ME00929B - NOVI POSTUPAK ZA DOBlJANJE KRISTALNOG OBLIKA V AGOMELATIN A - Google Patents
NOVI POSTUPAK ZA DOBlJANJE KRISTALNOG OBLIKA V AGOMELATIN AInfo
- Publication number
- ME00929B ME00929B MEP-2009-258A MEP25809A ME00929B ME 00929 B ME00929 B ME 00929B ME P25809 A MEP25809 A ME P25809A ME 00929 B ME00929 B ME 00929B
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- Montenegro
- Prior art keywords
- crystalline form
- formula
- fact
- compound
- agomelatine
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 8
- 238000004519 manufacturing process Methods 0.000 claims abstract description 7
- YJYPHIXNFHFHND-UHFFFAOYSA-N agomelatine Chemical compound C1=CC=C(CCNC(C)=O)C2=CC(OC)=CC=C21 YJYPHIXNFHFHND-UHFFFAOYSA-N 0.000 claims description 18
- 229960002629 agomelatine Drugs 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000007789 gas Substances 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 3
- 239000007921 spray Substances 0.000 claims description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- 238000009835 boiling Methods 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 238000001035 drying Methods 0.000 description 5
- 238000001694 spray drying Methods 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000000889 atomisation Methods 0.000 description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 102000006902 5-HT2C Serotonin Receptor Human genes 0.000 description 1
- 108010072553 5-HT2C Serotonin Receptor Proteins 0.000 description 1
- 208000027559 Appetite disease Diseases 0.000 description 1
- 208000019454 Feeding and Eating disease Diseases 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease 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
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002447 crystallographic data Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 210000002249 digestive system Anatomy 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- -1 for example Substances 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001193 melatoninergic effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 208000012672 seasonal affective disease Diseases 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
-
- 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
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P3/00—Drugs for disorders of the metabolism
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- 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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C07C231/24—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C233/08—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings
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Abstract
Postupak za dobijanje kristalnog oblika V jedinjenja formule (I):
Description
Ovaj pronalazak se odnosi na novi postupak dobijanja kristalnog oblika V agomelatina, ili N-[2-(7-metoksi-1-naftil)etil]acetamida, formule (I):
Agomelatin ili N-[2-(7-metoksi-1-naftil)etil]acetamid, poseduje korisna farmakološka svojstva.
Ustvari, ima dvostruke osobenosti, da je sa jedne strane agonist receptora melatoninergičnog sistema, a sa druge strane je antagonist receptora 5-HT2C receptora. Ova svojstva mu daju aktivnost u centralnom nervnom sistemu i, preciznije, u lečenju opšte depresije, sezonskih afektivnih poremećaja, poremećaja spavanja, kardiovaskularnih patologija, patologija digestivnog sistema, nesanice i umora kao posledice vremenske razlike, poremećaja apetita i gojaznosti.
Agomelatin, njegova proizvodnja i njegova upotreba u terapeutske svrhe, opisani su u evropskom patentu EP 0 447 285.
U smislu farmaceutske vrednosti ovog jedinjenja, najvažnije je njegovo dobijanje sa odličnim stepenom čistoće i, naročito, u savršeno reproducibilnom obliku što ima vredne osobenosti omogućavanja njegovog skladištenja u dužim vremenskim periodima bez posebnih zahteva u smislu temperature, svetla, vlažnosti ili nivoa kiseonika.
Patentna prijava EP 1 752 443 opisuje dobro-definisan kristalni oblik agomelatina, kristalni oblik V, koji je opisan svojim dijagramom difrakcije X-zraka praška u nastavku, koji je izmeren upotrebom Siemens D5005 difraktometra (bakarna antikatoda) i izražen u granicama međupovršinske udaljenosti d, Braggovog ugla 2 teta i, relativnog intenziteta (izražen kao procenat u odnosu na najintenzivniju liniju):
Ovaj savršeno definisani kristalni oblik, koji se dobija na reproducibilan način, ima visoko vredne morfološke karakteristike sa, posebno, specifičnom oblasti površine koja je mnogo veća nego za druge opisane oblike. Ipak, poseduje stabilnost u toku vremena koja je prilično kratka i, u svim slučajevima, manja od 6 meseci.
Podnosilac je sada razvio novi postupak za dobijanje agomelatina u kristalnom obliku V na savršeno reproducibilan način, gde je njegova stabilnost tokom vremena povećana. Ovaj novi postupak, prema tome, omogućava dobijanje agomelatina u kristalnom obliku V sa svojstvima koja su kompatibilna sa njegovom farmaceutskom upotrebom. Koristi se da bi se omogućilo dobijanje oblika V samo takozvanim “visoko-energetskim” mlevenjem ili putem zasejavanja te strukturno čiste forme koja se dobije mlevenjem. Podnosilac je sada otkrio, neočekivano, da je moguće dobiti ovaj oblik putem sušenja raspršivanjem. Sušenje raspršivanjem je zapravo tehnika koja se uobičajeno koristi za dobijanje čvrstih čestica u malim veličinama. Često, nastali materijal bude amorfan (Amorphous State, Polymorphism in pharmaceutical industry, Ed. R. Hilfiker, Wiley-VCH VVeinheim 2006, Chapter X, p. 259-285, S. Petit and G. Coquerel). Suprotno tome, u ovom pronalasku sušenje omogućava dobijanje dobro definisane kristalne forme, oblika V, koja pored toga ima, međutim, mnogo bolju stabilnost u toku vremena.
Preciznije, ovaj pronalazak se odnosi na novi postupak dobijanja agomelatina formule (I) u kristalnom obliku V, pri čemu se postupak odlikuje time da se rastvor agomelatina, koji je rastvoren u jednom ili dva rastvarača koja se mešaju u ma kom odnosu i čija je tačka ključanja manja od 120°C, atomizuje u sprej sušioniku.
Sušenje raspršivanjem je tehnika koja se uobičajeno koristi u oblastima poljoprivrede, prehrane i farmacije kako bi se osušio rastvor koji se raspršuje kroz vruć gas. U praksi, gas koji se koristi za sušenje rastvora je vazduh ali izvesni farmaceutski proizvodni postupci koriste organske rastvarače koji pak zahtevaju inertni gas kao gas za sušenje i na taj način se izbegavaju izvesni procesi razgradnje.
Postupci kristalizacije, koji su u skladu sa ovim pronalaskom, poželjno se izvode putem sušenja raspršivanjem. Još bolje, atomizacija u skladu sa pronalaskom se izvodi u skladu sa principom atomizacije putem raspršivača sa paralelnim strujnim tokom i poželjnije, sa ko-strujnim protokom, to jest, raspršenim rastvorom i protokom sušećeg gasa u istom smeru.
Pogodno, upotrebljeni gas je kompresovani vazduh ili inertni gas kao što je, na primer, azot.
Rastvarači koji imaju prednost u postupku koji je u skladu sa pronalaskom su: etanol, voda, izoprpoil etar, metanol, etil acetat ili aceton.
Minimalna koncentracija rastvora agomelatina koji se upotrebljava je 5 g/L a, poželjnije, koristi se rastvor od 10 g/L.
Pogodno, temperatura ulaza za postupak koji je u skladu sa pronalaskom je od 70°C do 120°C.
U procesu kristalizacije, koji je u skladu sa pronalaskom, moguće je upotrebiti agomelatin formule (I) koji se dobija ma kojim postupkom.
Primeri u nastavku ilustruju pronalazak ali ga ne ograničavaju ni na koji način.
Primer 1: Kristalni oblik V N-[2-(7-metoksi-1-naftil)etil]acetamida
10 g/L rastvora agomelatina u mešavini etanol/izopropil etra (50/50: v/v) unese se u atomizer BUCHI 190 tip Mini Spray Dryer. Temperatura ulaza komore za sušenje je 90°C, a temperatura izlaza je 66°C. Atomizirani prašak se dobija u crevu za sakupljanje i, opisuje se sledećim kristalografskim podacima:
1) dijagramom, koji se dobija upotrebom difraktometra Siemens D5005 sa opsegom ugla 3°-30° u granicama od 20, korak od 0. 04° i 4 s po koraku:
- kristalna struktura jedinične ćelije: monoklinska,
- parametri jedinične ćelije: a = 11. 967 Å, b = 17. 902 Å, c = 15. 423 Å, β = 124. 5°
- prostor grupe: P2|/n
- broj molekula u jediničnoj ćeliji: 8 (Z’=2)
- zapremina jedinične ćelije: Vjedinične ćelije=2720.0 Å3
2) sledeći dijagram difrakcije X-zraka praška, izmeren korišćenjem difraktometra Siemens D5005 (bakarna antikatoda) i izražen u granicama međupovršinske udaljenosti d, Braggovog ugla 2 teta i, relativnog intenziteta (izražen kao procenat u odnosu na najintenzivniju liniju):
Primer 2: Stabilnost tokom vremena kristalnog oblika V, dobijenogatomizacijom N-[2-(7-metoksi-1 -naftil)etil]acetamida
Uzorak od 1 g jedinjenja dobijenog u Primeru 1 je smešteno pod uobičajene uslove skladištenja: pritisak i temperatura sredine. Nakon 21 meseca, difraktogram uzorka koji je dobijen se nije promenio i zadržao je karakteristike dobijenog oblika V.
Claims (5)
1. Postupak dobijanja kristalnog oblika V agomelatina, formule (1): koji je n a z n a č e n t i m e što se rastvor agomelatina, koji je rastvoren u jednom ili dva rastvarača koja se mešaju u ma kojoj proporciji i čija je tačka ključanja manja od 120°C, atomizira u sprej sušioniku.
2.Postupak za proizvodnju kristalnog oblika V jedinjenja formule (1), kao u patentnom zahtevu 1, koji je n a z n a č e n t i m e što dobijena jedinjenje ima sledeće difrakcione dijagrame X-zrakova praška, merene upotrebom Siemens 05005 difraktometra (bakama antikatoda) i izražene u granicama međupovršinske udaljenosti d, Braggovog ugla 2 teta i, relativnog intenziteta (izražen kao procenat u odnosu na najintenzivniju liniju):
3.Postupak za proizvodnju kristalnog oblika V jedinjenja formule (1), kao u patentnom zahtevu 1, koji je n a z n a č e n t i m e što su upotrebljeni rastvarači etanol i izopropil etar.
4.Postupak za proizvodnju kristalnog oblika V jedinjenja formule (1), kao u patentnom zahtevu 1, koji je n a z n a č e n t i m e što je upotrebljeni gas azot.
5.Postupak za proizvodnju kristalnog oblika V jedinjenja formule (1), kao u patentnom zahtevu 1, koji je n a z n a č e n t i m e što je minimalna upotrebljena koncentracija rastvara agomelatina 5 g/L.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0804466A FR2934856B1 (fr) | 2008-08-05 | 2008-08-05 | Nouveau procede d'obtention de la forme cristalline v de l'agomelatine |
| EP09290608A EP2151430B1 (fr) | 2008-08-05 | 2009-08-04 | Nouveau procédé d'obtention de la forme cristalline v de l'agomélatine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ME00929B true ME00929B (me) | 2012-06-20 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| MEP-2009-258A ME00929B (me) | 2008-08-05 | 2009-08-03 | NOVI POSTUPAK ZA DOBlJANJE KRISTALNOG OBLIKA V AGOMELATIN A |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101781226B (zh) | 2009-12-23 | 2012-03-28 | 天津泰普药品科技发展有限公司 | 阿戈美拉汀及其药物组合物 |
| EP2705023A4 (en) * | 2011-01-04 | 2014-11-19 | Symed Labs Ltd | PROCESSES FOR THE PREPARATION OF N- [2- (7-METHOXY-1-NAPHTHYLLELYHYL) ACETAMIDE |
| WO2012130837A1 (en) | 2011-03-28 | 2012-10-04 | Ratiopharm Gmbh | Solid agomelatine in non-crystalline form |
| WO2014012571A1 (en) | 2012-07-16 | 2014-01-23 | Ratiopharm Gmbh | Complex of agomelatine and cyclodextrin |
| WO2015124496A1 (en) | 2014-02-19 | 2015-08-27 | Synthon B.V. | Pharmaceutical composition comprising amorphous agomelatine |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SU1703641A1 (ru) * | 1988-02-23 | 1992-01-07 | Ростовский государственный университет | Способ получени 3,5-ди-трет.бутил-4-оксиацетанилида |
| FR2658818B1 (fr) * | 1990-02-27 | 1993-12-31 | Adir Cie | Nouveaux derives a structure naphtalenique, leur procede de preparation et les compositions pharmaceutiques qui les contiennent. |
| YU48420B (sh) * | 1991-03-25 | 1998-07-10 | Hoechst Aktiengesellschaft | Postupak za dobijanje biološki razgradljivih mikročestica sa dugotrajnim delovanjem |
| FR2866335B1 (fr) * | 2004-02-13 | 2006-05-26 | Servier Lab | Nouveau procede de synthese de l'agomelatine |
| FR2889521B1 (fr) * | 2005-08-03 | 2007-12-28 | Servier Lab | Nouvelle forme cristalline iii de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent |
| FR2889522B1 (fr) * | 2005-08-03 | 2007-12-28 | Servier Lab | Nouvelle forme cristalline iv de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent |
| FR2889523B1 (fr) * | 2005-08-03 | 2007-12-28 | Servier Lab | Nouvelle forme cristalline v de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent |
| WO2008141033A1 (en) * | 2007-05-08 | 2008-11-20 | Auspex Pharmaceuticals Inc. | Substituted naphthalenes |
| FR2923482B1 (fr) * | 2007-11-09 | 2010-01-29 | Servier Lab | Nouvelle forme cristalline vi de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent |
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