Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-12-29
2002-05-28
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S255030, C544S373000, C544S394000
Reexamination Certificate
active
06395739
ABSTRACT:
TECHNICAL FIELD
The present invention relates to phenylpiperazine derivatives which have excellent &agr;
1
-adrenoceptor blocking activity and are useful as medicaments; and to a process for producing the same.
BACKGROUND ART
A blocking agent against an &agr;
1
-adrenoceptor, which dilates blood vessels or reduces resistance in the blood vessels, is known to be a preventive and therapeutic drug for hypertension such as essential hypertension or renal hypertension, congestive heart failure, myocardial ischemia, arrhythmia, and angina pectoris. Many compounds have been reported to serve as such a blocking agent. Moreover, an &agr;
1
-adrenoceptor has been found to participate to a considerable degree in constriction of the urinary bladder neck (J. Urol., 134, 396 (1985)) and therefore, the blocking agent against the receptor has become of interest as a pharmaceutical capable of selectively treating urinary obstruction, pollakiuria, and other symptoms caused by benign prostatic hyperplasia (BPH). For example, prazosin hydrochloride and urapidil (British Patent No. 1156973, German Patent No. 1942405, WO89/12634, WO90/03972) have been used as pharmaceuticals for treatment of hypertension or urinary obstruction caused by BPH, and tamsulosin hydrochloride has been used as a pharmaceutical for treatment of urinary obstruction caused by BPH (Japanese Patent Application Laid-Open (Kokai) No. 110665/1981).
However, conventional blocking agents against an &agr;
1
-adrenoreceptor do not necessarily exhibit sufficient effect for prevention and treatment of the above-described symptoms, and it is known that side effects such as orthostatic hypotension and loss of consciousness may result. In order to overcome these drawbacks, development of new drugs has still been demanded.
DISCLOSURE OF THE INVENTION
The present inventors have found that specific N-phenyl-N′-phenylpropylpiperazine derivatives exhibit excellent &agr;
1
-adrenoreceptor blocking activity and thus are useful as medicaments. The present invention has been achieved on the basis of this finding.
Accordingly, the present invention provides an N-phenyl-N′-phenylpropylpiperazine derivative represented by formula (1):
(wherein R
1
represents a lower alkyl group; R
2
represents a lower alkoxy group; and R
3
represents a cyano group, a carboxyl group, or an indolecarbonyl group) or a salt thereof, as well as a process for producing the derivative or the salt thereof.
The present invention also provides a medicament which comprises as an active component an N-phenyl-N′-phenylpropylpiperazine derivative represented by formula (1) or a salt thereof.
The present invention also provides a blocking agent against an &agr;
1
-adrenoceptor, which blocking agent comprises as an active component an N-phenyl-N′-phenylpropylpiperazine derivative represented by formula (1) or a salt thereof.
Further, the present invention provides a pharmaceutical composition which contains an N-phenyl-N′-phenylpropylpiperazine derivative represented by formula (1) or a salt thereof and a pharmaceutically acceptable carrier.
Further, the present invention provides use of an N-phenyl-N′-phenylpropylpiperazine derivative represented by formula (1) or a salt thereof as medicaments.
Furthermore, the present invention provides a treatment method for hypertension, congestive heart failure, myocardinal ischemia, arrhythmia, angina pectoris, or urinary obstruction and pollakiuria caused by BPH, characterized by administration of an N-phenyl-N′-phenylpropylpiperazine derivative represented by formula (1) or a salt thereof.
WO95/26955 and WO99/03831, which have been filed by the present inventors, describe that an indole butyrate derivative has &agr;
1
-adrenoceptor blocking activity, but are silent about the activity of the compound of formula (1).
BEST MODE FOR CARRYING OUT THE INVENTION
In the present invention, the term “lower” refers to the number of carbon atoms being 1 to 6 in a linear, branched, or cyclic carbon-containing group.
Accordingly, the term “a lower alkyl group” refers to a C1-C6 linear, branched, or cyclic alkyl group. Specific examples of such alkyl groups include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, 1-methylbutyl, 2-methylbutyl, isopentyl, tert-pentyl, 1,2-dimethylpropyl, neopentyl, 1-ethylpropyl, cyclopentyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, isohexyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-methyl-1-ethylpropyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, and cyclohexyl. Among these, C1-C4 linear or branched alkyl groups are preferred and a methyl group is most preferred.
The term “lower alkoxy group” refers to a C1-C6 linear, branched, or cyclic alkoxy group. Specific examples of such alkoxy groups include methoxy, ethoxy, propoxy, cyclopropoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, cyclobutoxy, pentyloxy, 1-methylbutoxy, 2-methylbutoxy, isopentyloxy, tert-pentyloxy, 1,2-dimethylpropoxy, neopentyloxy, 1-ethylpropoxy, cyclopentyloxy, hexyloxy, 1-methylpentyloxy, 2-methylpentyloxy, 3-methylpentyloxy, isohexyloxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-methyl-1-ethylpropoxy, 1-ethyl-2-methylpropoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, and cyclohexyloxy. Among these, C1-C4 linear or branched alkoxy groups are preferred and a methoxy group is most preferred.
In the present invention, the term “indolecarbonyl group” refers to a carbonyl group to which indole is bonded at one end. Specific examples of such indolecarbonyl groups include (indol-1-yl)carbonyl, (indol-2-yl)carbonyl, (indol-3-yl)carbonyl, (indol-4-yl)carbonyl, (indol-5-yl)carbonyl, (indol-6-yl)carbonyl, and (indol-7-yl)carbonyl. Among these, an (indol-3-yl)carbonyl group is most preferred.
In formula (1), R
1
is preferably a methyl group and R
2
is preferably a methoxy group. R
3
is preferably a cyano group, a carboxyl group, or an (indol-3-yl)carbonyl group and most preferably a cyano group or a carboxyl group.
The compound (1) of the present invention forms a salt with an acid or a base. Examples of salts formed with an acid include salts formed with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; and with acidic amino acids such as aspartic acid and glutamic acid. Examples of salts formed with a base include salts formed with inorganic bases such as sodium, potassium, magnesium, calcium, aluminum, and zinc; and ammonium salts.
The present invention encompasses a variety of solvates or crystal polymorphisms of the compound (1) and further, encompasses racemic modifications and R- and S-stereoisomers as well as optically active substances of the compound (1).
The compound (1) of the present invention may be produced according to the following reaction scheme.
(wherein R
1
and R
2
are the same as described above.)
4′-Lower alkyl-3-chloropropiophenone (2) which has been prepared according to a known method is reduced by use of a borohydride such as sodium borohydride to thereby yield 3-chloro-1-(4-alkylphenyl)-1-propanol (3). The reaction may be carried out in an alcoholic solvent such as methanol or ethanol, under cooled conditions, at room temperature, under warm conditions, or with heat. The obtained 3-chloro-1-(4-alkylphenyl)-1-propanol (3) can be divided into isomers including a variety of optical isomers and R- and S-isomers by optical resolution using an optical resolving agent such as optically active mandelic acid, tartaric acid, dibenzoyltartaric acid, or di(p-tol
Chikazawa Jun
Higashino Raita
Nagano Eiichi
Sato Hiroki
Takei Mineo
Bernhardt Emily
Zeria Pharmaceutical Co. Ltd.
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