Kinase inhibitors

Details Kinase inhibitors Kinase inhibitors

2001-01-12

2002-12-10

Stockton, Laura L. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C548S312100

Reexamination Certificate

active

06492409

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel compounds which are protein kinase C inhibitors. methods for their preparation, intermediates therefor and pharmaceutical compositions comprising them.
BACKGROUND OF THE INVENTION
Protein kinase C (PKC) is a family of phospholipid-dependent serine/threonine-specific protein kinases which play an important role in cellular growth control, regulation and differentiation.
Since the activation of PKC has been implicated in several human disease processes, including various forms of cancer, different forms of inflammatory and/or immunological disorders as well as some neurological disorders, inhibition of PKC could be of therapeutic value in treating these conditions.
Several classes of compounds have been identified as PKC inhibitors, e.g. isoquinoline sulphonamides, sphingosine and related sphingolipids, indolocarbazoles and bisindolyl-maleimides.
EP 0 328 026 describes the use of certain bisindolylmaleimides, a class of compounds related to the indolocarbazoles, in medicaments for the treatment of various conditions.
Baskakow et al.; SU 389096; 1973 describes 1,5 substituted diphenyl imidazolones although these are not suggested to be of any therapeutic potential.
Although PKC inhibitors are described in the prior art, there is a need for specific anti-inflammatory and immuno suppressive compounds, which are suitable for oral administration, and for inhalation. Furthermore. there is a need for such compounds, which are more soluble and less colored than the presently known PKC inhibitors.
SUMMARY OF THE INVENTION
The present invention provides kinase inhibitors that are particularly PKC inhibitors. methods for their preparation and intermediates used for their preparation.
The kinase inhibitors of the present invention are surprisingly more soluble and less colored than the kinase inhibitors, especially the PKC inhibitors, known in the prior art.
The present invention also provides the use of the compounds of the present invention for the treatment of inflammatory, immunological, bronchopulmonary, cardiovascular, oncological or CNS-degenerative disorders.
Also provided by the present invention are pharmaceutical compositions comprising a compound according to the present invention, as active ingredient, together with a pharmaceutically acceptable adjuvant, diluent or carrier.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides compounds of formula (I):
wherein:
Ar
1
or Ar
2
is an optionally substituted indole, and the other group is an optionally substituted aromatic or heteroaromatic group, suitably an optionally substituted bicyclic heteroaromatic group, preferably an optionally substituted indole.
X is O or S,
R is H, OH, NH
2
, C
1-6
alkyl, hydroxyC
1-6
alkyl, aminoC
1-6
alkyl, and
R1 is H, C
1-6
alkyl, fluoro substituted C
1-6
alkyl, phenyl, benzyl, carboC
1-6
alkoxy, carbobensyloxy, carbohydroxy, carbamoyl, or methyl(N-C
1-6
alkylcarbamoyl)
and salts and solvates thereof and solvates of such salts.
Preferred embodiments of formula (I) are compounds of formula (II), and (III)
wherein:
Ar is an optionally substituted aromatic or heteroaromatic group,
X is O or S,
R is H, OH, NH
2
, C
1-6
alkyl, hydroxyC
1-6
alkyl, aminoC
1-6
alkyl,
R1 is H, C
1-6
alkyl, fluoro substituted C
1-6
alkyl, phenyl, benzyl, carboC
1-6
alkoxy, carbobensyloxy, carbohydroxy, carbamoyl, or methyl(N-C
1-6
alkylcarbamoyl),
R2 is H, C
1-6
alkyl, benzyl, C
1-3
alkoxy substituted benzyl, hydroxy(C
1-6
)alkyl, hydroxy(C
3-7
)cycloalkyl, nitrile(C
1-6
)alkyl, azido(C
1-6
)alkyl, amino(C
1-6
)alkyl, amino(C
3-7
)cycloalkyl, aminomethyl(C
3-7
)cycloalkyl, amino(C
5-7
)cycloalkenyl, (mono- or di-C
1-6
alkyl) amino(C
1-6
)alkyl, benzylamino(C
1-6
)alkyl, (mono- or di-C
1-6
alkyl) amino(C
3-7
)cycloalkyl, (mono- or di-C
1-6
alkyl) aminomethyl(C
3-7
)cycloalkyl, (amino(C
1-3
)alkylphenyl)(C
1-3
)alkyl, amino(C
1-3
)alkylphenyl, guanidino(C
1-6
)alkyl, amidino(C
1-6
)alkyl, amidinothio(C
1-6
)alkyl, [N,N-di-(C
1-6
)alkyl]amidino(C
1-6
)alkyl, amidino(C
1-3
)alkylphenyl, [N,N-mono- or di-(C
1-6
)alkyl]amidino(C
1-3
)alkylphenyl, (N-benzyl)amidino(C
1-3
)alkylphenyl, (4-morpholinyl)imino(C
1-3
)alkylphenyl, benzimic acid methyl ester(C
1-3
)alkyl, hydroxy(C
1-3
)alkylamino (C
1-6
)alkyl, carboxy(C
1-3
)alkylamino (C
1-6
)alkyl, carboxymethyl(C
1-3
)alkylamino (C
1-6
)alkyl, amino(C
1-3
)alkyloxy (C
2-6
)alkyl, formamide(C
1-6
)alkyl, (N,N-dimethyl)imidoformamide(C
1-6
)alkyl, or a group of the formula
—(CH
2
)
n
—Het
in which
n is an integer of 0-6;
Z is carbonyl or methylene;
Het is an optionally substituted 5- or 6-membered heterocyclic group,
R3 and R5 are each independently H, halogen, C
1-6
alkyl, haloC
1-6
alkyl, hydroxyC
1-6
alkyl, C
1-6
alkoxy, hydroxy, amino, nitro, nitrile, and
R4 is H, C
1-3
alkyl or together with R2, forms an annulated ring which may be substituted by hydroxyC
1-3
alkyl, amidinothioC
1-3
alkyl, or aminoC
1-3
alkyl,
or a salt or solvate thereof or a solvate of a salt thereof.
Preferred embodiments of compounds of formula (II), and (III) are
wherein:
Ar is an optionally substituted aromatic or heteroaromatic group,
X is O or S,
R is H, OH, NH
2
, C
1-6
alkyl, hydroxyC
1-6
alkyl, aminoC
1-6
alkyl,
R1 is H, C
1-6
alkyl, fluoro substituted C
1-6
alkyl, phenyl, benzyl, carboC
1-6
alkoxy, carbobensyloxy, carbohydroxy, carbamoyl, or methyl(N-C
1-6
alkylcarbamoyl),
R2 is H, C
1-6
alkyl, haloC
1-6
alkyl, bensyl, C
1-3
alkoxy substituted bensyl, nitrileC
1-6
alkyl, hydroxyC
1-6
alkyl, aminoC
1-6
alkyl, (pyridinylmethyl)aminoC
1-6
alkyl, (mono- or di-C
1-6
alkyl)aminoC
1-6
alkyl, (mono- or di-C
1-3
haloalkyl)aminoC
1-6
alkyl, aminoC
3-7
cycloalkyl, (mono- or di-C
1-6
alkyl)aminoC
3-7
cycloalkyl, (aminoC
3-7
cycloalkyl)C
1-3
alkyl, (hydroxyC
1-6
alkyl)aminoC
1-6
alkyl, (aminoC
1-6
alkyl)aminoC
1-6
alkyl, (C
1-6
alkynyl)aminoC
1-6
alkyl, (bensyl)aminoC
1-6
alkyl, (mono- or di-C
1-3
alkoxy substituted bensyl)aminoC
1-6
alkyl, (aminoC
1-3
alkylphenyl)C
1-3
alkyl, (aminoC
1-3
alkylthiophenyl)C
1-3
alkyl, (aminoC
1-3
alkylpyridinyl)C
1-3
alkyl, guanidino C
1-6
alkyl, (guanidinoC
1-3
alkylphenyl)C
1-3
alkyl, amidinoC
1-6
alkyl or amidinothioC
1-6
alkyl or a group of the formula
—Z—(CH
2
)
n
—Het
in which
Z is carbonyl or methylene
n is an integer of 0-5, and
Het is an optionally substituted 5- or 6-membered heterocyclic group,
R3 and R5 are each independently H, halogen, C
1-6
alkyl, haloC
1-6
alkyl, hydroxyC
1-6
alkyl, C
1-6
alkoxy, hydroxy, amino, nitro, nitrile, and
R4 is H, C
1-3
alkyl or together with R2, forms an annulated ring which may be substituted by hydroxyC
1-3
alkyl, amidinothioC
1-3
alkyl, or aminoC
1-3
alkyl,
and salts and solvates thereof and solvates of such salts.
For compounds of formula (II) and (III), the following independent preferences apply:
Ar is an optionally substituted bicyclic aromatic or an optionally substituted bicyclic heteroaromatic group,
R is H
X is O
R1 is H or methyl; or if a fluoro substituted C
1-6
alkyl, is preferably CF
3,
when R4 is H, R2 is H, methyl, hydroxyC
1-6
alkyl, aminoC
1-6
alkyl, (mono- or di-C
1-6
alkyl)aminoC
1-6
alkyl, aminoC
3-7
cycloalkyl, (mono- or di-C
1-6
alkyl)aminoC
3-7
cycloalkyl, guanidino C
1-6
alkyl, amidinoC
1-6
alkyl or amidinothioC
1-6
alkyl,
when R2 and R4 together form an annulated ring, they together comprise 4 or 5 carbons,
R3 and R5 are independently H or methoxy.
In more preferred embodiments of formula (II) and (III), Ar comprises a single heteroatom selected from N, O and S.
In yet more preferred embodiments of formula (II) and (III), Ar is selected from benzothiophene, naphthyl, phenoxyphenyl, or an optionally substituted indolyl which if substituted is preferably substituted with aminopropyl, dimethylaminopropyl, aminobutyl, aminocyclopentyl, aminomethylbensyl, or amidinothiopropyl.
Preferred compounds according to the present invention include:
5-[1-(3-Aminopropyl)-3-indolyl]-1-(3-indolyl)-1,3-dihydroimidazol-2-one,
5-[1-(3-Aminopropyl)-3-indolyl]-1-(3-benzo[b]thoiphenyl-1,3-dihydroimidazol-2-

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