WO1999015202A1 - Medicaments contre la dysurie resultant d'une hypertrophie de la prostate - Google Patents

Medicaments contre la dysurie resultant d'une hypertrophie de la prostate Download PDF

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Publication number
WO1999015202A1
WO1999015202A1 PCT/JP1998/004234 JP9804234W WO9915202A1 WO 1999015202 A1 WO1999015202 A1 WO 1999015202A1 JP 9804234 W JP9804234 W JP 9804234W WO 9915202 A1 WO9915202 A1 WO 9915202A1
Authority
WO
WIPO (PCT)
Prior art keywords
adrenergic receptor
receptor subtype
highly selective
prostatic hypertrophy
blocker
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP1998/004234
Other languages
English (en)
Japanese (ja)
Inventor
Ikunobu Muramatsu
Satoshi Murata
Katsuyoshi Akiyama
Masami Kojima
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kissei Pharmaceutical Co Ltd
Original Assignee
Kissei Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kissei Pharmaceutical Co Ltd filed Critical Kissei Pharmaceutical Co Ltd
Priority to AU90959/98A priority Critical patent/AU9095998A/en
Publication of WO1999015202A1 publication Critical patent/WO1999015202A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil

Definitions

  • the present invention relates to a therapeutic agent for dysuria associated with prostatic hypertrophy, which contains a highly selective blocker for 1Xj adrenergic receptor subtype (hereinafter referred to as " 1L -AR”) as an active ingredient, does not affect blood pressure. is there.
  • 1L -AR 1Xj adrenergic receptor subtype
  • HI-AR adrenergic receptor subtype
  • AR adrenergic receptor subtype
  • a - called AR the presence of three adrenergic receptors Sabutipu non 1B adrenergic receptor called subtypes (hereinafter shed 1B -AR)
  • Oyobihi 10 Adore Nari emissions receptor subtypes hereinafter referred shed 1D -AR
  • Each of these receptor subtypes has a high affinity for brazosin and may be classified as the H-adrenergic receptor subtype (hereinafter 1TT -AR).
  • the receptor gene has not been cloned, the existence of a receptor subtype that has a low affinity for prazosin is presumed to be completely different from these lu -ARs in terms of functionality, despite its functional properties.
  • the subtype is classified as ILL adrenergic receptor subtype (hereinafter referred to as 1L- AR) in contrast to 1H -AR.
  • the affinity for 1Lj -AR is as high as possible.
  • a receptor-selective effect requires a difference of at least about 10-fold in the affinity for the receptor, but in the actual use as a drug, side effects through the other receptor are considered.
  • a 1B -AR for affinity weak a 1 ⁇ j - affinity force s high non AR high selective blocker for AR, specifically
  • highly selective blocking agents with an affinity for 1Li —AR that are at least about 50-fold higher in affinity for 1B —AR are most recommended.
  • the present inventors have conducted studies to find a highly selective blocking agent having an affinity for 1Lj —AR that is at least about 50 times greater than that for 1B —AR.
  • insulin derivatives JP-A-6-220015
  • indole derivatives JP-A-7-330726
  • Some compounds of the formula (1)-(R) —1- (3-hydroxypropyl) -1-5- [2 -— [[2— [2 -— (2,2,2-trifluoroethoxy) ) [Phenoxy] ethyl] amino] propyl] indoline-1-7-ruboxamide hereinafter referred to as KMD-3213
  • KMD-3213 1-[2- [[2— [2— (2, 2, 2-trifluoroethoxy) phenoxy] ethyl] Amino] propyl] indol
  • the present invention relates to a therapeutic agent for dysuria associated with prostatic hypertrophy, which contains a 1L adrenergic receptor subtype highly selective blocker as an active ingredient and does not affect blood pressure.
  • the present invention relates to a method for treating dysuria associated with prostatic hypertrophy, which does not affect blood pressure, by administering a highly selective blocker for 1 ⁇ - adrenoceptor subtype.
  • the present invention relates to the use of a highly selective 1L adrenergic receptor subtype blocker for the preparation of a preparation for treating dysuria associated with prostatic hypertrophy.
  • the present invention relates to the use of a highly selective adrenergic receptor subtype blocker as a therapeutic agent for dysuria associated with prostatic hypertrophy.
  • the present invention relates to a method for producing a medicament for treating dysuria associated with prostatic hypertrophy, which comprises using a highly selective blocker for 1L adrenergic receptor subtype as an active ingredient.
  • the pA2 value obtained by PNO-49B contraction showed high affinity regardless of the presence or absence of CEC treatment.
  • KMD-3213 is a highly selective blocker for 1Xj -AR, which has an affinity for 1Xj -AR, which is about 80 times higher than that for 1B -AR. It is expected to be a therapeutic agent for dysuria associated with prostatic hyperplasia, which does not affect the effect on dysfunction.
  • pK B value is an index of the affinity for the receptor blockers KMD- 3213 (dissociation constant), human It showed a high affinity of 9.76 for the prostate, but a low affinity of 7.53 and 7.89 for the omental and mesenteric arteries. This indicates that greater about 1 70-fold and about 75-fold more affinity for the affinity force?
  • Human omental arteries and mesenteric arteries to KMD- 3 213 human prostate, KMD- 32 13 Show that prostate contraction can be suppressed by only 1/170 to 1/75 of the amount that suppresses omental and mesenteric artery contraction.
  • KTH-3213 has an anti-AR blocking effect simultaneously with KMD-3213. The same was done for 6001. That Result, p K B values for the J TH- 60 1 of human prostate 8. 59, p K B values for the mesenteric artery is 7.39, affinity to J TH- 60 1 of human prostate human It is only about 16 times the affinity for the mesenteric artery.
  • a shall which have a KMD- 32 1 3 Wahi 1L one affinity for AR or more of at least about 7 0 times compared with the affinity for 1 B -AR high affinity of the present invention, human large It can suppress contraction of human prostate without suppressing contraction of retinal artery or human mesenteric artery.
  • the KM D-32 13 of the present invention showed a 50% lethal dose (LD 50 ) of 87 SmgZkg for both males and females, and showed no serious side effects. It is a safe compound.
  • a compound of the present invention for example, KM D-3213, KMD-3241, or a pharmacologically acceptable salt thereof as an active ingredient, it has no effect on blood pressure.
  • a suitable therapeutic agent for dysuria associated with prostatic hypertrophy can be obtained.
  • the active ingredients of the therapeutic agent of the present invention are known compounds and can be produced by the methods described in the literature (Japanese Patent Application Laid-Open Nos. — 330726).
  • pharmacologically acceptable salts of KM D-32 13 or KMD-3214 are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid , Citric acid, succinic acid, tartaric acid, 2,4-dimethylbenzenesulfonic acid, 2,5-dimethylbenzenesulfonic acid, 2,4,6-trimethylbenzenesulfonic acid, (+) camphorsulfonic acid, (I) Mono- or di-acid addition salts with sulfonic acid, 4-benzene sulfonic acid, 4-naphthylene sulfonic acid, 1-butanesulfonic acid, fumaric acid, glutamic acid
  • Compounds contained as an active ingredient in the therapeutic agent of the present invention include the above-mentioned compounds. And hydrates and solvates with pharmaceutically acceptable solvents such as ethanol.
  • dosage forms are used depending on the usage.
  • oral preparations such as powders, granules, fine granules, dry syrups, tablets and capsules
  • parenteral preparations such as injections, patches and suppositories. Can be.
  • compositions can be used in the form of excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives, etc., depending on the formulation used in the formulation. It can be produced by appropriately mixing, diluting and dissolving with pharmaceutical additives such as wetting agents, emulsifiers, dispersants, stabilizers, and solubilizing agents, and dispensing according to a conventional method.
  • powders may contain the active ingredient, for example, KM D-3213, KMD-3241, or a pharmaceutically acceptable salt thereof, as appropriate, suitable excipients, lubricants, etc. And mix well to make a powder.
  • Tablets may contain the active ingredient, for example, KMD-321, KMD-3241, or a pharmaceutically acceptable salt thereof, as appropriate, with suitable excipients, disintegrants, binders, A lubricant and the like are added, and the mixture is compressed into tablets according to a conventional method.
  • the tablets may be coated, if necessary, to give film-coated tablets, sugar-coated tablets, enteric coated tablets and the like.
  • Capsules are prepared by adding the active ingredient, for example, KMD-321, KMD-3241, or a pharmaceutically acceptable salt thereof, to a suitable excipient, lubricant, etc., if necessary. After mixing well, the mixture is filled into an appropriate capsule to form a capsule. In addition, after filling into granules or fine particles by an ordinary method, or after adding a dispersing agent, emulsifier, stabilizer, dissolution aid and the like to form a liquid, filling may be performed.
  • the active ingredient for example, KMD-321, KMD-3241, or a pharmaceutically acceptable salt thereof
  • the preparation may be administered as a sustained release preparation.
  • Sustained-release bases include hardened oil, stearyl alcohol, cetyl alcohol -Wax such as cellulose, paraffin, fatty acid monoglycerin, hydroxypropyl methylcellulose, hydroxypropylcellulose, ethylcellulose, carboxyvinyl polymer, vinyl acetate resin, ethyl methacrylate methacrylate copolymer, aminoalkyl Examples include methacrylate copolymers and methacrylic acid copolymers.
  • the dose of the active ingredient, the 1L-AR highly selective blocker is appropriately determined according to the gender, age, weight, degree of symptoms, etc. of the target patient. 5 ', for example, when using KMD-32 13 or KMD-3241 or a pharmacologically acceptable salt thereof as an active ingredient, orally, generally for adults 0.1 to 100 mg per day It is administered parenterally, generally in the range of 0.01 to 100 mg per adult per day.
  • the 1JJ adrenergic receptor subtype highly selective blocker used in the present invention does not affect blood pressure, and is therefore very suitable for treating dysuria associated with prostatic hypertrophy.
  • PA 2 values in the NA contraction of KMD-32 1 3 is 8. was 1 0.0 in 1 1, C EC after treatment with C EC untreated. This is, affinity to 1L -AR the KM D-32 13 is a 1B - shows that approximately 80 times higher affinity of affinity for AR. In addition, it showed high affinity for the contraction of PNO-49B regardless of the presence or absence of CEC treatment. Shows each p A 2 values in Table 1. [table 1
  • the human prostate is said to be mediated by spleen 1A -AR 5 ', and contraction is mediated by spleen 1L -AR (British Journal of Urology 1994, 74, 572-578).
  • mesenteric artery are supposed to be mediated by spleen 1B -AR, confirming tissue selectivity and subtype selectivity using human isolated prostate, human omental artery and human mesenteric artery artery specimens did.
  • p K B value is an index of the affinity for the receptor blocking agent by (dissociation constant) to confirm antagonism against NA contraction.
  • KMD- 3 2 1 3 p K B value is an index of the affinity for the receptor blockers (dissociation constant) exhibited high affinity and 9.76 against human prostate force?, Human It showed low affinity with 7.53 and 7.89 for omental and human mesenteric arteries. This suggests that the affinity of KM D-32 13 for human prostate is approximately 170 and 75 times higher than for human omental and mesenteric arteries. It shows that human prostate contraction is suppressed by a factor of 1/70 or 1/75 of that of human omental and human mesenteric arteries. Further, KMD- 3213 pK B value against the human prostate J TH- 601 embodying at the same time is 8. 59, p K B values for human mesenteric artery was 7.39. This indicates that the affinity of JTH-601 for human prostate is only about 16 times that of human mesenteric artery. Table 2 shows the results.
  • the mortality rate was 0% in 5 subjects in the 400 mg / kg group, 3 out of 5 subjects in the 800 mg / kg group, and 4 out of 5 subjects in the 1600 mg / kg group in both sexes, 50% in both sexes.
  • Lethal dose (LD 50) is also 8 78 mg / kg, the minimum lethal dose sexes were both sexes 8 0 0 mg / kg.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des médicaments contre la dysurie résultant d'une hypertrophie de la prostate, ces médicaments contenant un agent bloquant adrénergique α1L hautement sélectif comme ingrédient actif et n'influant pas sur la pression sanguine. Les médicaments sont préparés de manière classique, par incorporation d'une quantité effective de (-)-(R)-1-(3-hydroxypropyl)-5-[2-[[2-[2-(2,2,2-trifluoro-éthoxy)phénoxy]éthyl]amino]propyl]indoline-7-carboxamide, d'un sel de ce dernier acceptable du point de vue pharmacologique, ou d'un solvate de l'un ou l'autre; ou alors, de (-)-(R)-1-(3-hydroxypropyle)-5-[2-[[2-[2-(2,2,2-tri-fluoroéthoxy)phénoxy]éthyl]amino]propyl]indole-7-carboxamide, d'un sel de ce dernier acceptable de point de vue pharmacologique, ou d'un solvate de l'un ou l'autre.
PCT/JP1998/004234 1997-09-22 1998-09-21 Medicaments contre la dysurie resultant d'une hypertrophie de la prostate Ceased WO1999015202A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU90959/98A AU9095998A (en) 1997-09-22 1998-09-21 Remedies for dysuria resulting from prostatic hypertrophy

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP29613597 1997-09-22
JP9/296135 1997-09-22

Publications (1)

Publication Number Publication Date
WO1999015202A1 true WO1999015202A1 (fr) 1999-04-01

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1998/004234 Ceased WO1999015202A1 (fr) 1997-09-22 1998-09-21 Medicaments contre la dysurie resultant d'une hypertrophie de la prostate

Country Status (2)

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AU (1) AU9095998A (fr)
WO (1) WO1999015202A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6310086B1 (en) * 1998-02-27 2001-10-30 Kissei Pharmaceutical Co., Ltd. Indole derivatives and medicinal compositions containing the same
WO2004022538A1 (fr) * 2002-09-06 2004-03-18 Kissei Pharmaceutical Co., Ltd. Cristal pour medicament solide a administration orale et medicament solide a administration orale destine au traitement de la dysurie contenant ce cristal
WO2004054574A1 (fr) * 2002-12-16 2004-07-01 Kissei Pharmaceutical Co., Ltd. Medicament solide administre par voie orale
WO2005085195A1 (fr) 2004-03-05 2005-09-15 Kissei Pharmaceutical Co., Ltd. Composition thérapeutique destinée à prévenir ou à traiter une vessie hyperactive qui accompagne un trouble nerveux
WO2006038611A1 (fr) * 2004-10-05 2006-04-13 Kissei Pharmaceutical Co., Ltd. Agent pour le traitement prophylactique ou thérapeutique des troubles de collecte de l'urine dans la vessie consécutifs à l'obstruction du canal urinaire inférieur
JP2008044960A (ja) * 2002-12-16 2008-02-28 Kissei Pharmaceut Co Ltd 経口固形医薬
JPWO2006038619A1 (ja) * 2004-10-06 2008-05-15 キッセイ薬品工業株式会社 前立腺肥大症に対する手術療法への移行予防用医薬組成物
JP2012036217A (ja) * 2004-06-14 2012-02-23 Ocularis Pharma Inc 選択的α１拮抗薬を含有する眼科製剤
WO2014190942A1 (fr) * 2013-05-30 2014-12-04 中国科学院上海药物研究所 Composé d'indole, et procédé de préparation, composition pharmaceutique et utilisation de celui-ci
US8979809B2 (en) 1999-09-16 2015-03-17 Ocularis Pharma, Llc Night vision composition

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06220015A (ja) * 1992-12-02 1994-08-09 Kissei Pharmaceut Co Ltd インドリン誘導体
JPH07330726A (ja) * 1994-06-01 1995-12-19 Kissei Pharmaceut Co Ltd インドール誘導体

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06220015A (ja) * 1992-12-02 1994-08-09 Kissei Pharmaceut Co Ltd インドリン誘導体
JPH07330726A (ja) * 1994-06-01 1995-12-19 Kissei Pharmaceut Co Ltd インドール誘導体

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MORIYAMA N., ET AL.: "KMD-3213, A NOVEL ALPHA1A-ADRENOCEPTOR ANTAGONIST, POTENTLY INHIBITS THE FUNCTIONAL ALPHA1-ADRENOCEPTOR IN HUMAN PROSTATE.", EUROPEAN JOURNAL OF PHARMACOLOGY, ELSEVIER SCIENCE, NL, vol. 331., no. 01., 1 July 1997 (1997-07-01), NL, pages 39 - 42., XP002915061, ISSN: 0014-2999, DOI: 10.1016/S0014-2999(97)01009-1 *

Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6310086B1 (en) * 1998-02-27 2001-10-30 Kissei Pharmaceutical Co., Ltd. Indole derivatives and medicinal compositions containing the same
US8979809B2 (en) 1999-09-16 2015-03-17 Ocularis Pharma, Llc Night vision composition
US8889112B2 (en) 1999-09-16 2014-11-18 Ocularis Pharma, Llc Ophthalmic formulations including selective alpha 1 antagonists
HRP20050214B1 (hr) * 2002-09-06 2013-09-30 Kissei Pharmaceutical Co.Ltd. Opis kristala za oralni äśvrsti lijek i oralni äśvrsti lijek za tretiranje disurije koji sadržava isti
AU2003264385B2 (en) * 2002-09-06 2009-12-17 Kissei Pharmaceutical Co., Ltd. Crystal for oral solid drug and oral solid drug for dysuria treatment containing the same
WO2004022538A1 (fr) * 2002-09-06 2004-03-18 Kissei Pharmaceutical Co., Ltd. Cristal pour medicament solide a administration orale et medicament solide a administration orale destine au traitement de la dysurie contenant ce cristal
JPWO2004022538A1 (ja) * 2002-09-06 2005-12-22 キッセイ薬品工業株式会社 経口用固形医薬用結晶およびそれを含む排尿障害治療用経口用固形医薬
JP4532274B2 (ja) * 2002-09-06 2010-08-25 キッセイ薬品工業株式会社 経口用固形医薬用結晶およびそれを含む排尿障害治療用経口用固形医薬
CN1321111C (zh) * 2002-09-06 2007-06-13 橘生药品工业株式会社 口服固体药用晶体及治疗排尿困难的包含它的口服固体药
JP4633469B2 (ja) * 2002-12-16 2011-02-16 キッセイ薬品工業株式会社 経口固形医薬
WO2004054574A1 (fr) * 2002-12-16 2004-07-01 Kissei Pharmaceutical Co., Ltd. Medicament solide administre par voie orale
AU2003289320C1 (en) * 2002-12-16 2018-09-06 Kissei Pharmaceutical Co., Ltd. Solid drug for oral use
HRP20050544B1 (hr) * 2002-12-16 2017-12-01 Kissei Pharmaceutical Co., Ltd. Čvrsti oblik za oralnu upotrebu
AU2003289320B2 (en) * 2002-12-16 2008-08-21 Kissei Pharmaceutical Co., Ltd. Solid drug for oral use
CN100339078C (zh) * 2002-12-16 2007-09-26 橘生药品工业株式会社 固体口服剂型药物
EA008196B1 (ru) * 2002-12-16 2007-04-27 Киссеи Фармасьютикал Ко., Лтд. Твердая лекарственная форма для перорального применения
JPWO2004054574A1 (ja) * 2002-12-16 2006-04-20 キッセイ薬品工業株式会社 経口固形医薬
CN101069685B (zh) * 2002-12-16 2011-12-14 橘生药品工业株式会社 固体口服剂型药物
JP2008044960A (ja) * 2002-12-16 2008-02-28 Kissei Pharmaceut Co Ltd 経口固形医薬
TWI382838B (zh) * 2002-12-16 2013-01-21 Kissei Pharmaceutical 錠劑及其製造方法
JP5004215B2 (ja) * 2004-03-05 2012-08-22 キッセイ薬品工業株式会社 神経障害に伴う過活動膀胱の予防または治療用医薬組成物
WO2005085195A1 (fr) 2004-03-05 2005-09-15 Kissei Pharmaceutical Co., Ltd. Composition thérapeutique destinée à prévenir ou à traiter une vessie hyperactive qui accompagne un trouble nerveux
JP2012036217A (ja) * 2004-06-14 2012-02-23 Ocularis Pharma Inc 選択的α１拮抗薬を含有する眼科製剤
WO2006038611A1 (fr) * 2004-10-05 2006-04-13 Kissei Pharmaceutical Co., Ltd. Agent pour le traitement prophylactique ou thérapeutique des troubles de collecte de l'urine dans la vessie consécutifs à l'obstruction du canal urinaire inférieur
JPWO2006038611A1 (ja) * 2004-10-05 2008-05-15 キッセイ薬品工業株式会社 下部尿路閉塞疾患に伴う蓄尿障害の予防及び／又は治療剤
JPWO2006038619A1 (ja) * 2004-10-06 2008-05-15 キッセイ薬品工業株式会社 前立腺肥大症に対する手術療法への移行予防用医薬組成物
WO2014190942A1 (fr) * 2013-05-30 2014-12-04 中国科学院上海药物研究所 Composé d'indole, et procédé de préparation, composition pharmaceutique et utilisation de celui-ci
CN104211631A (zh) * 2013-05-30 2014-12-17 中国科学院上海药物研究所 一类吲哚类化合物、其制备方法、药物组合物及应用

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