Pyrazoloquinolinone derivatives as protein kinase C inhibitors

Details Pyrazoloquinolinone derivatives as protein kinase C inhibitors Pyrazoloquinolinone derivatives as protein kinase C inhibitors

2002-07-09

2004-02-03

Aulakh, C. S. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S082000, C544S126000, C514S232800

Reexamination Certificate

active

06686373

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to novel pyrazoloquinolinone derivatives. These compounds are useful as inhibitors of protein kinase C (PKC), and are thus useful in the treatment of neuropathic pain, Inflammatory Pain, Diabetic Neuropathy or the like in mammalian, especially human. The present invention also relates to a pharmaceutical composition comprising the above compounds.
BACKGROUND OF THE INVENTION
Protein kinase C (PKC) was originally identified as a phospholipid-dependent, calcium- and diacylglycerol (DAG)-stimulated protein serine/threonine kinase. PKC is categorized into three groups, conventional PKC (&agr;, &bgr;1, &bgr;2, &ggr;), novel PKC (&dgr;, &egr;, &eegr;, &thgr;) and atypical PKC (&igr;, &zgr;) based on the structural difference that foster differences on calcium and lipid binding properties. Early studies demonstrated that PKC is activated in vivo by the receptor-induced second messenger DAG/tumor promoting phorbol esters and calcium. This quickly established PKC as a key regulator of cell growth and differentiation, cell survival, neurotransmission and carcinogenesis(See Bell, R. M. and Burns, D. J., J. Biol. Chem. 266: 4661-4664 (1991); Nishizuka, Y. Science 258: 607-614 (1992)).
Protein kinase C (PKC) inhibitors are found to be useful for the treatment of a variety of diseases such as neuropathic pain, acute or chronic inflammatory pain, diabetic neuropathy, sepsis, shock, ARDS, asthma, HIV infection, Alzheimer, gastric ulcer, drug resistance, diabetes and cerebral ischemia. (See
Science,
1997, 278, 279-283;
European J. Pharmacology,
1999, 372, 221-228; ibid, 2000, 403, 81-85;
Shock,
1998, 9, 256-60;
J. Biol. Chem.,
1997, 272, 12289-94;
Brain Research,
1997, 769, 287-295;
Digestion,
1998, 59, 40-46;
Biochemical Pharmacology,
1999, 58, 1587-92;
Am. J. Physiology,
1999, 276, 691-699; and
Brain Research,
1998, 779, 254-58).
WO 97/40035 discloses N-substituted azaheterocyclic carboxylic acids and esters. WO99/36421 discloses Tricyclic N-acylated tricyclic azaheterorings compounds.
It would be desirable if there were provided protein kinase C (PKC) inhibitors which have more protein kinase C (PKC) inhibitory activities.
SUMMARY OF THE INVENTION
The present invention provides a compound of the following formula:
or the pharmaceutically acceptable salts thereof wherein
the dashed lines represent optional double bonds;
R
1
is C
1-4
alkyl;
R
2
is H, amino, mono- or di-(C
1-4
alkyl)amino or C
1-3
alkyl-(O═)CNH—;
R
3
is H, halo-CH
2
—, R
4
(R
5
)NCH
2
—, R
6
(R
7
)NC(═O)CH
2
—, cyano-CH
2
—, Q
1
CH
2
—, Q
1
-(O═)CCH
2
—, C
2-8
alkyl or Q
1
-, wherein said C
2-8
alkyl is optionally substituted with up to 3 substituents selected from halo, C
1-3
alkyl, R
4
(R
5
)N, C
1-4
alkylsulfonylamino, C
1-4
alkylthio, R
6
(R
7
)NC(═O)—, cyano, Q
1
-, Q
1
-(O═)C— and Q
1
-C
1-4
alkyl-O—;
Y
1
, Y
2
, Y
3
and Y
4
are independently selected from hydrogen, halo, C
1-4
alkyl, C
1-4
alkyl-O—, C
1-4
alkylthio, Q
1
-, R
6
(R
8
)N—, R
6
N(R
7
)C(═O)—, C
1-4
alkyl-O(O═)CCH═CH—, Q
1
-(O═)CNH— and R
6
OC(═O)—, wherein said C
1-4
alkyl is optionally substituted with up to 2 substituents selected from Q
1
, Q
2
-, R
6
(R
7
)N—, cyano, hydroxy and R
6
(R
7
)NC(═O)—;
Y
5
, Y
6
, Y
7
and Y
8
are hydrogen or are absent;
C
1
, C
2
, C
3
and C
4
are carbon atom;
R
4
is H, C
1-7
alkyl, HO—C
1-4
alkyl, Q
1
-, Q
1
-C
1-4
alkyl-, cyano- C
1-4
alkyl- or R
6
(R
7
)N C
1-4
alkyl-;
R
5
is H, C
1-7
alkyl, HO—C
1-4
alkyl or Q
1
-;
R
6
and R
7
are independently selected from H and C
1-4
alkyl
R
8
is aryl or heteroaryl;
Q
1
is a 4-12 membered monocyclic or bicyclic aromatic, partially saturated or fully saturated ring optionally containing up to 4 heteroatoms selected from O, N and S, and is optionally substituted with halo, C
1-4
alkyl, amino, hydroxy, R
6
(R
7
)NC
1-4
alkyl- or R
6
(R
7
)NC
1-4
alkyl-O—; and
Q
2
is a 5-12 membered monocyclic or bicyclic aromatic, partially saturated or fully saturated ring optionally containing up to 3 heteroatoms selected from O, N and S, and is optionally substituted with halo, C
1-4
alkyl-, hydroxy, C
1-4
alkoxy, nitro, amino, cyano, R
6
(R
7
)N—C
1-4
alkyl-, R
6
(R
7
)N—C
1-4
alkyl-O—, R
6
(R
7
)N(O═)C— or R
6
O(O═)C—;
with the proviso that when R
1
is methyl and R
2
and R
3
are H, Y
1
, Y
2
, Y
3
and Y
4
are not H simultaneously; and when R
1
is methyl and R
2
and R
3
are H, Y
2
is not chloro.
The pyrazoloquinolinone compounds of this invention have protein kinase C (PKC) inhibitory activities and are thus useful for the treatment of disease conditions mediated by PKC activities.
Thus, the present invention provides a pharmaceutical composition for the treatment of disease conditions mediated by protein kinase C, 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 neuropathic pain, acute or chronic inflammatory pain, auditory deficiency (synaptic repair), hypertension, forcal celebral ischemia, pulmonary fibrosis, diabetes, immune disease, colonic repair, drug resistance (MDR regulation), Alzheimer, sepsis, shock, ARDS, inflammation, ischemia, gastric acid regulation, diabetic neuropathy, asthma, HIV infection, gastric ulcer or cerebral ischemia or the like, which comprises a therapeutically effective amount of the imidazopyridine compound of formula (I) or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier.
Also, the present invention provides a method for the treatment of disease conditions mediated by protein kinase C activities, 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 the disease conditions as mentioned above.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term “halo” means fluoro, chloro, bromo and iodo, preferably fluoro or chloro.
As used herein, the term “alkyl” means straight or branched chain saturated radicals, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, secondary-butyl, tertiary-butyl.
As used herein, the term “alkoxy” means alkyl-O—, including, but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, secondary-butoxy, tertiary-butoxy.
As used herein, the term “aryl” means a monocyclic or bicyclic aromatic carbocyclic ring of 6 to 11 carbon atoms including, but not limited to, phenyl, naphthyl, indanyl, (1,2,3,4)-tetrahydronaphthyl, indenyl and isoindenyl, preferably phenyl and naphthyl.
As used herein, the term “heteroaryl” means a 5- to 10-membered monocyclic or bicyclic ring which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S. Examples of the heteroaryl include, but are not limited to, pyrazolyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrrolyl, thiophenyl, pyrazinyl, pyridazinyl, isooxazolyl, isothiazolyl, triazolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indolyl, isoindolyl, benzoxazolyl, benzothiazolyl, indazolyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl quinoxalinyl and the like.
As used herein, the term “4-12 membered monocyclic or bicyclic aromatic, partially saturated or fully saturated ring optionally containing up to 4 heteroatoms selected from O, N and S” may be, for example, but not limited to, phenyl, naphthyl, indanyl, (1,2,3,4)-tetrahydronaphthyl, indenyl, isoindenyl, azetidinyl, furyl, thienyl, pyrrolyl, pyrrolidinyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl, furazanyl, tetrazolyl, pyranyl, thienyl, pyridyl, piperidyl (or piperidinyl), piperidino, oxazinyl, morpholinyl, morphorino, thiamorpholino, thiazinyl, pyridazinyl, pyrimidinyl, pyraz

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