2,4-substituted pyrrolidine derivatives-CCR-3 receptor...

Details 2,4-substituted pyrrolidine derivatives-CCR-3 receptor... 2,4-substituted pyrrolidine derivatives-CCR-3 receptor...

2001-12-19

2003-04-22

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C544S318000, C548S571000

Reexamination Certificate

active

06552028

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to certain 2,4-substituted pyrrolidine 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 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 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)).
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.
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' co-pending U.S. patent application Ser. Nos. 09/134,013, issued as U.S. Pat. No.
6
,
323
,
223
filed Aug. 14, 1998 and WO 00/31032 discloses CCR-3 antagonists that inhibit eosinophilic recruitment by chemokine such as eotaxin. 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 pyrrolidine derivatives 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 a compound of Formula (I):
wherein:
R
1
is hydrogen, alkyl, acyl, heteroalkyl, —CONR
3
R
4
(where R
3
and R
4
are independently hydrogen or alkyl), —COOR
5
(where R
5
is hydrogen, alkyl or heteroalkyl), or —SO
2
R
6
where R
6
is alkyl;
alk
1
is an alkylene chain of 1 to 6 carbon atoms;
X is —NHCO— or —CONH—;
Y is an alkylene chain of 1 to 3 carbon atoms or an alkylene chain of 2 or 3 carbon atoms wherein one of the carbon atoms is replaced by a heteroatom selected from the group consisting of —O—, —NR
b
— [where R
b
is hydrogen, alkyl, acyl, —CONR
7
R
8
(where R
7
and R
8
are independently hydrogen or alkyl), —COOR
9
(where R
9
is hydrogen, alkyl or heteroalkyl), aryl, or aralkyl)] and —S(O)n— wherein n is 0 to 2;
Ar
1
is a heteroaryl group or phenyl group wherein the heteroaryl or phenyl group is substituted, in addition to the Ar
2
group, with a substituent selected from the group consisting of hydrogen, halo, alkyl, alkoxy, nitro, amido, aminosulfonyl and sulfonylamino;
Ar
2
is aryl;
alk
2
is an alkylene chain of 1 to 6 carbon atoms wherein one of the carbon atoms is optionally replaced by —CO—, —NRC— [where R
c
is hydrogen, alkyl, acyl, —CONR
10
R
11
(where R
10
and R
11
are independently hydrogen or alkyl), —COOR
12
(where R
12
is hydrogen, alkyl or heteroalkyl), aryl, or aralkyl)] or —S(O)n1— wherein n1 is 0 to 2;
Ar
3
is cycloalkyl, aryl or heteroaryl; or
a pharmaceutically acceptable salts thereof.
In a second aspect, this invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or it's 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 pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or it's pharmaceutically acceptable salt and a pharmaceutically acceptable excipient. The disease states include respiratory diseases such as asthma.
In a fourth aspect, this invention provides a process for preparing compounds of Formula (I).
In a fifth aspect, this invention provides the use of a compound of Formula (I) or it's pharmaceutically salt in the preparation of medicament for the treatment of a disease mediated by a CCR-3 receptor. 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 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, n-butyl, iso-butyl, tert-butyl, n-pentyl, 2-, 3-, methylbutyl, neo-pentyl, 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, (2-propyl)methylene, ethylene, methyethylene, (2-propyl)ethylene, propylene, 1- or 2-methylpropylene, 1- or 2-ethylpropylene, pentylene, and the like.
“Acyl” means a radical —C(O)R where R is alkyl, haloalkyl, alkyl substituted with carboxy, alkoxycarbonyl, heterocycle, or aryloxycarbonyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, e.g., acetyl, trifluoroacetyl, —C(O)CH
2
CO
2
H, —C(O)—CH
2
—CO
2
CH
3
, benzoyl, thenoyl, and the like.
“Halo” means fluoro, chloro, bromo or iodo, preferably fluoro and chloro.
“Haloalkyl” means alkyl substituted with one or more same or different halo atoms, e.g., —CH
2
Cl, —CF
3
, —CH
2
CF
3
, —CH
2
CCl
3
, and the like.
“Monoalkylamino” means a radical —NHR where R is alkyl, e.g., methylamino, ethylamino, (1-methylethyl)amino, and the like.
“Dialkylamino” means a radical —NRR′ where R and R′ are independently alkyl. Representative examples include, but are not limited to, dimethylamino, meth

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