ME02024B - Makrociklična jedinjenja hinoksalina kao inhibitori hcv ns3 proteaze - Google Patents
Makrociklična jedinjenja hinoksalina kao inhibitori hcv ns3 proteazeInfo
- Publication number
- ME02024B ME02024B MEP-2012-463A MEP46312A ME02024B ME 02024 B ME02024 B ME 02024B ME P46312 A MEP46312 A ME P46312A ME 02024 B ME02024 B ME 02024B
- Authority
- ME
- Montenegro
- Prior art keywords
- disorders
- agomelatine
- form iii
- crystalline form
- treatment
- Prior art date
Links
- 229940124771 HCV-NS3 protease inhibitor Drugs 0.000 title 1
- 125000001567 quinoxalinyl group Chemical class N1=C(C=NC2=CC=CC=C12)* 0.000 title 1
- YJYPHIXNFHFHND-UHFFFAOYSA-N agomelatine Chemical compound C1=CC=C(CCNC(C)=O)C2=CC(OC)=CC=C21 YJYPHIXNFHFHND-UHFFFAOYSA-N 0.000 claims description 14
- 229960002629 agomelatine Drugs 0.000 claims description 12
- 230000007170 pathology Effects 0.000 claims description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 claims description 6
- 208000035475 disorder Diseases 0.000 claims description 6
- 206010022437 insomnia Diseases 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 5
- 208000024714 major depressive disease Diseases 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 208000024827 Alzheimer disease Diseases 0.000 claims description 4
- 208000008589 Obesity Diseases 0.000 claims description 4
- 210000002249 digestive system Anatomy 0.000 claims description 4
- 230000002526 effect on cardiovascular system Effects 0.000 claims description 4
- 235000020824 obesity Nutrition 0.000 claims description 4
- 208000012672 seasonal affective disease Diseases 0.000 claims description 4
- 208000019116 sleep disease Diseases 0.000 claims description 4
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 3
- 208000019901 Anxiety disease Diseases 0.000 claims description 2
- 208000019695 Migraine disease Diseases 0.000 claims description 2
- 206010028980 Neoplasm Diseases 0.000 claims description 2
- 206010033664 Panic attack Diseases 0.000 claims description 2
- 208000018737 Parkinson disease Diseases 0.000 claims description 2
- 208000028017 Psychotic disease Diseases 0.000 claims description 2
- 206010039966 Senile dementia Diseases 0.000 claims description 2
- 201000001880 Sexual dysfunction Diseases 0.000 claims description 2
- 230000032683 aging Effects 0.000 claims description 2
- 230000036506 anxiety Effects 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 claims description 2
- 230000002490 cerebral effect Effects 0.000 claims description 2
- 230000004087 circulation Effects 0.000 claims description 2
- 206010012601 diabetes mellitus Diseases 0.000 claims description 2
- 206010015037 epilepsy Diseases 0.000 claims description 2
- 239000002955 immunomodulating agent Substances 0.000 claims description 2
- 229940121354 immunomodulator Drugs 0.000 claims description 2
- 230000001193 melatoninergic effect Effects 0.000 claims description 2
- 206010027599 migraine Diseases 0.000 claims description 2
- 231100000252 nontoxic Toxicity 0.000 claims description 2
- 230000003000 nontoxic effect Effects 0.000 claims description 2
- 208000019906 panic disease Diseases 0.000 claims description 2
- 230000001575 pathological effect Effects 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 201000000980 schizophrenia Diseases 0.000 claims description 2
- 231100000872 sexual dysfunction Toxicity 0.000 claims description 2
- 230000035882 stress Effects 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims 2
- 239000003814 drug Substances 0.000 claims 2
- 208000000044 Amnesia Diseases 0.000 claims 1
- 208000020401 Depressive disease Diseases 0.000 claims 1
- 208000026139 Memory disease Diseases 0.000 claims 1
- 230000036528 appetite Effects 0.000 claims 1
- 235000019789 appetite Nutrition 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000003112 inhibitor Substances 0.000 claims 1
- 201000003995 melancholia Diseases 0.000 claims 1
- 230000006984 memory degeneration Effects 0.000 claims 1
- 208000023060 memory loss Diseases 0.000 claims 1
- 230000016087 ovulation Effects 0.000 claims 1
- 230000000694 effects Effects 0.000 description 5
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 208000027559 Appetite disease Diseases 0.000 description 3
- 208000019454 Feeding and Eating disease Diseases 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- 102000006902 5-HT2C Serotonin Receptor Human genes 0.000 description 1
- 108010072553 5-HT2C Serotonin Receptor Proteins 0.000 description 1
- GABLTKRIYDNDIN-UHFFFAOYSA-N 7-methoxy-3,4-dihydro-2h-naphthalen-1-one Chemical compound C1CCC(=O)C2=CC(OC)=CC=C21 GABLTKRIYDNDIN-UHFFFAOYSA-N 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003433 contraceptive agent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000002584 immunomodulator Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000004089 microcirculation Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
-
- 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
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
-
- 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
- A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Virology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biophysics (AREA)
- Epidemiology (AREA)
- Gastroenterology & Hepatology (AREA)
- Biotechnology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Opis
Ovaj pronalazak se odnosi na novi kristalni III oblik agomelatina ili N-[2-(7-metoksi~ 1 -naftil)etil]acetamid formule (I):
postupak njegove proizvodnje, kao i na farmaceutske kompozicije koje ga sadrže.
Agomelatin ili N-[2-(7-metoksi-l-naftil)etil]acetamid ima korisna farmakološka
svojstva.
Ispoljava dejstvo dvostruke osobenosti, da je sa jedne strane agonist na receptorima melatoninergičnog sistema, a sa druge strane je antagonist receptora 5-HT2C. Ova svojstva mu daju aktivnost u centralnom nervnom sistemu i, preciznije, u lečenju depresije major, sezonskih depresija, poremećaja spavanja, kardiovaskularnih patologija, patologija digestivnog sistema, nesanica i umora kao posledica vremenske razlike, poremećaja apetita i gojaznosti.
Agomelatin, njegova proizvodnja i njegova upotreba u terapeutske svrhe, opisani su u evropskom patentu EP 0 447 285.
Uzimajući u obzir farmaceutsku korist od ovog jedinjenja, prioritet će biti dobijanje istog u stanju odlične čistoće i, pre svega, u obliku koji ima perfektnu reproducibilnost, koji ima povoljna svojstva koja olakšavaju formulisanje koje omogućava njegovo čuvanje u dužem vremenskom periodu bez posebnih uslova u pogledu temperature, svetia, vlažnosti ili sadržaja kiseonika.
Patent EP 0 447 285 opisuje dobijanje agomelatina u osam koraka polazeći od 7- metoksi-1 -tetralona. Međutim, ovaj dokument ne precizira uslove dobijanja agomelatina u obliku koji ima ove karakteristike na reproducibilan način.
Podnosilac zahteva sada ističe postupak dobijanja agomelatina u kristalnom obliku koji je dobro defmisan, savršeno reproduktibilan i ispoljava povoljne osobine u pogledu jednostavnog formulisanja.
Preciznije, ovaj pronalazak se odnosi na kristalan oblik III jedinjenja formule (I), koji je naznačen sledećim dijagramom đifrakcije X zraka na prašku, koji je izmeren na difraktometru Siemens D5005 (bakama antikatoda) i izražen pomoću međuravanske udaljenosti d, Bragg 2 teta ugla i relativnog intenziteta (izražen kao procenat u odnosu na traku najvećeg intenziteta):
Pronalazak se, takođe, odnosi na postupak izrade kristalnog oblika III jedinjenja formule (I), koji je naznačen time što se agomelatin greje na 110°C do potpunog topljenja, zatim se polako ohladi sve dok ne rekristališe.
Dobijanje ovog kristalnog oblika ima za prednost omogućavanje proizvodnje farmaceutskih formulacija koje će imati konstantan sastav i biti reproducibilne, što je od posebne prednosti s obzirom na to da su ove formulacije namenjene za oralnu primenu.
Tako, dobijeni rezultati farmakološkog istraživanja oblika III, pokazuju njegovu veoma važnu aktivnost u centralnom nervnom sistemu, kao i dejstvo na mikrocirkulaciju što mu omogućava primenu u lečenju stresa, poremećaja spavanja, anksioznosti, depresije major, sezonskih depresija, kardiovaskularnih patologija, patologija sistema za varenje, nesanica i umora kao posledica vremenske razlike, šizofrenije, napada panike, melanholije, poremećaja apetita, gojaznosti, nesanice, bola, psihotičnih poremećaja, epilepsije, dijabetesa, Parkinsonove bolesti, senilne demencije, različitih poremećaja povezanih sa normalnim ili patološkim starenjem, migrene, gubitka pamćenja, Alzheimerove bolesti, kao i poremećaja moždane cirkulacije. U drugom domenu aktivnosti, jasno je da se u lečenju, oblik III agomelatina može koristiti kod seksualnih disfunkcija, poseduje svojstva inhibitora ovulacije, imunomodulatora i može da se koristi u lečenju kancera.
Kristalni oblik III agomelatina se poželjno može koristiti za lečenje depresije major, sezonskih depresija, poremećaja spavanja, kardiovaskularnih patologija, patologija digestivnog sistema, nesanice i umora kao posledica vremenske razlike, poremećaja apetita i gojaznosti.
Pronalazak se, takođe, odnosi na farmaceutske kompozicije, koje kao aktivan princip sadrže kristalni oblik III jedinjenja formule (I) zajedno sa jednom ili više inertnih podloga, koje nisu toksične i koje su odgovarajuće. Od farmaceutskih kompozicija prema pronalasku, mogu se navesti preciznije one, koje su prikladne za oralno, parenteralno (intravensko ili subkutano), nazalno primenjivanje, jednostavne pilule ili dražeje. granule, sublingvalne tablete, želatinske kapsule, tablete, supozitorije, kremovi, masti, gelovi za kožu, injektabilni preparati, oralne suspenzije i paste za žvakanje.
Doziranje, koje će se primeniti, prilagodljivo je s obzirom na prirodu i težinu bolesti, način primenjivanja, kao i starost i težinu pacijenta. Ovo doziranje varira od 0. 1 mg do 1 g dnevno, u jednoj ili više doza.
Primeri u nastavku ilustruju pronalazak.
Primer 1: Kristalni oblik III N-(l-(7-metoksi-l-naftil)etil]acetamida
100 g N- [2-(7-metoksi-1 -naftil)etil] acetamida se greje na 110°C u sušnici dok se ne istopi, zatim se polako ohladi da bi došlo do rekristalizacije. Dobijeni oblik III je opisan sledećim dijagramom difrakcije X zraka na prašku, koji je izmeren na difraktometru Siemens D5005 (bakama antikatođa) i izražen pomoću međuravanske udaljenosti d, Bragg 2 teta ugla i relativnog intenziteta (izražen kao procenat u odnosu na traku najvećeg intenziteta):
Claims (5)
1. Kristalni oblik III agomelatina formule (I): naznačen sledećim dijagramom difrakcije X zraka na prašku, koji je izmeren na difraktometru Siemens D5005 (bakama antikatoda) i izražen pomoću međuravanske udaljenosti d, Bragg 2 teta ugla i relativnog intenziteta (izražen kao procenat u odnosu na traku najvećeg intenziteta):
2. Postupak proizvodnje kristalnog oblika III jedinjenja formule (I) prema zahtevu 1, naznačen time što se agomelatin greje na 110°C sve dok se potpuno ne istopi, a zatim se polako hladi dok se ne postigne rekristalizacija.
3. Farmaceutske kompozicije koje kao aktivan princip sadrže kristalni oblik III agomelatina prema zahtevu 1, u kombinaciji sa jednim ili više inertnih, netoksičnih i farmaceutski prihvatljivih nosača.
4. Farmaceutske kompozicije prema zahtevu 3 za upotrebu u proizvodnji lekova za lečenje poremećaja melatoninergičnog suistema.
5. Farmaceutske kompozicije prema zahtevu 3 za upotrebu u proizvodnji lekova za lečenje poremećaja spavanja, stresa, anksioznosti, sezonskih depresija ili depresije major, kardiovaskularnih patologija, patologija digestivnog sistema, nesanice i umora kao posledice vremenske razlike, šizofrenije, napada panike, melanholije, poremećaja apetita, gojaznosti, nesanice, psihotičnih poremećaja, epilepsije, dijabetesa, Parkinsonove bolesti, senilne demencije, različitih poremećaja koji su u vezi sa normalnim ili patološkim starenjem, migrene, gubitka pamćenja, Alzheimerove bolesti, poremećaja moždane cirkulacije, kao i u seksualnim disfunkcijama, kao inhibitori ovulacije i imunomodulatori i u lečenju kancera.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US13555908P | 2008-07-22 | 2008-07-22 | |
| PCT/US2009/050915 WO2010011566A1 (en) | 2008-07-22 | 2009-07-17 | Macrocyclic quinoxaline compounds as hcv ns3 protease inhibitors |
| EP09790553A EP2310095B1 (en) | 2008-07-22 | 2009-07-17 | Macrocyclic quinoxaline compounds as hcv ns3 protease inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ME02024B true ME02024B (me) | 2015-05-20 |
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ID=41130248
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| MEP-2012-463A ME02024B (me) | 2008-07-22 | 2009-07-17 | Makrociklična jedinjenja hinoksalina kao inhibitori hcv ns3 proteaze |
| MEP-2014-375A ME02132B (me) | 2008-07-22 | 2009-07-17 | Kombinacije makrocikličnog jedinjenja hinoksalina koje je inhibitor hcv ns3 proteaze sa drugim hcv sredstvima |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| MEP-2014-375A ME02132B (me) | 2008-07-22 | 2009-07-17 | Kombinacije makrocikličnog jedinjenja hinoksalina koje je inhibitor hcv ns3 proteaze sa drugim hcv sredstvima |
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Families Citing this family (60)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MY140680A (en) | 2002-05-20 | 2010-01-15 | Bristol Myers Squibb Co | Hepatitis c virus inhibitors |
| MY164469A (en) * | 2006-10-27 | 2017-12-15 | Msd Italia Srl | Hcv ns3 protease inhibitors |
| CA2720850A1 (en) * | 2008-04-28 | 2009-11-05 | Merck Sharp & Dohme Corp. | Hcv ns3 protease inhibitors |
| SI2540350T1 (sl) | 2008-07-22 | 2015-01-30 | Merck Sharp & Dohme Corp. | Kombinacije makrocikliäśnih kinoksalinske spojine, ki je hcv ns3 proteazni inhibitor z drugimi hcv uäśinkovinami |
| US20190127365A1 (en) | 2017-11-01 | 2019-05-02 | Merck Sharp & Dohme Corp. | Inhibitors of hepatitis c virus replication |
| NZ595410A (en) | 2009-03-27 | 2013-12-20 | Merck Sharp & Dohme | Inhibitors of hepatitis c virus replication |
| MX2011012155A (es) * | 2009-05-13 | 2012-02-28 | Enanta Pharm Inc | Compuestos macrociclicos como inhibidores del virus de hepatitis c. |
| US8937150B2 (en) | 2009-06-11 | 2015-01-20 | Abbvie Inc. | Anti-viral compounds |
| UA118080C2 (uk) * | 2009-06-11 | 2018-11-26 | Еббві Айрленд Анлімітед Компані | Противірусні сполуки |
| EP2459582B1 (en) | 2009-07-30 | 2015-05-27 | Merck Sharp & Dohme Corp. | Hepatitis c virus ns3 protease inhibitors |
| NZ605440A (en) | 2010-06-10 | 2014-05-30 | Abbvie Bahamas Ltd | Solid compositions comprising an hcv inhibitor |
| BR112013006693B1 (pt) * | 2010-09-21 | 2022-07-12 | Enanta Pharmaceuticals, Inc | Compostos inibidores da serino protease hcv derivada de prolina macrocíclica |
| CA2812779A1 (en) | 2010-09-29 | 2012-04-19 | Merck Sharp & Dohme Corp. | Fused tetracycle derivatives and methods of use thereof for the treatment of viral diseases |
| MX2013003634A (es) * | 2010-09-29 | 2013-05-20 | Merck Sharp & Dohme | Derivados policiclicos heterociclicos y metodos de uso de los mismos para el tratamiento de enfermedades virales. |
| WO2012082672A2 (en) | 2010-12-14 | 2012-06-21 | Merck Sharp & Dohme Corp. | Process and intermediates for preparing macrolactams |
| WO2012122716A1 (en) | 2011-03-17 | 2012-09-20 | Merck Sharp & Dohme Corp. | Tetracyclic xanthene derivatives and methods of use thereof for treatment of viral diseases |
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