Purine derivatives inhibitors of tyrosine protein kinase SYK

Details Purine derivatives inhibitors of tyrosine protein kinase SYK Purine derivatives inhibitors of tyrosine protein kinase SYK

2002-03-19

2003-07-08

Berch, Mark L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S263370, C514S263400, C544S118000, C544S276000, C544S277000

Reexamination Certificate

active

06589950

ABSTRACT:

This invention relates; to organic compounds, their preparation and their use as pharmaceuticals.
More particularly, the present invention relates to:
(a) compounds of formula
 in free or salt form, where
X is an oxygen or sulfur atom or a group NR
5
,
R
1
is an alkyl, alkenyl, cycloalkyl, benzocycloalkyl, cycloalkylalkyl or aralkyl group which optionally may be substituted by hydroxy, alkoxy, carboxy or alkoxycarbonyl or, when X is NR
5
, R
1
may alternatively be a heterocyclyl group or a group of formula
R
2
, R
3
, R
4
, R
6
, R
7
and R
8
are each independently hydrogen, halogen, alkyl, haloalkyl, alkoxy, carboxy, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, —N(R
9
)R
10
, —SO
2
N(R
11
)R
12
, C
1
-C
4
-alkylene-SO
2
N(R
11
)R
12
or —CON(R
13
)R
14
or, when two of R
2
, R
3
and R
4
, or two of R
6
, R
7
and R
8
, are attached to adjacent carbon atoms on the indicated benzene rings, they denote, together with the carbon atoms to which they are attached, a carbocyclic group having 5 to 10 ring atoms or a heterocyclic group having 5 to 10 ring atoms of which one, two or three are hetero atoms selected from nitrogen, oxygen and
R
5
is hydrogen or alkyl,
R
9
is hydrogen or alkyl and R
10
is hydrogen, alkyl or —COR
15
where R
15
is alkyl, haloalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, carboxyalkyl or alkoxycarbonylalkyl, or R
9
and R
10
, together with the nitrogen atom to which they are attached, denote a heterocyclic group having 5 or 6 ring atoms of which one or two are hetero atoms selected from nitrogen, oxygen and sulfur,
R
11
is hydrogen or alkyl and R
12
is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyalkyl or alkoxycarbonylalkyl, or R
11
and R
12
together with the nitrogen atom to which they are attached denote a heterocyclic group having 5 or 6 ring atoms of which one or two are hetero atoms selected from nitrogen, oxygen and sulfur, and
R
13
and R
14
are each independently hydrogen or alkyl; particularly to compounds of formula I in free or pharmaceutically acceptable salt form for use as pharmaceuticals; and
(b) compounds of formula I as hereinbefore defined in free or pharmaceutically acceptable salt form for use in the manufacture of medicaments for the treatment of conditions mediated by syk kinase.
In formula I, R
9
, R
10
, R
11
, R
12
, R
13
or R
14
in R
2
, R
3
or R
4
may be the same as, or may differ from, the respective group in R
6
, R
7
or R
8
.
In another aspect, the present invention provides compounds of formula I as hereinbefore defined in free or salt form, with the exception of 2-(p-n-butylanilino)-6-methoxypurine, 2-(p-n-butylanilino)-6-(methylthio)purine, 2,6-di(phenylamino)purine, 2,6-di(p-tolylamino)purine, and 2-(p-tolylamino)-6-(phenylamino)purine.
In a further aspect, the present invention provides compounds of formula I as hereinbefore defined in free or salt form, with the exception of compounds of formula I where (i) X is oxygen or sulfur, R
1
is alkyl, two of R
2
, R
3
and R
4
are hydrogen and one of R
2
, R
3
and R
4
is alkyl and (ii) X is NH, R
1
is a group of formula II in which two of R
6
, R
7
and R
8
are hydrogen and the remaining one is hydrogen or alkyl, one of R
2
, R
3
, and R
4
is hydrogen and the remaining two are each hydrogen or alkyl.
In a further aspect, the present invention provides a compound of formula I as hereinbefore described in free or salt form in which
(a) X is NR
5
and R
1
, R
2
, R
3
, R
4
and R
5
are as hereinbefore defined, with the proviso that when R
1
is a group of formula II, R
6
, R
7
and R
8
are each independently halogen, haloalkyl, alkoxy, carboxy, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, —N(R
9
)R
10
, —SO
2
N(R
11
)R
12
, C
1
-C
4
-alkylene-SO
2
N(R
11
)R
12
or —CON(R
13
)R
14
or, when two of R
6
, R
7
and R
8
are attached to adjacent carbon atoms on the indicated benzene ring, they denote, together with the carbon atoms to which they are attached, a carbocyclic group having 5 to 10 ring atoms or a heterocyclic group having 5 to 10 ring atoms of which one, two or three are hetero atoms selected from nitrogen, oxygen and sulfur, or one or two of R
6
, R
7
and R
8
are hydrogen; or
(b) X is oxygen or sulfur and R
1
, R
2
, R
3
and R
4
are as hereinbefore defined, with the proviso that when R
1
is alkyl, R
2
, R
3
and R
4
are each independently hydrogen, halogen, alkoxy, carboxy, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, —N(R
9
)R
10
, —SO
2
N(R
11
)R
12
, C
1
-C
4
-alkylene-SO
2
N(R
11
)R
12
or —CON(R
13
)R
14
or, when two of R
2
, R
3
and R
4
are attached to adjacent carbon atoms on the indicated benzene rings, they denote, together with the carbon atoms to which they are attached, a carbocyclic group having 5 to 10 ring atoms or a heterocyclic group having 5 to 10 ring atoms of which one, two or three are hetero atoms selected from nitrogen, oxygen and sulfur.
Terms used in this specification have the following meanings:
“Alkyl” denotes straight chain or branched alkyl, which may be, for example, C
1
to C
10
-alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, straight or branched pentyl, straight or branched hexyl, straight or branched heptyl, straight or branched nonyl or straight or branched decyl. Preferably alkyl is C
1
to C
4
-alkyl.
“Alkoxy” denotes straight chain or branched alkoxy and may be, for example, C
1
to C
10
alkoxy such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, or straight or branched pentoxy, hexyloxy, heptyloxy, octyloxy, nonyloxy or decyloxy. Preferably alkoxy is C
1
to C
4
-alkoxy.
“Alkenyl” means straight chain or branched alkenyl, which may be, for example, C
2
to C
10
-alkenyl such as vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, or straight or branched pentenyl, hexenyl, heptenyl, octenyl, nonenyl or decenyl. Preferred alkenyl is C
2
to C
4
-alkenyl.
“Cycloalkyl” means C
3
to C
10
-cycloalkyl having 3 to 8 ring carbon atoms and may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cycloheptyl, any of which can be substituted by one, two or more C
1
-C
4
alkyl groups, particularly methyl groups. Preferably, cycloalkyl is C
3
-C
6
-cycloalkyl.
“Benzocycloalkyl” means cycloalkyl, e.g. one of the C
3
to C
10
cycloalkyl groups mentioned hereinbefore, attached at two adjacent carbon atoms to a benzene ring. Preferably, benzocycloalkyl is benzo-C
5
-C
6
-cycloalkyl, especially benzocyclohexyl (tetrahydronaphthyl).
“Cycloalkylalkyl” means C
3
to C
10
-cycloalkyl —C
1
-C
10
alkyl where the C
3
to C
10
-cyloalkyl group has 3 to 8 ring carbon atoms and may be, for example, one of the C
1
-C
10
-alkyl groups mentioned hereinbefore, particularly one of the C
1
-C
4
-alkyl groups, substituted by one of the C
3
-C
10
-cycloalkyl groups mentioned hereinbefore. Preferably cycloalkylalkyl is C
3
-C
6
-cycloalkyl-C
1
-C
4
-alkyl.
“Aralkyl” means C
6
-C
10
-aryl-C
1
-C
10
alkyl and may be, for example, one of the C
1
-C
10
-alkyl groups mentioned hereinbefore, particularly one of the C
1
-C
4
-alkyl groups, substituted by phenyl, tolyl, xylyl or naphthyl. Preferably, aralkyl is phenyl-C
1
-C
4
-alkyl, particularly benzyl or 2-phenylethyl.
“Heterocyclyl” means a monovalent heterocyclic radical having up to 20 carbon atoms and one, two, three or four heteroatoms selected from nitrogen, oxygen and sulfur, the radical optionally having an alkyl, alkylcarbonyl, hydroxyalkyl, alkoxyalkyl or aralkyl group attached to a ring carbon or nitrogen atom and being linked to the remainder of the molecule through a ring carbon atom, and may be, for example, a radical, preferably a monocyclic radical, with one nitrogen, oxygen or sulfur atom such as pyrryl, pyridyl, piperidyl, furyl, tetrahydrofuryl or thienyl, or a radical, preferably a monocyclic radical, with two hetero atoms selected from nitrogen, oxygen and sulfur, such as imidazolyl, pyrimidinyl, piperazinyl, oxazolyl, isoxazolyl, thiazolyl, morpholinyl or thiomorpholinyl. Preferably, heterocyclyl is a monocyclic radical ha

Affiliated with

Also associated with

Rating

Purine derivatives inhibitors of tyrosine protein kinase SYK does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Purine derivatives inhibitors of tyrosine protein kinase SYK, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Purine derivatives inhibitors of tyrosine protein kinase SYK will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3036602