Heterocyclic compounds

Details Heterocyclic compounds Heterocyclic compounds

1999-07-20

2001-10-09

Solola, T. A. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S374000, C546S209000, C548S235000

Reexamination Certificate

active

06300344

ABSTRACT:

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 WO 95/17393.
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 pharmacological activities such as an inhibitory activity on platelet aggregation, vasodilating activity, antihypertensive activity or the like and are prostaglandin I
2
agonists, 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 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 suitable substituent(s),
R
3
is aryl which may have suitable substituent(s),
R
4
is hydrogen, lower alkyl, hydroxy or aryl,
A
1
is lower alkylene,
 (in which —A
4
— is bond, —CH
2
— or —CO—, and
 is cyclo-(C
5
-C
8
)alkene, cyclo(C
7
-C
8
)alkane, bicycloheptane, bicycloheptene, tetrahydrofuran, tetrahydrothiophene, azetidine, pyrrolidine or piperidine, each of which may have suitable substituent(s)) or —X—A
6
— [in which —X— is —O—,
 (in which R
5
is hydrogen, lower alkyl or acyl) and
A
6
is lower alkylene which may have suitable substituent (s)], and
n is 0 or 1.
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
, R
4
, n, A
1
,
 —A
3
— and —A
4
— are each as defined above,
Y
1
is acid residue,
R
a
1
is protected carboxy,
R
6
is imino protective group,
 is cyclo(C
7
-C
8
)alkene,
 is cyclo(C
7
-C
8
)alkane, and
Y
2
is halogen.
The starting compounds (II), (V) and (VI) are novel and can be prepared by the following process.
wherein
R
1
, R
2
, R
3
, R
4
, n, A
1
,
 —A
3
—, —A
4
— and Y
2
are each as defined above,
R
7
is hydroxy protective group, and
R
8
is acyl.
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.
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” and “aryl moiety” in the term “mono(or di or tri)aryl(lower)alkyl” 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 “lower alkyl” and “lower alkyl moiety” in the term “mono(or di or tri)aryl(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 “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 ester (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, hexyl ester, etc.) which may have at least one suitable substituent(s), for example, lower alkanoyloxy(lower)alkyl ester [e.g. acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 1(or 2)-acetoxyethyl ester, 1(or 2 or 3)-acetoxypropyl ester, 1(or 2 or 3 or 4)-acetoxybutyl ester, 1(or 2)-propionyloxyethyl ester, 1(or 2 or 3)-propionyloxypropyl ester, 1(or 2)-butyryloxyethyl ester, 1(or 2)-isobutyryloxyethyl ester, (1 or 2)-pivaloyloxyethyl ester, 1(or 2)-hexanoyloxyethyl ester, isobutyryloxymethyl ester, 2-ethylbutyryloxymethyl ester, 3,3-dimethylbutyryloxymethyl ester, 1(or 2)-pentanoyloxyethyl ester, etc.], lower alkylsulfonyl(lower)alkyl ester (e.g. 2-mesylethyl ester, etc.), mono(or di or tri)-halo(lower)alkyl ester (e.g. 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.), lower alkoxycarbonyloxy(lower)alkyl ester (e.g. methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, 2-methoxycarbonyloxyethyl ester, 1-ethoxycarbonyloxyethyl ester, 1-isopropoxycarbonyloxyethyl ester, etc.), phthalidylidene(lower)alkyl ester, or (5-lower alkyl-2-oxo-1,3-dioxol-4-yl)(lower)alkyl ester [e.g. (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester, (5-ethyl-2-oxo-1,3-dioxol-4-yl)methyl ester, (5-propyl-2-oxo-1,3-dioxol-4-yl) ethyl ester, etc.]; lower alkenyl ester (e.g. vinyl ester, allyl ester, etc.); lower alkynyl ester (e.g. ethynyl ester, propynyl ester, etc.); ar(lower)alkyl ester which may have at least one suitable substituent(s) such as mono(or di or tri)phenyl(lower) alkyl ester which may have at least one suitable substituent(s) (e.g. benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-tert-butylbenzyl ester, etc.); aryl ester which may have at least one suitable substituent(s) (e.g. phenyl ester, 4-chlorophenyl ester, tolyl ester, tert-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.); phthalidyl ester; and the like.
Suitable “substituent” in the term “aryl which may have suitable substituent(s)” may include halogen, amino, hydroxy, lower alkoxy, lower alkyl as exemplified above, and the like.
Suitable “halogen” may include chlorine, bromine, iodine and the like.
Suitable “lower alkoxy” may include methoxy, ethoxy propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy and the like.
Suitable “cyclo(C
5
-C
8
)alkene” may include cyclopentene, cyclohexene, cycloheptene and cyclooctene.
Suitable “cyclo(C
7
-C
8
)alkene” may include cycloheptene and cyclooctene.
Suitable “cyclo(C
7
-C
8
)alkane” may include cycloheptane and cyclooctane.
Suitable “bicycloheptane” may include bicyclo[2.2.1]heptane and the like.
Suitable “bicycloheptene” may include bicyclo[2.2.1]heptene (e.g., bicyclo[2.2.1]hept-2-en, etc.) and

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