Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
1999-09-15
2002-05-21
Davis, Brian J. (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S567000, C560S043000, C560S045000, C562S452000
Reexamination Certificate
active
06391915
ABSTRACT:
This application is a 371 of PCT/JP98/01112 filed Mar. 17, 1998.
1. Technical Field
This invention relates to new propanolamine derivatives and salts thereof which are useful as a medicament.
2. Background Art
Some propanolamine derivatives having spasmolytic activity and relaxing activity on smooth muscle contraction have known as described, for example, in PCT International Publication WO94/25427.
DISCLOSURE OF INVENTION
This invention relates to new propanolamine derivatives and salts thereof.
More particularly, it relates to new propanolamine derivatives and salts thereof which have gut selective sympathomimetic, anti-ulcerous, anti-pancreatitis, lipolytic and anti-pollakisuria activities, to processes for the preparation thereof, to a pharmaceutical composition comprising the same and to a method of using the same therapeutically in the treatment and/or prevention of gastro-intestinal disorders caused by smooth muscle contractions in human beings or animals, and more particularly to a method for the treatment and/or prevention of spasm or hyperanakinesia in case of irritable bowel syndrome, gastritis, gastric ulcer, duodenal ulcer, enteritis, cholecystopathy, cholangitis, urinary calculus and the like; for the treatment and/or prevention of ulcer such as gastric ulcer, duodenal ulcer, peptic ulcer, ulcer caused by non steroidal anti-inflammatory drugs, or the like; for the treatment and/or prevention of dysuria such as pollakisuria, urinary incontinence or the like in case of nervous pollakisuria, neurogenic bladder dysfunction, nocturia, unstable bladder, cystospasm, chronic cystitis, chronic prostatitis or the like; and for the treatment and/or prevention of pancreatitis, obesity, diabetes, glycosuria, hyperlipidemia, hypertension, atherosclerosis, glaucoma, melancholia, depression and the like.
One object of this invention is to provide new and useful propanolamine derivatives and salts thereof which have gut selective sympathomimetic, anti-ulcerous, lipolytic and anti-pollakisuria activities.
Another object of this invention is to provide processes for the preparation of said propanolamine derivatives and salts thereof.
A further object of this invention is to provide a pharmaceutical composition comprising, as an active ingredient, said propanolamine derivatives and salts thereof.
Still further object of this invention is to provide a therapeutical method for the treatment and/or prevention of aforesaid diseases in human beings or animals, using said propanolamine derivatives and salts thereof.
The object propanolamine derivatives of this invention are new and can be represented by the following general formula [I]:
wherein R
1
is hydrogen or lower alkenyloxy,
R
2
is carboxy(lower)alkoxy or protected carboxy(lower)alkoxy,
R
3
is hydrogen or N-protective group,
n is an integer of 1 or 2, and salts thereof (Hereinafter, these propanolamine derivatives may be mentioned as the object compound [I]).
The object compound [I] or its salt can be prepared by the following processes.
wherein R
1
, R
2
, R
3
and n are each as defined above, and
R
a
3
is N-protective group.
In the above and subsequent description of the present specification, suitable examples of the various definition to be included within the scope of the invention are explained in detail in the following.
The term “lower” is intended to mean a group having 1 to 6 carbon atom(s), unless otherwise provided.
Suitable “lower alkenyl” moiety in the term “lower alkenyloxy” may include vinyl, 1-(or 2-)propenyl, 1-(or 2- or 3-)butenyl, 1-(or 2- or 3- or 4-)pentenyl, 1-(or 2- or 3- or 4- or 5-)hexenyl, methylvinyl, ethylvinyl, 1-(or 2- or 3-)-methyl-1-(or 2-)propenyl, 1-(or 2- or 3-)ethyl-1-(or 2-)-propenyl, 1-(or 2- or 3- or 4-)methyl-1-(or 2- or 3-)butenyl, and the like, in which preferable example may be C
2
-C
4
alkenyl, and more preferable example may be propenyl.
Suitable “lower alkoxy” moiety in the terms of “carboxy(lower)alkoxy” and “protected carboxy(lower)alkoxy” may be a straight or branched one such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy or the like, in which preferable one is C
1
-C
4
ones and more preferably methoxy.
Suitable “protected carboxy” moiety in the term “protected carboxy(lower)alkoxy” may include esterified carboxy and the like. And suitable example of said esterified carboxy may be substituted or unsubstituted lower alkoxycarbonyl [e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, hexyloxycarbonyl, 2-iodoethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, etc.], substituted or unsubstituted aryloxycarbonyl [e.g. phenoxycarbonyl, 4-nitrophenoxycarbonyl, 2-naphthyloxycarbonyl, etc.], substituted or unsubstituted ar(lower)alkoxycarbonyl [e.g. benzyloxycarbonyl, phenethyloxycarbonyl, benzhydryloxycarbonyl, 4-nitrobenzyloxycarbonyl, etc.] and the like, in which preferable one is lower alkoxycarbonyl.
“N-Protective group” may be common N-protective group such as acyl, for example, substituted or unsubstituted lower alkanoyl [e.g. formyl, acetyl, propionyl, trifluoroacetyl, etc.], phthaloyl, lower alkoxycarbonyl [e.g. tert-butoxycarbonyl, tert-amyloxycarbonyl, etc.], substituted or unsubstituted aralkyloxycarbonyl [e.g. benzyyloxycarbonyl, p-nitrobenzyloxycarbonyl, etc.], substituted or unsubstituted arenesulfonyl [e.g. benzenesulfonyl, tosyl, etc.], nitrophenylsulfenyl, ar(lower) alkyl [e.g. trityl, benzyl, etc.] or the like, in which preferable one is phenyl(lower)alkyl such as benzyl.
Preferred embodiments of the object compound [I] are as follows:
R
1
is hydrogen or lower alkenyloxy,
R
2
is carboxy(lower)alkoxy or esterified carboxy(lower) alkoxy,
R
3
is hydrogen or ar(lower)alkyl, and
n is an integer of 1 or 2.
More preferred embodiments of the object compound [I] are as follows:
R
1
is hydrogen or lower alkenyloxy,
R
2
is lower alkoxycarbonyl(lower)alkoxy,
R
3
is hydrogen or benzyl, and
n is an integer of 1 or 2 (more preferably an integer of 2).
Suitable salts of the object propanolamine derivatives [I] are pharmaceutically acceptable salts and include conventional non-toxic salts such as an inorganic acid addition salt [e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.], an organic acid addition salt [e.g. formate, acetate, trifluoroacetate, oxalate, maleate, fumarate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.], an alkali metal salt [e.g. sodium salt, potassium salt, etc.] or the like.
The processes for preparing the object compound [I] are explained in detail in the following.
Process 1
The object compound [I] or its salt can be prepared by reacting a compound [II] with a compound [III] or its salt.
Suitable salt of the compound [III] may be the same as those exemplified for the compound [I].
The reaction is preferably carried out in the presence of a base such as an alkali metal carbonate [e.g. sodium carbonate, potassium carbonate, etc.], an alkaline earth metal carbonate [e.g. magnesium carbonate, calcium carbonate, etc.], an alkali metal bicarbonate [e.g. sodium bicarbonate, potassium bicarbonate, etc.], tri(lower)alkylamine [e.g. trimethylamine, triethylamine, etc.], picoline or the like.
The reaction is usually carried out in a conventional solvent, such as an alcohol [e.g. methanol, ethanol, propanol, isopropanol, etc.], diethyl ether, tetrahydrofuran, dioxane, or any other organic solvent which does not adversely influence the reaction.
The reaction temperature is not critical, and the reaction can be carried out under cooling to heating.
Process 2
The object compound [Ib] or its salt can be prepared by subjecting a compound [Ia] or its salt to elimination reaction of the N-protective group.
Suitable salts of the compounds [Ia] and [Ib] may be the same as those exemplified for the
Hashimoto Norio
Okamoto Takumi
Sakurai Minoru
Takasugi Hisashi
Taniguchi Kiyoshi
Davis Brian J.
Fujisawa Pharmaceutical Co. Ltd.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
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