HRP20110289T1 - Makrociklički inhibitori virusa hepatitisa c - Google Patents
Makrociklički inhibitori virusa hepatitisa c Download PDFInfo
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- HRP20110289T1 HRP20110289T1 HR20110289T HRP20110289T HRP20110289T1 HR P20110289 T1 HRP20110289 T1 HR P20110289T1 HR 20110289 T HR20110289 T HR 20110289T HR P20110289 T HRP20110289 T HR P20110289T HR P20110289 T1 HRP20110289 T1 HR P20110289T1
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- 241000711549 Hepacivirus C Species 0.000 title 1
- 239000003112 inhibitor Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract 29
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract 7
- 239000001257 hydrogen Substances 0.000 claims abstract 7
- 150000003839 salts Chemical class 0.000 claims abstract 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract 4
- 125000000217 alkyl group Chemical group 0.000 claims abstract 4
- 150000001204 N-oxides Chemical class 0.000 claims abstract 3
- 238000006243 chemical reaction Methods 0.000 claims 8
- 238000000034 method Methods 0.000 claims 3
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims 2
- WMSPXQIQBQAWLL-UHFFFAOYSA-N cyclopropanesulfonamide Chemical compound NS(=O)(=O)C1CC1 WMSPXQIQBQAWLL-UHFFFAOYSA-N 0.000 claims 2
- 239000003814 drug Substances 0.000 claims 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 2
- 230000002401 inhibitory effect Effects 0.000 claims 2
- 150000002678 macrocyclic compounds Chemical class 0.000 claims 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 2
- 230000010076 replication Effects 0.000 claims 2
- 238000006751 Mitsunobu reaction Methods 0.000 claims 1
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 230000000840 anti-viral effect Effects 0.000 claims 1
- 238000006254 arylation reaction Methods 0.000 claims 1
- 125000004429 atom Chemical group 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- 230000032050 esterification Effects 0.000 claims 1
- 238000005886 esterification reaction Methods 0.000 claims 1
- 125000000524 functional group Chemical group 0.000 claims 1
- 150000002431 hydrogen Chemical group 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000005649 metathesis reaction Methods 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 238000007363 ring formation reaction Methods 0.000 claims 1
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 claims 1
- 229960000311 ritonavir Drugs 0.000 claims 1
- 230000009466 transformation Effects 0.000 claims 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
-
- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines 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
- A61K31/13—Amines
- A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
- C07K5/06165—Dipeptides with the first amino acid being heterocyclic and Pro-amino acid; Derivatives thereof
-
- 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Molecular Biology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Virology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Peptides Or Proteins (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Abstract
Spoj koji ima formulu njegov N-oksid, sol ili stereoizomeri, naznačen time, dada isprekidana crta proizvoljno predstavlja dvostruku vezu između atoma C7 i C8; R1 je vodik ili Cl-6alkil; R2 je vodik ili Cl-6alkil; an je 3, 4, 5 ili 6. Patent sadrži još 14 patentnih zahtjeva.
Claims (15)
1. Spoj koji ima formulu
[image]
njegov N-oksid, sol ili stereoizomeri, naznačen time, da
da isprekidana crta proizvoljno predstavlja dvostruku vezu između atoma C7 i C8;
R1 je vodik ili Cl-6alkil;
R2 je vodik ili Cl-6alkil; a
n je 3, 4, 5 ili 6.
2. Spoj prema zahtjevu 1, naznačen time, da navedeni spoj ima formulu (I-c):
[image]
3. Spoj prema bilo kojem od zahtjeva 1-2, naznačen time, da navedeni spoj ima formulu (I-b):
[image]
4. Spoj prema bilo kojem od zahtjeva 1-3, naznačen time, da n je 4 ili 5.
5. Spoj prema bilo kojem od zahtjeva 1-3, naznačen time, da R1 je vodik ili metil.
6. Spoj prema bilo kojem od zahtjeva 1-3, naznačen time, da R2 je vodik.
7. Spoj prema bilo kojem od zahtjeva 1-3, naznačen time, da R2 je metil.
8. Spoj prema bilo kojem od zahtjeva 1-3, naznačeno time, da je navedeni spoj odabran iz
[image]
[image]
[image]
[image]
[image]
9. Spoj prema bilo kojem od zahtjeva 1-8, naznačen time, da je različit od N-oksida ili soli.
10. Kombinacija, naznačena time, da sadrži
(a) spoj kako je definirano u bilo kojem od zahtjeva 1 do 9 ili njegovu farmaceutski prihvatljivu sol; i
(b) ritonavir ili njegovu farmaceutski prihvatljivu sol.
11. Farmaceutska kompozicija, naznačena time, da sadrži nosač, a kao aktivni sastojak anti-virusnu učinkovitu količinu spoja kako je definirano u bilo kojem od zahtjeva 1-9 ili neku kombinaciju prema zahtjevu 10.
12. Spoj prema bilo kojem od zahtjeva 1-9 ili kombinacija prema zahtjevu 10, naznačeni time, da se koriste kao lijek.
13. Upotreba spoja prema bilo kojem od zahtjeva 1-9 ili kombinacije prema zahtjevu 10, naznačena time, da se koriste za proizvodnju lijeka za inhibiranje HCV replikacije.
14. Spoj prema bilo kojem od zahtjeva 1-9 ili učinkovita količina svake komponente iz kombinacije prema zahtjevu 10, naznačen time, da se upotrebljava kod postupka inhibicije HCV replikacije.
15. Postupak za dobivanje spoja prema bilo kojem od zahtjeva od 1-9, naznačen time, da navedeni proces sadrži:
(a) pripremu spoja formule (I) pri čemu veza između C7 i C8 je dvostruka veza, koja u stvari prikazuje spoj formule (I-a), kako je definirano u zahtjevu 2, pomoću formiranja dvostruke veze između C7 i C8, a naročito preko olefinske metatezne reakcije, a nakon toga pomoću ciklizacije u makrocikal kako je naznačeno u slijedećoj reakcijskoj shemi:
[image]
(b) pretvorbe spoja formule (I-a) u spoj formule (I) pri čemu veza između C7 i C8 u makrociklu je jednostruka veza, na primjer spoj formule (I-b), kako je definiran u zahtjevu 3, pomoću redukcije C7-C8 dvostruke veze u spoju formule (I-a);
(c) reakciju ciklopropilsulfonamida (IV) sa intermedijerom (III) preko reakcije koja formira amid kako je navedeno u slijedećoj reakcijskoj shemi:
[image]
(d) esterifikaciju intermedijera (V) sa kinolinom formule (VI) kako je navedeno u slijedećoj reakcijskoj shemi:
[image]
pri čemu X u (VI) predstavlja hidroksi ili izlaznu skupinu; a koja reakcija posebice je O-arilacijska reakcija pri čemu X predstavlja izlaznu skupinu ili neka Mitsunobu-ova reakcija pri čemu X je hidroksi;
(e) pripremu spoja formule (I) gdje R1 je vodik, a navedeni spoj je prikazan sa (I-d), iz odgovarajućeg intermedijera sa zaštićenim dušikom (VII), pri čemu PG predstavlja skupinu koja štiti dušik:
[image]
(f) pretvorbe spoja formule (I) jedan u drugi pomoću reakcije transformacije funkcionalne skupine; ili
(g) priprema soli pomoću reakcije slobodnog oblika spoja formule (I) sa kiselinom ili bazom.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP05107066 | 2005-07-29 | ||
| EP06101278 | 2006-02-03 | ||
| PCT/EP2006/064812 WO2007014918A1 (en) | 2005-07-29 | 2006-07-28 | Macrocyclic inhibitors of hepatitis c virus |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP20110289T1 true HRP20110289T1 (hr) | 2011-05-31 |
Family
ID=37102945
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HR20110289T HRP20110289T1 (hr) | 2005-07-29 | 2011-04-19 | Makrociklički inhibitori virusa hepatitisa c |
Country Status (32)
| Country | Link |
|---|---|
| US (1) | US8008251B2 (hr) |
| EP (1) | EP1913014B1 (hr) |
| JP (1) | JP5508713B2 (hr) |
| KR (1) | KR101321392B1 (hr) |
| CN (1) | CN101233147B (hr) |
| AR (1) | AR054881A1 (hr) |
| AT (1) | ATE496934T1 (hr) |
| AU (1) | AU2006274857B2 (hr) |
| BR (1) | BRPI0614515A2 (hr) |
| CA (1) | CA2616954C (hr) |
| CY (1) | CY1112001T1 (hr) |
| DE (1) | DE602006019879D1 (hr) |
| DK (1) | DK1913014T3 (hr) |
| EA (1) | EA200800485A1 (hr) |
| GT (1) | GT200600340A (hr) |
| HK (1) | HK1116503A1 (hr) |
| HR (1) | HRP20110289T1 (hr) |
| IL (1) | IL188281A (hr) |
| ME (1) | ME01233B (hr) |
| MX (1) | MX2008001394A (hr) |
| MY (1) | MY139987A (hr) |
| NO (1) | NO20081074L (hr) |
| NZ (1) | NZ564542A (hr) |
| PE (1) | PE20070210A1 (hr) |
| PL (1) | PL1913014T3 (hr) |
| PT (1) | PT1913014E (hr) |
| RS (1) | RS51776B (hr) |
| SG (1) | SG163610A1 (hr) |
| SI (1) | SI1913014T1 (hr) |
| TW (1) | TWI437993B (hr) |
| UY (1) | UY29702A1 (hr) |
| WO (1) | WO2007014918A1 (hr) |
Families Citing this family (35)
| Publication number | Priority date | Publication date | Assignee | Title |
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| MY140680A (en) | 2002-05-20 | 2010-01-15 | Bristol Myers Squibb Co | Hepatitis c virus inhibitors |
| WO2005073195A2 (en) | 2004-01-30 | 2005-08-11 | Medivir Ab | Hcv ns-3 serine protease inhibitors |
| WO2006116053A1 (en) * | 2005-04-22 | 2006-11-02 | Sciclone Pharmaceuticals, Inc. | Immunomodulator compounds as vaccine enhancers |
| PE20070211A1 (es) | 2005-07-29 | 2007-05-12 | Medivir Ab | Compuestos macrociclicos como inhibidores del virus de hepatitis c |
| US7741281B2 (en) | 2005-11-03 | 2010-06-22 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| EP2049474B1 (en) | 2006-07-11 | 2015-11-04 | Bristol-Myers Squibb Company | Hepatitis c virus inhibitors |
| US8343477B2 (en) | 2006-11-01 | 2013-01-01 | Bristol-Myers Squibb Company | Inhibitors of hepatitis C virus |
| US7772180B2 (en) | 2006-11-09 | 2010-08-10 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US7888464B2 (en) | 2006-11-16 | 2011-02-15 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US8003604B2 (en) | 2006-11-16 | 2011-08-23 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US7763584B2 (en) | 2006-11-16 | 2010-07-27 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| EA200970493A1 (ru) * | 2006-11-17 | 2009-10-30 | Тиботек Фармасьютикалз Лтд. | Макроциклические ингибиторы вируса гепатита с |
| US8383583B2 (en) | 2007-10-26 | 2013-02-26 | Enanta Pharmaceuticals, Inc. | Macrocyclic, pyridazinone-containing hepatitis C serine protease inhibitors |
| US8202996B2 (en) | 2007-12-21 | 2012-06-19 | Bristol-Myers Squibb Company | Crystalline forms of N-(tert-butoxycarbonyl)-3-methyl-L-valyl-(4R)-4-((7-chloro-4-methoxy-1-isoquinolinyl)oxy)-N- ((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)-L-prolinamide |
| AU2009210789B2 (en) | 2008-02-04 | 2014-01-30 | Idenix Pharmaceuticals, Inc. | Macrocyclic serine protease inhibitors |
| US8372802B2 (en) | 2008-03-20 | 2013-02-12 | Enanta Pharmaceuticals, Inc. | Fluorinated macrocyclic compounds as hepatitis C virus inhibitors |
| US8163921B2 (en) | 2008-04-16 | 2012-04-24 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US8044023B2 (en) | 2008-05-29 | 2011-10-25 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US7964560B2 (en) | 2008-05-29 | 2011-06-21 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US8207341B2 (en) | 2008-09-04 | 2012-06-26 | Bristol-Myers Squibb Company | Process or synthesizing substituted isoquinolines |
| US8044087B2 (en) | 2008-09-29 | 2011-10-25 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US8563505B2 (en) | 2008-09-29 | 2013-10-22 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US8283310B2 (en) | 2008-12-15 | 2012-10-09 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| TW201040181A (en) | 2009-04-08 | 2010-11-16 | Idenix Pharmaceuticals Inc | Macrocyclic serine protease inhibitors |
| TW201117812A (en) | 2009-08-05 | 2011-06-01 | Idenix Pharmaceuticals Inc | Macrocyclic serine protease inhibitors |
| WO2012109398A1 (en) | 2011-02-10 | 2012-08-16 | Idenix Pharmaceuticals, Inc. | Macrocyclic serine protease inhibitors, pharmaceutical compositions thereof, and their use for treating hcv infections |
| US8957203B2 (en) | 2011-05-05 | 2015-02-17 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US8691757B2 (en) | 2011-06-15 | 2014-04-08 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US9207002B2 (en) | 2011-10-12 | 2015-12-08 | International Business Machines Corporation | Contaminant separator for a vapor-compression refrigeration apparatus |
| EA025560B1 (ru) | 2012-10-19 | 2017-01-30 | Бристол-Майерс Сквибб Компани | Ингибиторы вируса гепатита с |
| WO2014070964A1 (en) | 2012-11-02 | 2014-05-08 | Bristol-Myers Squibb Company | Hepatitis c virus inhibitors |
| US9643999B2 (en) | 2012-11-02 | 2017-05-09 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
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| EP2914614B1 (en) | 2012-11-05 | 2017-08-16 | Bristol-Myers Squibb Company | Hepatitis c virus inhibitors |
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| PE20050431A1 (es) * | 2003-09-22 | 2005-07-19 | Boehringer Ingelheim Int | Peptidos macrociclicos activos contra el virus de la hepatitis c |
| WO2005073195A2 (en) * | 2004-01-30 | 2005-08-11 | Medivir Ab | Hcv ns-3 serine protease inhibitors |
| PE20070211A1 (es) * | 2005-07-29 | 2007-05-12 | Medivir Ab | Compuestos macrociclicos como inhibidores del virus de hepatitis c |
| MY139988A (en) * | 2005-07-29 | 2009-11-30 | Tibotec Pharm Ltd | Macrocylic inhibitors of hepatitis c virus |
| CN101273042B (zh) * | 2005-07-29 | 2013-11-06 | 泰博特克药品有限公司 | 丙型肝炎病毒的大环抑制剂 |
| CN101273038A (zh) * | 2005-07-29 | 2008-09-24 | 美迪维尔公司 | 丙型肝炎病毒的大环化合物抑制剂 |
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