Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-04-06
2003-02-25
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S188000, C546S189000, C546S191000
Reexamination Certificate
active
06525070
ABSTRACT:
FIELD AND BRIEF SUMMARY OF THE INVENTION
The present invention concerns piperidine derivatives having pharmaceutical activity, to processes for preparing such derivatives, to pharmaceutical compositions comprising such derivatives and to the use of such derivatives as active therapeutic agents.
DESCRIPTION OF RELATED ART
Pharmaceutically active piperidine derivatives are disclosed in WO99/38514, WO99/04794 and WO00/35877.
Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract macrophages, T cells, eosinophils, basophils and neutrophils to sites of inflammation and also play a rôle in the maturation of cells of the immune system. 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, or &agr;) and Cys—Cys (C—C, or &bgr;) 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.
Histamine is a basic amine, 2-(4-imidazolyl)-ethylamine, and is formed from histidine by histidine decarboxylase. It is found in most tissues of the body, but is present in high concentrations in the lung, skin and in the gastrointestinal tract. At the cellular level inflammatory cells such as mast cells and basophils store large amounts of histamine. It is recognised that the degranulation of mast cells and basophils and the subsequent release of histamine is a fundamental mechanism responsible for the clinical manifestation of an allergic process. Histamine produces its actions by an effect on specific histamine G-protein coupled receptors, which are of three main types, H1, H2 and H3. Histamine H1 antagonists comprise the largest class of medications used in the treatment of patients with allergic disorders, especially rhinitis and urticaria. H1 antagonists are useful in controlling the allergic response by for example blocking the action of histamine on post-capillary venule smooth muscle, resulting in decreased vascular permeability, exudation and oedema. The antagonists also produce blockade of the actions of histamine on the H1 receptors on c-type nociceptive nerve fibres, resulting in decreased itching and sneezing.
Viral infections are known to cause lung inflammation. It has been shown experimentally that the common cold increases mucosal output of eotaxin in the airways. Instillation of eotaxin into the nose can mimic some of the signs and symptoms of a common cold. (See, Greiff L et al Allergy (1999) 54(11) 1204-8 [Experimental common cold increase mucosal output of eotaxin in atopic individuals] and Kawaguchi M et al Int. Arch. Allergy Immunol. (2000) 122 S1 44 [Expression of eotaxin by normal airway epithelial cells after virus A infection].)
DETAILED DESCRIPTION OF THE INVENTION The present invention provides a compound of formula (I):
wherein:
q, s and t are, independently, 0 or 1;
n and r are, independently, 0, 1, 2, 3, 4 or 5;
m and p are, independently, 0, 1 or 2;
X is CH
2
, C(O), O, S, S(O), S(O)
2
or NR
37
; provided that when m and p are both 1 then X is not CH
2
;
Y is NHR
2
or OH;
T is C(O), C(S), S(O)
2
or CH
2
;
R
1
is hydrogen, C
1-6
alkyl, aryl or heterocyclyl;
R
2
and R
47
are, independently, hydrogen, C
1-6
alkyl, aryl(C
1-4
)alkyl or CO(C
1-6
alkyl);
R
3
is C
1-6
alkyl {optionally substituted by halogen, CO
2
R
4
or phthalimide}, CR
3a
R
3b
R
3c
, C
2-4
alkenyl {optionally substituted by aryl or heterocyclyl}, C
3-7
cycloalkyl {optionally substituted by C
1-4
alkyl, aryl or oxo}, C
3-7
cycloalkenyl {optionally substituted by oxo, C
1-6
alkyl or aryl}, aryl, heterocyclyl, thioaryl or thioheterocyclyl;
R
3a
is hydrogen, C
1-6
alkyl, C
1-6
alkoxy or C
3-7
cycloalkyl; R
3b
is aryl, heterocyclyl, S(O)
2
aryl or S(O)
2
heterocyclyl; and R
3c
is C
1-6
alkyl, C
1-4
haloalkyl, hydroxy, heterocyclyl(C
1-4
alkyl) or aryl;
wherein, unless stated otherwise, the foregoing aryl and heterocyclyl moieties are optionally substituted by: halogen, OH, SH, NO
2
, oxo, C
1-6
alkyl {itself optionally substituted by halogen, OC(O)C
1-6
alkyl, S(O)
2
R
48
, phenyl (itself optionally substituted by halogen (such as one or two chlorine or fluorine atoms), C
1-6
alkyl, S(O)
2
R
38
or C(O)NR
39
R
40
), naphthyloxy (itself optionally substituted by halo or C
2-6
alkenyl), C
3-10
cycloalkyl (itself optionally substituted by C
1-4
alkyl or oxo) or NR
41
C(O)OCH
2
(fluoren-9-yl)}, NR
41
(O)OCH
2
(fluoren-9-yl), C
1-6
alkoxy {itself optionally substituted by halogen, C
1-6
alkoxy, NHCO
2
(C
1-6
alkyl), CO
2
R
4
, NR
5
R
6
or phenyl (itself optionally substituted by halogen or NO
2
)}, C
1-6
alkylthio, C
1-6
haloalkylthio, C
3-10
cycloalkyl, NR
7
R
8
, NR
9
C(O)R
10
, CO
2
R
11
, C(O)NR
12
R
13
, C(O)R
14
, S(O)
d
R
15
, S(O)
2
NR
42
R
43
, NR
44
S(O)
2
R
45
, phenyl {itself optionally substituted by halogen, C
1-6
alkyl, C
1-6
haloalkyl, CN, NO
2
, C
1-6
alkoxy (itself optionally substituted by halogen, OH or pyridinyl), phenyl (itself optionally substituted by halogen, C
1-6
alkyl, C
1-6
haloalkyl, CN, NO
2
, C
1-6
alkoxy or C
1-6
haloalkoxy) or heterocyclyl (itself optionally substituted by halogen, C
1-6
alkyl, C
1-6
haloalkyl, CN, NO
2
, C
1-6
alkoxy or C
1-6
haloalkoxy)}, heterocyclyl {itself optionally substituted by halogen, C
1-6
alkyl, C
1-6
haloalkyl, CN, NO
2
, C
1-6
alkoxy, C
1-6
haloalkoxy, phenyl (itself optionally substituted by halogen, C
1-6
alkyl, C
1-6
haloalkyl, CN, NO
2
, C
1-6
alkoxy or C
1-6
haloalkoxy) or heterocyclyl (itself optionally substituted by halogen, C
1-6
alkyl, C
1-6
haloalkyl, CN, NO
2
, C
1-6
alkoxy or C
1-6
haloalkoxy)}, phenoxy {itself optionally substituted by halogen, C
1-6
alkyl, C
1-6
haloalkyl, CN, NO
2
, C
1-6
alkoxy, C
1-6
haloalkoxy, phenyl (itself optionally substituted by halogen, C
1-6
alkyl, C
1-6
haloalkyl, CN, NO
2
, C
1-6
alkoxy or C
1-6
haloalkoxy) or heterocyclyl (itself optionally substituted by halogen, C
1-6
alkyl, C
1-6
haloalkyl, CN, NO
2
, C
1-6
alkoxy or C
1-6
haloalkoxy)}, SCN, CN, SO
3
H (or an alkali metal salt thereof), methylenedioxy or difluoromethylenedioxy; when aryl is phenyl adjacent substituents may join to form, together with the phenyl ring to which they are attached, a dihydrophenanthrene moiety;
d is 0, 1 or 2;
R
4
, R
5
,R
6
, R
7
, R
8
, R
9
, R
10
, R
11
, R
12
, R
13
, R
14
, R
37
, R
39
, R
40
, R
41
, R
42
, R
43
and R
44
are, independently, hydrogen, C
1-6
alkyl, aryl (itself optionally substituted by halogen, C
1-6
alkyl, C
1-6
haloalkyl, CN, NO
2
, C
1-6
alkoxy or C
1-6
haloalkoxy) or heterocyclyl (itself optionally substituted b
Lawrence Louise
Rigby Aaron
Sanganee Hitesh
Springthorpe Brian
AstraZeneca AB
Desai Rita
Rotman Alan L.
LandOfFree
Bipiperidine derivatives as modulators of CCR3 activity and... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Bipiperidine derivatives as modulators of CCR3 activity and..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Bipiperidine derivatives as modulators of CCR3 activity and... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3150261