Piperazine derivatives useful as CCR5 antagonists

Details Piperazine derivatives useful as CCR5 antagonists Piperazine derivatives useful as CCR5 antagonists

2000-05-01

2002-05-21

Bernhardt, Emily (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Silicon containing doai

C514S064000, C514S252110, C514S252180, C514S253010, C514S253100, C514S253110, C514S253090, C544S229000, C544S295000, C544S360000, C544S364000

Reexamination Certificate

active

06391865

ABSTRACT:

BACKGROUND
The present invention relates to piperazine 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.
Related piperazine 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.
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 the treatment of HIV comprising administering to a mammal in need of such treatment an effective amount of a CCR5 antagonist represented by the structural formula I:
or a pharmaceutically acceptable salt thereof, wherein
R is R
8
-phenyl, R
8
-pyridyl, R
8
-thiophenyl or R
8
-naphthyl;
R
1
is hydrogen or C
1
-C
6
alkyl;
R
2
is R
9
, R
10
, R
11
-phenyl; R
9
, R
10
, R
11
-substituted 6-membered heteroaryl; R
9
, R
10
, R
11
-substituted 6-membered heteroaryl N-oxide; R
12
, R
13
-substituted 5-membered heteroaryl; naphthyl; fluorenyl;
R
3
is hydrogen, 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
-C
6
)alkyl, R
8
-phenyl, R
8
-phenyl(C
1
-C
6
)alkyl, R
8
-naphthyl, R
8
-naphthyl(C
1
-C
6
)alkyl, R
8
-heteroaryl or R
8
-heteroaryl(C
1
-C
6
)alkyl;
R
4
, R
5
, R
7
and R
13
are independently selected from the group consisting of hydrogen and (C
1
-C
6
)-alkyl;
R
6
is hydrogen, C
1
-C
6
alkyl or C
2
-C
6
alkenyl;
R
8
is 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, —CF
3
, CF
3
O—, CH
3
C(O)—, —CN, CH
3
SO
2
—, CF
3
SO
2
—, R
14
-phenyl, R
14
-benzyl, CH
3
C(═NOCH
3
), CH
3
C(═NOCH
2
CH
3
),
 —NH
2
, —NHCOCF
3
, —NHCONH(C
1
-C
6
alkyl), —NHCO(C
1
-C
6
alkyl), —NHSO
2
(C
1
-C
6
alkyl), 5-membered heteroaryl and
 wherein X is —O—, —NH— or —N(CH
3
)—;
R
9
and R
10
are independently selected from the group consisting of (C
1
-C
6
)alkyl, halogen, —NR
17
R
18
, —OH, —CF
3
, —OCH
3
, —O-acyl, —OCF
3
and —Si(CH
3
)
3
;
R
11
is R
9
, hydrogen, phenyl, —NO
2
, —CN, —CH
2
F, —CHF
2
, —CHO, —CH═NOR
17
, pyridyl, pyridyl N-oxide, pyrimidinyl, pyrazinyl, —N(R
17
)CONR
18
R
19
, —NHCONH(chloro-(C
1
-C
6
)alkyl), —NHCONH((C
3
-C
1
)cycloalkyl(C
1
-C
6
)alkyl), —NHCO(C
1
-C
6
)alkyl, —NHCOCF
3
, —NHSO
2
N((C
1
-C
6
)alkyl)
2
, —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
20
, —SOR
20
, —SO
2
R
20
, —SO
2
NH(C
1
-C
6
alkyl), —OSO
2
(C
1
-C
6
)alkyl, —OSO
2
CF
3
, hydroxy(C
1
-C
6
)alkyl, —CON R
17
R
18
, —CON(CH
2
CH
2
—O—CH
3
)
2
, —OCONH(C
1
-C
6
)alkyl, —CO
2
R
17
, —Si(CH
3
)
3
or —B(OC(CH
3
)
2
)
2
;
R
12
is (C
1
-C
6
)alkyl, —NH
2
or R
14
-phenyl;
R
14
is 1 to 3 substituents independently selected from the group consisting of hydrogen, (C
1
-C
6
)alkyl, —CF
3
, —CO
2
R
17
, —CN, (C
1
-C
6
)alkoxy and halogen;
R
15
and R
16
are independently selected from the group consisting of hydrogen and C
1
-C
6
alkyl, or R
15
and R
16
together are a C
2
-C
5
alkylene group and with the carbon to which they are attached form a spiro ring of 3 to 6 carbon atoms;
R
17
, R
18
and R
19
are independently selected from the group consisting of H and C
1
-C
6
alkyl; and
R
20
is C
1
-C
6
alkyl or phenyl.
Preferred are compounds of formula I wherein R is R
8
-phenyl or R
8
-naphthyl, especially wherein R
8
is a single substituent, and especially wherein the R
8
substituent is in the 4-position. For R
8
-phenyl, preferred R
8
substituents are —CF
3
, —OCF
3
, CH
3
SO
2
—, CH
3
CO—, CH
3
C(═NOCH
3
)—, Br and I. For R
8
-naphthyl, R
8
is preferably C
1
-C
6
alkoxy. Also preferred are compounds of formula I wherein R
3
is hydrogen, (C
1
-C
6
)alkyl, R
8
-phenyl. R
8
-benzyl or R
8
-pyridyl; more preferred definitions for R
3
are methyl, ethyl, phenyl, benzyl and pyridyl. R
1
is preferably hydrogen. For compounds of formula I, R
6
is preferably hydrogen or methyl, especially methyl. R
4
is preferably methyl; R
5
and R
7
are each preferably hydrogen.
In compounds of formula I, R
2
is preferably R
9
, R
10
, R
11
-phenyl, R
9
, R
10
, R
11
-pyridyl or an N-oxide thereof, or R
9
, R
10
, R
11
-pyrimidyl. When R
2
is pyridyl, it is preferably 3- or 4-pyridyl, and when pyrimidyl, it is preferably 5-pyrimidyl. The R
9
and R
10
substituents are preferably attached to carbon ring members adjacent to the carbon joining the ring to the rest of the molecule and the R
11
substituent can be attached to any of the remaining unsubstituted carbon ring members, for example as shown in the following structures:
Preferred R
9
and R
10
substituents are: (C
1
-C
6
)alkyl, especially methyl; halogen, especially chloro or bromo, —OH and —NH
2
. When R
2
is phenyl, R
11
is preferably hydrogen or —OH; when R
2
is pyridyl, R
11
is preferably hydrogen; and when R
2
is pyrimidyl, R
11
is preferably hydrogen, methyl or phenyl. Examples of particularly preferred R
2
groups are as follows:
Also claimed are novel CCR5 antagonist compounds represented by the structural formula II
or a pharmaceutically acceptable salt thereof, wherein
(1) R
a
is R
8a
-phenyl, R
8b
-pyridyl, R
8b
-thiophenyl o

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