Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-03-27
2004-02-10
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252110, C514S252130, C544S357000, C544S360000, C544S364000, C544S295000
Reexamination Certificate
active
06689783
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to aryl oxime-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 CCR5 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.
BACKGROUND OF THE INVENTION
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.
CCR5 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.
A-M. Vandamme et al.,
Antiviral Chemistry & Chemotherapy,
9:187 (1998) 203 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
In its many embodiments, the present invention provides a novel class of compounds as antagonists of the CCR5 receptor, methods of preparing such compounds, pharmaceutical compositions containing one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention or amelioration of one or more diseases associated with the CCR5 receptor. In one embodiment, the present application discloses a compound, including enantiomers, stereoisomers, rotamers, tautomers, racemates and prodrug of said compound, and pharmaceutically acceptable salts or solvates of said compound or of said prodrug, said compound having the general structure shown in formula I:
wherein:
X is-selected from the group consisting of H; F; Cl; Br; I; —CF
3
; —CF
3
O; —CN; CH
3
SO
2
—; and CF
3
SO
2
—;
R
1
is H; straight chain alkyl or a branched alkyl; fluoro-C
1
-C
6
alkyl; a C
1
-C
6
alkylene carrying a C
3
-C
7
cycloalkyl (for example, 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
2
is H; a C
1
-C
6
straight chain alkyl or a branched alkyl; or a C
2
-C
6
alkenyl;
R
3
is a C
1
-C
6
straight chain alkyl or branched alkyl; phenyl substituted with R
4
, R
5
, R
6
; 6-membered heteroaryl substituted with R
4
, R
5
, R
6
; 6-membered heteroaryl N-oxide substituted with R
4
, R
5
, R
6
; 5-membered heteroaryl substituted with R
7
, R
8
; naphthyl; fluorenyl; diphenylmethyl;
R
4
and R
5
may be the same or different and are independently selected from the group consisting of (C
1
-C
6
)alkyl, halogen, —NR
12
R
13
, —OH, —CF
3
,—OCH
3
, —O-acyl, —OCF
3
and —Si(CH
3
)
3
;
R
6
is R
4
; hydrogen; phenyl; —NO
2
; —CN; —CH
2
F; —CHF
2
; —CHO; —CH═NOR
12
; pyridyl; pyridyl N-oxide; pyrimidinyl; pyrazinyl; —N(R
12
)CONR
13
R
14
; —N HCONH(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
; —N HCO
2
(C
1
-C
6
)alkyl); C
3
-C
10
cycloalkyl; —SR
15
; —SOR
15
; —SO
2
R
15
; —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
12
R
13
; —CON(CH
2
CH
2
—O—CH
3
)
2
; —OCONH(C
1
-C
6
)alkyl; —CO
2
R
2
; —Si(CH
3
)
3
or —B(OC(CH
3
)
2
)
2
;
R
7
is (C
1
-C
6
)alkyl, —NH
2
or R
9
-phenyl;
R
9
is 1 to 3 substituents which may be the same or different and are independently selected from the group consisting of hydrogen, (C
1
-C
6
) alkyl, —CF
3
, —CO
2
R
12
, —CN, (C
1
-C
6
)alkoxy and halogen;
R
10
and R
11
may be the same or different and are independently selected from the group consisting of hydrogen and C
1
-C
6
alkyl, or R
10
and R
11
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
12
, R
13
and R
14
may be the same or different and are independently selected from the group consisting of H and C
1
-C
6
alkyl; and
R
15
is C
1
-C
6
alkyl or phenyl.
Preferred are compounds of formula I wherein R
1
is a C
1
-C
6
straight chain alkyl or branched alkyl, with methyl and ethyl being more preferred moieties for R
1
.
Preferred moieties for X are: halogen, —CF
3
and —CF
3
O.
Preferred definition for R
2
is a C
1
-C
6
straight chain alkyl or branched alkyl, with methyl being more preferred.
Preferred definitions for R
3
is 2,6-dialkylaryl or 2,6-dialkylheteroaryl, with the more preferred moieties for R
3
being:
and N-oxides thereof.
Another aspect of the invention is a pharmaceutical composition for treatment of HIV comprising an effective amount of a CCR5 antagonist of formula I in combination with a pharmaceutically acceptable carrier.
One more 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 a CCR5 antagonist of formula I in combination with a pharmaceutically acceptable carrier.
Yet another aspect of this invention is a method of treatment of HIV comprising administering to a human in need of such treatment an effective amount of a CCR5 antagonist compound of formula I.
Another aspect of the invention is a method of 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 administering to a human in need of such treatment an effective amount of a CCR5 antagonist compound of formula I.
Still another aspect of this invention is the use of a CCR5 antagonist of formula I of this invention in combination with one or more antiviral or other agent
Clader John W.
Lin Sue-Ing Y.
Mc Combie Stuart W.
Pushpavanam Pradeep B.
Vice Susan
Bernhardt Emily
Kalyanaraman Palaiyur S.
Schering Corporation
LandOfFree
Aryl oxime-piperazines useful as CCR5 antagonists does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Aryl oxime-piperazines useful as CCR5 antagonists, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Aryl oxime-piperazines useful as CCR5 antagonists will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3339710