Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
1999-12-07
2002-01-01
Killos, Paul J. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S032000, C560S125000, C560S163000, C548S251000, C548S252000, C548S253000, C514S381000
Reexamination Certificate
active
06335459
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to prostaglandin I
2
(IP) receptor modulators, particularly IP receptor agonists, especially certain aryl carboxylic acids and aryl tetrazole derivatives, pharmaceutical compositions containing them, and methods for their use as therapeutic agents.
2. Background of the Invention
Prostacyclin (PGI
2
) is a member of the prostaglandin family and is the endogenous agonist ligand for the IP receptor. PGI
2
exhibits numerous physiological and pharmacological effects throughout the body and has prominent actions on the cardiovascular system, especially blood vessels, various blood cells including platelets, kidneys, autonomic nerves, and components of the inflammatory and immune systems. For example, in the cardiovascular system, PGI
2
produces profound vasodilatation resulting ultimately in hypotension. It also acts on non-vascular smooth muscles to cause bronchodilatation, relaxation of the uterus, and contraction of gastrointestinal smooth muscle. In addition, it decreases the pH, pepsin content, and overall secretion of gastric acid. In the blood, PGI
2
inhibits the aggregation of platelets and contributes to the anti-thrombogenic properties of the intact vascular wall. The use of stable analog mimics of PGI
2
also suggests that it can inhibit platelet deposition on thrombogenic surfaces such as atherosclerotic plaques. In the kidney, PGI
2
provokes diuresis, natriuresis, kaliuresis, and causes secretion of renin from the renal cortex.
Due to the lability of PGI
2
, a variety of chemically unique analogs have been developed, but these lack receptor selectivity and/or are rapidly degraded by biotransformation. Currently, there is a need for potent, well-tolerated, highly selective IP receptor agonists with pharmacokinetics suitable for long-term, convenient (i.e., QD, BID, TID) oral dosing. The compounds of the present invention and compositions containing them address this need and are useful for the treatment of various disorders with fewer side effects.
3. Description of the Related Art
U.S. Pat. No. 3,649,637 (Howes et al.) refers to certain phenoxy tetrazole derivatives which are disclosed as being useful for treating inflammatory disorders.
U.S. Pat. No. 4,878,942 (Motegi et al.) refers to certain benzamide derivatives which are disclosed as having herbicidal and plant growth regulating activity.
U.S. Pat. Nos. 5,378,716, 5,536,736, 5,703,099, 5,935,985 (Hamaka et al.) and European Patent No. EP 558 062 B1 refer to certain phenoxyacetic acid derivatives which are disclosed as having IP receptor inhibitory activity on blood platelet aggregation.
U.S. Pat. No. 5,763,489 (Taniguchi et al.) and PCT Published Application WO 95/24393 refer to certain naphthalene derivatives which are disclosed as having IP receptor agonist activity useful for treating arterial obstruction, restenosis, arteriosclerosis, cerebrovascular disease or ischemic heart disease.
British Patent Application No. GB 1,079,414 (assigned to Smith & Nephew) refers to certain N-phenyl-o-carbamoylphenoxyacetic acid derivatives which are disclosed as having analgesic and anti-inflammatory activity.
German Patent Application No. DT 24 32 560 (assigned to Boehringer Mannheim) refers to certain 2-(4-carbaniloylalkyl)phenoxy alkanoic acid derivatives which are disclosed as being useful for treating atherosclerosis and as intermediates for antibiotics with &bgr;-lactam structure.
PCT Published Application WO 99/24397 (assigned to Fujisawa) refers to certain benzocycloheptene derivatives which are disclosed as having IP receptor agonist activity useful for treating arterial obstruction, cerebrovascular disease, hepatic cirrhosis, arteriosclerosis, ischemic heart disease, restenosis after percutaneous transluminal coronary angioplasty, hypertension, and dermatosis.
PCT Published Application WO 99/32435 (assigned to Fujisawa) refers to certain naphthalene derivatives which are disclosed as having IP receptor agonist activity useful for treating arteriosclerosis, cerebrovascular disease, ischemic heart disease, dermatosis, inflammatory bowel disease, and for inhibiting cancer metastasis.
Vavayannis et al.,
Eur. J. Med. Chem. Chim. Ther.
1985, 20, 37-42, refers to certain dimethylcarbamate derivatives which are disclosed as being having anticholinesterase activity.
Marsh et al.,
J. Chem. Soc. Chem. Commun.
1996, 8, 941-942 refers to certain solid phase polyamine linkers which are disclosed as being useful in the synthesis and preparation of directed libraries against trypanothione reductase.
All publications, patents, and patent applications cited herein, whether supra or infra, are each hereby incorporated by reference in their entirety.
SUMMARY OF THE INVENTION
This invention provides compounds of Formula I:
wherein:
R
1
and R
2
are each independently in each occurrence alkyl, aryl, aralkyl, heteroaryl, cycloalkyl, or heterocyclyl;
R
3
and R
4
are each independently in each occurrence hydrogen, alkyl, alkoxy, amino, halogen, haloalkyl, hydroxyalkyl, nitro, aryl, aralkyl, or heterocyclyl;
R
5
is independently in each occurrence —COOR
6
or tetrazolyl;
R
6
is independently in each occurrence hydrogen or alkyl;
A is independently in each occurrence alkylene or alkenylene;
B is independently in each occurrence —O(CH
2
)
m
— or —(CH
2
)
n
—;
m is independently in each occurrence an integer from 1 to 8 inclusive;
n is independently in each occurrence an integer from 0 to 8 inclusive; or individual isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof.
This invention further relates to pharmaceutical compositions comprising a therapeutically effective amount of at least one compound of Formula I, or individual isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof, in admixture with at least one suitable carrier. In a preferred embodiment, the pharmaceutical compositions are suitable for administration to a subject having a disease state that is alleviated by treatment with an IP receptor modulator, particularly an IP receptor agonist.
This invention further relates to pharmaceutical compositions suitable for administration to a subject comprising a therapeutically effective amount of at least one compound of Formula I, or individual isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof, in admixture with at least one pharmaceutically acceptable carrier.
This invention further relates to methods of treatment comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one compound of Formula I, or individual isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof. In a preferred embodiment the subject in need of such treatment suffers from a disease state associated with improper wound healing, tissue necrosis, premature uterine contraction, gastric ulceration, sexual dysfunction in males and females, severe menstrual pain, improper immunoregulation, improper platelet aggregation, or improper neutrophil function. In another preferred embodiment the compound of Formula I, or individual isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof, is an IP receptor modulator, particularly an IP receptor agonist.
This invention further relates to methods of treatment comprising administering to a subject suffering from a disease state associated with improper blood flow, a therapeutically effective amount of at least one compound of Formula I, or individual isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof. In a preferred embodiment, the subject has a cardiovascular disease state, a hypertensive disease state, an ischemia disease state, or a renal disease state. In a more preferred embodiment, the subject has a cardiovascular disease state which is peripheral arterial
Lopez-Tapia Francisco Javier
Muehldorf Alexander Victor
O'Yang Counde
Severance Daniel Lee
Kaku Janet
Killos Paul J.
Syntex (U.S.A.) LLC
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