Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-07-11
2003-11-25
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S235800, C514S253130, C544S121000, C544S362000, C544S364000, C544S365000
Reexamination Certificate
active
06653313
ABSTRACT:
This invention relates to 1,4-dihydropyridine compounds. These compounds are useful as antagonists of bradykinin, and are thus useful in the treatment of inflammation, asthma, allergic rhinitis, pain or the like in mammals, including humans. 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.
Bradykinin (“BK”) is generated under conditions in mammals by the action of various plasma enzymes such as kalikrein on high molecular weight kininogens. It is widely distributed in mammals, as are its two receptor subtypes, B
1
and B
2
. The actions of BK at the B
2
receptor include mainly contraction of arterial and venous preparations, although it can cause relaxation of peripheral resistance vessels as well.
Many of the more important functions of BK, such as increases in vascular permeability, pain, and vasodilatation, however, are mediated by the B
2
receptor. These effects at the B
2
receptor are believed to be responsible for BK's role in numerous diseases, such as inflammation, cardiovascular disease, pain, and common cold. Hence antagonists at the B
2
receptor should find considerable therapeutic applications. Most of the efforts in this area thus far have been studied as analgesics and antiflammatory agents.
Numerous 1,4-dihydropyridine compounds which are B
2
antagonists have been synthesized and disclosed in an number of patent publications such as U.S. Pat. No. 5,861,402, EP 899261A1 and WO 97/30048.
International Publication Number WO 96/06082 discloses a variety of 1,4-dihydropyridine compounds having a piperazinylcarbonylmethy group at the 2-position, which compounds are antagonists of bradykinin.
It would be desirable if there were provided a non-peptide antagonist against the B
2
receptor, having potent B
2
antagonistic activity without metabolic liability or drug—drug interactions, especially inhibition of P-450 isozymes such as CYP3A4.
SUMMARY OF THE INVENTION
the present invention relates to compounds of the formula
wherein A is independently halo;
Y is —(CH
2
)
m
—, —C(O)—or —S(O)-;
R
1
and R
2
are independently C
1-4
alkyl;
R
3
is selected from
(a) C
7-14
azacyclo-, azabicylo- or azatricyclo-alkyl, in which the nitrogen atom optionally has a substituent selected from C
1-4
alkyl, benzyl optionally substituted with one or two substituents independently selected from halo and halosubstituted—C
1-4
alkyl, C
1-4
alkoxycarbonyl optionally substituted with one or two halogen atoms and C
1-6
acyl;
(b) hydrogen, C
1-7
alkyl optionally substituted with one or two substituents independently selected from hydroxy, amino, C
1-4
alkylamino, di-C
1-4
alkylamino, pyridyl, carbamoyl, pyrrolidinylcarbonyl, C
1-4
alkylaminocarbonyl, piperidinylcarbonyl, morpholinocarbonyl, 2-oxopyrrolidinyl, C
1-4
alkysulfonylamino, cyano, C
1-6
acylamino, 1,1-dioxoisothiazolinyl, 2-oxo-1,3-oxazolidinyl, morpholino, C
1-4
alkyl-2-oxopyrrolidinyl, piperidinyl and oxo-piperidinyl;
(c) piperidinyl optionally substituted on the nitrogen atom with C
1-4
alkyl or C
1-4
alkoxycarbonyl;
(d) C
5-14
cycloalkyl, bicycloalkyl or tricycloalkyl, the C
5-14
cycloalkyl, bicycloalkyl or tricycloalkyl being optionally substituted with one or two substituents independently selected from oxo, hydroxy, amino, C
1-4
alkylamino, di-C
1-4
alkoxybenzamido, morpholino and oxopyrrolidinyl;
(e) C
7-10
bicycloalkenyl, benzo-C
5-7
cycloalkyl or heterocyclic optionally substituted with one or two subtituents independently selected from C
1-4
alkyl and halo; and
(f) C
1-6
alkyl-C
3-7
cycloalkyl, the cycloalkyl moiety being optionally substituted with one, two or three substituents independently selected from cyano, amino-C
1-4
alkyl-, C
1-4
alkylamino-C
1-4
alkyl-, C
1-6
acylamino-C
1-4
alkyl-, C
1-4
alkyl-sulfonylamino-C
1-4
alkyl, amino, oxopyrrolidinyl, C
4-7
cycloalkylamino-C
1-4
alkyl, di-C
1-4
alkylamino-C
1-4
alkyl-, hydroxyl, carbamoyl, C
1-6
acyl (C
1-4
alkyl)amino, C
1-6
acyl (C
1-4
alkyl)amino-C
1-4
alkyl, di-C
1-4
alkylamino, pyrrolidinyl-C
1-4
alkyl, oxopyrrolidinyl-C
1-4
alkyl and di-C
1-4
alkylamino-C
1-4
alkyl;
R
4
is phenyl substituted at the 2-position with substituent selected from
(a) C
1-4
alkyl substituted with one, two or three substituents independently selected from amino, amino-C
2-4
alkoxy, phenylthio, C
1-4
alkyl-phenylthio, di-C
1-4
alkylamino-C
2-4
alkoxy, C
1-4
alkylamino-C
2-4
alkoxy, C
1-4
alkylamino, di-C
1-4
alkylamino, hydroxy, C
1-4
alkoxy, piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C
2-4
alkylenedioxy, C
1-6
acyloxy, oxo, morpholino, C
1-4
alkylaminocarbonyl-C
1-4
acylamino, C
1-4
alkoxycarbonyl-C
1-6
acylamino, C
1-4
alkoxycarbonylpiperazinyl, C
1-6
acylpiperazinyl, C
1-4
alkylthio, heterocyclic-C
1-4
alkoxy, (di-C
1-4
alkylamino)(C
3-7
cycloalkyl)C
2-4
alkoxy, (C
1-4
alkylamino)(C
3-7
cycloalkyl)C
2-4
alkoxy and (amino)(C
3-7
cycloalkyl)C
2-4
alkoxy;
(b) C
5-7
alkyl optionally substituted with one, two or three substituents independently selected from amino, amino-C
2-4
alkoxy, phenylthio, C
1-4
alkyl-phenylthio, di-C
1-4
alkylamino-C
2-4
alkoxy, C
1-4
alkylamino-C
2-4
alkoxy, C
1-4
alkylamino, di-C
1-4
alkylamino, hydroxy, C
1-4
alkoxy, piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C
2-4
alkylenedioxy, C
1-6
acyloxy, oxo, morpholino, C
1-4
alkylaminocarbonyl-C
1-6
acylamino, C
1-4
alkoxycarbonyl-C
1-6
acylamino, C
1-4
alkoxycarbonylpiperazinyl, C
1-6
acylpiperazinyl, C
1-4
alkylthio, heterocyclic-C
1-4
alkoxy, (di-C
1-4
alkylamino)(C
3-7
cycloalkyl)C
2-4
alkoxy, (C
1-4
alkylamino)(C
3-7
cycloalkyl)C
2-4
alkoxy and (amino)(C
3-7
cycloalkyl)C
2-4
alkoxy;
(c) C
1-4
alkoxy or C
1-4
alkylthio, the C
1-4
alkoxy or C
1-4
alkylthio being substituted with one, two or three substituents independently selected from amino, amino-C
2-4
alkoxy, phenylthio, C
1-4
alkyl-phenylthio, di-C
1-4
alkylamino-C
2-4
alkoxy, C
1-4
alkylamino-C
2-4
alkoxy, C
1-4
alkylamino, di-C
1-4
alkylamino, hydroxy, C
1-4
alkoxy, piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C
2-4
alkylenedioxy, C
1-6
acyloxy, oxo, morpholino, C
1-4
alkylaminocarbonyl-C
1-6
-acylamino, C
1-4
alkoxycarbonyl-C
1-6
acylamino, C
1-4
alkoxycarbonylpiperazinyl, C
1-6
acylpiperazinyl, C
1-4
alkylthio, heterocyclic-C
1-4
alkoxy, (di-C
1-4
alkylamino)(C
3-7
cycloalkyl)C
2-4
alkoxy, (C
1-4
alkylamino)(C
3-7
cycloalkyl)C
2-4
alkoxy and (amino)(C
3-7
cycloalkyl)C
2-4
alkoxy;
(d) C
5-7
alkoxy or C
5-7
alkylthio, the C
5-7
alkoxy or C
5-7
alkylthio being optionally substituted with one, two or three substitiuents independently selected from amino, amino-C
2-4
alkoxy, phenylthio, C
1-4
alkyl-phenylthio, di-C
1-4
alkylamino-C
2-4
alkoxy, C
1-4
alkylamino-C
2-4
alkoxy, C
1-4
alkylamino, di-C
1-4
alkylamino, hydroxy, C
1-4
alkoxy, piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C
2-4
alkylenedioxy, C
1-6
acyloxy, oxo, morpholino, C
1-4
alkylaminocarbonyl-C
1
acylamino, C
1-4
alkoxycarbonyl-C
1-6
acylamino, C
1-4
alkoxycarbonylpiperazinyl, C
1-6
acylpiperazinyl, C
1-4
alkylthio, heterocyclic-C
1-4
alkoxy, (di-C
1-4
alkylamino)(C
3-7
cycloalkyl)C
2-4
alkoxy, (C
1-4
alkylamino)(C
3-7
cycloalkyl)C
2-4
alkoxy and (amino)(C
3-7
cycloalkyl)C
2-4
alkoxy;
(e) amino, C
1-4
alkylamino, C
1-6
acylamino, aminoacetylamino, C
1-4
alkylsulfonylamino, halosubstituted-C
1-4
alkylsulfonylamino, halosubstituted-C
1-4
alkylamino or C
1-4
alkoxycarbonylaminoacetylamino;
(f) piperazinylcarbonyl, morpholinocarbonyl, nitro, cyano, hydroxy, C
1-4
alkylsulfonyl, C
1-4
alkylsulfonyl or di-C
1-4
alkylaminosulphenyl;
(g) C
1-4
alkylthio, C
1-6
alkylthio, amino-C
1-6
acylthio, C
1-4
alkylsulfonylthio, halosubstituted-C
1-4
alkylthio or C
1-4
alkoxyaminoacetylthio;
(h) C
2-7
alkenyl or C
2-7
alkynyl, the C
2-7
alkenyl or C
2-7
alkynyl being optionally substituted with one, two or three substituents independently selected from amino, C
Ikeda Takafumi
Kato Tomoki
Katsu Yasuhiro
Kawai Makoto
Kawamura Mitsuhiro
Ashbrook Charles W.
Bernhardt Emily
Kurlandsky David R.
Warner-Lambert Company LLC
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