CN1129907A - (r)-氨氯地平对平滑肌细胞移行的抑制 - Google Patents

(r)-氨氯地平对平滑肌细胞移行的抑制 Download PDF

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CN1129907A
CN1129907A CN94193173A CN94193173A CN1129907A CN 1129907 A CN1129907 A CN 1129907A CN 94193173 A CN94193173 A CN 94193173A CN 94193173 A CN94193173 A CN 94193173A CN 1129907 A CN1129907 A CN 1129907A
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amlodipine
isomer
smooth muscle
muscle cell
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CN1060039C (zh
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S·B·查瓦拉
D·P·温斯劳
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Pfizer Research and Development Co NV SA
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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/04—Drugs for genital or sexual disorders; Contraceptives for inducing labour or abortion; Uterotonics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

虽然氨氯地平的R(+)异构体缺乏钙通道阻断活性，但它是有效的平滑肌细胞移行抑制剂。它可用于治疗动脉粥样硬化、血管成型术后再狭窄和子宫内膜异位。

Description

(R)-氨氯地平对平滑肌细胞移行的抑制
本发明涉及用具有已批准的非专有名称“氨氯地平”的化合物3-乙基-5-甲基-2-(2-氨基乙氧基甲基)-4-(2-氯苯基)-1，4-二氢-6-甲基吡啶-3，5-二羧酸酯(或盐)的R(+)异构体治疗涉及平滑肌细胞移行的医学病症。
氨氯地平是一种已知的具有血管舒张活性的钙通道阻断剂，现通常以可药用盐形式如其马来酸盐或苯甲酸盐用于治疗高血压和心绞痛。该化合物及其制备描述在欧洲专利0089167B1中。由于氨氯地平在二氢吡啶环4位处的对称性，所以它是一种外消旋化合物，其R-和S-对映体可以通过J.Med.Chem.1986 29 1696(Arrowsmith等人)和欧洲专利申请0331315A中所述的方法制备。早先人们相信，两个拆分出的异构体为R(-)和S-(+)异构体，但后来发现事实上它们分别是S(-)和R(+)异构体(参见J.Med.Chem.，35，3341-3344(1992)，Goldmann等人)。已知氨氯地平的钙通道阻断活性基本上限于S(-)形式以及R(+)和S(-)形式的外消旋混合物；R(+)异构体具有很小或没有钙通道阻断活性，所以当让病人服用后不可能具有显著的心血管作用。
已知钙通道阻断剂一般往往会抑制平滑肌细胞移行。因此，已发现它们阻止动脉粥样硬化的各种动物模型中的损害发展(参见ArterioSclerosis 5，250(1985)，Willis等人；Arteriosclerosis 6，237(1986)，Sugano等人)；一种叫伊拉地平的钙通道阻断剂也降低由气囊血管成形术引起的内皮细胞损伤后发生的各种平滑肌细胞增殖损害(参见Am.J.Pathol 124，88-93(1986)Handley等人)。在气囊血管成形术后再狭窄和动脉粥样化形成期间，心管平滑肌细胞从血管中层向内膜移行，在那儿它们增殖。据信气囊血管成形术后的再狭窄和动脉粥样硬化的动物模型中钙通道阻断剂的效能是由于抑制了血管平滑肌细胞移行以及随后减少了平滑肌细胞增殖和新内膜形成。
因此，预期钙通道阻断剂可用于治疗平滑肌细胞移行的病症，包括动脉粥样硬化、血管成形术后的再狭窄和子宫内膜异位。
现已令人惊奇地发现，与所有现有的理论相反，尽管氨氯地平的R(+)异构体缺乏钙通道阻断活性，但它是有效的平滑肌细胞移行抑制剂并且其在此方面的效力大于氨氯地平的S(-)异构体和一些其他已知的钙通道阻断剂的效力。因此，所述的R(+)异构体提供了一种治疗涉及平滑肌细胞移行的病症而不伴发任何心血管效应的手段。
因此，它适用于不希望降低血压的病人。
这样，本发明的一个方面包括用于治疗需要抑制血管平滑肌细胞移行的病症的氨氯地平的R(+)异构体或其可药用的盐。
本发明还提供了氨氯地平的R(+)异构体或其可药用的盐用于制备治疗需要抑制平滑肌细胞移行的病症的药物的应用。
本发明的另一方面提供了一种药物组合物，它包含氨氯地平的R(+)异构体或其可药用的盐以及可药用的载体或稀释剂，所述组合物基本上没有钙通道阻断活性。
本发明还提供了一种治疗需要抑制平滑肌细胞移行的病症的方法，它包括给予病人有效量的氨氯地平的R(+)异构体或其可药周的盐。
氨氯地平的可药用的盐包括马来酸盐和苯甲酸盐。所治疗的病症包括动脉粥样硬化、血管成形术后初发的再狭窄以及子宫内膜异位。氨氯地平的R(+)异构体可在没有S(-)异构体和任何其他起钙通道阻断剂作用的化合物的情况下使用。
氨氯地平的R(+)异构体对平滑肌细胞移行的效果用如在Atherosclerosis 86，227-237(1191)中所述的主动脉移植试验方法来说明，其中用兔主动脉平滑肌细胞的初级培养物来评估平滑肌细胞的调整、移行和增殖。在该方法中，将来自兔主动脉的内膜/中层组织的各均匀片状物在一个孔板的各孔中培养。通过向培养物中加入血小板衍生的生长因子来诱导移行。数天迟滞期后，平滑肌细胞从移植的组织移行并增殖。
测量长出的平滑肌细胞所覆盖的距离。
通过改变加到培养物中的试验化合物的浓度进行该试验，试验化合物是R(+)和S(-)氨氯地平的外消旋混合物的马来酸盐、R(+)和S(-)氨氯地平各自的马来酸盐以及已知的钙通道阻断剂尼群地平和异搏定。
所得结果示于表1中，其中记载了lnM和0.1M试验化合物浓度对平滑肌细胞移行的百分抑制。
也通过Burges等人J.Cardiovasc Pharmacol 9(1)，110-9所述的方法测试了氨氯地平马来酸盐的外消旋体、R(+)和S(-)形式对K+诱导的大鼠主动脉收缩的抑制；表1也记载了用nM表示的IC50(50％抑制浓度)值，它对钙通道阻断活性提供了一种量度。
                     表1
                  SMC从外植体    K+诱导的大鼠主
                  移行的抑制     动脉收缩的抑制化合物                 1nM   0.1nM    IC50(nM)氨氯地平(外消旋体)      33    39         2氨氯地平R(+)            39    36        1000氨氯地平S(-)            30    21         1尼群地平                28    14异搏定                  22    13
从这些结果很明显看出，氨氯地平的R(+)对映体虽然其作为钙通道阻断剂的活性可忽略，但它可有效地抑制平滑肌细胞移行。
对于人们服用R(+)氨氯地平或其盐来治疗或预防涉及平滑肌细胞移行的病症，对于平均成年人(体重70kg)来说口服剂量可以为每天2-10mg，该范围相似于用氨氯地平治疗高血压的剂量。然而，由于没有心血管效应，所以允许服用远大于对钙通道阻断S(-)异构体或外消旋体推荐的剂量，由此相应增强对细胞移行的作用。这样对于平均成年人来说R(+)氨氯地平或其盐的口服剂量可以为20mg或更高及最高达100mg/天，或甚至更高。所用的实际剂量将由主治医生考虑了病人的年龄、体重、状况或病史后确定。对于一般成年病人，各片剂或胶囊可能在合适的药物媒介物或载体中含有1-100mg活性化合物。静脉给药的剂量如所要求的就每个单剂量而言可为1-20mg活性化合物。这样，根据本发明的另一方面，提供了基本上没有钙通道阻断活性的药物组合物的单位剂量，它含有(对于口服来说)1-100mg、优选20-100mg氨氯地平的R(+)异构体或其可药用的盐。本发明的另一方面提供了对于静脉给药的这样一种单位剂量，它含有1-20mg氨氯地平的R(+)异构体或其盐。

Claims (7)

1.用于治疗需要抑制血管平滑肌细胞移行的病症的氨氯地平的R(+)异构体或其可药用的盐。
2.氨氯地平的R(+)异构体或其可药用的盐用于制备治疗需要抑制平滑肌细胞移行的病症的药物的应用。
3.一种治疗需要抑制平滑肌细胞移行的病症的方法，其中包括给予病人有效量的氨氯地平的R(+)异构体或其可药用的盐。
4.一种药物组合物，它包含氨氯地平的R(+)异构体或其可药用的盐和可药用的载体或稀释剂，所述组合物基本上没有钙通道阻断活性。
5.用于口服的权利要求4的组合物的单位剂量，它含有1-100mg氨氯地平的R(+)异构体或其可药用的盐。
6.根据权利要求5的单位剂量，它含有至少20mg氨氯地平的R(+)异构体或其可药用的盐。
7.用于静脉给药的权利要求4的组合物的单位剂量，它包含1-20mg氨氯地平的R(+)异构体或其可药用的盐。
CN94193173A 1993-08-26 1994-08-10 (r)-氨氯地平对平滑肌细胞移行的抑制 Expired - Fee Related CN1060039C (zh)

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US7129265B2 (en) * 1999-04-23 2006-10-31 Mason R Preston Synergistic effects of amlodipine and atorvastatin metabolite as a basis for combination therapy
GB0020842D0 (en) * 2000-08-23 2000-10-11 Pfizer Ltd Therapeutic compositions
US6737430B2 (en) 2000-11-09 2004-05-18 Pfizer, Inc. Mutual prodrug of amlodipine and atorvastatin
US7335380B2 (en) 2000-12-29 2008-02-26 Synthon Ip Inc. Amlodipine free base
AT5874U1 (de) * 2000-12-29 2003-01-27 Bioorg Bv Pharmazeutische zubereitungen enthaltend amlodipinmaleat
EP1345901A2 (en) * 2000-12-29 2003-09-24 Bioorganics B.V. Process for making amlodipine, derivatives thereof, and precursors therefor
CN1152013C (zh) * 2001-11-22 2004-06-02 张喜田 一类左旋氨氯地平盐的水合物及其制剂
BRPI0511095B8 (pt) * 2004-10-20 2021-05-25 Emcure Pharmaceuticals Ltd um processo para produção de enantiômero de anlodipino em alta pureza ótica
KR100828883B1 (ko) * 2006-10-27 2008-05-09 씨제이제일제당 (주) 라세믹 암로디핀으로부터 ｓ-(-)-암로디핀의 분리방법
KR100830003B1 (ko) * 2006-10-31 2008-05-15 씨제이제일제당 (주) 결정성 ｓ-(-)-암로디핀 아디핀산 염 무수물 및 이의 제조방법

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CA2170278A1 (en) 1995-03-02
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IL110700A (en) 1999-04-11
AU686658B2 (en) 1998-02-12
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ZA946475B (en) 1996-02-26
JPH08509004A (ja) 1996-09-24
US6080761A (en) 2000-06-27
ATE192337T1 (de) 2000-05-15
JP2000044475A (ja) 2000-02-15
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PT754043E (pt) 2000-09-29
DK0754043T3 (da) 2000-08-07
AU7612994A (en) 1995-03-21
EP0754043A1 (en) 1997-01-22
GB9317773D0 (en) 1993-10-13
KR0163840B1 (ko) 1998-12-01
CA2170278C (en) 1999-08-03
NO960730D0 (no) 1996-02-23
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