CCR5 modulators

Details CCR5 modulators CCR5 modulators

1999-12-01

2003-07-01

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S253030, C514S256000, C514S258100, C514S266400, C514S299000, C514S303000, C514S304000, C514S307000, C514S311000, C544S127000, C544S238000, C544S242000, C544S262000, C544S263000, C544S277000, C544S295000, C544S335000, C544S336000, C544S408000, C546S112000, C546S118000, C546S119000, C546S124000, C546S125000, C546S126000, C546S139000, C546S146000, C546S152000, C546S175000, C546S176000

Reexamination Certificate

active

06586430

ABSTRACT:

This application claims priority under 35 U.S.C. §119 of Great Britain applications 9828420.1 and 9921375.3, filed respectively on Dec. 23, 1998 and Sep. 10, 1999, the texts of which are hereby incorporated by reference herein in their entireties.
This invention relates to new chemical compounds. These compounds find particular not exclusive use as pharmaceuticals, especially as CCR5 modulators.
This invention also relates to formulations or dosage forms including these compounds, to use of these compounds in manufacture of pharmaceutical formulations or dosage forms and methods of treatment, especially treatment of ant-inflammatory diseases and conditions and in the treatment and prevention of HIV-1 and genetically related retroviral infections.
The compounds of the present invention may be modulators, especially antagonists, of the activity of chemokine CCR5 receptors, particularly those which occur on the surfaces of certain cells within the human body. Modulators of CCR5 receptor may be useful in the treatment and prevention of various inflammatory diseases and conditions, and in the treatment and prevention of infection by HIV-1 and genetically related retroviruses.
The name “chemokine”, is a contraction of “chemotactic cytokines”. The chemokines comprise a large family of proteins which have in common important structural features and which have the ability to attract leukocytes. As leukocyte chemotactic factors, chemokines play an indispensable role in the attraction of leukocytes to various tissues of the body, a process which is essential for both inflammation and the body's response to infection. Because chemokines and their receptors are central to the pathophysiology of inflammatory and infectious diseases, agents which are active in modulating, preferably antagonizing, the activity of chemokines and their receptors, are useful in the therapeutic treatment of such inflammatory and infectious diseases.
The chemokine receptor CCR5 is of particular importance in the context of treating inflammatory and infectious diseases. CCR5 is a receptor for chemokines, especially for the macrophage inflammatory proteins (MIP) designated MIP-1&agr; and MIP-1&bgr;, and for a protein which is regulated upon activation and is normal T-cell expressed and secreted (RANTES). The relationship between modulators, especially antagonists of CCR5 activity and therapeutic usefulness in treating inflammation and HIV infection, and the manner in which such a relationship may be demonstrated, is explained in more detail further below.
There is ongoing in the art a substantial investigation of different classes of modulators of chemokine receptor activity, especially that of the CCR5 chemokine receptor. A representative disclosure is Mills et al. WO 98/25617 relating to substituted aryl piperazines as modulators of chemokine receptor activity. However, the compositions described therein are not the same as, nor suggestive of those of the present invention. Further disclosures are: WO 98/025605; WO 98/025604; WO 98/002151; WO 98/004554; and WO 97/024325.
The present invention relates to compounds which may be conveniently considered to have four independently variable regions, reading from the left-hand side to right-hand side of said compound: R
egion
&agr;, R
egion
&bgr;, R
egion
&ggr;, and R
egion
&dgr;, of Formula (I):
[R
egion
&agr;]-[R
egion
&bgr;]-[R
egion
&ggr;]-[R
egion
&dgr;]  (I)
and pharmaceutically acceptable salts and prodrug derivatives thereof. The compounds of the present invention may be selective CCR5 receptor modulators and are non-peptidyl in structure.
The compounds as exemplified by Formula (I) may contain one or more stereogenic centers and the present invention includes the recited compounds in both their separated and their unseparated forms. The separated forms can be obtained by conventional means, e.g., by asymmetric synthesis, by using high performance liquid chromatography employing a chiral stationary phase, or by chemical resolution via the formation of suitable salts or derivatives. It will be understood that the separate optically active forms of the compositions of the present invention, as well as reacemic mixtures thereof, will usually vary with respect to their biological properties because of the chirality-dependent conformation of the active site of an enzyme, receptor, etc.
The description which follows provides details of the particular moieties which comprise each of said R
egions
. In order to present said details in an orderly and space-saving fashion, each major group in each Region is set out with a single dash (“-”), and each successive subdivision within each said group is set out in turn with two, three, etc. dashes as required.
In this specification and claims a reference to a range or class of groups for example (C
1
-C
3
)alkyl is to be understood as an express disclosure and reference of each member of the range or class, including isomers.
According to the present invention there is provided a compound of Formula (I):
[R
egion
&agr;]-[R
egion
&bgr;]-[R
egion
&ggr;]-[R
egion
&dgr;]  (I)
wherein [R
egion
&agr;] is selected from the group consisting of:
A. Aryl heterocyclyl substituent components comprising:
1. hetero-phenylmethylene moieties of partial Formula (1.0.0):
wherein: the symbol “*” indicates the point of attachment of the moiety of partial Formula (1.0.0) to R
egion
&bgr;, as hereinafter defined;
R
5
is a member selected from the group consisting of a direct bond; —O—; —C(═O)—; —NR
4
—; and —S(═O)
p
—; where:
R
4
is hydrogen or (C
1
-C
2
)alkyl;
R
6
is a member selected from the group consisting of hydrogen; (C
1
-C
2
)alkyl; (C
1
-C
2
)alkoxy; —CN; —OH; and —C(═O)NH
2
;
j is an integer selected from 0, 1, and 2;
m is an integer selected from 0, 1, and 2;
R
7
and R
8
are each a member selected from the group consisting of —F; —Cl; —CO
2
R
4
; —OH; —CN; —CONR
4
a
R
4
b
; —NR
4
a
R
4
b
—; —NR
4
a
C(═O)R
4
b
; —NR
4
a
C(═O)OR
4
b
; —NR
4
a
S(═O)
p
R
4
b
; —S(═O)
p
NR
4
a
R
4
b
; (C
1
-C
4
)alkyl, and (C
1
-C
4
)alkoxy wherein said alkyl and alkoxy are each substituted with 0 to 3 substituents independently selected from F and Cl; (C
1
-C
2
)alkoxycarbonyl; (C
1
-C
2
)alkylcarbonyl; and (C
1
-C
2
)alkylcarbonyloxy; where:
p is an integer selected from 0, 1, and 2;
R
4
a
and R
4
b
are each independently selected from hydrogen and (C
1
-C
2
)alkyl;
the moiety represented by partial Formula (1.0.1):
 in partial Formula (1.0.0) represents a monocyclic heterocyclic group, or a bicyclic benzo-fused ring system containing said heterocyclic group wherein said heterocyclic group contains a total of 5- or 6-members of which one or two of said members is nitrogen, the presence of the optional second nitrogen atom being represented by: “[N]”; wherein said heterocyclic group or ring system are selected from the group consisting of pyrrolyl; pyrazolyl; imidazolyl; pyridinyl; pyrazinyl; pyrimidinyl; pyridazinyl; piperazinyl; indolyl; indazolinyl; benzimidazolyl; quinolinyl; iso-quinolinyl; and quinazolinyl; wherein:
R
12
a
is a member selected from the group consisting of hydrogen; F; Cl; —CO
2
R
4
; oxo; —OH; CN; NH
2
; NH(C
1
-C
2
)alkyl; N(C
1
-C
2
)
2
dialkyl; —CF
3
; (C
1
-C
4
)alkyl; (C
2
-C
4
)alkenyl; (C
1
-C
4
)alkoxy; (C
3
-C
7
)cycloalkyl; and phenyl; wherein said alkyl, alkenyl, alkoxy, cycloalkyl and phenyl are substituted with 0 to 2 substituents R
9
where:
R
9
is a member independently selected from the group consisting of F; Cl; —CO
2
R
4
; —OH; cyano; —CONR
4
a
R
4
b
; —NR
4
a
R
4
b
—; —NR
4
a
C(═O)R
4
b
; —NR
4
a
C(═O)OR
4
b
; —NR
4
a
S(═O)
p
R
4
b
; —S(═O)
p
NR
4
a
R
4
b
; (C
1
-C
4
)alkyl including dimethyl, and (C
1
-C
4
)alkoxy wherein said alkyl and alkoxy are each independently substituted with 0 to 3 substituents independently selected from F and Cl; (C
1
-C
2
)alkoxycarbonyl; (C
1
-C
2
)alkylcarbonyl; and (C
1
-C
2
)al

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