Thieno[2,3-d] pyrimidinediones, their preparation...

Details Thieno[2,3-d] pyrimidinediones, their preparation... Thieno[2,3-d] pyrimidinediones, their preparation...

2001-10-17

2002-10-22

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...

Reexamination Certificate

active

06469014

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 IL-2 promoter is essential for IL2 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 is —C(O)Ar
1
, —C(R
4
)(R
5
)Ar
1
, or Ar
2
;
Ar
1
is naphthyl, quinolyl, isoquinolyl, indolyl, benzofuranyl or benzothienyl, each of which can be optionally substituted by one or more substituents selected from C
1-4
alkyl, C
1-4
alkoxy, halogen or trifluoromethyl, or Ar
1
is phenyl optionally substituted by one or more substituents selected from 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
alkylsulphonylamino, —NHC(O)R
6a
, CO
2
R
7
or —C(O)NR
8
R
8a
;
R
4
represents H or C
1-4
alkyl;
R
5
represents H or OH;
each R
6
independently represents H or C
1-4
alkyl, preferably methyl or ethyl;
R
6a
represents H, C
1-6
alkyl, aryl or arC
1-4
alkyl, wherein the aryl group or aryl moiety in the aralkyl group is phenyl or pyridyl, each of which may be optionally substituted by one or more substituents selected from C
1-4
alkyl, C
1-4
alkoxy, C
1-4
alkylcarbonylamino, halogen or trifluoromethyl;
R
7
represents H or C
1-4
alkyl, preferably methyl or ethyl;
R
8
and R
8a
each independently represent H, C
1-4
alkyl, preferably methyl or ethyl, phenyl or pyridyl;
Ar
2
is acenaphthenyl, indanyl, iminodihydrobenzofuranyl or fluorenyl, each of which can be optionally substituted by one or more substituents selected from OH, C
1-4
alkyl, C
1-4
alkoxy, halogen, or trifluoromethyl;
R
1
and R
2
are independently H, C
1-6
alkyl, C
3-6
alkenyl, CH
2
C
3-5
cycloalkyl or C
3-6
cycloalkyl;
R
3
represents H, X—R
9
or X—Ar
3
;
X represents S(O)
n
, C(O)NR
10
, C(O)O, NH(CO)NR
10
, NH(CO)O or SO
2
NR
10
;
n is 0, 1 or 2;
R
9
represents a methyl group optionally substituted by one or more substituents selected from CN, CO
2
H, C
1-5
alkoxycarbonyl, 5-tetrazolyl, SO
2
NH
2
, or C(O)NR
11
R
12
, or R
9
represents C
2-6
alkyl or C
3-6
alkenyl, each of which may be optionally substituted by one or more substituents selected from OH, CN, CO
2
H, C
1-5
alkoxy, C
1-5
alkoxycarbonyl, 5-tetrazolyl, azide, 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 H or C
1-4
alkyl, R
15
represents C
1-4
alkyl, C
1-4
alkoxy, di(C
1-4
alkyl)amino, or alkoxyalkylene containing up to 6 carbon atoms, and R
16
represents C
1-4
alkyl or trifluoromethyl; 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 heterocyclic ring which may be optionally substituted by one or more OH groups;
R
10
represents H, C
1-6
alkyl or is linked to R
9
as defined above; and
Ar
3
is phenyl, pyridyl or pyridine N-oxide, each of which may be optionally substituted by one or more substituents selected from OH, NO
2
, NH
2
, NHSO
2
CF
3
, C
1-4
alkoxy, bis-C
1-4
alkanesulphonylamino, 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. Where a substituent in an alkenyl group is OH, phthalimido, NR
13
R
14
or NHC(O)R
15
, the substituent is not attached to an unsaturated carbon atom. The alkyl moieties in a di(C
1-4
alkyl)amino group may be the same or different.
The group R is —C(O)Ar
1
, —C(R
4
)(R
5
)Ar
1
, or Ar
2
.
The group R
4
represents H or C
1-4
alkyl, preferably methyl or ethyl, and the group R
5
represents H or OH.
Preferably Ar
1
is naphthyl, quinolyl, isoquinolyl, indolyl, benzofuranyl or benzothienyl, each of which can be optionally substituted by one to four, particularly one or two, substituents selected from C
1-4
alkyl (e.g. methyl or ethyl), C
1-4
alkoxy (e.g. methoxy or ethoxy), halogen (e.g. fluorine, chlorine or bromine) or trifluoromethyl, or Ar
1
is phenyl optionally substituted by one to four, particularly one or two, substituents selected from C
1-4
alkyl (e.g. methyl or ethyl), C
1-4
alkoxy (e.g. methoxy or ethoxy), halogen (e.g. fluorine, chlorine or bromine), trifluoromethyl, amino, nitro, cyano, trifluoromethoxy, phenoxy, —CH
2
N(R
6
)
2
, —NHSO
2
CF
3
, C
1-4
alkylsulphonylamino, —NHC(O)R
6a
, CO
2
R
7
or —C(O)NR
8
R
8a
.
Most preferably Ar
1
is naphthyl, quinolyl or benzofuranyl, or a phenyl group optionally substituted by one or two substituents selected from C
1-4
alkyl, C
1-4
alkoxy, halogen, trifluoromethyl, nitro, amino, cyano, phenoxy or —NHC(O)R
6a
.
The group Ar
2
is preferably acenaphthenyl, indanyl, iminodihydrobenzofuranyl or fluorenyl, each of which can be optionally substituted by one to four, particularly one or two, substituents selected from OH, C
1-4
alkyl (e.g. methyl or ethyl), C
1-4
alkoxy (e.g. methoxy or ethoxy), halogen (e.g. fluorine, chlorine or bromine) or trifluoromethyl. Especially preferred are indanyl, iminodihydrobenzofuranyl and hydroxy-substituted indanyl groups.
R
6a
is preferably H, C
1-6
, particularly C
1-4
, alkyl, aryl or arC
1-4
alkyl, wherein the aryl group or aryl moiety in the aralkyl group is phenyl or pyridyl, each of which may be optionally substituted by one to four, especially one or two, substituents selected from C
1-4
alkyl (e.g. methyl or ethyl), C
1-4
alkoxy (e.g. methoxy or ethoxy), C
1-4
alkylcarbonylamino (e.g. methyl- or ethylcarbonylamino), halogen (e.g. fluorine, chlorine or bromine) or trifluoromethyl.
Most preferably, R
6a
represents a phenyl or phenylC
1-4
alkyl group substituted in the aromatic ring by one or two substituents selected from methoxy and methylcarbonylamino.
Preferably R
1
and R
2
are independently H, C
1-4
alkyl, C
3-4
alkenyl or C
3-6
cycloalkyl.
It is preferred that R
1
is C
3-4
alkyl or C
4
alkenyl, in particular 1-methylethyl, 2-methylpropyl or 2-methylpropenyl.
It is preferred that R
2
is H or, especially, methyl.
R
3
represents H, X—R
9
or X—Ar
3
.
X represents S(O)
n
where n is 0, 1 or 2, C(O)NR
10
, C(O)O, NH(CO)NR
10
, NH(CO)O or SO
2
NR
10
.
Preferably R
9
represents a methyl group optionally substituted by CN, CO
2
H, C
1-5
alkoxycarbonyl, 5-tetrazolyl, SO
2
NH
2
or C(O)NR
11
R
12
, or R
9
preferably represents C
2-6
alkyl or C
3-6
alkenyl, each of which may be optionally substituted by one to four, particularly one or two, substituents selected from OH, CN, CO
2
H, C
1-5
alkoxy, C
1-5
alkoxycarbonyl, 5-tetrazolyl, azide, 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 H or C
1-4
alkyl, particularly methyl or ethyl, R
15
represents C
1-4
alkyl, particularly methyl or e

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