Thieno[2,3-d]pyrimidine-2,4-diones

Details Thieno[2,3-d]pyrimidine-2,4-diones Thieno[2,3-d]pyrimidine-2,4-diones

1999-10-13

2001-10-09

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C544S278000

Reexamination Certificate

active

06300334

ABSTRACT:

This invention relates to pharmaceutically useful compounds, processes for their production, pharmaceutical compositions containing them and methods of treatment involving their use.
T-cells play an important role in the immune response, however in autoimmune disease T-cells are activated against particular tissues, e.g. causing the inflammation associated with rheumatoid arthritis. Interleukin-2 (IL-2) is an essential autocrine growth factor for T-cells and hence inhibition of IL-2 transcription is beneficial in the modulation of autoimmune disease. Formation of a transcriptional complex of the protein nuclear factor of activated T-cells-1 (NFAT-1) on the EL-2 promoter is essential for IL-2 transcription. NFAT-1 mediated transcription has therefore been proposed as appropriate molecular target for immunomodulation, Y. Baine et al.,
J. Immunol
, 1995, 154, 3667-3677.
W. F. Michne et al, in
J. Med. Chem
. (1995) 38, 2557-2569 disclose a number of quinazoline-2,4-diones and pyrrolo[3,4-d]pyrimidine-2,4-diones which inhibit transcription regulated by the DNA region bound by the NFAT-1 protein.
We have now found novel thieno[2,3-d]pyrimidinediones which exhibit pharmacological activity, in particular immunosuppressive activity.
In a first aspect the invention therefore provides a compound of formula (I):
wherein:
R represents a group —C(O)Ar
1
or —C(R
4
)(R
5
)Ar
1
;
Ar
1
represents a heterocyclic group comprising a total of from 5 to 10 atoms which include from 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, which group Ar
1
may be optionally substituted by one or more substituents independently selected from oxo, hydroxyl, C
1-4
alkyl, C
1-4
alkoxy, halogen, trifluoromethyl, amino, nitro, cyano, trifluoromethoxy, phenoxy, —CH
2
N(R
6
)
2
, —NHSO
2
CF
3
, C
1-4
alkylsulfonylamino, —NHC(O)R
6a
, CO
2
R
7
or —C(O)NR
8
R
8a
, with the proviso that Ar
1
does not represent an optionally substituted benzofuranyl, benzothienyl, indolyl, quinolyl or isoquinolyl group; R
4
represents a hydrogen atom or a C
1-4
alkyl group;
R
5
represents a hydrogen atom or a hydroxyl group;
each R
6
independently represents a hydrogen atom or a C
1-4
alkyl (e.g. methyl, ethyl, propyl or butyl) group, preferably a methyl or ethyl group;
R
6a
represents a hydrogen atom or a C
1-6
alkyl, aryl or arC
1-4
alkyl group, wherein the aryl group or aryl moiety in the aralkyl group is phenyl or pyridinyl, each of which may be optionally substituted by one or more substituents independently selected from C
1-4
alkyl, C
1-4
alkoxy, C
1-4
alkylcarbonylamino, halogen or trifluoromethyl;
R
7
represents a hydrogen atom or a C
1-4
alkyl (e.g. methyl, ethyl, propyl or butyl) group, preferably a methyl or ethyl group;
R
8
and R
8a
each independently represent a hydrogen atom or a C
1-4
alkyl (e.g. methyl, ethyl, propyl or butyl, preferably methyl or ethyl), phenyl or pyridinyl group;
R
1
and R
2
each independently represent a hydrogen atom or a C
1-6
alkyl, C
3-6
alkenyl, CH
2
C
3-5
cycloalkyl or C
3-6
cycloalkyl group;
R
3
represents a hydrogen atom or a group X—R
9
or X—Ar
2
;
X represents an oxygen atom, S(O)
n
, C(O)NR
10
, C(O)O, NH(CO)NR
10
, NH(CO)O or SO
2
NR
10
, with the proviso that when X represents an oxygen atom and R represents a group —C(R
4
)(R
5
)Ar
1
, then R
4
and R
5
both represent a hydrogen atom; n is 0, 1 or 2;
R
9
represents a methyl group optionally substituted by one or more substituents independently selected from cyano, carboxyl, C
1-5
alkoxycarbonyl, 5-tetrazolyl or C(O)NR
11
R
12
, or R
9
represents a C
2-6
alkyl or C
3-6
alkenyl group, each of which may be optionally substituted by one or more substituents independently selected from hydroxyl, cyano, carboxyl, C
1-5
alkoxy, C
1-5
alkoxycarbonyl, 5-tetrazolyl, azido, phthalimido, SO
2
NH
2
, C(O)NR
11
R
12
, NR
13
R
14
, NHC(O)R
15
or NHSO
2
R
16
where R
11
, R
12
, R
13
and R
14
each independently represent a hydrogen atom or a C
1-4
alkyl group, R
15
represents a C
1-4
alkyl, C
1-4
alkoxy, amino or (di)C
1-4
alkylamino group or an alkoxyalkylene group containing up to 6 carbon atoms, and R
16
represents a C
1-4
alkyl or trifluoromethyl group; or, additionally, in the case where X represents C(O)NR
10
, NH(CO)NR
10
or SO
2
NR
10
, R
9
and R
10
together with the nitrogen atom to which they are attached may form a 4- to 7-membered saturated heterocyclic ring which may be optionally substituted by one or more hydroxyl groups;
R
10
represents a hydrogen atom or a C
1-6
alkyl group or is linked to R
9
as defined above; and
Ar
2
is phenyl, pyridinyl, thienyl, pyridone or pyridine N-oxide, each of which may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, nitro, amino, NHSO
2
CF
3
, C
1-4
alkyl, C
1-4
alkoxy, bis-C
1-4
alkanesulfonylamino, C
1-4
alkylcarbonylamino or C
1-4
alkoxycarbonylamino;
or a pharmaceutically-acceptable salt or solvate thereof.
In the present specification, unless otherwise indicated, an alkyl or alkenyl group or an alkyl or alkenyl moiety in a substituent group may be linear or branched. When R
9
represents an optionally substituted C
2-4
alkyl or C
3-6
alkenyl group, it should be understood that certain optional substituents (e.g. hydroxyl, C
1-5
alkoxy, azido, phthalimido, SO
2
NH
2
, NR
13
R
14
, NHC(O)R
15
or NHSO
2
R
16
) may not be attached to the carbon atom of the alkyl or alkenyl group which is directly bonded to X. Furthermore, where the substituent in the alkenyl group is hydroxyl, phthalimido, NR
13
R
14
or NHC(O)R
15
, the substituent will not be attached to an unsaturated carbon atom. When R
9
and R
10
form a 4- to 7-membered heterocyclic ring optionally substituted by hydroxyl, the hydroxyl group(s) will not be attached to the carbon atoms directly bonded to the nitrogen atom.
The alkyl moieties in a di-C
1-4
alkylamino group may be the same or different.
The group R represents —C(O)Ar
1
or —C(R
4
)(R
5
)Ar
1
. It should be understood that when R represents —C(O)Ar
1
the group Ar
1
is bonded through a carbon atom and not a heteroatom to the moiety —C(O). Also, in the case when X represents an oxygen atom and R represents —C(R
4
)(R
5
)Ar
1
, the group Ar
1
is bonded through a carbon atom and not a heteroatom to the C(R
4
)(R
5
) moiety of the group R.
The group R
4
represents a hydrogen atom or a C
1-4
alkyl, preferably methyl or ethyl, group and the group R
5
represents a hydrogen atom, or a hydroxyl group (in the case where Ar
1
is attached through a carbon atom to the moiety —C(R
4
)(R
5
)).
Preferably Ar
1
represents a heterocyclic group comprising a total of from 5 to 10 atoms which include from 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, which may be optionally substituted by one, two, three or four substituents independently selected from oxo, hydroxyl, C
1-4
alkyl (e.g. methyl, ethyl, propyl or butyl), C
1-4
alkoxy (e.g. methoxy, ethoxy, propoxy or butoxy), halogen (e.g. fluorine, chlorine, bromine or iodine), trifluoromethyl, amino, nitro, cyano, trifluoromethoxy, phenoxy, —CH
2
N(R
6
)
2
, —NHSO
2
CF
3
, C
1-4
alkylsulfonylamino, —NHC(O)R
6a
, CO
2
R
7
or —C(O)NR
8
R
8a
, with the proviso that Ar
1
does not represent an optionally substituted benzofuranyl, benzothienyl, indolyl, quinolyl or isoquinolyl group. Preferred substituents to use are halogen atoms and C
1-4
alkyl groups.
The group Ar
1
may represent an optionally substituted saturated heterocyclic group but is preferably an optionally substituted unsaturated heterocyclic group, examples of which include pyrazolyl, thienyl, oxazolyl, imidazolyl, pyridinyl, pyridopyrrolyl, benzimidazolyl, indazolyl, benzothiazolyl, benzoxazolyl, thiazolyl, benzotriazolyl,
R
6a
is preferably a hydrogen atom or a C
1-6
, particularly C
1-4
, alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl), aryl or arC
1-4
alkyl group, wherein the aryl group or aryl moiety in the aralkyl group is phenyl or pyridinyl, each of which may be optionally substitut

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