Compounds

Details Compounds Compounds

1999-05-03

2002-10-01

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S344000

Reexamination Certificate

active

06458792

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 bisindolylmaleimides.
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.
SUMMARY OF THE INVENTION
The present invention provides PKC inhibitors, methods for their preparation and intermediates used for their preparation.
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 optionally substituted and/or annulated compounds of formula (I):
wherein:
one of: R1 and R2, R2 and R3 or R3 and R4, together form a 5 or 6 membered ring and the two groups of R1, R2, R3 and R4 not forming a ring, are H;
and salts thereof.
More specifically, the present invention provides optionally substituted and/or annulated compounds of formula (I), with the proviso that 3-[3-(3-Oxo-3,4-dihydro-benzo[g]quinoxalin-2-yl)-indol-1-yl]-propyl ammonium acetate is excluded from the compounds of formula (I).
Salts of the compounds according to the invention are preferably pharmaceutically acceptable salts. Other, non-pharmaceutically acceptable salts may be useful as intermediates e.g. in the preparation of pharmaceutically acceptable salts or other compound of the present invention.
Included within the scope of the present invention are all enol tautomers of compounds of the present invention.
Preferred compounds of formula (I) are those of formula (II):
wherein:
one of: R1 and R2, R2 and R3 or R3 and R4, together form a 5 or 6 membered ring and the two groups of R1, R2, R3 and R4 not forming a ring, are H;
R5 is H, C
1-6
alkyl, hydroxyC
1-6
alkyl, aminoC
1-6
alkyl, (aminoC
1-3
alkylphenyl)C
1-3
alkyl, amidinothioC
1-6
alkyl, (aminoC
1-3
alkylpyridyl)C
1-3
alkyl;
R6 is H, C
1-6
alkyl, phenylC
1-6
alkyl, (C
1-6
alkoxycarbonyl)C
1-6
alkyl;
R7 and R8 is each independently H, dibenzylamino, nitro, hydroxy, halogen, C
1-6
alkoxy, phenylC
1-6
alkoxy, C
1-6
alkyl or carboxyC
1-6
alkyl ester; or when R7 and R8 are adjacent they may together form amethylenedioxy;
R9 is H, C
1-6
alkyl, phenyl, halophenyl, or benzyl and wherein when R5 and R9 together comprise 3-5 carbons they may be linked to generate a cyclic moiety which may be aminoC
1-6
alkyl substituted;
and salts thereof.
Compounds of formula (II), in which R5 carries an amino or hydroxy group; and pharmaceutically acceptable salts thereof, may be prepared by,
a) deprotecting a compound of formula (III) corresponding to formula (II) but in which R5 carries a protected amino or hydroxy group, or
b) converting:
i) a compound of formula (II), in which R5 carries an amino group to a salt, preferably a pharmaceutically acceptable salt thereof, or vice versa; or
ii) a salt, preferably a pharmaceutically acceptable salt of a compound of formula (II) into a different pharmaceutically acceptable salt.
Compounds of formula (II), in which R6 is hydrogen, may be prepared by reacting a compound of formula (IV):
wherein,
R5, R7, R8, and R9 are as defined in formula (II) and LG is a leaving group, e.g.:
 with a compound of formula (V):
 wherein,
one of: R1 and R2, R2 and R3 or R3 and R4, together form a 5 or 6 membered ring and the two groups of R1, R2, R3 and R4 not forming a ring, are H; conveniently in a solvent, e.g. tetrandrofuran (THF), at about 10-30° C., e.g. for about 16 hours.
When R5 in formula (IV) carries an amino or hydroxy group, these groups are preferably protected. The protecting groups may be removed in a subsequent deprotecting step.
Compounds of formula (II), when R6 is other than H, may be prepared by reacting a compound of formula (III) which corresponds to formula (II), but in which R6 is H, with an alkylating agent in the presence of a base, e.g. sodium hydride. The alkylating step may be carried out in a suitable solvent e.g. dimethyl formamide at about 10-30° C. for e.g. 2 hours.
When R5 in formula (III) carries an amino or hydroxy group, such groups are preferably protected. The protecting groups may be removed in a subsequent deprotecting step.
Compounds of formula (III) may be prepared by reacting a compound of formula (IV), as defined above, with a compound of formula (V), as defined above, in a solvent e.g. THF, at about 10-30° C., e.g. for 16 h ,or when R5 in formula (IV) carries an amino or hydroxy group, these are preferably in a protected form.
In all processes above, the protecting groups and conditions for deprotection are well known to those skilled in the art. Suitable protecting groups for amino groups include e.g. phthaloyl groups and the deprotecting agent may be methylamine in e.g. water. The deprotecting step may be carried out in a solvent, e.g. THF at about 10-30° C., e.g. for about 5 hours. The hydroxy groups may be protected as their corresponding acetoxy groups and the deprotecting agent may be methylamine in e.g. water. The deprotecting step may be carried out in a suitable solvent, e.g. tetrahydrofuran at about 10-30° C., e.g. for about 16 hours.
In process b) the conversion may be carried out analogously to conventional processes, e.g.
i) reaction of a free base with an acid containing the desired anion, or by careful basification of the salt, or
ii) reaction of a free acid with a base containing the desired cation, or by careful acidification of the salt.
The reaction may be carried out in a solvent, e.g. methanol ormethylene chloride.
Compounds of formula (I) which are not of formula (II) may be made by analogous processes to those described above for compounds of formula (II).
Compounds of formula (I), which are not of formula (II), carrying functional groups which might be sensitive to or interfere with the reaction conditions in the above processes, may be made by analogous processes to those described above for compounds of formula (II), but in which the functional groups are protected, followed by subsequent deprotection.
When a compounds of the present invention are synthesised as regiochemical mixtures, such mixtures may be separated by techniques well known to those skilled in the art.
Functional groups that might be sensitive for or interfere with the reaction conditions in the above processes, as well as suitable protecting groups and deprotecting methods, are evident to those skilled in the art.
Starting materials for the above processes may be made by the methods as illustrated in the Examples set out belowor by methods analogous thereto. Other methods for making the starting materials will be evident to those skilled in the art.
Compounds of formula (I) and pharmaceutically acceptable salts thereof, are useful because they demonstrate pharmacological activity. In particular they demonstrate activity as kinase inhibitors, especially PKC inhibitors, e.g. as is shown by their activity in the in

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