Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-03-01
2003-05-27
Rao, Deepak (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252030, C514S252050, C514S255050, C514S255060, C514S256000, C514S332000, C514S337000, C514S341000, C514S342000, C514S352000, C514S407000, C544S224000, C544S238000, C544S295000, C544S296000, C544S322000, C544S333000, C544S405000, C544S407000, C546S263000, C546S275400, C546S281400, C546S284100, C546S308000, C548S364400, C548S365700, C548S372500
Reexamination Certificate
active
06569860
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to certain alkoxycarbonylamino-heteroaryl carboxylic acid derivatives, and associated pharmaceutical compositions, methods for use as prostaglandin IP (I
2
, or PGI
2
) antagonists, and methods of preparation thereof.
BACKGROUND OF THE INVENTION
Prostaglandins or prostanoids (PGs) 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 they 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.
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
(also known as prostacyclin) is the major prostaglandin released from the human bladder. There are some 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 bladder disorders such as bladder outlet obstruction, urinary incontinence, reduced bladder capacity, frequency of micturition, urge incontinence, stress incontinence, bladder hyperreactivity, benign prostatic hypertrophy (BPH), prostatitis, detrusor hyperreflexia, urinary frequency, nocturia, urinary urgency, overactive bladder, pelvic hypersensitivity, urethritis, pelvic pain syndrome, prostatodynia, cystitis, idiophatic bladder hypersensitivity, and the like.
PGI
2
also 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, 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 prevent conditions associated with excessive bleeding such as, but not limited to, hemophilia and hemorrhaging, may relieve hypotension related to septic shock, and may reduce edema formation.
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).
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. Thus antagonists which can selectively treat the above mentioned conditions by acting on the IP receptor, are desirable.
DESCRIPTION OF THE RELATED ART
International Patent Application WO 01/68591 assigned to Hoffmann-La Roche AG refers to certain carboxylic acid derivatives as IP antagonists.
U.S. Pat. No. 6,184,242 assigned to Syntex LLC refers to certain imidazoline derivatives as IP antagonists.
U.S. Pat. No. 5,908,842 assigned to Merck & Co. refers to certain substituted acylamino-pyridine compounds useful as inhibitors of nitric oxyde synthase.
Bley et al.,
Trends in Pharmacological Sciences
1998, 19 (4), 141-147 refer to the role of IP prostanoid receptors in inflammatory pain.
Smith et al.,
British Journal of Pharmacology
1998, 124(3), 513-523 refer to characterization of prostanoid receptor-evoked responses in rat sensory neurons.
Murata. et al.,
Nature
1997, 388 (6643), 678-682 refer to altered pain perception and inflammatory response in mice lacking prostacyclin receptors.
Anderson et al.,
Pharmacological Reviews
1993, 45(3), 253-308 refer to Pharmacology of lower urinary tract smooth muscles and penile erectile tissues.
Coleman et al,
Pharmacological Review
1994, 46(2), 205-229 refer to 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:
G
1
is selected from the groups a and b;
A is selected from the group phenyl, pyridinyl, pyrimidinyl, and thienyl, all opt. substituted with lower alkyl, halogen, haloalkyl, alkoxy, cyano, nitro, —SO
2
R′, —NSO
2
R′, —SO
2
NR′R″, —NR′R″, or —COR′;
R′ and R″ are each independently hydrogen or lower alkyl,
G
2
stands for a heteroaryl group substituted with a carboxylic acid group, said heteroaryl ring containing one or two nitrogen atoms is selected from the group represented by the Formula c, d, e, f, g, h, i, and j:
R
1
and R
2
are independently in each occurrence hydrogen, lower alkyl, halo, haloalkyl, nitro, —NR′R″, —OR′, —SO
2
R′, —NSO
2
R′, —COR′, cyano, nitro, phenyl optionally substituted with halo, alkyl, cyano, nitro, or alkoxy; or heteroaryl optionally substituted with halo, alkyl, cyano, nitro, or alkoxy;
R
1
and R
2
, if adjacent, taken together with the carbons to which they are attached may also form an aromatic ring, optionally substituted with one or two substitutents selected from lower alkyl, halo, cyano, or lower alkoxy, or individual isomers, racemic or non-racemic mixtures of isomers, prodrugs, or pharmaceutically acceptable salts or solvates thereof.
In another aspect the invention relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formula (I) in admixture with at last one pharmaceutically acceptable carrier.
In another aspect, the invention relates to methods for treating a subject having a disease state that is alleviated by treatment with an IP receptor antagonist, which comprises administering to such a subject a therapeutically effective amount of at least a compound of Formula (I). In a preferred embodiment, the disease state is associated with the urinary tract, pain, inflammation, respiratory states, edema formation, or hypotensive vascular diseases.
In another aspect, the invention relates to a process which comprises:
acylation of the esters of general Formula 2, 3, 4, 5, 6, 7, 8, or 9 with phosgene;
wherein R is a lower alkyl or a trimethylsilylethyl group, and R
1
and R
2
are as defined herein;
reaction with a compound of general Formula 1
wherein G
1
is as defined he
Lopez-Tapia Francisco Javier
Nitzan Dov
O'Yang Counde
Hall Robert C.
Peries Rohan
Pfister Gloria
Rao Deepak
Roćhe Palo Alto LLC
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