Pharmaceutically active compounds

Details Pharmaceutically active compounds Pharmaceutically active compounds

2000-09-25

2002-12-10

Gersil, Robert (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C548S263200, C548S264600

Reexamination Certificate

active

06492406

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.
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.
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 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 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 a compound of formula (I):
wherein: one of Ar
1
and Ar
2
is optionally substituted bicyclic heteroaryl or optionally substituted tricyclic heteroaryl and the other is optionally substituted heteroaryl or optionally substituted aryl; X is O or, when one of Ar
1
and Ar
2
is optionally substituted bicyclic heteroaryl or optionally substituted tricyclic heteroaryl and the other is optionally substituted heteroaryl then X may also be S; and R is H, OH, NH
2
or C
1-6
alkyl (itself optionally substituted by amino or hydroxy); or a salt or solvate thereof, or a solvate of a salt thereof; provided that when X is O, R is hydrogen and one of Ar
1
and Ar
2
is phenyl or phenyl optionally mono-substituted by halogen or C
1-4
alkyl then the other is not 3,4-methylenedioxyphenyl, unsubstituted benzthiazol-2-yl, a phthalimide or 1,8-naphthalimide.
Heteroaryl includes monocyclic, bicyclic and tricyclic heteroaryl. Heteroaryl includes pyridinyl, pyridin-2-onyl, thienyl, furyl, pyrrolyl, pyrazolyl, quinolinyl, isoquinolinyl, xanthen-9-yl, quinolizin-3-yl, benzothienyl, benzofuryl, indazolyl, 9H-pyrido[3,4-b]indolyl, 1H-pyrrolo[2,3-b]pyridinyl, 6,7,8,9-tetrahydro-pyrido[1,2-a]indolyl, 2,3-dihydro-1H-pyrrolo[1,2-a]indolyl, indolyl and benzothiophenyl. In one aspect the present invention provides a compound of formula (I) wherein Ar
1
and Ar
2
are both bicyclic heteroaryl (wherein each heteroaryl has a single heteroatom, such as a N, O or S atom).
It is preferred that aryl is phenyl or naphthyl.
In another aspect Ar
1
and Ar
2
are selected from pyridinyl, pyridin-2-onyl, thienyl, furyl, pyrrolyl, pyrazolyl, quinolinyl, isoquinolinyl, xanthen-9-yl, quinolizin-3-yl, benzothienyl, benzofuryl, indazolyl, 9H-pyrido[3,4-b]indolyl, 1H-pyrrolo[2,3-b]pyridinyl, 6,7,8,9-tetrahydro-pyrido[1,2-a]indolyl, 2,3-dihydro-1H-pyrrolo[1,2-a]indolyl, indolyl, benzothiophenyl, naphthyl and phenyl.
In a further aspect the present invention provides a compound of formula (I) wherein heteroaryl and bicyclic heteroaryl are, independently, substituted indolyl, such as substituted indol-3-yl, for example substituted at the 1 position.
In another aspect the optional substituents on the heteroaryl (such as mono-, bi- or tri-cyclic heteroaryl) and aryl groups are selected from the group comprising: halo, cyano, nitro, hydroxy, CO
2
(C
1-4
alkyl), C
1-8
alkyl (optionally substituted by halo, hydroxy, cyano, C
1-4
alkoxy (optionally substituted by NH
2
, CO
2
(C
1-4
alkyl)), NR
a
R
b
, SC(═NH)NH
2
, C(═NH)NR
c
R
d
, N═C(R
e
)NR
f
R
g
, N(R
h
)C(═O)R
i
, NHC(═NH)NH
2
, heterocyclyl (optionally substituted by C
1-4
alkyl or phenyl(C
1-4
)alkyl), phenyl (optionally substituted by C
1-4
alkyl (itself optionally substituted by amino), C(═NH)OR
j
, C(═NH)NR
k
R
l
), pyridinyl (optionally substituted by C
1-4
alkyl (itself optionally substituted by amino))), C
5-6
cycloalkyl (optionally substituted by hydroxy, NR
m
R
n
or alkyl (itself optionally substituted by NR
o
R
p
)), C
5-6
cycloalkenyl (optionally substituted by NR
q
R
r
or alkyl (itself optionally substituted by NR
s
R
t
)), heterocyclyl (optionally substituted by C
1-4
alkyl or C
1-4
haloalkyl), phenyl (optionally substituted by halo), C
1-6
alkoxy (optionally substituted by phenyl), phenoxy and amino (optionally substituted by C
1-4
alkyl); wherein R
a
, R
b
, R
m
, R
n
, R
o
, R
p
, R
q
, R
r
, R
s
and R
t
are, independently, hydrogen or C
1-4
alkyl (itself optionally substituted by hydroxy, phenyl, CO
2
H or CO
2
(C
1-4
alkyl)); and, R
c
, R
d
, R
e
, R
f
, R
g
, R
h
, R
i
, R
j
, R
k
and R
l
are, independently, hydrogen, C
1-4
alkyl or phenyl(C
1-4
)alkyl; or R
k
and R
l
join to form a heterocyclic ring (such as morpholine).
In a further aspect X is oxygen.
Salts of the compounds of formula (I) are preferably pharmaceutically acceptable salts. pharmaceutically acceptable salts of compounds of the present invention are preferably those well known in the art as being suitable and are, for example, acid addition salts (such as hydrochloride, hydrobromide or acetate salts) or a salt of a compound of formula (I) with an alkyl halide (such as methyl bromide).
Solvates of the compounds or salts of the present invention are conveniently hydrates, such as monohydrates or dihydrates.
Compounds of the present invention include all stereoisomers and mixtures thereof in all proportions.
In a still further aspect the present invention provides a compound of formula (II) or (II):
wherein: Ar
1
and Ar
2
are optionally substituted heteroaryl or optionally substituted aryl: R is hydrogen or C
1-3
alkyl; X is O or, when Ar
1
or Ar
2
is optionally substituted heteroaryl X may also be S; R1 and R2 are each independently H, C
1-6
alkyl, halogen, C
1-3
alkoxy, benzyloxy, hydroxy, cyano, fluoro substituted (C
1-3
) alkyl, carboxy or carbo(C
1-3
)alkoxy; R3 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
3-7
)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, hy

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