Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-03-05
2004-08-17
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...
C548S451000
Reexamination Certificate
active
06777437
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to cyclopropylindole derivatives and pharmaceutical compositions comprising said derivatives useful for the treatment of various psychiatric disorders and premature ejaculation.
BACKGROUND OF THE INVENTION
Selective serotonin reuptake inhibitors (SSRIs) are effective for the treatment of mental depression and have been reported to be useful for treating chronic pain. See R. W. Fuller, Pharmacologic Modification of Serotonergic Function: Drugs for the Study and Treatment of Psychiatric and Other Disorders,”
J. Clin. Psychiatry,
47:4 (Suppl.) April 1986, pp. 4-8 and Selective Serotonin Reuptake Inhibitors. Edited by J P Feighner and W F Boyer, Chichester, England. John Wiley & Sons, 1991, pp 89-108. SSRI's have also demonstrated efficacy for the treatment of anxiety disorders. More recently, SSRI's have demonstrated efficacy in the treatment of premature ejaculation. See Kim and Paick, Short-term Analysis of the Effects of As Needed Use of Sertraline at 5 pm for the Treatment of Premature Ejaculation,
Urology
54:544-547 (1999); Kim and Paick, Self Therapy with Sertraline given PRN at 5 pm in treatment of Premature Ejaculation,
Journal of Urology
54:544-547 (1998); McMahon and Touma, Treatment of Premature Ejaculation with Paroxetine Hydrochloride As Needed: 2 Single-Blind Placebo Controlled Crossover Studies
Journal of Urology
161:1826-1830 (1999); Haensal et al., Clomipramine and sexual function in men with premature ejaculation and controls
Journal of Urology
158:1310-1315 (1998); and McMahon and Touma, Treatment of Premature Ejaculation with Paraoxetine Hydrochloride
International Journal Impotence Research
11:241-246 (1999). Thus novel SSRI's effective for the treatment of these and other disorders would be greatly advantageous.
SUMMARY OF THE INVENTION
Thus according to a first embodiment of a first aspect of the present invention are provided compounds of Formula (I)
and pharmaceutically acceptable salts or solvates thereof
wherein
A
1
and A
2
are each independently C
1-4
alkylene or a bond;
A
3
is C
1-4
alkylene or C
1-4
alkylidene;
A
4
is C
1-4
alkylene or a bond and is attached to X, X
1
or X
2
;
X, X
1
, X
2
and X
3
are independently C or CH;
J is C
1-4
alkyl;
p is 0 or 1;
R
1
and R
2
are independently H, C
1-3
alkyl, C
3-6
cycloalkyl, phenyl, —O-phenyl, —N(H)C(O)O—C
1-4
alkyl or C
1-4
alkyl-N(H)C(O)O—;
said C
3-6
cycloalkyl, phenyl or O-phenyl being independently and optionally substituted with C
1-4
alkyl, C
1-3
alkoxy or halo;
or are independently selected from the group of heterocyclic moieties consisting of thienyl, furanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridyl, pyrimidinyl, piperidinyl, piperazinyl, morpholino, adamantyl, indolyl, isoindolyl, indolinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl and tetrahydroisoquinolinyl, wherein said heterocyclic moieties are optionally substituted with halo, C
1-4
alkyl, C
1-4
alkoxy or cyano;
or wherein —A
1
—R
1
and —A
2
—R
2
together with the nitrogen to which they are attached form pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridyl, pyrimidinyl, piperidinyl, piperazinyl, morpholino, adamantyl, indolyl, isoindolyl, indolinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl or tetrahydroisoquinolinyl and are optionally substituted with halo, C
1-4
alkyl, C
1-4
alkoxy, cyano or benzyl;
R
3
is H or C
1-4
alkyl;
m is 0 or 1;
R
4
and R
5
are independently hydrogen, cyano, halo, nitro or C
1-3
perfluoroalkyl;
wherein said R
4
or R
5
may be independently attached to X, X
1
, X
2
or X
3
;
n is 0 or 1;
G is N, O or S;
G
1
is N or CH;
Y is (D)H wherein D is C; and
Z is (E)H wherein E is C;
provided that
both R
4
and R
5
are not attached to the same of said X, X
1
, X
2
or X
3
;
if G is O or S, then m is 0;
if G is N, then m is 1;
if R
1
is —N(H)C(O)O—C
1-4
alkyl, C
1-4
alkyl-N(H)C(O)O— or said heterocyclic moiety wherein said heterocyclic moiety contains a nitrogen atom and said nitrogen atom is attached to A
1
, then A
1
is C
2-4
alkylene;
if R
2
is —N(H)C(O)O—C
1-4
alkyl, C
1-4
alkyl-N(H)C(O)O— or said heterocyclic moiety wherein said heterocyclic moiety contains a nitrogen atom and said nitrogen atom is attached to A
2
, then A
2
is C
2-4
alkylene;
if R
1
is N(H)C(O)O—C
1-4
alkyl, C
1-4
alkyl-N(H)C(O)O— or a heterocyclic moiety selected from the group consisting of thienyl, furanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridyl, pyrimidinyl, piperidinyl, piperazinyl, morpholino, adamantyl, indolyl, isoindolyl, indolinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl and tetrahydroisoquinolinyl, wherein said heterocyclic moieties are optionally substituted with halo, C
1-4
alkyl, C
1-4
alkoxy or cyano, then R
2
is H or C
1-3
alkyl;
if R
2
is —N(H)C(O)O—C
1-4
alkyl, C
1-4
alkyl-N(H)C(O)O— or a heterocyclic moiety selected from the group consisting of thienyl, furanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridyl, pyrimidinyl, piperidinyl, piperazinyl, morpholino, adamantyl, indolyl, isoindolyl, indolinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl and tetrahydroisoquinolinyl, wherein said heterocyclic moieties are optionally substituted with halo, C
1-4
alkyl, C
1-4
alkoxy or cyano, then R
1
is H or C
1-3
alkyl;
if A
4
, R
4
or R
5
are attached to X, then X is C;
if A
4
, R
4
or R
5
are attached to X
1
, then X
1
is C;
if A
4
, R
4
or R
5
are attached to X
2
, then X
2
is C;
if R
4
or R
5
are attached to X
3
, then X
3
is C;
if R
4
is F and is attached to X and if A
3
is methylene, then —A
1
—R
1
and —A
2
—R
2
together with the nitrogen to which they are attached is not N-methyl-piperazinyl; and
if R
4
is F and is attached to X and if A
3
is methylene, then —A
1
—R
1
and —A
2
—R
2
together with the nitrogen to which they are attached is not tetrahydroquinolinyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein p is 0.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein G is N and G
1
is CH.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein G is S and G
1
is CH.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein G is N and G
1
is N.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein G is S and G
1
is N.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein G is O and G
1
is N.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R
1
is methyl and R
2
is methyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein A
1
is a bond, R
1
is methyl, A
2
is a bond and R
2
is methyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of
Catt John D.
Denhart Derek John
Deskus Jeffrey A.
Ditta Jonathan L.
Epperson James R.
Bristol--Myers Squibb Company
Makujina Shah R.
McKane Joseph K.
Saeed Kamal
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