Substituted-phenyl ketone derivatives as IP antagonists

Details Substituted-phenyl ketone derivatives as IP antagonists Substituted-phenyl ketone derivatives as IP antagonists

2001-11-13

2002-07-09

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S139000, C544S366000, C548S333100, C514S401000, C514S254050

Reexamination Certificate

active

06417186

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to certain substituted-phenyl ketone derivatives as prostaglandin I
2
(IP) receptor antagonists, and associated pharmaceutical compositions containing them, and methods for their use as therapeutic agents.
2. Background of the Invention
Prostaglandins or prostanoids (PG's) are a group of bioactive compounds derived from membrane phospholipids and are formed from 20-carbon essential fatty acids containing three, four, or five double bonds, and a cyclopentane ring. They fall into several main classes designated by the letters D, E, F, G, H, or I, and are distinguished by substitutions to the cyclopentane ring. The main classes are further subdivided by subscripts 1, 2, or 3, which reflect their fatty acid precursors. Thus, PGI
2
has a double ring structure, and the subscript 2 indicates that it is related to arachidonic acid.
PGI
2
(also known as prostacyclin) acts on platelets and blood vessels to inhibit aggregation and to cause vasodilation, and is thought to be important for vascular homeostasis. It has been suggested that PGI
2
may contribute to the antithrombogenic properties of the intact vascular wall. PGI
2
is also thought to be a physiological modulator of vascular tone that functions to oppose the actions of vasoconstrictors. The importance of these vascular actions is emphasized by the participation of PGI
2
in the hypotension associated with septic shock. Although prostaglandins do not appear to have direct effects on vascular permeability, PGI
2
markedly enhances edema formation and leukocyte infiltration by promoting blood flow in the inflamed region. Therefore, IP receptor antagonists may relieve hypotension related to septic shock, may reduce edema formation, and may prevent conditions associated with excessive bleeding such as, but not limited to, hemophilia and hemorrhaging.
Several in vivo analgesia studies in rodents suggest that PGI
2
plays a major role in the induction of hyperalgesia. Likewise, in vitro studies provide substantial evidence to suggest that “PGI
2
-preferring” (IP) receptors act as important modulators of sensory neuron function (K. Bley et al,
Trends in Pharmacological Sciences
1998, 19(4):141-147). Since IP receptors in sensory neurons are coupled to activation of both adenylyl cyclase and phospholipase C, and hence, cAMP-dependent protein kinase and protein kinase C, these receptors can exert powerful effects on ion channel activity and thus neurotransmitter release. Evidence of a prominent role for IP receptors in inflammatory pain has been obtained from recent studies in transgenic mice lacking the IP receptor (T. Murata et al.,
Nature
1997, 388, 678-682).
In addition to being mediators of hyperalgesia, prostaglandins are known to be generated locally in the bladder in response to physiologic stimuli such as stretch of the detrusor smooth muscle, injuries of the vesical mucosa, and nerve stimulation (K. Anderson,
Pharmacological Reviews
1993, 45(3), 253-308). PGI
2
is the major prostaglandin released from the human bladder. There are suggestions that prostaglandins may be the link between detrusor muscle stretch produced by bladder filling and activation of C-fiber afferents by bladder distension. It has been proposed that prostaglandins may be involved in the pathophysiology of bladder disorders. Therefore, antagonists of prostaglandin IP receptors are expected to be useful in the treatment of such conditions.
Antagonists of IP receptors are also expected to find a utility in respiratory allergies wherein PGI
2
production in response to an allergen is present or in respiratory conditions such as asthma.
Additional information relating to prostaglandins and their receptors is described in
Goodman & Gillman's, The Pharmacological Basis of Therapeutics
, ninth edition, McGraw-Hill, New York, 1996, Chapter 26, pages 601-616.
DESCRIPTION OF THE RELATED ART
U.S. Pat. No. 6,184,242 (Bley et al.) refer to certain 2-(substituted-phenyl)amino imidazoline derivatives.
U.S. Patent Nos. 5,364,944 and 5,218,124 (Failli et al.) refer to certain substituted benzoylbenzene-, biphenyl-, and 2-oxazole-alkanoic acid derivatives which are disclosed as having lipoxygenase inhibitory, phospholipase A2 inhibitory, and leukotriene antagonist activity, which are useful as anti-inflammatory, anti-allergic, and cytoprotective agents.
U.S. Pat. No. 5,326,776 (Winn et al.) refers to certain substituted phenyl derivatives which are disclosed as angiotensin II receptor antagonists useful for treating hypertension, edema, renal failure, benign prostatic hypertrophy, diabetic nephropathy, diabetic retinopathy, Alzheimer's disease or congestive heart failure, glaucoma, atherosclerosis, stroke, a variety of obesity-related disorders, and CNS disorders.
U.S. Pat. Nos. 4,889,868 and 4,588,737 (Huang) refer to certain bis-imidazolinoamino derivatives which are disclosed as lipoxygenase and phospholipase C inhibitors and platelet-activating factor receptor antagonists which possess anti-inflammatory, anti-asthmatic, and anti-allergic properties and are additionally useful for treating myocardial infarctions.
U.S. Pat. Nos. 4,396,617 and 4,374,143 (Dolman and Kuipers) refer to certain 2-arylimino-imidazolidines which are disclosed as being fungicides active against rust of beans, brown rust of wheat and mildew on cereals.
U.S. Pat. No. 4,287,201 (Olson et al.) refers to certain 2-(substituted phenylimino)imidazolidine derivatives which are disclosed as being useful in delaying the onset of egg production in young pullets, interrupting egg production in mature hens, and in producing an artificial molt.
U.S. Pat. No. 3,931,216 (Franzmair) refers to a process for the preparation of 2-arylamino-2-imidazoline derivatives.
British Patent Application No. GB 2 038 305 (assigned to Duphar International Research) refers to certain imidazolidine compounds which are disclosed as inhibiting growth of side shoots tobacco or tomato plants, or inhibiting lawn growth, or dwarf ornamental plants.
European Published Application No. 0 017 484 (assigned to Fujisawa Pharmaceutical) refers to certain 2-imidazoline derivatives which are disclosed as being useful for the treatment of hypertensive, inflammatory and gastrointestinal disorder and relief from pain of various origins.
Srivastava, V. K. et al.,
Pharmazie
1986, 41, 598-599, refers to certain 1-[4-(4,5-dihydro-1H-imidazol-2-yl)aminophenyl]-3-substituted phenyl)-2-propene-1-one derivatives which are disclosed as antiparkinsonian agents.
Bley et al.,
Trends in Pharmacological Sciences
1998, 19 (4), 141-147 refers to the role of IP prostanoid receptors in inflammatory pain.
Smith et al.,
British Journal of Pharmacology
1998, 124(3), 513-523 refers to the characterization of prostanoid receptor-evoked responses in rat sensory neurons.
Murata et al.,
Nature
1997, 388 (6643), 678-682 refers to altered pain perception and inflammatory response in mice lacking prostacyclin receptors.
Anderson, K-E.,
Pharmacological Reviews
1993, 45(3), 253-308 refers to the pharmacology of lower urinary tract smooth muscles and penile erectile tissues.
Coleman et al,
Pharmacological Review
1994, 46(2), 205-229 refers to the classification of prostanoid receptors: properties, distribution and structure of prostanoid receptors and their subtypes.
All publications, patents, and patent applications cited herein, whether supra or infra, are each hereby incorporated by reference in its entirety.
SUMMARY OF THE INVENTION
This invention relates to compounds comprising Formula I:
wherein:
R
1
is an optionally substituted aryl; wherein R
1
is optionally substituted by one, two, or three substituents independently selected from lower alkyl, alkoxy, aryloxy, aralkyloxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, nitro, cycloalkyl, amino, alkylamino, dialkylamino, methylenedioxy, ethylenedioxy, and optionally substituted heterocyclyl;
R
2
is hydrogen, lower alkyl, or halogen;
A is —C(O)—(CH
2
)
n
— or —C(O)CH
2
O—; and
the subscript n is an int

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