Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-10-21
2004-10-19
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S280000
Reexamination Certificate
active
06806273
ABSTRACT:
The present invention relates to certain thiazolopyrimidine compounds, processes and intermediates used in their preparation, pharmaceutical compositions containing them and their use in therapy.
The compound 2,7-diamino-5-methylmercapto-thiazolo[4,5-d]pyrimidine is known from J. Amer. Chem. Soc., 73, 4226-4227 (1951).
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 and CXCR4. 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 general formula
wherein R
1
represents a hydrogen atom, or a group —NR
3
R
4
;
R
3
and R
4
each independently represent a hydrogen atom, or a 4-piperidinyl, C
3
-C
6
to cycloalkyl or C
1
-C
8
alkyl group, which latter two groups may be optionally substituted by one or more substituent groups independently selected from halogen atoms and —NR
5
R
6
, —CONR
5
R
6
, —OR
7
, —COOR
7
, —NR
8
COR
9
, —SR
10
, —SO
2
R
10
, —SO
2
NR
5
R
6
, —NR
8
SO
2
R
9
, morpholinyl, C
1
-C
4
alkyl, C
3
-C
6
cycloalkyl, tetrahydrofuranyl and aryl groups, wherein an aryl substituent group may be a phenyl, naphthyl, thienyl, pyridinyl, imidazolyl or indolyl group, each of which may be optionally substituted by one or more substituents independently selected from halogen atoms and cyano, nitro, —NR
5
R
6
, —CONR
5
R
6
, —OR
7
, —NR
8
COR
9
, —SO
2
NR
5
R
6
, —NR
8
SO
2
R
9
, C
1
-C
6
alkyl and trifluoromethyl groups, or R
3
and R
4
together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring system, which ring system may be optionally substituted by one or more substituent groups independently selected from
—NR
5
R
6
, —CONR
5
R
6
, —OR
7
, —COOR
10
, —NR
8
COR
9
, and C
1
-C
6
alkyl optionally substituted by one or more substituents independently selected from halogen atoms and —NR
11
R
12
and —OR
7
groups;
X represents a group —OH or —NR
13
R
14
;
R
13
and R
14
each independently represent a hydrogen atom, a 4-piperidinyl group optionally substituted by a C
1
-C
4
alkylphenyl substituent group, or a C
3
-C
7
carbocyclic, C
1
-C
8
alkyl, C
2
-C
6
alkenyl or C
2
-C
6
alkynyl group, which latter four groups may be optionally substituted by one or more substituent groups independently selected from halogen atoms and —NR
5
R
6
, —CONR
5
R
6
, —OR
7
, —COOR
7
, —NR
8
COR
9
, —SR
10
, —SO
2
R
10
, —SO
2
NR
5
R
6
, —NR
8
SO
2
R
9
, morpholinyl, C
1
-C
4
alkyl, C
3
-C
6
cycloalkyl and aryl groups, wherein an aryl substituent group may be a phenyl, naphthyl, thienyl, pyridinyl, imidazolyl or indolyl group, each of which may be optionally substituted by one or more substituents independently selected from halogen atoms and cyano, nitro, —NR
5
R
6
, —CONR
5
R
6
, —OR
7
, —NR
8
COR
9
, —SO
2
NR
5
R
6
, NR
8
S
2
R
9
, C
1
-C
6
alkyl and trifluoromethyl groups,
or R
13
and R
14
together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring system, which ring system may be optionally substituted by one or more substituent groups independently selected from —NR
5
R
6
, —CONR
5
R
6
, —OR
7
, —COOR
7
, —NR
8
COR
9
, and C
1
-C
6
alkyl optionally substituted by one or more substituents independently selected from halogen atoms and phenyl, —NR
11
R
12
and —OR
7
groups;
R
2
represents a C
1
-C
6
alkyl or C
2
-C
6
alkenyl group optionally substituted by a phenyl or phenoxy group, wherein the phenyl or phenoxy group may itself be optionally substituted by one or more substituents independently selected from halogen atoms and nitro, C
1
-C
6
alkyl, trifluoromethyl, —OR
7
, —C(O)R
7
, —SR
10
, —NR
15
R
16
and phenyl groups;
R
5
and R
6
each independently represent a hydrogen atom or a C
1
-C
6
alkyl or phenyl group, each 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
, 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 comprising 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
17
, —COOR
17
, —NR
15
R
16
, —CONR
15
R
16
, —NR
15
COR
16
, —SONR
15
R
16
, and C
1
-C
6
alkyl optionally substituted by one or more substituents independently selected from halogen atoms and —NR
15
R
16
and —OR
17
groups;
R
7
and R
9
each independently represent a hydrogen atom or a C
1
-C
6
, particularly C
1
-C
4
, alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl) or phenyl group, each of which may be optionally substituted by one or more (e.g. one, two, three or four) substituent groups independently selected from halogen atoms (e.g. fluorine, chlorine, bromine or iodine), phenyl, —OR
17
and —NR
15
R
16
; and
each of R
8
, R
10
, R
11
, R
12
, R
15
, R
16
and R
17
independently represents a hydrogen atom or a C
1
-C
6
, particularly C
1
-C
4
, alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl) or phenyl group; with the proviso that when R
1
and X both represent —NH
2
, then R
2
does not represent a methyl group;
or a pharmaceutically acceptable salt or solvate thereof.
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. Where a substituent in an alkenyl group is a phenoxy group, the phenoxy group is not attached to an unsaturated carbon atom. A carbocyclic group is a saturated hydrocarbyl group that may be monocyclic or polycyclic (e.g. bicyclic). Similarly, a saturated heterocyclic ring system may be monocyclic or polycyclic (e.g. bicyclic).
In formula (I) above, the group R
1
represents a hydrogen atom, or a group —NR
3
R
4
. Particularly advantageous compounds of formula (I) are those in which R
1
represents a group —NR
3
R
4
.
Preferably, R
3
and R
4
each independently represent a hydrogen atom, or a 4-piperidinyl, C
3
-C
6
cycloalkyl (i.e. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) or C
1
-C
8
, particularly C
1
-C
6
, alkyl group (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl or octyl), which latter two groups may be optionally substituted by one, two, three or four substituent groups independently selected from halogen atoms (e.g. fluorine, chlorine, bromine or iodine) and —NR
5
R
6
, —CONR
5
R
6
, —OR
7
, —COOR
7
, —NR
8
COR
9
, —SR
10
, —SO
2
R
10
, —SO
2
NR
5
R
6
, —NR
8
SO
Austin Rupert
Baxter Andrew
Bonnert Roger
Hunt Fraser
Kinchin Elizabeth
AstraZeneca AB
Nixon & Vanderhye
Truong Tamthom N.
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