CN102099026A - 含美西特田的治疗组合物 - Google Patents
含美西特田的治疗组合物 Download PDFInfo
- Publication number
- CN102099026A CN102099026A CN2009801279936A CN200980127993A CN102099026A CN 102099026 A CN102099026 A CN 102099026A CN 2009801279936 A CN2009801279936 A CN 2009801279936A CN 200980127993 A CN200980127993 A CN 200980127993A CN 102099026 A CN102099026 A CN 102099026A
- Authority
- CN
- China
- Prior art keywords
- acceptable salt
- medical acceptable
- chemical compound
- medical
- butoxy
- 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.)
- Granted
Links
- 239000000203 mixture Substances 0.000 title claims description 10
- 230000001225 therapeutic effect Effects 0.000 title description 10
- 229960001039 macitentan Drugs 0.000 title description 2
- JGCMEBMXRHSZKX-UHFFFAOYSA-N macitentan Chemical compound C=1C=C(Br)C=CC=1C=1C(NS(=O)(=O)NCCC)=NC=NC=1OCCOC1=NC=C(Br)C=N1 JGCMEBMXRHSZKX-UHFFFAOYSA-N 0.000 title description 2
- 150000003839 salts Chemical class 0.000 claims abstract description 60
- 150000001875 compounds Chemical class 0.000 claims abstract description 57
- 108091006335 Prostaglandin I receptors Proteins 0.000 claims abstract description 41
- 239000000556 agonist Substances 0.000 claims abstract description 39
- 102000009079 Epoprostenol Receptors Human genes 0.000 claims abstract 13
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 22
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 18
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 17
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 17
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 17
- 201000010099 disease Diseases 0.000 claims description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- -1 5,6-diphenyl pyrazine-2-yl Chemical group 0.000 claims description 11
- 102000002045 Endothelin Human genes 0.000 claims description 10
- 108050009340 Endothelin Proteins 0.000 claims description 10
- ZUBDGKVDJUIMQQ-UBFCDGJISA-N endothelin-1 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@H]2CSSC[C@@H](C(N[C@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@@H](CO)NC(=O)[C@H](N)CSSC1)C1=CNC=N1 ZUBDGKVDJUIMQQ-UBFCDGJISA-N 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 8
- 206010020772 Hypertension Diseases 0.000 claims description 7
- 239000004305 biphenyl Substances 0.000 claims description 7
- 229960002890 beraprost Drugs 0.000 claims description 5
- CTPOHARTNNSRSR-APJZLKAGSA-N beraprost Chemical compound O([C@H]1C[C@@H](O)[C@@H]([C@@H]21)/C=C/[C@@H](O)C(C)CC#CC)C1=C2C=CC=C1CCCC(O)=O CTPOHARTNNSRSR-APJZLKAGSA-N 0.000 claims description 5
- 229960001123 epoprostenol Drugs 0.000 claims description 5
- 229960002240 iloprost Drugs 0.000 claims description 5
- HIFJCPQKFCZDDL-ACWOEMLNSA-N iloprost Chemical compound C1\C(=C/CCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)C(C)CC#CC)[C@H](O)C[C@@H]21 HIFJCPQKFCZDDL-ACWOEMLNSA-N 0.000 claims description 5
- 229960005032 treprostinil Drugs 0.000 claims description 5
- PAJMKGZZBBTTOY-ZFORQUDYSA-N treprostinil Chemical group C1=CC=C(OCC(O)=O)C2=C1C[C@@H]1[C@@H](CC[C@@H](O)CCCCC)[C@H](O)C[C@@H]1C2 PAJMKGZZBBTTOY-ZFORQUDYSA-N 0.000 claims description 5
- 206010002383 Angina Pectoris Diseases 0.000 claims description 4
- 206010019280 Heart failures Diseases 0.000 claims description 4
- 200000000007 Arterial disease Diseases 0.000 claims description 3
- 206010012601 diabetes mellitus Diseases 0.000 claims description 3
- 208000005069 pulmonary fibrosis Diseases 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- KAQKFAOMNZTLHT-VVUHWYTRSA-N epoprostenol Chemical compound O1C(=CCCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-VVUHWYTRSA-N 0.000 claims 2
- 102100026476 Prostacyclin receptor Human genes 0.000 description 27
- 241000700159 Rattus Species 0.000 description 13
- 239000000047 product Substances 0.000 description 12
- QPNKYNYIKKVVQB-UHFFFAOYSA-N crotaleschenine Natural products O1C(=O)C(C)C(C)C(C)(O)C(=O)OCC2=CCN3C2C1CC3 QPNKYNYIKKVVQB-UHFFFAOYSA-N 0.000 description 11
- QVCMHGGNRFRMAD-XFGHUUIASA-N monocrotaline Chemical compound C1OC(=O)[C@](C)(O)[C@@](O)(C)[C@@H](C)C(=O)O[C@@H]2CCN3[C@@H]2C1=CC3 QVCMHGGNRFRMAD-XFGHUUIASA-N 0.000 description 11
- QVCMHGGNRFRMAD-UHFFFAOYSA-N monocrotaline Natural products C1OC(=O)C(C)(O)C(O)(C)C(C)C(=O)OC2CCN3C2C1=CC3 QVCMHGGNRFRMAD-UHFFFAOYSA-N 0.000 description 11
- 230000004872 arterial blood pressure Effects 0.000 description 9
- 238000012360 testing method Methods 0.000 description 8
- 230000000694 effects Effects 0.000 description 5
- 230000003203 everyday effect Effects 0.000 description 5
- 210000001147 pulmonary artery Anatomy 0.000 description 5
- 230000002685 pulmonary effect Effects 0.000 description 5
- LMHIPJMTZHDKEW-XQYLJSSYSA-M Epoprostenol sodium Chemical compound [Na+].O1\C(=C/CCCC([O-])=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 LMHIPJMTZHDKEW-XQYLJSSYSA-M 0.000 description 4
- 238000013459 approach Methods 0.000 description 4
- 238000011552 rat model Methods 0.000 description 4
- 210000005241 right ventricle Anatomy 0.000 description 4
- 238000010998 test method Methods 0.000 description 4
- OJQMKCBWYCWFPU-UHFFFAOYSA-N ACT-333679 Chemical compound C=1C=CC=CC=1C1=NC(N(CCCCOCC(O)=O)C(C)C)=CN=C1C1=CC=CC=C1 OJQMKCBWYCWFPU-UHFFFAOYSA-N 0.000 description 3
- 229940118365 Endothelin receptor antagonist Drugs 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000002308 endothelin receptor antagonist Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 241000700157 Rattus norvegicus Species 0.000 description 2
- 208000000924 Right ventricular hypertrophy Diseases 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 229960003065 bosentan Drugs 0.000 description 2
- GJPICJJJRGTNOD-UHFFFAOYSA-N bosentan Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2N=CC=CN=2)OCCO)=C1NS(=O)(=O)C1=CC=C(C(C)(C)C)C=C1 GJPICJJJRGTNOD-UHFFFAOYSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000002079 cooperative effect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 230000001631 hypertensive effect Effects 0.000 description 2
- 230000002269 spontaneous effect Effects 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 101100230376 Acetivibrio thermocellus (strain ATCC 27405 / DSM 1237 / JCM 9322 / NBRC 103400 / NCIMB 10682 / NRRL B-4536 / VPI 7372) celI gene Proteins 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Natural products C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 1
- 241000006808 Sessiliflorae Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 210000003489 abdominal muscle Anatomy 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000002269 analeptic agent Substances 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- XTEGARKTQYYJKE-UHFFFAOYSA-N chloric acid Chemical compound OCl(=O)=O XTEGARKTQYYJKE-UHFFFAOYSA-N 0.000 description 1
- 229940005991 chloric acid Drugs 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 231100000762 chronic effect Toxicity 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 210000005240 left ventricle Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 210000003200 peritoneal cavity Anatomy 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000010187 selection method Methods 0.000 description 1
- 238000011699 spontaneously hypertensive rat Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 208000037905 systemic hypertension Diseases 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- 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
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
-
- 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
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/5578—Eicosanoids, e.g. leukotrienes or prostaglandins having a pentalene ring system, e.g. carbacyclin, iloprost
-
- 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
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Landscapes
- Health & Medical Sciences (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)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明关于一种产品，其包含下式(I)的化合物
Description
本发明关于一种产品，其包含美西特田(MACITENTAN)，即以下式(I)的化合物
或该化合物的医药可接受的盐，并与至少一种具有前列腺环素受体(IP)激动剂性质的化合物或其医药可接受的盐组合，及此产品的治疗用途，其是同时、分别或在一段时间内用于治疗涉及内皮素的疾病。
PCT公开案WO 02/053557叙述包括式(I)的化合物的内皮素受体拮抗剂，及以该内皮素受体拮抗剂在治疗涉及内皮素的各种疾病(特别指心衰竭、心绞痛、肺高血压及全身性高血压及勃起障碍)中的用途。
具有前列腺环素受体(IP)激动剂性质的化合物在下列文献已有特别说明：
此外，WO 2004/017993叙述内皮素受体拮抗剂波生坦(bosentan)与前列腺环素受体激动剂依前列醇钠(epoprostenol)一起用于治疗肺动脉高血压。
本申请人现已发现美西特田与具有前列腺环素受体(IP)激动剂性质的化合物的组合在治疗涉及内皮素的疾病中可产生强力协同效应。另外，与具有前列腺环素受体(IP)激动剂性质的化合物相关的可能副作用(例如潮红或全身性血压过低)可望减少。
因此，本发明的第一主题是有关一种产品，其包含美西特田或其医药可接受的盐，及至少一种(及较佳是一种)具有前列腺环素受体(IP)激动剂性质的化合物，或其医药可接受的盐。
本发明的进一步主题为一种用于治疗的产品，该产品包含美西特田或其医药可接受的盐，并与至少一种(及较佳是一种)具有前列腺环素受体(IP)激动剂性质的化合物，或其医药可接受的盐组合，以同时、分别或在一段时间内治疗涉及内皮素的疾病。
以下段落提供用于本专利申请案中的各种术语的定义，这些定义在整个说明书及权利要求书中通用，除非另外明确陈述的定义提供更宽或更窄的定义。
美西特田为当前提议用于式(I)的化合物的INN，因此该名称在本专利申请案中用于代表式(I)的化合物。
“同时地”或“同时”，当指治疗用途时，其在本申请案中意为：相关的治疗用途包括经相同途径及在相同时间下给予两种或多种活性成分。
“分别地”或“分别”，当指治疗用途时，在本申请案中意为：相关的治疗用途包括在约相同时间经至少两种不同途径给予两种或多种活性成分。
“在一段时间内”医治疗性给药在本申请案中是指在不同时间给予两种或多种成分，特别是一种先全部给予其中一种活性成分然后再开始给予另一或其它活性成分的给药方法。以此方式，可能先给予其中一种活性成分几个月，然后再给予其它活性成分。在该情况下，不出现同时给药的情况。另一种在一段时间内的医药性给药包括利用不同频率给予各活性成分而在一段时间内给予两或多种活性成分的组合，因此在某些时间点发生同时给予所有活性成分组合，而在其它时间点仅给予该组合的一部分活性成分(例如，就美西特田与NS-304的组合而言，在一段时间内的医药性给药可为一天给予一次美西特田，而一天给予两次NS-304)。
“涉及内皮素的疾病”特别指高血压、肺高血压(包括肺动脉高血压)、糖尿病性动脉病、心衰竭、勃起障碍、心绞痛或肺纤维化。
“具有前列腺环素受体(IP)激动剂性质的化合物”是指一种化合物，当进行在本专利申请案中所述的“测定前列腺环素受体(IP)激动剂EC50的测试”时，具有等于或小于500nM的EC50值。
具有前列腺环素受体(IP)激动剂性质的化合物的具体实例包括曲前列环素及其医药可接受盐、依前列醇及其医药可接受盐、伊洛前列素及其医药可接受盐、贝前列素及其医药可接受盐、2-{4-[(5，6-二苯基吡嗪-2-基)(异丙基)氨基]丁氧基}-N-(甲基磺酰基)乙酰胺(NS-304)及其医药可接受盐，及{4-[(5，6-二苯基吡嗪-2-基)(异丙基)氨基]丁氧基}乙酸(MRE-269)及其医药可接受盐。
术语“医药可接受的盐”是指无毒、无机或有机酸及/或碱加成盐。可参考“碱性药物的盐选择法(Salt selection for basic drugs)”，Int.J.Pharm.(1986)，33，201-217。
此外，当适当及有利时，任何提及美西特田或具有前列腺环素受体(IP)激动剂性质的化合物亦指其医药可接受的盐。
较佳的根据本发明产品是美西特田及具有前列腺环素受体(IP)激动剂性质的化合物，同时或在一段时间内给予，用于医治疗。
根据本发明的一个较佳变形为由美西特田及具有前列腺环素受体(IP)激动剂性质的化合物同时给予。
根据本发明的另一较佳变形为由美西特田及具有前列腺环素受体(IP)激动剂性质的化合物在一段时间内给予。
用于根据本发明的产品的治疗用途的时间期为至少一周，及较佳是至少一个月或多个月(例如六个月)。该时间期亦可为接受该产品的病人的终生。根据本发明的特定给予模式，美西特田是与具有前列腺环素受体(IP)激动剂性质的化合物交替给予，且两种给予之间的间隔不超过两或三天(及更优选是不超过一天)。根据本发明另一特定给予模式，就美西特田与NS-304的组合而言，在一段时间内的治疗性给药可为一天给予一次美西特田，而NS-304是每日给予两次。
具有前列腺环素受体(IP)激动剂性质的化合物较佳选自2-{4-[(5，6-二苯基吡嗪-2-基)(异丙基)氨基]丁氧基}-N-(甲基磺酰基)乙酰胺(NS-304)及其医药可接受盐，及{4-[(5，6-二苯基吡嗪-2-基)(异丙基)氨基]丁氧基}乙酸(MRE-269)及其医药可接受盐。根据本发明特佳的变形，具有前列腺环素受体(IP)激动剂性质的化合物为2-{4-[(5，6-二苯基吡嗪-2-基)(异丙基)氨基]丁氧基}-N-(甲基磺酰基)乙酰胺(NS-304)或其医药可接受盐。
美西特田及具有前列腺环素受体(IP)激动剂性质的化合物的给予途径较佳相同。特定而言，美西特田及具有前列腺环素受体(IP)激动剂性质的化合物的常用给予途径是经口。
尽管根据本发明的产品的精确给予剂量必须由主治医师决定，然预期每千克病人体重以每日给予0.05至2mg(较佳0.1至1mg)剂量的美西特田为适宜。同样，预期每千克病人体重以每日两次给予0.5至30μg(较佳1.5至15μg)剂量的具有前列腺环素受体(IP)激动剂性质的化合物为适宜。
欲由根据本发明的产品治疗的疾病较佳选自高血压、肺高血压、糖尿病性动脉病、心衰竭、勃起障碍、心绞痛及肺纤维化。欲由根据本发明的产品治疗的疾病更佳选自高血压及肺高血压。欲由根据本发明的产品治疗的疾病特别为肺高血压(尤其为肺动脉高血压)。
本发明亦关于一种医药组合物，其包含作为活性成分的美西特田或该化合物的医药可接受盐，与至少一种(较佳是一种)具有前列腺环素受体(IP)激动剂性质的化合物或其医药可接受盐，及至少一种赋形剂组合。
本发明进一步关于一种以美西特田或该化合物的医药可接受的盐，与至少一种(及较佳是一种)具有前列腺环素受体(IP)激动剂性质的化合物或其医药可接受的盐组合，在制造用于治疗涉及内皮素的疾病的药剂中的用途。
此外，对于本发明的产品所指出的优选方式经必要的变更后，当然亦适用于本发明的医药组合物及用途中。
本发明的特定实施例是在下列实施例中叙述，此等实施例用于更详细地说明本发明，而不以任何方式限制其范围。
实施例
为说明本发明的有用性，以每日10mg/kg剂量经口给予的美西特田与每日两次以1mg/kg剂量经口给予的NS-304组合，在两个不同的高血压模型(即肺高血压野百合碱大鼠模型及自发性高血压大鼠模型)中进行研究。当然可同样测试其它组合。可使用的程序是在下文中名为“本发明化合物的药理学性质”的部分中有详述。
本发明化合物的药理学性质
试验法
下文叙述的试验法可用于说明本发明化合物的药理学性质。
肺高血压野百合碱大鼠模型
雄性Wistar大鼠购自哈伦(Harlan)(荷兰)，并按照当地指南(Basel-Landschaft cantonal veterinary office)保持在指定条件下。所有大鼠安置于光照∶黑暗周期比为12∶12小时的环境控制条件下，并自由摄取食物及水。在经吸入2.5％异氟烷(于70％O2+30％N2O)而麻醉下植入遥测系统。在无菌条件下，将感压式无线电波发射器植入腹膜腔，并将感测导管插入肺动脉中。将该发射器缝合至腹部肌肉，封闭皮肤。接收器平台可将无线电信号转换成数字化输入，发送至专用个人计算机(Compaq，Deskpro)。藉由来自环境压力参考值的输入，校准肺动脉血压测量值。遥测装置是从Data Sciences(St.Paul，MN，USA)获得。野百合碱(MCT；Sigma Chemicals，St Louis，MO，USA)是经皮下(sc)单次注射(60mg/kg)给予3ml/kg的体积，及让年龄相当的对照组大鼠接受等体积的生理食盐水。
变型1：慢性效应评定
动物随机分配至实验组，并在注射MCT后24h内开始处理，持续4周。美西特田及具有前列腺环素受体(IP)激动剂性质的化合物是经口给予。美西特田、具有前列腺环素受体(IP)激动剂性质的化合物及其组合对肺动脉血压的效果是每间隔5分钟收集数据而测量。计算每一大鼠的每小时平均肺动脉压。在记录结束时，处死大鼠。移出心脏并称重，并计算器官重量与体重之比(BW)。分离右心室(RV)及左心室加上隔膜，并称重；RV/BW之比是用作右心室肥大的指标。RV/BW之比越小，测试的用于减轻右心室肥大程度的项目(群)的效果越强。
变形2：急性效应评定
在注射MCT后四周，大鼠出现肺高血压，并由平均肺动脉压评估单一口服美西特田、具有前列腺环素受体(IP)激动剂性质的化合物及其组合后的各自效果。
自发性高血压大鼠模式
采用与肺高血压野百合碱大鼠模型相同的程序，但改用自发性高血压大鼠(SHR)代替经野百合碱处理的大鼠。SHR大鼠是购自Harlan(荷兰)。
测定前列腺环素受体(IP)激动剂EC50的测试法
在37℃，95％空气及5％CO2的湿润氛围下，将稳定表现达人类IP受体的CHO细胞于包含10％胎牛血清的Ham′s F-12培养基中培养。以1×105细胞/孔在24孔板中接种细胞，并培养达48小时。洗涤并在37℃下用试验缓冲剂培养1小时后，在IBMX(500μM)存在下，以不同浓度的测试化合物处理细胞。在除去上清液后，藉由添加0.2M过氯酸而中止反应。在-80℃下，将黏附细胞冷冻2小时，并解冻以提取细胞内cAMP。上清液收集于试管内，用2M KHCO3溶液中和，然后在4℃下以14,000g离心10分钟，获得样本，藉由EIA系统测量cAMP浓度。在1N NaOH溶液中溶解后，测量附着于培养板的细胞碎片的蛋白质含量。cAMP浓度是以pmol cAMP/mg蛋白质表示。EC50值是自非线性回归分析浓度-反应曲线而决定，并定义为引起50％观察最大效应反应的测试化合物浓度的负对数值。
试验结果
实例1：美西特田、NS-304及其组合在野百合碱处理组大鼠中对平均肺动脉压的急性效应
根据标题为“试验法”部分的“肺高血压野百合碱大鼠模型”部分中说明的野百合碱模型，在使用野百合碱导致的肺高血压雄性Wistar大鼠中进行试验。
在野百合碱处理后25至30天，分成四个组(6只大鼠/组)并进行研究：
-第一组既不用美西特田亦不用NS-304处理(对照组)；
-第二组仅用美西特田(10mg/kg，经口)处理；
-第三组仅用NS-304(30mg/kg，经口)处理；
-第四组用美西特田(10mg/kg，经口)及NS-304(30mg/kg，经口)的组合处理。
随时间测量平均肺动脉压。由平均肺动脉压与时间的关系绘成图。在口服不同处理物后，计算每组大鼠的曲线下面积(AUC)(若平均肺动脉血压增加，则可见正区；若平均肺动脉血压减少，则可见负区)。这样获得的结果概括于下表1中。
表1
在肺动脉高血压的野百合碱模型中获得的此等数据证实，美西特田及NS-304的组合在处理先前曾接受野百合碱给予的大鼠时具有协同效应。
Claims (15)
1.一种产品，该产品包含美西特田或该化合物的医药可接受盐，与至少一种具有前列腺环素受体(IP)激动剂性质的化合物或其医药可接受盐组合。
2.根据权利要求1的产品，其中所述具有前列腺环素受体(IP)激动剂性质的化合物选自曲前列环素及其医药可接受盐、依前列醇及其医药可接受盐、伊洛前列素及其医药可接受盐、贝前列素及其医药可接受盐、2-{4-[(5，6-二苯基吡嗪-2-基)(异丙基)氨基]丁氧基}-N-(甲基磺酰基)乙酰胺及其医药可接受盐，及{4-[(5，6-二苯基吡嗪-2-基)(异丙基)氨基]丁氧基}乙酸及其医药可接受盐。
3.根据权利要求2的产品，其中所述具有前列腺环素受体(IP)激动剂性质的化合物选自2-{4-[(5，6-二苯基吡嗪-2-基)(异丙基)氨基]丁氧基}-N-(甲基磺酰基)乙酰胺及其医药可接受盐，及{4-[(5，6-二苯基吡嗪-2-基)(异丙基)氨基]丁氧基}乙酸及其医药可接受盐。
4.根据权利要求3的产品，其中所述具有前列腺环素受体(IP)激动剂性质的化合物为2-{4-[(5，6-二苯基吡嗪-2-基)(异丙基)氨基]丁氧基}-N-(甲基磺酰基)乙酰胺或其医药可接受盐。
5.一种用于治疗的产品，该产品包含美西特田或该化合物的医药可接受盐，与至少一种具有前列腺环素受体(IP)激动剂性质的化合物或其医药可接受盐组合，以同时、分别或在一段时间内治疗涉及内皮素的疾病。
6.根据权利要求5的产品，其中所述具有前列腺环素受体(IP)激动剂性质的化合物选自曲前列环素及其医药可接受盐、依前列醇及其医药可接受盐、伊洛前列素及其医药可接受盐、贝前列素及其医药可接受盐、2-{4-[(5，6-二苯基吡嗪-2-基)(异丙基)氨基]丁氧基}-N-(甲基磺酰基)乙酰胺及其医药可接受盐，及{4-[(5，6-二苯基吡嗪-2-基)(异丙基)氨基]丁氧基}乙酸及其医药可接受盐。
7.根据权利要求6的产品，其中所述具有前列腺环素受体(IP)激动剂性质的化合物选自2-{4-[(5，6-二苯基吡嗪-2-基)(异丙基)氨基]丁氧基}-N-(甲基磺酰基)乙酰胺及其医药可接受盐，及{4-[(5，6-二苯基吡嗪-2-基)(异丙基)氨基]丁氧基}乙酸及其医药可接受盐。
8.根据权利要求7的产品，其中所述具有前列腺环素受体(IP)激动剂性质的化合物为2-{4-[(5，6-二苯基吡嗪-2-基)(异丙基)氨基]丁氧基}-N-(甲基磺酰基)乙酰胺或其医药可接受盐。
9.根据权利要求5至8中任一项的产品，其中涉及内皮素的疾病选自高血压、肺高血压、糖尿病性动脉病、心衰竭、勃起障碍、心绞痛及肺纤维化。
10.根据权利要求9的产品，其中涉及内皮素的疾病为肺高血压。
11.一种医药组合物，该医药组合物包含作为活性成分的美西特田或其医药可接受盐，与至少一种具有前列腺环素受体(IP)激动剂性质的化合物或其医药可接受盐，及至少一种医药可接受的赋形剂组合。
12.根据权利要求10的医药组合物，其中所述具有前列腺环素受体(IP)激动剂性质的化合物或其医药可接受盐为2-{4-[(5，6-二苯基吡嗪-2-基)(异丙基)氨基]丁氧基}-N-(甲基磺酰基)乙酰胺或其医药可接受盐。
13.一种美西特田或其医药可接受盐与至少一种具有前列腺环素受体(IP)激动剂性质的化合物或其医药可接受盐组合在制造用于治疗涉及内皮素疾病的药剂中的用途。
14.根据权利要求13的用途，其中所述具有前列腺环素受体(IP)激动剂性质的化合物或其医药可接受盐为2-{4-[(5，6-二苯基吡嗪-2-基)(异丙基)氨基]丁氧基}-N-(甲基磺酰基)乙酰胺或其医药可接受盐。
15.根据权利要求13或14的用途，其中欲被治疗的疾病为肺高血压。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IBPCT/IB2008/053252 | 2008-08-13 | ||
| IB2008053252 | 2008-08-13 | ||
| PCT/IB2009/053553 WO2010018549A2 (en) | 2008-08-13 | 2009-08-12 | Therapeutic compositions containing macitentan |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102099026A true CN102099026A (zh) | 2011-06-15 |
| CN102099026B CN102099026B (zh) | 2012-08-29 |
Family
ID=41346591
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009801279936A Active CN102099026B (zh) | 2008-08-13 | 2009-08-12 | 含美西特田的治疗组合物 |
Country Status (30)
| Country | Link |
|---|---|
| US (3) | US8809334B2 (zh) |
| EP (2) | EP3300729B1 (zh) |
| JP (3) | JP5764061B2 (zh) |
| KR (1) | KR101678699B1 (zh) |
| CN (1) | CN102099026B (zh) |
| AR (1) | AR073031A1 (zh) |
| AU (1) | AU2009280843B2 (zh) |
| BR (1) | BRPI0917661B8 (zh) |
| CA (1) | CA2731370C (zh) |
| CY (2) | CY1119826T1 (zh) |
| DK (2) | DK2315587T3 (zh) |
| ES (2) | ES2763176T3 (zh) |
| HK (1) | HK1253355B (zh) |
| HR (2) | HRP20171917T1 (zh) |
| HU (2) | HUE036071T2 (zh) |
| IL (1) | IL211143A0 (zh) |
| LT (2) | LT3300729T (zh) |
| MA (1) | MA32614B1 (zh) |
| MX (1) | MX350011B (zh) |
| MY (1) | MY178894A (zh) |
| NO (1) | NO2315587T3 (zh) |
| NZ (1) | NZ591601A (zh) |
| PL (2) | PL3300729T3 (zh) |
| PT (2) | PT3300729T (zh) |
| RU (1) | RU2519161C2 (zh) |
| SI (2) | SI3300729T1 (zh) |
| SM (2) | SMT201700592T1 (zh) |
| TW (1) | TWI446911B (zh) |
| WO (1) | WO2010018549A2 (zh) |
| ZA (1) | ZA201101900B (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113194953A (zh) * | 2018-12-21 | 2021-07-30 | 埃科特莱茵药品有限公司 | 用于治疗肺动脉高血压的药物组合物 |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BRPI0615898B8 (pt) | 2005-09-12 | 2021-05-25 | Actelion Pharmaceuticals Ltd | composição farmacêutica, e, uso de um composto ou de um sal, um solvato, um hidrato ou uma forma morfológica do mesmo farmaceuticamente aceitável |
| MX2010001837A (es) | 2007-08-17 | 2010-03-10 | Actelion Pharmaceuticals Ltd | Derivados de 4-pirimidinasulfamida. |
| CN104761509A (zh) | 2008-02-28 | 2015-07-08 | 日本新药株式会社 | 纤维化抑制剂 |
| PT3300729T (pt) | 2008-08-13 | 2020-01-20 | Actelion Pharmaceuticals Ltd | Composições terapêuticas contendo macitentan |
| WO2014110491A1 (en) | 2013-01-11 | 2014-07-17 | Theratrophix Llc | Prodrugs of treprostinil |
| US9505737B2 (en) | 2013-01-11 | 2016-11-29 | Corsair Pharma, Inc. | Treprostinil derivative compounds and methods of using same |
| US9394227B1 (en) | 2015-06-17 | 2016-07-19 | Corsair Pharma, Inc. | Treprostinil derivatives and compositions and uses thereof |
| US9643911B2 (en) | 2015-06-17 | 2017-05-09 | Corsair Pharma, Inc. | Treprostinil derivatives and compositions and uses thereof |
| US9794795B1 (en) | 2016-04-29 | 2017-10-17 | Corning Optical Communications Wireless Ltd | Implementing a live distributed antenna system (DAS) configuration from a virtual DAS design using an original equipment manufacturer (OEM) specific software system in a DAS |
| CN110381951A (zh) | 2016-12-14 | 2019-10-25 | 瑞必治公司 | 用于治疗肺性高血压和其他肺病症的方法及组合物 |
| CA3109851C (en) * | 2018-09-14 | 2024-02-20 | Pharmosa Biopharm Inc. | Pharmaceutical composition for controlled release of weak acid drugs and uses thereof |
| TW202042818A (zh) | 2019-01-25 | 2020-12-01 | 瑞士商艾克泰聯製藥有限公司 | 用於治療慢性血栓性肺高血壓之醫藥組成物 |
| PH12022551294A1 (en) | 2019-11-29 | 2023-11-20 | Actelion Pharmaceuticals Ltd | Methods of treating pulmonary arterial hypertension |
| WO2021126884A1 (en) | 2019-12-16 | 2021-06-24 | Tenax Therapeutics, Inc. | LEVOSIMENDAN FOR TREATING PULMONARY HYPERTENSION WITH HEART FAILURE WITH PRESERVED EJECTION FRACTION (PH-HF-pEF) |
| EP4456897A1 (en) | 2021-12-31 | 2024-11-06 | Tenax Therapeutics, Inc. | Oral formulations of levosimendan for treating pulmonary hypertension with heart failure with preserved ejection fraction |
Family Cites Families (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1097239A (en) | 1976-05-11 | 1981-03-10 | Salvador Moncada | Enzymatic preparation of prostacyclin and its salts |
| DE2845770A1 (de) | 1978-10-19 | 1980-04-30 | Schering Ag | Neue prostacyclin-derivate und verfahren zu ihrer herstellung |
| JPS58124778A (ja) * | 1982-01-20 | 1983-07-25 | Toray Ind Inc | ５，６，７−トリノル−４，８−インタ−ｍ−フエニレンＰＧＩ↓２誘導体 |
| US4683330A (en) * | 1984-03-08 | 1987-07-28 | The Upjohn Company | Interphenylene carbacyclin derivatives |
| ES2260318T3 (es) * | 2000-12-18 | 2006-11-01 | Actelion Pharmaceuticals Ltd. | Nuevas sulfamidas y su utilizacion como antagonistas del receptor de endotelina. |
| MXPA03005393A (es) * | 2000-12-19 | 2003-09-25 | Merck Patent Gmbh | Formulacion farmaceutica que contiene pirazolo (4,3-d) pirimidinas y antitromboticos, antagonistas de calcio, prostaglandinas o derivados de prostaglandina. |
| DE10100426B4 (de) | 2001-01-08 | 2006-04-06 | Steag Hamatech Ag | Verfahren und Vorrichtung zum Zusammenfügen von Substraten |
| TWI316055B (zh) * | 2001-04-26 | 2009-10-21 | Nippon Shinyaku Co Ltd | |
| WO2004017993A1 (en) * | 2002-08-12 | 2004-03-04 | Actelion Pharmaceuticals Ltd | Combination of prostacyclin or prostacyclin analogues and endothelin receptor antagonists for the treatment of pulmonary arterial hypertension |
| ATE423103T1 (de) * | 2002-12-02 | 2009-03-15 | Actelion Pharmaceuticals Ltd | Pyrimidin-sulfonamide und ihre verwendung als endothelin-rezeptor-antagonisten |
| US20050101608A1 (en) | 2003-09-24 | 2005-05-12 | Santel Donald J. | Iloprost in combination therapies for the treatment of pulmonary arterial hypertension |
| TW200628467A (en) * | 2004-11-11 | 2006-08-16 | Actelion Pharmaceuticals Ltd | Novel sulfamides |
| BRPI0615898B8 (pt) * | 2005-09-12 | 2021-05-25 | Actelion Pharmaceuticals Ltd | composição farmacêutica, e, uso de um composto ou de um sal, um solvato, um hidrato ou uma forma morfológica do mesmo farmaceuticamente aceitável |
| AR062501A1 (es) | 2006-08-29 | 2008-11-12 | Actelion Pharmaceuticals Ltd | Composiciones terapeuticas |
| SI2254570T1 (sl) | 2008-02-20 | 2014-03-31 | Actelion Pharmaceuticals Ltd. | Kombinacija, obsegajoča paklitaksel, za zdravljenje raka na jajčnikih |
| PT3300729T (pt) | 2008-08-13 | 2020-01-20 | Actelion Pharmaceuticals Ltd | Composições terapêuticas contendo macitentan |
-
2009
- 2009-08-12 PT PT171910334T patent/PT3300729T/pt unknown
- 2009-08-12 MY MYPI2011000637A patent/MY178894A/en unknown
- 2009-08-12 HU HUE09786912A patent/HUE036071T2/hu unknown
- 2009-08-12 EP EP17191033.4A patent/EP3300729B1/en not_active Revoked
- 2009-08-12 PL PL17191033T patent/PL3300729T3/pl unknown
- 2009-08-12 SI SI200932016T patent/SI3300729T1/sl unknown
- 2009-08-12 JP JP2011522608A patent/JP5764061B2/ja not_active Expired - Fee Related
- 2009-08-12 MX MX2011001625A patent/MX350011B/es active IP Right Grant
- 2009-08-12 ES ES17191033T patent/ES2763176T3/es active Active
- 2009-08-12 LT LTEP17191033.4T patent/LT3300729T/lt unknown
- 2009-08-12 SM SM20170592T patent/SMT201700592T1/it unknown
- 2009-08-12 CN CN2009801279936A patent/CN102099026B/zh active Active
- 2009-08-12 KR KR1020117003547A patent/KR101678699B1/ko active Active
- 2009-08-12 WO PCT/IB2009/053553 patent/WO2010018549A2/en active Application Filing
- 2009-08-12 NO NO09786912A patent/NO2315587T3/no unknown
- 2009-08-12 NZ NZ591601A patent/NZ591601A/xx unknown
- 2009-08-12 HU HUE17191033A patent/HUE047767T2/hu unknown
- 2009-08-12 SM SM20190740T patent/SMT201900740T1/it unknown
- 2009-08-12 ES ES09786912.7T patent/ES2652590T3/es active Active
- 2009-08-12 US US13/058,639 patent/US8809334B2/en active Active
- 2009-08-12 HR HRP20171917TT patent/HRP20171917T1/hr unknown
- 2009-08-12 AR ARP090103113A patent/AR073031A1/es not_active Application Discontinuation
- 2009-08-12 CA CA2731370A patent/CA2731370C/en active Active
- 2009-08-12 EP EP09786912.7A patent/EP2315587B1/en not_active Revoked
- 2009-08-12 BR BRPI0917661A patent/BRPI0917661B8/pt not_active IP Right Cessation
- 2009-08-12 SI SI200931770T patent/SI2315587T1/en unknown
- 2009-08-12 DK DK09786912.7T patent/DK2315587T3/en active
- 2009-08-12 TW TW098127151A patent/TWI446911B/zh active
- 2009-08-12 AU AU2009280843A patent/AU2009280843B2/en active Active
- 2009-08-12 RU RU2011109084/15A patent/RU2519161C2/ru active
- 2009-08-12 LT LTEP09786912.7T patent/LT2315587T/lt unknown
- 2009-08-12 DK DK17191033.4T patent/DK3300729T3/da active
- 2009-08-12 PL PL09786912T patent/PL2315587T3/pl unknown
- 2009-08-12 PT PT97869127T patent/PT2315587T/pt unknown
-
2011
- 2011-02-10 IL IL211143A patent/IL211143A0/en active IP Right Grant
- 2011-03-07 MA MA33675A patent/MA32614B1/fr unknown
- 2011-03-11 ZA ZA2011/01900A patent/ZA201101900B/en unknown
-
2014
- 2014-07-18 US US14/335,657 patent/US9173881B2/en active Active
-
2015
- 2015-06-12 JP JP2015119021A patent/JP5956026B2/ja active Active
- 2015-06-12 JP JP2015119020A patent/JP5956025B2/ja active Active
- 2015-10-02 US US14/873,787 patent/US9597331B2/en active Active
-
2018
- 2018-01-19 CY CY20181100074T patent/CY1119826T1/el unknown
- 2018-10-03 HK HK18112650.6A patent/HK1253355B/zh not_active IP Right Cessation
-
2019
- 2019-12-06 HR HRP20192204TT patent/HRP20192204T1/hr unknown
-
2020
- 2020-01-08 CY CY20201100016T patent/CY1122641T1/el unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113194953A (zh) * | 2018-12-21 | 2021-07-30 | 埃科特莱茵药品有限公司 | 用于治疗肺动脉高血压的药物组合物 |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102099026B (zh) | 含美西特田的治疗组合物 | |
| CH683749A5 (de) | Pharmazeutische Nasalzusammensetzung. | |
| CN110151747B (zh) | Ferrostatin-1在治疗骨质疏松疾病中的用途 | |
| US20210346324A1 (en) | Niclosamide Formulations and Methods of Use | |
| TW200613012A (en) | Sustained-release composition, process for producing the same and use of the same | |
| HK1157221B (zh) | 含美西特田的治療組合物 | |
| HK1157221A (zh) | 含美西特田的治療組合物 | |
| CN102218062B (zh) | 一种治疗糖尿病的药物组合物 | |
| RU2571067C2 (ru) | Хронотерапевтическая фармацевтическая композиция | |
| Yoon et al. | Hypertrophic cardiomyopathy secondary to severe right and left ventricular outflow tract obstruction in a Maltese dog | |
| CA3213205A1 (en) | Use of mebendazole for treating viral infection | |
| CN103497237B (zh) | 治疗活性的α-MSH类似物 | |
| Nikolewski | The Effect of Cyclophosphamide (Cytoxan) on the Bladder Mucosa | |
| Radlinsky | How I treat tracheal collapse. | |
| Kim et al. | Surgical implantation of intra-abdominal radiotransmitter and observation of postoperative behaviour in the River Otter (Lutra lutra) of Korea |
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 |