Urotensin-II receptor antagonists

Details Urotensin-II receptor antagonists Urotensin-II receptor antagonists

2002-06-13

2003-04-08

Ramsuer, Robert W. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S141000, C544S372000, C546S208000, C546S224000, C548S517000, C548S518000, C548S523000, C548S526000, C548S557000

Reexamination Certificate

active

06544992

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates generally to pyrrolyl and pyridyl derivatives, pharmaceutical compositions containing them and their use as urotensin II antagonists.
BACKGROUND OF THE INVENTION
The integrated control of cardiovascular homeostasis is achieved through a combination of both direct neuronal control and systemic neurohormonal activation. Although the resultant release of both contractile and relaxant factors is normally under stringent regulation, an aberration in this status quo can result in cardiohemodynamic dysfunction with pathological consequences.
The principal mammalian vasoactive factors that comprise this neurohumoral axis, namely angiotensin-II, endothelin-1, norepinephrine, all function via an interaction with specific G-protein coupled receptors (GPCR). Urotensin-II, represents a novel member of this neurohumoral axis.
In the fish, this peptide has significant hemodynamic and endocrine actions in diverse end-organ systems and tissues:
smooth muscle contraction
both vascular and non-vascular in origin including smooth muscle preparations from the gastrointestinal tract and genitourinary tract. Both pressor and depressor activity has been described upon systemic administration of exogenous peptide
osmoregulation:
effects which include the modulation of transepithelial ion (Na
+
, Cl
−
) transport. Although a diuretic effect has been described, such an effect is postulated to be secondary to direct renovascular effects (elevated GFR)
metabolism:
urotensin-II influences prolactin secretion and exhibits a lipolytic effect in fish (activating triacylglycerol lipase resulting in the mobilization of non-esterified free fatty acids)
(Pearson, et. al.
Proc. Natl. Acad. Sci.
(
U.S.A.
) 1980, 77, 5021; Conlon, et. al.
J. Exp. Zool.
1996, 275, 226.)
In studies with human Urotensin-II it was found that it:
was an extremely potent and efficacious vasoconstrictor
exhibited sustained contractile activity that was extremely resistant to wash out
had detrimental effects on cardiac performance (myocardial contractility)
Human Urotensin-II was assessed for contractile activity in the rat-isolated aorta and was shown to be the most potent contractile agonist identified to date. Based on the in vitro pharmacology and in vivo hemodynamic profile of human Urotensin-II it plays a pathological role in cardiovascular diseases characterized by excessive or abnormal vasoconstriction and myocardial dysfunction. (Ames et. al.
Nature
1999, 401, 282)
Compounds that antagonize the Urotensin-II receptor may be useful in the treatment of congestive heart failure, stroke, ischemic heart disease (angina, myocardial ischemia), cardiac arrhythmia, hypertension (essential and pulmonary), COPD, restenosis, asthma, (Hay DWP, Luttmann Mass., Douglas SA: 2000, Br J Pharmacol: In press.) neurogenic inflammation and metabolic vasculopathies all of which are characterized by abnormal vasoconstriction and/or myocardial dysfunction. Since U-II and GPR14 are both expressed within the mammalian CNS (Ames et. al.
Nature
1999, 401, 282), they also may be useful in the treatment of addiction, schizophrenia, impulsivity, anxiety, stress, depression, and neuromuscular function. Functional U-II receptors are expressed in rhabdomyosarcomas cell lines and therefore may have oncological indications. Urotensin may also be implicated in various metabolic diseases such as diabetes (Ames et. al.
Nature
1999, 401, 282, Nothacker et al.,
Nature Cell Biology
1: 383-385, 1999)
SUMMARY OF THE INVENTION
In one aspect this invention provides for pyrrolyl and pyridyl derivatives, and pharmaceutical compositions containing them.
In a second aspect, this invention provides for the use of pyrrolyl and pyridyl derivatives as antagonists of urotensin II.
In another aspect, this invention provides for the use of pyrrolyl and pyridyl derivatives for treating conditions associated with urotensin II imbalance.
In an yet another aspect, this invention provides for the use of these pyrrolyl and pyridyl derivatives for the treatment of congestive heart failure, stroke, ischemic heart disease (angina, myocardial ischemia), cardiac arrhythmia, hypertension (essential and pulmonary), COPD, restenosis, asthma, neurogenic inflammation and metabolic vasculopathies, addiction, schizophrenia, impulsivity, anxiety, stress, depression, neuromuscular function, and diabetes.
The urotensin antagonist may be administered alone or in conjunction with one or more other therapeutic agents, said agents being selected from the group consisting of endothelin receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, vasopeptidase inhibitors, diuretics, digoxin, and dual non-selective &bgr;-adrenoceptor and &agr;
1
-adrenoceptor antagonists.
Other aspects and advantages of the present invention are described further in the following detailed description of the preferred embodiments thereof.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the invention are represented by structural Formula I:
wherein:
n is 1 or 2;
m is 1 or 2;
R1 is benzofuranyl, naphthyl or phenyl, substituted or unsubstituted with one or two halogen, methyl, trifluoromethyl, methoxy or methylenedioxy groups;
R2 is hydrogen, one or two halogens, methyl, methoxy, nitro or 2,3-(1,3-butadien-1,4-yl);
R3 is 3-dimethylaminopropyl, 2-(pyrrolidin-1-yl)ethyl, 2-(1-morpholino)ethyl, 2-(1-piperazinyl)ethyl, (1-methylpyrrolidin-2(S)-yl)methyl, 1-methylpyrrolidin:-3(±)-yl, 1-benzylpiperidin-4-yl, 2(S)-(aminocarbonyl)pyrrolidin-4(S)-yl, pyrrolidin-3(S)-yl, piperidin-4-yl, pyrrolidin-3(R)-yl, or cis-4-aminocyclohexyl;
or a pharmaceutically acceptable salt thereof.
When used herein, the terms ‘halogen’ and ‘halo’ include fluorine, chlorine, bromine and iodine and fluoro, chloro, bromo and iodo, respectively.
The compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active form. All of these compounds and their diastereoisomers are contemplated to be within the scope of the present invention.
R
1
is preferably phenyl substituted with one or two halogen, or methyl groups.
R
2
preferably is hydrogen, halogen, or methoxy.
R
3
preferably is, 2-(1-piperazinyl)ethyl, pyrrolidin-3(S)-yl, piperidin-4-yl, pyrrolidin-3(R)-yl, 1-methylpyrrolidin-3(±)-yl, or 3-dimethylaminopropyl.
Preferred Compounds are:
3,4-Dichloro-N-{(S)-1-[4-(3-dimethylamino-propoxy)-benzyl]-pyrrolidin-3-yl}-benzamide;
3,4-Dichloro-N-{(R)-1-[4-(3-dimethylamino-propoxy)-benzyl]-pyrrolidin-3-yl}-benzamide;
3,4-Dichloro-N-{1-[4-(3dimethylamino-propoxy)-benzyl]-piperidin-4-}-benzamide;
3,4-Dichloro-N-{(S)-1-[4-iodo-3-(2-piperazin-1-yl-ethoxy)-benzyl]-pyrrolidin-3-yl}-benzamide;
N-{(S)-1-[3-Bromo-4-(1-methyl-pyrrolidin-3-yloxy)-benzyl]-pyrrolidin-3-yl}-3,4-dichloro-benzamide;
4-Bromo-N-{(S)-1-[4-(3-dimethylamino-propoxy)-benzyl]-pyrrolidin-3-yl}-benzamide;
4-Bromo-N-{(R)-1-[4-(3-dimethylamino-propoxy)-benzyl]-pyrrolidin-3-yl}-benzamide;
3,4-Dichloro-N-{(S)-1-[3-(3-dimethylamino-propoxy)-4-iodo-benzyl]-pyrrolidin-3-yl}-benzamide;
3,4-Dichloro-N-{(S)-1-[3-chloro-4-(1-methyl-pyrrolidin-3-yloxy)-benzyl]-pyrrolidin-3-yl}-benzamide
3,4-Dichloro-N-{(S)-1-[2-methoxy-4-(2-piperazin-1-yl-ethoxy)-benzyl]-pyrrolidin-3-yl}-benzamide;
N-{(S)-1-[3-Bromo-4-(piperidin-4-yloxy)-benzyl]-pyrrolidin-3-yl}-3,4-dichloro-benzamide;
N-{(S)-1-[3-Bromo-4-((R)-pyrrolidin-3-yloxy)-benzyl]-pyrrolidin-3-yl}-3,4-dichloro-benzamide;
N-{(S)-1-[3-chloro-4-(piperidin-4-yloxy)-benzyl]-pyrrolidin-3-yl}3,4-dichloro-benzamide;
3,4-Dichloro-N-((S)-1-{2-[4-(piperidin-4-yloxy)-3-chlorophenyl]ethyl}-pyrrolidin-3-yl)-benzamide.
3,4-Dichloro-N-((S)-1-{2-[4-(piperidin-4-yloxy)-3-bromophenyl]-ethyl}-pyrrolidin-3-yl)-benzamide.
3,4-Dichloro-N-((S)-1-{2-&

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