Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-09-29
2002-05-28
Ford, John M. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S252020, C514S252140
Reexamination Certificate
active
06395741
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel agent for prophylaxis or treatment of dysuria, more particularly, to an agent for prophylaxis or treatment of dysuria, which comprises as an active ingredient a benzenesulfonamide derivative of the formula [I] as described below.
BACKGROUND ART
With the increase in the population of aged people, prostatic hyperplasia tends to show a yearly increase in numbers thereof, and when prostatic hyperplasia progresses, the prostatic urethral pressure is increased thereby, and as a result, prostatic hyperplasia is accompanied by clinical symptoms such as dysuria. In the current treatment of dysuria accompanying with prostatic hyperplasia, an agent having an activity of lowering the prostatic urethral pressure, for example, an &agr;1 receptor antagonist such as tamsulosin hydrochloride (chemical name: 5-[2-[[2-(ethoxyphenoxy)ethyl]amino]propyl]-2-methoxybenzenesulfonamide hydrochloride) is generally employed.
Recently, various studies have been done as to physiological effects of endothelin on the prostate, and it has been reported that endothelin-1, which is a peptide having a potent vasocontractile activity, exhibits an activity of increasing the prostatic urethral pressure, and that such an activity of endothelin-1 has not been inhibited by an &agr;1 receptor antagonist (cf. Journal of Urology, vol. 158, p. 253, 1997).
There is a report that a cyclic peptide compound of the following formula inhibited the contractions of the smooth muscle of hypertrophied prostatic adenoma induced by endothelin-1 (Journal of Japanese Urology Society, vol. 84, No. 9, p. 1649-54, 1993).
Moreover, it is suggested that a specific phenoxyphenylacetic acid derivative (i.e., N-(4-isopropylbenzenesulfonyl)-&agr;-(4-carboxy-2-n-propylphenoxy)-3,4-methylenedioxyphenylacetamide dipotassium salt) shows an activity of inhibiting the prostatic contractions induced by endothelin-1, and therefore said phenoxyphenylacetic acid compound may be used in the treatment of dysuria accompanying with prostatic hyperplasia (JP-A-8-508034).
On the other hand, the benzenesulfonamide derivative [I] of the active ingredient of the present invention has been known to show an excellent endothelin receptor antagonistic activity and to be useful in the treatment of circulatory diseases such as hypertension, pulmonary hypertension, renal hypertension, Raynaud's disease, myocardial infarction, atherosclerosis, etc. (JP-A-9-59160), but it has not been reported yet that said compound shows an activity of improving dysuria accompanying with prostatic hyperplasia.
DISCLOSURE OF INVENTION
An object of the present invention is to provide a novel agent for prophylaxis or treatment of dysuria, which comprises as an active ingredient a benzenesulfonamide derivative.
The present inventors have intensively studied, and found that some kinds of benzenesulfonamide derivatives effectively inhibit the increase in prostatic urethral pressure induced by endothelin-1, and they have accomplished the present invention.
Namely, the present invention relates to an agent for prophylaxis or treatment of dysuria, which comprises as an active ingredient a compound of the formula [I]:
wherein Ring A is a hydroxy-lower alkyl-substituted phenyl group, Ring B is a lower alkyl-substituted phenyl group, Alk is a lower alkylene group, and R is a substituted or unsubstituted nitrogen-containing 6-membered aromatic heteromonocyclic group, or a pharmaceutically acceptable salt thereof.
BEST MODE FOR CARRYING OUT THE INVENTION
In the benzenesulfonamide derivative [I] of the active ingredient of the present invention, the nitrogen-containing 6-membered aromatic heteromonocyclic group is, for example, pyridyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl group, etc. The substituent of said aromatic heterocyclic group is, for example, a halogen atom (e.g., bromine atom, chlorine atom, fluorine atom), and the like.
Examples of the above active ingredient [I] of the present invention are the compounds of the formula [I] wherein Ring A is a hydroxy-C
1-6
alkyl-substituted phenyl group, Ring B is a C
1-6
alkyl-substituted phenyl group, Alk is a C
1-6
alkylene group, and R is a nitrogen-containing 6-membered aromatic heteromonocyclic group (e.g., pyrimidinyl group, etc.) which may optionally be substituted by a halogen atom (e.g., bromine atom, etc.), etc.
Among the above active ingredients, preferable ones are, for example, the compounds of the formula [I] wherein Ring A is a hydroxy-C
1-4
alkyl-substituted phenyl group (e.g., 2-hydroxy-1,1-dimethylethylphenyl group), Alk is ethylene group, Ring B is a C
1-4
alkyl-substituted phenyl group (e.g., methylphenyl group), and R is bromopyrimidinyl group.
Among them, especially preferable compound is 4-(2-hydroxy-1,1-dimethylethyl)-N-[6-{2-(5-bromopyrimidin-2-yl-oxy)ethoxy}-5-(4-methylphenyl)pyrimidin-4-yl]benzenesulfonamide or a pharmaceutically acceptable salt thereof (e.g., an alkali metal salt such as sodium salt).
The benzenesulfonamide derivative [I] of the active ingredient of the present invention may clinically be used either in a free form or in the form of a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable salt may be an acid addition salt with an inorganic acid or organic acid, or a salt with an inorganic base, organic base or amino acid, and includes, for example, hydrochloride, sulfate, hydrobromide, methanesulfonate, acetate, fumarate, maleate, oxalate, an alkali metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., magnesium salt, calcium salt, etc.), triethylamine salt, and a salt with lysine.
Besides, the benzenesulfonamide derivative [I] or a pharmaceutically acceptable salt of the active ingredient of the present invention thereof may include an internal salt, an adduct, a complex, a hydrate, and a solvate thereof.
The benzenesulfonamide derivative [I] or a pharmaceutically acceptable salt thereof of the active ingredient of the present invention may be administered either orally or parenterally, and can be formulated together with a pharmaceutically acceptable carrier or diluent into a pharmaceutical preparation such as tablets or injections.
The dosage form for oral administration may be solid preparations such as tablets, granules, capsules, powders, or liquid preparations such as solution preparation and suspension preparations. The pharmaceutically acceptable carrier or diluent for oral preparations may be conventional ones, for example, binders (e.g., syrup, acacia gum, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone, etc.), excipients (e.g., lactose, white sugar, corn starch, potassium phosphate, sorbitol, glycine, etc.), lubricants (e.g., magnesium stearate, talc, polyethylene glycol, silica, etc.), disintegrators (e.g., potato starch, etc.), and wetting agents (e.g., sodium laurylsulfate, etc.).
On the other hand, the dosage forms for parenteral administration are preferably injection preparations or drip infusion preparations using distilled water for injection, physiological saline or aqueous glucose solution.
The dose of the benzenesulfonamide derivative [I] or a pharmaceutically acceptable salt thereof of the active ingredient of the present invention may vary according to the administration route, age, weight or conditions of a patient, or severity of the disease to be cured, but the daily dose thereof is usually in the range of about 0.01 mg to 100 mg, preferably in the range of 0.01 mg to 10 mg.
The benzenesulfonamide derivative [I] or a pharmaceutically acceptable salt thereof of the active ingredient of the present invention shows an excellent inhibitory activity against the increase in urethral resistance induced by endothelin, and is useful in the prophylaxis or treatment of dysuria caused by endothelin (e.g., dysuria accompanying with prostatic hyperplasia).
For example, as shown in Exper
Nosaka Kunio
Yamada Koichiro
Finnegan, Henderson, Farabow, Garrett & Dunner, L.L.C.
Ford John M.
Tanabe Seiyaku Co. Ltd.
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