Piperidine quaternary salts- CCR- 3 receptor antagonists

Details Piperidine quaternary salts- CCR- 3 receptor antagonists Piperidine quaternary salts- CCR- 3 receptor antagonists

1999-11-18

2002-01-29

Chang, Ceila (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S316000, C514S318000, C514S321000, C514S324000, C514S326000, C514S330000, C546S233000, C546S234000, C546S235000, C546S237000

Reexamination Certificate

active

06342509

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to certain piperidine quaternary salts that are CCR-3 receptor antagonists, pharmaceutical compositions containing them, methods for their use and methods for preparing these compounds.
BACKGROUND INFORMATION
Tissue eosinophilia is a feature of a number of pathological conditions such as asthma, rhinitis, eczema and parasitic infections ((see Bousquet, J. et al.
N. Eng. J. Med
. 323: 1033-1039 (1990) and Kay, A. B. and Corrigan. C. J.
Br. Med. Bull
. 48:51-64 (1992)). In asthma, eosinophil accumulation and activation are associated with damage to bronchial epithelium and hyperresponsiveness to constrictor mediators. Chemokines such as RANTES, eotaxin and MCP-3 are known to activate eosinophils ((see Baggiolini, M. and Dahinden, C. A.
Immunol. Today
. 15:127-133 (1994), Rot, A. M. et al.
J. Exp. Med
. 176, 1489-1495 (1992) and Ponath. P. D. et al.
J. Clin. Invest
., Vol. 97, #3, 604-612 (1996)). However, unlike RANTES and MCP-3 which also induce the migration of other leukocyte cell types, eotaxin is selectively chemotactic for eosinophils ((see Griffith-Johnson, D. A et al.
Biochem. Biophy. Res. Commun
. 197:1167 (1993) and Jose, P. J. et al.
Biochem. Biophy. Res. Commun
. 207, 788 (1994)). Specific eosinophil accumulation was observed at the site of administration of eotaxin whether by intradennal or intraperitoneal injection or aerosol inhalation ((see Griffith-Johnson, D. A et al.
Biochem. Biophy. Res. Commun
. 197:1167 (1993); Jose, P. J. et al.
J. Exp. Med
. 179, 881-887 (1994); Rothenberg, M. E. et al.
J. Exp. Med
. 181, 1211 (1995) and Ponath. P. D.
J. Clin. Invest
., Vol. 97, #3, 604-612 (1996)).
Glucocorticoids such as dexamethasone, methprednisolone and hydrocortisone have been used for treating many eosinophil-related disorders, including bronchial asthma ((R. P. Schleimer et. al.,
Am. Rev. Respir. Dis
., 141, 559 (1990)). The glucocorticoids are believed to inhibit IL-5, IL3 mediated eosinophil survival in these diseases. However, prolonged use of glucocorticoids can lead to side effects such as glaucoma, osteoporosis and growth retardation in the patients ((see Hanania N. A et al.,
J. Allergy and Clin. Immunol
., Vol. 96, 571-579 (1995) and Saha M. T. et al,
Acta Paediatrica
, Vol. 86, #2, 138-142 (1997)). It is therefore desirable to have an alternative means of treating eosinophil related diseases without incurring these undesirable side effects.
Recently, the CCR-3 receptor was identified as a major chemokine receptor that eosinophils use for their response to eotaxin, RANTES and MCP-3. When transfected into a murine pre-&bgr; lymphoma line, CCR-3 bound eotaxin, RANTES and MCP-3 and conferred chemotactic responses on these cells to eotaxin, RANTES and MCP-3 ((see Ponath. P. D. et al.
J. Exp. Med
. 183, 2437-2448 (1996)). The CCR-3 receptor is expressed on the surface of eosinophils, T-cells (subtype Th-2), basophils and mast cells and is highly selective for eotaxin.
Studies have shown that pretreatment of eosinophils with an anti-CCR-3 mAb completely inhibits eosinophil chemotaxis to eotaxin, RANTES and MCP-3 ((see Heath H. et al.
J. Clin. Invest
., Vol. 99, #2, 178-184 (1997)). Applicants' U.S. patent application Ser. No. 09/134,013, filed Aug. 14, 1998 discloses compounds that are CCR-3 antagonists and inhibit eosinophilic recruitment by chemokines such as eotaxin. PCT Application WO 98/04554 discloses piperidine analogs that are CCR-3 receptor antagonists.
Therefore, blocking the ability of the CCR-3 receptor to bind RANTES, MCP-3 and eotaxin and thereby preventing the recruitment of eosinophils should provide for the treatment of eosinophil-mediated inflammatory diseases.
The present invention concerns novel piperidine quaternary salts which are capable of inhibiting the binding of eotaxin to the CCR-3 receptor and thereby provide a means of combating eosinophil induced diseases, such as asthma.
SUMMARY OF THE INVENTION
In a first aspect, this invention provides compounds selected from the group of compounds represented by Formula (I):
wherein:
One of T and U is —N
+
R
5
— where R
5
is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, amidoalkyl, sulfonylaminoalkyl, or aralkyl and the other is —CH—;
X
−
is a pharmaceutically acceptable counterion;
R
1
and R
2
are, independently of each other, hydrogen or alkyl;
m is an integer from 0 to 3 provided that when T is —N
+
R
5
— then m is at least 1;
Ar and Ar
1
are, independently of each other, aryl or heteroaryl;
F is alkylene, alkenylene, or a bond;
R is hydrogen or alkyl; or R together with either R
3
or R
4
and the atoms to which they are attached forms a carbocycle or a heterocycle;
R
3
and R
4
are, independently of each other, hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heteroalkyl, or -(alkylene)-C(O)—Z where Z is alkyl, haloalkyl, alkoxy, haloalkyloxy, hydroxy, amino, mono- or disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy, or heteroaralkyloxy;
E is —C(O)N(R
6
)—, —SO
2
N(R
6
)—, —N(R
7
)C(O)N(R
6
)—, —N(R
7
)SO
2
N(R
6
)—, —N(R
7
)C(S)N(R
6
)—, —N(R
7
)C(O)— or —N(R
7
)SO
2
— where:
R
6
and R
7
are, independently of each other, hydrogen, alkyl, acyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heteroalkyl, or -(alkylene)-C(O)—Z where Z is alkyl, haloalkyl, alkoxy, haloalkyloxy, hydroxy, amino, mono- or disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy, or heteroaralkyloxy;
Q is —CO— or an alkylene chain optionally interrupted by —C(O)—, —NR
8
—, —O—, —S(O)
0−2
—, —C(O)N(R
8
)—, —N(R
8
)C(O)—, —N(R
8
)SO
2
—, —SO
2
N(R
8
)—, —N(R
9
)C(O)N(R
10
)—, —N(R
9
)SO
2
N(R
10
)— or —N(R
9
)C(S)N(R
10
)— where:
R
8
, R
9
and R
10
are, independently of each other, hydrogen, alkyl, acyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heterocyclylalkyl, heteroalkyl, or -(alkylene)-C(O)—Z where Z is alkyl, haloalkyl, alkoxy, haloalkyloxy, hydroxy, amino, mono- or disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy, or heteroaralkyloxy; and
prodrugs, individual isomers, mixtures of isomers, and pharmaceutically acceptable salts thereof.
In a second aspect, this invention provides pharmaceutical compositions containing a therapeutically effective amount of a compound of Formula (I) or its pharmaceutically acceptable salt and a pharmaceutically acceptable excipient.
In a third aspect, this invention provides a method of treatment of a disease in a mammal treatable by administration of a CCR-3 receptor antagonist, comprising administration of a therapeutically effective amount of a compound of Formula (I) or its pharmaceutically acceptable salt. The disease states include respiratory diseases such as asthma.
In a fourth aspect, this invention provide a process for preparing compounds of Formula (I).
DETAILED DESCRIPTION OF THE INVENTION
Definitions
Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:
“Alkyl” means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, pentyl, and the like.
“Alkenyl” means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e.g., ethenyl, propenyl, and the like.
“Alkylene” means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, e.g., methylene, ethylene, propylene, 2-methylpropylene, pentylene, and the like.
“Alkenylene” means a linear divalent hydrocarbon radical of two to six carbon atoms or

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