CN1575185A - 用中等剂量的lhrh拮抗剂治疗痴呆和神经变性疾病 - Google Patents

用中等剂量的lhrh拮抗剂治疗痴呆和神经变性疾病 Download PDF

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CN1575185A
CN1575185A CNA028042964A CN02804296A CN1575185A CN 1575185 A CN1575185 A CN 1575185A CN A028042964 A CNA028042964 A CN A028042964A CN 02804296 A CN02804296 A CN 02804296A CN 1575185 A CN1575185 A CN 1575185A
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lhrh antagonist
methyl
treatment
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CN1317030C (zh
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J·恩格尔
R·弗格里
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Aeterna Zentaris GmbH
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Zentaris AG
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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
    • 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拮抗剂治疗痴呆和神经变性疾病
本发明涉及用不导致去势的中等剂量的LHRH拮抗剂治疗痴呆和神经变性疾病。
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。
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。
本发明涉及使用中等剂量的LHRH拮抗剂治疗痴呆和神经变性疾病，其中所述拮抗剂优选为西曲瑞克、teverelix、antide或abarelix。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 00/55190 A1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。
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 (12)

1.LHRH拮抗剂用于制备通过中等剂量施用而治疗人的痴呆和神经变性疾病的药物的应用，所述应用不导致去势。
2.根据权利要求1的应用，其特征在于月单一剂量范围为10-100mg LHRH拮抗剂。
3.根据权利要求1和2的应用，其特征在于月单一剂量为大约30至大约60mg LHRH拮抗剂。
4.根据权利要求1-3之一的应用，其特征在于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，其特征在于所述治疗疾病为阿耳茨海默氏病。
6.根据权利要求1-5之一的应用，其特征在于所述LHRH拮抗剂为西曲瑞克。
7.根据权利要求1-5之一的应用，其特征在于所述LHRH拮抗剂为teverelix。
8.根据权利要求1-5之一的应用，其特征在于所述LHRH拮抗剂为antide。
9.根据权利要求1-5之一的应用，其特征在于所述LHRH拮抗剂为abarelix。
10.根据权利要求1-5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)。
11.根据权利要求1-5之一的应用，其特征在于所述LHRH拮抗剂为拟肽。
12.根据权利要求11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)

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NO20034322D0 (no) 2003-09-26
KR20040000446A (ko) 2004-01-03
NO20034322L (no) 2003-09-26
PL362319A1 (en) 2004-10-18
ZA200305326B (en) 2003-07-30
HUP0400067A2 (hu) 2004-04-28
UA80679C2 (en) 2007-10-25
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ES2307760T3 (es) 2008-12-01
IL156777A0 (en) 2004-02-08
JP2004529207A (ja) 2004-09-24
PT1392348E (pt) 2008-09-09
BR0209290A (pt) 2004-07-13
DE60227507D1 (de) 2008-08-21
SK14512003A3 (sk) 2004-08-03
SI1392348T1 (sl) 2008-12-31
MXPA03008666A (es) 2004-10-15
ATE400287T1 (de) 2008-07-15
CZ20033167A3 (cs) 2004-08-18
EP1392348B1 (en) 2008-07-09
WO2002102401A1 (en) 2002-12-27
CA2444876A1 (en) 2002-12-27
US20020177556A1 (en) 2002-11-28
CN1317030C (zh) 2007-05-23
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EP1392348A1 (en) 2004-03-03
NZ544417A (en) 2008-03-28
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