Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-03-08
2002-04-23
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S259500, C544S279000, C544S284000, C544S287000
Reexamination Certificate
active
06376500
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to substituted 2-(4-piperidyl)-4(3H)-quinazolinone and 2-(4-piperidyl)-4(3H)-azaquinazolinone derivatives, associated pharmaceutically acceptable salts, hydrates and N-oxides thereof, associated pharmaceutical compositions, and methods for use as alpha
1A/B
-adrenergic receptor (alpha
1A/B
-adrenoceptor) antagonists.
BACKGROUND OF THE INVENTION
Alpha1-adrenergic receptors are G-protein coupled transmembrane receptors that mediate various actions of the sympathetic nervous system through the binding of the catecholamines, epinephrine and norepinephrine. Currently, several subtypes of the alpha
1
-adrenergic receptors are known to exist for which the genes have been cloned: alpha
1A
(previously known as alpha
1C
), alpha
1B
and alpha
1D
. The existence of an additional subtype, the alpha
1L
-adrenergic receptor subtype, has been proposed; however, the gene for the alpha
1L
-adrenergic receptor subtype has yet to be cloned.
Alpha1-adrenoceptor antagonists have been shown in numerous clinical studies to be effective in relieving the symptoms associated with benign prostatic hypertrophy (BPH). However, these compounds are all non-subtype-selective, and have the potential to cause significant side-effects, particularly cardiovascular effects such as postural hypotension, and CNS effects including aesthenia (tiredness). These effects can limit dosing, and thus clinical efficacy in reducing symptoms associated with BPH.
Pharmacological studies resulting in the subdivision of alpha
1
-adrenoceptors into alpha
1A
-, alpha
1B
- and alpha
1D
-adrenoceptors have led to the suggestion that development of subtype-selective antagonists may allow improved symptomatic treatment of BPH/unstable bladder with a lower incidence of dose-limiting side-effects. An alpha
1A
-subtype-selective antagonist may, via a selective and significant decrease in outlet resistance, lead to improved pharmacotherapy for BPH. However, it must be noted that in BPH, it is often the irritative symptoms which prompt the patient to seek treatment, and that these irritative symptoms may be present even in patients with no demonstrable obstruction (i.e. normal urine flow rates). By combining both alpha
1A
- and alpha
1B
-subtype-selectivity in a drug molecule, a reduction of both obstructive and irritative symptoms in patients with BPH may be achieved. Lower levels or lack of alpha
1D
-adrenoceptor antagonism should lead to reduced or fewer side effects than those associated with the use of non-subtype-selective agents.
All publications, patents, and patent applications cited herein, whether supra or infra, are each hereby incorporated by reference in its entirety.
DESCRIPTION OF THE RELATED ART
U.S. application No. 60/124,721 assigned to Syntex (U.S.A.) Inc. refers to certain methods for screening compounds to identify certain alpha
1B
-adrenergic receptor ligands that bind to the alpha
1B
-adrenergic receptor to provide an analgesic effect.
U.S. Pat. No. 4,522,945 assigned to Janssen Pharm. refers to certain (piperdinylalkyl)-quinazoline derivatives as serotonin antagonists.
U.S. Pat. No. 5,196,425 and U.S. Pat. No. 5,321,028 assigned to Janssen Pharm. refer to certain antihypertensive 3-piperidinyl-indazole derivatives as antagonists of neurotransmitters.
PCT published application WO 9401437 assigned to Janssen Pharm. refers to certain benzofuranyl and benzothienyl piperidinyl derivatives as antidopaminergic agents.
Japanese patent application JP 08027149 assigned to Meiji Seika Kaisha Ltd. refers to certain fused pyrimidinone derivatives useful as antipsychotic drugs.
Hori et al., Chem. Pharm.Bull. 1991, 39(2), 367-371, refer to certain 4-alkoxy-2-(1-piperazinyl)quinazoline derivatives useful as nootropic agents.
Teng et al., European Journal of Pharmacology 1994, 265, 61-66, refer to certain functional identification of alpha
1
-adrenoceptor subtypes in human prostate.
Nishi et al., Urologia Internationalis 1998, 61, 147-153, refer to certain properties of alpha-1 adrenergic receptors in the rat prostate.
Nishi et al., Journal of Urology 1998, 160, 196-205, refer to certain characterization, localization and distribution of alpha
1
-adrenoceptor subtype in male rabbit urethra.
Yang et al, Journal of Pharmacology and Experimental Therapeutics 1998, 286(2), 841-847, refer to certain murine alpha
1
-adrenoceptor subtypes.
Hanft et al, British Journal of Pharmacology 1989, 97, 691-700, refer to certain subclassification of alpha
1
-adrenoceptor recognition sites by urapidil derivatives and other selective antagonists.
Faure et al., Life Sciences 1994, 54 (21), 1595-1605, refer to certain identification of alpha
1
-adrenoceptor subtypes present in the human prostate.
Furuya et al., Journal of Urology 1982, 128, 836-839, refer to certain alpha-adrenergic activity and urethral pressure in prostatic zone in benign prostatic hypertrophy.
Hatano etal., Br. J. Pharmacol. 1994, 113, 723-728, refer to certain pharmacological evidence of distinct alpha
1
-adrenoceptor subtypes mediating the contraction of human prostatic urethra and peripheral artery.
Taniguchi et al., Archives of Pharmacology 1997, 355, 412-416, refer to certain identification of alpha
1
-adrenoceptor subtypes in the human prostatic urethra.
Price et al., Journal of Urology 1993, 150, 546-551, refer to certain identification, quantification, and localization of mRNA for three distinct alpha
1
-adrenergic receptor subtypes in human prostate.
Marshall et al., Br. Journal of Pharmacology 1995, 5, 781-786, refer to certain noradrenaline contractions of human prostate mediated by alpha
1A
-(
1C
-) adrenoceptor subtype.
SUMMARY OF THE INVENTION
This invention relates to compounds comprising Formula I:
wherein:
A—B is independently in each occurrence NH—C, NH—N , O—C, or S—C;
Z is a benzene or a pyridine ring;
R
1
, R
2
, R
3
, and R
4
are each independently in each occurrence hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, trifluoromethyl, CO—NR′R″, NR′R″, or NR′—CO—NR′R″;
R′ and R″ are each independently in each occurrence hydrogen or lower alkyl;
m is an integer ranging from 0 to 3 inclusive;
n is an integer ranging from 1 to 6 inclusive; or pharmaceutically acceptable salts, hydrates or N-oxides thereof.
In a more preferred embodiment, m is 0. More preferably m is 0 and n is 2.
In another preferred embodiment, R
1
, R
2
, R
3
, and R
4
are each independently in each occurrence hydrogen, halogen, or lower alkoxy.
In another preferred embodiment Z is a benzene ring.
In another preferred embodiment Z is a pyridine ring.
In a preferred embodiment the compound is 2-{1-[2-(1H-indol-3-yl)-ethyl]-piperidin-4-yl-3H-quinazolin-4-one; 6-chloro-2-{1-[2-(1H-indol-3-yl)-ethyl]-piperidin-4-yl}-3H-quinazolin-4-one; 7-chloro-2-(1-[2-(1H-indol-3-yl)-ethyl]-piperidin-4-yl}-3H-quinazolin-4-one; 7-fluoro-2-{1-[2-(1H-indol-3-yl)-ethyl]-piperidin-4-yl}-3H-quinazolin 4-one; 6,7-difluoro-2-{1-[2-(1H-indol-3-yl)-ethyl]-piperidin-4-yl}-3H-quinazolin-4-one; 2-{1-[2-(6-fluoro-1H-indol-3-yl)-ethyl]-piperidin-4-yl}-3H-quinazolin-4-one; 5-chloro-2-{1-[2-(6-fluoro-1H-indol-3-yl)-ethyl]-piperidin-4-yl}-3H-quinazolin-4-one; 6-chloro-2-{1-[2-(6-fluoro-1H-indol-3-yl)-ethyl]-piperidin-4-yl}-3H-quinazolin-4-one; 7-chloro-2-{1-[2-(6-fluoro-1H-indol-3-yl)-ethyl]-piperidin-4-yl}-3H-quinazolin-4-one; 5-fluoro-2-{1-[2-(6-fluoro-1H-indol-3-yl)-ethyl]-piperidin-4-yl}-3H-quinazolin-4-one; 6-fluoro-2-{1-[2-(6-fluoro-1H-indol-3-yl)-ethyl]-piperidin-4-yl}-3H-quinazolin-4-one; 7-fluoro-2-{1-[2-(6-fluoro-1H-indol -3-yl)-ethyl]-piperidin-4-yl}-3H-quinazolin-4-one; 6,7-difluoro-2-{1-[2-(6-fluoro-1H-indol-3-yl)-ethyl]-piperidin-4-yl}-3H-quinazolin-4-one; 2-{1-[2-(6-fluoro-1H-indol-3-yl)-ethyl]-piperidin-4-yl}-3H-quinazolin-4-
Clark Robin Douglas
O'Yang Counde
Pfister Gloria
Shah Mukund J.
Syntex (U.S.A.) LLC
Truong Tamthom N.
LandOfFree
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