CCR5 antagonists useful for treating aids

Details CCR5 antagonists useful for treating aids CCR5 antagonists useful for treating aids

2002-03-27

2004-04-13

Bernhardt, Emily (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S252110, C514S253110, C514S253130, C514S316000, C544S357000, C544S295000, C544S364000, C546S187000, C546S189000

Reexamination Certificate

active

06720325

ABSTRACT:

BACKGROUND
The present invention relates to piperidine derivatives useful as selective CCR5 antagonists, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds. The invention also relates to the use of a combination of a CCR5 antagonist of this invention and one or more antiviral or other agents useful in the treatment of Human Immunodeficiency Virus (HIV). The invention further relates to the use of a CCR-5 antagonist of this invention, alone or in combination with another agent, in the treatment of solid organ transplant rejection, graft v. host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis.
The global health crisis caused by HIV, the causative agent of Acquired Immunodeficiency Syndrome (AIDS), is unquestioned, and while recent advances in drug therapies have been successful in slowing the progression of AIDS, there is still a need to find a safer, more efficient, less expensive way to control the virus.
It has been reported that the CCR5 gene plays a role in resistance to HIV infection. HIV infection begins by attachment of the virus to a target cell membrane through interaction with the cellular receptor CD4 and a secondary chemokine co-receptor molecule, and proceeds by replication and dissemination of infected cells through the blood and other tissue. There are various chemokine receptors, but for macrophage-tropic HIV, believed to be the key pathogenic strain that replicates in vivo in the early stages of infection, the principal chemokine receptor required for the entry of HIV into the cell is CCR5. Therefore, interfering with the interaction between the viral receptor CCR5 and HIV can block HIV entry into the cell. The present invention relates to small molecules which are CCR5 antagonists.
CCR-5 receptors have been reported to mediate cell transfer in inflammatory diseases such as arthritis, rheumatoid arthritis, atopic dermatitis, psoriasis, asthma and allergies, and inhibitors of such receptors are expected to be useful in the treatment of such diseases, and in the treatment of other inflammatory diseases or conditions such as inflammatory bowel disease, multiple sclerosis, solid organ transplant rejection and graft v. host disease.
Piperidine derivatives which are muscarinic antagonists useful in the treatment of cognitive disorders such as Alzheimer's disease are disclosed in U.S. Pat. Nos. 5,883,096; 6,037,352; 5,889,006; 5,952,349; and 5,977,138.
Piperidine and piperazine derivatives useful in the treatment of AIDS are disclosed in WO 00/66559 and WO 00/66558.
A-M. Vandamme et al.,
Antiviral Chemistry & Chemotherapy
, 9: 187-203 (1998) disclose current clinical treatments of HIV-1 infections in man including at least triple drug combinations or so-called Highly Active Antiretroviral Therapy (“HAART”); HAART involves various combinations of nucleoside reverse transcriptase inhibitors (“NRTI”), non-nucleoside reverse transcriptase inhibitors (“NNRTI”) and HIV protease inhibitors (“PI”). In compliant drug-naive patients, HAART is effective in reducing mortality and progression of HIV-1 to AIDS. However, these multidrug therapies do not eliminate HIV-1 and long-term treatment usually results in multidrug resistance. Development of new drug therapies to provide better HIV-1 treatment remains a priority.
SUMMARY OF THE INVENTION
The present invention relates to compounds useful as CCR5 antagonist represented by the structural formula I
or a pharmaceutically acceptable salt or isomer thereof, wherein:
Q, X and Z are independently selected from the group consisting of CH and N, provided that one or both of Q and Z is N;
R, R
4
, R
5
, R
6
and R
7
are independently selected from the group consisting of H and (C
1
-C
6
)alkyl;
R
1
is H, (C
1
-C
6
)alkyl, fluoro-(C
1
-C
6
)alkyl-, R
9
-aryl(C
1
-C
6
)alkyl-, R
9
-heteroaryl-(C
1
-C
6
)alkyl-, (C
1
-C
6
)alkyl-SO
2
—, (C
3
-C
6
)cycloalkyl-SO
2
—, fluoro-(C
1
-C
6
)alkyl-SO
2
—, R
9
-aryl-SO
2
—, R
9
-heteroaryl-SO
2
—, N(R
22
)(R
23
)—SO
2
—, (C
1
-C
6
)alkyl-C(O)—, (C
3
-C
6
)cyclo-alkyl-C(O)—, fluoro-(C
1
-C
6
)alkyl-C(O)—, R
9
-aryl-C(O)—, NH—(C
1
-C
6
)alkyl-C(O)— or R
9
-aryl-NH—C(O)—;
R
2
is H or (C
1
-C
6
)alkyl, and R
3
is H, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy(C
1
-C
6
)alkyl-, (C
3
-C
10
)-cycloalkyl-, (C
3
-C
10
)cycloalkyl(C
1
-
6
)alkyl-, R
9
-aryl, R
9
-aryl(C
1
-C
6
)-alkyl-, R
9
-heteroaryl, or R
9
-heteroaryl(C
1
-C
6
)alkyl-, provided that both X and Z are not each N;
or R
2
and R
3
together are ═O, ═NOR
10
, ═N—NR
11
R
12
or ═CH(C
1
-C
6
)alkyl, provided that when one or both of X and Z is N, R
2
and R
3
together are not ═CH(C
1
-C
6
)alkyl;
and when X and Z are each CH, R
3
can also be (C
1
-C
6
)alkoxy, R
9
-aryloxy, R
9
-heteroaryloxy, (C
1
-C
6
)alkyl-C(O)O—, (C
1
-C
6
)alkyl-NH—C(O)O—, N((C
1
-C
6
)alkyl)
2
—C(O)O—, (C
1
-C
6
)alkyl-C(O)—NR
13
—, (C
1
-C
6
)alkyl-O—C(O)—NR
13
—, (C
1
-C
6
)alkyl-NH—C(O)—NR
13
—, or N((C
1
-C
6
)alkyl)
2
—C(O)—NR
13
—;
R
8
is (R
14
,R
15
,R
16
)-substituted phenyl, (R
14
,R
15
,R
16
)-substituted 6-membered heteroaryl, (R
14
,R
15
,R
16
)-substituted 6-membered heteroaryl N-oxide, (R
17
,R
18
)-substituted 5-membered heteroaryl, naphthyl, fluorenyl, diphenylmethyl,
R
9
is 1, 2 or 3 substituents independently selected from the group consisting of H, halogen, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, —CF
3
, —OCF
3
, CH
3
C(O)—, —CN, CH
3
SO
2
—, CF
3
SO
2
— and —N(R
22
)(R
23
);
R
10
is H, (C
1
-C
6
)alkyl, fluoro(C
1
-C
6
)alkyl-, (C
3
-C
10
)cycloalkyl(C
1
-C
6
)alkyl-, hydroxy(C
2
-C
6
)alkyl-, (C
1
-C
6
)alkyl-O—(C
2
-C
6
)alkyl-, (C
1
-C
6
)alkyl-O—C(O)—(C
1
-C
6
)alkyl- or N(R
22
)(R
23
)—C(O)—(C
1
-C
6
)alkyl-;
R
11
and R
12
are independently selected from the group consisting of H, (C
1
-C
6
)alkyl and (C
3
-C
10
)cycloalkyl, or R
11
and R
12
together are C
2
-C
6
alkylene and form a ring with the nitrogen to which they are attached;
R
14
and R
15
are independently selected from the group consisting of (C
1
-C
6
)alkyl, halogen, —NR
22
R
23
, —OH, —CF
3
, —OCH
3
, —O-acyl and —OCF
3
;
R
16
is R
14
, hydrogen, phenyl, —NO
2
, —CN, —CH
2
F, —CHF
2
, —CHO, —CH═NOR
24
, pyridyl, pyridyl N-oxide, pyrimidinyl, pyrazinyl, —N(R
24
)CONR
25
R
26
, —NHCONH(chloro-(C
1
-C
6
)alkyl), —NHCONH((C
3
-C
10
)cycloalkyl(C
1
-C
6
)alkyl), —NHCO(C
1
-C
6
)alkyl, —NHCOCF
3
, —NHSO
2
N(R
22
)(R
23
), —NHSO
2
(C
1
-C
6
)alkyl, —N(SO
2
CF
3
)
2
, —NHCO
2
—(C
1
-C
6
)alkyl, C
3
-C
10
cycloalkyl, —SR
27
, —SOR
27
, —SO
2
R
27
, —SO
2
NH(R
22
), —OSO
2
(C
1
-C
6
)alkyl, —OSO
2
CF
3
, hydroxy(C
1
-C
6
)alkyl-, —CON R
24
R
25
, —CON(CH
2
CH
2
OCH
3
)
2
, —OCONH(C
1
-C
6
)alkyl, —CO
2
R
24
, —Si(CH
3
)
3
or —B(OC(CH
3
)
2
)
2
;
R
17
is (C
1
-C
6
)alkyl, —N(R
22
)(R
23
) or R
19
-phenyl;
R
13
, R
18
, R
22
, R
23
, R
24
, R
25
and R
26
are independently selected from the group consisting of H and (C
1
-C
6
)alkyl;
R
19
is 1, 2 or 3 substituents independently selected from the group consisting of H, (C
1
-C
6
)alkyl, —CF
3
, —CO
2
R
25
, —CN, (C
1
-C
6
)alkoxy and halogen;
R
20
and R
21
are independently selected from the group consisting of H and (C
1
-C
6
)alkyl, or R
20
and R
21
together with the carbon to which they are attached form a spiro ring of 3 to 6 carbon atoms; and
R
27
is (C
1
-C
6
)alkyl or phenyl.
Another aspect of the invention is a pharmaceutical composition for treatment of HIV comprising an effective amount of at least one compound of formula I in combination with a pharmaceutically acceptable carrier. Another aspect of the invention is a pharmaceutical composition for treatment of solid organ transplant rejection, graft v. host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis comprising an effective amount of at least one compound of formula I in combination with a pharmaceutically acceptable carrier.
Yet another aspect of this invention is a method of treatment of HIV comprisin

Affiliated with

Also associated with

Rating

CCR5 antagonists useful for treating aids does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with CCR5 antagonists useful for treating aids, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and CCR5 antagonists useful for treating aids will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3196812