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US4868181A Expired / Lapsed US ⏱️ 0.0 years remaining

1,4-dihydropyridine derivatives with calcium agonist and alpha1 -antagonist activity

Assignee: Bristol Myers Squibb Pharma Co
•
Filing: 1987-06-30
•
Granted: 1989-09-19
•
Expires: 2007-06-30
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Abstract

Abstract 1,4-Dihydropyridine derivatives which combine both calcium agonist and alpha 1 -antagonist activity are useful in treating congestive heart failure. These derivatives are compounds having the formula: ##STR1## wherein Ar, R 3 , R 4 , R 5 and R 6 are defined in the specification.

Inventors

  • 👤 Alexander L. Johnson
  • 👤 Philip Ma
  • 👤 Petrus B. M. W. M. Timmermans
  • 👤 Ruth R. Wexler

Bibliographic Details

Application Number —
Jurisdiction US
Data Source google_patents
Last Synchronized 2026-10-25 04:43
CPC Classifications
C; C07; C07D; C07D211/00; C07D211/04; C07D211/80; C07D211/82; C07D401/00; C07D401/02; C07D401/04; A; A61; A61P; A61P9/00; A61P9/04; C07D211/84; C07D211/90; C07D401/12; C07D491/00; C07D491/02; C07D491/04

Claims Analysis

Total Claims: 74
Claim 1
Independent Claim 457 words
Compounds having the formula: ##STR362## or a pharmaceutically acceptable salt thereof wherein Ar is ##STR363## where Z and R 5 are taken together as ##STR364## where t is 0 to 6; R 1 and R 2 independently are H, alkyl of 1-4 carbon atoms, haloalkyl of 1-4 carbon atoms, haloalkoxy of 1-4 carbon atoms, alkoxy of 1-10 carbon atoms, halogen, NO 2 , (CH 2 ) q XR 7 , XCH 2 (C 2 -C 9 alkenyl)R 7 , or XCH 2 (C 2 -C 9 alkynyl)R 7 ; provided that both R 1 and R 2 are not hydrogen except when R 5 is CO 2 R 7 or COR 7 ; R 3 independently is NO 2 , H, CN, or CONH 2 , or taken together with R 4 is ##STR365## R 4 and R 6 independently are alkyl of 1-4 carbon atoms CN, CH 2 OH, or CH 2 OCH 2 CH 2 NH 2 ; R 5 independently is CO 2 R 7 or COR 7 when R 1 and R 2 are other than (CH 2 ) q XR 7 , XCH 2 (C 2 -C 9 alkenyl)R 7 , or XCH 2 (C 2 -C 9 alkynyl)R 7 , and can also be an alkyl ester of 1-10 carbon atoms, ##STR366## NO 2 , or ##STR367## when one of R 1 or R 2 is (CH 2 ) q XR 7 , XCH 2 (C 2 -C 9 alkenyl)R 7 , or XCH 2 (C 2 -C 9 alkynyl)R 7 , or is taken together with Z as ##STR368## R 7 is selected from --(A) r --NH--Y--Ar', or ##STR369## where A is a straight or branched alkyl, alkenyl or alkynyl chain; Ar' is phenyl with one or two substituents selected from alkyl of 1-4 carbon atoms, haloalkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms, halogen, and NO 2 ; 2-, 3- or 4-pyridine; 2,6-pyrimidine; ##STR370## R 8 is H or OCH 3 ; R 9 is H, halogen, NO 2 , alkoxy of 1-4 carbon atoms, or alkyl of 1-4 carbon atoms; X is O, S or NH; Y is (CH 2 ) q , (CH 2 ) n O, (CH 2 ) n NH or (CH 2 ) n S; n is independently 1, 2 or 3; p is 0 to 10; q is 0, 1 or 2 and: r is 1 to 10 provided that: (1) when R 5 is CO 2 R 7 and R 7 is ##STR371## or where R 2 is (CH 2 ) q XR 7 , then p cannot be 0; and (2) when R 5 is COR 7 , then R 7 must be ##STR372## and p must be 0.
Claim 2
Dependent Claim 457 words
Compounds having the formula: ##STR362## or a pharmaceutically acceptable salt thereof wherein Ar is ##STR363## where Z and R 5 are taken together as ##STR364## where t is 0 to 6; R 1 and R 2 independently are H, alkyl of 1-4 carbon atoms, haloalkyl of 1-4 carbon atoms, haloalkoxy of 1-4 carbon atoms, alkoxy of 1-10 carbon atoms, halogen, NO 2 , (CH 2 ) q XR 7 , XCH 2 (C 2 -C 9 alkenyl)R 7 , or XCH 2 (C 2 -C 9 alkynyl)R 7 ; provided that both R 1 and R 2 are not hydrogen except when R 5 is CO 2 R 7 or COR 7 ; R 3 independently is NO 2 , H, CN, or CONH 2 , or taken together with R 4 is ##STR365## R 4 and R 6 independently are alkyl of 1-4 carbon atoms CN, CH 2 OH, or CH 2 OCH 2 CH 2 NH 2 ; R 5 independently is CO 2 R 7 or COR 7 when R 1 and R 2 are other than (CH 2 ) q XR 7 , XCH 2 (C 2 -C 9 alkenyl)R 7 , or XCH 2 (C 2 -C 9 alkynyl)R 7 , and can also be an alkyl ester of 1-10 carbon atoms, ##STR366## NO 2 , or ##STR367## when one of R 1 or R 2 is (CH 2 ) q XR 7 , XCH 2 (C 2 -C 9 alkenyl)R 7 , or XCH 2 (C 2 -C 9 alkynyl)R 7 , or is taken together with Z as ##STR368## R 7 is selected from --(A) r --NH--Y--Ar', or ##STR369## where A is a straight or branched alkyl, alkenyl or alkynyl chain; Ar' is phenyl with one or two substituents selected from alkyl of 1-4 carbon atoms, haloalkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms, halogen, and NO 2 ; 2-, 3- or 4-pyridine; 2,6-pyrimidine; ##STR370## R 8 is H or OCH 3 ; R 9 is H, halogen, NO 2 , alkoxy of 1-4 carbon atoms, or alkyl of 1-4 carbon atoms; X is O, S or NH; Y is (CH 2 ) q , (CH 2 ) n O, (CH 2 ) n NH or (CH 2 ) n S; n is independently 1, 2 or 3; p is 0 to 10; q is 0, 1 or 2 and: r is 1 to 10 provided that: (1) when R 5 is CO 2 R 7 and R 7 is ##STR371## or where R 2 is (CH 2 ) q XR 7 , then p cannot be 0; and (2) when R 5 is COR 7 , then R 7 must be ##STR372## and p must be 0.
Claim 3
Dependent Claim 24 words
A compound of claim 1 wherein Ar is ##STR373## wherein R 1 , R 2 and R 9 are as defined in claim 1.
Claim 4
Dependent Claim 39 words
A compound of claim 2 wherein one of R 1 and R 2 is hydrogen and the other is Cl, CF 3 , NO 2 , OCH 3 or OR 7 , and R 9 is H or halogen.
Claim 5
Dependent Claim 21 words
A compound of claim 1 wherein R 3 independently is NO 2 , or taken together with R 4 is ##STR374##
Claim 6
Dependent Claim 18 words
A compound of claim 1 wherein R 4 and R 6 independently are alkyl of 1-4 carbon atoms.
Claim 7
Dependent Claim 47 words
A compound of claim 1 wherein R 5 is CO 2 R 7 or COR 7 and R 1 and R 2 are other than (CH 2 q XR 7 , XCH 2 (C 2-C 9 alkenyl)R 7 or XCH 2 (C 2-C 9 alkynyl)R 7 .
Claim 8
Dependent Claim 34 words
A compound of claim 1 wherein R 5 is an alkyl ester of 1-10 carbon atoms, NO 2 , or phenyl NHCO and one of R 1 or R 2 is OR 7 .
Claim 9
Dependent Claim 27 words
A compound of claim 1 wherein R 7 is --(CH 2 ) r --NH(CH 2 ) n --O--Ar', or ##STR375## where Ar' is ##STR376## 2-pyridine, or 2,6-pyrimidine.
Claim 10
Dependent Claim 82 words
A compound of claim 2 wherein R 3 independently is NO 2 , or taken together with R 4 is ##STR377## R 4 and R 6 independently are alkyl of 1-4 carbon atoms; and R 5 is an alkyl ester of 1-10 carbon atoms, NO 2 , or phenyl NHCO; one of R 1 or R 2 is OR 7 and the other is H, Cl, CF 3 , NO 2 or OCH 3 ; and R 9 is H or halogen.
Claim 11
Dependent Claim 28 words
A compound of claim 9 wherein R 7 is --(CH 2 ) r --NH(CH 2 ) n 3 O--Ar', or ##STR378## where Ar' is ##STR379## 2-pyridine, or 2,6-pyrimidine.
Claim 12
Dependent Claim 75 words
A compound of claim 2 wherein one of R 1 and R 2 is H and the other is C1, CF 3 , NO 2 , or OCH 3 ; R 9 is H or halogen; R 3 independently is NO 2 , or taken together with R 4 is ##STR380## R 4 and R 6 independently are alkyl of 1-4 carbon atoms; and R 5 is CO 2 R 7 or COR 7 .
Claim 13
Dependent Claim 25 words
A compound of claim 11 wherein R 7 is --(CH 2 )r--NH(CH 2 ) n --O--Ar', or ##STR381## where Ar' is ##STR382## 2-pyridine, or 2,6-pyrimidine.
Claim 14
Dependent Claim 12 words
A compound of claim 10 wherein R 3 is NO 2 .
Claim 15
Dependent Claim 12 words
A compound of claim 12 wherein R 3 is NO 2 .
Claim 16
Dependent Claim 29 words
A compound of claim 13 wherein R 5 is CO 2 CH 3 or NO 2 , and R 7 is ##STR383## where Ar' is ##STR384## 2-pyridine, or 2,6-pyrimidine.
Claim 17
Dependent Claim 17 words
A compound of claim 14 wherein R 7 is ##STR385## where Ar' is ##STR386## 2-pyridine, or 2,6-pyrimidine.
Claim 18
Dependent Claim 10 words
The compound of claim 1 which is 1,4-Dihydro-2,6e dimethyl-5-nitro-4-[3-(trifluoromethyl)-1piperazinyl]-ethyl]ester-3-pyridinecarboxylic acid.
Claim 19
Dependent Claim 10 words
The compound of claim 1 which is 1,4-Dihydro-2,6dimethyl-4-[3-(2-((4(2-methoxyphenyl)-1-piperazinyl))ethoxy)-phenyl]-5-nitro-methyl ester-3-pyridinecarboxylic acid.
Claim 20
Dependent Claim 11 words
The compound of claim 1 which is 1,4-Dihydro-2,6-dimethyl-4-[2-(2-((4(2-methoxyphenyl)-1-piperazinyl))ethoxy)-phenyl]-5-nitro-methyl ester 3-pyridinecarboxylic acid.
Claim 21
Dependent Claim 9 words
The compound of claim 1 which is 1,4-Dihydro-2,6-dimethyl-4-[2-(2-((4-(2-methoxyphenyl)-1-piperazinyl))ethoxy)-3-(trifluoromethyl)phenyl]-5nitro-methylester-3-pyridinecarboxylic acid.
Claim 22
Dependent Claim 9 words
The compound of claim 1 which is 1,4-Dihydro-2,dimethyl-4-[2-(3-((4-(2-methoxyphenyl)-1-piperazinyl))propoxy)-phenyl]-5-methylester-3pyridinecarboxylic acid.
Claim 23
Dependent Claim 9 words
The compound of claim 1 which is 1-4-Dihydro-2,6dimethyl-5-nitro-4-[2-(4-(4-(2-pyrimidinyl)-piperazinyl)-butoxy)phenyl]-methylester-3pyridinecarboxlic acid.
Claim 24
Dependent Claim 9 words
The compound of claim 1 which is 1,4-Dihydro-2,dimethyl-4-[2-(5-(4-(2-methoxyphenyl)-1-piperazinyl)pentoxyl)-penyl]-5-nitro-methyl-ester-3-pyridinecarboxylic acid.
Claim 25
Dependent Claim 9 words
The compound of claim 1 which is 1,4-Dihydro-4-[2(10-(4-(2-methoxyphenyl)-piperazinyl)decyloxy)phenyl]-5-nitro-methylester-3-pyridinecarboxylic acid.
Claim 26
Dependent Claim 26 words
A pharmaceutical composition for treating congestive heart failure consisting essentially of a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1.
Claim 27
Dependent Claim 21 words
A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 2.
Claim 28
Dependent Claim 21 words
A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of aim 3.
Claim 29
Dependent Claim 21 words
A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of aim 3.
Claim 30
Dependent Claim 21 words
A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 4.
Claim 31
Dependent Claim 21 words
A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 5.
Claim 32
Dependent Claim 21 words
A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 6.
Claim 33
Dependent Claim 21 words
A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 7.
Claim 34
Dependent Claim 21 words
A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 8.
Claim 35
Dependent Claim 21 words
A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 9.
Claim 36
Dependent Claim 21 words
A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 10.
Claim 37
Dependent Claim 21 words
A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 11.
Claim 38
Dependent Claim 21 words
A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 12.
Claim 39
Dependent Claim 21 words
A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 13.
Claim 40
Dependent Claim 21 words
A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 14.
Claim 41
Dependent Claim 21 words
A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 15.
Claim 42
Dependent Claim 21 words
A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 16.
Claim 43
Dependent Claim 21 words
A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 17.
Claim 44
Dependent Claim 21 words
A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 18.
Claim 45
Dependent Claim 21 words
A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 19.
Claim 46
Dependent Claim 21 words
A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 20.
Claim 47
Dependent Claim 21 words
A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 21.
Claim 48
Dependent Claim 21 words
A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 22.
Claim 49
Dependent Claim 21 words
A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 23.
Claim 50
Dependent Claim 21 words
A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 24.
Claim 51
Dependent Claim 26 words
A method for treating congestive heart failure in a mammal which comprises administering to the mammal a therapeutically effective amount of a compound of claim 1.
Claim 52
Dependent Claim 26 words
A method for treating congestive heart failure in a mammal which comprises administering to the mammal a therapeutically effective amount of a compound of claim 2.
Claim 53
Dependent Claim 26 words
A method for treating congestive heart failure in a mammal which comprises administering to the mammal a therapeutically effective amount of a compound of claim 3.
Claim 54
Dependent Claim 26 words
A method for treating congestive heart failure in a mammal which comprises administering to the mammal a therapeutically effective amount of a compound of claim 4.
Claim 55
Dependent Claim 26 words
A method for treating congestive heart failure in a mammal which comprises administering to the mammal a therapeutically effective amount of a compound of claim 5.
Claim 56
Dependent Claim 26 words
A method for treating congestive heart failure in a mammal which comprises administering to the mammal a therapeutically effective amount of a compound of claim 6.
Claim 57
Dependent Claim 26 words
A method for treating congestive heart failure in a mammal which comprises administering to the mammal a therapeutically effective amount of a compound of claim 7.
Claim 58
Dependent Claim 26 words
A method for treating congestive heart failure in a mammal which comprises administering to the mammal a therapeutically effective amount of a compound of claim 8.
Claim 59
Dependent Claim 26 words
A method for treating congestive heart failure in a mammal which comprises administering to the mammal a therapeutically effective amount of a compound of claim 9.
Claim 60
Dependent Claim 26 words
A method for treating congestive heart failure in a mammal which comprises administering to the mammal a therapeutically effective amount of a compound of claim 10.
Claim 61
Dependent Claim 26 words
A method for treating congestive heart failure in a mammal which comprises administering to the mammal a therapeutically effective amount of a compound of claim 11.
Claim 62
Dependent Claim 26 words
A method for treating congestive heart failure in a mammal which comprises administering to the mammal a therapeutically effective amount of a compound of claim 12.
Claim 63
Dependent Claim 26 words
A method for treating congestive heart failure in a mammal which comprises administering to the mammal a therapeutically effective amount of a compound of claim 13.
Claim 64
Dependent Claim 26 words
A method for treating congestive heart failure in a mammal which comprises administering to the mammal a therapeutically effective amount of a compound of claim 14.
Claim 65
Dependent Claim 26 words
A method for treating congestive heart failure in a mammal which comprises administering to the mammal a therapeutically effective amount of a compound of claim 15.
Claim 66
Dependent Claim 26 words
A method for treating congestive heart failure in a mammal which comprises administering to the mammal a therapeutically effective amount of a compound of claim 16.
Claim 67
Dependent Claim 26 words
A method for treating congestive heart failure in a mammal which comprises administering to the mammal a therapeutically effective amount of the compound of claim 17.
Claim 68
Dependent Claim 26 words
A method for treating congestive heart failure in a mammal which comprises administering to the mammal a therapeutically effective amount of the compound of claim 18.
Claim 69
Dependent Claim 26 words
A method for treating congestive heart failure in a mammal which comprises administering to the mammal a therapeutically effective amount of the compound of claim 19.
Claim 70
Dependent Claim 26 words
A method for treating congestive heart failure in a mammal which comprises administering to the mammal a therapeutically effective amount of the compound of claim 20.
Claim 71
Dependent Claim 26 words
A method for treating congestive heart failure in a mammal which comprises administering to the mammal a therapeutically effective amount of the compound of claim 21.
Claim 72
Dependent Claim 26 words
A method for treating congestive heart failure in a mammal which comprises administering to the mammal a therapeutically effective amount of the compound of claim 22.
Claim 73
Dependent Claim 26 words
A method for treating congestive heart failure in a mammal which comprises administering to the mammal a therapeutically effective amount of the compound of claim 23.
Claim 74
Dependent Claim 26 words
A method for treating congestive heart failure in a mammal which comprises administering to the mammal a therapeutically effective amount of the compound of claim 24.

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3.5 Years (Year 4) 1992-09-18 1993-03-20 1993-09-19 $2000.00 Window Closed / Lapsed
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