RS52083B - Amidi fumarne kiseline - Google Patents
Amidi fumarne kiselineInfo
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- RS52083B RS52083B YU56003A YUP56003A RS52083B RS 52083 B RS52083 B RS 52083B YU 56003 A YU56003 A YU 56003A YU P56003 A YUP56003 A YU P56003A RS 52083 B RS52083 B RS 52083B
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- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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Description
Ovaj pronalazak se odnosi na upotrebu diamide fumarne kiseline, odnosno monoamido monoestara fumarne kiseline za pripremanje leka i lekova koji sadrže takva jedinjenja.
STANJE TEHNIKE
Dugo vremena, dialkil estri fumarne kiseline kao monoalkil estri fumarne kiseline i soli dobijene od njih su uspešno upotrebljavani za lečenje psorijaze. Pomenuta upotreba je opisana u brojnim patentima, na primer EP-A-0 188 749, DE-25 30 327, DE 26 21 214 ili EP-B-0 312 697.
Upotreba mono- ili diestara fumarne kiseline je takođe opisana za lečenje autoimunih bolesti kao što su poliartritis, skleroza multipleks (cf. DE 197 21 099.6 i DE 198 53 487.6), ali takođe i za upotrebu u transplantacionoj medicini (cf. DE 198 53 487.6 i DE 198 39 566.3). Upotreba mono- ili diestara fumarne kiseline za lečenje sa NF-kappaB posredovanih bolesti i lečenje mitohondričnih bolesti je takođe poznato iz neobjavljenih Nemačkih prijava DE 101 01 307.8 i DE 100 00 577.2. Pa ipak, sva navedena dokumenta samo opisuju mono- i diestre fumarne kiseline, opciono u obliku određenih soli, odnosno jedinjenje pri čemu su jedna ili obe funkcije fumarne kiseline esterifikovane sa alkoholom.
B. Bellier et al. "Replacement of Glvcine with Dicarbonvl and related Moieties in analogues of the C-terminal pentapeptide of cholecvstokinin: CCK(2)agoinsts displaving a novel binding mode", Journal of Medicinal Chemistrv, 43, 2000, 3614-23 opisuju između ostalog određene amide fumarne kiseline koji predstavljaju derivate fumarne kiseline neuropeptidina i njihovu terapijsku upotrebu.
WO 89/019A opisuje određene amide fumarne kiseline, njihove estre i soli i njihovu upotrebu za olakšanje simptoma psorijaze i za stimulisanje varenja i apetita.
John L. Krstenanski et al. "Development of MDL 28, 050, a small stable antitrombin agent based on a functional domain of the leech protein, hidrudin" Thrombosis and Haemostasis, 63(2), 1990, 208-14 opisuju određene peptidhormon konjugate fumarne kiseline sa 10 amino kiselina i njihovu upotrebu kao efikasne u lečenju tromboze u modelima in-vivo.
Pa ipak, zbog njihove isparljivosti, odnosno sublimacije, gore pomenuti estri fumarne kiseline imaju nedostatak da je teško sa njima rukovati kada se pripremanju farmaceutski proizvodi, posebno oni u čvrstom obliku za oralnu administraciju. Specifično pripremanje takvih proizvoda traži zaštitne mere kao što je upotreba maski za disanje, rukavica, zaštitne odeće.
Dodatno, estri fumarne kiseline se absorbuju u gastro-intestinalnom traktu posle oralne administracije i putem protoka krvi upijeni od strane svih ćelija. Prema tome, neophodno je administrirati visoke doze da bi se obezbedio terapeutski efikasan nivo aktivnog sastojka na ili u ćelije mete.
Takve visoke doze povratno vode od poznatih sporednih efekata terapije fumarnom kiselinom kao što su simptomi navale krvi (rumenilo) ili gastrointestinalna iritacija (mučnina, proliv, vetrovi). lako sporedni efekti mogu biti značajno smanjeni administriranje aktivnog sastojka u obliku mikro-tableta kako je to opisano u gore navedenoj ranijoj nauci, ali u potpunosti ne mogu biti izbegnuti.
U isto vreme, estri fumarne kiseline se brzo hidrolizuju u krvi i proizvodi navedene hidrolize, alkohol i fumarna kiselina odnosno monoestar fumarne kiseline, metabolizuju. Da bi se održali terapeutski efektivni nivoi neophodna je ponovljena i česta administracija, lako je primećena određena adaptacija u pogledu sporednih efekata, dalje smanjenje razmere sporednog efekta je poželjno.
OPIS PRONALASKA
Prema tome, predmet je ovog pronalaska je da obezbedi derivate fumarne kiseline i upotreba takvih derivata koji se mogu administrirati strategijski, koji su otporniji na hidrolizu i lakši za upravljanje.
Ovaj zadatak se rešava određenim mono- i diamidima fumarne kiseline odnosno monoamido monoestrima fumarne kiseline njihovom upotrebom za pripremanje lekova za lečenje određenih bolesti i lekovima koji to i sadrže.
Diamidi odnosno monoamidi fumarne kiseline su takođe opisani u US-A-5,242,905 i US-A-5,214,196 prema Blank-u za lečenje psorijaze. Pa ipak, navedene publikacije samo opisuju pripremanje jedino mono- ili diamida fumarne kiseline pojedinačno, ali ne i proizvodnju farmaceutskih proizvoda i primenu amida na ljudska bića. Teoretska prednost amida fumarne kiseline nad estrima fumarne kiseline navedena u ovim publikacijama je snabdevanje određenih amiho kiselina iz amida fumarne kiseline u keratinocite da bi se dopunili metabolički nedostatci kod psorijaze.
Iznenađujuće, pronalazači su sada pronašli da mono- i diamid fumarne kiseline odnosno monoamido monoestri fumarne kiseline mogu biti upotrebljenji sa prednošću za lečenje različitih bolesti. Tačnije, prvi aspekt sadašnjeg pronalaska se prema tome odnosi na upotrebu amida fumarne kiseline formule (I)
pri čemu
R1predstavlja OR3ili za D- ili L-radikal amino kiseline -NH-CHR4-COOH koji je vezan preko amidne veze, pri čemu je R3s lancem u normalnom nizu ili račvasti alkil radikal, izabran od grupe koja sadrži metil, etil, n-propil, izopropil, n-butil, sek-butil, t-butil, pentil, ciklopentil, 2-etilheksil, heksil, cikloheksil, heptil, cikloheptil, oktil, i
R2predstavalja D- ili L-radikal amino kiseline-NH-CHR5-COOH koji je vezan preko amidne veze, u kojoj su R4i R5nezavisno jedan od drugog izabrani iz grupe koja se sastoji oiz bočnog lanca Ala, Val, Leu, Trp, Phe, Met, Tyr, Thr, Cys, Asn, Gin, Asp, Glu, Lys, Arg, His, Citrullin, Chy, Hse, Hyp, Hyl, Om, Sar i Me-Gly, tako da
Ako je Rt= -NH-CHR4-COOH-NH-CHR onda R2predstavlja -NH-CHR5COOH, pri čemu je R5izabran iz grupe koja se sastoji od bočnih lanaca Asn, Gin, Lys, Arg ili His
za pripremanje leka
(1) za lečenje autoimune bolesti odabrane od grupe koja se sastoji od poliartritisa, posebno reumatidnog artritisa, skleroze - multipleks, presad-spram-domaćina reakcije, mladalački-početni dijabetis, Hashimoto-ov tiroiditis, Grave-ova bolest ili Bazedovv-ova bolest, sistemski Lupus ervthematodes (SLE), Sjogren-ov sindrom, pernicious anemija i hronično aktivni (=lupoidni) hepatitis; (2) za upotrebu u transplantacionoj medicini (Domaćin-spram-presada-reakcije); (3) za lečenje mitohondrične bolesti odabrane od grupe koja se sastoji od Parkinson-ovog sindroma, Alchajmerove bolesti,
Chorea Huntington-ove bolesti, rethinopathia pigmentosa ili oblika mitohondrične encefalomiopatije; kao i
(4) za lečenje sa NF-kappaB posredovanim bolestima odabranim od grupe koja se sastoji od bolesti kao što su progresivna sistemska sklerodermija, osteochondritis svphilitica (Wegener-ova bolest), cutis marmorata (livedo reticularis), Behcet-ova bolest, panarteriitis, ulcerozni kolitis, vaskulitis, osteoartritis, podagra, aretrioskleroza, Reiter-ova bolest, pulmonalna granulomatoza, tipovi encefalitisa, endotoksični šok (septični/toksični šok), sepsa, pneumonija, encefalomijelitis, anorexia nervosa, hepatitis (akutni hepatitis, hronični hepatitis, toksični hepatitis, alkoholom izazvani hepatitis, virusni hepatitis, žutica, insuficijencija jetre i
citomegalovirusni hepatitis), Rennert T-limfomatoza, mesangial nefritis, post-angioplastična restenoza, reperfuzioni sindrom, citomegavirusna retinopatija, adenovirusne bolesti kao što su adenovirusni nazebi, adenovirusna faringokonjuktivistična groznica i adenovirusna oftalmija, AIDS, Guillain-Barre sindrom, post-herpetična ili post-zoster neuralgia, inflamatorna demijelizirajuća polineuropatija, mononeuropatija multipleks, muskoviscidoza, Bechterew-ova bolest, Barett-ov ezofagus, EBV (Epstein-Barr virusna) infekcija, srčano remodelovanje, intersticijalni cistitis, dijabetis mellitus tip II, humani radioaktivno senzibilni tumor, multi-otpornost malignih ćelija na hemoterapeutska sredstva (otpornost mulitleka u hemoterapiji), granualoma annulare i kanceri kao što su karcinom dojke, karcinom debelog creva, melanom, primarni karcinom ćelije jetre, adenokarcinom, Kapošijev sarkom, karcinom prostate, leukemija
kao stoje akutna mijeloidna leukemija, višestruki mijelom (plasmocvtoma), Burkitt-ov limfosarkom i Castelman-ov tumor.
Pojam "bočni lanac prirodne ili sintetičke amino kiseline" znači radikale svake prirodne ili sintetičke amino kiseline pozicionirane na a-atomu ugljenika. Radikali amino kiseline R^i R2mogu biti prisutni u D- i L-konfiguraciji, pri čemu je prirodna L-konfiguracija pretpostavljena. Dole, uobičajene skraćenice odnosno označavanja u kodu od 3 slova se upotrebljavaju da bi se karakterisale amino kiseline.
Prema jednoj realizaciji, posebno se upotrebljavaju odnosno traže jedinjenja formule (I) pri čemu R^predstavlja radikal amino kiseline -NH-CHR4-COOH, a R2predstavlja -NH-CHR5-COOH pri čemu R4i R5mogu biti isti ili različiti i imaju gore navedeno značenje. Poželjnije, R4i R5su nezavisno odabrani od grupe koja se sastoji od bočnih lanaca Ala, Val, Leu, Trp, Phe, Met, Tyr, Thr, Cys, Asn, Cln, Alp, Glu, Lys, Arg, His, Citrullin-a, Hcy, Hse, Hyp, Hyl, Om, Sar i Me-Gly.
Prema drugoj realizaciji, upotrebljavaju se, odnosno traže jedinjenja formule (I) u kojima R^stoji za OR3i R2za L radikal amino kiseline NH-CHR5COOH, pri čemu je R5izabran iz grupe koja se sastoji od bočnih lanaca Ala, Val, Leu, Trp, Phe, Met, Tyr, Thr, Cys, Asn.'Gin, Asp, Glu, Lys, Arg, His, Citrullin, Hcy, Hse, Hyp, Hyl, Orn, Sar i Me-Gly.
Pretpostavljeno se kod R5u obe realizacije radi0polarnim amino kiselinama, a još poželjnije je da se radi0punjenju koje nosi amino kiselina, izabrana od grupe koja se sastoji od asparagina, glutamina, lizina, arginina i histidina.
Kada radikal Pmpredstavlja -OR3, odnosno ako je jedinjenje formule (I) koje se traži ili se ima upotrebiti prema pronalasku monoestar monoamido fumarne kiseline R3 je pretpostavljeno odabran od grupe koja sadrži metil, etil, n-propil, izopropil, n-butil, sek-butil, t-butil, pentii, ciklopentil, 2-etilheksil, heksil, cikloheksil, heptil, cikloheptil, oktil. Najpoželjnije je da je R3metil ili etil.
Amidi fumarne kiseline prema pronalasku mogu biti proizvedeni prema gore navedenom patentu po Blank-u.
U daljem aspektu ovaj opis prikazuje lek koji sadrži amid fumarne kiseline kako je gore opisano ili njihove smeše. Lekovi dobijeni upotrebom prema pornalasku i/ili kroz upotrebu opisanih amida fumarne kiseline mogu biti prisutni u oblicima pogodnim za oralno, nazalno, parenteralno, rektalno, pulmonaino, oftalno ili transdermalno davanje.
Pretpostavljeno, lek prema pronalasku je namenjen za oralno davanje i prisutan je u obliku tableta, obloženih tableta, kapsula, granulata, rastvora za piće, lipozoma, nano-kapsula, mikro-kapsula, mikro-tableta, pilula ili pudera kao i granulata, mikro-tablete, pilula i pudera napunjenog u kapsule, mikro-tableta napunjenih u kapsule i pudera napunjenog u kapsule.
Prema posebno poželjnoj realizaciji, lek dobijen prema pronalasku je čvrst oblik oralne doze, još poželjnije, ima enteričnu oblogu (oblogu otpornu na želudačnu kiselinu). Na primer takva obloga može biti predviđena za tablete, dražeje, mikro-tablete, pilule ili kapsule.
Kao stvar principa, lek dobijen prema pronalasku može da sadrži pogodne farmaceutski prihvatljive nosače, inertne punioce, aditive itd. Oni su poznati stručnjacima iz ove oblasti nauke i ne zahtevaju objašnjenje.
Upotreba mikro-tableta ili pilula je najpoželjnija. Pretpostavljeno, one imaju prečnik srednje veličine od 300 do 5000 um, poželjnije 300 do 2000 (.im, kada su neobložene.
Kada se obavlja davanje parenteralno ubrizgavanjem, sastav je prisutan u obliku koji je pogodan za ovu svrhu. Svi uobičajeni tečni nosači pogodni za ubrizgavanje mogu biti upotrebljeni.
U svakom siučaju, pretpostavljeno je da jedinična doza leka sadrži količinu amida fumarne kiseline formule (I) koja odgovara ili je . ekvivalentna količini od 1 do 500 mg, poželjno 10 do 300 mg a najpoželjnije 10 do 200 mg fumarne kiseline.
Claims (10)
1. Upotreba amida fumarne kiseline formule (I)
pri čemu
Rtpredstavlja OR3ili za D- ili L-radikal amino kiseline-NH-CHR4-COOH koji je vezan preko amidne veze, pri čemu je R3s lancem u normalnom nizu ili račvasti alkil radikal, izabran od grupe koja sadrži metil, etil, n-propil, izopropil, n-butil, sek-butil, t-butil, pentil, ciklopentil, 2-etilheksil, heksil, cikloheksil, heptil, cikloheptil, oktil, i R2predstavalja D- ili L-radikal amino kiseline -NH-CHR5-COOH koji je vezan preko amidne veze, u kojoj su R4i R5nezavisno jedan od drugog izabrani iz grupe koja se sastoji oiz bočnog lanca Ala, Val, Leu, Trp, Phe, Met, Tyr, Thr, Cys, Asn, Gin, Asp, Glu, Lys, Arg, His, Citrullin, Chy, Hse, Hyp, Hyl, Om, Sar i Me-Gly, tako da
ako je Rt= -NH-CHR4-COOH-NH-CHR onda R2predstavlja -NH-CHR5COOH, pri čemu je R5izabran iz grupe koja se sastoji od-bočnih lanaca Asn, Gin, Lys, Arg ili His,
za pripremanje leka
(1) za lečenje autoimune bolesti odabrane od grupe koja se sastoji od poliartritisa, posebno reumatidnog artritisa, skleroze multipleks, presad-spram-domaćina reakcije, mladalački-početni dijabetis, Hashimoto-ov tiroiditis, Grave-ova bolest, sistemski Lupus ervthematodes (SLE), Sjogren-ov sindrom, pernicious anemija i hronično aktivni (=lupoidni) hepatitis;
(2) za upotrebu u transplantacionoj medicini;
(3) za lečenje motohondrične bolesti odabrane od grupe koja se sastoji od Parkinson-ovog sindroma, Alchajmerove bolesti, Chorea Huntington-ove bolesti, rethinopathia pigmentosa ili oblika mitohondrične encefalomiopatije; kao i
(4) za lečenje sa NF-kappaB posredovanim bolestima odabranim od grupe koja se sastoji od bolesti kao što su progresivna sistemska sklerodermija, osteochondritis svphilitica (Wegener-ova bolest), cutis marmorata (livedo reticularis), Behcet-ova bolest, panarteriitis, ulcerozni kolitis, vaskulitis, osteoartritis, podagra, aretrioskleroza, Reiter-ova bolest, pulmonalna granulomatoza, tipovi encefalitisa, endotoksični šok (septični/toksični šok), sepsa, pneumonija, encefalomijelitis, anorexia nervosa, hepatitis (akutni hepatitis, hronični hepatitis, toksični hepatitis, alkoholom izazvani hepatitis, virusni hepatitis, žutica, insuficijencija jetre i citomegalovirusni hepatitis), Rennert T-limfomatoza, mesangial nefritis, post-angioplastična restenoza, reperfuzioni sindrom, citomegavirusna retinopatija, adenovirusne bolesti kao što su adenovirusni nazebi, adenovirusna faringokonjuktivistična groznica i adenovirusna oftalmija, AIDS, Guillain-Barre sindrom, post-herpetična ili post-zoster neuralgia, inflamatorna demijelizirajuća polineuropatija, mononeuropatija multipleks, muskoviscidoza, Bechterew-ova bolest, Barett-ov ezofagus, EBV (Epstein-Barr virusna) infekcija, srčano remodelovanje, intersticijalni cistitis, dijabetis mellitus tip II, humani radioaktivno senzibilni tumor, multi-otpornost malignih ćelija na hemoterapeutska sredstva (otpornost mulitleka u hemoterapiji), granualoma annulare i kanceri kao što su karcinom dojke, karcinom debelog creva, melanom, primarni karcinom ćelije jetre, adenokarcinom, Kapošijev sarkom, karcinom prostate, leukemija kao što je akutna mijeloidna leukemija, višestruki mijelom (plasmocvtoma), Burkitt-ov limfosarkom i Castelman-ov tumor.
2. Upotreba prema zahtevu 1 gde Rtpredstavlja -OR3a R2predstavlja L-radikal amino kiseline-NH-CHR5-COOH.
3. Upotreba prema zahtevu 1 gde Rtpredstavlja L-radikal amino kiseline -NH-CHR4-COOH a R2predstavlja L-radikal amino kiseline -NH-CHR5-COOH.
4. Upotreba prema zahtevu 1 ili 2 gde je R3metil ili etil.
5. Upotreba prema zahtevu 1, 2 ili 3 gde je R5 odabra od grupe koja se sastoji od Gin, Asn, Lys, Arg, His.
6. Upotreba prema bilo kom od zahteva 1 do 5, pri čemu je navedeni lek u obliku pogodnom za oralno, nazalno, parenteralno, rektalno, pulmonalno, oftalno ili transdermalno davanje.
7. Upotreba prema bilo kom od zahteva 1 do 5, pri čemu je navedeni lek namenjen za oralno davanje i prisutan je u obliku tableta, obloženih tableta, kapsula, granulata, rastvora za piće, lipozoma, nano-kapsula, mikro-kapsula, mikro-tableta, pilula ili pudera; ili u obliku granulata, mikro-tableta, pilula i pudera napunjenih u kapsule.
8. Upotreba prema zahtevu 7 gde je navedeni lek čvrsti oblik oralne doze i ima enteričnu oblogu (oblogu otpornu na želudačnu kiselinu).
9. Upotreba prema zahtevu 7 gde mikro-tablete ili pilule bez obloge imaju prečnik srednje veličine od 300 do 5000 |am, pretpostavljeno 300 do 2000 um.
10. Upotreba prema bilo kom od zahteva 1 do 9 gde navedeni lek sadrži količinu navedenog amida fumarne kiseline formule (I) koja odgovara prema 1 do 500 mg, pretpostavljeno 10 do 300 mg fumarne kiseline po jednoj dozi.
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| PCT/EP2002/000107 WO2002055063A2 (de) | 2001-01-12 | 2002-01-08 | Fumarsäureamide |
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| DE19853487A1 (de) | 1998-11-19 | 2000-05-25 | Fumapharm Ag Muri | Verwendung von Dialkylfumaraten |
| DE10000577A1 (de) | 2000-01-10 | 2001-07-26 | Fumapharm Ag Muri | Verwendung von Fumarsäurederivaten zur Behandlung mitochondrialer Krankheiten |
| ATE380027T1 (de) | 2003-09-09 | 2007-12-15 | Fumapharm Ag | Verwendung von fumarsäure-derivaten zur behandlung von herzinsuffizienz und asthma |
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2002
- 2002-01-08 AU AU2002219236A patent/AU2002219236B2/en not_active Ceased
- 2002-01-08 DE DE50213989T patent/DE50213989D1/de not_active Expired - Lifetime
- 2002-01-08 RS YU56003A patent/RS52083B/sr unknown
- 2002-01-08 PL PL392750A patent/PL392750A1/pl not_active Application Discontinuation
- 2002-01-08 CA CA2425599A patent/CA2425599C/en not_active Expired - Fee Related
- 2002-01-08 SK SK827-2003A patent/SK288238B6/sk not_active IP Right Cessation
- 2002-01-08 PL PL02364222A patent/PL364222A1/xx not_active IP Right Cessation
- 2002-01-08 CZ CZ2003-1919A patent/CZ304198B6/cs not_active IP Right Cessation
- 2002-01-08 HU HU0302656A patent/HU230252B1/hu not_active IP Right Cessation
- 2002-01-08 NZ NZ526100A patent/NZ526100A/en not_active IP Right Cessation
- 2002-01-08 CA CA2776023A patent/CA2776023A1/en not_active Abandoned
- 2002-01-08 AT AT02729423T patent/ATE447945T1/de not_active IP Right Cessation
- 2002-01-08 EP EP02729423A patent/EP1372634B1/de not_active Expired - Lifetime
- 2002-01-08 US US10/433,295 patent/US7157423B2/en not_active Expired - Lifetime
- 2002-01-08 RU RU2003124752/15A patent/RU2290946C2/ru not_active IP Right Cessation
- 2002-01-08 WO PCT/EP2002/000107 patent/WO2002055063A2/de not_active Ceased
- 2002-01-08 JP JP2002555797A patent/JP2004523511A/ja active Pending
- 2002-01-08 ME MEP-2008-206A patent/ME00135B/me unknown
- 2002-01-08 PL PL392748A patent/PL392748A1/pl not_active Application Discontinuation
- 2002-01-08 EE EEP200300280A patent/EE05472B1/xx not_active IP Right Cessation
-
2003
- 2003-04-15 NO NO20031748A patent/NO333992B1/no not_active IP Right Cessation
- 2003-05-09 BG BG107795A patent/BG66256B1/bg unknown
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2006
- 2006-05-31 US US11/421,083 patent/US7432240B2/en not_active Expired - Lifetime
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