Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-09-21
2001-03-13
Robinson, Allen J. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S294000
Reexamination Certificate
active
06200981
ABSTRACT:
The invention provides new pharmaceutically active compounds, composition 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 eutrophils 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, arthereosclerosis, 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 Gastroenterolgy, (1997), 112(4) suppl. page A1198) and may be involved in the development of cancer. Antagonists may therefore be useful in treatment of cancer.
According to the invention there is provided a compound of formula (I) or salts thereof:
in which:
X is a bond, CH
2
or a C
1-3
alkylene group optionally interrupted by oxygen;
R 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 is hydroxy, phenyl optionally substituted by CH
2
CO
2
H, or CONR
3
R
4
where R
3
and R
4
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
1
is NR
5
R
6
or CH
2
NR
5
R
6
where R
5
and R
6
are independently hydrogen, CH
2
CO
2
H, CHPh
2
or C(=S)CH
2
CH
2
CO
2
H, or R
1
is CH
2
NR
7
CH
2
CO
2
H where R
7
is hydrogen, C
1-6
alkyl or CO
2
CH
2
Ph, or R
1
is C
1-8
alkyl optionally interrupted by one or more oxygen, nitrogen or sulphur atoms and optionally substituted by CO
2
H, or R
1
is R
8
-PO(OH)
2
, or -R
8
tetrazol-5-yl where R
8
is a bond, OCH
2
, SCH
2
, CONH, CONHCH
2
, CONHCH
2
CONH, NHCH
2
CONH NHCH(R
3
), NR
9
(CH
2
)q where R
9
is hydrogen or C
1-6
alkyl and q is 1 or 2 or R
20
—CO
2
H where R
20
is a bond, CONHCH
2
or NHCH(R
3
) where R
3
is as defined above or R
1
is a group of formula (i):
where B is a 4-, 5-, or 6 membered saturated ring containing a nitrogen atom optionally substituted by hydroxy and substituted by CO
2
H or CONH-Het where Het is tetrazol-5-yl, or a thiazole or thiadiazole ring substituted by CO
2
H or CH
2
CO
2
H, or B is phenyl or a 5-membered aromatic heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen or sulphur optionally substituted by one or more groups selected from CF
3
, or CO
2
H, CH
2
OH, C
1-6
alkyl optionally interrupted by one or more oxygen atoms, CH
2
CH
2
CO
2
H, C(CO
2
H)═N—OMe, tetrazol-5-yl or CH
2
tetrazol-5-yl; and
R
10
is a bond, sulphur atom, —CONH—, CH
2
CH
2
O, a group —NR
11
—CH(CO
2
H)—CH
2
—, or a group CONR
11
(CH
2
)
p
CONR
12
— or —NR
11
—(CH
2
)
p
—CONR
12
— where R
11
and R
12
are independently hydrogen or C
1-6
alkyl and p is a 1 or 2;
R
2
is a group of formula (ii) or (iii):
where R
13
groups are independently hydrogen, halogen, methoxy, methylthio or C
1-2
alkyl (optionally substituted by one or more fluorine atoms);
R
14
groups are independently hydrogen, halogen, hydroxy, C
1-3
alkylthio, C
1-4
alkyl (optionally substituted by one or more fluorine atoms), C
3-4
cycloalkyl, MeOCH
2
, MeSCH
2
or C
1-2
alkoxy;
R
15
groups are independently hydrogen, halogen or methyl (optionally substituted by one or more fluorine atoms);
Z
1
CH═CH, CF═CH or CF═CF;
Z
2
is a single bond, oxygen, sulphur, CH
2
CH═CH, CH
2
CH═CHCH
2
or C
1-4
alkylene group optionally interrupted by an oxygen or sulphur atom;
R
16
are independently hydrogen, halogen, C
1-2
alkyl, CF
3
or a methylthio group or hydroxy;
Q
1
and Q
2
each independently represent an O or S;
or a salt thereof,
provided that when Q
1
is oxygen, R
2
is a group of formula (ii).
Alkyl groups, whether alone or as part of another group, can be straight chain or branched. Unless stated otherwise, the term alkyl as used herein refers to C
1-6
alkyl groups, such as methyl, ethyl, propyl and butyl groups.
Certain compounds of formula (I) are capable of existing in steroisomeric 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 sterospecific or asymmetric synthesis. The invention also extends to any tautomeric forms and mixtures thereof.
Suitably X is a bond, CH
2
or a C
1-3
alkylene group optionally interrupted by oxygen.
Preferably X is CH
2
, a bond or CH
2
CH
2
O, more preferably X is CH
2
.
Suitably R 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 is hydroxy, phenyl optionally substituted by CH
2
CO
2
H, or CONR
3
R
4
where R
3
and R
4
are independently hydrogen, C
1-6
alkyl optionally substituted by hydroxy or CO
2
H and/or optionally interrupted by oxygen, nitrogen or sulphur. Preferably R is meta or para relative to the X group. Preferred R groups includes hydrogen, C
1-6
alkoxy, C
1-8
alkyl optionally interrupted by one or two oxygen atoms and optionally substituted by CO
2
H, CH
2
OH, hydroxy and halogen. More preferably R is hydrogen, methoxy, CH
2
OCH
2
CH
2
OCH
3
, CH
2
OCH
2
CH
3
, CH
2
OH, CH
3
, hydroxy, OCH
2
CO
2
H or O(CH
2
)
3
CO
2
H.
Suitably R
1
is NR
5
R
6
or CH
2
NR
5
R
6
where R
5
and R
6
are independently hydrogen, CH
2
CO
2
H, CHPh
2
or C(═S)CH
2
CH
2
CO
2
H, or R
1
is CH
2
NR
7
CH
2
CO
2
H where R
7
is hydrogen, C
1-6
alkyl or CO
2
CH
2
Ph, or R
1
is C
1-8
alkyl optionally interrupted by one ore more oxygen, nitrogen or sulphur atoms and optionally substituted by CO
2
H, or R
1
is —R
8
—PO(OH)
2
, or —R
8
-tetrazol-5-yl where R
8
is a bond, OCH
2
, SCH
2
, CONH, CONHCH
2
, CONHCH
2
CONH, NHCH
2
CONH, NHCH(R
3
) or —R
8
—CO
2
H where R
8
is a bond, CONHCH
2
NHCH(R
3
) where R
3
is as defined above or R
8
is NR
9
(CH
2
)
q
where R
9
is hydrogen or C
1-6
alkyl and q is 1 or 2, or R
1
is a group of formula (i) as defined above.
When X is CH
2
, R
1
is preferably meta or para with respect to the X linkage. Preferably R
1
is CO
2
H, —PO(OH)
2
, C
1-8
alkyl optionally interrupted by one or two oxygen atoms and optionally substituted by CO
2
H, or R
1
is a group of formula (i) where B is ph
Kindon Nicholas
Meghani Premji
Thom Stephen
AstraZeneca UK Limited
Badio Barbara
Nixon & Vanderhye
Robinson Allen J.
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