RS60800B1 - Kv1.3 inhibitori i njihova medicinska primena - Google Patents

Kv1.3 inhibitori i njihova medicinska primena

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Publication number
RS60800B1
RS60800B1 RS20201037A RSP20201037A RS60800B1 RS 60800 B1 RS60800 B1 RS 60800B1 RS 20201037 A RS20201037 A RS 20201037A RS P20201037 A RSP20201037 A RS P20201037A RS 60800 B1 RS60800 B1 RS 60800B1
Authority
RS
Serbia
Prior art keywords
diazepine
tetrahydro
oxo
ethoxy
carboxamide
Prior art date
Application number
RS20201037A
Other languages
English (en)
Inventor
Stefan Tasler
Ilga Krimmelbein
Original Assignee
4Sc Ag
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by 4Sc Ag filed Critical 4Sc Ag
Publication of RS60800B1 publication Critical patent/RS60800B1/sr

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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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    • 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
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Description

Kristalni oblicilS- fl a ( 2S*, 3R*), 9 a]- 6, 10- diokso- N-( 2- etoksi- 5- okso- tetrahidro- 3-
furunil)- 9- ff( l- izuhiiwlinil) karbonilj- amino] uktahidro- 6H- piridazino [ 1, 2- a] [ 1, 2]
diazepin- l- kar boksa miila
Predmetni pronalazak ima za objekat dva kristalna oblika 1S-[1 a (2S<*>,3R<*>), 9 a]-6,10-diokso-N-(2-etoksi-5-okso-tetrahidro-3-furanil)-9-[[( 1-izohinolinil) karbon i l]-amino] okta-hidro-6H-piridazino [1,2-a] [1,2] diazepin-l-karboksamida (anhidrovani ili hidratisani), postupak za njihovo dobijanje i farmaceutske preparate koji ih obuhvataju.
Patentna prijava W0 9722619 opisuje 1S-[1 a (2S<*>,3R<*>), 9 a]-6,10-diokso-N-(2-etoksi-5-okso-tetrahidro-3-furanil)-9-[[(l-izohinolinil) karbonil]-amino] oktahidro-6H-piridazino [1,2-a] [1,2] diazepin-l-karboksamid isto kao i njegove farmaceutski prihvatljive soli (proizvod 412 f: Jedinjenje I) kao inhibitore enzima za konverziju inetrleukina-lp<1>:
Jedinjenje (I) takvo kao što je opisno i dobijeno u ovoj prijavi WO 9722619 se nalazi u amorfnom obliku. Ovaj oblik je principijelno neodgovarajući usled svoje higroskopnosti.
Dobijanje jedinjenja (1) se vrši na sledeći način: Vrši se reakcija amidifikacije između (1S, 9S) 9-(izohinolin-1 -oilamino)-6,10-diokso-1,2,3,4,7,8,9,10-oktahidro-6H-piridazino [ 1,2-a]
[1,2] diazepin-l-karboksilne kiseline i (3S, 2S) 3-aliloksikarbonil-2-benziloksi-5-oksotetra-hidrofurana u prisustvu dimetilbarbutirne kiseline, paladijum tetrakistrifenilfosfma, 1-hidroksibenzoU'iazola i l-(3-dimetil aminopropil)-3-etilkarbodiimid hidrohlorida u metilen hloridu, dimetilformamidu ili smeši ova dva rastvarača. Proizvod se' prečišćava pomoću hromatografije (etil acetat/dihlorometan) radi dobijanje jedinjenja (I) u amorfnom obliku.
Pronalazak'ima za objekat nalaženje jedne ili više novih kristalnih olika koji ne poseduju nepodesnost koju poseduje amorfni oblik.
Čvrsti oblici, i uglavnom farmaceutski preparati mogu da budu prisutni u više od jednog kristalnog oblika. To je ono što se naziva polimorfizam.
Polimorfni oblici jadnog istog molekula pokazuju uglavnom različite fizičke osobine takve kao što su rastvorljivost, higroskopnost i stabilnost. Treba istaći da ne postoje u ovom momentu postupci koji dozvoljavaju predviđanje postojanja takvog polimorfa kao ni predviđanje njegovih fizičkih osobina.
Dobijanje novih oblika polimorfa molekula koji poseduju terapeutsku aktivnost predstavlja veliki interes za farmaceutsku industriju uglavnom sa tačke gledišta njihovog dobijanja na industrijskom nivou, njihovog ugrađivanja u farmaceutske preparate, istraživanja njihove bolje stabilnosti i bolje bioraspoloživosti. (Byrn S. R.,Solid- State Chemistrv of Drugs,Nevv York, Academ. Press (1982); Kuhnert-Brandstatter M.,Thermomicroscopy In rhe Analvsis of Pharmaceuticals,Nevv York, Peigamon Press (1971); J. Halebian et al.,J. Pharm. Science
(1969) vol. 58 (8) 911; J.Halebian et al., J. Pharm. Science (1975) vol.64 (8) 1269-1288).
Pod polimorfnim oblikom podrazumevaju se svi nesolvatisani oblici kristalisanog molekula i svi pseudo-polimorfni solvatisani oblici.
Postupci analize kristalnih oblika su kao što sledi:
Termičke karakteristike: ove karakteristike se određuju pomoću DSC (diferencijalna skanirajuća kalorimetrija) (diferencijalna kalorimetrijska analiza): 2 do 5 mg supstance koja se proučava se odmeri u ne-hermetičku kapsulu koja je zalivena aluminijumom. Analiza se vrši pod strujom azota u temperaturskoin intervalu od 25 do 350"C sa brzinom podizanja temperature od 20°C/min.
1R (infracrvena spektroskopija): Supstanca koja se proučava se disperguje u ulje tečnog parafina. Analiza se vrši na infracrvenom spektrofotometru sa Foureir-ovim transformacijom u oblasti 4000 do 600 cm"<1>.
RX (difrakcija X zraka na prahu): Supstanca koja se proučava se rasporedi u alveoli od stakla koja nosi probu. Analiza se vrši u oblasti od 2° do 38° (2 0) sa korakom od 0,02° i sa 1 sekundom očitavanja koraka. Izvor X zraka je bakarna cev (45 kV, 30 mA).
Potrebno je dati evidenciju dvaju novih kristalnih oblika (oblik A i oblik B). Oblik A koji je anhidrovan i oblik B koji je hidrtaisan. Kristalni oblik A poseduje, između drugih prednosti koje su citirane ovde napred, odsustvo higroskopnosti (vidi test ovde niže).
Pronalazak ima dakle najpre za objekt novi kristalni oblik ahidrovanog 1S-[1 a (2S<*>,3R<*>), 9 aJ-6,10-diokso-N-(2-etoksi-5-okso-tetrahidro-3-furanil)-9-[[(l-izohinolmil) karbonilj-ammoj oktahidro-6I I-piridazino [1,2-a] [1,2] diazepin-1-karboksamida koji se naziva oblik .A.
Ovaj oblik A poseduje osobine koje slede:
Kristalni sistem: triciklični
a (A): 8,02; b(A):9,21; c(A): 17,70; oc(°): 91,38; p (°): 93,62; y(°):90,43;
prostorna grupa Pl: Z 2.
Pronalazak podjednako za objekat ima jedan novi hidratisani kristalni oblik 1 S-[ 1 a (2S<*>,3R<*>), 9 a]-6,10-diokso-N-(2-etoksi-5-okso-tetrahidro-3-furanil)-9-[[(l-izohinolinil) karbonil]-amino] cktahidro-6H-piridazino [1,2-a] [1,2] diazepin-l-karboksamida koji se naziva oblik B.
Oblik A poseduje sledeće karakteristike
Anhidrovano jedinjenje formule (I), tako kao što je dobijeno pomoću jednog od postupaka koji su identični sa onim koji je dat ovde niže, poseduje određen kristalni oblik (oblik A). Fizičke karakteristike su opisane na slikama 1A (DSC), 2A (IR) i 3A (RX).
DSC: Endotermno topljenje počinje na 168°C.
IR ( nužol, cm' 1) : 3253; 1789; 1702; 1681; 1644.
RX ( d, Angstrem) : 17,73; 8,87; 8,fl; 7,50; 7,17; 6,31; 6,09; 5,81.
Oblik B poseduje sledeće karakteristike
Hidratisano jedinjenje formule (I), tako kao što je dobijeno pomoću jednog od postupaka koji su identični sa onim koji je dat ovde niže, poseduje određen kristalni oblik (oblik B). Fizičke karakteristike su opisane na slikama 1B (DSC), 2B (IR) i 3B (RX).
DSC: Endotermna dehidratacija je između 50 i 110°C i između 110 i 130°C. Opaža se da endotermno topljenje počinje na 162°C.
IR ( nužol, cm' 1) : 3569; 3447; 3322; 1778; 1682; 1660.
RX( d, Angstrem) : 11,34; 10,80; 10,06; 7,59; 7,16; 6,71; 6,41; 6,11; 5,44.
Pronalazak dakle ima za objekat oblik A takav kao što je definisano predhodno koji ima bar jednu od osobina koje slede i poželjno sve osobine koje slede:
a) endotermno topljenje počinje od 168°C,
b) infracrveni spektar koji poseduje absorpcione karakteristke na oko (nužol, cm"<1>): 3253; 1789; 1702; 1681; 1644, c) difrakcioni dijagram koji poseduje međuravanska rastojanja koja su jednaka (d, A): 17,73; 8,87; 8,11; 7,50; 7,17; 6,31; 6,09; 5,81.
Pronalazak sasvim određeno za objekat ima oblik A takav kao što je definisano predhodno koji poseduje infracrveni spektar koji je uglavnom identičan sa onim na slici 2A i difrakcioni dijagram koji je uglavnom identičan sa onim na slici 3A.
Pronalazak dakle ima za objekat oblik B takav kao što je definisano predhodno koji ima bar jednu od osobina koje slede i poželjno sve osobine koje slede: a) endotermna dehidratacija između 50 i 110°C i između 110 i 130°C i endotermno topljenje koje počinje od 162°C, b} infracrveni spektar oblika B koji poseduje absorpcione karakteristke na oko (nužol, cm"<1>): 3569; 3447; 3322; 1778; 1682; 1660, c) difrakcioni dijagram oblika B koji poseduje međuravanska rastojanja koja su jednaka (d, Angstrem): 11,34; 10,80; 10,06; 7,5.9; 7,16; 6,71; 6,41; 6,11; 5,44.
Pronalazak'sasvim određeno za objekat ima oblik B takav kao što je definisano predhodno koji poseduje infracrveni spektar koji je uglavnom identičan sa onim na slici 2B i difrakcioni dijagram koji je uglavnom identičan sa onim na slici 3B.
Predmetni pronalazak podjcdanko za objekat ima postupak za. dobijanje oblika A ili B, koji je okarkatreisan time što se vrši rastvaranje amorfnog jedinjenja (I) koje je dobijeno prema postupku koji je opisan ovde napred u organskom rastvaraču ili smeši ovih rastvarača, i uglavnom na sobnoj temperaturi i dobijanje posle kristalizacije očekivanog oblika A ili oblika
B.
Dobijanje oblika A se vrši poželjno pomoću kristalizacije u alkoholu ili etru i uglavnom izopropil alkoholu, butanolu ili izopropanolu.
Dobijanje oblika A se takođe vrši pomoću kristalizacije u smeši rastvarača, uglavnom u smeši etanol/izorpoil etar.
Dobijanje oblika B se vrši sasvim određeno pomoću kristalizacije u toluenu.
Dobijanje očekivanih oblika A ili B može da bude, u tom slučaju, inicirano pomoću zasejavanja rastvora sa nekoliko kristala odgovarajućih oblika A ili B.
Izolovanje oblika A ili B se vrši prema postupcima koji su poznati stručnjaku u ovoj oblasti tehnike.
Kristalni oblici A ili B jedinjenja formule (I) poseduju iste terapeutske aktivnosti kao one koje su opisane za amorfno jedinjenja (I) u patentnim prijavama WO 97/22169 i WO 95/35308.
Ovi oblici poseduju inhibitorsku aktivnost 1CE (enzimske konverzije u interleukin-ip) i naročito su primenljivi u tretiranju zapaljivih obolenja, auto-imunih i neurodegenerativnih obolenja.
Pronalazak dakle ima za objekat kristalne oblike A ili B, takve kao što je opisano predhodno kao medikament.
Kristalni oblici A ili B jedinjenja formule (I) mogu da budu korišćeni na jedan od sledećih načina: oralno, parenteralno, topikalno, inhalatorno ili pomoću implanta. Ovi oblici mogu da budu prisutni u obliku prostih tableta ili dražeja, gelula, granula, supozitorija, ovula, injektibilnih preparata, pomada, kremova, gelova, mikrosfera, implanata, impregniranih obloga, koji se dobijaju prema uobičajenim postupcima.
Kristalni oblici A ili B jedinjenja formule (I) mogu da budu izmešani sa ekscipijentima, razblaživačima i svim nosačima koji su poznati stručnjaku u ovoj oblasti za proizvodnju farmaceutskih preparata. Radi primera ekscipijenata koji se uobičajeno korišćeni u ovim farmaceutskim preparatima mogu da se citiraju talk, guma arabika, laktoza, amidon magnezijum stearat, kakao buter, vodeni ili ne-vodeni nosači, masti biljnog ili animalnog porekla, parafinski derivati, glikoli, razni agensi za kvašenje, disperzanti ili emulgatori, konzervansi.
Pronalazak'se odnosi tako na farmaceutske preparate koji obuhvataju kao aktivan princip bar jedan od kristalnih oblika A ili B jedinjenja formule (I), tako kao što je definisano ovde niže i jedan ili više ekscipijenata, razblaživača ili nosača koji su farmaceutski prihvatljivi.
Pronalazak ima podjednako za objekat primenu kristalnih oblika A ili B jedinjenja formule (I) tako kao što je definisano ovde niže za dobijanje medikamenta koji su namenjeni za inhibiranje aktivnosti ICE (enzimska konverzija interleukina-1P).
Primeri koji slede ilustruju pronalazak bez bilo kakvog ograničavanja.
Primer 1:Pobijanje oblika A pomoću kristalizacije u n - butanolu
U 300 mg amorfnog jedinjenja formule (I) (koje je dobijeno prema postupku koji je opisan u prijavi WO 9722619) se doda 1,5 ml n-butanola i meša se na sobnoj temperaturi tokom dva časa i 15 minuta. Opaža se kristalizacija proizvoda koji se procedi i osuši na 20°C na pritisku od 4 mbara. Dobija se 160 mg anhidrovanog jedinjenja formule (1) (oblik A).
Primer 2:Pobijanje oblika A pomoću kristalizacije u izopropcmolu
U 300 mg amorfnog jedinjenja formule (I) (koje je dobijeno prema postupku koji je opisan u prijavi WO 9722619) se doda 1,5 ml izopropanola i meša se na sobnoj temperaturi tokom 16 časova. Opaža se kristalizacija proizvoda koji se procedi i osuši na 20°C na pritisku od 4 mbara. Dobija se 166 mg anhidrovanog jedinjenja formule (I) (oblik A).
Primer 3:Pobijanje oblika B pomoću kristalizacije u toluenu
U 300 mg amorfnog jedinjenja formule (I) (koje je dobijeno prema postupku koji je opisan u prijavi WO 9722619) se doda 1,5 ml toluena i meša se na sobnoj temperaturi tokom 16 časova. Opaža se kristalizacija proizvoda koji se procedi i osuši na 20°C na pritisku od 4 mbara. Dobija se hidratisano jedinjenje formule (I) (oblik B).
Primer 1:Pobijanje oblika A pomoću kristalizacije u smeši izopropil etar / etanol
U 11,9 g amorfnog jedinjenja formule (I) se doda pod azotom i mešanjem 23,8 ml apsolutnog etanola i suspenzija se zagreje na 60° ± 2° radi dobijanja rastvora. Ohladi se na 40°C ± 2°, i tada kreće kristalizacija koja se održava jedan čas na ovoj temperaturi. Zatim se doda 119 ml izopropil etra tokom 15 minuta na 40°C ± 2° i sve se održava na ovoj temperaturi tokom 15 minuta. Ohladi se na 20°C ± 2° tokom 15 minuta i sve se održava u ovim uslovima tokom jednog časa, zatim se ohladi ponovo na 0°, +5°C tokom 15 minuta i održava se na ovoj temperaturi tokom dva časa. Procedi se, ispere se sa izopropil etrom, osuši se pod sniženim pritiskom na 20°C tokom 12 časova i dobija se 11,3 g anhidrovanog jedinjenja formule (I)
(oblik A).
Kriva higroskopnosti ( ili izoterma sorpcije vode )
Izoterme sorpcije vode su dobijene pomoću aparaturePynamic Vapor Sorption PVS 1 ( Surface Measuremenls Systems Ltd)na konstantnoj temperaturi i pod avmsoferom azota koji je manje ili više hidratisan. Stepen relativne vlažnosti (HR) atmosfere je modifikovan pomoću podržavača. Provođenje podrživača koje sledi se vrši dok masa probe koja se analizira ne dostigne konstantnu vrednost.
Tokom ciklusa sorpcije oblik A nije higroskopan (< 0,2%). Ne-higroskopičnost je potvrđena držanjem probe tokom sedam dana u prostoriji sa 96% relativne vlažnosti (na 32°C). Opažena je absorpcija vode približno od 0,15%. Hidratisani oblik (oblik B) je najhigroskopniji (7%> vode) pod istim uslovima. Isto se odnosi na amorfni oblik.

Claims (1)

1) Kristalni oblik anhidrovanog 1S-[1 a (2S<*>,3R<*>), 9 a]-6,10-diokso-N-(2-etoksi-5-okso-tetrahidro-3-furanil)-9-[[( 1 -izohinolinil) karbonil]-amino] oktahidro-6H-piridazino [1,2-a] [1,2] diazepin-1 -karboksamida (oblik A).
2) Kristalni oblik anhidrovanog 1S-[1 a (2S<*>,3R<*>), 9 a]-6,10-diokso-N-(2-etoksi-5-okso-tetrahidro-3-furanil)-9-[[( 1 -izohinolinil) karbonilj-amino] oktahidro-6H-piridazino [ 1,2-a] [1,2] diazepin-1-karboksamida (oblik A) prema zahtevu 1 koji poseduje bar jednu od osobina koje slede: (a) endotermno topljenje počinje na 168°C, (b) infracrveni spektar koji poseduje absorpcione karakteristike približno (nužol, cm"1): 3253; 1789; 1702; 1681; 1644, (c) difrakcioni dijagram RX koji poseduje međuravanska rastojanja (d, Angstrem): 17,73; 8,87; 8,11; 7,50; 7,17; 6,31; 6,09; 5,81.
3) Kristalni oblik anhidrovanog 1S-[1 a (2S<*>,3R<*>), 9 a]-6,10-diokso-N-(2-etoksi-5-okso-tetrahidro-3-furanin-9-[[(l -izohinolinil) karboni l]-amino] oktahidro-6H-piridazino [1,2-a] [1,2] diazepin-l-karboksamida (oblik A) prema zahtevu 2 koji poseduje karakteristike a, b i c.
4) Kristalni oblik anhidrovanog 1 S-[ 1 a (2S<*>,3R<*>), 9 a]-6,10-diokso-N-(2-etoksi-5-okso-tetrahidro-3-furanil)-9-[[( 1 -izohinolinil) karbonil]-amino] oktahidro-6H-piridazino [ 1,2-a] [1,2] diazepin-l-karboksamida (oblik A) prema zahtevu 2 ili 3, koji poseduje infracrveni spektar koji je uglavnom identičan sa onim na slici 2A i difrakcioni dijagram koji je uglavnom identičan sa onim na slici 3A.
5) Kristalni oblik hidratisanog 1S-[1 a (2S<*>,3R<*>), 9 a]-6,10-diokso-N-(2-etoksi-5-okso-tetrahidro-3-furanil)-9-[[( 1-izohinolinil) karbonil]-amino] oktahidro-6H-piridazino [1,2-a] [ 1,2] diazepin-1 -karboksamida (oblik B).
6) . Kristalni oblik hidratisanog 1S-[1 a (2S<*>,3R<*>), 9 a]-6,10-diokso-N-(2-etoksi-5-okso-tetrahidro-3-furanilV9-[[(l-izohinolinil) karbonil]-amino] oktahidro-6H-piriđazino [1,2-a] [1,2] diazepin-l-karboksamida (oblik B) prema zahtevu 5 koji poseduje bar jednu od osobina koje slede: (a) endotermna dehidratacija je između 50 i 1 10°C i između 1 10 i 130°C, endotermno topljenje počinje na 162°C, (b) infracrveni spektar koji poseduje absorpcione karakteristike približno (nužol, cm"<1>): 3569; 3447, 3322, 1778; 1682; 1660, (c) difrakcioni dijagram RX koji poseduje međuravanska rastojanja (d, Angstrem): 1 1,34; 10,80; 10,06; 7,59; 7,16; 6,71; 6,41; 6,11; 5,44.
7) Kristalni oblik hidratisanog 1S-[1 a (2S<*>,3R<*>), 9 a]-6,10-dio,kso-N-(2-etoksi-5-okso-tetrahidro-3-furanil)-9-[[( 1-izohinolinil) karbonilj-amino] oktahidro-6H-piriclazino [1,2-a] [1,2] diazepin-l-karboksamida (oblik B) prema zahtevu 6 koji poseduje karakteristike a, b i c.
8) Kristalni oblik hidratisanog 1S-[1 a (2S<*>,3R<*>), 9-a]-6,10-diokso-N-(2-etoksi-5-okso-tetrahidro-3-furanil)-9-[[( 1 -izohinolinil) karbonil]-amino] oktahidro-6H-piridazino [1,2-a] [1,2] diazepin-1-karboksamida (oblik B) prema zahtevu 6 ili 7, koji poseduje infracrveni spektar koji je uglavnom identičan sa onim na slici 2B i difrakcioni dijagram koji je uglavnom identičan sa onim na slici 3B.
9) Postupak za dobijanje oblika A ili B takvih kao stoje okarakterisano u jednom od zahteva 1 do 8,okarakterisan timešto se meša amorfni 1S-[1 a. (2S*,3R*), 9 a]-6,1 0-điokso-N-(2-etoksi-5-okso-tetrahidro-3-furanil)-9-[ [(1 -izohinolinil) karbonil]-amino] oktahidro-6H-piridazino [1,2-a] [1,2] diazepin-1-karboksamid u odgovarajućem organskom rastvaraču ili smeši ovih rastvarača, uglavnom na sobnoj temperaturi i dobija se posle kristalizacije očekivani oblik A ili B.
10) Postupak dobijanja oblika A, prema zahtevu 9,okarakteriscm timešto rastvarač je etar i uglavnom je to izopropil etar.
12) Postupak dobijanja oblika A, prema zahtevu 9,okar akter isan timešto se kristalizacija vrši u smeši alkohola i etra i uglavnom u smeši etanol/izopropil etar.
13) Postupak dobijanja oblika B, prema zahtevu 9,okarakterisan timešto rastvarač je toluen.
14) Kao medikament kristalni oblici A ili B takvi kao što je definisano u zahtevima 1 do 8.
15) Farmaceutski preparati koji obuhvataju bar jedan medikament takav kao što je definisano u zahtevu 13 i jedan ili više ekscipijenata, razblaživača ili nosača koji su farmaceutski prihvatljivi.
16) Primena kristalnih oblika, takvih kao što je definisano u nekom od zahteva 1 do 8, za dobijanje medikamenta koji je namenjen za inhibiranje ICE (enzimska konverzija interleukina-1 P).
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