Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-04-26
2001-10-02
Higel, Floyd D. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S235000
Reexamination Certificate
active
06297267
ABSTRACT:
This application is a 371 of PCT/JP98/04455 filed Oct. 1, 1998.
1. Technical Field
This invention relates to new 4,5-diaryloxazole compounds and pharmaceutically acceptable salts thereof which are useful as a medicament.
2. Background 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 and 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 INVENTION
This invention relates to 4,5-diaryloxazole compounds having novel structures. More particularly, it relates to new 4,5-diaryloxazole compounds and pharmaceutically acceptable salts thereof, their production process, 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 4,5-diaryloxazole compounds and pharmaceutically acceptable salts thereof.
Another object of this invention is to provide processes for the production of the 4,5-diaryloxazole compounds and salts thereof.
A further object of this invention is to provide a pharmaceutical composition containing, as an active ingredient, said 4,5-diaryloxazole compounds or pharmaceutically acceptable salts thereof.
Another object of this invention is to provide a use of the 4,5-diaryloxazole compounds and pharmaceutically acceptable salts thereof as a prostaglandin I
2
agonist.
Still further object of this invention is to provide a use of the 4,5-diaryloxazole compounds 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 after percutaneous transluminal coronary angioplasty, hypertension, dermatosis or the like.
The 4,5-diaryloxazole compounds of this invention can be represented by the following formula (I):
wherein R
1
is a hydrogen atom or a carboxy protective group,
R
2
, R
5
, R
6
and R
7
are each a hydrogen atom or a hydroxy group,
R
3
and R
4
are each a hydrogen atom, or are combined together to form an epoxy group or a single bond,
R
8
and R
9
are each an optionally substituted aryl group, and
X is a single bond or a methylene group, in addition to the above definitions,
R
2
and R
3
may be combined together to form a single bond;
provided that when R
2
, R
5
, R
6
and R
7
are each a hydrogen atom,
then R
3
and R
4
are combined together to form an epoxy group;
when R
3
and R
4
are combined together to form a single bond,
then at least one of R
2
, R
5
, R
6
and R
7
is a hydroxy
group and the other(s) is(are) hydrogen atom(s); and
when R
3
and R
4
are each a hydrogen atom,
then at least one of R
2
, R
5
, R
6
and R
7
is a hydroxy group and the other(s) is(are) hydrogen atom(s), and
X is a methylene group.
The new 4,5-diaryloxazole compounds (I) can be prepared by the following processes.
wherein R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
and X are as defined above,
Y
1
is a leaving group,
R
10
is a hydroxy protective group,
R
1
a
is a carboxy protective group, any one of R
2
a
and R
5
a
is a hydroxy group and the other is a hydrogen atom or a hydroxy group,
R
2
b
, R
5
b
, R
6
b
and R
7
b
are each a hydrogen atom, a hydroxy group or a protected hydroxy group, and
R
3
b
and R
4
b
are each a hydrogen atom or are combined
together to form a single bond, in addition to the above definitions,
R
2
b
and R
3
b
may be combined together to form a single bond.
Some of the starting compounds are novel and can be prepared by the following processes.
wherein R
2
, R
5
, R
6
, R
7
, R
8
, R
9
, R
10
and X are as defined above, and R
11
is a hydroxy protective group; AIBN means 2,2′-azobis(isobutyronitrile) and p-TSA means p-toluenesulphonic acid.
Suitable pharmaceutically acceptable salts of the object compounds (I) are conventional non-toxic salts, specifically metal salts such as alkali 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 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.
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 thereof are explained in detail as follows.
The term “lower” is intended to mean 1 to 6 carbon atoms, unless otherwise indicated.
Suitable lower alkyl groups may include straight or branched ones having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, hexyl or the like, preferably the one having 1 to 4 carbon atoms.
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, cumenyl and naphthyl.
Suitable carboxy protective groups may include lower alkyl groups (e.g., methyl, ethyl or tert-butyl), mono-(or di- or tri-)halo(lower)alkyl groups (e.g., 2-iodomethyl or 2,2,2-trichloroethyl), ar(lower)alkyl groups (e.g., benzyl) and the like, among which the lower alkyl group is preferred.
Suitable hydroxy protective groups may include lower alkyl, benzyl, acyl, tri(lower)alkylsilyl, diaryl(lower)alkylsilyl and the like.
Suitable examples of the lower alkyl groups are those as exemplified above.
Suitable examples of the acyl groups may include aliphatic acyl groups such as a lower alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl or pivaloyl), a lower alkoxycarbonyl (e.g., methoxycarbonyl or ethoxycarbonyl), a lower alkanesulfonyl (e.g., mesyl or ethanesulfonyl), and an arenesulfonyl (e.g. benzenesulfonyl or tosyl); and acyl groups containing an aromatic or heterocyclic ring such as an aroyl (e.g., benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl or indancarbonyl), an ar(lower)alkanoyl (e.g., phenylacetyl or phenylpropionyl), an ar(lower)alkoxycarbonyl (e.g., benzyloxycarbonyl or phenethyloxycarbonyl), and the like.
Suitable examples of the tri(lower)alkylsilyl groups may include trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, tert-butyldimethylsilyl and the like.
Suitable examples of the diaryl(lower)alkylsilyl groups may include tert-butyldiphenylsilyl and the like.
Suitable leaving groups may include a halogen (e.g., chlorine, bromine, iodine or fluorine), a lower alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy or butoxy) and the like.
Preferred embodiments of the object compounds (I) are as follows:
Compounds of the formula (I), wherein R
1
is a hydrogen atom or a carboxy protective group,
any one of R
2
, R
5
, R
6
and R
7
is a hydroxy group and the others are hydrogen atoms,
R
3
and R
4
are each a hydrogen atom,
R
8
and R
9
are each a phenyl group, and
X is a methylene group; compounds of the formula (I),
wherein R
1
is a hy
Fujii Naoaki
Hattori Kouji
Takamura Fujiko
Tanaka Akira
Fujisawa Pharmaceutical Co. Ltd.
Higel Floyd D.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Sackey Ebenezer
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