Compounds

Details Compounds Compounds

2000-06-01

2003-02-11

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...

C546S217000, C546S225000, C514S330000

Reexamination Certificate

active

06518286

ABSTRACT:

The present invention relates to novel compounds, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
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 CCR 1, 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.
Certain piperidinyl derivatives and piperazinyl derivatives are known from U.S. Pat. Nos. 3,787,419, 4,559,349 and 5,210,086 for use respectively as central nervous system depressants, antipsychotic agents and as &agr;
1
-adrenoreceptor antagonists.
In accordance with the present invention, there is therefore provided a compound of general formula
wherein:
R
1
represents a C
1
-C
12
alkyl group optionally substituted by one or more substituents independently selected from cyano, hydroxyl, C
1
-C
6
alkoxy, C
1
-C
6
alkylthio and C
1
-C
6
alkoxycarbonyl groups, or
R
1
represents a 3- to 10-membered saturated or unsaturated ring system which may comprise up to two ring carbon atoms that form carbonyl groups and which may comprise up to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, the ring system being optionally substituted by one or more substituents independently selected from halogen atoms, and cyano, nitro, hydroxyl, C
1
-C
6
alkyl, C
3
-C
6
cycloalkyl, C
3
-C
6
alkoxy, C
1
-C
6
alkoxycarbonyl, C
1
-C
6
haloalkyl, C
1
-C
6
haloalkoxy, —NR
5
R
6
, C
3
-C
6
cycloalkylamino, C
1
-C
6
alkylthio, C
1
-C
6
alkylthioC
1
-C
6
alkyl, C
1
-C
6
alkylcarbonylamino, —C(O)NR
7
R
8
, sulphonamido (—SO
2
NH
2
), (di)C
1
-C
6
alkylsulphonamido, phenyl, phenylamino, nitrophenyl, pyridyl, pyridylthio, benzodioxanyl, thienyl, furanyl, and C(O)R
9
-substituted C
1
-C
6
alkyl or C
1
-C
6
alkoxy groups;
M is 0 or 1;
Q represents a group OCH
2
, C
1
-C
4
alkylene or C
2
-C
4
alkenylene;
T represents a group C(O)NH, or when m is 0, T may additionally represent a bond or a group NH, or when m is 1 and Q represents C
1
-C
4
alkylene, T may additionally represent a group NH;
n is 1, 2, 3 or 4;
each R2 independently represents a hydrogen atom or a C
1
-C
4
alkyl group;
each R
3
independently represents a hydrogen atom or a C
1
-C
4
alkyl group;
V represents a nitrogen atom;
W represents a nitrogen atom or a group CH;
X represents an oxygen atom or a group C(O), CH(OH), NH or N(C
1
-C
6
alkyl), provided that when W represents a nitrogen atom, then X represents C(O);
R
4
represents a phenyl group optionally substituted by one or more substituents independently selected from halogen atoms, and amino, nitro, cyano, sulphonyl (—SO
3
H), sulphonamido (—SO
2
NH
2
), C
1
-C
6
alkyl, C
1
-C
6
haloalkyl, C
1
-C
6
haloalkoxy and C
1
-C
6
alkylsulphonyl groups;
R
5
and R
6
each independently represent a hydrogen atom or a C
1
-C
6
alkyl or hydroxyC
1
-C
6
alkyl group, 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;
R
7
and R
8
each independently represent a hydrogen atom or a C
1
-C
6
alkyl group; and
R
9
represents a hydroxyl or —NR
7
R
8
group;
with the provisos that
(a) when m is 0, T is CONH, n is 2, 3 or 4 and each R
2
and R
3
represents hydrogen, W is CH, X is C(O) or CH(OH) and R
1
represents a substituted 3- to 10-membered unsaturated ring system, then the one or more substituents in the ring system do not include hydroxyl, halogen, C
1
-C
6
alkoxy or C
1
-C
6
haloalkoxy, and
(b) when W is N, X is C(O), R
4
represents 3-trifluoromethylphenyl, m is 0 and T is a bond, then R
1
and (CR
2
R
3
)
n
taken together do not represent a C
1
-C
6
alkyl group, and
(c) when W is CH, X is O, n is 2 or 3 and each R
2
and R
3
represents hydrogen, m is 0 and T is NH, then R
1
does not represent a group
or a pharmaceutically acceptable salt or solvate thereof.
In the context of the present specification, an alkyl substituent group or an alkyl moiety in a substituent group may be linear or branched. Further, the alkyl moieties in a dialkylamino, di(hydroxyalkyl)amino or dialkylsulphonamido substituent group may be the same or different.
R
1
represents a C
1
-C
12
, preferably C
1
-C
10
, alkyl group optionally substituted by one or more (e.g. one, two, three or four) substituents independently selected from cyano, hydroxyl, C
1
-C
6
, preferably C
1
-C
4
, alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy, pentoxy or hexoxy), C
1
-C
6
, preferably C
1
-C
4
, alkylthio (e.g. methyl-, ethyl-, propyl-, butyl-, pentyl- or hexylthio) and C
1
-C
6
, preferably C
1
-C
4
, alkoxycarbonyl (e.g. methoxy-, ethoxy-, propoxy-, butoxy-, pentoxy- or hexoxycarbonyl) groups, or R
1
represents a 3- to 10-membered saturated or unsaturated ring system comprising up to two ring carbon atoms that form carbonyl groups and comprising up to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, the ring system being optionally substituted by one or more (e.g. one, two, three or four) substituents independently selected from halogen atoms (fluorine, chlorine, bromine or iodine), and cyano, nitro, hydroxyl, C
1
-C
6
alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl or hexyl), C
3
-C
6
cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), C
1
-C
6
alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy, pentoxy or hexoxy), C
1
-C
6
alkoxycarbonyl (e.g. methoxy-, ethoxy-, propoxy-, butoxy-, pentoxy- or hexoxycarbonyl), C
1
-C
6
haloalkyl (e.g. trifluoromethyl), C
1
-C
6
haloalkoxy (e.g. trifluoromethoxy), —NR
5
R
6
, C
3
-C
6
cycloalkylamino (cyclopropyl-, cyclobutyl-, cyclopentyl- or cyclohexylamino), C
1
-C
6
alkylthio (e.g. methyl-, ethyl-, propyl-, butyl-, pentyl- or hexylthio), C
1
-C
6
alkylthioC
1
-C
6
alkyl (e.g. methylthiomethyl), C
1
-C
6
alkylcarbonylamino (e.g. methyl-, ethyl-, propyl-, butyl-, pentyl- or hexylcarbonylamino), —C(O)NR
7
R
8
, sulphonamido (—SO
2
NH
2
), (di)C
1
-C
6
alkylsulphonamido (e.g. (di)methylsulphonamido or (di)ethylsulphonamido), phenyl, phenylamino, nitrophenyl, pyridyl, pyridylthio, benzodioxanyl, thienyl, furanyl, and C(O)R
9
-substituted C
1
-C
6
alkyl or C
1
-C
6
alkoxy groups, the alkyl and alkoxy moieties being as defined above.
The 3- to 10-membered saturated or unsaturated ring system in the group R
1
may be monocyclic, or polycyclic comprising 2 or more fused rings, examples of which include cyclobutyl, cyclopentyl, cyclohexyl, norbornylenyl, adamantyl, piperidyl, phenyl, naphthyl, naphthyridinyl, 1,3-benzodioxolyl, pyrazolyl, furanyl, pyridyl, thienyl, benzoxazolyl, benzothiazolyl, chromonyl, imidazolyl, quinolinyl, isoquinolinyl, ben

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