Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-01-06
2001-06-05
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...
C544S373000
Reexamination Certificate
active
06242449
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel 3-benzoylindole derivatives which have testosterone 5&agr;-reductase inhibitory action and thus are effective in the treatment and/or prevention of diseases caused by overproduction of dihydrotestosterone, e.g., prostatic hypertrophy or accompanying urination disorder, male pattern alopecia, and acne (acne, pimples, etc.); and which have &agr;
1
-adrenergic receptor blocking action and thus are capable of selectively curing disorders regarding passage through the bladder neck to thereby improve urination disorder.
BACKGROUND ART
Testosterone 5&agr;-reductase is an enzyme that reduces testosterone, a male hormone (androgen), into dihydrotestosterone. The produced dihydrotestosterone has been elucidated to play an important role in the mechanism of the generation and progress of prostatic hypertrophy, male pattern alopecia, and acne (acne, pimples, etc.) (
J. Steroid Biochemistry
, 11, 609 (1979);
J. Clinical Endocrinol and Metabolism
, 56, 139 (1983); and Japanese Patent Application Laid-Open (kokai) No. 1-139558). Indoles are known as compounds that exhibit testosterone 5&agr;-reductase inhibitory activities, (Japanese Patent Application Laid-Open (kokai) No. 4-244061, WO 93/02050).
&agr;-Adrenergic receptors are known to participate in contraction of smooth muscles. Particularly, recent research has revealed that &agr;
1
-adrenergic receptors strongly participate in contraction of the sphincter in the human bladder neck (J. Urol., 134, 396 (1985)). Therefore, blockers of the receptors are considered to serve as drugs that are capable of selectively treating urination disorders and frequent urination accompanied by prostatic hypertrophy. As compounds that have a blocking action against such &agr;
1
-adrenergic receptors, there are known piperazine derivatives (WO89/12634, WO90/03972).
Disurea, which aged people frequently suffer, is caused by constriction of urethra due to the tonus of sympathetic nerves present in the bladder neck or by urinary obstruction associated with prostatic hypertrophy, and makes urination difficult. In recent years, disurea has been treated by the combined use of an &agr;
1
-adrenergic receptor blocking agent and an anti androgenic agent. However, this is not satisfactory in view of the drug administration schedule.
Therefore, it is desired to develop drugs having both benefits of symptomatic therapy, which exerts immediate effects as exerted by &agr;
1
-adrenergic receptors, and of radical therapy, which exhibits its effect slowly but radically, as in the case of testosterone 5a-reductase inhibitors.
Although International Patent Publication No. WO 95/26955 discloses indole derivatives that have both an &agr;
1
-adrenergic receptor blocking action and a testosterone 5&agr;-reductase inhibiting action in combination, further enhancement of the effects and activity thereof must be attained.
DISCLOSURE OF THE INVENTION
The present inventors have conducted earnest studies in order to solve the above-described problems, and have found that a certain group of 3-benzoylindole derivatives have both a strong &agr;-adrenergic receptor blocking action and a strong testosterone 5&agr;-reductase inhibiting action. The present invention has been accomplished on the basis of this finding.
Accordingly, the present invention provides a 3-benzoylindole derivative represented by following formula (I) or a salt thereof:
(wherein R
1
represents a lower alkyl group, n is an integer from 1 to 5; each of R
2
and R
3
are the same or different and each independently represents a hydrogen atom, a lower alkyl group, or a phenyl group which may have one or more substituents selected from among a lower alkyl group, a halo-substituted lower alkyl group, a lower alkoxy group, and a halogen atom; and R
4
represents a hydrogen atom, a lower alkyl group, or a benzyl group).
The present invention also provides a medicament comprising the above 3-benzoylindole derivative (I) or a salt thereof as an active ingredient.
The present invention also provides an &agr;
1
-adrenergic receptor blocker and a testosterone 5&agr;-reductase inhibitor comprising the above 3-benzoylindole derivative (I) or a salt thereof as an active ingredient.
The present invention also provides a preventive or therapeutic agent for prostatic hypertrophy, urination disorders associated with prostatic hypertrophy, alopecia, or acne, which comprises as an active ingredient the above 3-benzoylindole derivative (I) or a salt thereof.
The present invention also provides a pharmaceutical composition comprising the above 3-benzoylindole derivative (I) or a salt thereof and a pharmaceutically useful carrier.
The present invention also provides use of the above 3-benzoylindole derivative (I) or a salt thereof as a medicament.
The present invention also provides a method for treating prostatic hypertrophy, urination disorders associated with prostatic hypertrophy, alopecia, or acne, characterized by administering an effective amount of the above 3-benzoylindole derivative (I) or a salt thereof.
BEST MODE FOR CARRYING OUT THE INVENTION
In the present invention, unless specifically described otherwise, the term “lower” refers to a linear or branched carbon chain having 1 to 6 carbon atoms.
Accordingly, “lower alkyl groups” include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, hexyl, and isohexyl. Of these, linear or branched alkyl groups having 1 to 4 carbon atoms are preferred, with methyl, ethyl, propyl isopropyl, and butyl being particularly preferred.
Also “lower alkoxy groups” include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 1-ethylpropoxy, 1,2-dimethylpropoxy, hexyloxy, and isohexyloxy. Of these, linear or branched alkoxy groups having 1 to 4 carbon atoms are preferred, with methoxy and ethoxy being particularly preferred.
“Halogen atoms” include fluorine, chlorine, bromine, and iodine.
In the present invention, the term “halo-substituted lower alkyl group” refers to a group which is formed by bonding of one or more the above-described halogen atoms to one of the above-described lower alkyl group (represented as halo-substituted C1-C6 alkyl group). Specific examples include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 3,3,3-trifluoropropyl, 3,3,3-trichloropropyl, 4,4,4-trifluorobutyl, and 4,4,4-trichlorobutyl. These alkyl groups are preferably substituted by from 1 to 3 halogen atoms.
The term “phenyl group which may have one or more substituents selected from among a lower alkyl group, a halo-substituted lower alkyl group, a lower alkoxy group, and a halogen atom” refers to a phenyl group per se and a phenyl group of which benzene ring is substituted by one or more substituents selected from among a lower alkyl group, a halo-substituted lower alkyl group, a lower alkoxy group, and a halogen atom. Specific examples include phenyl, methylphenyl, ethylphenyl, propylphenyl, isopropylphenyl, butylphenyl, isobutylphenyl, methoxyphenyl, ethoxyphenyl, propoxyphenyl, isopropoxyphenyl, butoxyphenyl, isobutoxyphenyl, fluorophenyl, chlorophenyl, bromophenyl, (trifluoromethyl)phenyl, (chloromethyl)phenyl, (dichloromethyl)phenyl, (trichloromethyl)phenyl, (2,2,2-trifluoroethyl)phenyl, dimethylphenyl, diethylphenyl, dipropylphenyl, diisopropylphenyl, dibutylphenyl, diisobutylphenyl, dimethoxyphenyl, diethoxyphenyl, dipropoxyphenyl, diisopropoxyphenyl, dibutoxyphenyl, diisobutoxyphenyl, difluorophenyl, dichlorophenyl, dibromophenyl, di(trifluoromethyl)phenyl, di(chloromethyl)phenyl, di(dichloromethyl)phenyl, di(trichloromethyl)phenyl, di(2,2,2-trifluoroethyl)phenyl, trimethylphenyl, triethylphenyl, tripropylphenyl, truisopropylphenyl, tributylphenyl, tr
Chikazawa Jun
Fukuda Yoichi
Nagano Eiichi
Sato Hiroki
Takei Mineo
Bernhardt Emily
Oblon,Spivak, McClelland, Maier & Neustadt, P.C.
Zeria Pharmaceutical Co. Ltd.
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