[go: up one dir, main page]

CN1217656C - 用于调节脂浓度的方法和药物组合物 - Google Patents

用于调节脂浓度的方法和药物组合物 Download PDF

Info

Publication number
CN1217656C
CN1217656C CN961980109A CN96198010A CN1217656C CN 1217656 C CN1217656 C CN 1217656C CN 961980109 A CN961980109 A CN 961980109A CN 96198010 A CN96198010 A CN 96198010A CN 1217656 C CN1217656 C CN 1217656C
Authority
CN
China
Prior art keywords
phenyl
methylethyl
atorvastatin
cholesterol
combination
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
CN961980109A
Other languages
English (en)
Other versions
CN1201389A (zh
Inventor
T·M·A·博坎
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.)
Warner Lambert Co LLC
Original Assignee
Warner Lambert Co LLC
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
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=21719566&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=CN1217656(C) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Warner Lambert Co LLC filed Critical Warner Lambert Co LLC
Publication of CN1201389A publication Critical patent/CN1201389A/zh
Application granted granted Critical
Publication of CN1217656C publication Critical patent/CN1217656C/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
    • 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
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/255—Esters, e.g. nitroglycerine, selenocyanates of sulfoxy acids or sulfur analogues thereof
    • 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
    • A61K31/325—Carbamic acids; Thiocarbamic acids; Anhydrides or salts thereof
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • 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
    • A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/36—Antigestagens
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Emergency Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Diabetes (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Endocrinology (AREA)
  • Cardiology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

本发明涉及ACAT抑制剂，例如氨基磺酸、〔〔2、4、6-三(1-甲基乙基)苯基〕乙酰基〕-、2、6-二(1-甲基乙基)苯基酯、与HMG-CoA还原酶抑制剂，例如阿托伐他汀(atorvastatin)，的组合，该组合对脂的调节有效。药剂的组合导致比单独使用两者任一个时更大地降低血浆VLDL和LDL胆固醇并升高HDL胆固醇，导致一种较少致动脉粥样硬化的脂蛋白分布。这种组合用于治疗易于患有或处于产生局部缺血综合症的病人以恢复内源血管内皮依赖性活性。

Description

用于调节脂浓度的方法和药物组合物
发明背景
具有或易于产生局部缺血综合症的病人用3-羟基-3-甲基戊二酰基辅酶A(HMG-CoA)还原酶抑制剂药剂治疗，以降低总的和低密度(LDL)胆固醇是为人熟知的。这么做是为了恢复内源血管的内皮依赖性活性，包括但不局限于调节血管弹性和血流的血管舒张反应、血管壁的粘附性、和血小板的抗凝作用(国际公开号WO 95/13063)。
来自动物模型的证据表明抑制酶、酰基辅酶A：胆固醇酰基转移酶(ACTA)的化合物将是有效的抗动脉粥样硬化剂，( Curr，Med.Chem，1994；1：204-225)。非常确定的是当血浆中的大多数胆固醇是被含载脂蛋白B的脂蛋白携带，如低密度脂蛋白(LDL-C)和极低密度脂蛋白(VLDL-C)上时，人患冠状动脉疾病的风险增加。( 循环，1990；81：1721-1733)。相反地，被高密度脂蛋白(HDL-C)携带的高含量的胆固醇对冠状动脉疾病具有预防作用( 美国内科学杂志，1977；62：707-714)。因此，一种降低致动脉粥样硬化的LDL-C和VLDL-C的含量而提高预防性的HDL-C的含量的药物会引起较少致动脉粥样硬化的脂蛋白的分布并因此产生对动脉粥样硬化疾病及其并发症的有益的作用。这种有益作用在用降低LDL-C，升高HDL-C，并减少冠状动脉疾病的发病率的脂调节剂吉非贝齐对人体的赫尔辛基心脏研究中得到了证实( 新英格兰医学杂志，1987；317：1237-1245)。
本发明概述
我们现已证明当在chow/fat食谱中给予ACTA抑制剂和HMG-CoA还原酶抑制剂的混合物时比单独使用任何一种时会导致含apo B脂蛋白的更大降低并且可实现血浆脂蛋白分布的正常化。这意谓着组合治疗引起了与降低冠状动脉疾病危险性相关的血浆脂蛋白分布。
我们还证明ACTA抑制剂和HMG-CoA还原酶抑制剂的组合降低了已存的动脉粥样硬化斑块的胆固醇酯(CE)的富集，达到了与单独使用HMG-CoA还原酶抑制剂时的同样程度，但动脉粥样硬化斑块的组织学特征不太复杂了。这意谓着斑块不太倾向于引起心肌梗死了。
本发明的详细描述
本发明的新的治疗方法和新的药物组合物包括对易于产生动脉粥样硬化的病人或已被诊断出该疾病的病人给予ACTA抑制剂和HMG-CoA还原酶抑制剂，它们将恢复内源血管的内皮依赖性活性，包括改善内皮正常的舒张能力。此方法可用于诱导血管舒张调节血管弹性和血流。其它的在血管内皮依赖性活性方面的改善包括降低血管壁的粘附性和降低血小板的凝结。适用于本发明的方法的受治疗者包括那些目前表现出动脉粥样硬化症状的个体、那些易于产生各种急性局部缺血综合症的个体，包括有高血压、糖尿病、或高血脂的个体，以及那些抽烟的个体。
可通过本发明的方法治疗的各种急性局部缺血综合症包括：心绞痛、冠状动脉疾病(CAD)、高血压、脑血管意外伤害、瞬时的局部缺血发作、慢性阻塞性肺病、慢性缺氧肺病、肺动脉高压症、肾性高血压、慢性肾病、糖尿糖微血管并发症，以及镰形细胞贫血的血管闭塞并发症。
用于新方法的HMG-CoA还原酶抑制剂可选自阿托伐他汀(atorvastatin)、洛伐他汀、辛伐他汀、普伐他汀、氟伐他汀(fluvastatin)、和利伐他汀(rivastatin)；优选阿托伐他汀、洛伐他汀、或辛伐他汀；最优选阿托伐他汀。
HMG-CoA还原酶抑制剂起抗高胆固醇血药剂的作用是为人熟知的。它们通过抑制在胆固醇生物合成、羟甲基戊二酸到甲羟戊酸的转化中催化早期、限速步骤的HMG-CoA还原酶降低肝胆固醇。熟知的HMG-CoA还原酶抑制剂包括阿托伐他汀、MEVACOR(洛伐他汀)、ZOCOR(辛伐他汀)、PRAVACHOL(普伐他汀)、LESCOL(氟伐他汀)、和利伐他汀。
设想的用于本发明的HMG-CoA还原酶抑制剂的剂量是约每天5到80毫克，优选一次或分次服用。
优选病人在用HMG-CoA还原酶抑制剂治疗过程中处于谨慎的降脂饮食中。
用HMG-CoA还原酶抑制剂的降脂疗法使具有高胆固醇血症和/或冠状动脉疾病的病人的血管功能正常化，而不要求动脉粥样硬化斑块的明显消退。在高胆固醇血症和动脉粥样硬化疾病存在下表现显著受损的内皮依赖性舒张反应但通常无动脉粥样化的冠状微循环可能显示出明显的改善，表明降脂治疗能阻断人贲门上部动脉的动脉粥样硬化的进展和/或促进消退。
阿托伐他汀公开于美国专利号5,273,995中。相关化合物公开于美国专利号4,681,893中。
洛伐他汀及相关化合物公开于美国专利号4,231,938中；辛伐他汀及相关化合物公开于美国专利号4,450,171和美国专利号4,346,227中；普伐他汀及相关化合物公开于美国专利号4,346,227中而氟伐他汀及相关化合物公开于美国专利号4,739,073中；利伐他汀及相关化合物公开于美国专利号5,177,080和5,006,530中。
能有效抑制酶、酰基辅酶A：胆固醇酰基转移酶(ACAT)的化合物阻止饮食中胆固醇的肠吸收进入血流或通过身体的自我调节作用将已被释放进肠中的胆固醇的再吸收。ACAT抑制化合物提供了高胆固醇血症和动脉粥样硬化的治疗。这类化合物包括，例如式I的化合物
或其药物可接受的盐，其中：
x和y是选自氧、硫和(CR′R″)n，其中n是从1到4的整数，R′和R″每一个独立地是氢、烷基、烷氧基、卤素、羟基、酰氧基、环烷基、选择性取代的苯基或R′和R″一起形成一螺环烷基或羰基；
附带条件是至少x和y中一个是(CR′R″)n并且更进一步的附带条件是当x和y两者都是(CR′R″)n，而R′和R″是氢，n是1时，R1和R2是芳基；
R是氢、从1到8个碳原子的直链或支链烷基或苄基；
R1和R2每一个独立地选自
(a)苯基或苯氧基，其每一个是未取代或被1到5个取代基取代的，取代基选自
苯基，
具有1到6个碳原子的直链或支链的烷基基团，
具有1到6个碳原子的直链或支链的烷氧基基团，
苯氧基，
羟基，
氟，
氯，
溴，
硝基，
三氟甲基，
-COOH，
-COO烷基，其中烷基具有1到4个碳原子并且是直链或支链的，
-(CH2)pNR3R4，其中p是0或1，而R3和R4每一个是选自氢或具有1到4个碳原子的直链或支链烷基基团；
(b)未取代或被1到3个取代基取代的1-或2-萘基，取代基选自苯基，
具有1到6个碳原子的直链或支链的烷基基团，
具有1到6个碳原子的直链或支链的烷氧基基团；
羟基，
苯氧基，
氟，
氯，
溴，
硝基，
三氟甲基，
-COOH，
-COO烷基，其中的烷基具有1到4个碳原子并且是直链或支链的，
-(CH2)pNR3R4，其中P、R3和R4具有上面所定义的意义；
(c)芳基烷基；
(d)具有1到20个碳原子并且是饱和或含有1到3个双键的直链或支链烷基链；或
(e)金刚烷基或环烷基基团，其中环烷基部分具有3到6个碳原子；
附带条件是：
(i)式中x是(CH2)n，y是氧，并且R1是取代的苯基，那么R2是取代的苯基；
(ii)式中y是氧，x是(CH2)n，R2是苯基或萘基，那么R1不是直链或支链的烷基链；和
(iii)如下化合物排除在外：
 X         Y          R          R1                  R2
CH2       O          H         (CH2)2CH3         苯基
CH2       O          H         CH3                  苯基
CH2       O          H             异丙基
用于新方法的ACAT抑制剂可选自任何有效的化合物，尤其是上面式I的化合物，尤其是氨基磺酸、〔〔2、4、6-三(甲基乙基)-苯基〕乙酰基〕-2、6-二〔(1-甲基乙基)苯基酯〕；2、6-二(1-甲基乙基)苯基-〔〔2、6-二(1-甲基乙基)-苯基〕磺酰基〕甲氨酸一钠盐；N-(2、6-二异丙基-苯基)-2-苯基-丙酰胺酸十二烷基酯；N-(2、6-二异丙基-苯基)-2-(2-十二烷基-2H-5-四唑基)-2-苯基-乙酰胺；2、2-二甲基-N-(2、4、6-三甲氧基苯基)-十二烷酰胺；和N-〔2、6-二(1-甲基乙基)苯基〕-N′-〔〔1-〔4-(二甲基-氨基)苯基〕环戊基〕甲基脲一盐酸盐。
设想的用于本发明的ACAT抑制剂的剂量是大约每天50到1500毫克，优选一次或分次服用。
一种特别有用的ACAT抑制剂是2、6-二(1-甲基乙基)苯基〔〔2、4、6-三(1-甲基乙基)苯基〕乙酰基〕氨基磺酸酯，公开于1994.4.13提出申请的美国专利申请号08/223,932中，这里通过参考文献并入本发明。
其它ACAT抑制剂是2、6-二-(1-甲基乙基)-苯基〔〔2、6-二(1-甲基乙基)苯氧基〕-磺酰基〕-甲氨酸一钠盐；相似的化合物公开于美国专利号5,245,068中；N-(2、6-二异丙基-苯基)-2-苯基-丙酰胺酸十二烷基酯；相似的化合物公开于美国专利号5,420,339中；N-(2、6-二异丙基苯基)-2-(2-十二烷基-2H-5-四唑基)-2-苯基-乙酰胺；相似的化合物公开于美国专利号5,366,987和分案申请5,441,975中；N-〔2、6-二(1-甲基乙基)苯基〕-N′-〔〔1-〔4-(二甲氨基)苯基〕环戊基〕甲基〕脲一盐酸盐，公开于美国专利号5,015,644中，和2、2-二甲基-N-(2、4、6-三甲氧基苯基)十二烷酰胺，相似的化合物公开于美国专利号4,716,175中。
在兔的动脉粥样硬化模型中进行了2、6-二(1-甲基乙基)苯基〔〔2、4、6-三(1-甲基乙基)苯基〕乙酰基〕氨基磺酸酯、阿托伐他汀和两种化合物的组合对脂改善和抗动脉粥样硬化作用的评估，在该模型中高胆固醇血症和慢性的髂股动脉内皮的剥脱相结合促进了斑块发展。
动脉粥样硬化模型包括15周的斑块诱导期，跟随着8周的药物介入期。此方案的主要特征是在9周的0.5％的胆固醇(C)、3％的花生(PNO)、3％的椰子(CNO)油饮食后，血浆胆固醇含量在给药前通过喂给0％的C、3％的PNO、3％的CNO饮食而正常。动物根据其平均血浆总胆固醇水平随机选择并在此后8周单独给服0％的C、3％的PNO、3％的CNO饮食，或含N-(2、6-二异丙基-苯基)-2-(2-十二烷基-2H-5-四唑基)-2-苯基-乙酰胺10mg/kg，阿托伐他汀5mg/kg，或N-(2、6-二异丙基-苯基)-2-(2-十二烷基-2H-5-四唑基)-2-苯基-乙酰胺+阿托伐他汀10+5mg/kg。
相对于非治疗的、喂食胆固醇的对照组，给予2、6-二(1-甲基乙基)苯基〔〔2、4、6-三(1-甲基乙基)苯基〕乙酰基〕氨基磺酸酯的血浆总胆固醇水平不变，但用阿托伐他汀和2、6-二(1-甲基乙基)-苯基〔〔2、4、6-三(1-甲基乙基)苯基〕乙酰基〕氨基磺酸酯+阿托伐他汀分别降低了43％和67％。伴随着血浆总胆固醇的变化，血浆脂蛋白分布有显著的改变。2、6-二(1-甲基乙基)苯基〔〔2、4、6-三(1-甲基乙基)苯基〕乙酰基〕氨基磺酸酯降低了极低密度脂蛋白胆固醇(VLDL-C)的百分数而增加低密度脂蛋白胆固醇(LDL-C)的百分数；阿托伐他汀的作用有限；而对于组合治疗，VLDL-C的百分数和LDL-C的百分数降低，而高密度脂蛋白胆固醇的百分数增加。
结果总结于下面表I中。
表I。以总血浆胆固醇百分数表示的脂蛋白分布
VLDL    LDL    HDL
进展对照组 16     60     24
2、6-二(1-甲基乙基)-苯基〔〔2、4、6-三(1-甲基乙基)苯基〕乙酰基〕氨基磺酸酯(10mg/kg)阿托伐他汀(5mg/kg)2、6-二(1-甲基乙基)-苯基〔〔2、4、6-三(1-甲基乙基)苯基〕乙酰基〕氨基磺酸酯+阿托伐他汀(10+5mg/kg) 5144     734835     223860
还进行了血管胆固醇脂(CE)富集、复合动脉粥样硬化斑块的发生率、胸主动脉动脉粥样硬化的大概范围、以及髂股斑块的大小和组成的分析。2、6-二(1-甲基乙基)苯基〔〔2、4、6-三(1-甲基乙基)苯基〕乙酰基〕氨基磺酸酯对胸主动脉和髂股动脉CE的富集以及对在胸主动脉上斑块涉及的大致范围没有影响；然而，在髂股动脉中复合纤维斑块的发生率由50％降至14％。阿托伐他汀在不改变胸斑块的大致范围和纤维斑块发生率的情况下，降低了两血管区域CE的富集27％到41％。2、6-二(1-甲基乙基)苯基〔〔2、4、6-三(1-甲基乙基)苯基〕乙酰基〕氨基磺酸酯+阿托伐他汀对胸主动脉CE的富集和胸主动脉斑块的大致范围没有影响；然而，髂股CE含量降低23％而且纤维斑块的发生率降至17％。与零时间对照组的数据比较，例如，在给药之前，单独给予阿托伐他汀和与2、6-二(1-甲基乙基)苯基〔〔2、4、6-三(1-甲基乙基)苯基〕乙酰基〕氨基磺酸酯组合显著地降低了髂股动脉的CE富集。髂股动脉的形态测定分析揭示阿托伐他汀降低了斑块的大小，而阿托伐他汀和2、6-二(1-甲基乙基)苯基〔〔2、4、6-三(1-甲基乙基)苯基〕乙酰基〕氨基磺酸酯的组合显著降低了斑块的单核巨噬细胞的含量而不改变斑块的大小。单独给予2、6-二(1-甲基乙基)苯基〔〔2、4、6-三(1-甲基乙基)苯基〕乙酰基〕氨基磺酸酯对髂股斑块大小或组成没有影响。
因此，很清楚N-(2、6-二异丙基苯基)-2-(2-十二烷基-2H-5-四唑基)-2-苯基乙酰胺和阿托伐他汀在chow/fat饮食中组合给药比两者任一单独给药引起了血浆中含apo B的脂蛋白更大的减少，并且实现了血浆脂蛋白分布的正常化。阿托伐他汀不但减弱了脉管系统胆固醇酯的富集而且降低了已存在动脉粥样硬化斑块的脂富集。2、6-二(1-甲基乙基)苯基〔〔2、4、6-三(1-甲基乙基)苯基〕乙酰基〕氨基磺酸酯+阿托伐他汀降低了已存在的动脉粥样硬化斑块的CE的富集达到了与单独使用阿托伐他汀时同样的程度，而就其组织学特征而言，动脉粥样硬化斑块不太复杂了。
为了从本发明的化合物制备药物组合物，惰性的、药物可接受的载体可以是固体或者液体。固体形式的制剂包括粉剂、片剂、可分散的颗粒剂、胶囊剂、和扁胶囊剂。
固体载体可以是一种或多种物质，它们也可作为稀释剂、调味剂、助溶剂、润滑剂、悬浮剂、粘合剂、或片剂崩解剂；它还可以是一种封入物质。
在粉剂中，载体是一种细碎的固体，它在一种与细碎的活性成分的混合物中。在片剂中，活性成分与具有必需的粘合性的载体以适当比例混合并压制成期望的形状和大小。
粉剂和片剂优选含约5％到约70％重量的活性成分。合适的载体是碳酸氢镁、硬脂酸镁、滑石、乳糖、蔗糖、果胶、糊精、淀粉、黄蓍胶、甲基纤维素、羧甲基纤维素钠、一种低熔点的蜡、可可油、和诸如此类。
术语“制剂”包括以封装物为载体的活性化合物制剂，该载体提供一种胶囊，其中的活性成分(有或无其它载体)是被一种载体环绕着的，因此它是与之相结合的。以相似的方式还包括扁胶囊和透皮体系。
片剂、粉剂、扁胶囊和胶囊可作为适合口服给药的固体剂型。
液体型制剂包括适合口服给药的溶液、悬浮液、或乳剂。用于口服给药的水溶液可通过把活性化合物溶于水中并加入适当的香味剂、着色剂、稳定剂、和所需的增稠剂来制备。用于口服使用的水悬浮液可通过把细碎的活性成分连同一种粘稠的物质如天然或合成的树胶、树脂、甲基纤维素、羧甲基纤维素钠、和其它药物制剂技术已知的悬浮剂一起分散于水中制成。
优选药物制剂是以单位剂量形式。在这种形式中，制剂被分成含合适量的活性成分的单位剂量。单位剂量形式可以是含个别制剂量的包装的制剂，例如，包装的片剂、胶囊、和在管瓶或安瓿中的粉剂。单位剂量形式还可以是一种胶囊、扁胶囊、或片剂本身，或者它可以是适当数量的这些包装形式。
这些剂型对于医生来说是熟知的，他们对每日给药时间和其它相关条件这些因素是熟悉的。

Claims (2)

1.一种在哺乳动物中调节脂浓度的药物组合物，包括治疗有效量的2，6-二(1-甲基乙基)-苯基-〔〔2，4，6-三(1-甲基乙基)苯基〕乙酰基〕氨基磺酸酯和3-羟基-3-甲基戊二酰基辅酶A还原酶抑制剂，连同药物可接受的载体，其中所述3-羟基-3-甲基戊二酰基辅酶A还原酶抑制剂是一种或多种化合物，选自利伐他汀、洛伐他汀、辛伐他汀、普伐他汀、氟伐他汀和阿托伐他汀。
2.根据权利要求1的药物组合物，其中3-羟基-3-甲基戊二酰基辅酶A还原酶抑制剂是阿托伐他汀。
CN961980109A 1995-11-02 1996-10-02 用于调节脂浓度的方法和药物组合物 Expired - Fee Related CN1217656C (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US615595P 1995-11-02 1995-11-02
US60/006,155 1995-11-02

Related Child Applications (1)

Application Number Title Priority Date Filing Date
CNA2005100517235A Division CN1679953A (zh) 1995-11-02 1996-10-02 用于调节脂浓度的联合用药

Publications (2)

Publication Number Publication Date
CN1201389A CN1201389A (zh) 1998-12-09
CN1217656C true CN1217656C (zh) 2005-09-07

Family

ID=21719566

Family Applications (2)

Application Number Title Priority Date Filing Date
CN961980109A Expired - Fee Related CN1217656C (zh) 1995-11-02 1996-10-02 用于调节脂浓度的方法和药物组合物
CNA2005100517235A Pending CN1679953A (zh) 1995-11-02 1996-10-02 用于调节脂浓度的联合用药

Family Applications After (1)

Application Number Title Priority Date Filing Date
CNA2005100517235A Pending CN1679953A (zh) 1995-11-02 1996-10-02 用于调节脂浓度的联合用药

Country Status (27)

Country Link
US (3) US6124309A (zh)
EP (1) EP0858336B1 (zh)
JP (1) JPH11515025A (zh)
KR (2) KR100449604B1 (zh)
CN (2) CN1217656C (zh)
AR (1) AR004527A1 (zh)
AT (1) ATE348607T1 (zh)
AU (1) AU720853B2 (zh)
BG (1) BG64018B1 (zh)
BR (1) BR9611410A (zh)
CZ (1) CZ127198A3 (zh)
DE (1) DE69636783T2 (zh)
EA (1) EA000514B1 (zh)
ES (1) ES2279526T3 (zh)
GE (1) GEP20001898B (zh)
HK (1) HK1016509A1 (zh)
HU (1) HUP9901865A3 (zh)
IL (1) IL123902A (zh)
IS (1) IS4720A (zh)
NO (1) NO981961L (zh)
NZ (2) NZ512484A (zh)
PL (1) PL186714B1 (zh)
RO (1) RO120816B1 (zh)
SK (1) SK284142B6 (zh)
UA (1) UA46069C2 (zh)
WO (1) WO1997016184A1 (zh)
ZA (1) ZA969187B (zh)

Families Citing this family (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6268392B1 (en) * 1994-09-13 2001-07-31 G. D. Searle & Co. Combination therapy employing ileal bile acid transport inhibiting benzothiepines and HMG Co-A reductase inhibitors
EA000514B1 (ru) * 1995-11-02 1999-10-28 Варнер-Ламберт Компани Способ нормализации липопротеидного профиля плазмы крови у млекопитающего и фармацевтическая композиция для его осуществления
GT199800127A (es) * 1997-08-29 2000-02-01 Combinaciones terapeuticas.
EP1514543A1 (en) * 1997-08-29 2005-03-16 Pfizer Inc. Combination therapy comprising atorvastatin and an antihypertensive agent
GT199800126A (es) * 1997-08-29 2000-01-29 Terapia de combinacion.
JP2002506818A (ja) * 1998-03-17 2002-03-05 ワーナー−ランバート・カンパニー スタチン−マトリックスメタロプロテイナーゼ阻害剤組み合わせ物
US6221897B1 (en) * 1998-06-10 2001-04-24 Aventis Pharma Deutschland Gmbh Benzothiepine 1,1-dioxide derivatives, a process for their preparation, pharmaceuticals comprising these compounds, and their use
JP2002525321A (ja) * 1998-09-30 2002-08-13 ワーナー−ランバート・カンパニー カテーテルによる血管再生を予防または遅らせる方法
CO5140104A1 (es) 1999-02-16 2002-03-22 Novartis Ag Derivados de mevinolina y preparacion farmaceuticas que los contienen
US20010006656A1 (en) * 1999-02-17 2001-07-05 University Of Washington Methods and compositions for inhibiting inflammation associated with pulmonary disease
AU7717500A (en) * 1999-09-30 2001-04-30 Merck & Co., Inc. Anti-hypercholesterolemic drug combination
EP1092432A1 (fr) 1999-10-15 2001-04-18 Societe De Conseils De Recherches Et D'applications Scientifiques S.A. (S.C.R.A.S.) Composes anti-ischemiques
KR20020050257A (ko) * 1999-11-05 2002-06-26 로즈 암스트롱, 크리스틴 에이. 트러트웨인 Ａｃａｔ 저해제에 의한 플라크 파열의 방지
SK2552003A3 (en) * 2000-09-01 2003-08-05 Sankyo Co Medicinal compositions for the treatment and prevention of xanthoma and atherosclerosis
US7304093B2 (en) * 2000-10-11 2007-12-04 Esperion Therapeutics, Inc. Ketone compounds and compositions for cholesterol management and related uses
US20040122091A1 (en) * 2000-10-11 2004-06-24 Esperion Therapeutics, Inc. Sulfoxide and bis-sulfoxide compounds and compositions for cholesterol management and related uses
JP2004529069A (ja) 2000-10-11 2004-09-24 エスペリオン セラピューティクス，インコーポレイテッド コレステロール管理用のエーテル化合物及び組成物ならびに関連する使用
US6699910B2 (en) 2000-10-11 2004-03-02 Esperion Therapeutics, Inc. Ketone compounds and compositions for cholesterol management and related uses
BR0114623A (pt) 2000-10-11 2005-12-13 Esperion Therapeutics Inc Composto, composição farmacêutica, métodos para tratar ou prevenir uma doença cardiovascular, uma dislipidemia, uma dislipoproteinemia, um distúrbio do metabolismo da glicose, trombótico e associado com o receptor ativado do proliferador de peroxissoma, a doença de alzheimer, a sìndrome x ou sìndrome metabólica, a septicemia, a obesidade, pancreatite, a hipertensão, doença renal, câncer, a inflamação e a impotência, em um paciente e para reduzir o teor de gordura da carne em animal de criação e de colesterol de ovos de aves domésticas
BR0114619A (pt) 2000-10-11 2005-12-13 Esperion Therapeutics Inc Composto, composição farmacêutica, métodos para tratar ou prevenir uma doença cardiovascular, uma dislipidemia, uma dislipoproteinemia, um distúrbio do metabolismo da glicose, trombótico e associado com o receptor ativado do proliferador de peroxissoma, a doença de alzheimer, a sìndrome x ou sìndrome metabólica, a septicemia, a obesidade, pancreatite, a hipertensão, doença renal, câncer, a inflamação e a impotência, em um paciente e para reduzir o teor de gordura da carne em animal de criação e de colesterol de ovos de aves domésticas
CA2369967A1 (en) * 2001-02-12 2002-08-12 Joseph Anthony Cornicelli Methods of treating nuclear factor-kappa b mediated diseases and disorders
US20030114497A1 (en) * 2001-07-31 2003-06-19 Laman Alani Pharmaceutical compositions of amlodipine and atorvastatin
US20050020694A1 (en) * 2001-10-11 2005-01-27 Dasseux Jean-Louis Henri Sulfide and disulfide compounds and compositions for cholesterol management and related uses
US20040204502A1 (en) * 2001-10-11 2004-10-14 Dasseux Jean-Louis Henri Sulfoxide and bis-sulfoxide compounds and compositions for cholesterol management and related uses
US20040192771A1 (en) * 2001-10-11 2004-09-30 Dasseux Jean-Louis Henri Ether compounds and compositions for cholesterol management and related uses
AU2003218004A1 (en) * 2002-03-12 2003-09-29 Merck & Co., Inc. Drug combination therapy
CA2480415A1 (en) * 2002-04-10 2003-10-23 Esperion Therapeutics, Inc. Mimics of acyl coenzyme-a, compositions thereof, and methods of cholesterol management and related uses
JP4187141B2 (ja) * 2002-04-12 2008-11-26 興和株式会社 新規なトロンボモジュリン発現促進剤
DK2404890T3 (en) 2003-01-23 2017-10-16 Esperion Therapeutics Inc Hydroxyl compounds and compositions for controlling cholesterol and related uses
US7884106B2 (en) 2003-08-29 2011-02-08 Kowa Company, Ltd. Method of stabilizing lipid-rich plaque and method of preventing rupture thereof
CA2546079A1 (en) * 2003-11-17 2005-05-26 Toyo Shinyaku Co., Ltd. Lipometabolism improver containing pine bark extract
WO2005068412A1 (en) 2003-12-24 2005-07-28 Esperion Therapeutics, Inc. Ketone compounds and compositions for cholesterol management and related uses
CA2563693C (en) * 2004-04-19 2010-07-06 Loma Linda University Composition and method of decreasing renal ischemic damage
TW200605890A (en) * 2004-07-28 2006-02-16 Sankyo Co Pharmaceutical compositions for inhibiting arteriosclerosis
WO2006046593A1 (ja) * 2004-10-27 2006-05-04 Daiichi Sankyo Company, Limited ２以上の置換基を有するベンゼン化合物
TW200619204A (en) * 2004-12-10 2006-06-16 Kowa Co Method for reduction, stabilization and prevention of rupture of lipid rich plaque
EP1948599A1 (en) * 2005-11-08 2008-07-30 Ranbaxy Laboratories Limited Process for (3r, 5r)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- [(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-1-yl]-3, 5-dihydroxy-heptanoic acid hemi calcium salt
PL2018153T3 (pl) 2006-04-26 2012-09-28 Rosemont Pharmaceuticals Ltd Ciekłe kompozycje doustne
US20130254787A1 (en) 2006-05-02 2013-09-26 Invidi Technologies Corporation Method and apparatus to perform real-time audience estimation and commercial selection suitable for targeted advertising
US20070269503A1 (en) * 2006-05-16 2007-11-22 James Walter Burgess Combinations of HMG CoA reductase inhibitors and negatively charged phospholipids and uses thereof
US8314080B2 (en) 2010-04-06 2012-11-20 Kuwait University Method of treating type I diabetes
CN103288702B (zh) * 2010-12-03 2015-09-16 上海科州药物研发有限公司 一种阿托伐他汀氨基酸盐的制备方法
US8586527B2 (en) * 2011-10-20 2013-11-19 Jaipal Singh Cerivastatin to treat pulmonary disorders
US20140243281A1 (en) 2011-10-28 2014-08-28 Lumena Pharmaceuticals, Inc. Bile acid recycling inhibitors for treatment of pediatric cholestatic liver diseases
EP2770990A4 (en) 2011-10-28 2015-03-11 Lumena Pharmaceuticals Inc Gallic acid refluxing agent for the treatment of hypertension and chronic liver disease
CN103304496A (zh) * 2012-03-08 2013-09-18 南京工业大学 一种合成申嗪霉素方法
WO2013171100A1 (en) 2012-05-16 2013-11-21 Joachim Hans Polyhydroxylated pentacyclic triterpene acids as hmg-coa reductase inhibitors
CN107530307A (zh) 2015-03-13 2018-01-02 艾斯柏伦治疗公司 包含etc1002和依泽替米贝的固定剂量组合和制剂以及治疗心血管疾病或降低心血管疾病风险的方法
MA41793A (fr) 2015-03-16 2018-01-23 Esperion Therapeutics Inc Associations de doses fixes comprenant du etc1002 et une ou plusieurs statines permettant de traiter ou de réduire un risque cardiovasculaire
WO2020257573A1 (en) 2019-06-21 2020-12-24 Esperion Therapeutics, Inc. Salt forms of bempedoic acid and methods for using the same

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4739073A (en) * 1983-11-04 1988-04-19 Sandoz Pharmaceuticals Corp. Intermediates in the synthesis of indole analogs of mevalonolactone and derivatives thereof
CA2003478A1 (en) * 1988-12-12 1990-06-12 Leonard G. Dennick Combination of an hmg coa reductase inhibitor and other type of serum cholesterol reducing agent and method for lowering serum cholesterol using such combination
FI94339C (fi) * 1989-07-21 1995-08-25 Warner Lambert Co Menetelmä farmaseuttisesti käyttökelpoisen /R-(R*,R*)/-2-(4-fluorifenyyli)- , -dihydroksi-5-(1-metyylietyyli)-3-fenyyli-4-/(fenyyliamino)karbonyyli/-1H-pyrroli-1-heptaanihapon ja sen farmaseuttisesti hyväksyttävien suolojen valmistamiseksi
CA2048395A1 (en) * 1990-08-23 1992-02-24 Henry Y. Pan Method for preventing onset of or treating type iii hyperlipoproteinemia employing pravastatin
TW223059B (zh) 1991-07-23 1994-05-01 Schering Corp
WO1994009774A1 (en) * 1992-10-26 1994-05-11 Merck & Co., Inc. Biologically active compounds and process therefor
LT3300B (en) 1992-12-23 1995-06-26 Schering Corp Combination of a cholesterol biosynhtesis inhibitor and a beta- lactam cholesterol absorbtion inhibitor
US5491172A (en) * 1993-05-14 1996-02-13 Warner-Lambert Company N-acyl sulfamic acid esters (or thioesters), N-acyl sulfonamides, and N-sulfonyl carbamic acid esters (or thioesters) as hypercholesterolemic agents
IL109431A (en) * 1993-05-14 2001-01-11 Warner Lambert Co Pharmaceutical compositions containing n-acyl sulfamic acid esters (or thioesters), n-acyl sulfonamides, and n-sulfonyl carbamic acid esters (or thioesters), for regulating plasma cholesterol concentration, and certain such novel compounds
WO1995013063A1 (en) * 1993-11-09 1995-05-18 Merck & Co., Inc. HMG-CoA REDUCTASE INHIBITORS IN THE NORMALIZATION OF VASCULAR ENDOTHELIAL DYSFUNCTION
EA000514B1 (ru) * 1995-11-02 1999-10-28 Варнер-Ламберт Компани Способ нормализации липопротеидного профиля плазмы крови у млекопитающего и фармацевтическая композиция для его осуществления

Also Published As

Publication number Publication date
KR19990067270A (ko) 1999-08-16
AR004527A1 (es) 1998-12-16
DE69636783D1 (de) 2007-02-01
RO120816B1 (ro) 2006-08-30
AU7253996A (en) 1997-05-22
KR20040029459A (ko) 2004-04-06
EA199800420A1 (ru) 1998-10-29
IL123902A (en) 2003-01-12
WO1997016184A1 (en) 1997-05-09
EP0858336A1 (en) 1998-08-19
ES2279526T3 (es) 2007-08-16
HK1016509A1 (en) 1999-11-05
ZA969187B (en) 1997-05-29
IL123902A0 (en) 1998-10-30
BG64018B1 (bg) 2003-10-31
JPH11515025A (ja) 1999-12-21
KR100449604B1 (ko) 2004-11-16
PL186714B1 (pl) 2004-02-27
US6143755A (en) 2000-11-07
ATE348607T1 (de) 2007-01-15
UA46069C2 (uk) 2002-05-15
US6093719A (en) 2000-07-25
SK55798A3 (en) 1999-06-11
IS4720A (is) 1998-04-17
NZ319906A (en) 2000-02-28
HUP9901865A3 (en) 2000-06-28
BG102417A (en) 1999-01-29
US6124309A (en) 2000-09-26
CN1679953A (zh) 2005-10-12
NZ512484A (en) 2003-02-28
NO981961L (no) 1998-05-04
BR9611410A (pt) 1999-01-05
AU720853B2 (en) 2000-06-15
CN1201389A (zh) 1998-12-09
EP0858336B1 (en) 2006-12-20
GEP20001898B (en) 2000-01-05
DE69636783T2 (de) 2007-10-18
PL326365A1 (en) 1998-09-14
HUP9901865A2 (hu) 1999-10-28
EA000514B1 (ru) 1999-10-28
NO981961D0 (no) 1998-04-30
SK284142B6 (sk) 2004-10-05
CZ127198A3 (cs) 1998-12-16

Similar Documents

Publication Publication Date Title
CN1217656C (zh) 用于调节脂浓度的方法和药物组合物
JP4875491B2 (ja) メトホルミンとスタチンとの組み合わせを含む医薬組成物
RU2363458C2 (ru) Комбинированная лекарственная терапия для лечения ожирения
JP2007528886A (ja) 肥満の治療又は予防用のメトホルミン及びオルリスタットの使用
PT1150678E (pt) &#39;&#39;utulização de inibidores de 3-hidroxi-3-metilglutaril coenzima a redutase para o fabrico de um medicamento para o tratamento de neuropatia diabética&#39;&#39;
EP0455042A1 (en) Combination of pravastatin and a fibric acid derivative, and method for treating dyslipidemia using such combination
EP0475148A1 (en) Pravastatin alone or in combination with a fibric acid derivative for preventing onset of or treating type III hyperlipoproteinemia
IL133492A (en) Pharmaceutical preparations containing alkanol L - carnitine in combination with a statin for the treatment of diseases caused by a change in lipid metabolism
CA2233558C (en) Method and pharmaceutical composition for regulating lipid concentration
BG107373A (bg) Нов състав, съдържащ бета-блокер и евентуално средство, понижаващо холестерола
EP3791874A1 (en) Medication useful for cardiovascular diseases
JP2003535125A (ja) カルボキシアルキルエーテル−ａｃａｔ阻害剤の組合せ
JP2007508242A (ja) トロンボキサンａ２受容体アンタゴニストとシクロオキシゲネーゼ−１の阻害剤との組み合わせを伴う組成物および方法
JPH05271189A (ja) インシュリン耐性被験者の高血圧症治療用ｎ´−置換ｎ−フェニルスルホニル尿素含有医薬組成物

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
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