Protein kinase inhibitors

Details Protein kinase inhibitors Protein kinase inhibitors

1999-10-25

2002-02-12

Higel, Floyd D. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C514S397000

Reexamination Certificate

active

06346625

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 sulfonamides, sphingosine and related sphingolipids, indolocarbazoles and bisindolylmaleimides.
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.
SU 389096 to Baskakov et al 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 immunosuppressive 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 which 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 CNSdegenerative 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, and
R2 is H, hydroxy, amino, C
1-6
alkyl, hydroxyC
1-6
alkyl or aminoC
1-6
alkyl,
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, C
1
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, guanidinoC
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
R1 is H or C
1-3
alkyl
R2 is H, C
1-3
alkyl, hydroxy, amino, hydroxyC
1-3
alkyl or aminoC
1-3
alkyl
R3 and R4 are each independently H, hydroxy, C
1-6
alkyl, hydroxyC
1-6
alkyl, haloC
1-6
alkyl, C
1-3
alkoxy, carboC
1-6
alkoxy, halogen, nitrile, nitro or amino,
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 aminoC
1-6
alkyl, especially aminoethyl, aminopropyl and aminobutyl, (mono- or di-C
1-6
alkyl)aminoC
1-6
alkyl, aminoC
3-7
cycloalkyl, especially aminocyclopentyl, (mono- or di-C
1-6
alkyl)aminoC
3-7
cycloalkyl, (aminoC
1-3
alkylphenyl)C
1-3
alkyl, guanidinoC
1-6
alkyl, especially guanidinopropyl, amidinoC
1-6
alkyl especially amidinobutyl, amidinothioC
1-6
alkyl, especially amidinothiopropyl, or aminomethyl benzyl,
—R2 is H,
—X is O.
In more preferred embodiments of formula (II) and (III), when Ar is a heteroaromatic or bicyclic heteroaromatic group it includes 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, optionally substituted phenyl and optionally substituted indolyl. Optional substituents for Ar include alkyl, e.g. methyl, ethyl, propyl, or tert-butyl; alkoxy, e.g. methoxy; aryloxy, e.g. phenoxy; nitro; alkoxycarbonyl, e.g. ethoxycarbonyl; or alkylamino, e.g. propylamino. Preferably alkyl group-containing optional substituents contain 1-6 carbon atoms in each alkyl group.
Preferred compounds according to the present invention include:
5-[1-(3-Aminopropyl)-3-indolyl]-4-cyano-1-(3-indolyl)-2,3-dihydroimidazol-2-one
5-[1-(4-Aminobutyl)-3-indolyl]-4-cyano-1-(3-indolyl)-2,3-dihydroimdazol-2-one
5-[1-(2-Aminoethyl)-3-indolyl]-4-cyano-1-(3-indolyl)-2,3-dihydroimidazol-2-one
5-[1-(3-Aminopropyl)-3-indolyl]-4-cyano-1-(1-methyl-3-indolyl)-2,3-dihydroimidazol-2-one
5-[1-(4-Aminobutyl)-3-indolyl]-4-cyano-1-(1-propyl-3-indolyl)-2,3-dihydroimidazol-2-one
5-[1-(3-Aminopropyl)-3-indolyl]-1-(benzo[b]thiophen-3-yl)-4-cyano-2,3-dihydroimidazol-2-one
5-[1-(3-Amidinothiopropyl)-3-indolyl]-4-cyano-1-(3-indolyl)-2,3-dihydroimidazol-2-one
5-[1-(4-Amidinobutyl)-3-indolyl]-4-cyano-1-(3-indolyl)-2,3-dihydroimidazol-2-one
4-Cyano-5-[1-(3-guanidinopropyl)-3-indolyl]-1-(3-indolyl)-2,3-dihydroimidazol-2-one
5-{1-[3-(Aminomethyl)benzyl]-3-indolyl}-4-cyano-1-(3-indolyl)-2,3-dihydroimidazol-2-one
5-{1-[2-(Aminomethyl)benzyl]-3-indolyl}-4-cyano-1-(1-methyl-3-indolyl)-2,3-dihydroimidazol-2-one
5-{1-[3-(Aminomethyl)benzyl]-3-indolyl}-4-cyano-1-(1-methyl-3-indolyl)-2,3-dihydroimnidazol-2-one
5-{1-[4-(Aminomethyl)benzyl]-3-indolyl}-4-cyano-1-(1-methyl-3-indolyl)-2,3-dihydroimidazol-2-one
5-{1-[6-(Aminomethyl)-2-pyridylmethyl]-3-indolyl}-1-(1-methyl-3-indolyl)-2,3-dihydroimidazol-2-one
5-{1-[5-(Aminomethyl)-2-thiophenylmethyl]-3-indolyl}-4-cyano-1-methyl-3-indolyl)-2,3-dihydroimidazol-2-one
4-Cyano-5-[1-(N,N-dimethylaminopropyl)-3-indolyl]-1-(1-methyl-3-indolyl)-2,3-dihydroimidazol-2-one
5-[1-(4-Aminobutyl)-3-indolyl]-4-cyano-1-(3-nitrophenyl)-2,3-dihydroimidazol-2-one
4-Cyano-5-[1-(N-isopropylamino)propyl)-3-indolyl]-1-(1-methyl-3-indolyl)-2,3-dihydroimidazol-2-one
5-[1-(3-Aminocyclopentyl)-3-indolyl]-4-cyano-(1-methyl-3-indolyl)-2,3-dihihydroimidazol-2-one
4-Cyano-5-[1-(3-hydroxypropyl)-3-indolyl]-1-(3-indolyl)-2,3-dihydroimidazol-2-one
4-Cyano-5-[1-(4-cyanobutyl)-3-indolyl]-1-[1-(ethoxycarbonyl)-3-indolyl]-1,3-dihydroimidazol-2-one
5-[1-(4-Aminobutyl)-3-indolyl]-4-cyano-1-(4-methoxyphenyl)-2,3-dihydroimidazol-2-one
5-[1-(4-Aminobutyl)-3-indolyl]-4-cyano-1-(4-phenoxyphenyl)-2,3-dihydroimidazol-2-one
5-[1-(4-Aminobutyl)-3-indolyl]-1-(4-tert-butylphenyl

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