is hydrogen, CH 3 CO--, NH 2 , or hydroxy; and AA is an amino acid residue.
Claim 53
Independent Claim
180 words
A method for treating congestive heart failure associated with myocardial injury in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of a protein kinase C inhibitor, wherein the protein kinase C inhibitor has the following formula: ##STR31## wherein: W is --O--, --S--, --SO--, --SO 2 --, --CO--, C 2 -C 6 alkylene, substituted alkenylene, C 2 -C 6 alkenylene, -aryl-, -aryl(CH 2 ) m O--, -heterocycle-, -heterocycle-(CH 2 ) m O--, -fused bicyclic-, -fused bicyclic-(CH 2 ) m O--, --NR 3 --, --NOR 3 , --CONH--, or --NHCO--; X and Y are independently C 1 -C 1 alkylene, substituted alkylene, or together X, Y, and W combine to form --(CH 2 ) n --AA--; R 1 s are hydrogen or up to four optional substituents independently selected from halo, C 1 -C 4 alkyl, hydroxy, C 1 -C 1 -alkoxy, haloalkyl, nitro, NR 4 R 5 , or --NHCO(C 1 -C 4 alkyl); R 2 is hydrogen, CH 3 CO--, NH 2 , or hydroxy; and AA is an amino acid residue.
Claim 54
Dependent Claim
98 words
The method of claim 43 wherein the protein kinase C inhibitor has the following formula: ##STR32## wherein Z is --(CH 2 ) p -- or --(CH 2 ) p --O--(CH 2 ) p --; R 4 is hydroxy, --SH, C 1 -C 4 alkyl, (CH 2 ) m aryl, --NH(aryl), --N(CH 3 )(CF 3 ), --NH(CF 3 ), or --NR 5 R 6 ; R 5 is hydrogen or C 1 -C 4 alky; R 6 is hydrogen, C 1 -C 4 alkyl or benzyl; p is 0, 1, or 2; and m is independently 2 or 3.
Claim 55
Dependent Claim
68 words
The method of claim 43 wherein the protein kinase C inhibitor has the following formula: ##STR33## wherein Z is --(CH 2 ) p --; R 4 is --NR 5 R 6 , --NH(CF 3 ), or --N(CH 3 )(CF 3 ); R 5 and R 6 are independently H or C 1 -C 4 alkyl; p is 0, 1, or 2; and m is independently 2 or 3.
Claim 56
Dependent Claim
18 words
The method of claim 43, wherein the protein kinase C inhibitor comprises (S)-3,4- N,N'-1,1'-((2"-ethoxy)-3'"(O)-4'"-(N,N-dimethylamino)-butane)-bis-(3,3-indolyl)!-1(H)-pyrrole-2,5-dione or its acid salt.
Claim 57
Independent Claim
179 words
A method for treating congestive heart failure associated with atherosclerosis in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of a protein kinase C inhibitor, wherein the protein kinase C inhibitor has the following formula: ##STR34## wherein: W is --O--, --S--, --SO--, --SO 2 --, --CO--, C 2 -C 6 alkylene, substituted alkylene, C 2 -C 6 alkenylene, -aryl-, -aryl(CH 2 ) m O--, -heterocycle-, -heterocycle-(CH 2 ) m O--, -fused bicyclic-, -fused bicyclic-(CH 2 ) m O--, --NR 3 --, --NOR 3 --, --CONH--, or --NHCO--; X and Y are independently C 1 -C 4 alkylene, substituted alkylene, or together X, Y, and W combine to form --(CH 2 ) n --AA--; R 1 s are hydrogen or up to four optional substituents independently selected from halo, C 1 -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy, haloalkyl, nitro, NR 4 R 5 , or --NHCO(C 1 -C 4 alkyl); R 2 is hydrogen, CH 3 CO--, NH 2 , or hydroxy; and AA is an amino acid residue.
Claim 58
Independent Claim
179 words
A method for treating congestive heart failure associated with atherosclerosis in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of a protein kinase C inhibitor, wherein the protein kinase C inhibitor has the following formula: ##STR34## wherein: W is --O--, --S--, --SO--, --SO 2 --, --CO--, C 2 -C 6 alkylene, substituted alkylene, C 2 -C 6 alkenylene, -aryl-, -aryl(CH 2 ) m O--, -heterocycle-, -heterocycle-(CH 2 ) m O--, -fused bicyclic-, -fused bicyclic-(CH 2 ) m O--, --NR 3 --, --NOR 3 --, --CONH--, or --NHCO--; X and Y are independently C 1 -C 4 alkylene, substituted alkylene, or together X, Y, and W combine to form --(CH 2 ) n --AA--; R 1 s are hydrogen or up to four optional substituents independently selected from halo, C 1 -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy, haloalkyl, nitro, NR 4 R 5 , or --NHCO(C 1 -C 4 alkyl); R 2 is hydrogen, CH 3 CO--, NH 2 , or hydroxy; and AA is an amino acid residue.
Claim 59
Dependent Claim
98 words
The method of claim 47 wherein the protein kinase C inhibitor has the following formula: ##STR35## wherein Z is --(CH 2 ) p -- or --(CH 2 ) p --O--(CH 2 ) p --; R 4 is hydroxy, --SH, C 1 -C 4 alkyl, (CH 2 ) m aryl, --NH(aryl), --N(CH 3 )(CF 3 ), --NH(CF 3 ), or --NR 5 R 6 ; R 5 is hydrogen or C 1 -C 4 alky; R 6 is hydrogen, C 1 -C 4 alkyl or benzyl; p is 0, 1, or 2; and m is independently 2 or 3.
Claim 60
Dependent Claim
68 words
The method of claim 47 wherein the protein kinase C inhibitor has the following formula: ##STR36## wherein Z is --(CH 2 ) p --; R 4 is --NR 5 R 6 , --NH(CF 3 ), or --N(CH 3 )(CF 3 ); R 5 and R 6 are independently H or C 1 -C 4 alkyl; p is 0, 1, or 2; and m is independently 2 or 3.
Claim 61
Dependent Claim
18 words
The method of claim 47, wherein the protein kinase C inhibitor comprises (S)-3,4- N,N'-1,1'-(2"-ethoxy)-3'"(O)-4'"-(N,N-dimethylamino)-butane)-bis-(3,3'-indolyl)!-1(H)-pyrrole-2,5-dione or its acid salt.
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