Uracil compounds as P2-purinoreceptor 7-transmembrane...

Details Uracil compounds as P2-purinoreceptor 7-transmembrane... Uracil compounds as P2-purinoreceptor 7-transmembrane...

1998-12-09

2001-04-17

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Phosphorus containing other than solely as part of an...

C514S212060, C514S215000, C514S235800, C514S236200, C514S236500, C514S236800, C514S274000, C514S295000, C540S521000, C544S123000, C544S243000, C544S295000, C544S310000, C544S311000, C544S314000

Reexamination Certificate

active

06218376

ABSTRACT:

The invention provides new pharmaceutically active compounds, compositions containing them and processes for their preparation. The compounds are useful in therapy because they are P2-purinoceptor 7-transmembrane (TM) G-protein coupled receptor antagonists.
ATP receptors have been shown to be present on a wide number of different cell types (Dubyak et al Am J Physiol (1993) 265, C577-C606). Neutrophils, monocytes and macrophages have been isolated from several species including humans and ATP and/or UTP have been shown to increase intracellular calcium levels. Activation of these receptors on leukocytes can either directly stimulate certain types of inflammatory response or can prime the effector cells to other inflammatory mediators in vivo. ATP can upregulate the expression of adhesion molecules (Freyer et al J Immun. (1988) 141, 580-586) which causes enhanced adhesion of circulating leukocytes to endothelial cells and their enhanced migration into the tissue space. ATP has also been shown to promote chemotaxis of both neutrophils and eosinophils (Verghese et al J. B. C. (1996) 271, 15597-15601 and Burders et al Blood (1993) 81, 49-55) which may promote an inflammatory response. ATP priming of neutrophils can also potentiate superoxide production (Seifert et al Eur J Biochem (1989) 181, 277-285). ATP receptors are also present on a number of other cell types such as chondrocytes, keratinocytes, microglia and goblet cells (Leong et al BBA (1994) 1201, 298-304; Pillai et al J Clin Invest (1992) 90, 42-51; Walz et al J Neuroscience (1993) 13, 4403-4411 and Abdullah et al Biochem J (1996) 316, 943-951). Stimulation of the receptors on these cells can stimulate or enhance inflammatory responses and antagonist of the receptor may therefore be of use in a number of inflammatory diseases such as asthma, inflammatory bowel disease, ARDS, psoriasis, rheumatoid arthritis, myocardial ischaemia, COPD, cystic fibrosis, atherosclerosis, restenosis, peridontal disease, septic shock, osteoarthritis and stroke. ATP receptors have also been reported on tumour cells (Dubyak et al J. Biol. Chem., (1985) 260, 10653-10661 and Wagner et al Gastroenterology, (1997), 112(4) suppl. page A1198) and may be involved in the development of cancer. Antagonists may therefore be useful in treatment of cancer.
The invention provides new pharmaceutically active compounds, compositions containing them and processes for their preparation. The compounds are useful in therapy as P2-purinoceptor-7-transmembrane (TM) G-protein coupled receptor antagonists.
It has now been found that a series of pyrimidine derivatives are useful as P2-purinoceptor 7-transmembrane (TM) G-protein coupled receptor antagonists. In a first aspect the invention therefore provides a compound of formula (I) or a salt thereof:
where
Y is hydrogen, C
1-4
alkyl, C
1-4
alkyl optionally substituted by hydroxy, alkoxy, amino, alkylamino, dialkylamino, phenyl, nitrogen and/or oxygen or optionally substituted by a C
3-8
cycloalkyl ring which optionally contains 1 to 3 heteroatoms and optionally substituted by C
1-4
alkyl; or Y is a group of formula (i):
where
A is a 6 membered ring containing 0-3 nitrogen atoms, a five membered heterocyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen or sulphur or A is a fused 5,6-bicyclic ring containing 4 nitrogen atoms;
R is a group of formula (ii):
where
R
4
is hydrogen, halogen, C
1-3
alkoxy, C
1-3
alkylthio or C
1-3
alkyl (optionally substituted by one or more fluorine atoms);
R
5
is hydrogen, hydroxy, halogen, C
1-3
alkylthio, C
1-4
alkyl (optionally substituted by one or more fluorine atoms), C
3-4
cycloalkyl, MeOCH
2
, MeSCH
2
, phenyl, pyridyl, or C
1-3
alkoxy; or R
4
and R
5
are —(CH
2
)t- where t is 3 or 4 forming a fused ring;
R
6
is hydrogen, halogen, C
1-3
alkoxy, C
1-3
alkylthio, or C
1-3
alkyl (optionally substituted by one or more fluorine atoms); or R
6
together with R
4
is a group —(CH
2
)t- where t is 3 or 4 forming a fused ring;
R
7
is hydrogen, hydroxy, C
1-3
alkoxy, amino, hydroxyC
1-3
alkyl, —NHC
1-3
alkyl, —NC
1-3
dialkyl, —NHC
3-8
cycloalkyl, —N
3-8
cycloalkyl, —NHphenyl, —NHC
1-3
alkylphenyl, (heterocycle)C
1-3
alkyl-, (heterocycle)C
1-3
alkylthio-, (heterocycle)C
1-3
alkyloxy-, (heterocycle)C
1-3
alkylamino-, (heterocycle)thio-, (heterocycle)oxy-, (heterocycle)amino-, C
1-3
alkylthio-, cyano, thiol, C
1-3
alkyl (optionally substituted by one or more fluorine atoms), —C
1-3
alkylamino, —C
1-3
alkylaminoalkyl, carboxamidoC
1-3
alkyl, acetoxyC
1-3
alkyl, or C
3-4
cycloalkyl;
S is 1 or 2;
B is a 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatoms selected from sulphur, oxygen or nitrogen;
Z is a bond, —O—, —S—, —SO
2
—, —CH
2
—, —NH—, —Nalkyl-, —CH═CH—, —CF═CH—, —CH═CF—, —CF═CF—, —CH
2
CH
2
—, —CH═Calkyl-, —Calkyl=CH—, —CH═C(halogen)-, —C(halogen)=CH—, —NHCO—, —CONH—, —SO
2
NH—, —NHSO
2
—, or a group —R
8
CH
2
— or —CH
2
R
8
— where R
8
is NH, Nalkyl, NCOalkyl, CO, O or S;
R
2
is hydrogen, NO
2
, NH
2
, N(C
1-6
alkyl)
2
, CO
2
H, CH
2
OH, halogen, CO
2
C
1-6
alkyl, C
1-8
alkyl optionally interrupted by one or more oxygen, nitrogen or sulphur atoms and optionally substituted by CO
2
H or R
2
is hydroxy, imidazol-1-ylCH
2
—, phenyl optionally substituted by CH
2
CO
2
H or CONR
9
R
10
where R
9
and R
10
are independently hydrogen, C
1-6
alkyl optionally substituted by hydroxy or CO
2
H and/or optionally interrupted by oxygen, nitrogen or sulphur;
R
3
is hydrogen, R
11
CO
2
H, R
11
PO(OH)
2
, R
12
tetrazol-5-yl, COR
13
, NR
14
R
15
, CH
2
NR
16
CH
2
CO
2
H, C
1-8
alkyl optionally interrupted by one or more oxygen, sulphur or nitrogen atoms and optionally substituted by COH or R
3
is a group of formula (iii):
where D is a 4,5 or 6 membered saturated ring containing a nitrogen optionally substituted by hydroxy and substituted by CO
2
H or CONH-het where het is tetrazol-5-yl or a thiazole or a thiadiazole ring substituted by CH
2
CO
2
H or D is a phenyl ring or a 5 membered aromatic heterocylic ring containing 1-3 heteroatoms selected from nitrogen, oxygen or sulphur optionally substituted by one or more groups selected from CF
3
, CO
2
H, CH
2
OH, C
1-6
alkyl optionally interrupted by one or more oxygen atoms, (CH
2
)pCO
2
H, C(CO
2
H)═NOMe, tetrazol-5-yl, CH
2
tetrazol-5-yl, CH
2
CON(CH
2
CO
2
H)
2
, or CH
2
COR
18
; where R
11
is OCH
2
, (CH
2
)p, SCH
2
, CONHCH
2
, NHCH(R
19
) or NR
20
(CH
2
)p; R
12
is a bond, (CH
2
)p, OCH
2
, SCH
2
, CONH, CONHCH
2
, CONHCH
2
CONH, NHCH
2
CONH, NHCH(R
9
);
R
13
is OH, N(CH
2
CO
2
H)
2
, NHS(O)
2
R
21
or a group of formula (iv):
R
14
and R
15
are independently hydrogen, CH
2
CO
2
H, CHPh
2
or C(═S)CH
2
CH
2
CO
2
H;
R
16
is hydrogen, C
1-6
alkyl or CO
2
CH
2
Ph;
R
17
is a bond, sulphur atom, CONH, CH
2
, CH
2
O, OCH
2
, a group —NR
22
CH(CO
2
H)CH
2
— group or a group CONR
22
(CH
2
)pCONR
23
or NR
22
(CH
2
)pCONR
23
;
R
18
is a group of formula (iv) as defined above or a group of formula (v):
R
19
is hydrogen, C
1-6
alkyl optionally substituted by hydroxy and/or optionally interrupted by oxygen, nitrogen or sulphur;
R
20
is hydrogen or C
1-6
alkyl;
p is 1 or 2;
R
21
is NH
2
or C
1-6
alkyl optionally interrupted by oxygen or nitrogen;
R
22
and R
23
are independently hydrogen, C
1-6
alkyl; and
Q
1
and Q
2
each independently represent an O or S atom.
Alkyl groups, whether alone or as part of another group, can be straight chain or branched.
Certain compounds of formula (I) are capable of existing in stereoisomeric forms including enantiomers and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates. The different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis. The invention also extends to any tautomeric forms and mixtures thereof.
Suitably Y is hydrogen, C
1-4
alkyl, C
1-4
alkyl optionally substituted by hydroxy, alkoxy, amino, alkylamino, dialkylamino, phenyl, nitrogen and/or oxyg

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