Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-12-07
2002-09-03
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S253100, C514S318000, C544S364000, C546S194000
Reexamination Certificate
active
06444677
ABSTRACT:
TECHNICAL FIELD
This invention relates to novel 1,4-dihydropyridine compounds. These compounds are useful as antagonists of bradykinin, and are thus useful in the treatment of inflammation, cardiovascular disease or the like in mammalian, especially humans. The present invention also relates to a pharmaceutical composition comprising the above compounds.
BACKGROUND ART
Bradykinin (“BK”) is generated under normal conditions in mammalia by the action of various plasma enzymes such as kallikrein 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 the 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 directed at peptidic analogues of the BK structure, some of which have been studied as analgesics and antiinflammatory agents.
International Publication Number WO 96/06082 discloses a variety of 1,4-dihydropyridine compounds having a piperazinylcarbonylmethy group at the 2-position, as antagonists of bradykinin.
It would be desirable if there were provided a non-peptide antagonist of the B
2
receptor, having an improved B
2
antagonistic activity and a good metabolic stability against human liver microsomes.
BRIEF DISCLOSURE OF THE INVENTION
The present invention provides a compound of the following formula:
or the pharmaceutically acceptable salts thereof wherein
A is independently halo;
Y
1
is —(CH
2
)
m
—, C(O) or S(O);
Y
2
is N or CH;
R
1
and R
2
are independently C
1-4
alkyl;
R
3
is selected from the following:
(a) —(CH
2
)
p
—C
3-7
cycloalkyl, the cycloalkyl moiety being optionally substituted with one, two or three substituents selected from cyano, amino-C
1-4
alkyl-, C
1-4
alkylamino-C
1-4
alkyl-, C
1-3
alkyl-carbonylamino-C
1-4
alkyl-, C
1-4
alkylsulfonylamino-C
1-4
alkyl, amino, 2-oxopyrrolidinyl, C
4-7
cycloalkylamino-C
1-4
alkyl, di-C
1-4
alkylamino-C
1-4
alkyl-, hydroxyl, carbamoyl, C
1-3
alkylcarbonyl(C
1-4
alkyl)amino, C
1-4
alkylcarbonyl(C
1-4
alkyl)amino-C
1-4
alkyl, di-C
1-4
alkylamino, pyrrolidinyl-C
1-4
alkyl, 2-oxopyrrolidinyl-C
1-4
alkyl and di-C
1-4
alkylamino-C
1-4
alkyl;
(b) —C
5-7
alkyl optionally substituted with one or two substituents selected from 2-oxopyrrolidinyl, C
1-3
alkylsuflonylamino, cyano, C
1-3
alkylcarbonylamino, 1,1-dioxoisothiazolinyl, 2-oxo-1,3-oxazolidinyl, amino, C
1-4
alkylamino, morpholinylcarbonyl, morpholino, C
1-3
alkyl-2-oxopyrrolidinyl, piperidinyl and 2-oxo-piperidinyl;
(c) —C
1-4
alkyl substituted with one or two substituents selected from 2-oxopyrrolidinyl, C
1-3
alkylsuflonylamino, cyano, C
1-3
alkylcarbonylamino, 1,1-dioxoisothiazolinyl, 2-oxo-1,3-oxazolidinyl, morpholino, C
1-3
alkyl-2-oxopyrrolidinyl, piperidinyl and 2-oxo-piperidinyl; and
(d) C
7-9
bicycloalkyl optionally substitued with di-C
1-4
alkylamino and oxopyrrolidinyl;
R
4
is thiazolyl, imidazolyl or oxazolyl, the thiazolyl, imidazolyl or oxazolyl being optionally substituted with one or two substituents independently selected from C
1-4
alkyl and halo;
X is S, —NH, —N—C
1-4
alkyl or O;
R
5
is hydrogen or C
1-4
alkyl;
R
6
is C
1-4
alkyl or halo;
m is 0, 1 or 2;
n is 0, 1, 2, 3, 4 or 5; and
p is 0, 1, 2, 3, 4, 5 or 6.
The 1,4-dihydropyridine compounds of this invention have excellent bradykinin antagonistic activity and are thus useful for the treatment of medical conditions caused by bradykinin such as inflammation, rheumatoid arthritis, cystitis, post-traumatic and post ischemic cerebral edema, liver cirrhosis, Alzheimer's disease, cardiovascular disease, pain, common cold, allergies, asthma, pancreatitis, burns, virus infection, head injury, multiple trauma, rhinitis, hepatorenal failure, diabetes, metastasis, pancreatitis or the like in mammalian, especially humans.
The 1,4-dihydropyridine compounds of this invention have excellent bradykinin antagonistic activity and are thus useful for the treatment of medical conditions caused by bradykinin such as Amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, Multiple sclerosis, Stroke, head trauma, Post-surgical brain edema, Brain edema (general), Cytotoxic brain edema (such as that associated with brain tumors, stroke, head trauma, etc.), Brain edema associated with metabolic diseases (renal failure, pediatric metabolic diseases, etc.), Rheumatoid arthritis, Osteoarthritis, Migraine, Neuropathic Pain, Pruritis, Brain Tumor, Pseudotumor cerebri, Glaucoma, Hydrocephalus, Spinal cord trauma, Spinal cord edema, newrogenerative diseases, respiratory diseases, diuresis, natriuresis calciuresis, COPD (chronic obstructive pulmonary disease), post-traumatic brain injury, itching, Sepsis or the like in mammalian, especially humans.
The present invention provides a pharmaceutical composition for the treatment of disease conditions caused by bradykinin, in a mammalian subject, which comprises administering to said subject a therapeutically effective amount of a compound of formula (I).
Further, the present invention also provides a pharmaceutical composition for the treatment of inflammation, rheumatoid arthritis, cystitis, post-traumatic and post ischemic cerebral edema, liver cirrhosis, Alzheimer's disease, cardiovascular disease, pain, common cold, allergies, asthma, pancreatitis, bums, virus infection, head injury, multiple trauma, rhinitis, hepatorenal failure, diabetes, metastasis, pancreatitis or the like, which comprises a therapeutically effective amount of the 1,4-dihydropyridine compound of formula (I) or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier.
Further, the present invention also provides a pharmaceutical composition for the treatment of Amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, Multiple sclerosis, Stroke, head trauma, Post-surgical brain edema, Brain edema (general), Cytotoxic brain edema (such as that associated with brain tumors, stroke, head trauma, etc.), Brain edema associated with metabolic diseases (renal failure, pediatric metabolic diseases, etc.), Rheumatoid arthritis, Osteoarthritis, Migraine, Neuropathic Pain, Pruritis, Brain Tumor, Pseudotumor cerebri, Glaucoma, Hydrocephalus, Spinal cord trauma, Spinal cord edema, newrogenerative diseases, respiratory diseases, diuresis, natriuresis calciuresis, COPD (chronic obstructive pulmonary disease), post-traumatic brain injury, itching or Sepsis, which comprises a therapeutically effective amount of a compound of formula (I) or its pharmaceutically acceptable carrier.
Also, the present invention provides a pharmaceutical formulation comprising a compound of formula (I), a pharmaceutically acceptable carrier and, optionally, one or more other pharmacologically active ingredients.
Also, the present invention provides a method for the treatment of disease conditions caused by bradykinin, in a mammalian subject, which comprises administering to said subject a therapeutically effective amount of a compound of formula (I).
Further, the present invention provides a method for the treatment of inflammation, rheumatoid arthritis, cystitis, post-traumatic and post ischemic cerebral edema, liver cirrhosis, Alzheimer's disease, cardiovascular disease, pain, common cold, allergies, asthma, pancreatitis, bums, virus infection, head injury, multiple trauma, rhinitis, hepatorenal failure, diabetes, metastasis, pancreatitis or the like, in a mammalian subject, which comprises administering to said subject a therapeutically effective am
Ikeda Takafumi
Kawai Makato
Kawamura Mitsuhiro
Murase Noriaki
Nukui Seiji
Djuardi Elsa
Ginsburg Paul H.
Kifle Bruck
Pfizer Inc.
Richardson Peter C.
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