Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-03-29
2004-09-14
Wilson, James O. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S255000
Reexamination Certificate
active
06790850
ABSTRACT:
The present invention relates to certain thiazolopyrimidinone compounds, processes and intermediates used in their preparation, pharmaceutical compositions containing them and their use in therapy.
WO 98/08847 and EP0778277 each disclose a series of 6,5-hetero bicyclic compounds said to be useful as CRF antagonists.
Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. These small secreted molecules are a growing superfamily of 8-14 kDa proteins characterised by a conserved four cysteine motif. The chemokine superfamily can be divided into two main groups exhibiting characteristic structural motifs, the Cys-X-Cys (C-X-C) and Cys-Cys (C-C) families. These are distinguished on the basis of a single amino acid insertion between the NH-proximal pair of cysteine residues and sequence similarity.
The C-X-C chemokines include several potent chemoattractants and activators of neutrophils such as interleukin-8 (IL-8) and neutrophil-activating peptide 2 (NAP-2).
The C-C chemokines include potent chemoattractants of monocytes and lymphocytes but not neutrophils such as human monocyte chemotactic proteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on Activation, Normal T Expressed and Secreted), eotaxin and the macrophage inflammatory proteins 1&agr; and 1&bgr; (MIP-1&agr; and MIP-1&bgr;).
Studies have demonstrated that the actions of the chemokines are mediated by subfamilies of G protein-coupled receptors, among which are the receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3, CXCR4 and CX3CR1. These receptors represent good targets for drug development since agents which modulate these receptors would be useful in the treatment of disorders and diseases such as those mentioned above.
In accordance with the present invention, there is therefore provided a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof:
in which
R
1
represents a C
3
-C
7
carbocyclic, C
1
-C
8
alkyl, C
2
-C
6
alkenyl or C
2
-C
6
alkynyl group, each of the groups being optionally substituted by one or more substituent groups independently selected from halogen atoms, —OR
4
, —NR
5
R
6
, —CONR
5
R
6
, —COOR
7
, —NR
8
COR
9
, —SR
10
, —SO
2
R
10
, —SO
2
NR
5
R
6
, —NR
8
SO
2
R
9
or an aryl or heteroaryl group, both of which may be optionally substituted by one or more substituents independently selected from halogen atoms, cyano, nitro, —OR
4
, —NR
5
R
6
, —CONR
5
R
6
, —COOR
7
, —NR
8
COR
9
, —SR
10
, —SO
2
R
10
, —SO
2
NR
5
R
6
, —NR
8
SO
2
R
9
, C
1
-C
6
alkyl or trifluoromethyl groups;
R
2
and R
3
each independently represent a hydrogen atom, or a C
3
-C
7
carbocyclic, C
1
-C
8
alkyl, C
2
-C
6
alkenyl or C
2
-C
6
alkynyl group, the latter four groups may be optionally substituted by one or more substituent groups independently selected from:
(a) halogen atoms, —OR
4
, —NR
5
R
6
, —CONR
5
R
6
, —COOR
7
, —NR
8
COR
9
, —SR
10
, —SO
2
R
10
, —SO
2
NR
5
R
6
, —NR
8
SO
2
R
9
;
(b) a 3-8 membered ring optionally containing one or more atoms selected from O, S, NR
8
and itself optionally substituted by C
1
-C
3
alkyl or halogen; or
(c) an aryl group or heteroaryl group each of which may be optionally substituted by one or more substituents independently selected from halogen atoms, cyano, nitro, —OR
4
, —NR
5
R
6
, —CONR
5
R
6
, —NR
8
COR
9
, —SO
2
NR
5
R
6
, —NR
8
SO
2
R
9
, C
1
-C
6
alkyl and trifluoromethyl groups;
R
4
represents hydrogen, C
1
-C
6
alkyl or a phenyl group the latter two of which may be optionally substituted by one or more substituent groups independently selected from halogen atoms, phenyl, —OR
11
and —NR
12
R
13
R
5
and R
6
independently represent a hydrogen atom or a C
1
-C
6
alkyl or phenyl group the latter two of which may be optionally substituted by one or more substituent groups independently selected from halogen atoms, phenyl, —OR
14
and —NR
15
R
16
, —CONR
15
R
16
, —NR
15
COR
16
, —SONR
15
R
16
, NR
15
SO
2
R
16
or
R
5
and R
6
together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring system optionally containing a further heteroatom selected from oxygen and nitrogen atoms, which ring system may be optionally substituted by one or more substituent groups independently selected from phenyl, —OR
14
, —COOR
14
, —NR
15
R
16
, —CONR
15
R
16
, —NR
15
COR
16
, —SONR
15
R
16
, NR
15
SO
2
R
16
or C
1
-C
6
alkyl, itself optionally substituted by one or more substituents independently selected from halogen atoms and —NR
15
R
16
and —OR
17
groups;
R
10
represents a hydrogen atom or a C
1
-C
6
-alkyl or a phenyl group, the latter two of which may be optionally substituted by one or more substituent groups independently selected from halogen atoms, phenyl, —OR
17
and —NR
15
R
16
; and
each of R
7
, R
8
, R
9
, R
11
, R
12
, R
13
, R
14
, R
15
, R
16
, R
17
independently represents a hydrogen atom or a C
1
-C
6
, alkyl, or a phenyl group.
In the context of 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. Aryl groups include phenyl and naphthyl. Heteroaryl groups include 5- or 6-membered aromatic rings containing one or more heteroatoms selected from N, S, O. Examples include pyridine, pyrimidine, thiazole, oxazole, pyrarole, imidazole, furan.
Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and mixture thereof including racemates. Tautomers and mixtures thereof also form an aspect of the present invention.
In formula (I) above, the group R
1
represents a C
3
-C
7
carbocyclic, C
1
-C
8
alkyl, C
2
-C
6
alkenyl or C
2
-C
6
alkynyl group, each of the groups being optionally substituted by one or more substituent groups independently selected from halogen atoms, —OR
4
, —NR
5
R
6
, —CONR
5
R
6
, —COOR
7
, —NR
8
COR
9
, —SR
10
, —SO
2
R
10
, —SO
2
NR
5
R
6
, —NR
8
SO
2
R
9
or an aryl or heteroaryl group, both of which may be optionally substituted by one or more substituents independently selected from halogen atoms, cyano, nitro, —OR
4
, —NR
5
R
6
, —CONR
5
R
6
, —COOR
7
, —NR
8
COR
9
, —SR
10
, —SO
2
R
10
, —SO
2
NR
5
R
6
, —NR
8
SO
2
R
9
, C
1
-C
6
alkyl or trifluoromethyl groups. Particularly advantageous compounds of formula (I) are those in which R
1
represents an optionally substituted benzyl group. More preferably R
1
represents benzyl or benzyl substituted by one or more C
1
-C
6
alkyl, C
1
-C
6
alkoxy or halogen atoms.
When R
2
and R
3
represent a group substituted by one or more 3-8 membered rings optionally containing one or more atoms selected from O, S or NR
8
, examples of such groups include piperidine, pyrrolidine, piperazine and morpholine.
Preferably one of R
2
and R
3
is hydrogen and the other is C
1
-C
8
alkyl substituted by hydroxy and one or more methyl or ethyl groups. More preferably one of R
2
and R
3
is hydrogen and the other is CH(CH
3
)CH
2
OH, CH(Et)CH
2
OH, C(CH
3
)
2
CH
2
OH or CH(CH
2
OH)
2
. When one of R
2
and R
3
is hydrogen and the other is CH(CH
3
)CH
2
OH or CH(Et)CH
2
OH the resulting compounds of formula (I) are preferably in the form of the (R) isomer.
Particularly preferred compounds of the invention include:
7-[(2-Hydroxy-1,1-dimethylethyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-2(3H)-one,
(R)-7-[[1-(Hydroxymethyl)propyl]amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-2(3H)-one,
(R)-7-[(2-Hydroxy-1-methylethyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-2(3H)-one,
5-[[(2,3-Difluorophenyl)methyl]thio]-7-[(2-hydroxy-1,1-dimethylethyl)amino]thiazolo[4,5-d]pyrimidin-2(3H
Bonnert Roger Victor
Hunt Simon Fraser
Walters Iain Alistair Stewart
Willis Paul Andrew
AstraZeneca UK Limited
Fish & Richardson P.C.
McKenzie Thomas
Wilson James O.
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