RS57497B2 - Prolekovi fumarata i njihova upotreba u lečenju raznih bolesti - Google Patents

Prolekovi fumarata i njihova upotreba u lečenju raznih bolesti

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Publication number
RS57497B2
RS57497B2 RS20180914A RSP20180914A RS57497B2 RS 57497 B2 RS57497 B2 RS 57497B2 RS 20180914 A RS20180914 A RS 20180914A RS P20180914 A RSP20180914 A RS P20180914A RS 57497 B2 RS57497 B2 RS 57497B2
Authority
RS
Serbia
Prior art keywords
compound
substituted
unsubstituted
alkyl
pharmaceutically acceptable
Prior art date
Application number
RS20180914A
Other languages
English (en)
Inventor
Tarek A Zeidan
Scott Duncan
Christopher P Hencken
Thomas Andrew Wynn
Carlos N Sanrame
Original Assignee
Alkermes Pharma Ireland Ltd
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
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=51529940&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=RS57497(B2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Alkermes Pharma Ireland Ltd filed Critical Alkermes Pharma Ireland Ltd
Publication of RS57497B1 publication Critical patent/RS57497B1/sr
Publication of RS57497B2 publication Critical patent/RS57497B2/sr

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    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/225—Polycarboxylic acids
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/221—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having an amino group, e.g. acetylcholine, acetylcarnitine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • 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
    • 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
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    • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C219/06—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having the hydroxy groups esterified by carboxylic acids having the esterifying carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms of an acyclic saturated carbon skeleton
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    • C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C219/08—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the hydroxy groups esterified by a carboxylic acid having the esterifying carboxyl group bound to an acyclic carbon atom of an acyclic unsaturated carbon skeleton
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    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/20—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the carbon skeleton
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    • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C07C229/12—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of acyclic carbon skeletons
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    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C07C229/16—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of hydrocarbon radicals substituted by amino or carboxyl groups, e.g. ethylenediamine-tetra-acetic acid, iminodiacetic acids
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    • 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
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    • C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings 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
    • C07C233/68—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings 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
    • C07C233/69—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings 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 of an acyclic saturated carbon skeleton
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    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
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    • C07C279/08—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by singly-bound oxygen atoms
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    • C07C309/17—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing carboxyl groups bound to the carbon skeleton
    • C07C309/18—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing carboxyl groups bound to the carbon skeleton containing amino groups bound to the same carbon skeleton
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    • C07C333/14—Dithiocarbamic acids; Derivatives thereof
    • C07C333/18—Esters of dithiocarbamic acids
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    • C07D207/06—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
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Description

[0001] Opis
[0002] POVEZANE PRIJAVE
[0003] Ova prijava zahteva prioritet U.S. privremene prijave br.61/782,445, podnete 14. marta 2013., i U.S. privremene prijave br.61/934,365, podnete 31. januara 2014.
[0005] OBLAST PRONALASKA
[0006] Ovaj pronalazak odnosi se na razne prolekove monometil fumarata kako je definisano u patentim zahtevima. Određenije, ovaj pronalazak odnosi se na derivate monometil fumarata kako je definisano u patentim zahtevima koji nude poboljšana svojstva u odnosu na dimetil fumarat. Ovaj pronalazak takođe se odnosi na upotrebu pomenutih jedinjenja u postupcima lečenja raznih bolesti.
[0008] POZADINA PRONALASKA
[0009] Estri fumarne kiseline (FAE) odobreni su u Nemačkoj za lečenje psorijaze, pri čemu su procenjeni u Sjedinjenim Državama za lečenje psorijaze i multipla skleroze, a predloženi su za upotrebu u lečenju širokog opsega imunoloških, autoimunih i zapaljenskih bolesti, i WO2010022177 opisuje derivate fumarata korisne za lečenje multipla skleroze. FAE i ostali derivati fumarne kiseline predloženi su za upotrebu u lečenju širokog spektra bolesti i stanja koji uključuju imunološke, autoimune, i/ili zapaljenske procese uključujući psorijazu (Joshi i Strebel, WO 1999/49858; U.S. Pat. br.6,277,882; Mrowietz i Asadullah, Trends Mol Med 2005, 111(1), 43-48; i Yazdi i Mrowietz, Clinics Dermatology 2008, 26, 522-526); astmu i hronične opstruktivne bolesti pluća (Joshi et al., WO 2005/023241 i US 2007/0027076); srčane insuficijencije uključujući insuficijenciju leve komore, infarkt miokarda i anginu pektoris (Joshi et al., WO 2005/023241; Joshi et al., US 2007/0027076); mitohondrijalne i neurodegenerativne bolesti kao što su Parkinsonova bolest, Alchajmerova bolest, Huntingtonova bolest, retinopatija pigmentoza i mitohondrijska encefalomiopatija (Joshi i Strebel, WO 2002/055063, US 2006/0205659, U.S. Pat. br. 6,509,376, U.S. Pat. br.6,858,750, i U.S. Pat. br.7,157,423); transplataciju (Joshi i Strebel, WO 2002/055063, US 2006/0205659, U.S. Pat. br.6,359,003, U.S. Pat. br.6,509,376, i U.S. Pat. br.
[0010] 7,157,423; i Lehmann et al., Arch Dermatol Res 2002, 294, 399-404); autoimune bolesti (Joshi i Strebel, WO 2002/055063, U.S. Pat. br.6,509,376, U.S. Pat. br.7,157,423, i US 2006/0205659) uključujući multipla sklerozu (MS) (Joshi i Strebel, WO 1998/52549 i U.S. Pat. br.6,436,992; Went i Lieberburg, US 2008/0089896; Schimrigk et al., Eur J Neurology 2006, 13, 604-610; i Schilling et al., Clin Experimental Immunology 2006, 145, 101-107); ishemiju i reperfuzionu povredu (Joshi et al., US 2007/0027076); AGE-indukovano oštećenje genoma (Heidland, WO 2005/027899); zapaljenske bolesti creva kao što su Kronova bolest i ulcerativni kolitis; artritis; i ostale (Nilsson et al., WO 2006/037342 i Nilsson i Muller, WO 2007/042034).
[0012] Fumaderm®, enterično obložena tableta koja sadrži mešavinu soli monoetil fumarata i dimetil fumarata (DMF) koji brzo hidrolizuje u monometil fumarat, koji se smatra glavnim bioaktivnim metabolitom, odobren je u Nemačkoj 1994. za lečenje psorijaze. Fumaderm® dozira se TID sa 1-2 grama/dan datim za lečenje psorijaze. Fumaderm® pokazuje visok stepen varijabilnosti među pacijentima u odnosu na apsorpciju leka, a hrana snažno smanjuje bioraspoloživost. Smatra se da se apsorpcija javlja u tankom crevu sa nivoima pika postignutim 5-6 sati nakon oralnog davanja. Značajni neželjeni efekti javljaju se kod 70-90% pacijenata (Brewer i Rogers, Clin Expt'l Dermatology 2007, 32, 246-49; i Hoefnagel et al., Br J Dermatology 2003, 149, 363-369). Neželjeni efekti trenutne FAE terapije uključuju gastrointestinalni poremećaj koji uključuje mučninu, povraćanje, dijareju i/ili prolazno crvenilo kože.
[0014] Multipla skleroza (MS) je autoimuna bolest sa autoimunom aktivnošću usmerenom prema antigenima centralnog nervnog sistema (CNS). Bolest se karakteriše zapaljenjem u delovima CNS, što dovodi do gubitka mijelinskog plašta oko neuronskih aksona (postepena demijelinizacija), gubitka aksona, i eventualne smrti neurona, oligodendrocita i glijalnih ćelija.
[0016] Dimetil fumarat (DMF) je aktivna komponenta eksperimentalnog terapeutika, BG-12, ispitivanog za lečenje povratno-reemitujuće MS (RRMS). U Fazi IIb RRMS studije, BG-12 značajno je smanjio gadolinijum-pojačane lezije mozga. U predkliničkim studijama, DMF davanje pokazalo je da inhibira CNS zapaljenje u mišjem i pacovskom EAE. Takođe je otkriveno da DMF može da inhibira astrogliozu i mikroglijalne aktivacije povezane sa EAE. Videti, npr., US objavljenu prijavu br.2012/0165404.
[0018] Postoje četiri glavna klinička tipa MS: 1) povratno-reemitujuća MS (RRMS), koja se karakteriše jasno definisanim recidivima sa potpunim povratkom ili sa posledicama i rezidualnim deficitom usled povratka; periodima između recidiva bolesti koji se karakterišu nedostatkom progresije bolesti; 2) sekundarno progresivna MS (SPMS), koja se karakteriše početnim recidivom koji odlaže tok praćenim progresijom sa ili bez povremenih recidiva, manjih remisija, i platoa; 3) primarno progresivna MS (PPMS), koja se karakteriše progresijom bolesti od pojave sa povremenim platoima i trenutnim manjim poboljšanjima dozvoljenim; i 4) progresivna povratna MS (PRMS), koja se karakteriše pojavom progresivne bolesti, sa jasnim akutnim recidivima, sa ili bez potpunog povratka; pri čemu se periodi između recidiva karakterišu kontinuiranom progresijom.
[0019] Klinički, bolest najčešće predstavlja povratno-reemitujuću bolest i, u manjoj meri, stabilnu progresiju neurološke nesposobnosti. Povratno-reemitujuća MS (RRMS) predstavljena je u obliku ponavljajućih napada fokalne ili multifokalne neurološke disfunkcije. Napadi mogu da se javljaju, reemituju, i vraćaju, naizgled slučajno dugi niz godina. Remisija je često nepotpuna i jedan napad prati drugi, postepena progresija nadole nastaje sa povećanjem trajnog neurološkog deficita. Uobičajeni tok RRMS karakteriše se ponovljenim recidivima povezanim, za većinu pacijenata, sa eventualnom pojavom progresije bolesti. Sledeći tok bolesti je nepredvidiv, iako će se kod većine pacijenata sa povratnoreemitujućom bolesti eventualno razviti sekundarna progresivna bolest. U povratno-reemitujućoj fazi, recidivi se menjaju sa periodima kliničke neaktivnosti i mogu ili ne moraju da budu obeleženi posledicama koje zavise od prisustva neuroloških deficita između epizoda. Periodi između recidiva tokom povratno-reemitujuće faze klinički su stabilni. S druge strane, pacijenti sa progresivnom MS pokazuju stabilno povećanje u deficitima, kao što je definisano gore i ili od pojave ili nakon perioda epizoda, ali ova oznaka ne isključuje dalju pojavu novih recidiva.
[0021] Uprkos gore navedenom, dimetil fumarat takođe je povezan sa značajnim nedostacima.
[0023] Na primer, poznato je da dimetil fumarat izaziva neželjene efekte usled oralnog davanja, kao što su crvenilo i gastrointestinalni slučajevi uključujući, mučninu, dijareju, i/ili bol u gornjem abdomenu kod subjekata. Videti, npr., Gold et al., N. Eng. J. Med, 2012, 367(12), 1098-1107. Dimetil fumarat dozira se BID ili TID sa ukupnom dnevnom dozom od oko 480 mg do oko 1 gram ili više.
[0024] Dalje, pri upotrebi leka za dugoročnu terapiju, poželjno je da se lek formuliše tako da je pogodan za davanje jedanput ili dvaput dnevno da pomogne saradnju pacijenta. Učestalost doziranja od jedanput dnevno ili manje je čak poželjnija.
[0026] Drugi problem sa dugotrajnom terapijom je zahtev za određivanjem optimalne doze koju pacijent može da toleriše. Ako se takva doza ne odredi, to može da dovede do smanjenja u efikasnosti leka koji se daje.
[0028] Prema tome, cilj ovog pronalaska je da obezbedi jedinjenja i/ili kombinacije koje su pogodne za dugotrajno davanje.
[0030] Dalji cilj ovog pronalaska je da obezbedi upotrebu farmaceutski aktivnog agensa na način koji omogućava da se postigne tolerišući nivo stabilnog stanja za lek u subjektu koji se njime leči.
[0031] Zbog nedostataka dimetil fumarata opisanih gore, i dalje postoji potreba da se smanji učestalost doziranja, smanje negativni efekti i/ili poboljšaju fizičkohemijska svojstva povezana sa DMF. Prema tome, ostaje stvarna potreba u lečenju neuroloških bolesti, kao što je MS, za proizvodom koji zadržava farmakološke prednosti DMF ali koji prevazilazi svoje nedostatke u formulaciji i/ili neželjene efekte nakon davanja. Ovaj pronalazak bavi se tim potrebama.
[0033] KRATAK OPIS NACRTA
[0034]
[0035] Fig.1 prikazuje hidrolizu jedinjenja 16 pri pH 7,9, 25°C, prikazujući vinilni region, kao što je posmatrano pomoću NMR tokom 90 minuta.
[0036] Fig.2 prikazuje hidrolizu jedinjenja 16 pri pH 7,9, 25°C, prikazujući vinilni region, kao što je posmatrano pomoću NMR tokom 19 sati.
[0037] Fig.3 prikazuje hidrolizu jedinjenja 16 pri pH 7,9, 25°C, prikazujući alifatični region, kao što je posmatrano pomoću NMR tokom 19 sati.
[0038] Fig.4 prikazuje hidrolizu referentnog jedinjenja A pri pH 7,9, 37°C, prikazujući vinilni region, kao što je posmatrano pomoću NMR tokom 15 sati.
[0039] Fig.5 prikazuje hidrolizu referentnog jedinjenja A pri pH 7,9, 37°C, prikazujući alifatični region, kao što je posmatrano pomoću NMR tokom 15 sati.
[0040] Fig.6 prikazuje grafik gubitka mase vs vreme za jedinjenje 14 i DMF.
[0041] Fig.7 prikazuje jediničnu ćeliju za kristalno jedinjenje 14.
[0043] SAŽETAK PRONALASKA
[0044] Ovaj pronalazak usmeren je na iznenađujuće i neočekivano otkriće novih prolekova i odnosnih postupaka korisnih u lečenju neuroloških bolesti. Postupci i kombinacije opisani ovde obuhvataju jedan ili više prolekova (npr., aminoalkil prolekove) monometil fumarata (MMF). Postupci i kombinacije obezbeđuju za terapeutski efektivnu količinu aktivnog dela u subjektu za vremenski period od najmanje oko 8 sati do najmanje oko 24 sata.
[0046] Preciznije, jedinjenja ovog pronalaska mogu da se konvertuju in vivo, usled oralnog davanja, u monometil fumarat. Nakon konverzije, aktivni deo (tj., monometil fumarat) je efikasan u lečenju subjekata koji boluju od neurološke bolesti.
[0048] [0018] Ovaj pronalazak odnosi se na upotrebu jedinjenja kao što je definisano u patentim zahtevima u postupcima za lečenje neurološke bolesti davanjem subjektu kom je to potrebno, neke terapeutski efektivne količine pomenutog jedinjenja, tako da se leči bolest.
[0050] Ovaj pronalazak takođe se odnosi na upotrebu jedinjenja kao što je definisano u patentim zahtevima u postupcima za lečenje multipla skleroze davanjem subjektu kom je to potrebno, neke terapeutski efektivne količine pomenutog jedinjenja, tako da se leči multipla skleroza.
[0052] Ovaj pronalazak takođe se odnosi na upotrebu jedinjenja kao što je definisano u patentim zahtevima u postupcima za lečenje povratno-reemitujuće multipla skleroze (RRMS) davanjem subjektu kom je to potrebno, neke terapeutski efektivne količine pomenutog jedinjenja formule opisane ovde, ili njegove farmaceutski prihvatljive soli, polimorfa, hidrata, solvata ili kokristala, tako da se leči multipla skleroza.
[0054] Ovaj pronalazak takođe obezbeđuje jedinjenje kao što je definisano u patentim zahtevima za upotrebu u postupcima za lečenje sekundarno progresivne multipla skleroze (SPMS) davanjem subjektu kom je to potrebno, neke terapeutski efektivne količine jedinjenja formule opisane ovde, ili njegove farmaceutski prihvatljive soli, polimorfa, hidrata, solvata ili kokristala, tako da se leči multipla skleroza.
[0056] Ovaj pronalazak takođe obezbeđuje postupke za lečenje primarno progresivne multipla skleroze (PPMS) davanjem subjektu kom je to potrebno, neke terapeutski efektivne količine jedinjenja formule opisane ovde, ili njegove farmaceutski prihvatljive soli, polimorfa, hidrata, solvata ili kokristala, tako da se leči multipla skleroza. Ovaj pronalazak takođe obezbeđuje postupke za lečenje progresivne povratne multipla skleroze (PRMS) davanjem subjektu kom je to potrebno, neke terapeutski efektivne količine jedinjenja formule opisane ovde, ili njegove farmaceutski prihvatljive soli, polimorfa, hidrata, solvata ili kokristala, tako da se leči multipla skleroza.
[0058] Ovaj pronalazak takođe obezbeđuje postupke za lečenje Alchajmerove bolesti davanjem subjektu kom je to potrebno, neke terapeutski efektivne količine jedinjenja formule opisane ovde, ili njegove farmaceutski prihvatljive soli, polimorfa, hidrata, solvata ili kokristala, tako da se leči Alchajmerova bolest.
[0060] Ovaj pronalazak takođe obezbeđuje postupke za lečenje cerebralne paralize davanjem subjektu kom je to potrebno, neke terapeutski efektivne količine jedinjenja formule opisane ovde, ili njegove farmaceutski prihvatljive soli, polimorfa, hidrata, solvata ili kokristala, tako da se leči cerebralna paraliza.
[0061] Ovaj pronalazak takođe obezbeđuje jedinjenja i kombinacije koji omogućuju poboljšane oralne formulacije sa kontrolisanim ili produženim oslobađanjem. Posebno, dimetil fumarat se daje dvaput ili triput dnevno za lečenje povratno-reemitujuće multipla skleroze. Nasuprot tome, jedinjenja i kombinacije ovog pronalaska mogu da omoguće formulacije sa modifikovanim trajanjem terapeutske efikasnosti za smanjenje brzina recidiva kod subjekata sa multipla sklerozom. Na primer, ova jedinjenja i kombinacije obezbeđuju terapeutski efektivne količine monometil fumarata kod subjekata za najmanje oko 8 sati, najmanje oko 12 sati, najmanje oko 16 sati, najmanje oko 20 sati ili najmanje oko 24 sata.
[0063] Ovaj pronalazak takođe obezbeđuje jedinjenja, kombinacije i postupke koji mogu da rezultuju smanjenim neželjenim efektima nakon davanja subjektu u odnosu na dimetil fumarat. Na primer, irutacija želuca i crvenilo poznati su kao neželjeni efekti oralnog davanja dimetil fumarata kod nekih subjekata. Jedinjenja, kombinacije i postupci ovog pronalaska mogu da se koriste kod subjekata koji su doživeli ili su pod rizikom od razvoja takvih neželjenih efekata.
[0065] Ovaj pronalazak takođe obezbeđuje za jedinjenja i kombinacije koji pokazuju poboljšanu fizičku stabilnost u odnosu na dimetil fumarat. Posebno, dimetil fumarat je poznat u ovoj oblasti da podleže sublimaciji u uslovima ambijentalne i povišene temperature. Jedinjenja ovog pronalaska poseduju veću fizičku stabilnost nego dimetil fumarat u kontrolisanim uslovima temperature i relativne vlažnosti. Posebno, u jednom primeru izvođenja, jedinjenja formule opisane ovde pokazuju smanjenu sublimaciju u odnosu na dimetil fumarat.
[0067] Dalje, takođe je poznato da je dimetil fumarat iritantan pri kontaktu. Videti npr., Bezbednosni list materijala za DMF. U jednom primeru izvođenja, jedinjenja ovog pronalaska pokazuju smanjenu iritaciju pri kontaktu u odnosu na dimetil fumarat. Na primer, jedinjenja formule opisane ovde pokazuju smanjenu iritaciju pri kontaktu u odnosu na dimetil fumarat.
[0069] Ovaj pronalazak takođe obezbeđuje za jedinjenja i kombinacije koji pokazuju smanjeni efekat hrane u odnosu na dimetil fumarat. Poznato je u ovoj oblasti da će se bioraspoloživost dimetil fumarata smanjiti kada se daje sa hranom. Posebno, u jednom primeru izvođenja, jedinjenja formule opisane ovde pokazuju smanjeni efekat hrane u odnosu na dimetil fumarat.
[0071] [0030] Osim ukoliko nije drugačije definisano, svi tehnički i naučni izrazi korišćeni ovde imaju isto značenje kao što je obično shvaćeno od strane prosečnog stručnjaka u oblasti kojoj ovaj pronalazak pripada. U specifikaciji, oblici jednine takođe uključuju množinu, osim ukoliko kontekst jasno ne diktira drugačije. Iako postupci i materijali slični ili jednaki onima opisanim ovde mogu da se koriste u praksi ili ispitivanju ovog pronalaska, pogodni postupci i materijali opisani su dole. Reference navedene ovde nisu prihvaćene kao stanje tehnike ovog pronalaska. U slučaju konflikta, ova specifikacija, uključujući definicije, će kontrolisati. Dodatno, materijali, postupci i primeri samo su ilustrativni, a ne ograničavajući.
[0073] Ostale karakteristike i prednosti ovog pronalaska biće jasne iz detaljnog opisa i patentnih zahteva koji slede.
[0075] DETALJAN OPIS PRONALASKA
[0076] Ovaj pronalazak obezbeđuje nova jedinjenja i postupke za lečenje neurološke bolesti davanjem jedinjenja formule (III), i farmaceutskih kombinacija koje sadrže jedinjenje formule (III).
[0078] Ovaj pronalazak takođe se odnos na upotrebu jedinjenja kako je definisano u patentim zahtevima u postupcima za lečenje psorijaze davanjem subjektu kom je to potrebno, terapeutski efektivne količine pomenutog jedinjenja, ili njegove farmaceutski prihvatljive soli.
[0080] Neurološka bolest može da bude multipla skleroza. Ovaj pronalazak dalje obezbeđuje upotrebu jedinjenja formule (III), ili njegove farmaceutski prihvatljive soli, za pripremu leka korisnog za lečenje neurološke bolesti.
[0082] [0035] Prema ovom pronalasku, neurološka bolest je poremećaj mozga, kičmene moždine ili nerava kod subjekta. U jednom primeru izvođenja, neurološka bolest se karakteriše demijelinizacijom, ili degeneracijom mijelinskog plašta, centralnog nervnog sistema. Mijelinski plašt olakšava transmisiju nervnih impulsa kroz nervno vlakno ili akson. U drugom primeru izvođenja, neurološka bolest je odabrana iz grupe koju čine multipla skleroza, Alchajmerova bolest, cerebralna paraliza, oštećenje kičmene moždine, amiotrofična lateralna skleroza (ALS), moždani udar, Huntingtonova bolest, Parkinsonova bolest, optički neuritis, Devikova bolest, transverzalni mijelitis, akutni diseminovani encefalomijelitis, adrenoleukodistrofija i adrenomijeloneuropatija, akutna zapaljenska demijelinizirajuća polineuropatija (AIDP), hronična zapaljenska demijelinizirajuća polineuropatija (CIDP), akutni transverzalni mijelitis, progresivna multifokalna leukoencefalopatija (PML), akutni diseminovani encefalomijelitis (ADEM), i ostali nasledni poremećaji, kao što su leukodistrofije, Leberova optička atrofija, i Charcot-Marie-Tooth bolest. U nekim primerima izvođenja, neurološki poremećaj je autoimuna bolest. U jednom primeru izvođenja, neurološka bolest je multipla skleroza. U drugom primeru izvođenja, neurološka bolest je moždani udar. U drugom primeru izvođenja, neurološka bolest je Alchajmerova bolest. U drugom primeru izvođenja, neurološka bolest je cerebralna paraliza. U drugom primeru izvođenja, neurološka bolest je oštećenje kičmene moždine. U drugom primeru izvođenja, neurološka bolest je ALS. U drugom primeru izvođenja, neurološka bolest je Huntingtonova bolest. Videti, npr., US Patent br.8,007,826, WO2005/099701 i WO2004/082684.
[0084] U daljem primeru izvođenja, ovaj pronalazak obezbeđuje upotrebu jedinjenja kao što su definisana u patentim zahtevima u postupcima za lečenje neke bolesti ili nekog simptoma bolesti opisane ovde davanjem subjektu kom je to potrebno, terapeutski efektivne količine jedinjenja formule (III), ili njegove farmaceutski prihvatljive soli. Ovaj pronalazak dalje obezbeđuje upotrebu jedinjenja formule (III), ili njegove farmaceutski prihvatljive soli, za pripremu leka korisnog za lečenje neke bolest ili simptoma bolesti opisane ovde.
[0086] Ovaj pronalazak obezbeđuje jedinjenje formule (III), ili njegovu farmaceutski prihvatljivu so, i upotrebu pomenutog jedinjenja u postupku za lečenje neurološke bolesti davanjem subjektu kom je to potrebno terapeutski efektivne količine jedinjenja formule (III), ili njegove farmaceutski prihvatljive soli:
[0088]
[0090] u kojoj:
[0091] R<1>je nesupstituisan C<1>-C<6>alkil;
[0093]
[0095] m je 0, 1, 2, ili 3;
[0096] t je 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, ili 10;
[0097] R<6>, R<7>, R<8>i R<9>su svaki, nezavisno, H, supstituisan ili nesupstituisan C<1>-C<6>alkil, supstituisan ili nesupstituisan C<2>-C<6>alkenil, supstituisan ili nesupstituisan C<2>-C<6>alkinil ili C(O)OR<a>; i
[0098] R<a>je H ili supstituisan ili nesupstituisan C<1>-C<6>alkil; i
[0099] svaki R<10>je, nezavisno, H, halogen, supstituisan ili nesupstituisan C<1>-C<6>alkil, supstituisan ili nesupstituisan C<2>-C<6>alkenil, supstituisan ili nesupstituisan C<2>-C<6>alkinil, supstituisan ili nesupstituisan C<3>-C<10>karbocikl, supstituisan ili nesupstituisan heterocikl koji se sastoji od jednog ili dva 5- ili 6-članih prstenova i 1-4 heteroatoma odabrana od N, O i S, ili supstituisan ili nesupstituisan heteroaril koji se sastoji od jednog ili dva 5- ili 6-članih prstenova i 1-4 heteroatoma odabrana od N, O i S;
[0100] ili, alternativno, dva R<10>vezana za isti atom ugljenika, zajedno sa atomom ugljenika za koji su vezani, obrazuju karbonil, supstituisan ili nesupstituisan C<3>-C<10>karbocikl, supstituisan ili nesupstituisan heterocikl koji se sastoji od jednog ili dva 5- ili 6-članih prstenova i 1-4 heteroatoma odabrana od N, O i S, ili supstituisan ili nesupstituisan heteroaril koji se sastoji od jednog ili dva 5- ili 6-članih prstenova i 1-4 heteroatoma odabrana od N, O i S;
[0101] ili, alternativno, dva R<10>vezana za različite atome, zajedno sa atomima za koje su vezani, obrazuju supstituisan ili nesupstituisan C<3>-C<10>karbocikl, supstituisan ili nesupstituisan heterocikl koji se sastoji od jednog ili dva 5- ili 6-članih prstenova i 1-4 heteroatoma odabrana od N, O i S, ili supstituisan ili nesupstituisan heteroaril koji se sastoji od jednog ili dva 5- ili 6-članih prstenova i 1-4 heteroatoma odabrana od N, O i S.
[0103] Na primer, neurološka bolest je multipla skleroza.
[0105] Na primer, neurološka bolest je povratno-reemitujuća multipla skleroza (RRMS).
[0107] Na primer, u jedinjenju formule (III), R<1>je metil.
[0109] Na primer, u jedinjenju formule (III), R<1>je etil.
[0111] U jedinjenju formule (III),
[0113]
[0116] Na primer, u jedinjenju formule (III), R<6>je supstituisan ili nesupstituisan C<1>-C<6>alkil, a R<7>, R<8>i R<9>su svaki H.
[0118] Na primer, u jedinjenju formule (III), R<6>je nesupstituisan C<1>-C<6>alkil, a R<7>, R<8>i R<9>su svaki H.
[0120] Na primer, u jedinjenju formule (III), R<8>je supstituisan ili nesupstituisan C<1>-C<6>alkil, a R<6>, R<7>i R<9>su svaki H.
[0121] Na primer, u jedinjenju formule (III), R<8>je nesupstituisan C<1>-C<6>alkil, a R<6>, R<7>i R<9>su svaki H.
[0123] Na primer, u jedinjenju formule (III), R<6>i R<8>su svaki, nezavisno, supstituisan ili nesupstituisan C<1>-C<6>alkil, a R<7>i R<9>su svaki H.
[0125] Na primer, u jedinjenju formule (III), R<6>i R<8>su svaki, nezavisno, nesupstituisan C<1>-C<6>alkil, a R<7>i R<9>su svaki H.
[0127] Na primer, u jedinjenju formule (III), R<6>i R<7>su svaki, nezavisno, supstituisan ili nesupstituisan C<1>-C<6>alkil, a R<8>i R<9>su svaki H.
[0129] Na primer, u jedinjenju formule (III), R<6>i R<7>su svaki, nezavisno, nesupstituisan C<1>-C<6>alkil, a R<8>i R<9>su svaki H.
[0131] Na primer, u jedinjenju formule (III), R<8>i R<9>su svaki, nezavisno, supstituisan ili nesupstituisan C<1>-C<6>alkil, a R<6>i R<7>su svaki H.
[0133] Na primer, u jedinjenju formule (III), R<8>i R<9>su svaki, nezavisno, nesupstituisan C<1>-C<6>alkil, a R<6>i R<7>su svaki H.
[0135] U jednom primeru izvođenja formule (III):
[0136] R<1>je nesupstituisan C<1>-C<6>alkil;
[0138]
[0140] m je 0, 1, 2, ili 3;
[0141] t je 2, 4, ili 6;
[0142] R<6>, R<7>, R<8>i R<9>su svaki, nezavisno, H, nesupstituisan C<1>-C<6>alkil, ili C(O)OR<a>, u kojoj R<a>je H ili nesupstituisan C<1>-C<6>alkil; i
[0143] dva R<10>vezana za isti atom ugljenika, zajedno sa atomom ugljenika za koji su vezani, obrazuju karbonil.
[0145] Na primer, jedinjenje je jedinjenje dato u Tabeli 1 ovde.
[0146] Reprezentativna jedinjenja ovog pronalaska uključuju jedinjenja navedena u Tabeli 1 i u Tabeli 2.
[0147] Tabela 1.
[0149]
[0150]
[0151]
[0153] A<->je farmaceutski prihvatljiv anjon.
[0155] Ovaj pronalazak takođe obezbeđuje farmaceutske kombinacije koje se sastoje od jednog ili više jedinjenja formule (III) i jednog ili više farmaceutski prihvatljivih nosača.
[0157] U jednom primeru izvođenja, farmaceutska kombinacija je kombinacija sa kontrolisanim oslobađanjem koja se sastoji od jedinjenja formule (III) i jednog ili više farmaceutski prihvatljivih nosača, pri čemu ta kombinacija sa kontrolisanim oslobađanjem obezbeđuje terapeutski efektivnu količinu monometil fumarata subjektu. U drugom primeru izvođenja, farmaceutska kombinacija je kombinacija sa kontrolisanim oslobađanjem koja se sastoji od jedinjenja formule (III) i jednog ili više farmaceutski prihvatljivih nosača, pri čemu ta kombinacija sa kontrolisanim oslobađanjem obezbeđuje terapeutski efektivnu količinu monometil fumarata subjektu za najmanje oko 8 sati do najmanje oko 24 sata. U drugom primeru izvođenja, farmaceutska kombinacija je kombinacija sa kontrolisanim oslobađanjem koja se sastoji od jedinjenja formule (III) i jednog ili više farmaceutski prihvatljivih nosača, pri čemu ta kombinacija sa kontrolisanim oslobađanjem obezbeđuje terapeutski efektivnu količinu monometil fumarata subjektu za najmanje oko 8 sati, najmanje oko 10 sati, najmanje oko 12 sati, najmanje oko 13 sati, najmanje oko 14 sati, najmanje oko 15 sati, najmanje oko 16 sati, najmanje oko 17 sati, najmanje oko 18 sati, najmanje oko 19 sati, najmanje oko 20 sati, najmanje oko 21 sata, najmanje oko 22 sata, najmanje oko 23 sata ili najmanje oko 24 sata ili duže. Na primer, najmanje oko 18 sati. Na primer, najmanje oko 12 sati. Na primer, duže od 12 sati. Na primer, najmanje oko 16 sati. Na primer, najmanje oko 20 sati. Na primer, najmanje oko 24 sata.
[0159] [0058] U drugom primeru izvođenja, jedinjenje formule (III) efikasno se konvertuje u aktivne vrste, tj., monometil fumarat, usled oralnog davanja. Na primer, oko 50 molskih procenata, oko 55 molskih procenata, oko 60 molskih procenata, oko 65 molskih procenata, oko 70 molskih procenata, oko 75 molskih procenata, oko 80 molskih procenata, oko 85 molskih procenata, oko 90 molskih procenata, ili više od 90 molskih procenata date ukupne doze jedinjenja formule (III) konvertuje se u monometil fumarat usled oralnog davanja. U drugom primeru izvođenja, jedinjenje formule (III) konvertuje se u aktivne vrste, tj., monometil fumarat, usled oralnog davanja efikasnije nego dimetil fumarat. U drugom primeru izvođenja, jedinjenje formule (III) konvertuje se u aktivne vrste, tj., monometil fumarat, usled oralnog davanja efikasnije nego jedno ili više jedinjenja opisanih u US 8,148,414. Na primer, jedinjenje formule (III) u suštini se potpuno konvertuje u aktivne vrste, tj., monometil fumarat, usled oralnog davanja.
[0161] U drugom primeru izvođenja, bilo koje od prethodno navedenih primera jedinjenja prema ovom pronalasku efikasno se konvertuje u aktivne vrste, tj., monometil fumarat, usled oralnog davanja. Na primer, oko 50 procenata, oko 55 procenata, oko 60 procenata, oko 65 procenata, oko 70 procenata, oko 75 procenata, oko 80 procenata, oko 85 procenata, oko 90 procenata, ili više od 90 procenata date ukupne doze bilo kojeg od prethodno navedenih primera jedinjenja prema ovom pronalasku konvertuje se u monometil fumarat usled oralnog davanja. U drugom primeru izvođenja, bilo koje od prethodno navedenih primera jedinjenja prema ovom pronalasku konvertuje se u aktivne vrste, tj., monometil fumarat, usled oralnog davanja efikasnije nego dimetil fumarat. U drugom primeru izvođenja, bilo koje od prethodno navedenih primera jedinjenja prema ovom pronalasku konvertuje se u aktivne vrste, tj., monometil fumarat, usled oralnog davanja efikasnije nego jedno ili više jedinjenja opisanih u US 8,148,414. Na primer, bilo koje od prethodno navedenih primera jedinjenja prema ovom pronalasku potpuno se konvertuje u aktivne vrste, tj., monometil fumarat, usled oralnog davanja.
[0163] [0060] Da bi lek postigao svoj terapeutski efekat, potrebno je da se održava potreban nivo koncentracije u krvi ili plazmi. Mnogi lekovi, uključujući dimetil fumarat, moraju da se daju više puta dnevno da bi se održala potrebna koncentracija. Dalje, čak i sa višestrukim davanjima takvog leka po danu, koncentracije aktivnog sastojka u krvi ili plazmi mogu i dalje da variraju sa vremeno, tj., u određenim vremenskim tačkama između davanja postoje više koncentracije aktivnog sastojka nego u ostalim vremenima. Prema tome, u određenim vremenskim tačkama 24-časovnog perioda, pacijent može da primi terapeutski efektivne količine aktivnog sastojka, dok u ostalim vremenskim tačkama koncentracija aktivnog sastojka u krvi može da padne ispod terapeutskih nivoa. Dodatni problemi sa takvim lekovima uključuju to da višestruko dnevno doziranje često negativno utiče na pacijentovu usaglašenost sa lečenjem. Prema tome, poželjno je da ima dozni oblik leka u kom se aktivni sastojak dostavlja na takav kontrolisani način kojim može da se postigne konstantan ili suštinski konstantan nivo koncentracije aktivnog sastojka u krvi ili plazmi sa jednom ili najviše dve doze dnevno. Prema tome, ovaj pronalazak obezbeđuje formulacije sa kontrolisanim oslobađanjem kao što je opisano dole. Uopšteno, takve formulacije poznate su prosečnim stručnjacima u ovoj oblasti ili su dostupne upotrebom konvencionalnih postupaka.
[0165] Kako se ovde koristi, "kontrolisano oslobađanje" znači dozni oblik kod kog je oslobađanje aktivnog agensa kontrolisano ili modifikovano tokom nekog vremenskog perioda. Kontrolisano može da znači, na primer, produženo, odloženo ili pulsirajuće oslobađanje u određeno vreme. Na primer, kontrolisano oslobađanje može da znači da je oslobađanje aktivnog sastojka produženo za više od toga kada je on u doznom obliku sa trenutnim oslobađanjem, tj., najmanje više od nekoliko sati.
[0167] Kako se ovde koristi, "trenutno oslobađanje" znači dozni oblik kod kog se više od ili jednako oko 75% aktivnog sastojka oslobađa u okviru dva sati, ili, određenije, u okviru jednog sata, od davanja. Trenutno oslobađanje ili kontrolisano oslobađanje mogu takođe da se okarakterišu njihovim profilima rastvaranja.
[0169] Formulacije mogu takođe da se okarakterišu njihovim farmakokinetičkim parametrima. Kako se ovde koristi, "farmakokinetički parametri" opisuju in vivo karakteristike aktivnog sastojka tokom vremena, uključujući, na primer, koncentraciju aktivnog sastojka u plazmi. Kako se ovde koristi, "C<max>" predstavlja izmerenu koncentraciju aktivnog sastojka u plazmi u tački maksimalne koncentracije. "T<max>" odnosi se na vreme u kom je koncentracija aktivnog sastojka u plazmi najviša. "AUC" je oblast ispod krive grafikona koncentracije aktivnog sastojka (obično koncentracija u plazmi) vs. vreme, merena od jednog trenutka do drugog.
[0171] Formulacije sa kontrolisanim oslobađanjem obezbeđene ovde obezbeđuju željena svojstva i prednosti. Na primer, formulacije mogu da se daju jedanput dnevno, što je naročito poželjno za subjekte opisane ovde. Formulacija može da obezbedi mnoge terapeutske koristi koje se ne postižu sa odgovarajućim kraćim delovanjem, ili preparatima sa trenutnim oslobađanjem. Na primer, formulacija može da održi niže, stabilnije vrednosti pika u plazmi, na primer, C<max>, tako da se redukuju učestalost i ozbiljnost mogućih neželjenih efekata.
[0173] [0065] Dozni oblici sa produženim oslobađanjem oslobađaju svoj aktivni sastojak u gastrointestinalni trakt pacijenta tokom produženog vremenskog perioda nakon davanja doznog oblika pacijentu. Posebni dozni oblici uključuju: (a) one u kojima je aktivni sastojak je ugrađen u matricu iz koje se oslobađa difuzijom ili erozijom; (b) one u kojima je aktivni sastojak prisutan u jezgru koje je obloženo membranom koja kontroliše brzinu oslobađanja; (c) one u kojima je aktivni sastojak prisutan u jezgru obezbeđenim spoljašnjim omotačem nepropusnim za aktivni sastojak, pri čemu taj spoljašnji omotač ima otvor (koji može da se izbuši) za oslobađanje aktivnog sastojka; (d) one u kojima se aktivni sastojak oslobađa kroz polupropustljivu membranu, što omogućava da lek difunduje kroz membranu ili kroz pore napunjene tečnošću unutar membrane; i (e) one u kojima je aktivni sastojak prisutan kao neki jonoizmenjivački kompleks.
[0175] Prosečnim stručnjacima u ovoj oblasti biće očigledno da neka od sredstava postizanja produženog oslobađanja mogu da se kombinuju, na primer, matrica koja sadrži aktivno jedinjenje može da se formira u višečestičnim i/ili obloži sa nepropusnim omotačem izveden sa otvorom.
[0177] Formulacije sa pulsirajućim oslobađanjem oslobađaju aktivno jedinjenje nakon produženog vremenskog perioda nakon davanja doznog oblika pacijentu. Oslobađanje može onda da bude u obliku trenutnog ili produženog oslobađanja. Ovo odlaganje može da se postigne oslobađanjem leka u određenim tačkama u gastrointestinalnom traktu ili oslobađanjem leka nakon prethodno određenog vremena. Formulacije sa pulsirajućim oslobađanjem mogu da budu u obliku tableta ili višečestične ili kombinacija oba. Određeni dozni oblici uključuju: (a) oslobađanje izazvano osmotskim potencijalom (videti U.S. Pat. br.3,952,741); (b) sabijene obložene dvoslojne tablete (videti U.S. Pat. br.5,464,633); (c) kapsule koje sadrže erozivnu plombu (videti U.S. Pat. br.5,474,784); sigmoidalno oslobađajuće pelete (pomenute u U.S. Pat. br.5,112,621); i (d) formulacije obložene sa ili koje sadrže pH-zavisne polimere uključujući šelak, derivate ftalata, derivate poliakrilne kiseline i kopolimere krotonske kiseline.
[0179] Formulacije sa dvostrukim oslobađanjem mogu da kombinuju aktivni sastojak u obliku sa trenutnim oslobađanjem sa dodatnim aktivnim sastojkom u obliku sa kontrolisanim oslobađanjem. Na primer, dvoslojna tableta može da se formira sa jednim slojem koji sadrži aktivni sastojak sa trenutnim oslobađanjem i drugi sloj koji sadrži aktivni sastojak ugrađen u matricu iz koje se oslobađa difuzijom ili erozijom. Alternativno, jedna ili više perlica sa trenutnim oslobađanjem može da se kombinuje sa jednom ili više perlica koje su obložene membranom koja kontroliše brzinu oslobađanja u kapsuli da bi se dobila formulacija sa dvostrukim oslobađanjem. Formulacije sa produženim oslobađanjem u kojima je aktivni sastojak prisutan u jezgru obezbeđenom spoljašnjim omotačem nepropusnim za aktivni sastojak, pri čemu taj spoljašnji omotač ima otvor (koji može da se izbuši) za oslobađanje aktivnog sastojka, mogu da se oblože lekom u obliku sa trenutnim oslobađanjem da bi se dobila formulacija sa dvostrukim oslobađanjem. Formulacije sa dvostrukim oslobađanjem takođe mogu da kombinuju lek u obliku sa trenutnim oslobađanjem sa dodatnim lekom u obliku sa pulsirajućim oslobađanjem. Na primer, kapsula koja sadrži erozivnu plombu može da oslobodi lek na početku i, nakon unapred određenog vremenskog perioda, oslobodi dodatni lek u obliku sa trenutnim ili produženim
[0180] oslobađanjem.
[0181] U nekim primerima izvođenja, dozni oblici koji će se koristiti mogu da se obezbede kao sa kontrolisanim oslobađanjem u odnosu na njihov jedan ili više aktivnih sastojaka upotrebom, na primer, hidroksipropilmetil celuloze, ostalih polimernih matrica, gelova, propustljivih membrana, osmotskih sistema, višeslojnih omotača, mikročestica, lipozoma, ili mikrosfera ili neke njihove kombinacije da bi se obezbedio željeni profil oslobađanj u različitim razmerama. Pogodne formulacije sa kontrolisanim oslobađanjem poznate prosečnim stručnjacima u ovoj oblasti, uključujući one opisane ovde, mogu se lako odabrati za upotrebu sa farmaceutskim kombinacijama ovog pronalaska. Prema tome, pojedinačni jedinični dozni oblici pogodni za oralno davanje, kao što su tablete, kapsule, gel kapsule, i pilule koji su prilagođene za kontrolisano oslobađanje obuhvaćeni su ovim pronalaskom.
[0183] Najviše formulacija sa kontrolisanim oslobađanjem izrađuje se da inicijalno oslobodi neku količinu leka koja neodložno proizvodi željeni terapeutski efekat, i postepeno i kontinuirano oslobodi dodatne količine leka da bi se održalo ovaj nivo terapeutskog efekta tokom nekog produženog vremenskog perioda. Da bi se održao ovaj konstantni nivo leka u telu, lek mora da se oslobodi iz doznog oblika brzinom kojom će se zameniti količina leka koja je metabolisana i izlučena iz tela.
[0185] Kontrolisano oslobađanje nekog aktivnog sastojka može da se stimuliše raznim izazivačima, na primer, pH, temperatura, enzimi, koncentracija, ili ostali fiziološki uslovi ili jedinjenja.
[0187] Praškaste i granulirane formulacije farmaceutskog preparata ovog pronalaska mogu da se pripreme upotrebom poznatih postupaka. Takve formulacije mogu da se daju direktno subjektu, korišćene, na primer, da formiraju tablete, da napune kapsule, ili da se pripremi vodena ili uljana suspenzija ili rastvor dodavanjem vodenog ili uljanog nosača njima. Svaka od ovih formulacija može dalje da obuhvata jedan ili više od dispergujućeg agensa, agensa za kvašenje, suspendujućeg agensa, i konzervansa. Dodatni ekscipijensi, kao što su punioci, zaslađivači, arome, ili agensi za bojenje, mogu takođe da budu uključeni u ovim formulacijama.
[0189] Formulacija farmaceutske kombinacije ovog pronalaska pogodna za oralno davanje može da se pripremi ili upakuje u obliku diskretne čvrste dozne jedinice uključujući, ali ne ograničavajući se na, tabletu, tvrdu ili meku kapsulu, pilulu, pastilu, ili lozengu, pri čemu svaka sadrži unapred određenu količinu aktivnog sastojka. U jednom primeru izvođenja, formulacija farmaceutske kombinacije ovog pronalaska pogodna za oralno davanje obložena je enteričnim omotačem.
[0191] [0074] Tableta koja se sastoji od aktivnog sastojka može, na primer, da se izradi sabijanjem ili kalupovanjem aktivnog sastojka, opciono sa jednim ili više dodatnih sastojaka. Sabijene tablete mogu da se pripreme sabijanjem, u određenom uređaju, aktivnog sastojka u slobodno tekućem obliku kao što je praškasti ili granulirani preparat, opciono umešan sa jednim ili više od veziva, lubrikanta, ekscipijensa, površinski aktivnog agensa i dispergujućeg agensa. Ukalupljene tablete mogu da se pripreme kalupovanjem, u pogodnom uređaju, mešavine aktivnog sastojka, farmaceutski prihvatljivog nosača, i najmanje dovoljno tečnosti za vlaženje mešavine. Farmaceutski prihvatljivi ekscipijensi korišćeni u proizvodnji tableta uključuju, ali nisu ograničeni na, inertne razblaživače, agense za granulisanje i dezintegrisanje, vezujuće agense i agense za podmazivanje. Poznati dispergujući agensi uključuju, ali nisu ograničeni na, krompirov skrob i natrijum skrobni glikolat. Poznati površinski aktivni agensi uključuju, ali nisu ograničeni na, natrijum lauril sulfat i poloksamere. Poznati razblaživači uključuju, ali nisu ograničeni na, kalcijum karbonat, natrijum karbonat, laktozu, microkristalnu celulozu, kalcijum fosfat, kalcijum hidrogen fosfat, i natrijum fosfat. Poznati agensi za granulisanje i dezintegrisanje uključuju, ali nisu ograničeni na, kukuruzni skrob i algininsku kiselinu. Poznati vezujući agensi uključuju, ali nisu ograničeni na, želatin, akaciju, prethodno želatizirani kukuruzni skrob, polivinilpirolidon, i hidroksipropil metilcelulozu. Poznati agensi za podmazivanje uključuju, ali nisu ograničeni na, magnezijum stearat, stearinsku kiselinu, silicijumdioksid, i talk.
[0193] Tablete mogu da budu neobložene ili mogu da budu obložene upotrebom poznatih postupaka da bi se postigla odložena dezintegracija u gastrointestinalnom traktu subjekta, čime se obezbeđuje produženo oslobađanje i apsorpcija aktivnog sastojka. Primera radi, materijal kao što je gliceril monostearat ili gliceril distearat može da se koristi za oblaganje tableta. Dalje primera radi, tablete mogu da se oblože upotrebom postupaka opisanih u U.S. Pat. br.4,256,108; 4,160,452; i 4,265,874 da bi se formirale tablete sa osmotski kontrolisanim oslobađanjem, opciono, laserskim bušenjem. Tablete mogu dalje da obuhvataju zaslađivač, agens za aromu, agens za bojenje, konzervans, ili neku njihovu kombinaciju da bi se obezbedile farmaceutski elegantne i ukusne formulacije.
[0195] Tvrde kapsule koje se sastoje od aktivnog sastojka mogu da se izrade upotrebom fiziološki razgradive kombinacije, kao što je želatin ili HPMC. Takve tvrde kapsule obuhvataju aktivni sastojak, i mogu dalje da obuhvataju dodatne sastojke uključujući, na primer, neki inertni čvrsti razblaživač kao što je kalcijum karbonat, kalcijum fosfat, ili kaolin.
[0197] Meke želatinske kapsule koje se sastoje od aktivnog sastojka mogu da se izrade upotrebom fiziološki razgradive kombinacije, kao što je želatin. Takve meke kapsule obuhvataju aktivni sastojak, koji može da bude umešan sa vodom ili nekim uljanim medijumom kao što je ulje kikirikija, tečni parafin, ili maslinovo ulje.
[0198] Kako se ovde koristi, "alkil", "C<1>, C<2>, C<3>, C<4>, C<5>ili C<6>alkil" ili "C<1>-C<6>alkil" namenjen je da uključuje C<1>, C<2>, C<3>, C<4>, C<5>ili C<6>ravnolančane (linearne) zasićene alifatične ugljovodonične grupe i C<3>, C<4>, C<5>ili C<6>razgranate zasićene alifatične ugljovodonične grupe. Na primer, C<1>-C<6>alkil namenjen je da uključuje C<1>, C<2>, C<3>, C<4>, C<5>i C<6>alkil grupe. Primeri alkila uključuju, delove koji imaju od jedan do šest atoma ugljenika, kao što su, ali ne ograničavajući se na, metil, etil, n-propil, i-propil, n-butil, s-butil, t-butil, n-pentil, spentil, ili n-heksil.
[0200] U određenim primerima izvođenja, ravnolančani ili razgranati alkil ima šest ili manje atoma ugljenika (npr., C<1>-C<6>za ravnolančani, C<3>-C<6>za razgranati lanac), a u drugom primeru izvođenja, ravnolančani ili razgranati alkil ima četiri ili manje atoma ugljenika.
[0202] Kako se ovde koristi, "alkil linker" namenjen je da uključuje C<1>, C<2>, C<3>, C<4>, C<5>, ili C<6>ravnolančane (linearne) zasićene alifatične ugljovodonične grupe i C<3>, C<4>, C<5>, ili C<6>razgranate zasićene alifatične ugljovodonične grupe. Na primer, C<1>-C<6>alkil linker namenjen je da uključuje C<1>, C<2>, C<3>, C<4>, C<5>, i C<6>alkil linker grupe. Primeri alkil linkera uključuje, delove koji imaju od jedan do šest atomaugljenika, kao što su, ali ne ograničavajući se na, metil (-CH<2>-), etil (-CH<2>CH<2>-), n-propil (-CH<2>CH<2>CH<2>-), i-propil (-CHCH<3>CH<2>-), n-butil (-CH<2>CH<2>CH<2>CH<2>-), s-butil (-CHCH<3>CH<2>CH<2>-), i-butil (-C(CH<3>)<2>CH<2>-), n-pentil (-CH<2>CH<2>CH<2>CH<2>CH<2>-), s-pentil (-CHCH<3>CH<2>CH<2>CH<2>-) ili n-heksil (-CH<2>CH<2>CH<2>CH<2>CH<2>CH<2>-). Izraz "supstituisan alkil linker" odnosi sena alkil linkere koji imaju supstituente koji zamenjuju jedan ili više atoma vodonika na jednom ili više atoma ugljenika ugljovodonične kičme. Takvi supstituenti ne menjaju sp3-hibridizaciju atoma ugljenika za koji su vezani i uključuju one navedene dole za "supstituisan alkil."
[0204] "Heteroalkil" grupe su alkil grupe, kao što je prethodno definisano, koje imaju atom kiseonika, azota, sumpora ili fosfora koji zamenjuje jedan ili više atoma ugljenika ugljovodonične kičme.
[0206] Kako se ovde koristi, izraz "cikloalkil", "C<3>, C<4>, C<5>, C<6>, C<7>ili C<8>cikloalkil" ili "C<3>-C<8>cikloalkil" namenjen je da uključuje ugljovodonične prstenove koji imaju od tri do osam atoma ugljenika u svojoj prstenastoj strukturi. U jednom primeru izvođenja, neka cikloalkil grupa ima pet ili šest atoma ugljenika u prstenastoj strukturi.
[0208] [0083] Izraz "supstituisan alkil" odnosi se na alkil ostatke koji imaju supstituente koji zamenjuju jedan ili više atoma vodonika na jednom ili više atoma ugljenika ugljovodonične kičme. Takvi supstituenti mogu da uključuju, na primer, alkil, alkenil, alkinil, halogen, hidroksil, alkilkarboniloksi, arilkarboniloksi, alkoksikarboniloksi, ariloksikarboniloksi, karboksilat, alkilkarbonil, arilkarbonil, alkoksikarbonil, aminokarbonil, alkilaminokarbonil, dialkilaminokarbonil, alkiltiokarbonil, alkoksil, fosfat, fosfonato, fosfinato, amino (uključujući alkilamino, dialkilamino, arilamino, diarilamino i alkilarilamino), acilamino (uključujući alkilkarbonilamino, arilkarbonilamino, karbamoil i ureido), amidino, imino, sulfhidril, alkiltio, ariltio, tiokarboksilat, sulfate, alkilsulfinil, sulfonato, sulfamoil, sulfonamido, nitro, trifluorometil, cijano, azido, heterociklil, alkilaril, ili aromatični ili heteroaromatični deo. Cikloalkili mogu da budu dalje supstituisani, npr., supstituentima prethodno opisanim. Neki "alkilaril" ili neki "aralkil" ostatak je neki alkil supstituisan nekim arilom (npr., fenilmetil(benzil)).
[0210] Osim ukoliko nije broj atoma ugljenika drugačije specificiran, "niži alkil" uključuje neku alkil grupu, kako je prethodno definisana, koja ima od jedan do šest, ili u drugom primeru izvođenja od jedan do četiri, atoma ugljenika u svojoj strukturi kičme. "Niži alkenil" i "niži alkinil" imaju dužine lanaca od, na primer, dva do šest ili od dva do četiri atoma ugljenika.
[0212] "Aril" uključuje grupe sa aromatičnošću, uključujući "konjugovane", ili višeciklične, sisteme sa najmanje jednim aromatičnim prstenom. Primeri uključuju fenil, benzil, naftil, itd. "Heteroaril" grupe su aril grupe, kao što su prethodno definisane, koje imaju od jedan do četiri heteroatoma u prstenastoj strukturi, i mogu takođe da se nazivaju "aril heterocikli" ili "heteroaromatične grupe". Kako se ovde koristi, pojam "heteroaril" namenjen je da uključuje stabilan 5-, 6-, ili 7-člani monociklični ili 7-, 8-, 9-, 10-, 11- ili 12-člani biciklični aromatični heterociklični prsten koji se sastoji od atoma ugljenika i jednog ili više heteroatoma, npr., 1 ili 1-2 ili 1-3 ili 1-4 ili 1-5 ili 1-6 heteroatoma, nezavisno odabrana iz grupe koju čine azot, kiseonik i sumpor. Atom azota može da bude supstituisan ili nesupstituisan (tj., N ili NR u kojoj R je H ili drugi supstituenti, kao što je definisano). Heteroatomi azota i sumpora mogu opciono da se oksiduju (tj., N→O i S(O)<p>, gde p=1 ili 2). Treba napomenuti da ukupan broj atoma S i O u heteroaril nije veći od 1.
[0214] Primeri heteroaril grupa uključuju pirol, furan, tiofen, tiazol, izotiazol, imidazol, triazol, tetrazol, pirazol, oksazol, izoksazol, piridin, pirazin, piridazin, pirimidin, i slično.
[0216] Kako se ovde koristi, "Ph" se odnosi na fenil, a "Py" se odnosi na piridinil.
[0218] Dalje, pojmovi "aril" i "heteroaril" uključuju multiciklične aril i heteroaril grupe, npr., triciklične, biciklične, npr., naftalen, benzoksazol, benzodioksazol, benzotiazol, benzoimidazol, benzotiofen, metilendioksifenil, kvinolin, izokvinolin, naftridin, indol, benzofuran, purin, benzofuran, deazapurin, ili indolizin.
[0219] U slučaju multicikličnih aromatičnih prstenova, samo jedan od prstenova treba da je aromatičan (npr., 2,3-dihidroindol), iako bi svi prstenovi mogli da budu aromatični (npr., kvinolin). Drugi prsten može takođe da bude fuzionisan ili premošćen.
[0221] Arilni ili heteroarilni aromatični prsten može da bude supstituisan na jednom ili više položaja u prstenu takvim supstituentima kao što su opisani gore, na primer, alkil, alkenil, akinil, halogen, hidroksil, alkoksi, alkilkarboniloksi, arilkarboniloksi, alkoksikarboniloksi, ariloksikarboniloksi, karboksilat, alkilkarbonil, alkilaminokarbonil, aralkilaminokarbonil, alkenilaminokarbonil, alkilkarbonil, arilkarbonil, aralkilkarbonil, alkenilkarbonil, alkoksikarbonil, aminokarbonil, alkiltiokarbonil, fosfat, fosfonato, fosfinato, amino (uključujući alkilamino, dialkilamino, arilamino, diarilamino, i alkilarilamino), acilamino (uključujući alkilkarbonilamino, arilkarbonilamino, karbamoil, i ureido), amidino, imino, sulfhidril, alkiltio, ariltio, tiokarboksilat, sulfati, alkilsulfinil, sulfonato, sulfamoil, sulfonamido, nitro, trifluorometil, cijano, azido, heterociklil, alkilaril, ili neka aromatična ili heteroaromatična grupa. Aril grupe takođe mogu da budu fuzionisane ili premošćene sa alicikličnim ili heterocikličnim prstenovima, koji nisu aromatični tako da se formira multiciklični sistem (npr., tetralin, metilendioksifenil).
[0223] Kako se ovde koristi, "karbocikl" ili "karbociklični prsten" namenjen je da uključuje bilo koji stabilan monociklični, biciklični ili triciklični prsten koji ima određeni broj atoma ugljenika, od kojih bilo koji može da bude zasićen, nezasićen, ili aromatičan. Na primer, neki C<3>-C<14>karbocikl namenjen je da uključuje monociklični, biciklični ili triciklični prsten koji ima 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 ili 14 atoma ugljenika. Primeri karbocikla uključuju, ali nisu ograničeni na, ciklopropil, ciklobutil, ciklobutenil, ciklopentil, ciklopentenil, cikloheksil, cikloheptenil, cikloheptil, cikloheptenil, adamantil, ciklooktil, ciklooktenil, ciklooktadienil, fluorenil, fenil, naftil, indanil, adamantil, i tetrahidronaftil. Premošćeni prstenovi takođe su uključeni u definiciju karbocikla, uključujući, na primer, [3.3.0]biciklooktan,
[0224] [4.3.0]biciklononan, [4.4.0]biciklodekan i [2.2.2]biciklooktan. Premošćen prsten dobija se kada jedan ili više atoma ugljenika povezuju dva nesusedna atoma ugljenika. U jednom primeru izvođenja, premošćeni prstenovi su jedan ili dva atoma ugljenika. Treba napomenuti da most uvek konvertuje monociklični prsten u triciklični prsten. Kada je prsten premošćen, supstituenti navedeni za prsten mogu takođe da budu prisutni na mostu. Fuzionisani (npr., naftil, tetrahidronaftil) i spiro prstenovi takođe su uključeni.
[0226] [0092] Kako se ovde koristi, "heterocikl" uključuje bilo koju prstenastu strukturu (zasićenu ili delimično nezasićenu) koja sadrži najmanje jedan heteroatom u prstenu (npr., N, O ili S). Primeri heterocikla uključuju, ali nisu ograničeni na, morfolin, pirolidin, tetrahidrotiofen, piperidin, piperazin, i tetrahidrofuran.
[0228] Primeri heterocikličnih grupa uključuju, ali nisu ograničeni na, akridinil, azocinil, benzimidazolil, benzofuranil, benzotiofuranil, benzotiofenil, benzoksazolil, benzoksazolinil, benztiazolil, benztriazolil, benztetrazolil, benzizoksazolil, benzizotiazolil, benzimidazolinil, karbazolil, 4aH-karbazolil, karbolinil, hromanil, hromenil, cinolinil, dekahidrokvinolinil, 2H,6H-1,5,2-ditiazinil, dihidrofuro[2,3-b]tetrahidrofuran, furanil, furazanil, imidazolidinil, imidazolinil, imidazolil, 1H-indazolil, indolenil, indolinil, indolizinil, indolil, 3H-indolil, izatinoil, izobenzofuranil, izohromanil, izoindazolil, izoindolinil, izoindolil, izokvinolinil, izotiazolil, izoksazolil, metilendioksifenil, morfolinil, naftiridinil, oktahidroizokvinolinil, oksadiazolil, 1,2,3-oksadiazolil, 1,2,4-oksadiazolil, 1,2,5-oksadiazolil, 1,3,4-oksadiazolil, 1,2,4-oksadiazol5(4H)-on, oksazolidinil, oksazolil, oksindolil, pirimidinil, fenantridinil, fenantrolinil, fenazinil, fenotiazinil, fenoksatinil, fenoksazinil, ftalazinil, piperazinil, piperidinil, piperidonil, 4-piperidonil, piperonil, pteridinil, purinil, piranil, pirazinil, pirazolidinil, pirazolinil, pirazolil, piridazinil, piridooksazol, piridoimidazol, piridotiazol, piridinil, piridil, pirimidinil, pirolidinil, pirolinil, 2H-pirolil, pirolil, kvinazolinil, kvinolinil, 4H-kvinolizinil, kvinoksalinil, kvinuklidinil, tetrahidrofuranil, tetrahidroizokvinolinil, tetrahidrokvinolinil, tetrazolil, 6H-1,2,5-tiadiazinil, 1,2,3-tiadiazolil, 1,2,4-tiadiazolil, 1,2,5-tiadiazolil, 1,3,4-tiadiazolil, tiantrenil, tiazolil, tienil, tienotiazolil, tienooksazolil, tienoimidazolil, tiofenil, triazinil, 1,2,3-triazolil, 1,2,4-triazolil, 1,2,5-triazolil, 1,3,4-triazolil, i ksantenil.
[0230] Pojam "supstituisan", kako se ovde koristi, znači da je bilo koji ili više atoma vodonika na naznačenom atomu zamenjeno sa izborom od naznačenih grupa, pri čemu je obezbeđeno da normalna valentnost naznačenog atoma nije premašena, i da supstitucija rezultuje stabilnim jedinjenjem. Kada supstituent predstavlja keto (tj., =O), onda su 2 atoma vodonika na atomu zamenjena. Keto supstituenti nisu prisutni na aromatičnim grupama. Dvostruke veze u prstenovima, kako se ovde koriste, su dvostruke veze koje su formirane između dva susedna atoma u prstenu (npr., C=C, C=N ili N=N).
[0231] "Stabilno jedinjenje" i "stabilna struktura" treba da označavaju jedinjenje koje je prilično robusno tako da može da preživi izolovanje do korisnog stepena čistoće iz reakcione mešavine, i formulisanje u efikasni terapeutski agens.
[0233] [0095] Pojam "acil", kako se ovde koristi, uključuje grupe koje sadrže acil radikal (--C(O)--) ili karbonil grupu. "Supstituisan acil" uključuje acil grupe gde je jedan ili više atoma vodonika zamenjeno sa, na primer, alkil grupama, alkinil grupama, halogenom, hidroksilom, alkilkarboniloksi, arilkarboniloksi, alkoksikarboniloksi, ariloksikarboniloksi, karboksilatom, alkilkarbonilom, arilkarbonilom, alkoksikarbonilom, aminokarbonilom, alkilaminokarbonilom, dialkilaminokarbonilom, alkiltiokarbonilom, alkoksil, fosfatom, fosfonato, fosfinato, amino (uključujući alkilamino, dialkilamino, arilamino, diarilamino i alkilarilamino), acilamino (uključujući alkilkarbonilamino, arilkarbonilamino, karbamoil i ureido), amidino, imino, sulfhidrilom, alkiltio, ariltio, tiokarboksilatom, sulfatima, alkilsulfinilom, sulfonato, sulfamoilom, sulfonamido, nitro, trifluorometilom, cijano, azido, heterociklilom, alkilarilom, ili nekom aromatičnom ili heteroaromatičnom grupom.
[0235] Opis ovog pronalaska ovde treba da se tumači u skladu sa zakonima i principima hemijskog vezivanja. Na primer, može da bude potrebno da se ukloni atom vodonika da bi se smestio neki supstituent u bilo koji dati položaj. Dalje, podrazumeva se da definicije varijabli (tj., "R grupe"), kao i položaja veze generičke formule ovog pronalaska, biće u skladu sa zakonima hemijskog vezivanja poznati u ovoj oblasti. Takođe se podrazumeva da će sva jedinjenja ovog pronalaska opisana gore dalje uključivati veze između susednih atoma i/ili atoma vodonika kao što je potrebno da bi se zadovoljila valenca svakog atoma. To jest, veze i/ili atomi vodonika dodaju se da bi se obezbedio sledeći broj ukupnih veza to za svaki od sledećih tipova atoma: ugljenik: četiri veze; azot: tri veze; kiseonik: dve veze; i sumpor: dve-šest veza.
[0237] Kako se ovde koristi, "subjekt kom je to potrebno" je subjekt koji ima neurološku bolest. U jednom primeru izvođenja, subjekt kom je to potrebno ima multipla sklerozu. "Subjekt" uključuje sisara. Sisar može da bude npr., bilo koji sisar, npr., čovek, primat, ptica, miš, pacov, živina, pas, mačka, krava, konj, koza, kamila, ovca ili svinja. U jednom primeru izvođenja, sisar je čovek.
[0239] Ovaj pronalazak obezbeđuje postupke za sintezu jedinjenja formule opisane ovde. Ovaj pronalazak takođe obezbeđuje detaljne postupke za sintezu raznih opisanih jedinjenja ovog pronalaska prema šemama koje slede i kao što je prikazano u Primerima.
[0241] U ovom opisu, gde su kombinacije opisane kao koje imaju, koje uključuju, ili koje obuhvataju specifične komponente, podrazumeva se da se kombinacije takođe sastoje suštinski od, ili sastoje od, navedenih komponenata. Slično, gde su postupci ili procesi opisani kao koji imaju, koji uključuju, ili koji obuhvataju specifične faze postupka, postupci se takođe sastoje suštinski od, ili sastoje se od, navedenih faza postupka. Dalje, podrazumeva se da redosled faza ili redosled izvođenja određenih akcija nije značajan sve dok ovaj pronalazak ostaje operabilan. Štaviše, dve ili više faza ili akcija može da se izvodi istovremeno.
[0243] [0100] Postupci sinteze ovog pronalaska mogu da tolerišu širok spektar funkcionalnih grupa; prema tome, razni supstituisani polazni materijali mogu da se koriste. Uopšteno postupci obezbeđuju željeno krajnje jedinjenje na ili blizu kraja sveukupnog postupka, iako može biti poželjno u određenim slučajevima da se dalje konvertuje jedinjenje do njegove farmaceutski prihvatljive soli, polimorfa, hidrata, solvata ili kokristala.
[0245] Jedinjenja ovog pronalaska može da se pripremi na različite načine upotrebom komercijalno dostupnih polaznih materijala, jedinjenja poznatih u literaturi, ili od lako pripremljenih intermedijera, korišćenjem standardnih postupaka i procedura sinteze koji su poznati prosečnim stručnjacima u ovoj oblasti, ili koji će biti očigledni obučenom stručnjaku u svetlu učenja ovde. Standardni postupci i procedure sinteze za pripremu organskih molekula i transformacije i manipulacije funkcionalnim grupama, mogu da se dobiju iz relevantne naučne literature ili iz standardnih priručnika u ovoj oblasti. Iako ne ograničavajući se na bilo koji jedan ili više izvora, klasični tekstovi kao što su Smith, M. B., March, J., March's Advanced Organic Chemistry Reactions, Mechanisms, i Structure, 5th edition, John Wiley & Sons: New York, 2001; i Greene, T. W., Wuts, P. G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999, su korisni i prepoznati referentni priručnici organskih sinteza poznati stručnjacima u ovoj oblasti. Sledeći opisi postupaka sinteze dati su da ilustruju, a ne da ograniče, opšte procedure za pripremu jedinjenja ovog pronalaska.
[0247] Jedinjenja ovog pronalaska mogu da se konvencionalno pripreme raznim postupcima poznatim prosečnim stručnjacima u ovoj oblasti. Jedinjenja ovog pronalaska formule opisane ovde mogu da se pripreme prema sledećim procedurama od komercijalno dostupnih polaznih materijala ili polaznih materijala koji mogu da se pripreme upotrebom procedura iz literature. Ove procedure pokazuju pripremu reprezentativnih jedinjenja ovog pronalaska.
[0249] EKSPERIMENTI
[0250] Opšta procedura 1
[0251] Mešavini monometil fumarata (MMF) (1,0 ekvivalent) i HBTU (1,5 ekvivalenata) u DMF (25 ml po g MMF) dodata je Hünig-ova baza (2,0 ekvivalenata). Tamno smeći rastvor mešan je tokom 10 minuta, pri čemu se promenio u smeđu suspenziju, pre dodavanja alkohola (1,0 – 1,5 ekvivalenata). Reakcija je mešana tokom 18 sati na sobnoj temperaturi. Dodata je voda i proizvod je ekstrahovan u etil acetat tri puta. Kombinovani organski slojevi isprani su vodom tri puta, osušeni magnezijum sulfatom, filtrirani i koncentrovani u vakuumu na 45 °C da bi se dobio sirovi proizvod. Sirovi proizvod prečišćen je hromatografijom sa silicijumdioksidom i u nekim slučajevima dalje prečišćen trituracijom sa dietil etrom da bi se dobio čist željeni estarski proizvod. Svi alkoholi su ili komercijalno dostupni ili izrađeni prema poznatim procedurama u literaturi.
[0252] Kao alternativa HBTU (N,N,N',N'-Tetrametil-O-(1H-benzotriazol-1-il)uronijum heksafluorofosfatu), bilo koji od sledećih reagenasa za vezivanje može da se koristi: EDCI/HOBt (N-(3-dimetilaminopropil)-N'-etilkarbodiimid hidrohlorid/hidroksibenzotriazol hidrat); COMU ((1-cijano-2-etoksi-2-oksoetilidenaminooksi)dimetilamino-morfolino-karbenijum heksafluorofosfat); TBTU (O-(benzotriazol-1-il)-N,N,N',N'-tetrametiluronijum tetrafluoroborat); TATU (O-(7-azabenzotriazol-1-il)-1,1,3,3-tetrametiluronijum tetrafluoroborat); Oxyma (etil (hidroksiimino)cijanoacetat); PyBOP ((benzotriazol-1-iloksi) tripirolidinofosfonijum heksafluorofosfat); HOTT (S-(1-oksido-2-piridil)-N,N,N',N'-tetrametiltiuronijum heksafluorofosfat); FDPP (pentafluorofenil difenilfosfinat); T3P (anhidrid propilfosforaste kiseline); DMTMM (4-(4,6-dimetoksi-1,3,5-triazin-2-il)-4-metilmorfolinijum tetrafluoroborat); PyOxim ([etil cijano(hidroksiimino)acetato-O<2>]tri-1-pirolidinilfosfonijum heksafluorofosfat); TSTU (N,N,N',N'-tetrametil-O-(N-sukcinimidil)uronijum tetrafluoroborat); TDBTU (O-(3,4-dihidro-4-okso-1,2,3-benzotriazin-3-il)-N,N,N',N'-tetrametiluronijum tetrafluoroborat); TPTU (O-(2-okso-1(2H)piridil)-N,N,N',N'-tetrametiluronijum tetrafluoroborat); TOTU (O-[(etoksikarbonil)cijanometilenamino]-N,N,N',N'-tetrametiluronijum tetrafluoroborat); IIDQ (izobutil 1,2-dihidro-2-izobutoksi-1-kvinolinkarboksilat); ili PyCIU (hlorodipirolidinokarbenijum heksafluorofosfat),
[0254] Kao alternativa Hünig-ovoj bazi (diizopropiletilamin), bilo koja od sledećih aminskih baza može da se koristi: trietilamin; tributilamin; trifenilamin; piridin; lutidin (2,6-dimetilpiridin); kolidin (2,4,6-trimetilpiridin); imidazol; DMAP (4-(dimetilamino)piridin); DABCO (1,4-diazabiciklo[2.2.2]oktan); DBU (1,8-diazabiciklo[5.4.0] undek-7-en); DBN (1,5-diazabiciklo[4.3.0]non-5-en); ili proton sponge® (N,N,N',N'-tetrametil-1,8-naftalendiamin).
[0256] Opšta procedura 2- Konverzija estarskog proizvoda u hidrohloridnu so
[0257] Mešavini estarskog proizvoda u dietil etru (25 ml po g) dodata je 2M HCl u dietil etru (1,5 ekvivalenata). Mešavina je mešana na sobnoj temperaturi tokom dva sata. Rastvarač je dekantovan, dodato je još dietil etra i rastvarač je dekantovan ponovo. Zaostala mešavina je zatim koncentrovana u vakuumu na 45 °C i dalje osušena u vakuumskoj peći na 55 °C tokom 18 sati da bi se dobila čvrsta HCl so.
[0259] Opšta procedura 3
[0260] [0107] U bocu od 100 mL sa jednim grlom i okruglim dnom snabdevenom magnetnom mešalicom i ulazom/izlazom azota, dodato je 11 mL MTBE rastvora koji sadrži sveže pripremljen monometil fumaril hlorid (4,9 g, 33 mmol) i 50 mL dodatnog MTBE na 20 °C. Dobijeni žuti rastvor ohlađen je do <20 °C ledenim vodenim kupatilom. Zatim, alkohol, (33 mmol, 1 eq) je dodavan u kapima, špricem, tokom oko 10 minuta. Reakciona mešavina ostavljena je da se meša na <20 °C tokom 10 minuta, a nakon tog vremena uklonjeno je kupatilo za hlađenje i reakcija je ostavljena da se zagreje do 20 °C i meša na temperaturi od 20 °C tokom 16 sati. Da je reakcija gotova određeno je pomoću TLC nakon 16 sati na ST. Reakciona mešavina je filtrirana kroz srednji stakleni fritovani levak da bi se prikupile prljavo bele čvrste supstance. Čvrste supstance osušene su u vakuumskoj peći na 25 °C tokom noći da bi se dobio krajnji proizvod kao neka HCI so. Svi alkoholi bili su ili komercijalno dostupni ili izrađeni prema poznatim procedurama u literaturi.
[0262] Opšta procedura 4- Alkilovanje sa odgovarajućim alkil mezilatom
[0263] Mešavina monometil fumarata (MMF) (1,3 ekvivalent), alkil mezilata (1 ekvivalent), i kalijum karbonata (1,5 ekvivalent) u acetonitrilu (50 ml po g MMF) zagrevana je u refluksu tokom noći.
[0264] Mešavina je podeljena između etil acetata i zasićenog vodenog natrijum hidrogen karbonata, i organska faza je osušena (MgSO<4>). Filtracija i uklanjanje rastvarača pod sniženim pritiskom dalo je sirovi proizvod koji je prečišćen u svakom slučaju hromatografijom sa silicijumdioksidom.
[0266] Opšta procedura 5- Alkilovanje sa odgovarajućim alkil hloridom
[0267] Mešavina monometil fumarata (MMF) (1,3 ekvivalent), alkil hlorida (1 ekvivalent), i kalijum karbonata (1,5 ekvivalent) z acetonitrilu ili dimetilformamidu (50 ml po g MMF) zagrevana je na 20 do 65 °C tokom noći. Mešavina je podeljena između etil acetata i zasićenog vodenog natrijum hidrogen karbonata, i organska faza je osušena (MgSO<4>). Filtracija i uklanjanje rastvarača pod sniženim pritiskom dalo je sirovi proizvod koji je dalje prečišćen hromatografijom sa silicijumdioksidom.
[0269] Hemijska analiza/procedure
[0270] NMR spektri opisani ovde dobijeni su sa Varian 400 MHz NMR spektrometrom upotrebom standardnih tehnika poznatih u ovoj oblasti.
[0272] Primeri
[0273] 2-(4,4-difluoropiperidin-1-il)etil metil fumarat hidrohlorid (5)
[0274]
[0276]
[0279] 2-(4,4-difluoropiperidin-1-il)etil metil fumarat 5 sintetizovan je prema opštoj proceduri 1 i konvertovan je u HCI so: 2-(4,4-difluoropiperidin-1-il)etil metil fumarat hidrohlorid (procedura 2) (780 mg, 87 %).
[0280] <1>H NMR (300 MHz, DMSO): δ 11,25 (1H, bs); 6,84 (2H, dd, J = 16,1 Hz); 4,50 (2H, bs); 3,35-4,00 (8H, m); 3,05-3,30 (2H, m); 2,20-2,45 (3H, s). [M+H]<+>= 278,16.
[0282] 2-(2,5-dioksopirolidin-1-il)etil metil fumarat (14)
[0283]
[0285]
[0288] 2-(2,5-dioksopirolidin-1-il)etil metil fumarat 14 sintetizovan je prema opštoj proceduri 1 (1,03 g, 35 %).
[0290] <1>H NMR (400 MHz, DMSO): δ 6,81 (2H, dd, J = 15,8 Hz); 4,36 (2H, t, J = 5,3 Hz); 3,84 (2H, t, J = 5,1 Hz); 3,80 (3H, s); 2,73 (4H, s). [M+H]<+>= 256,07.
[0292] Metil (2-(piperidin-1-il)etil) fumarat hidrohlorid (15)
[0293]
[0295]
[0298] Metil (2-(piperidin-1-il)etil) fumarat hidrohlorid 15 sintetizovan je prema opštoj proceduri 3.
[0299] <1>H NMR (400 MHz, DMSO-d6) δ 10,76 (s, 1H), 6,94 – 6,77 (m, 2H), 4,58 – 4,51 (m, 2H), 3,76 (s, 3H), 3,48 – 3,36 (m, 4H), 2,94 (dddd, J = 15,9, 12,1, 9,2, 4,4 Hz, 2H), 1,91 – 1,64 (m, 5H), 1,37 (dtt, J = 16,4, 11,3, 4,9 Hz, 1H). [M+H]<+>= 241,93.
[0301] 2-(1,4-dioksa-8-azaspiro[4.5]dekan-8-il)etil metil fumarat hidrohlorid (17)
[0303]
[0306] 2-(1,4-dioksa-8-azaspiro[4.5]dekan-8-il)etil metil fumarat hidrohlorid 17 sintetizovan je prema opštoj proceduri 3.
[0308] <1>H NMR (400 MHz, DMSO-d6) δ 11,26 (s, 1H), 6,91 (d, J = 15,9 Hz, 1H), 6,82 (d, J = 15,9 Hz, 1H), 4,58 – 4,51 (m, 2H), 3,93 (s, 4H), 3,76 (s, 3H), 3,57 – 3,43 (m, 4H), 3,22 – 3,03 (m, 2H), 2,20 – 2,02 (m, 2H), 1,89 – 1,79 (m, 2H). [M+H]<+>= 300,00.
[0309] Metil (2-(pirolidin-1-il)etil) fumarat hidrohlorid (18)
[0310]
[0312]
[0315] Metil (2-(pirolidin-1-il)etil) fumarat hidrohlorid 18 sintetizovan je prema opštoj proceduri 3.
[0316] <1>H NMR (400 MHz, DMSO-d6) δ 11,12 (s, 1H), 6,94 (d, J = 15,8 Hz, 1H), 6,82 (d, J = 15,8 Hz, 1H), 4,53 – 4,46 (m, 2H), 3,76 (s, 3H), 3,61 – 3,45 (m, 4H), 3,11 – 2,94 (m, 2H), 2,06 – 1,79 (m, 4H). [M+H]<+>= 228,46.
[0318] 2-(3,3-difluoropirolidin-1-il)etil metil fumarat hidrohlorid (21)
[0319]
[0321]
[0324] 2-(3,3-Difluoropirolidin-1-il)etil metil fumarat 21 sintetizovan je iz 2-(3,3-difluoropirolidin-1-il)etanola prema opštoj proceduri 1.
[0326] 2-(3,3-difluoropirolidin-1-il)etil metil fumarat konvertovan je u 2-(3,3-difluoropirolidin-1-il)etil metil fumarat hidrohlorid prema opštoj proceduri 2 (0,55 g, 69 %).
[0328] <1>H NMR (300 MHz, DMSO); δ 6,79 (2H, d); 4,20-4,39 (2H, m), 3,81 (2H, t), 3,66 (3H, s), 3,53-3,65 (4H, m), 2,54 (2H, sep). m/z [M+H]<+>= 264,14.
[0330] 2-(2,4-Diokso-3-azabiciklo[3.1.0]heksan-3-il)etil metil fumarat (22)
[0331]
[0333]
[0336] 3-oksabiciklo[3.1.0]heksan-2,4-dion (1,0 g, 8,9 mmol) i etanolamin (545 mg, 8,9 mmol) bili su zagrevani pažljivo na 200 °C tokom 2 sata. Sirova reakciona mešavina prečišćena je hromatografijom sa silicijumdioksidom (EtOAc) dajući 3-(2-Hidroksietil)-3-azabiciklo[3.1.0]heksan-2,4-dion (1,06 g, 77%).
[0337] <1>H NMR (300 MHz, CDCl<3>): δ 3,71 (2H, t), 3,56 (2H, t), 2,51 (2H, dd), 1,95 (1H, br s), 1,59-1,43 (2H, m).
[0339]
[0340] 2-(2,4-diokso-3-azabiciklo[3.1.0]heksan-3-il)etil metil fumarat 22 sintetizovan je iz 3-(2-Hidroksietil)-3-azabiciklo[3.1.0]heksan-2,4-diona prema opštoj proceduri 1 (452 mg, 53 %).
[0341] <1>H NMR (300 MHz, CDCl<3>): δ 6,81 (2H, d), 4,28 (2H, t), 3,80 (3H, s), 3,69 (2H, t), 2,48 (2H, dd), 1,59-1,49 (1H, m), 1,44-1,38 (1H, m). m/z [M+H]<+>= 268,11.
[0343]
[0346] 2-(2,2-Dimetil-5-oksopirolidin-1-il)etil metil fumarat 24 sintetizovan je iz 1-(2-hloroetil)-5,5-dimetilpirolidin-2-ona prema opštoj proceduri 5 (1,02 g, 41 %).
[0347] <1>H NMR (300 MHz, CDCl<3>); 6,85 (2H, d), 4,33 (2H, t), 3,80 (3H, s), 3,41 (2H, t), 2,39 (2H, t), 1,88 (2H, t), 1,23 (6H, s). m/z [M+H]<+>= 270,17.
[0349] 2-(1,3-Dioksoizoindolin-2-il)etil metil fumarat (36)
[0350]
[0352]
[0354] 2-(1,3-Dioksoizoindolin-2-il)etil metil fumarat 36 sintetizovan je iz 2-(2-hidroksietil)izoindolin-1,3-diona prema opštoj proceduri 1 (0,63 g, 79%).
[0355] <1>H NMR (300 MHz, MeOD); 7,87-7,77 (4H, m), 6,74-6,73 (2H, m), 4,45-4,40 (2H, m), 4,01-3,96 (2H, m), 3,76 (3H, s). m/z [M+H]<+>= 304,1
[0357] 2-(3,3-Dimetil-2,5-dioksopirolidin-1-il)etil metil fumarat (36)
[0358]
[0360]
[0363] 2-(3,3-Dimetil-2,5-dioksopirolidin-1-il)etil metil fumarat 36 sintetizovan je iz 1-(2-hidroksietil)-3,3-dimetilpirolidin-2,5-diona prema opštoj proceduri 1 (0,72 g, 74%).
[0364] <1>H NMR (300 MHz, CDCl<3>); 6,83 (1H, d), 6,77 (1H, d), 4,38 (2H, t), 3,82 (1H, t), 3,80 (3H, s), 2,55 (2H, s), 1,31 (6H, s). m/z [M+H]<+>= 284,1
[0365] Metil (2-(2-oksopirolidin-1-il)etil) fumarat (38)
[0367]
[0370] Metil (2-(2-oksopirolidin-1-il)etil) fumarat 38 sintetizovan je iz 1-(2-hidroksietil)pirolidin-2-ona prema opštoj proceduri 1 (0,68 g, 73%).
[0372] <1>H NMR (300 MHz, MeOD); 6,85 (2H, s), 4,33 (2H, t), 3,80 (3H, s), 3,59 (2H, t), 3,46 (2H, t), 2,37 (2H, t), 2,03 (2H, dt). [M+H]<+>= 242,1
[0374] 2-((3R,4S)-3,4-Dimetil-2,5-dioksopirolidin-1-il)etil metil fumarat (23)
[0376]
[0379] Racemski 2-((3R,4S)-3,4-dimetil-2,5-dioksopirolidin-1-il)etil metil fumarat 23 sintetizovan je iz racemskog (3R,4S)-1-(2-hidroksietil)-3,4-dimetilpirolidin-2,5-diona prema opštoj proceduri 1 (0,54 g, 44%).
[0381] <1>H NMR (300 MHz, CDCl<3>); 6,81-6,80 (2H, m), 4,37 (2H, t), 3,82 (2H, t), 3,80 (3H, s), 3,00-2,88 (2H, m), 1,25-1,18 (6H, m). m/z [M+H]<+>= 284,2
[0383] Referentno jedinjenje A
[0384] 2-(dietilamino)-2-oksoetil metil fumarat
[0385]
[0387]
[0390] 2-(dietilamino)-2-oksoetil metil fumarat sintetizovan je prema opštoj proceduri 3 i u skladu sa prijavljenim podacima u US Patentu br.8,148,414.
[0392] Primer 2- Hemijska stabilnost nekoliko jedinjenja u vodenom rastvoru
[0393] Štok rastvori jedinjenja u acetonitrilu ili acetonitrilu/metanolu pripremljeni su sa 20 mg/mL i 20 µL, spajkovani u 3mL puferskog fosfata (100mM) i inkubirani na 37 °C. Alikvoti (50 µL) su uzorkovani u različitim vremenskim tačkama i razblaženi 20 puta sa amonijum formatom (pH 3,5)/acetonitrilom. Razblaženi uzorci analizirani su pomoću HPLC. Oblasti pika koje odgovaraju jedinjenjima plotirane su sa vremenom i podaci su podešeni u mono-eksponencijalni pad prvog reda gde su određeni konstanta brzine i poluživot (Tabela 3). U nekim slučajevima, u kojima je poluživot suviše dug (>360min), procenjena vrednost poluživota je prijavljena upotrebom početnog nagiba pri niskoj konverziji (<10%). Tabela 3.
[0395]
[0397] Štok rastvori jedinjenja u acetonitrilu ili acetonitrilu/MeOH pripremljeni su pri 0,05M.0,010 mL alikvota štoka spajkovano je u 1 mL 50 mM puferskog fosfata pH 8 i inkubirano na 37 °C. Obično, alikvoti (0,010 mL) su uzorkovani u različitim vremenskim tačkama i odmah injektirani u HPLC sa UV detekcijom (211nm). Oblasti pika koje odgovaraju jedinjenjima plotirane su sa vremenom i podaci su podešeni u mono-eksponencijalni pad prvog reda gde su određeni konstanta brzine i poluživot iz nagiba (Tabela 4). Tabela 4.
[0399]
[0402] Primer 3- Evaluacija hemijske stabilnosti u vodenom rastvoru sa NMR
[0403] Hemijska hidroliza praćena je rastvaranjem estra u fosfat puferovanom D<2>O (pH 7,9) u NMR epruveti, zagrevanjem NMR epruvete do 37° C i periodičnim beleženjem spektara. Ove razne vrste proizvedene hidrolizom diestara praćene su tokom vremena. Videti Fig.1-5.
[0405] Primer 4- Dostava MMF u pacove usled oralnog davanja prolekova
[0406] Pacovi su nabavljeni komercijalno i prethodno su kanulirani u vratnu venu. Životinje su svesne u vreme eksperimenta. Sve životinje izgladnjivane su tokom noći i do 4 sata nakon doziranja proleka u opisu.
[0408] Uzorci krvi (0,25 mL/uzorak) prikupljeni su iz svih životinja u različitim vremenskim tačkama sve do 24 sata nakon doze u epruvete koje sadrže natrijum fluorid/natrijum EDTA. Uzorci su centrifugirani da bi se dobila plazma. Uzorci plazme preneti su u čiste epruvete i čuvani na ili ispod -70° C pre analize.
[0410] Da bi se pripremili standardi za analizu, 20 uL standarda pacovske plazme ugašen sa 60 uL internim standardom. Epruvete sa uzorkom vorteksovane su za najmanje 1 min i zatim centrifugirane sa 3000 o/min tokom 10 min.50 uL supernatanta zatim je preneto na ploče sa 96 bazenčića koje sadrže 100 µL vode za analizu pomoću LC-MS-MS.
[0412] LC-MS/MS analiza je izvedena upotrebom API 4000 opremljenog sa HPLC i autosampler. Sledeći uslovi u HPLC koloni su korišćeni: HPLC kolona: Waters Atlantis T3; brzina protoka 0,5 mL/min; radno vreme 5 min; mobilna faza A: 0,1% mravlje kiseline u vodi; mobilna faza B: 0,1% mravlje kiseline u acetonitrilu (ACN); gradijent: 98% A/2% B u 0,0 min; 98% A/2% B u 1 min; 5% A/95% B u 3 min; 5% A/95% B u 3,75 min; 97% A/3% B u 4 min; i 98% A/2% B u 5,0 min. MMF je praćen u pozitivnom jonskom režimu.
[0414] MMF, DMF ili MMF prolek dat je oralnom gavažom grupama od dva do šest odrasla mužjaka Sprague-Dawley pacova (oko 250 g). Životinje su svesne u vreme eksperimenta. MMF, DMF ili MMF prolek dat je oralno u vodenom rastvoru 0,5% hidroksipropil metil celuloze (HPMC), 0,02% polisorbata 80, i 20 mM citratnog pufera (pH 5), u dozi od 10 mg-ekvivalenata MMF po kg telesne mase.
[0416] Procentna apsolutna bioraspoloživost (F%) MMF određena je poređenjem oblasti ispod krive MMF koncentracija vs vreme (AUC) nakon oralnog davanja MMF, DMF ili MMF proleka sa AUC krive MMF koncentracija vs vreme nakon intravenoznog davanja MMF na normalizovanoj osnovi doze.
[0418] [0147] MMF prolekovi, kada su dati oralno pacovima u dozi od 10 mg/kg MMF-ekvivalenata u vodenom nosaču, pokazali su apsolutnu oralnu bioraspoloživost (u odnosu na IV) koja je u opsegu od oko 3% do oko 96% (Videti Tabele 5 i 6). Tabele 5 i 6 prikazuju podatke iz dve nezavisne studije.
[0419] Tabela 5.
[0421]
[0424] Primer 5- Dostavljanje MMF kod pasa usled oralnog davanja prolekova
[0425] Mužjaci pasa vrste bigl nabavljeni su iz kolonija ne-domaćih životinja za testiranje. Sve životinje su izgladnjivane tokom noći pre davanja doze.
[0427] Oralne doze date su oralnom gavažom. Epruveta za gavažu isprana je sa 10 mL vode pre uklanjanja.
[0429] Sve životinje su posmatrane prilikom doziranja i pri svakom planiranom prikupljanju. Sve abnormalnosti su zabeležene.
[0431] Uzorci krvi su prikupljeni u epruvetama sa natrijum fluoridom/Na<2>EDTA i čuvani na mokrom ledu do obrade do plazme centrifugiranjem (300 o/min na 5oC) u okviru 30 minuta od prikupljanja. Svi uzorci plazme su preneti u odvojene ploče sa 96 bazenčića (epruvete matrice) i čuvani na - 80 °C do analize koncentracije koja je izvedena pomoću LC/MS/MS upotrebom RGA 3 ogleda.
[0433] Procedura ekstrakcije:
[0434] Napomena: Istopljeni testirani uzorci na 4°C. (čuvani u ledu dok je na klupi).
[0435] 1. Alikvotirano 20uL ispitivanog uzorka, standardno, i QC uzorci u obeleženoj ploči sa 96 bazenčića.
[0436] 2. Dodato je 120uL odgovarajućeg internog standardnog rastovra (125ng/mL mišjeg embrio fibroblasta (MEF)) u svaku epruvetu, osim za dvostruko lažni kom jedodato 120uL odgovarajućeg acetonitrila:FA (100:1).
[0437] 3. Zatvoreni su i vorteksovani za jedan minut.
[0438] 4. Centrifugirani pri 3000 o/min tokom 10 minuta.
[0439] 5. Prenetio je 100uL supernatanta na čistu ploču sa 96 bazenčića koja sadrži 100uL vode.
[0440] 6. Zatvoreni su i vorteksovani blago za 2 minuta.
[0442] Procentna apsolutna bioraspoloživost (F%) MMF određena je poređenjem oblasti ispod krive MMF koncentracija vs vreme (AUC) nakon oralnog davanja MMF proleka sa AUC krive MMF koncentracija vs vreme nakon intravenoznog davanja MMF na normalizovanoj osnovi doze.
[0444] MMF prolekovi, kada su dati oralno psima u dozi od 10 mg/kg MMF-ekvivalenata u vodenom nosaču, pokazali su apsolutnu oralnu bioraspoloživost (u odnosu na IV) koja je u opsegu od oko 31% do oko 78% (Videti Tabelu 7).
[0445] Tabela 7
[0447]
[0450] Primer 6- Fizička stabilnost trenutnih prolekova i DMF u kristalnom obliku
[0451] Fizička stabilnost jedinjenja ovog pronalaska i DMF izmerena je termogravimetrijskom analizom (TGA). Fig.6 prikazuje grafikon gubitka mase na 60 °C vs vreme za jedinjenje 14 (12,15 mg), nema promene, i DMF (18,40 mg), ∼100 % gubitka mase za manje od 4 sata. Ovi podaci ukazuju da DMF podleže sublimaciji dok je jedinjenje 14 fizički stabilno u sličnim uslovima.
[0453] Primer 7- Podaci za X-zrake na monokristalu za jedinjenje 14
[0454] Jedinjenje 14 proizvedeno pomoću postupka opisanog u Primeru 1 ispitivano je. Fig.7 prikazuje jedinične ćelije. Podaci za X-zrake na monokristalu uključeni su dole:
[0455] Podaci o monokristalu:
[0456] Empirijska formula: C11 H13 N O6
[0457] Masa formule: 255,22
[0458] Temperatura: 173(2) K
[0459] Talasna dužina: 1.54178 Å
[0460] Razmak grupa: P-1
[0461] Dimenzije jedinične ćelije:
[0462] a = 6,07750(10) Å α= 84,9390(10)°.
[0463] b = 7,96290(10) Å β= 80,0440(10)°.
[0464] c = 12,7850(2) Å γ = 71,9690(10)°.
[0465] Zapremina: 579,080(15) Å<3>
[0466] Z: 2
[0467] Gustina (izračunata): 1,464 Mg/m<3>
[0468] Apsorpcija coefficient: 1,034 mm<-1>
[0469] F(000): 268
[0470] Veličina kristala: 0,37 x 0,15 x 0,15 mm<3>
[0471] Prikupljene refleksije: 8446
[0472] Nezavisne refleksije: 2229 [R(int) = 0,0249]
[0473] Postupak prečišćavanja: Najmanji kvadrati pune matrice na F<2>Pogodnost modela na F<2>:1,049
[0474] Konačni R indeksi [I>2sigma(I)] R1 = 0,0317, wR2 = 0,0850 R indeksi (svi podaci): R1 = 0,0334, wR2 = 0,0864

Claims (14)

1. Patentni zahtevi
1. Jedinjenje formule (III), ili njegova farmaceutski prihvatljiva so:
R<1>je nesupstituisan C<1>-C<6>alkil;
R<6>, R<7>, R<8>i R<9>su svaki, nezavisno, H, supstituisan ili nesupstituisan C<1>-C<6>alkil, supstituisan ili nesupstituisan C<2>-C<6>alkenil, supstituisan ili nesupstituisan C<2>-C<6>alkinil ili C(O)OR<a>;
R<a>je H ili supstituisan ili nesupstituisan C<1>-C<6>alkil;
m je 0, 1, 2, ili 3;
t je 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 ili 10; i
svaki R<10>je, nezavisno, H, halogen, supstituisan ili nesupstituisan C<1>-C<6>alkil, supstituisan ili nesupstituisan C<2>-C<6>alkenil, supstituisan ili nesupstituisan C<2>-C<6>alkinil, supstituisan ili nesupstituisan C<3>-C<10>karbocikl, supstituisan ili nesupstituisan heterocikl koji se sastoji od jednog ili dva 5- ili 6-članih prstenova i 1-4 heteroatoma odabrana od N, O i S, ili supstituisan ili nesupstituisan heteroaril koji se sastoji od jednog ili dva 5- ili 6-članih prstenova i 1-4 heteroatoma odabrana od N, O i S;
ili, alternativno, dva R<10>vezana za isti atom ugljenika, zajedno sa atomom ugljenika za koji su vezani, obrazuju karbonil, supstituisan ili nesupstituisan C<3>-C<10>karbocikl, supstituisan ili nesupstituisan heterocikl koji se sastoji od jednog ili dva 5- ili 6-članih prstenova i 1-4 heteroatoma odabrana od N, O i S, ili supstituisan ili nesupstituisan heteroaril koji se sastoji od jednog ili dva 5- ili 6-članih prstenova i 1-4 heteroatoma odabrana od N, O i S;
ili, alternativno, dva R<10>vezana za različite atome, zajedno sa atomima za koje su vezani, obrazuju supstituisan ili nesupstituisan C<3>-C<10>karbocikl, supstituisan ili nesupstituisan heterocikl koji se sastoji od jednog ili dva 5- ili 6-članih prstenova i 1-4 heteroatoma odabrana od N, O i S, ili supstituisan ili nesupstituisan heteroaril koji se sastoji od jednog ili dva 5- ili 6-članih prstenova i 1-4 heteroatoma odabrana od N, O i S.
2. Jedinjenje prema zahtevu 1, u kom R<1>je metil.
3. Jedinjenje prema zahtevu 1, u kom R<6>, R<7>, R<8>i R<9>su svaki H.
4. Jedinjenje prema zahtevu 1, u kom m je 2 ili 3.
5. Jedinjenje prema zahtevu 1, u kom t je 0, 1, 2, 3 ili 4.
6. Jedinjenje prema zahtevu 1, u kom dva R<10>vezana za isti atom ugljenika, zajedno sa atomom ugljenika za koji su vezani, obrazuju karbonil.
7. Jedinjenje prema zahtevu 1, pri čemu je to jedinjenje:
ili njegova farmaceutski prihvatljiva so.
8. Jedinjenje prema zahtevu 1, pri čemu je to jedinjenje:
ili njegova farmaceutski prihvatljiva so.
9. Jedinjenje prema zahtevu 1, pri čemu je to jedinjenje:
ili njegova farmaceutski prihvatljiva so.
10. Jedinjenje prema zahtevu 1, pri čemu je to jedinjenje odabrano iz grupe koju čine:
ili njegova farmaceutski prihvatljiva so.
11. Farmaceutska kombinacija koja se sastoji od:
(i) jedinjenja formule (III), ili njegove farmaceutski prihvatljive soli, prema bilo kom od zahteva 1-10; i (ii) farmaceutski prihvatljivog nosača.
12. Jedinjenje formule (III), njegova farmaceutski prihvatljiva so, prema bilo kom od zahteva 1-10, ili kombinacija prema zahtevu 11, za upotrebu u lečenju neurološke bolesti.
13. Jedinjenje ili kombinacija za upotrebu prema zahtevu 12, u kojoj neurološka bolest predstavlja multipla sklerozu.
14. Jedinjenje ili kombinacija za upotrebu prema zahtevu 12, u kojoj je neurološka bolest odabrana od povratno-reemitujuće multipla skleroze, sekundarno progresivne multipla skleroze, primarno progresivne multipla skleroze, ili progresivne povratne multipla skleroze.
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