Benzocycloheptene derivatives

Details Benzocycloheptene derivatives Benzocycloheptene derivatives

2000-04-27

2002-05-07

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...

C549S355000, C549S545000, C560S012000

Reexamination Certificate

active

06384072

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to new benzocycloheptene derivatives and salts thereof which are useful as a medicament.
RELATED ART
Prostaglandins are known as autacoids that show a various kind of biological effects. Specifically, prostaglandin I
2
(hereinafter, referred as PGI
2
) is known to have inhibitory activity on platelet aggregation, vasodilating activity, antihypertensive activity or the like. Therefore, PGI
2
agonists are expected to show the above activities which are useful as a medicament for therapeutic and/or prophylactic treatment of arterial obstruction, cerebrovascular disease, hepatic cirrhosis, arteriosclerosis, ischemic heart disease, restenosis after percutaneous transluminal coronary angioplasty, hypertension, dermatosis or the like.
So far, some 4,5-diaryloxazole compounds having pharmacological activities as PGI
2
agonists have been known, for example, in WO 95/17393, WO 95/24393, WO 97/03973, EP 0 542 203 and U.S. Pat. No. 5,362,879.
DISCLOSURE OF THE INVENTION
This invention relates to benzocycloheptene derivatives having novel structure. More particularly, it relates to new benzocycloheptene derivatives and pharmaceutically acceptable salts thereof, their production processes, a pharmaceutical composition containing the same and a use thereof for the manufacture of medicaments.
Accordingly, an object of this invention is to provide new and useful benzocycloheptene derivatives and pharmaceutically acceptable salts thereof.
Another object of this invention is to provide processes for the production of the benzocycloheptene derivatives and salts thereof.
A further object of this invention is to provide a pharmaceutical composition containing, as an active ingredient, said benzocycloheptene derivatives or pharmaceutically acceptable salts thereof.
Another object of this invention is to provide a use of the benzocycloheptene derivatives and pharmaceutically acceptable salts thereof as a prostaglandin I
2
agonist.
Still further object of this invention is to provide a use of the benzocycloheptene derivatives and pharmaceutically acceptable salts thereof for the manufacture of medicament for therapeutic and/or prophylactic treatment of arterial obstruction, cerebrovascular disease, hepatic cirrhosis, arteriosclerosis, ischemic heart disease, restenosis or ischemic complications after coronary angioplasty, hypertension, dermatosis or the like.
The benzocycloheptene derivatives of this invention can be represented by the following formula (I):
wherein
R
1
is a carboxy group or a protected carboxy group,
R
2
and R
3
are each a hydrogen atom, a hydroxy group or a protected hydroxy group, or may be combined together to form an oxo group or a lower alkylene group,
R
4
is a hydrogen atom, a hydroxy group or a protected hydroxy group,
R
5
and R
6
are each an optionally substituted aryl group,
A
1
and A
2
are each a lower alkylene group, and
A and two adjacent carbon atoms of the benzene ring to be bonded with A form a seven-membered ring optionally containing an oxygen atom and optionally substituted with an epoxy group.
Suitable pharmaceutically acceptable salts of the object compounds (I) and compounds (II) and (IV) are conventional non-toxic salts, specifically metal salts such as alkaline metal salts (e.g., sodium or potassium salt) and alkaline earth metal salts (e.g., calcium or magnesium salt), ammonium salts, organic base salts (e.g., trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine or N,N′-dibenzylethylenediamine salt), organic acid salts (e.g., acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate or trifluoroacetate), inorganic acid salts (e.g., hydrochloride, hydrobromide, sulfate or phosphate), salts with an amino acid (e.g., arginine salt, aspartate or glutamate) and the like.
It is to be noted that the object compounds (I) may include one or more stereoisomers due to asymmetric carbon atoms and double bond, and that all of such isomers and a mixture thereof are included within the scope of the present invention.
It is also to be noted that the solvating form of the compounds (I) (e.g., hydrate, etc.) and any crystalline form of the compounds (I) are included within the scope of the present invention.
Also included in the scope of invention are radiolabelled derivatives of the compounds (I) which are suitable for biological studies.
The new benzocycloheptene derivatives (I) and salts thereof can be prepared by processes which are illustrated in following scheme.
wherein R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, A, A
1
and A
2
are each as defined above,
R
1
a
is a protected carboxy group,
R
2
a
and R
3
a
are each a hydrogen atom,
R
2
b
and R
3
b
are combined together to form an oxo group,
X
1
and X
2
are each a leaving group.
It is to be noted that isomerization or rearrangement of the object compounds (I) may occur due to the effect of the light, acid, base or the like, and compounds obtained as the result of said isomerization or rearrangement are also included within the scope of the present invention.
Some of the starting compounds are novel and can be prepared by following processes.
wherein R
2
, R
3
, R
5
, R
6
, A
2
, R
2
a
, A,
and X
2
are each as defined above,
R
2
c
and R
3
c
are combined together to form a lower alkylene group,
R
7
is a protected hydroxy group.
In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention includes within the scope are explained in detail as follows.
The term “lower” is intended to mean 1 to 6 carbon atoms, unless otherwise indicated.
Suitable aryl groups may contain 6 to 12 carbon atoms and may be optionally substituted with suitable substituent(s) such as a halogen, amino, hydroxy, a lower alkyl, a lower alkoxy or the like. Specific examples thereof are phenyl, tolyl, xylyl, mesityl, naphthyl and the like.
Suitable lower alkylene groups may include straight or branched ones having 1 to 6 carbon atoms. Examples thereof are methylene, ethylene, trimethylene, tetramethylene, 2-methyltrimethylene, pentamethylene, hexamethylene and the like. Among them, the one having 1 to 3 carbon atoms is preferred.
Suitable lower alkyl groups may include straight or branched ones having 1 to 6 carbon atoms. Examples thereof are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, t-pentyl, hexyl and the like. Among them, the one having 1 to 4 carbon atoms is preferred.
Suitable protected carboxy groups may include esterified carboxy groups and the like.
Suitable examples of the ester moieties of the esterified carboxy groups may include lower alkyl groups(e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl or hexyl) which may have suitable substituent(s), for example, lower alkanoyloxy(lower)alkyl groups[e.g., acetoxymethyl, propionyloxymethyl, butyryloxymethyl, valeryloxymethyl, pivaloyloxymethyl, hexanoyloxymethyl or acetoxyethyl], halo(lower)alkyl groups (e.g., 2-iodoethyl or 2,2,2-trichloroethyl), and lower alkoxycarbonyloxy(lower)alkyl groups (e.g., methoxycarbonyloxymethyl or 2-methoxycarbonyloxyethyl); lower alkenyl groups (e.g., vinyl or allyl); lower alkynyl groups (e.g., ethynyl or propynyl); ar(lower)alkyl groups which may have suitable substituent(s) such as phenyl(lower)alkyl groups (e.g., benzyl, 4-methoxybenzyl, 4-nitrobenzyl, phenethyl, trityl, bis(methoxyphenyl)methyl, 3,4-dimethoxybenzyl or 4-hydroxy-3,5-di-tert-butylbenzyl); aryl groups which may have suitable substituent(s) (e.g., phenyl, 4-chlorophenyl, tolyl, tert-butylphenyl, xylyl, mesityl or cumenyl); and the like.
Suitable protected hydroxy groups may include lower alkoxy, ar(lower)alkoxy, acyloxy, tri(lower)alkylsilyloxy, diaryl(lower)alkylsilyloxy groups and the like.
Suitable examples of the lower alkoxy groups may include methoxy, ethoxy, tert-butoxy and the like.
Suitable examples of the ar(lower)alkoxy groups may include benzyloxy, phenethyloxy and the like.
Suitable acyl moieties in

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