Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-07-05
2004-06-15
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S341000, C514S406000, C514S407000, C546S211000, C546S275700, C548S376100, C548S370400
Reexamination Certificate
active
06750230
ABSTRACT:
This invention relates to the use of pyrazole derivatives in the manufacture of a reverse transcriptase inhibitor or modulator, to certain novel such pyrazole derivatives and to processes for the preparation of and compositions containing such novel derivatives.
The present pyrazole derivatives bind to the enzyme reverse transcriptase and are modulators, especially inhibitors thereof. Reverse transcriptase is implicated in the infectious lifecycle of HIV, and compounds which interfere with the function of this enzyme have shown utility in the treatment of conditions including AIDS. There is a constant need to provide new and better modulators, especially inhibitors, of HIV reverse transcriptase since the virus is able to mutate, becoming resistant to their effects.
The present pyrazole derivatives are useful in the treatment of a variety of disorders including those in which reverse transcriptase is implicated. Disorders of interest include those caused by Human Immunodificiency Virus (HIV) and genetically related retroviruses, such as Acquired Immune Deficiency Syndrome (AIDS).
European Patent Application EP 0 786 455 A1 discloses a class of imidazole compounds which inhibit the growth of HIV. A class of N-phenylpyrazoles which act as reverse transcriptase inhibitors are disclosed in
J. Med. Chem
., 2000, 43, 1034. Antiviral activity is ascribed to a class of N-(hydroxyethyl)pyrazole derivatives in U.S. Pat. No. 3,303,200.
According to the present invention there is provided the use of a compound of the formula
or a pharmaceutically acceptable salt or solvate thereof, wherein
either (i) R
1
is H, C
1
-C
6
alkyl, C
3
-C
7
cycloalkyl, phenyl, benzyl, halo, —CN, —OR
7
,
—OR
8
, —CO
2
R
5
, —CONR
5
R
5
, —OCONR
5
R
5
, —NR
5
CO
2
R
7
, —NR
5
—NR
5
, —NR
5
COR
5
,
NR
5
—CO—(C
1
-C
6
alkylene)—OR
5
, —NR
5
CONR
5
R
5
, —NR
5
SO
2
R
7
or R
8
, said C
1
-C
6
alkyl, C
3
-C
7
cycloalkyl, phenyl and benzyl being optionally substituted by halo, —CN,
—OR
5
, —OR
8
, —CO
2
R
5
, —CONR
5
R
5
, —OCONR
5
R
5
, —NR
5
CO
2
R
7
, —NR
5
R
5
, —NR
8
R
9
,
—NR
5
COR
5
, —NR
5
COR
6
, —NR
5
COR
8
, —SO
2
NR
5
R
5
, —NR
5
CONR
5
R
5
, —NR
5
SO
2
R
7
or R
6
, and
R
2
is H or —Y—Z,
or, (ii) R
1
and R
2
, when taken together, represent unbranched C
3
-C
4
alkylene, optionally wherein one methylene group of said C
3
-C
4
alkylene is replaced by an oxygen atom or a nitrogen atom, said nitrogen atom being optionally substituted by R
5
or R
8
;
Y is a direct bond or C
1
-C
3
alkylene;
Z is R
10
or, where Y is C
1
-C
3
alkylene, Z is —NR
5
COR
10
, —NR
5
CONR
5
R
10
,
—NR
5
CONR
5
COR
10
or —NR
5
SO
2
R
10
;
R
3
is H, C
1
-C
6
alkyl, C
3
-C
7
cycloalkyl, phenyl, benzyl, —CN, halo, —OR
7
, —CO
2
R
5
,
—CONR
5
R
5
, —OCONR
5
R
5
, —NR
5
CO
2
R
7
, —NR
5
R
5
, —NR
5
COR
5
, —NR
5
CONR
5
R
5
,
—NR
5
SO
2
R
7
or R
6
, said C
1
-C
6
alkyl, C
3
-C
7
cycloalkyl, phenyl and benzyl being optionally substituted by halo, —CN, —OR
5
, —CO
2
R
5
, —CONR
5
R
5
, —OCONR
5
R
5
,
—NR
5
CO
2
R
7
, —NR
5
R
5
, —NR
5
COR
5
, —SO
2
NR
5
R
5
, —NR
5
CONR
5
R
5
, —NR
5
SO
2
R
7
or R
6
;
R
4
is phenyl or pyridyl, each being optionally substituted by R
6
, halo, —CN, C
1
-C
6
alkyl, fluoro-(C
1
-C
6
)-alkyl, C
3
-C
7
cycloalkyl or C
1
-C
6
alkoxy;
each R
5
is independently either H, C
1
-C
6
alkyl, C
3
-C
7
cycloalkyl, fluoro-(C
1
-C
6
)-alkyl, phenyl or benzyl, or, when two such groups are attached to the same nitrogen atom, those two groups taken together with the nitrogen atom to which they are attached represent azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl or morpholinyl, said azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl and morpholinyl being optionally substituted by C
1
-C
6
alkyl or C
3
-C
7
cycloalkyl and said piperazinyl and homopiperazinyl being optionally substituted on the nitrogen atom not taken together with the two R
5
groups to form the ring by —COR
7
or —SO
2
R
7
;
R
6
is a four to six-membered, aromatic, partially unsaturated or saturated heterocyclic group containing (i) from 1 to 4 nitrogen heteroatom(s) or (ii) 1 or 2 nitrogen heteroatom(s) and 1 oxygen or 1 sulphur heteroatom or (iii) 1 or 2 oxygen or sulphur heteroatom(s), said heterocyclic group being optionally substituted by —OR
5
, —NR
5
R
5
, —CN, oxo, C
1
-C
6
alkyl, C
3
-C
7
cycloalkyl, —COR
7
or halo;
R
7
is C
1
-C
6
alkyl, C
3
-C
7
cycloalkyl, fluoro-(C
1
-C
6
)-alkyl, phenyl or benzyl;
R
8
is C
1
-C
6
alkyl substituted by phenyl, phenoxy, pyridyl or pyrimidinyl, said phenyl, phenoxy, pyridyl and pyrimidinyl being optionally substituted by halo,
—CN, —CONR
5
R
5
, —SO
2
NR
5
R
5
, —NR
5
SO
2
R
7
, —NR
5
R
5
, —(C
1
-C
6
alkylene)—NR
5
R
5
, C
1
-C
6
alkyl, fluoro-(C
1
-C
6
)-alkyl, C
3
-C
7
cycloalkyl or C
1
-C
6
alkoxy;
R
9
is H, C
1
-C
6
alkyl or C
3
-C
7
cycloalkyl, said C
1
-C
6
alkyl and C
3
-C
7
cycloalkyl being optionally substituted by —OR
5
, —NR
5
R
5
, —NR
5
COR
5
, —CONR
5
R
5
or R
6
;
R
10
is C
1
-C
6
alkyl, C
3
-C
6
alkenyl, C
3
-C
6
alkynyl, C
3
-C
7
cycloalkyl, phenyl, benzyl or C-linked R
6
, said C
1
-C
6
alkyl, C
3
-C
7
cycloalkyl, phenyl and benzyl being optionally substituted by halo, —OR
5
, —OR
12
, —CN, —CO
2
R
7
, —CONR
5
R
5
, —OCONR
5
R
5
,
—C(═NR
5
)NR
5
OR
5
, —CONR
5
NR
5
R
5
, —OCONR
5
CO
2
R
7
, —NR
5
R
5
, —NR
5
R
12
, —NR
5
COR
5
,
—NR
5
CO
2
R
7
, —NR
5
CONR
5
R
5
, —NR
5
COCONR
5
R
5
, —NR
5
SO
2
R
7
, —SO
2
NR
5
R
5
or R
6
;
X is —CH
2
—, —CHR
11
—, —CO—, —S—, —SO— or —SO
2
—;
R
11
is C
1
-C
6
alkyl, C
3
-C
7
cycloalkyl, fluoro-(C
1
-C
6
)-alkyl or C
1
-C
6
alkoxy; and
R
12
is C
1
-C
6
alkyl substituted by R
6
, —OR
5
, —CONR
5
R
5
, —NR
5
COR
5
or —NR
5
R
5
;
in the manufacture of (a) a reverse transcriptase inhibitor or modulator or (b) a medicament for the treatment of a human immunodeficiency viral (HIV), or genetically related retroviral, infection or a resulting acquired immunodeficiency syndrome (AIDS).
The present invention also provides a novel compound of the formula
or a pharmaceutically acceptable salt or solvate thereof, wherein
either (i) R
1
is H, C
1
-C
6
alkyl, C
3
-C
7
cycloalkyl, phenyl, benzyl, halo, —CN, —OR
7
, —CO
2
R
5
, —CONR
5
R
5
, —OCONR
5
R
5
, —NR
5
CO
2
R
7
, —NR
5
R
5
, —NR
5
COR
5
, —NR
5
CO—(C
1
-C
6
alkylene)-OR
5
, —NR
5
CONR
5
R
5
, —NR
5
SO
2
R
7
or R
6
, said C
1
-C
6
alkyl, C
3
-C
7
cycloalkyl, phenyl and benzyl being optionally substituted by halo, —CN, —OR
5
, —OR
8
, —CO
2
R
5
, —CONR
5
R
5
, —OCONR
5
R
5
, —NR
5
CO
2
R
7
, —NR
5
R
5
, —NR
8
R
9
, —NR
5
COR
5
, —NR
5
COR
6
, —NR
5
COR
8
, —SO
2
NR
5
R
5
, —NR
5
CONR
5
R
5
, —NR
5
SO
2
R
7
or R
6
and
R
2
is —Y—Z,
or, R
1
and R
2
, when taken together, represent unbranched C
3
-C
4
alkylene, optionally wherein one methylene group of said C
3
-C
4
alkylene is replaced by an oxygen atom or a nitrogen atom, said nitrogen atom being optionally substituted by R
5
or R
8
,
and R
3
is H, C
1
-C
6
alkyl, C
3
-C
7
cycloalkyl, phenyl, benzyl, —CN, halo, —OR
7
, —CO
2
R
5
, —CONR
5
R
5
, —OCONR
5
R
5
, —NR
5
CO
2
R
7
, —NR
5
R
5
, —NR
5
COR
5
, —NR
5
CONR
5
R
5
, —NR
5
SO
2
NR
7
or R
6
, said C
1
-C
6
alkyl, C
3
-C
7
cycloalkyl, phenyl and benzyl being optionally substituted by halo, —CN, —OR
5
, —CO
2
R
5
, —CONR
5
R
5
, —OCONR
5
R
5
, —NR
5
CO
2
R
7
, —NR
5
R
5
, —NR
5
COR
5
, —SO
2
NR
5
R
5
, —NR
5
CONR
5
R
5
, —NR
5
SO
2
R
7
or R
6
,
or (ii) R
1
and R
3
are each independently C
1
-C
6
alkyl, C
3
-C
7
cycloalkyl or halo-(C
1
-C
6
alkyl), and R
2
is H,
provided that
(a) for definition (i), R
1
and R
3
are not both H,
(b) for definition (i), R
1
and R
3
are not both optionally substituted phenyl, as defined therein,
(c) for definition (i), when R
1
and R
3
are both methyl, R
2
is not phenyl or methyl, and
(d) for definition (ii), R
1
and R
3
are not both methyl;
Y is a direct bond or C
1
-C
3
alkylene;
Z is R
10
or, where Y is C
1
-C
3
alkylene, Z is —NR
5
COR
10
, —NR
5
CONR
5
R
10
,
—NR
5
CONR
5
COR
10
or —NR
5
SO
2
R
10
;
R
4
is phenyl or
Corbau Romuald Gaston
Mowbray Charles Eric
Perros Manoussos
Stupple Paul Anthony
Wood Anthony
Hutchinson Keith D.
McKane Joseph K.
Pfizer Inc.
Richardson Peter C.
Saeed Kamal
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