Pharmaceutically active compounds

Details Pharmaceutically active compounds Pharmaceutically active compounds

1997-12-18

2001-08-07

Bernhardt, Emily (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S250000, C544S344000, C544S350000, C544S354000, C544S257000, C548S455000, C548S468000

Reexamination Certificate

active

06271231

ABSTRACT:

The present invention relates to novel compounds which are protein kinase C inhibitors, methods for their preparation, intermediates therefor and pharmaceutical compositions comprising them.
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 sulphonarnides, 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.
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.
The present invention provides optionally substituted and/or annulated compounds of formula (I)
wherein X, Y, Z and A is each independently carbon or nitrogen, and at least two of X, Y, Z and A are carbon;
and pharmaceutically acceptable salts thereof with the proviso that the following compounds are not included in formula (I):
3-(1H-Indol-3-yl)-1H-quinoxalin-2-one,
3-(2-Methyl-1H-indol-3-yl)-1H-quinoxalin-2-one, and
3-(1,2-Diphenyl-1H-indol-3-yl)-1H-quinoxalin-2-one.
Preferred compounds of formula (I) are those of formula (IA):
wherein X, Y, Z and A are as defined above,
R
1
, R
2
, R
3
, and R
4
is each independently H, hydroxy, amino, nitro, halo, C
1-6
alkyl, phenylC
1-6
alkyl, C
1-6
alkoxy, haloC
1-6
alkyl, carboxyC
1-6
alkyl ester or R
1
and R
2
or R
2
and R
3
or R
3
and R
4
form an annulated aromatic ring, or when the atom to which it would be attached is nitrogen, is absent;
R
5
and R
6
is each independently H, C
1-6
alkyl, hydroxyC
1-6
alkyl, aminoC
1-6
alkyl, phenylC
1-6
alkyl, carboxyC
1-6
alkyl, C
1-6
alkenyl, (phenylC
1-3
alkoxy)C
1-3
alkyl, (C
1-6
acyloxy)C
1-6
alkyl, (C
1-6
alkoxycarbonyl)C
1-6
alkyl, (mono- or di-C
1-6
alkyl)aminoC
1-6
alkyl (C
1-6
alkyl)aminocarbonylC
1-6
alkyl, (C
1-6
acylamino)C
1-6
alkyl, (aminoC
1-3
alkylphenyl)C
1-3
alkyl, or aminodeoxysugar;
R
7
and R
8
is each independently H, amino, nitro, hydroxy, halogen, C
1-6
alkoxy, phenylC
1-6
alkoxy or carboxyC
1-6
alkyl ester;
R
9
is H, C
1-6
alkyl, phenyl, halophenyl or phenylC
1-6
alkyl and wherein when R
5
and R
9
together comprise 3-5 carbons they may be linked to generate a cyclic moiety which may be aminoC
1-6
alkyl substituted;
and wherein at least one of R
1
to R
9
is not H and wherein when the only one of R
1
to R
9
which is not H is R
9
, R
9
is not methyl;
and pharmaceutically acceptable salts thereof.
The compounds of formula (IA), in which at least one of R
5
and R
6
carries an amino, carboxy or hydroxy group; and pharmaceutically acceptable salts thereof, may be prepared by,
a) deprotecting a compound of formula (II) corresponding to formula (IA) but in which at least one of R
5
and R
6
carries a protected amino, carboxy or hydroxy group, or
b) converting a compound of formula (IA), in which at least one of R
5
and R
6
carries an amino or carboxy group
i) to a pharmaceutically acceptable salt thereof, or vice versa; or
ii) a pharmaceutically acceptable salt of a compound of formula (IA) into a different pharmaceutically acceptable salt.
The compounds of formula (IA), in which R
6
is hydrogen, may be prepared by reacting a compound of formula (I):
wherein R
5
, R
7
, R
8
, and R
9
are as defined in formula (IA) and LG is a leaving group, e.g:
with a compound of formula (IV):
wherein A, X, Y, and Z are as defined in formula (I), and R
1
-R
4
are as defined in formula (IA), in a suitable solvent, e.g. THF, at about 10-30° C., e.g. for about 16 hours.
When R
5
in formula (III) carries an amino, carboxy or hydroxy group, these groups should be suitably protected. The protecting groups may be removed in a subsequent deprotecting step.
The compounds of formula (IA), when R
6
is other than H, may be prepared by reacting a compound of formula (II) which corresponds to formula (IA), but in which R
6
is H, with a suitable alkylating agent, e.g methyl iodide 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 R
5
in formula (II) and/or the alkylating agent carries an amino, carboxy or hydroxy group, such groups should be suitably protected. The protecting groups may be removed in a subsequent deprotecting step.
The compounds of formula (II) may be prepared by
(i) reacting a compound of formula (III), as defined above, with a compound of formula (IV), as defined above, in a suitable solvent e.g. THF, at about 10-30° C., e.g. for 16 h ,or
(ii) by alkylating the product of (i) with a suitable alkylating agent
when R
5
in formula (III) and/or the alkylating agent carries an amino, carboxy or hydroxy group, these should be 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 are e.g phthaloyl 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 5 hours. Suitable protecting groups for carboxy groups are e.g t-butyl groups and the deprotection step may be carried out in trifluoro acetic acid at about 10-30 ° C., e.g for about 4 hours. The hydroxy groups are 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 by conventional processes, e.g.
i) reaction of the free base with an acid containing the desired anion, or by careful basification of the salt, or
ii) reaction of the free acid with a base containing the desired cation, or by careful acidification of the salt.
The reaction may be carried out in a suitable solvent, e.g. methanol or methylene chloride.
Compounds of formula (I) which are not of formula (IA) may be made by analogous processes to those described above for compounds of formula (IA).
The starting materials for the above processes may be made by the methods set out in the Examples or by methods analogous thereto. Other conventional methods for making the starting materials will be evident to those skilled in the art.
The 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 vitro assays described in Granet, R. A. et al, Analyt. Biochem. 1987; 163, 458-463; Olsson, H. et al, Cell Signal 1989, 1, 405-410; Chakravarthy, B. R. et al, Analyt. Biochem. 1991, 196, 144-150 and Bergstrand, H et al, J. Pharm. Exp. Ther. 1992; 263(3), 1334-1346.
In appropriate cellular systems, the compounds of formula (I) and pharmaceutical acceptable salts thereof, can also reduce the generation of inflammatory mediators. For

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