KR20010032779A - 비만 치료 방법 - Google Patents
비만 치료 방법 Download PDFInfo
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- KR20010032779A KR20010032779A KR1020007006075A KR20007006075A KR20010032779A KR 20010032779 A KR20010032779 A KR 20010032779A KR 1020007006075 A KR1020007006075 A KR 1020007006075A KR 20007006075 A KR20007006075 A KR 20007006075A KR 20010032779 A KR20010032779 A KR 20010032779A
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- Prior art keywords
- obesity
- drugs
- endocelin
- med
- chem
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- 208000008589 Obesity Diseases 0.000 title claims abstract description 13
- 235000020824 obesity Nutrition 0.000 title claims abstract description 13
- 238000000034 method Methods 0.000 title description 2
- 239000003814 drug Substances 0.000 claims abstract description 10
- 229940079593 drug Drugs 0.000 claims abstract description 10
- 239000002464 receptor antagonist Substances 0.000 claims abstract description 9
- 229940044551 receptor antagonist Drugs 0.000 claims abstract description 9
- 201000010099 disease Diseases 0.000 claims abstract description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 5
- 238000004519 manufacturing process Methods 0.000 claims abstract description 3
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 239000007903 gelatin capsule Substances 0.000 description 6
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- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 4
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- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
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- UWHBIISPHYTOGL-PFSAEEMXSA-L disodium;2-[(2r,5s,8s,11s,14s,17r)-8-(carboxylatomethyl)-17-(1h-indol-3-ylmethyl)-14-(2-methylpropyl)-3,6,9,12,15,18-hexaoxo-5-[2-oxo-2-(4-phenylpiperazin-1-yl)ethyl]-11-thiophen-2-yl-1,4,7,10,13,16-hexazacyclooctadec-2-yl]acetate Chemical compound [Na+].[Na+].C([C@H]1C(=O)N[C@@H](CC([O-])=O)C(=O)N[C@@H](C(=O)N[C@H](C(N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@H](CC([O-])=O)C(=O)N1)=O)CC(C)C)C=1SC=CC=1)C(=O)N(CC1)CCN1C1=CC=CC=C1 UWHBIISPHYTOGL-PFSAEEMXSA-L 0.000 description 1
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- LJGUZUROJOJEMI-UHFFFAOYSA-N n-(3,4-dimethyl-1,2-oxazol-5-yl)-2-[4-(1,3-oxazol-2-yl)phenyl]benzenesulfonamide Chemical compound CC1=NOC(NS(=O)(=O)C=2C(=CC=CC=2)C=2C=CC(=CC=2)C=2OC=CN=2)=C1C LJGUZUROJOJEMI-UHFFFAOYSA-N 0.000 description 1
- ORJRYNKVKJAJPY-UHFFFAOYSA-N n-[[2-[2-[(4,5-dimethyl-1,2-oxazol-3-yl)sulfamoyl]phenyl]-5-(1,3-oxazol-2-yl)phenyl]methyl]-n,3,3-trimethylbutanamide Chemical compound CC(C)(C)CC(=O)N(C)CC1=CC(C=2OC=CN=2)=CC=C1C1=CC=CC=C1S(=O)(=O)NC1=NOC(C)=C1C ORJRYNKVKJAJPY-UHFFFAOYSA-N 0.000 description 1
- 229940124706 obesity therapeutics Drugs 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
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- 201000011303 renal artery atheroma Diseases 0.000 description 1
- 229960002578 sitaxentan Drugs 0.000 description 1
- PHWXUGHIIBDVKD-UHFFFAOYSA-N sitaxentan Chemical compound CC1=NOC(NS(=O)(=O)C2=C(SC=C2)C(=O)CC=2C(=CC=3OCOC=3C=2)C)=C1Cl PHWXUGHIIBDVKD-UHFFFAOYSA-N 0.000 description 1
- COKFAUSKNMGISZ-BMGIYVBOSA-M sodium;(z)-2-(2,1,3-benzothiadiazol-5-yl)-4-(4-methoxyphenyl)-4-oxo-3-[(3,4,5-trimethoxyphenyl)methyl]but-2-enoate Chemical compound [Na+].C1=CC(OC)=CC=C1C(=O)C(\CC=1C=C(OC)C(OC)=C(OC)C=1)=C(/C([O-])=O)C1=CC2=NSN=C2C=C1 COKFAUSKNMGISZ-BMGIYVBOSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
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- 239000004408 titanium dioxide Substances 0.000 description 1
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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
- A61K31/495—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
-
- 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
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
-
- 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
- A61P3/04—Anorexiants; Antiobesity agents
-
- 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
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- 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
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Diabetes (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Epidemiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Child & Adolescent Psychology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Plant Substances (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
본 발명은 비만 또는 비만에 의해 유발되는 질병을 치료하는 약물 제조를 위한 엔도셀린 수용체 길항제의 용도에 관한 것이다.
Description
본 발명은 비만 및 비만으로 인한 질병을 제어하는 방법에 관한 것이다.
펩티드 호르몬인 엔도셀린은 그의 강한 혈관 수축 특성으로 알려져있다. 따라서 엔도셀린 수용체 길항제는 주로 심혈관계 병리에서 시험되고 있다.
본 발명은 비만 및 비만으로 인한 질병을 제어하는 약물을 제조하기 위한 엔도셀린 수용체 길항제의 용도에 관한 것이다.
엔도셀린A및 혼합된 엔도셀린A/B수용체 길항제 모두가 사용될 수 있다.
특히 적합한 엔도셀린 수용체 길항제는 하기와 같다.
1. TBC-11251 (J. Med. Chem., 40, No. 11, 1690-97, 1997),
2. BMS-193884 (EP 558,258),
3. BMS-207940 (Pharmaprojects (13. 06. 97)),
4. BQ-123 (Exp. Opin. Invest. Drugs, 1997, 6, No. 5, 475-487),
5. SB-209670 (Exp. Opin. Invest. Drugs, 1997, 6, No. 5, 475-487),
6. SB-217242 (Exp. Opin. Invest. Drugs, 1997, 6, No. 5, 475-487),
7. SB-209598 (Trends in Pharmacol. Sci., 17, 177-81, 1996),
8. TAK-044 (Exp. Opin. Invest. Drugs, 1997, 6, No. 5, 475-487),
9. Bosentan (Trends in Pharmacol. Sci., 18, 408-12, 1997),
10. PD-156707 (J. Med. Chem., 40, No. 7, 1063-74, 1997),
11. L-749327 (Bioorg. Med. Chem. Lett., 7, No. 3, 275-280, 1997),
12. L-754142 (Exp. Opin. Invest. Drugs, 1997, 6, No. 5, 475-487),
13. ABT-627 (J. Med. Chem., 40, No. 20, 3217-27, 1997),
14. A-127772 (J. Med. Chem., 39, No. 5, 1039-1048, 1996),
15. A-206377 (213thAmerican Chemical Society National Meeting, San Francisco, California, USA, 13-17 April, 1997, Poster, MEDI 193),
16. A-182086 (J. Med. Chem., 40, No. 20, 3217-27, 1997),
17. EMD-93246 (211thAmerican Chemical Society National Meeting, New Orleans, USA, 1996, Poster, MEDI 143),
18. EMD-122801 (Bioorg. Med. Chem. Lett., 8, No. 1, 17-22, 1998),
19. ZD-1611 (Trends in Pharmacol. Sci., 18, 408-12, 1997),
20. AC-610612 (R & D Focus Drug News (18. 05. 98)),
21. T-0201 (70th Annual Meeting of the Japanese Pharmacological Society, Chiba, Japan, 22-25 March 1997, Lecture, O-133), 및
22. J-104132 (R & D Focus Drug News (15. 12. 97)).
특히 비만이란 체중이 정상 체중을 20%이상 초과할 때 사용되는 용어이다. 비만의 원인은 과식 또는 예를 들어 유전적 고콜레스테롤혈증과 같은 음식의 잘못된 이용 때문이다. 비만에 의해 또는 종종 비만과 관련되어 유발되는 질병으로는 특히 고혈압, 타입 2 당뇨병, 고지혈증, 만성 신부전 및 아테롬성 동맥경화증이 있으며 또한 요산증도 가능하다.
지금까지 동물 실험에 있어서 비만의 병리 상태를 모사하기는 매우 어려웠다(극히 과량의 콜레스테롤 투여). 그러나, 최근에 아포지단백질 E에 대한유전자가 결핍된 마우스가 개량되어 이를 비만 치료 물질 시험에 사용할 수 있게 되었다.
엔도셀린 수용체 길항물질 23의 효과는 apoE에 대한 유전자가 결핍된 상기 마우스의 동물 모델로 조사하였다. 대조 래트에서 예측한대로 고지방 규정식을 섭취하는 동물의 체중은 크게 증가하였다. 이는 간의 지방 분해화 함께 간의 크기 증가와 관련된다. 대등한 군에서, 시험 동물을 물질 23(50mg/kg/일)으로 처리하였다. 이 군에서 체중 및 간의 중량의 증가는 완벽하게 방지되었다. 또한 간은 조직학적으로 특이성을 보이지 않았다.
엔도셀린A및 엔도셀린A/B수용체 길항제는 일생동안 투여되어야 하며, 그 투여량은 50 내지 500mg/환자/일이다.
엔도셀린A및 엔도셀린A/B수용체 길항제는 예를 들어 비코팅, 코팅 또는 당의정, 경질 및 연질 젤라틴 캅셀, 용액, 유화액 및 현탁액의 형태로 일반적으로 경구로 투여된다. 그러나 또한 예를 들어 좌제 형태로서 직장으로, 또는 예를 들어 주사액제 형태로서 비경구로 투여될 수도 있다.
비코팅, 코팅 및 당의정 및 경질 젤라틴 캅셀을 제조하기 위해, 본 발명에 따른 조합물을 제약상 불활성인 무기 또는 유기 부형제로 가공할 수 있다. 비코팅 및 당의정 및 경질 젤라틴 캅셀에 사용할 수 있는 이런 종류의 부형제는 락토오스, 옥수수 전분 또는 그의 유도체, 탈크, 스테아르 산 또는 그의 염이 있다. 연질 젤라틴 캅셀에 적합한 부형제는 식물성유, 왁스, 지방, 반고상 또는 액상 폴리올이다.
용액제 및 시럽제를 제조하는데 적합한 부형제는 예를 들어 물, 폴리올, 수크로오스, 전화당, 포도당 등이다. 주사용제에 적합한 부형제는 물, 알콜, 폴리올, 글리세롤, 식물성유이다. 좌제에 적합한 부형제는 천연 또는 경화유, 왁스, 지방, 반고상 또는 액상 폴리올 등이다.
또한 제약 제제는 방부제, 용해제, 안정화제, 습윤제, 유화제, 감미제, 착색제, 방향제, 삼투압을 바꾸기 위한 염, 완충제, 코팅제 및(또는) 항산화제를 추가로 함유할 수도 있다.
하기의 실시예는 본 발명을 설명한다.
〈실시예 1〉
하기의 조성을 갖는 코팅정을 제조하였다:
화합물 23 300.0mg
무수락토오스 30.0mg
미세결정형 셀룰로오스 30.0mg
폴리비닐피롤리돈 20.0mg
마그네슘 스테아레이트 5.0mg
폴리에틸렌 글리콜 6000 0.8mg
황색 산화아연 1.2mg
이산화티타늄 0.3mg
탈크 0.7mg
화합물 23, 락토오스, 셀룰로오스 및 폴리비닐피롤리돈을 습윤 과립화하고 건조하였다. 체로 거른 과립을 마그네슘 스테아레이트와 혼합하고, 그 혼합물을 각 390.0mg의 무게의 타원형 정제핵으로 압착하였다. 이후 핵을 코팅정의 최종 무게가 400mg이 될 때까지 코팅하였다.
〈실시예 2〉
300mg의 화합물 23 대신 화합물 26을 300mg 함유하는 코팅정을 실시예 1에서와 유사한 방법으로 제조하였다.
〈실시예 3〉
하기의 조성을 가지는 경질 젤라틴 캅셀의 제조:
화합물 23 250.0mg
결정형 락토오스 18.0mg
폴리비닐피롤리돈 15.0mg
미세결정형 셀룰로오스 17.5mg
소듐 카르복실메틸 전분 10.0mg
탈크 0.7mg
마그네슘 스테아레이트 3.0mg
상위의 5개 물질을 습윤 과립화하여 건조하였다. 과립을 소듐 카르복실메틸 전분, 탈크 및 마그네슘 스테아레이트와 혼합하고, 혼합물을 크기 0의 경질 젤라틴 캅셀로 패킹하였다.
Claims (1)
- 비만 및 비만에 의해 유발되는 질병을 조절하는 약물을 제조하기 위한 엔도셀린 수용체 길항제의 용도.
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DE19754082.1 | 1997-12-05 | ||
DE19754082A DE19754082A1 (de) | 1997-12-05 | 1997-12-05 | Methode zur Bekämpfung der Fettleibigkeit |
PCT/EP1998/007501 WO1999029308A2 (de) | 1997-12-05 | 1998-11-21 | Methode zur bekämpfung der fettleibigkeit |
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KR20010032779A true KR20010032779A (ko) | 2001-04-25 |
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US (1) | US6197780B1 (ko) |
EP (1) | EP1035851B1 (ko) |
JP (1) | JP2002512173A (ko) |
KR (1) | KR20010032779A (ko) |
CN (1) | CN1152685C (ko) |
AT (1) | ATE204172T1 (ko) |
AU (1) | AU751053B2 (ko) |
BR (1) | BR9815335A (ko) |
CA (1) | CA2311423C (ko) |
CZ (1) | CZ300442B6 (ko) |
DE (2) | DE19754082A1 (ko) |
ES (1) | ES2162493T3 (ko) |
HK (1) | HK1037141A1 (ko) |
HU (1) | HUP0100171A3 (ko) |
NO (2) | NO324694B1 (ko) |
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DE19533023B4 (de) * | 1994-10-14 | 2007-05-16 | Basf Ag | Neue Carbonsäurederivate, ihre Herstellung und Verwendung |
EP1130027A1 (de) * | 2000-02-29 | 2001-09-05 | Aventis Pharma Deutschland GmbH | Memno-Peptide, Verfahren zu ihrer Herstellung und Verwendung derselben |
US20050175667A1 (en) * | 2004-02-10 | 2005-08-11 | Wenda Carlyle | Use of endothelin antagonists to prevent restenosis |
CA2904447C (en) | 2007-08-22 | 2017-01-03 | Abbvie Deutschland Gmbh & Co Kg | Therapy for complications of diabetes |
SI2776038T1 (en) * | 2011-11-11 | 2018-06-29 | Gilead Apollo, Llc | ACC INHIBITORS AND THEIR USE |
WO2016099233A2 (ru) * | 2014-10-20 | 2016-06-23 | Товарищество С Ограниченной Ответственностью "Фармацевтическая Компания "Ромат" | Фармацевтическая композиция для лечения туберкулеза |
AR106472A1 (es) | 2015-10-26 | 2018-01-17 | Gilead Apollo Llc | Inhibidores de acc y usos de los mismos |
HUE053175T2 (hu) | 2015-11-25 | 2021-06-28 | Gilead Apollo Llc | ACC-gátló észterek és azok alkalmazása |
CA3004747A1 (en) | 2015-11-25 | 2017-06-01 | Gilead Apollo, Llc | Fungicidal compositions containing derivatives of 2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidine |
ES2939977T3 (es) | 2015-11-25 | 2023-04-28 | Gilead Apollo Llc | Inhibidores de triazol ACC y usos de los mismos |
EP3380480B1 (en) | 2015-11-25 | 2022-12-14 | Gilead Apollo, LLC | Pyrazole acc inhibitors and uses thereof |
CA3155220C (en) | 2016-03-02 | 2024-01-16 | Gilead Apollo, Llc | Solid forms of a thienopyrimidinedione acc inhibitor and methods for production thereof |
ES2927019T3 (es) | 2017-03-28 | 2022-11-02 | Gilead Sciences Inc | Combinaciones terapéuticas para el tratamiento de enfermedades hepáticas |
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AU6603996A (en) * | 1995-08-24 | 1997-03-19 | Warner-Lambert Company | Furanone endothelin antagonists |
JP3116347B2 (ja) * | 1996-11-13 | 2000-12-11 | 田辺製薬株式会社 | 医薬組成物 |
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- 1998-11-21 DE DE59801230T patent/DE59801230D1/de not_active Expired - Lifetime
- 1998-11-21 KR KR1020007006075A patent/KR20010032779A/ko not_active Application Discontinuation
- 1998-11-21 JP JP2000523980A patent/JP2002512173A/ja active Pending
- 1998-11-21 HU HU0100171A patent/HUP0100171A3/hu unknown
- 1998-11-21 AT AT98965685T patent/ATE204172T1/de active
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- 1998-11-21 CZ CZ20002006A patent/CZ300442B6/cs not_active IP Right Cessation
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Also Published As
Publication number | Publication date |
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NO20002777D0 (no) | 2000-05-30 |
CN1152685C (zh) | 2004-06-09 |
ES2162493T3 (es) | 2001-12-16 |
CZ300442B6 (cs) | 2009-05-20 |
EP1035851A2 (de) | 2000-09-20 |
EP1035851B1 (de) | 2001-08-16 |
RU2003138080A (ru) | 2005-06-10 |
CN1301162A (zh) | 2001-06-27 |
NO20074419L (no) | 2000-06-02 |
CA2311423C (en) | 2008-01-29 |
AU2153599A (en) | 1999-06-28 |
HUP0100171A3 (en) | 2003-10-28 |
BR9815335A (pt) | 2000-10-17 |
DE59801230D1 (de) | 2001-09-20 |
RU2292891C2 (ru) | 2007-02-10 |
CA2311423A1 (en) | 1999-06-17 |
JP2002512173A (ja) | 2002-04-23 |
NO324694B1 (no) | 2007-12-03 |
US6197780B1 (en) | 2001-03-06 |
CZ20002006A3 (cs) | 2000-11-15 |
DE19754082A1 (de) | 1999-06-10 |
HUP0100171A2 (hu) | 2003-02-28 |
ATE204172T1 (de) | 2001-09-15 |
AU751053B2 (en) | 2002-08-08 |
WO1999029308A2 (de) | 1999-06-17 |
WO1999029308A3 (de) | 1999-09-30 |
HK1037141A1 (en) | 2002-02-01 |
NO20002777L (no) | 2000-06-02 |
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