Cyclic amine derivatives-CCR-3 receptor antagonists

Details Cyclic amine derivatives-CCR-3 receptor antagonists Cyclic amine derivatives-CCR-3 receptor antagonists

1998-11-20

2002-01-15

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S398000, C544S400000

Reexamination Certificate

active

06339087

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to certain cyclic amine derivatives 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, inflammatory bowel diseases 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 hyper responsiveness to constrictor mediators. It is established that chemokines such as RANTES, eotaxin, MCP-2, MCP-3 and MCP-4 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 intradermal 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)).
The CCR-3 receptor has been identified as a major chemokine receptor which eosinophils use for their response to eotaxin, RANTES and MCP-3. It is expressed predominantly on the surface of eosinophils and is highly selective for eotaxin. When transfected into a murine pre-&bgr; lymphoma line, the CCR-3 receptor bound eotaxin, RANTES and MCP-3 and conferred chemotactic responses on these cells to these chemokines ((see Ponath. P. D. et al.
J. Exp. Med
. 183, 2437-2448 (1996)).
Recently, 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)) indicating that CCR-3 antagonists are useful for the treatment of eosinophil-mediated inflammatory diseases. PCT Application WO 98/04554 discloses piperidine analogs that are CCR-3 receptor antagonists.
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, IL-3 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.
The present invention provides 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:
T and U are both nitrogen; or
one of T and U is —N— and the other is carbon; or
one of T and U is —(N
+
R
10
)-X
−
and the other is carbon where R
10
is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, amidoalkyl, sulfonylaminoalkyl, or aralkyl and X
−
is a pharmaceutically acceptable counterion provided that n is 1;
R
1
and R
2
are, independently of each other, hydrogen or alkyl;
n is an integer from 0 to 2, provided that when n is 0, either T or U is carbon;
m is an integer from 0 to 3;
Ar and Ar
1
are, independently of each other, aryl or heteroaryl;
F is alkylene, alkenylene or a bond, provided that when T and U are nitrogen and F is alkylene, then R
4
is not aryl.
Each R is independently hydrogen or alkyl, or R together with either R
3
or R
4
and the atoms to which they are attached form a carbocycle or a heterocycle;
R
3
and R
4
are, independently of each other, selected from:
(i) hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heteroalkyl, cyano 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, provided that when T and U are both nitrogen or one of T and U is —N— and the other is carbon, then both R
3
and R
4
are not hydrogen; or
(ii) R
3
and R
4
together with the carbon atom to which they are attached form a carbocycle or a heterocycle;
E is —C(O)N(R
5
)—, —SO
2
N(R
5
)—, —N(R
6
)C(O)N(R
5
)—, —N(R
6
)SO
2
N(R
5
)—, —N(R
6
)C(S)N(R
5
)—, —N(R
6
)C(O)—, —N(R
6
)C(O)O—, —OC(O)N(R
6
)— or —N(R
6
)SO
2
— wherein:
R
5
is:
(i) 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; or
(ii) R
5
together with either R
3
or R
4
and the atoms to which they are attached forms a heterocycloamino group; and
R
6
is 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,
provided that when T is nitrogen and E is —C(O)N(R
5
)—, —SO
2
N(R
5
)—, —N(R
6
)C(O)N(R
5
)—, —N(R
6
)SO
2
N(R
5
)— or —N(R
6
)C(S)N(R
5
)—, then m>0; Q is —R
7
—W—R
8
— wherein:
R
7
is an alkylene chain of between 1-6 carbon atoms inclusive;
R
8
is a bond or an alkylene chain of between 1-4 carbon atoms inclusive;
W is a bond or a group selected from —C(O)—, —NR
9
—, —O—, —S(O)
0-2
—, —C(O)N(R
9
)—, —N(R
9
)C(O)—, —N(R
9
)SO
2
—, —SO
2
N(R
9
)—, —N(R
9
)C(O)N(R
9
)—, —N(R
9
)SO
2
N(R
9
)— or —N(R
9
)C(S)N(R
9
)— wherein:
R
9
is 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,
provided that when T is nitrogen and U is carbon then W is not —C(O)N(R
9
)—, 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.
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

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