Pegylated interferon alfa-CCR5 antagonist combination HIV...

Details Pegylated interferon alfa-CCR5 antagonist combination HIV... Pegylated interferon alfa-CCR5 antagonist combination HIV...

2000-05-01

2003-10-21

Padmanabhan, Sreeni (Department: 1617)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S252180, C514S253010, C514S253110, C514S253100, C514S253090, C514S340000, C424S085700

Reexamination Certificate

active

06635646

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to methods of treating patients having immunodeficiency virus type-1 (“HIV-1”) infections by administering a therapeutically effective amount of pegylated interferon-alfa in association with a therapeutically effective amount of a CCR5 antagonist sufficient to lower HIV-1-RNA.
The global health crisis caused by Human Immunodeficiency Virus-1 (“HIV-1”), 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 the use of small molecules which are CCR5 antagonists in assoiation with pegylated interferon-alfa to treat patients having HIV-1 infections.
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 provides a method of treating patients having HIV-1 infections which comprises administering a therapeutically effective amount of pegylated interferon-alfa in association with a therapeutically effective amount of a CCR5 antagonist sufficient to lower HIV-1-RNA plasma levels.
The present invention also provides a method of treating patients having HIV-1 infections which comprises administering a therapeutically effective amount of pegylated interferon-alfa in association with a therapeutically effective amount of a CCR5 antagonist represented by the structural formula I or II or III or IV
or a pharmaceutically acceptable salt of I or II or III or IV, sufficient to lower HIV-1-RNA plasma levels;
wherein in the CCR5 antagonist compounds represented by structural formula I:
X is —C(R
13
)
2
—, —C(R
13
)(R
19
)—, —C(O)—, —O—, —NH—, —N((C
1
-C
6
)alkyl)-,
R is R
6
-phenyl, R
6
-pyridyl, R
6
-thiophenyl or R
6
-naphthyl;
R
1
is hydrogen, C
1
-C
6
alkyl or C
2
-C
6
alkenyl;
R
2
is R
7
, R
8
, R
9
-phenyl; R
7
, R
8
, R
9
-substituted 6-membered heteroaryl;
R
7
, R
8
, R
9
-substituted 6-membered heteroaryl N-oxide;
R
10
, R
11
-substituted 5-membered heteroaryl; naphthyl; fluorenyl; diphenylmethyl
 or
R
3
is R
6
-phenyl, R
6
-heteroaryl or R
6
-naphthyl;
R
4
is hydrogen, C
1
-C
6
alkyl, fluoro-C
1
-C
6
alkyl, cyclopropylmethyl, —CH
2
CH
2
OH, —CH
2
CH
2
—O—(C
1
-C
6
)alkyl, —CH
2
C(O)—O—(C
1
-C
6
)alkyl, —CH
2
C(O)NH
2
, —CH
2
C(O)—NH(C
1
-C
6
)alkyl or —CH
2
C(O)—N((C
1
-C
6
)alkyl)
2
;
R
5
and R
11
are independently selected from the group consisting of hydrogen and (C
1
-C
6
)-alkyl;
R
6
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
7
and R
8
are independently selected from the group consisting of (C
1
-C
6
)alkyl, halogen, —NR
20
R
21
, —OH, —CF
3
, —OCH
3
, —O-acyl, and —OCF
3
;
R
9
is R
7
, hydrogen, phenyl, —NO
2
, —CN, —CH
2
F, —CHF
2
, —CHO, —CH═NOR
20
, pyridyl, pyridyl N-oxide, pyrimidinyl, pyrazinyl, —N(R
20
)CONR
21
R
22
, —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((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
23
, —SOR
23
, —SO
2
R
23
, —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
20
R
21
, —CON(CH
2
CH
2
—O—CH
3
)
2
, —OCONH(C
1
-C
6
)alkyl, —CO
2
R
20
, —Si(CH
3
)
3
or —B(OC(CH
3
)
2
)
2
;
R
10
is (C
1
-C
6
)alkyl, —NH
2
or R
12
-phenyl;
R
12
is 1 to 3 substituents independently selected from the group consisting of hydrogen, (C
1
-C
6
) alkyl, —CF
3
, —CO
2
R
20
, —CN, (C
1
-C
6
)alkoxy and halogen;
R
13
, R
14
, R
15
and R
16
are independently selected from the group consisting of hydrogen and (C
1
-C
6
)alkyl;
R
17
and R
18
are independently selected from the group consisting of hydrogen and C
1
-C
6
alkyl, or R
17
and R
18
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
19
is R
6
-phenyl, R
6
-heteroaryl, R
6
-naphthyl, C
3
-C
10
cycloalkyl, (C
3
-C
10
)cycloalkyl(C
1
-C
6
)alkyl or (C
1
-C
6
)alkoxy(C
1
-C
6
)alkyl;
R
20
, R
21
and R
22
are independently selected from the group consisting of H and C
1
-C
6
alkyl; and
R
23
is C
1
-C
6
alkyl or phenyl;
and wherein in the CCR5 antagonist compounds represented by the structural formula II:
or a pharmaceutically acceptable salt thereof, wherein
(1)
X
a
is —C(R
13
)
2
—, —C(R
13
)(R
19
)—, —C(O)—, —O—, —NH—, —N((C
1
-C
6
)alkyl)-,
R
a
is R
6a
-phenyl, R
6a
-pyridyl, R
6a
-thiophenyl or R
6
-naphthyl;
R
1
is hydrogen, C
1
-C
6
alkyl or C
2
-C
6
alkenyl;
R
2
is R
7
, R
8
, R
9
-phenyl; R
7
, R
8
, R
9
-substituted 6-membered heteroaryl;
R
7
, R
8
, R
9
-substituted 6-membered heteroaryl N-oxide;
R
10
, R
11
-substituted 5-membered heteroaryl; naphthyl; fluorenyl; diphenylmethyl
 or
 R
3
is R
10
-phenyl, pyridyl, pyrimidyl, pyrazinyl or thiazolyl;
R
4
is hydrogen, C
1
-C
6
alkyl, fluoro-C
1
-C
6
alkyl, cyclopropylmethyl, —CH
2
CH
2
OH, —CH
2
CH
2
—O—(C
1
-C
6
)alkyl, —CH
2
C(O)—O—(C
1
-C
6
)alkyl, —CH
2
C(O)NH
2
, —CH
2
C(O)—NH(C
1
-C
6
)alkyl or —CH
2
C(O)—N((C
1
-C
6
)alkyl)
2
;
R
5
and R
11
are independently selected from the group consisting of hydrogen and (C
1
-C
6
)-alkyl;
R
6a
is 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, —CF
3
, CF
3
O—, —CN, —CF
3
SO
2
—, R
12
-phenyl, —NHCOCF
3
, 5-membered heteroaryl and
 wherein X is —O—, —NH— or —N(CH
3
)—;
R
6
is independently selected from the group consisting of R
6a
and CH
3
SO
2
—;
R
7
and R
8
are independently selected from the group consisting of (C
1
-C
6
)alkyl, halogen, —NR
20
R
21
, —OH, —CF
3
, —OCH
3
, —O-acyl, and —OCF
3
;
R
9
is R
7
, hydrogen, phenyl, —NO
2
, —CN, —CH
2
F, —CHF
2
, —CHO, —CH═NOR
20
, pyridyl, pyridyl N-oxide, pyrimidinyl, pyrazinyl, —N(R
20
)CONR
21
R
22
, —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((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
23
, —SOR
23
, —SO
2
R
23
, —SO
2
NH(C
1
-C
6
alkyl), —OSO
2
(C
1

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