CN1317030C - 用中等剂量的lhrh拮抗剂治疗阿尔茨海默氏病 - Google Patents
用中等剂量的lhrh拮抗剂治疗阿尔茨海默氏病 Download PDFInfo
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- CN1317030C CN1317030C CNB028042964A CN02804296A CN1317030C CN 1317030 C CN1317030 C CN 1317030C CN B028042964 A CNB028042964 A CN B028042964A CN 02804296 A CN02804296 A CN 02804296A CN 1317030 C CN1317030 C CN 1317030C
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/10—Peptides having 12 to 20 amino acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
- A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Abstract
本发明涉及用中等剂量的不导致去势的LHRH拮抗剂治疗痴呆和神经变性疾病如阿耳茨海默氏病。优选的LHRH拮抗剂为西曲瑞克。
Description
发明领域
本发明涉及用不导致去势的中等剂量的LHRH拮抗剂治疗阿尔茨海默氏病。
发明背景
FURUYA,Shuichi等人在WO 01/78780中教导包含具有GnRH拮抗性的化合物用于阿尔茨海默尔氏病预防剂和治疗剂具有预防和治疗阿耳茨海默氏病的作用和少量毒性。
Bowen R.L等人的研究已表明卵泡刺激素(FSH)和促黄体激素(LH)的血清浓度在患有痴呆如阿耳茨海默氏病的个体中明显较高。Bowen R.L.等人在专利申请CA 2,309,395(US优先权1999年6月4日,09/326,180)提出使用去势剂量的LH释放激素(LHRH)的类似物,超激动剂或拮抗剂而将FSH和LH降至最低水平。
这种治疗伴随极不期望的副作用,如将性激素水平降至去势水平,从而导致性欲、性要求和性能力丧失或降低。在男性和绝经前女性当中,这种治疗还导致性激素下降的典型症状,如潮红等。女性还将患有骨矿物质损失,这将限制治疗。
这些副作用可以通过激素替代疗法而减少。
本发明的目的是克服上述困难,或至少提供有用的选择方法。
已发现中等剂量的LHRH拮抗剂的治疗导致FSH和LH次最大降低至正常水平,从而使性激素水平保持在去势阈值之上。
这种治疗是非常有用的,因为它导致FSH和LH水平正常化的理想结果,并没有不良的激素阻断副作用。因此,额外的性激素替代治疗变得多余。
发明内容
本发明涉及使用中等剂量的LHRH拮抗剂治疗阿尔茨海默氏病,其中所述拮抗剂优选为西曲瑞克、替维瑞克、安肽或阿巴瑞克。所述拮抗剂还可以是LHRH拮抗剂D-63153(Ac-D-Nal-D-pCl-Phe-D-Pal-Ser-N-Me-Tyr-D-Hci-Nle-Arg-Pro-D-Ala-NH2),如在PCT申请WO 00/55190A1中所述。
所述的LHRH拮抗剂还可以表现出杂环骨架结构。例如这些拟肽可以是
-1-[7-氯-3-(3,5-二甲基-苯基)-2-氧代-4-(2-哌啶-2-基-乙氧基)-1,2二氢-喹啉-6-基]-3-吡啶-2-基-脲(WO 97/44339所述),
-3-[苄基-甲基-氨基)-甲基]-2-叔丁基-8-(2-氟-苄基)-6-(3-甲氧基-苯基)-7-甲基-8H-咪唑并[1,2-a]嘧啶-5-酮(WO01/29044所述),
-2-(2,5-二甲基-呋喃-3-基)-8-(2-氟-苄基)-3-([甲基-(2-吡啶-2-基-乙基)-氨基]-甲基)-5-氧代-5,8-二氢-咪唑并[1,2-a]嘧啶-6-甲酸1-乙基-丙基酯(WO 00/69859所述),
-3-((2-[2-(3,5-二氟代-苯基)-1-(2-甲氧基-苯甲酰基)-2-氧代-亚乙基]-2,3-二氢-1H-苯并咪唑-5-基-氨基)-甲基)-苄腈(WO 02/02533所述)。
LHRH拮抗剂以月剂量10-100mg/月施用,并每月、每两个月重复施用或持续数月施用。
在一个优选的实施方案中,LHRH拮抗剂以月剂量30-60mg/月施用,并每月、每两个月重复施用或持续数月施用。
例如,适于治疗控制痴呆和神经变性疾病的LHRH拮抗剂的药剂可以是
a)浓度为1mg/1ml或更低的活性化合物的乙酸盐制剂,其中可以将冻干粉溶于注射用水或葡萄糖酸;
b)浓度为1.5mg/1ml-5.0mg/1ml,优选2.5mg/1ml的活性化合物的乙酸盐制剂,其中可以将冻干粉溶于注射用水或葡萄糖酸;
c)浓度为10mg/1ml-30mg/1ml,优选15mg/1ml的活性化合物的双嗪盐制剂,其中可以将冻干粉溶于葡萄糖酸或注射用水。
例如,适宜的赋形剂和剂型如以下文献所述:K.H.Bauer,K.-H.Fromming和C.Fuhrer,Lehrbuch der Pharmazeutischen Technologie,6′h edition,Stuttgart 1999,163-186页(赋形剂)和227-386页(剂型),包括其引用的参考资料。
例如,LHRH拮抗剂可以皮下、口、肌内或吸入施用。
例如所述的疾病可以根据以下的方案治疗。
具体实施方案
实施例
在本发明一个实施方案中,每月通过注射施用单一剂量的30-60mg的西曲瑞克。持续所述治疗,每月一次。
在另一个实施方案中,在单一剂量施用后持续所述治疗每两个月一次或持续治疗数个月。
Claims (11)
1.LHRH拮抗剂用于制备通过中等剂量施用而治疗人的阿尔茨海默氏病的药物的应用,其特征在于所述药物适合以月单一剂量范围为10-100mg LHRH拮抗剂给药。
2.根据权利要求1的应用,其特征在于月单一剂量为30至60mgLHRH拮抗剂。
3.根据权利要求1的应用,其特征在于所述药物适合以每个月或每两个月持续施用或持续施用数个月。
4.根据权利要求2的应用,其特征在于所述药物适合以每个月或每两个月持续施用或持续施用数个月。
5.根据权利要求1-4之一的应用,其特征在于所述LHRH拮抗剂为西曲瑞克。
6.根据权利要求1-4之一的应用,其特征在于所述LHRH拮抗剂为替维瑞克。
7.根据权利要求1-4之一的应用,其特征在于所述LHRH拮抗剂为安肽。
8.根据权利要求1-4之一的应用,其特征在于所述LHRH拮抗剂为阿巴瑞克。
9.根据权利要求1-4之一的应用,其特征在于所述LHRH拮抗剂为D-63 153(Ac-D-Nal-D-pCI-Phe-D-Pal-Ser-N-Me-Tyr-D-Hci-Nle-Arg-Pro-D-Ala-NH2)。
10.根据权利要求1-4之一的应用,其特征在于所述LHRH拮抗剂为拟肽。
11.根据权利要求10的应用,其中所述拟肽为化合物
-1-[7-氯-3-(3,5-二甲基-苯基)-2-氧代-4-(2-哌啶-2-基-乙氧基)-1,2-二氢-喹啉-6-基]-3-吡啶-2-基-脲
-3-[苄基-甲基-氨基)-甲基]-2-叔丁基-8-(2-氟-苄基)-6-(3-甲氧基-苯基)-7-甲基-8H-咪唑并[1,2-a]嘧啶-5-酮
-2-(2,5-二甲基-呋喃-3-基)-8-(2-氟代-苄基)-3-([甲基-(2-吡啶-2-基乙基)-氨基]-甲基)-5-氧代-5,8-二氢-咪唑并[1,2-a]嘧啶-6-甲酸1-乙基-丙基酯或
-3-((2-[2-(3,5-二氟代-苯基)-1-(2-甲氧基-苯甲酰基)-2-氧代-亚乙基]-2,3-二氢-1H-苯并咪唑-5-基-氨基)-甲基)-苄腈。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US28743401P | 2001-04-30 | 2001-04-30 | |
US60/287,434 | 2001-04-30 |
Publications (2)
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CN1575185A CN1575185A (zh) | 2005-02-02 |
CN1317030C true CN1317030C (zh) | 2007-05-23 |
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CNB028042964A Expired - Fee Related CN1317030C (zh) | 2001-04-30 | 2002-04-27 | 用中等剂量的lhrh拮抗剂治疗阿尔茨海默氏病 |
Country Status (28)
Country | Link |
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US (1) | US7288517B2 (zh) |
EP (1) | EP1392348B1 (zh) |
JP (1) | JP2004529207A (zh) |
KR (1) | KR20040000446A (zh) |
CN (1) | CN1317030C (zh) |
AT (1) | ATE400287T1 (zh) |
AU (1) | AU2002310788B2 (zh) |
BG (1) | BG108339A (zh) |
BR (1) | BR0209290A (zh) |
CA (1) | CA2444876A1 (zh) |
CZ (1) | CZ20033167A3 (zh) |
DE (1) | DE60227507D1 (zh) |
DK (1) | DK1392348T3 (zh) |
ES (1) | ES2307760T3 (zh) |
HK (1) | HK1072000A1 (zh) |
HU (1) | HUP0400067A2 (zh) |
IL (1) | IL156777A0 (zh) |
MX (1) | MXPA03008666A (zh) |
NO (1) | NO20034322L (zh) |
NZ (1) | NZ544417A (zh) |
PL (1) | PL362319A1 (zh) |
PT (1) | PT1392348E (zh) |
RU (1) | RU2319501C2 (zh) |
SI (1) | SI1392348T1 (zh) |
SK (1) | SK14512003A3 (zh) |
UA (1) | UA80679C2 (zh) |
WO (1) | WO2002102401A1 (zh) |
ZA (1) | ZA200305326B (zh) |
Families Citing this family (16)
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US6828415B2 (en) * | 1993-02-19 | 2004-12-07 | Zentaris Gmbh | Oligopeptide lyophilisate, their preparation and use |
US20020077327A1 (en) * | 1999-09-23 | 2002-06-20 | Neurocrine Biosciences, Inc. | Gonadotropin-releasing hormone receptor antagonists and methods relating thereto |
EP1300398B1 (en) * | 2000-07-05 | 2006-04-05 | Astellas Pharma Inc. | Propane-1,3-dione derivatives |
DE10137174A1 (de) * | 2001-07-31 | 2003-02-13 | Zentaris Ag | Verwendung von LHRH-Antagonisten in nichtkastrierenden Dosen zur Verbesserung der T-Zellen-vermittelten Immunität |
EP1752452A4 (en) | 2004-06-04 | 2010-07-14 | Astellas Pharma Inc | DERIVATIVE OF PROPANE-1, 3-DIONE OR ITS SALT |
US20080171736A1 (en) * | 2004-12-23 | 2008-07-17 | Gregory Christopher W | Treatment of Alzheimer's Disease and Mild Cognitive impairment using GnRH-I analogs and one or more of acetylcholinesterase inhibitors and NMDA receptor antagonists |
WO2006071274A2 (en) * | 2004-12-23 | 2006-07-06 | Voyager Pharmaceutical Corporation | Leuprolide acetate and acetylcholinesterase inhibitors or nmda receptor antagonists for the treatment of alzheimer’s disease |
ES2392859T3 (es) * | 2005-03-31 | 2012-12-14 | Astellas Pharma Inc. | Derivado de propano-1,3-diona o una de sus sales |
EP2091943B1 (en) * | 2006-10-21 | 2013-11-20 | AbbVie Deutschland GmbH & Co KG | Heterocyclic compounds and their use as glycogen synthase kinase 3 inhibitors |
KR20100061483A (ko) * | 2007-09-11 | 2010-06-07 | 몬도바이오테크 래보래토리즈 아게 | 치료제로서의 혈소판 피브리노겐 수용체 헥사펩티드 길항제 및 알파-엔도르핀의 용도 |
US20100210567A1 (en) * | 2007-09-11 | 2010-08-19 | Dorian Bevec | Use of a tuftsin as a therapeutic agent |
EP2095818A1 (en) * | 2008-02-29 | 2009-09-02 | AEterna Zentaris GmbH | Use of LHRH antagonists at non-castrating doses |
WO2009145690A1 (en) * | 2008-05-29 | 2009-12-03 | Isr Immune System Regulation Ab | Method and means for treating viral disease, in particular hiv/aids |
JP5998142B2 (ja) | 2010-09-27 | 2016-09-28 | アボット ゲーエムベーハー ウント カンパニー カーゲー | 複素環化合物およびグリコーゲンシンターゼキナーゼ−3阻害薬としてのその使用 |
US9090592B2 (en) | 2010-12-30 | 2015-07-28 | AbbVie Deutschland GmbH & Co. KG | Heterocyclic compounds and their use as glycogen synthase kinase-3 inhibitors |
EP3560555A1 (en) * | 2018-04-26 | 2019-10-30 | LifeArc | A composition for treating one or more estrogen related diseases |
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US3135743A (en) | 1960-06-29 | 1964-06-02 | Sterling Drug Inc | Steroido[2. 3-d]isoxazoles and preparation thereof |
WO1997044339A1 (en) | 1996-05-20 | 1997-11-27 | Merck & Co., Inc. | Antagonists of gonadotropin releasing hormone |
DE19911771B4 (de) | 1999-03-17 | 2006-03-30 | Zentaris Gmbh | LHRH-Antagonist, Verfahren zu seiner Herstellung und seiner Verwendung |
WO2000069859A1 (en) * | 1999-05-14 | 2000-11-23 | Neurocrine Biosciences, Inc. | Imidazo- and pyrrolo[1,2-a]pyrimid-4-ones as gonadotropin-releasing hormone receptor antagonists |
CA2309395A1 (en) | 1999-06-04 | 2000-12-04 | Richard Lloyd Bowen | Methods for preventing and treating alzheimer's disease |
JP2003512379A (ja) | 1999-10-15 | 2003-04-02 | ニューロクライン バイオサイエンシーズ, インコーポレイテッド | 性腺刺激ホルモン放出ホルモンレセプターアンタゴニストおよびそれに関連する方法 |
AU2001248760A1 (en) | 2000-04-13 | 2001-10-30 | Takeda Chemical Industries Ltd. | Preventives/remedies for alzheimer's disease |
EP1300398B1 (en) | 2000-07-05 | 2006-04-05 | Astellas Pharma Inc. | Propane-1,3-dione derivatives |
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2002
- 2002-04-27 KR KR10-2003-7014128A patent/KR20040000446A/ko not_active Application Discontinuation
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Also Published As
Publication number | Publication date |
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PT1392348E (pt) | 2008-09-09 |
NO20034322D0 (no) | 2003-09-26 |
SI1392348T1 (sl) | 2008-12-31 |
AU2002310788B2 (en) | 2007-04-05 |
KR20040000446A (ko) | 2004-01-03 |
NO20034322L (no) | 2003-09-26 |
US20020177556A1 (en) | 2002-11-28 |
EP1392348A1 (en) | 2004-03-03 |
DK1392348T3 (da) | 2008-09-29 |
IL156777A0 (en) | 2004-02-08 |
MXPA03008666A (es) | 2004-10-15 |
PL362319A1 (en) | 2004-10-18 |
RU2319501C2 (ru) | 2008-03-20 |
WO2002102401A1 (en) | 2002-12-27 |
HK1072000A1 (en) | 2005-08-12 |
RU2003134949A (ru) | 2005-02-10 |
CZ20033167A3 (cs) | 2004-08-18 |
ZA200305326B (en) | 2003-07-30 |
CN1575185A (zh) | 2005-02-02 |
NZ544417A (en) | 2008-03-28 |
EP1392348B1 (en) | 2008-07-09 |
BG108339A (bg) | 2004-11-30 |
CA2444876A1 (en) | 2002-12-27 |
JP2004529207A (ja) | 2004-09-24 |
ATE400287T1 (de) | 2008-07-15 |
ES2307760T3 (es) | 2008-12-01 |
BR0209290A (pt) | 2004-07-13 |
SK14512003A3 (sk) | 2004-08-03 |
US7288517B2 (en) | 2007-10-30 |
UA80679C2 (en) | 2007-10-25 |
DE60227507D1 (de) | 2008-08-21 |
HUP0400067A2 (hu) | 2004-04-28 |
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