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 PDF

Info

Publication number
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
Authority
CN
China
Prior art keywords
application
lhrh antagonist
methyl
continue
treatment
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.)
Expired - Fee Related
Application number
CNB028042964A
Other languages
English (en)
Other versions
CN1575185A (zh
Inventor
J·恩格尔
R·弗格里
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.)
Aeterna Zentaris GmbH
Original Assignee
Zentaris AG
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 Zentaris AG filed Critical Zentaris AG
Publication of CN1575185A publication Critical patent/CN1575185A/zh
Application granted granted Critical
Publication of CN1317030C publication Critical patent/CN1317030C/zh
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • 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

用中等剂量的LHRH拮抗剂治疗阿尔茨海默氏病
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。
CNB028042964A 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 Expired - Fee Related CN1317030C (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US28743401P 2001-04-30 2001-04-30
US60/287,434 2001-04-30

Publications (2)

Publication Number Publication Date
CN1575185A CN1575185A (zh) 2005-02-02
CN1317030C true CN1317030C (zh) 2007-05-23

Family

ID=23102886

Family Applications (1)

Application Number Title Priority Date Filing Date
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
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) NO20034322D0 (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)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN1186326C (zh) 2000-07-05 2005-01-26 山之内制药株式会社 丙－1,3－二酮衍生物
DE10137174A1 (de) * 2001-07-31 2003-02-13 Zentaris Ag Verwendung von LHRH-Antagonisten in nichtkastrierenden Dosen zur Verbesserung der T-Zellen-vermittelten Immunität
MXPA06014131A (es) 2004-06-04 2007-03-07 Astellas Pharma Inc Derivado de propano-1,3-diona o su sal.
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
EP1827468B1 (en) * 2004-12-23 2012-08-22 Curaxis Pharmaceutical Corporation Acetylcholinesterase Inhibitors and leuprolide acetate for the treatment of Alzheimer's disease
AU2006232469B2 (en) * 2005-03-31 2011-03-31 Astellas Pharma Inc. Propane-1,3-dion derivative or salt thereof
RU2009119181A (ru) * 2006-10-21 2010-11-27 Эбботт Гмбх Унд Ко.Кг (De) Гетероциклические соединения и их применение в качестве ингибиторов гликогенсинтаза-киназы-3
JP2010538994A (ja) * 2007-09-11 2010-12-16 モンドバイオテック ラボラトリーズ アクチエンゲゼルシャフト 例えば肺炎連鎖球菌感染症を治療するためのｂｆｇｆ１−２４および任意での（ａｒｇ８）バソプレシンの使用
WO2009033765A2 (en) * 2007-09-11 2009-03-19 Mondobiotech Laboratories Ag Use of a peptide as a therapeutic agent
EP2095818A1 (en) * 2008-02-29 2009-09-02 AEterna Zentaris GmbH Use of LHRH antagonists at non-castrating doses
US20110129532A1 (en) * 2008-05-29 2011-06-02 Isr Immune System Regulation Ab Method and means for treating viral disease, in particular hiv/aids
US9266855B2 (en) 2010-09-27 2016-02-23 AbbVie Deutschland GmbH & Co. KG Heterocyclic compounds and their use as glycogen synthase kinase-3 inhibitors
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

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3135743A (en) 1960-06-29 1964-06-02 Sterling Drug Inc Steroido[2. 3-d]isoxazoles and preparation thereof
US6150352A (en) * 1996-05-20 2000-11-21 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
CA2372044A1 (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
MXPA02003614A (es) * 1999-10-15 2002-10-23 Neurocrine Biosciences Inc Antagonistas del receptor de la hormona liberadora de ganadotropina y metodos relacionados con los mismos..
WO2001078780A1 (fr) 2000-04-13 2001-10-25 Takeda Chemical Industries, Ltd. Agents preventifs/remedes pour la maladie d'alzheimer
CN1186326C (zh) 2000-07-05 2005-01-26 山之内制药株式会社 丙－1,3－二酮衍生物

Also Published As

Publication number Publication date
HK1072000A1 (en) 2005-08-12
EP1392348B1 (en) 2008-07-09
ATE400287T1 (de) 2008-07-15
AU2002310788B2 (en) 2007-04-05
PT1392348E (pt) 2008-09-09
NO20034322L (no) 2003-09-26
RU2003134949A (ru) 2005-02-10
NZ544417A (en) 2008-03-28
CZ20033167A3 (cs) 2004-08-18
CN1575185A (zh) 2005-02-02
CA2444876A1 (en) 2002-12-27
BG108339A (bg) 2004-11-30
KR20040000446A (ko) 2004-01-03
US20020177556A1 (en) 2002-11-28
ES2307760T3 (es) 2008-12-01
SI1392348T1 (sl) 2008-12-31
WO2002102401A1 (en) 2002-12-27
UA80679C2 (en) 2007-10-25
JP2004529207A (ja) 2004-09-24
BR0209290A (pt) 2004-07-13
SK14512003A3 (sk) 2004-08-03
NO20034322D0 (no) 2003-09-26
ZA200305326B (en) 2003-07-30
MXPA03008666A (es) 2004-10-15
HUP0400067A2 (hu) 2004-04-28
RU2319501C2 (ru) 2008-03-20
PL362319A1 (en) 2004-10-18
US7288517B2 (en) 2007-10-30
DK1392348T3 (da) 2008-09-29
EP1392348A1 (en) 2004-03-03
DE60227507D1 (de) 2008-08-21
IL156777A0 (en) 2004-02-08

Similar Documents

Publication Publication Date Title
CN1317030C (zh) 用中等剂量的lhrh拮抗剂治疗阿尔茨海默氏病
US6939853B2 (en) Combined use of a GLP-1 compound and another drug for treating dyslipidemia
US6936601B2 (en) Compositions for treating pain
EP2671584A2 (en) Compositions and methods for treating disorders associated with salt or fluid retention
US20100184690A1 (en) Combined Use Of A GLP-1 Compound And A Modulator Of Diabetic Late Complications
US20090163408A1 (en) Salicylanilides enhance oral delivery of therapeutic peptides
JP2020040971A (ja) 他の薬物と組み合わせたグアニル酸シクラーゼ受容体アゴニスト
JP2015199769A (ja) 高コレステロール血症、アテローム性動脈硬化症、冠動脈性心疾患、胆石、肥満症、および他の心血管疾患の処置のために有用なグアニル酸シクラーゼのアゴニスト
EP1012188A1 (de) Zusammensetzung zur therapie von diabetes mellitus und fettsucht
AU2002310788A1 (en) Treatment of dementia and neurodegenerative diseases with intermediate doses of LHRH antagonists
JP2010517987A (ja) 塩基性ペプチド及びその複合型抗細菌−抗真菌剤としての使用
US6437093B1 (en) Methods of treatment comprising administration of Substance P
CA2173839C (en) Transferrin compositions to alleviate the side effects of cytotoxic drugs
KR960033468A (ko) 혈전용해 치료를 받지않은 환자에서 히루딘 및 아세틸살리실산으로 급성 심근 경색을 치료하는 방법
JP4287523B2 (ja) 抗腫瘍剤
DE60308710T2 (de) Pharmazeutische zusammensetzung mit einem retro-inverso isomerpeptid
JP2004359675A (ja) 脳卒中の治療および予防剤
DE19810515A1 (de) Zusammensetzung zur Therapie von Diabetes mellitus und Fettsucht

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1072000

Country of ref document: HK

C14 Grant of patent or utility model
GR01 Patent grant
C19 Lapse of patent right due to non-payment of the annual fee
CF01 Termination of patent right due to non-payment of annual fee