US 2002/0161006 A1 · 1,4-dihydropyridine compounds as bradykinin antagonists

Abstract

The present invention relates to compounds of the formula 1 wherein each A is independently halo; Y is —(CH2)m—, —C(O)— or —S(O)—; R1 and R2 are independently C1-4 alkyl; R3 is substituted azacycloalkyl etc.; R4 is phenyl substituted at the 2-position with a substituent selected from substituted C1-7 alkyl, substituted C1-7 alkoxy, amine, etc; R5 is hydrogen or C1-4 alkyl; m is 0, 1 or 2; and n is 0, 1, 2, 3, 4 or 5. The present invention also relates to pharmaceutical compositions containing such compounds and to the use of such compounds in the treatment and prevention of inflammation, asthma, allergic rhinitis, pain and other disorders.

A compound of the formula

22
wherein
A is independently halo;
Y is —(CH2)m, —C(O)— or —S(O)—;
R1 and R2 are independently C1-4 alkyl;
R3 is selected from
(a) C7-14 azacyclo-, azabicyclo- or azatricyclo-alkyl, in which the nitrogen atom optionally has a substituent selected from C1-4 alkyl, benzyl optionally substituted with one or two substituents independently selected from halo and halosubstituted-C1-4 alkyl, C1-4 alkoxycarbonyl optionally substituted with one or two halogen atoms and C1-6 acyl;
(b) hydrogen, C1-7 alkyl optionally substituted with one or two substituents independently selected from hydroxy, amino, C1-4 alkylamino, di-C1-4 alkylamino, pyridyl, carbamoyl, pyrrolidinylcarbonyl, C1-4 alkylaminocarbonyl, piperidinylcarbonyl, morpholinocarbonyl, 2-oxopyrrolidinyl, C1-4 alkylsulfonylamino, cyano, C1-6 acylamino, 1,1-dioxoisothiazolinyl, 2-oxo-1,3-oxazolidinyl, morpholino, C1-4 alkyl-2-oxopyrrolidinyl, piperidinyl and oxo-piperidinyl;
(c) piperidinyl optionally substituted on the nitrogen atom with C1-4 alkyl or C1-4 alkoxycarbonyl;
(d) C5-14 cycloalkyl, bicycloalkyl or tricycloalkyl, the C5-14 cycloalkyl, bicycloalkyl or tricycloalkyl being optionally substituted with one or two substituents independently selected from oxo, hydroxy, amino, C1-4 alkylamino, di-C1-4 alkylamino, C1-4 alkoxybenzamido, morpholino and oxopyrrolidinyl;
(e) C7-10 bicycloalkenyl, benzo-C5-7 cycloalkyl or heterocyclic optionally substituted with one or two substituents independently selected from C1-4 alkyl and halo;
and
(f) C1-6 alkyl-C3-7 cycloalkyl, the cycloalkyl moiety being optionally substituted with one, two or three substituents independently selected from cyano, amino-C1-4 alkyl-, C1-4 alkylamino-C1-4 alkyl-, C1-6 acylamino-C1-4 alkyl-, C1-4 alkyl-sulfonylamino-C1-4 alkyl, amino, oxopyrrolidinyl, C4-7 cycloalkylamino-C1-4 alkyl, di-C1-4 alkylamino-C1-4 alkyl-, hydroxyl, carbamoyl, C1-6 acyl(C1-4 alkyl)amino, C1-6 acyl(C1-4 alkyl)amino-C1-4 alkyl, di-C1-4 alkylamino, pyrrolidinyl-C1-4 alkyl, oxopyrrolidinyl-C1-4 alkyl and di-C1-4 alkylamino-C1-4 alkyl;
R4 is phenyl substituted at the 2-position with substituent selected from
(a) C1-4 alkyl substituted with one, two or three substituents independently selected from amino, amino-C2-4 alkoxy, phenylthio, C1-4 alkyl-phenylthio, di-C1-4 alkylamino-C2-4 alkoxy, C1-4 alkylamino-C2-4 alkoxy, C1-4 alkylamino, di-C1-4 alkylamino, hydroxy, C1-4 alkoxy, piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C2-4 alkylenedioxy, C1-6 acyloxy, oxo, morpholino, C1-4 alkylaminocarbonyl-C1-6 acylamino, C1-4 alkoxycarbonyl-C1-6 acylamino, C1-4 alkoxycarbonylpiperazinyl, C1-6 acylpiperazinyl, C1-4 alkylthio, heterocyclic-C1-4 alkoxy, (di-C1-4 alkylamino)(C3-7 cycloalkyl)C2-4 alkoxy, (C1-4 alkylamino)(C3-7 cycloalkyl)C2-4 alkoxy and (amino)(C3-7 cycloalkyl)C2-4 alkoxy;
(b) C5-7 alkyl optionally substituted with one, two or three substituents independently selected from amino, amino-C2-4 alkoxy, phenylthio, C1-4 alkyl-phenylthio, di-C1-4 alkylamino-C2-4 alkoxy, C1-4 alkylamino-C2-4 alkoxy, C1-4 alkylamino, di-C1-4 alkylamino, hydroxy, C1-4 alkoxy, piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C2-4 alkylenedioxy, C1-6 acyloxy, oxo, morpholino, C1-4 alkylaminocarbonyl-C1-6 acylamino, C1-4 alkoxycarbonyl-C1-6 acylamino, C1-4 alkoxycarbonylpiperazinyl, C1-6 acylpiperazinyl, C1-4 alkylthio, heterocyclic-C1-4 alkoxy, (di-C1-4 alkylamino)(C3-7 cycloalkyl)C2-4 alkoxy, (C1-4 alkylamino)(C3-7 cycloalkyl)C2-4 alkoxy and (amino)(C3-7 cycloalkyl)C2-4 alkoxy;
(c) C1-4 alkoxy or C1-4 alkylthio, the C1-4 alkoxy or C1-4 alkylthio being substituted with one, two or three substituents independently selected from amino, amino-C2-4 alkoxy, phenylthio, C1-4 alkyl-phenylthio, di-C1-4 alkylamino-C2-4 alkoxy, C1-4 alkylamino-C2-4 alkoxy, C1-4 alkylamino, di-C1-4 alkylamino, hydroxy, C1-4 alkoxy, piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C2-4 alkylenedioxy, C1-6 acyloxy, oxo, morpholino, C1-4 alkylaminocarbonyl-C1-6 acylamino, C1-4 alkoxycarbonyl-C1-6 acylamino, C1-4 alkoxycarbonylpiperazinyl, C1-6 acylpiperazinyl, C1-4 alkylthio, heterocyclic-C1-4 alkoxy, (di-C1-4 alkylamino)(C3-7 cycloalkyl)C2-4 alkoxy, (C1-4 alkylamino)(C3-7 cycloalkyl)C2-4 alkoxy and (amino)(C3-7 cycloalkyl)C2-4 alkoxy;
(d) C5-7 alkoxy or C5-7 alkylthio, the C5-7 alkoxy or C5-7 alkylthio being optionally substituted with one, two or three substituents independently selected from amino, amino-C2-4 alkoxy, phenylthio, C1-4 alkyl-phenylthio, di-C1-4 alkylamino-C2-4 alkoxy, C1-4 alkylamino-C2-4 alkoxy, C1-4 alkylamino, di-C1-4 alkylamino, hydroxy, C1-4 alkoxy, piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C2-4 alkylenedioxy, C1-6 acyloxy, oxo, morpholino, C1-4 alkylaminocarbonyl-C1-6 acylamino, C1-4 alkoxycarbonyl-C1-6 acylamino, C1-4 alkoxycarbonylpiperazinyl, C1-6 acylpiperazinyl, C1-4 alkylthio, heterocyclic-C1-4 alkoxy, (di-C1-4 alkylamino)(C3-7 cycloalkyl)C2-4 alkoxy, (C1-4 alkylamino)(C3-7 cycloalkyl)C2-4 alkoxy and (amino)(C3-7 cycloalkyl)C2-4 alkoxy;
(e) amino, C1-4 alkylamino, C1-6 acylamino, aminoacetylamino, C1-4 alkylsulfonylamino, halosubstituted-C1-4 alkylsulfonylamino, halosubstituted-C1-4 alkylamino or C1-4 alkoxycarbonylaminoacetylamino;
(f) piperazinylcarbonyl, morpholinocarbonyl, nitro, cyano, hydroxy, C1-4 alkylsulfonyl, C1-4 alkylsulfinyl or di-C1-4 alkylaminosulphenyl;
(g) C1-4 alkylthio, C1-6 acylthio, amino-C1-6 acylthio, C1-4 alkylsulfonylthio, halosubstituted-C1-4 alkylthio or C1-4 alkoxyaminoacetylthio;
(h) C2-7 alkenyl or C2-7 alkynyl, the C2-7 alkenyl or C2-7 alkynyl being optionally substituted with one, two or three substituents independently selected from amino, C1-3 alkylamino, di-C1-4 alkylamino, hydroxy, C1-4 alkoxy, piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C2-4 alkylenedioxy, halo, C1-6 acyloxy, oxo, morpholino, C1-4 alkylaminocarbonyl-C1-6 acylamino, C1-4 alkoxycarbonyl-C1-6 acylamino, C1-4 alkoxycarbonylpiperazinyl, C1-6 acylpiperazinyl and C1-4 alkylthio;
and
(i) C7-14 azacycloalkyl optionally substituted with one or two substituents independently selected from oxo and C1-4 alkyl;
R5 is hydrogen or C1-4 alkyl;
m is 0, 1 or 2;
and
n is 0, 1, 2, 3, 4 or 5;
or a pharmaceutically acceptable salt thereof.

26 more elements

1,4-dihydropyridine compounds as bradykinin antagonists

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1,4-dihydropyridine compounds as bradykinin antagonists

Life of this patent

Abstract

Claims27