Naphthalene derivatives

Details Naphthalene derivatives Naphthalene derivatives

2000-08-04

2001-10-16

Aulakh, C S. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

N-c doai

C560S019000, C560S043000, C514S510000, C514S533000, C514S539000

Reexamination Certificate

active

06303649

ABSTRACT:

TECHNICAL FIELD
This invention relates to new naphthalene derivatives and pharmaceutically acceptable salts thereof which are useful as a medicament.
BACKGROUND ART
Some compounds having pharmacological activities such as an inhibitory activity on platelet aggregation have been known, for example, in WO 95/17393, WO 95/24393, WO 97/03973, EP 0 542 203, U.S. Pat. No. 5,362,879.
DISCLOSURE OF INVENTION
This invention relates to new naphthalene derivatives. More particularly, this invention relates to new naphthalene derivatives 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
(hereinafter referred as PGI
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 naphthalene derivatives and pharmaceutically acceptable salts thereof.
Another object of this invention is to provide processes for production of the naphthalene derivatives and salts thereof.
A further object of this invention is to provide a pharmaceutical composition containing, as an active ingredient, said naphthalene derivatives or pharmaceutically acceptable salts thereof.
Still further object of this invention is to provide a use of the naphthalene derivatives 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 or ischemic complications after coronary angioplasty, hypertension, inflammatory bowel disease, dermatosis or the like.
The naphthalene derivatives of this invention can be represented by the following formula (I).
wherein
R
1
is carboxy or protected carboxy,
R
2
and R
3
are each independently hydrogen, hydroxy or protected hydroxy,
R
4
is hydrogen or halogen,
R
5
is aryl substituted with halogen, hydroxy or protected hydroxy,
R
6
is aryl optionally substituted with halogen, hydroxy or protected hydroxy,
A
1
and A
2
are each independently lower alkylene, and
and its salt.
According to the present invention, the new naphthalene derivatives (I) can be prepared by the processes which are illustrated in the following scheme.
wherein R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, A
1
, A
2
and
are each as defined above,
R
a
1
is protected carboxy,
R
b
1
is carboxy,
R
a
2
is hydroxy,
X
1
is leaving group, and
X
2
is leaving group.
The starting compound (II) is novel and can be prepared by the following processes. And, the starting compound (IV) is prepared in a similar manner to that of the Preparations and the Examples in WO 95/24393.
wherein R
2
, R
3
, R
4
, R
5
, R
6
, A
2
,
and X
2
are each as defined above,
R
7
is protected hydroxy.
Suitable pharmaceutically acceptable salts of the object compounds (I) and (I-1) to (I-6), and the compounds (II) to (V) 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.
It is to be noted the object compound (I) may include one or more stereoisomers due to asymmetric carbon atom(s) and double bond, and all of such isomers and a mixture thereof are included within the scope of the present invention.
It is further to be noted isomerization or rearrangement of the object compound (I) may occur due to the effect of the light, acid, base or the like, and the compound obtained as the result of said isomerization or rearrangement is also included within the scope of the present invention.
It is also to be noted that the solvating form of the compound (I) (e.g. hydrate, etc.) and any form of the crystal of the compound (I) are included within the scope of the present invention.
Also included in the scope of the invention are radiolabeled derivatives of the compound of the formula (I) which are suitable for biological studies.
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, tolyl, xylyl, mesityl, naphthyl and the like.
Suitable “lower alkylene” may include straight or branched one having 1 to 6 carbon atom(s), such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene or the like, preferably one having 1 to 3 carbon atom(s).
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 “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, etc.], halo(lower)alkyl ester (e.g. 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.), or lower alkoxycarbonyloxy(lower)alkyl ester (e.g. methoxycarbonyloxymethyl ester, 2-methoxycarbonyloxyethyl 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 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, 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, ethylphenyl ester, propylphenyl ester, tert-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.); and the like.
Suitable “protected hydroxy” may include lower alkoxy, acyloxy, tri(lower) alkylsilyloxy, diaryl(lower)alkylsilyloxy, and the like. Suitable examples of said “lower alkoxy” may include methoxy, ethoxy, tert-butoxy, and the like. Suitable “acyl moiety” in said “acyloxy” may include aliphatic acyl group and acyl group containing an aromatic or heterocyclic ring. And, suitable examples of the said acyl may be lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.); lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, etc.); lower alkylsulfonyl (e.g. mesyl, ethanesulfonyl, etc.); arylsulfonyl (e.g. benzenesulfonyl, tosyl, etc.); aroyl (e.g. benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl, indancarbonyl, etc.); ar(lower)alkanoyl (e.g. phenylacetyl, phenylpropionyl, etc.); ar(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, phenethyloxycarbonyl, etc.); and the like. Suitable example of tri(lower)alkylsilyl moiety in said “tri(lower)a

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