4.5-diaryloxazole compounds with prostaglandin I2 (PGI2)...

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

Reexamination Certificate

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C548S235000

Reexamination Certificate

active

06660759

ABSTRACT:

This application is 371 of PCT/JP00/05453 Aug. 14, 2000.
TECHNICAL FIELD
This invention relates to new heterocyclic compounds and pharmaceutically acceptable salts thereof which are useful as a medicament.
BACKGROUND ART
Some heterocyclic compounds have been known as described, for example, in WO95117393, WO95124393, WO97/03973, U.S. Pat. No. 5,362,879 and EP-A-434034.
DISCLOSURE OF INVENTION
This invention relates to new heterocyclic compounds. More particularly, this invention relates to new heterocyclic compounds and pharmaceutically acceptable salts thereof which have prostaglandin I
2
(hereinafter referred as PGI
2
) agonistic activity and pharmacological activities such as an inhibitory activity on platelet aggregation, vasodilating activity, antihypertensive activity or the like, to processes for their production, to a pharmaceutical composition containing the same and to a use thereof for manufacture of medicaments.
Accordingly, one object of this invention is to provide new and useful heterocyclic compounds and pharmaceutically acceptable salts thereof.
Another object of this invention is to provide processes for production of the heterocyclic compounds and salts thereof.
A further object of this invention is to provide a pharmaceutical composition containing, as an active ingredient, said heterocyclic compounds or pharmaceutically acceptable salts thereof.
Still further object of this invention is to provide use of the heterocyclic compounds and pharmaceutically acceptable salts thereof for manufacture of medicaments for the therapeutic and/or prophylactic treatment of arterial obstruction, cerebrovascular disease, hepatic cirrhosis, arteriosclerosis, ischemic heart disease, restenosis after percutaneous transluminal coronary angioplasty, hypertension, dermatitis or the like.
The heterocyclic compounds of this invention can be represented by the following formula (I):
wherein R
1
is carboxy or protected carboxy,
R
2
is aryl which may have substituent(s),
R
3
is aryl which may have substituent(s),
X is oxygen or a pair of hydrogen and R
5
(wherein R
5
is hydroxy or protected hydroxy), and
A
1
and A
2
are each independently lower alkylene and prodrug thereof, and its salt.
According to the present invention, the new heterocyclic compounds (I) can be prepared by the processes which are illustrated in the following scheme.
wherein R
1
, R
2
, R
3
, X, A
1
and A
2
are each as defined above,
Y is leaving group,
R
1a
is protected carboxy, and
R
1b
is carboxy.
Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and include a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt, etc.), an organic acid salt (e.g. acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, trifluoroacetate, etc.), an inorganic acid salt (e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.), a salt with an amino acid (e.g. arginine, aspartic acid, glutamic acid, etc.), and the like.
The “prodrug” means the derivatives of compounds of the present invention having a chemically or metabolically degradable group, which becomes pharmaceutically active after biotransformation.
In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention include within the scope thereof are explained in detail as follows.
The term “lower” is intended to mean 1 to 6 carbon atom(s), unless otherwise indicated.
Suitable “aryl” may include phenyl, naphthyl and the like.
Suitable “lower alkylene” may include straight one having 1 to 6 carbon atom(s), such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene and hexamethylene, preferably one having 1 to 3 carbon atom(s).
Suitable “protected carboxy” may include esterified carboxy and the like. Suitable example of the ester moiety of an esterified carboxy may be the ones such as lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc.) which may have at least one substituent(s), for example, lower alkanoyloxy(lower)alkyl [e.g. acetoxymethyl, propionyloxymethyl, butyryloxymethyl, valeryloxymethyl, pivaloyloxymethyl, hexanoyloxymethyl, 1(or 2)-acetoxyethyl, 1(or 2 or 3)-acetoxypropyl, 1(or 2 or 3 or 4)-acetoxybutyl, 1(or 2)-propionyloxyethyl, 1(or 2 or 3)-propionyloxypropyl, 1(or 2)-butyryloxyethyl, 1(or 2)-isobutyryloxyethyl, (1 or 2)-pivaloyloxyethyl, 1(or 2)-hexanoyloxyethyl, isobutyryloxymethyl, 2-ethylbutyryloxymethyl, 3,3-dimethylbutyryloxymethyl, 1(or 2)-pentanoyloxyetbyl, etc.], lower alkylsulfonyl(lower)alkyl (e.g. 2-mesylethyl, etc.), mono(or di or tri)-halo(lower)alkyl (e.g. 2-iodoethyl, 2,2,2-trichloroethyl, etc.), lower alkoxycarbonyloxy(lower)alkyl (e.g. methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, 2-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, 1-isopropoxycarbonyloxyethyl, etc.), phthalidylidene(lower)alkyl or (5-lower alkyl-2-oxo-1,3-dioxol-4-yl)(lower)alkyl [e.g. (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, (5-ethyl-2-oxo-1,3-dioxol-4-yl)methyl, (5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl, etc.]; lower alkenyl (e.g. vinyl, allyl, etc.); lower alkynyl (e.g. ethynyl, propynyl, etc.); ar(lower)alkyl which may have at least one substituent(s) such as mono(or di or tri)phenyl(lower)alkyl which may have at least one substituent(s) (e.g. benzyl, 4-methoxybenzyl, 4-nitrobenzyl, phenethyl, trityl, benzhydryl, bis(methoxyphenyl)methyl, 3,4-dimethoxybenzyl, 4-hydroxy-3,5-di-tert-butylbenzyl, etc.); aryl which may have at least one substituent(s) (e.g. phenyl 4-chlorophenyl, tolyl, tert-butylphenyl, xylyl, mesityl , cumenyl, etc.); phthalidyl; and the like.
Suitable “substituent” in the term “aryl which may have substituent(s)” may include halogen, amino, hydroxy, lower alkoxy, lower alkyl as exemplified above, and the like.
Suitable “halogen” may include fluoro, chloro, bromo and iodo.
Suitable “lower alkyl” may include straight or branched one having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, t-pentyl, hexyl or the like, preferably one having 1 to 4 carbon atom(s).
Suitable “lower alkoxy” may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy and the like.
Suitable “acyl” may include (1) lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.); (2) lower alkanesulfonyl (e.g. mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, etc.); (3) arenesulfonyl (e.g. benzenesulfonyl, tosyl, etc.); (4) aroyl (e.g. benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl, indancarbonyl, etc.); (5) ar(lower)alkanoyl (e.g. phenylacetyl, phenylpropionyl, etc.); and the like.
Suitable “protected hydroxy” may include lower alkoxy as exemplified above, acyloxy, siloxy which may have one to three substituent(s), and the like.
Suitable “substituent” in the term “siloxy which may have one to three substituent(s)” may include lower alkyl as exemplified above, aryl as exemplified above, and the like.
Suitable “substituent” in the term “lower alkylene which may have substituent(s)” may include lower alkyl as exemplified above, hydroxy(lower)alkyl (e.g. hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, etc.) and the like.
Suitable “leaving group” may include halogen as exemplified above, acyloxy (e.g. acetyloxy, methanesulfonyloxy), and the like.
Preferred embodiments of the object compound (I) are as follows:
R
1
is carboxy or protected carboxy (more preferably esterified carboxy, most preferably lower alkoxycarbonyl),
R
2
is aryl which may have lower alkyl (more preferably phenyl or lower alkylph

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