SI9200351A - Organic salts of n,n'-diacetyl cystine - Google Patents
Organic salts of n,n'-diacetyl cystine Download PDFInfo
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- SI9200351A SI9200351A SI19929200351A SI9200351A SI9200351A SI 9200351 A SI9200351 A SI 9200351A SI 19929200351 A SI19929200351 A SI 19929200351A SI 9200351 A SI9200351 A SI 9200351A SI 9200351 A SI9200351 A SI 9200351A
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- diacetyl
- dinac
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/22—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of hydropolysulfides or polysulfides
- C07C319/24—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of hydropolysulfides or polysulfides by reactions involving the formation of sulfur-to-sulfur bonds
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- 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
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
- C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
- C07C323/59—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton with acylated amino groups bound to the carbon skeleton
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Description
Ta izum se nanaša na organske soli N,N'-diacetil čistina, v tekstu, ki sledi je ta označen z DiNAc, ki kažejo imunomodultorno aktivnost, kakor tudi na farmacevtske sestavke zasnovane na teh soleh in na postopke za njihovo farmacevtsko uporabo. Izum se posebej tiče metod za pridobivanje kristalnih, nehigroskopnih in kemično stabilnih soli, ki vsebujejo netoksične organske katione, ki so koristni za zdravljenje bolezni pri katerih je indicirana pomanjkljivost v imunem sistemu.
Ozadje tehnike
N-acetil-L-cistein je dobro znana spojina, ki jo rutinsko uporabljamo kot terapevtsko sredstvo zoper kronične obstruktivne bolezni in kroničen bronhitis. Čeprav je prvi patent vpisan 1964 (GB 954268), mehanizem delovanja spojine ni bil ustanovljen. Nedavno je odkrito, da ustrezen disulfid N-acetil-L-cisteina, tj. L-DiNAc, deluje kot močan imunostimulator (Švedska patentna prijava No SE 9002067-8) ki kaže aktivnost, ki se da primerjati s sodobnimi imunostimulatorji, kot je natrijev dietil ditiokarbamat ali 2,2'-ditiobisetanol.
Načine za pripravo DiNAc so objavili v več patentih (US Patent No 4,827,016 4,724,239 in 4,708,965, Evropski Patent No 300100 in Nemški Patent No 2326444). Toda, DiNAc je amorfna in higroskopna spojina, tako da jo je težko izolirati in oblikovati v farmacevtske sestavke in se normalno daje samo v obliki vodnih raztopin. Večina soli DiNAc z anorganskimi ali organskimi kationi imajo enake neprimerne fizikalne lastnosti kot prosta dikislina. V patentni literaturi (US patent No 3,647,834, JP patent No 56155298 in FR patent No 8106592) so se pojavili primeri soli drugih aminokislin, ki vsebujejo žveplo.
Odkritje izuma
Mi smo sedaj presenetljivo odkrili, da nekaj soli DiNAc z organskimi bazami kažejo želeno kombinacijo nehigroskopnosti in sposobnosti tvorbe kristalov, ki omogočata izoliranje in oblikovanje teh soli v trdni obliki in njihovo dajanje z inhalacijo v trdni obliki, ali v drugih suhih oblikah, če je to klinično zaželeno.
Ta izum omogoča pridobivanje organskih soli DiNAc, ki imajo formulo la ali Ib:
'OOC s-s· NHCOCH
COO' 3 NHCOCHg
2R ali 'OOC ‘s-s NHCOCH
COO'
NHCOCH.
R2 kjer je R+ in r2+ mono- , oziroma diprotonirani organski amin. Organski amin izberemo med liziniumom, etilendiaminiumom, N,N'-dibenziletilendiaminiumom, N-benzil-2feniletilaminiumom, piperaziniumom in 1-adamantanaminiumom.
Lizinium je lahko v njegovi D- ali L- obliki. Največjo prednost ima L-oblika.
Izum vključuje hidratirane in solvatirane soli, npr. solvatirane z nižjimi alkani. Izum vključuje soli DiNAc v njegovih posameznih izomerih, tj. D- in L- oblikah in mezo-oblikah, kakor tudi v njegovi racemski obliki. Največjo prednost imajo L-oblike teh soli.
Mi smo odkrili, da nove soli izuma izpopolnjujejo zahteve po lahkoti kristalizacije, nehigroskopnosti in kemijski stabilnosti, ob tem pa še vedno obdržijo imunomodulatorno aktivnost DiNAc, in so tako medicinsko koristne.
Ta izum tako omogoča spojine s prednostnimi lastnostmi za zdravljenje bolezni, pri katerih se lahko sumi na anergijo imunega odgovora ali na nenormalni imuni odgovor ali na neučinkovito obrambo organizma. Take bolezni vključujejo kroničen bronhitis, za katerega so prej poročali, da se hitrost poslabšanja zmanjša z modifikatorji imunega odgovora, takimi kot je Biostim (Radermecke, M. et al. Int.J/Immunopharmac. 10, 913-917, 1988; Scheffer, J. et al. Arzneim. Forsch/Drug Res. 41, 815820, 1991), Ribomunyl in BronchoVaxom (Paupe, J. Respiration 58, 150-154, 1991) kakor tudi z N-acetilcisteinom (videti Bergstrand, H. et al J. Free Radie. Biol. Med. 2, 119-127, 1986).
Take bolezni vključujejo tudi nekatere oblike malignih obolenj. Tako je cilj mnogih raziskovalnih inštitutov po celem svetu najti načine za stimulacijo imunega odgovora pri pacientih z različnimi oblikami malignih bolezni, in mnogi pregledni članki v literaturi se ukvarjajo s tem pristopom (Stevenson, F.K. FASEB J 5: 2250-2257, 1991). Da omenimo en primer, pri pacientih z intrakranialnimi tumorji (gliomi) pride do velikega zmanjšanja imunitete, verjetno zaradi pomanjkljivosti v izločanju IL-2, kakor tudi v ekspresiji IL-2 receptorjev v T celicah takih pacientov (Roszman, T. et al. Immunology Today 12 370-374, 1991). Še več, v primeru imunostimulatorja Levamisole je dokumetiran pomemben dodatni učinek pri imunoterapiji melanoma in karcinoma črevesja (kolona) (Van Wauve, J. & Janssen, P.A.J. Int. J. Immunopharmac. 13, 3-9, 1991) in imunoterapija z IL-2 in vivo ali zdravljenje z IL-2 ex vivo pacientovih celic ubijalcev, aktiviranih z limfokinom , sta povzročila nazadovanje raka pri izbranih pacientih (Rosenberg, S.A. Immunology Today 9, 58-, 1988). Maligne bolezni za katere lahko pričakujemo, da bo spojina I kazala koristne učinke, vključujejo tumorje mezenhimskega porekla vrste sarkomov, kot je fibrosarkom, miksosarkom, liposarkom, hondrosarkom, osteogenski sarkom ali hordosarkom, sarkome, kot je angiosarkom, endoteliosarkom, limfangiosarkom, sinoviosarkom ali mezoteliosarkom, leukemije in limfome, kot je granulocitna leukemija, monocitna leukemija, limfocitna leukemija, maligni limfom, plazmocitom, sarkom retikulumskih celic ali Hodkinsova bolezen, sarkome, kot je leiomiosarkom ali rabdomisarkom, tumorje epitelskega porekla (karcinomi), kot je karcinom skvamoznih celic, karcinom bazalnih celic, karcinom znojnih žlez, karcinom lojnih žlez, adenokarcinom, papilarni karcinom, papilarni adenokarcinom, cistadenokarcinom, medularni karcinom, nediferencirani karcinom, bronhogenski karcinom, melanom, karcinom ledvičnih celic, hepatom-karcinom celic jeter, karcinom žolčevoda-holangiokarcinom, papilarni karcinom, karcinom prehodnih celic, karcinom skvamoznih celic, horiokarcinom, semonom ali embrionalni karcinom, tumorji centralnega živčnega sistema, kot je gliom, meningom, meduloblastom, schwannom ali ependimom.
Razen tega, imajo spojine lahko tudi prednostne lastnosti za zdravljenje kroničnih infekcij kot je herpes, aftni stomatitis in sindrom najmanjše spremembe, v primeru katerega je že prej objavljeno, da je doseženo klinično izboljšanje pri zdravljenju z imunostimulatorjem kot je Levamisole, kakor tudi drugih kroničnih vnetij v urinarnem traktu ali ušesu, nosu ali grlu, kateremu koristi obravnava z imunostimulatorji kot je Biostim, Broncho-Vaxom in Ribomunyl, ali HIV infekcije ali AIDSa.
Vrh tega je postulirano, da v primeru atopičnih bolezni, kot je atopičen dermatitis, rinitis in astma, obstoja oslabitev, pomanjkljivost ali neravnotežje imunega odgovora (Katz, D.H. Transplantation Reviews 41, 77-108, 1977). Ker teoretično obravnavanje sugerira da bi bila stimulacija imunega odgovora verjetno najboljši način za vzpostavitev neravnotežja in autoimunosti (Varela, F.J. & Coutinho, A. Immunology Today 12, 159-166, 1991), lahko pričakujemo, da imajo spojine prednostne lastnosti tudi pri zdravljenju astme, rinitisa, atopičnega dermatitisa in autoimunih bolezni kot je sladkorna bolezen, ki ni posledica debelosti, sistemski lupus erythematosus, sklerodermia, Sjogrenov sindrom, dermatomiozitis ali multipla skleroza, reumatoidni artritis in verjetno psorijazis.
Razen tega, lahko pričakujemo, da bodo spojine imele, zahvaljujoč temu, da stimulirajo imuni odgovor, prednostne lastnosti kot dodatki v različnih oblikah vakcinskih pripravkov.
Končno, lahko pričakujemo, da bodo spojine imele prednostne lastnosti za zdravljenje ateroskleroze če bo, ali pa ne, vplivala na verjetne inflamatorne procese v takem stanju (Hansson, G.K. et al. Proč. Nat. Acad. Sci. USA 88, 10530, 1991).
Pomen imunostimulirajočih zdravil na tumorski izrastek smo pokazali na naših ustreznih sistemih za testiranje tumorskih izrastkov. Eksperimentalni modeli tumorja podgane, ki jih opisujemo zatem, zelo dobro kažejo tumorostatično učinkovitost spojin tega izuma v primerjavi z dobro utemeljenim imunostimulatorskim zdravilom Levamisolom, in oni odražajo klinično zelo dobro tumor, ki hitro napreduje, karcinom dojk, in tumor, ki počasi progresivno raste, gliom, in v obeh sistemih ima zdravilo odličen statičen učinek na tumorski izrastek.
Posebej primerne za zdravljenje s spojinami tega izuma so: malignitete kot je melanom, karcinom dojk, gastrointestinalni karcinom, gliom, karcinom mehurja in karcinom skvamoznih celic predela vratu in glave;
infekcije kot je kroničen bronhitis, hepatitis, postinfektivna anergija in pridobljene imune deficijence kot je AIDS;
posttraumatske imunološke anergije, in autoimune bolezni kot je reumatoidni artritis, multipla skleroza in psoriazis.
Učinkovite doze za zdravljenje zgoraj omenjenih bolezni so v območju od 0,1 - 100 mg, predvsem 1,0 - 60 mg dnevno.
Postopki za pripravo
Organske soli formule la in Ib običajno pripravimo z mešanjem DiNAc in organske baze, kakor smo prej definirali, pri tem je vsak raztopljen v topilu ali zmesi topil.
Lahko se uporabijo topila kot je voda, alkoholi, glikoli, ketoni, amidi, sulfoksidi ali druga polarna topila ali zmesi topil. Sol lahko tvori oborino neposredno iz reakcijske zmesi, ali pa jo pridobimo z dodatkom manj polarnega topila ali s uparevanjem ali liofilizacijo. Reakcijo izpeljemo pri zvišani temperaturi ali pri sobni temperaturi, odvisno od topnosti v medijumu. Alternativno lahko sol pripravimo z oksidacijo primerne soli N-acetil cisterna v vodni ali alkoholni raztopini, ki ji sledi precipitacija tako kot zgoraj. Oksidacijo lahko izpeljemo kemično, npr. z vodikovim peroksidom ali halogenom, ali elektrokemično.
Farmacevtski sestavki
V skladu s tem izumom lahko spojine formule la in Ib oblikujemo za dajanje z inhalacijo, kakor tudi na druge načine, npr. oralno ali na obolelem delu, z ali brez farmacevtsko sprejemljivega nosilca.
Substanco lahko inhaliramo iz inhalatorja z odmerjeno dozo pod pritiskom, iz inhalatorja za suhi prašek, npr. TurbuhalerR ali iz inhalatorja za suhi prašek, uporabljajoč želatinske, plastične ali drugačne kapsule. Sprašeni substanci lahko dodamo netoksične in kemično inertne substance, npr. laktozo, trehalozo, manitol ali glukozo.
Substanco lahko dajemo tudi oralno, v obliki kapsul ali tablet, pri tem je kapsula, tableta ali sama aktivna substanca obložena ali pa ne. Ta obloga se lahko sestoji iz, na primer, hidroksipropil celuloze in aerosila v izopropanolu ali drugih primernih topilih. Netoksično in kemično inertno substanco lahko dodamo sprašeni substanci, da bi dobili želene fizikalne ali farmacevtske lastnosti.
Možno je tudi parenteralno dajanje novih spojin.
Farmakološki eksperimenti
Sposobnost spojine di-L-lizinium-N,N'-diacetil-L-cistinata (la; R = lizin), da modulira imune odgovore, smo pokazali z njeno učinkovitostjo v testu živalske hipersenzitivnosti tipa z zamudo (animal delayed type hypersensitivity - DTH) na miši.
Uporabili smo in samce in samice, teške 18-20 g, miši Balb/c, ki smo jih dobili iz Bomholtsgaarda (Danska). V tem testu je kot antigen poslužil 4-etoksimetilen-2feniloksazolin-5-on (ΟΧΑ), kupljen pri BDH (Anglija).
Miši smo senzitirali, na dan O, z epikutanozno aplikacijo 150 yU 1 raztopine ΟΧΑ (3%) v absolutnem etanolu-acetonu (3:1) na obrit abdomen.Tretman z disulfidno soljo ali nosilcem (0,9% NaCl) smo začeli z oralnim hranjenjem takoj po senzitaciji in nadaljevali enkrat dnevno do dneva 6. Sedem dni (dan 6) po senzitaciji smo obe strani obeh ušes vseh miši izzvali z aplikacijo 20 /il 1% ΟΧΑ raztopljenega v kikirikijevem olju. Pred nem in 24 ali 48 ur po izzivanju smo izmerili debelost ušes uporabljajoč Oditest spring calliper. Izzivanja in meritve smo izvajali pod lahko pentobarbitalno anestezijo.
Intenziteto DTH reakcij smo izražali po formuli:
Tt24/48_TtO /Jin enote, kjer tO, t24 in t48 predstavljajo debelost ušes pred in 24 oziroma 48 ur po izzivanju, v posameznih testih (T). Rezultate smo izrazili kot srednjo vrednost + S.E.M. Nivo signifikantnosti med srednjimi vrednostimi skupin smo dobili s Študentovim t-testom. Tabele 1 in 2 kažejo rezultate meritev po 24 oziroma 48 urah, iz reprezentativnega eksperimenta. Imunostimulirajoča učinkovitost spojine se kaže v signifikantni razliki v povečanju debelosti ušesa v primerjavi s kontrolo. Tako je pri tretiranih živalih, po 24 urah odgovor bil približno dvakrat večji kot pri kontrolnih živalih (15 μιη v primerjavi z 8 μιη, tabela 1).
Tabela 1.
Debelost ušesa 24 ur po izzivanju živali tretiranih z indiciranimi dozami di-L-lizinium-N,N'-diacetil-Lcistinata ali nosilca (NaCl).
Doza N Dif. S.E.M. Sign.
fimol/kg Tt24“TtO
NaCl | 10 | 8.25 | 0.56 | |
0.03 | 10 | 15.00 | 0.42 | ★ ★ + |
3.0 | 10 | 15.80 | 0.77 | *** |
*** P<0.001.
Tabela 2.
Debelost ušesa 48 ur po izzivanju živali tretiranih z indiciranimi dozami di-L-lizinium-N.N'-diacetil-Lcistinata ali nosilca (NaCl). ***
Doza gmol/kg | N | Did. S.E.M. Tt48’TtO | Sign | |
NaCl | 10 | 8.83 | 0.31 | |
0.03 | 10 | 12.55 | 0.41 | ♦** |
3.0 | 10 | 13.20 | 0.28 |
*** P<0.001.
Sposobnost iste spojine, ki smo jo testirali, da podaljša ali poveča preživetje podgan, ki bolujejo od tumorjev, smo pokazali z dvema različnima eksperimentoma z inokulacijo tumorja v podganah.
Subkutano smo inokulirali dve skupini, ki sta vsaka vsebovali deset podgan seva Wistar Furth, z 10^ celic karcinoma dojke po podgani, in merili velikost tumorja dvakrat na teden. Podgane iz ene skupine so pile navadno vodo in tiste iz druge skupine spojino, ki smo jo testirali, raztopljeno v vodi na tak način, da je doza bila 0,03 ^nmol/kg/dan mase živali. Po 38 dnevih je ena žival iz skupine, ki je pila vodo še bila pri življenju, v skupini kateri smo dajali spojino je pa bilo živih sedem živali.
V drugem eksperimentu smo subkutano inokulirali tri skupine, ki so vsaka vključile deset podgan seva Lewis, z 10^ celic glioma po podgani, in velikost tumorja merili dvakrat na teden. Podgane iz ene skupine so pile navadno vodo, tiste iz druge skupine so pile spojino, ki smo jo testirali , raztopljeno v vodi tako, da je doza bila 0,03 ^imol/kg/dan po masi živali, medtem ko so podgane iz tretje skupine pile vodo, ki je vsebovala Levamisole, dobro znano zdravilo za zdravljenje raka, tudi v dozi 0,03 jumol/kg/dan po masi živali. Po 119 dnevih ni preživela nobena podgana iz skupine, ki je pila vodo. V skupini, kateri smo dajali spojino, ki smo jo testirali, je bilo živih še šest podgan, medtem ko so v skupini, ki je dobijala Levamisole, po 119 dnevih preživele tri podgane.
V obeh eksperimentih s tumorji je pogostnost tumor pozitivnih živali bila manjša in v obeh eksperimentih je obstojala inhibicija rasta tumorja v primeru razvitih tumorjev pri skupinah, ki so dobijale spojino raztopljeno v vodi.
V drugem eksperimentu smo inokulirali dve skupini, ki sta vsaka vključili osem miši SCID (miši z imunim defektom Severe Combined Immunodeficiency Disease - bolezen resne kombinirane imunodeficijence) z 2*10^ celic karcinoma dojk in merili izrastek dvakrat na teden. V eni skupini so miši pile navadno vodo in v drugi skupini spojino, ki smo jo testirali, raztopljeno v vodi tako, da je doza bila 0,03 /imol/kg/dan po masi živali. Ni bilo signifikantnih razlik med skupinami glede hitrosti rasta in učinka. To kaže, da spojina nima neposrednega učinka na celice tumorja, temveč deluje preko imunega aparata.
V živalskem modelu lupusa, eksperimentalnem sistemskem lupus eritematosus (SLE), miši MRL Ipr/Ipr spontano razvijejo limfoidno hiperplazijo, dermatitis, artritis in glomerulonefritis. Na tem modelu smo preučevali učinek diL-lizinium-N,N'-diacetil-L-cistinata na glomerulonefritis, kot na proteinurio in hematurio, in tudi na stopnjo preživetja živali. Di-L-lizinium-N,N'-diacetil-L-cistinat smo dajali v vodi za pitje, srednjo dozo smo pa izračunali tako, da je bila 0,03 ^um/kg/dan. Kontrolne miši so dobijale vodo s pipe. S tretmanom smo začeli ko so živali dosegle starost 8 tednov in nadaljevali do smrti ali 46 tednov starosti, ko smo raziskavo zaključili.
Ocenitev proteinurie in hematurie smo izvedli s uporabo reagentnih trakov, Eour-Test*, Boehringer Manheim.
Stopnjo preživetja smo z dajanjem di-L-lizinium-N,N'diacetil-L-cistinata signifikantno izboljšali, v primerjavi s kontrolnimi mišmi. Stopnja smrtnosti je pri netretirani skupini (21 živali) dosegla 50% pri približno 25 tednih starosti. Pri MRL-Ipr/Ipr miših tretiranih z di-Llizinium-Ν,Ν'-diacetil-L-cistinatom ta stopnja smrtnosti ni bila dosežena pred 44. tednom.
Ta oblika tretmana signifikantno izboljša tudi rezultat za proteinurio in hematurio merjene kot arbitrarne enote reagentnih trakov, v primerjavi z netretirano skupino.
Ti rezultati kažejo imunomodulatorno učinkovitost spojin tega izuma, posebej z ozirom na SLE.
Delovni primeri
Farmacevtske oblike
Sledeči primeri so reprezentativni za farmacevtske oblike namenjene različnim načinom lokalnega in sistemskega dajanja zdravil.
Primer 1. Aerosoli za inhalacijo pod pritiskom.
Aerosolni sistem je tako urejen, da vsaka odmerjena doza vsebuje 0,1-1,0 mg.
Spojina la ali Ib, mikronizirana | 1,0 | % | m/m |
Sorbitan trioleat | 0,7 | % | m/m |
Trikloromonofluorometan | 24,4 | % | m/m |
Diklorotetrafluoroetan | 24,4 | % | m/m |
Diklorodifluorometan | 49,5 | % | m/m |
Primer 2. Aerosol v prašku, za inhalacijo čiste substance.
Čista substanca pripravljena za inhalacijo iz TurbehalerjaVsaka posamezna doza vsebuje 0,1-1,0 mg.
Spojina la ali Ib, obdelana
0,1 - 1,0 mg
Primer 3. Aerosol v prašku, za inhalacijo.
Vsaka posamezna doza vsebuje 0,1-1,0 mg v kapsuli.
Spojina I, mikronizirana Laktoza
0,1 - 1,0 mg 50 mg
Primer 4. Raztopina za nebulizacijo.
Raztopina vsebuje Γ,0-10,0 mg/mL in 1-3 mL, lahko se daje v posamezni dozi.
Spojina I 1,0 - 10,0 mg
Voda za injekcijo do 1,0 mL
Primer 5. Tablete.
Vsaka tableta vsebuje:
Spojino I 0,1 - 100 mg Kuruzni škrob 50 mg Laktozo 150 mg Polividon* 7 mg Mikrokristalinično celulozo 20 mg Magnezijev stearat 2 mg
Pojasnilo komercialnih imen navajamo na strani 17.
Primer 6. Raztopina za oralno uporabo.
Posamezna doza od 10 mL vsebuje 10-100 mg.
Spojina I Sorbitol 70 % Glicerol
Natrijev benzoat Okus
Prečiščena voda
- 10 mg 150 mg 100 mg mg
g. s.
do 1,0 mL
Primer 7. Tablete za kontrolirano sprostitev tableta:
Spojina I 1 - 100 mg Parafin Special 145 mg Laktoza v prahu 50 mg Koloidni silicijev dioksid 5 mg Etilna celuloza 10 cps 13 mg Etanol 99,5 vol % 85 mg Magnezijev stearat 2,5 mg
Primer 8. Granulat za kontrolirano sprostitev g granulata:
Spojina I
- 100 mg
Dispergirana etilna celuloza 10 mg Acetiltributilcitrat 0,5 mg Eudragit L 100-55* 55 mg Trietilcitrat 5 mg Talk 30 mg Voda, sveže destilirana 350 mg Nevtralni trdni dodatki do 1000 mg
Primer 9. Raztopina za injekcijo.
mL posamezne doze vsebuje 1,0-10,0 mg.
Spojina la ali Ib 1,0 - 10,0 mg
Natrijev klorid 8,9 - 7,7 mg
Voda za injekcijo do 1,0 mL
Primer 10. Krema za zunanjo uporabo.
g kreme vsebuje:
Spojino I 0,1 - 1 mg Beli mehki parafin 75 mg Tekoči parafin 10 mg Cetostearilni alkohol 75 mg Cetamakrogol 1000* 20 mg Metagin* 0,8 mg Propagin* 0,2 mg Prečiščeno vodo do 1,0 g
Pojasnilo komercialnih imen navajamo na strani 17.
Primer 11. Mazilo za zunanjo uporabo.
Ig mazila vsebuje:
Spojino I 0,1 - 1 mg Tekoči parafin 150 mg Beli mehki parafin do 1,0 g
Primer 12. Raztopina za oči.
Ena doza od 2 kapljic vsebuje 0,01 - 0,1 mg spojine I.
Spojina I | 0,1 - 1 | mg |
Benzalkonijev klorid | 0,1 | mg |
Natrijev klorid | 9,0 | mg |
Sterilna voda | do 1,0 | mL |
* V zgornjih farmacevtskih primerih navedene | sestavine | lah- |
ko pripravimo s standardnimi kemijskimi postopki ali so tržno raspoložljive in sicer:
- plividon je trivialno ime za poli -(1-vinil-2-pirolidinon) ;
- eudraoit L 100-50 je akrilni polimer, ki ga uporabljamo za tvorbo kapsul;
- cetamakrogol 1000 je polietilenglikol monoacetil eter in ga uporabljamo kot emulzijsko sredstvo;
- metagin se sestoji iz metil hidroksibenzoata in ga uporabljamo kot konzervirno sredstvo, trivialno ime je E 218;
- propagin se sestoji iz propil hidroksibenzoata in ga uporabljamo kot konzervirno sredstvo, trivialno ime je E 216.
Kemija
Primer 13
Di-L-lizinium-N,N'-diacetil-L-cistinat (la; R — H2N(COOH)CH(CH2)4NH3):
N-Acetil-L-cistein (22 molov, 3,59 kg) smo raztopili v 2,6 L deionizirane vode. Dodali smo 45% natrijev hidroksid v vodi (22 molov, 1,92 kg) ob mešanju in pri temperaturi pod 20θΟ. Potem ko smo temperaturo uravnali na 5θ(3, smo pazljivo, po kapljicah, v času 90 minut, dodali vodikov peroksid (11,0 molov, 0,95 L). V času tega dodajanja nismo dovolili, da temperatura preide 10θ0. Raztopini, ki smo jo tako pridobili, smo dodali 9 L aktiviranega močno kislega kationskega izmenjevalca. Po mešanju v teku 10 minut je pH bil 2,0 in smo s filtriranjem ionski izmenjevalec odstranili. Filtrat je vseboval 9,65 molov N,N'-diacetil-Lcistina, kot je določeno s HPLC, ob uporabi standarda, ki smo ga pripravili iz čiste substance. Tej neprečiščeni raztopini smo dodali L-lizin (19,3 mola, 3,17 kg). Gosto raztopino, ki se je tvorila, smo počasi dodali v 50 L etanola, ki je refluktiral in ki je vseboval 0,23 kg kristalnega di-L-lizinium-N,N'-diacetil-L-cistinata. Po dodajanju smo gosto raztopino pustili, da se je ohladila in kristale izločili s filtriranjem. Z izpiranjem z etanolom (8 L) in sušenjem (vakuum, 40θΩ) v času 12 ur smo pridobili 5,36 kg (90%) substance iz naslova, kot belo kristalno trdno snov.
Fizikalni podatki: tališče: 210θΟ (dek.); [\ZJ β25=_70 (c=0,54, H2O); 1h-NMR (D2O) 6: 1,36-1,60 (4H,m,Lys J CH2) ,
1,73 (4H, p Lys ό CH2), 1,84-1,96 (4H, m, Lys β CH2), 2,05 (6Η, s CH3) , 2,95 (2H, dd, CH2S), 3,02 (4H, t, Lys £ CH2), 3,25 (2H, dd, CH2S), 3,76 (2H, t, Lys oCCH), 4,50 (2H, dd, CHN)
13C-NMR (D2O) <5 :24,27; 24,80; 29,24; 32,72; 41,89; 42,78; 52,96; 57,30; 176,53; 177,41; 179,74; analiza: izračunano za C22H44O10N6S2, C: 42,8 H: 7,2 N: 13,6 najdeno, C: 42,6 H: 7,4 N: 13,7; MS m/z = 325 (MH+), m/z = 471 (MLysH+), m/z = 617 (MLys2H+).
Primer 14
Etilend±aminium-N,N*-diacetil-L-cistinat (Ib;
R = H3NCH2CH2NH3):
N,N'-Diacetil-L-cistinu (30,9 mmolov, 10 g), ki smo ga raztopili v 20 mL vode, smo dodali etilendiamin (61,8 mmol, 3,73 g) in etanol (30 mL) . Raztopino smo skoncentrirali do goste paste, ki smo jo zopet raztopili v 80 mL etanola. Do kristalizacije je prišlo po 2 urah mešanja pri ΙΟθΟ. S filtriranjem in sušenjem smo dobili 6,2 g (45%) spojine iz naslova.
Fizikalni podatki: tališče 185,2-192,4θ<3. 1-H-NMR (D2O) <5 ; 2,06 (6H, s, CH3), 2,96 (2H, dd, CH2S), 3,26 (2H, dd,
CH2S), 3,28 (4H, s, H3N+CH2CH2N+H3), 4,50 (2H, dd, CHN). 13C-NMR (D2O) 0: 24,78; 39,99; 42,74; 56,98; 176,55;
179,82; analiza: izračunano, C: 37,5 H: 6,3 N: 14,6 S: 16,7; najdeno, C: 37,3 H: 6,8 N: 15,3 S: 15,2; MS m/z =385 (M(H2NCH2CH2NH22)H+).
Primer 15
N,N'-dibenziletilendiaminium-Ν,Ν'-diacetil-L-cistinat (Ib; R = PhCH2NH2CH2CH2NH2CH2Ph)‘
V 63% raztopino N,N'-diacetil-L-cistina v vodi (67 mmolov,
21,8 g) smo dodali N,N'-dibenziletilendiamin (67 mmolov, 16,0 g). Egzotermna reakcija je dala rahlo oljnat produkt, ki smo ga lahko prekristalizirali iz vode, da smo dobili 12,0 g (32%) substance iz naslova, kot bele kristalne iglice.
Fizikalni podatki: tališče 163,8-165,3θ<2. 1h-NMR (D2O) δ: 2,04 (6H, s, CH3), 2,93 (2H, dd, CH2S), 3,22 (2H, dd, CH2S), 3,44 (4H, s, CH2NBn), 4,27 (4H, s, PhCH2N), 4,47 (2H, dd, CHN), 7,44-7,54 (10H, m, Ph).
13c-NMR (D2O) δ : 24,82, 42,82, 45,71, 54,47, 56,99, 132,22, 132,58, 132,67, 133,52, 176,56, 179,80. Analiza (monohidrat) : izračunano, C: 53,6 H: 6,6 N: 9,6 S: 11,0. Najdeno, C: 54,5 H: 6,6 N: 9,6 S: 11,2.
Primer 16
Di- (1-adamantanaminium, -N, N' -diacetil-L-cistinat (la ; R= C(l) CH(3,5,7) CH2(2,4,6,8,9,10) NH3;
N,N'-Diacetil-L-cistinu (5,35 mmolov, 1,73 g), ki smo ga raztopili v 5 mL vode, smo dodali 1-adamantanamin (10,7 mmolov, 1,61 g). Tej raztopini smo po kapljicah dodali 60 mL acetona. Kristalno sol, ki smo je tako pridobili, smo filtrirali in posušili v vakuumu, ter dobili 2,3 g (67%) spojine iz naslova.
Fizikalni podatki: tališče 162θΟ, 1h-NMR (D2O) ό: 1,71 (12H, široki dd, CH2(4,6,10)), 1,87 (12H, d, CH2(2,8,9)), 2,05 (6H, s, CH3), 2,17 (6H, široki s, CH(3,5,7)), 2,96 (2H, dd, CH2S), 3,26 (2H, dd, CH2S), 4,50 (2H, dd, CHN).
Primer 17
Di- ( N-hf»nzi Ί-2-feni leti lami ni nm) —N , N ' -L—cistinat (la ; R = PhCH2CH2NH2CH2Ph)J
N,N'-Diacetil-L-cistinu (28,7 mmolov, 9,3 g), ki smo ga raztopili v 20 mL vode, smo dodali N-benzil-2feniletilamin (57,4 mmolov, 12,1 g). Raztopino smo koncentrirali do goste paste, iz katere je počasi kristalizirala sol. Kristalno spojino iz naslova smo izolirali in posušili.
Fizikalni podatki: tališče 87θΟ. 1h-NMR (D2O) δ: 2,05 (6H, s, CH3), 2,95 (2H, dd, CH2S), 3,04 (4H, t, PhCH2C), 3,24 (2H, dd, CH2S), 3,33 (4H, t, CH2NBn), 4,25 (4H, s, PhCH2N), 4,49 (2H, dd, CHN), 7,30-7,52 (20H, m, Ph).
Primer 18
Pipcrazinium-Ν,Ν'-diacetil-L-cistinat Ib; R = NH2(1,4) CH2(2,3,5,6)J
N,N'-Diacetil-L-cistinu (4,60 mmolov, 1,49 g), ki smo ga raztopili v 5 mL vode, smo dodali piperazin (4,60 mmolov, 0,90 g). Tej raztopini smo dodali zadosti izopropanola, da smo povzročili tvorbo olja, ki počasi postaja trdno. Sol smo izolirali in posušili.
Fizikalni podatki: tališče>1700c (dek. ) 1h-NMR (D2O) <$ : 2,05 (6H, s, CH3), 2,96 (2H, dd, CH2S), 3,26 (2H, dd, CH2S), 3,42 (8H, s, CH2(2,3,5,6)), 4,49 (2H, dd, CHN).
Primer 19
Di-L—lizinium-N,N' -diacetil-L-cistinat (la;
R = H2N(COOH)CH(CH2)4NH3)
N-Acetil-L-cistein (37 mmolov, 6,0 g) in L-Lizin (37 mmolov, 5,4 g) smo raztopili v 10 mL deionizirane vode. Po kapljicah smo ob mešanju dodali vodikov peroksid (18 mmol,
1,5 mL), pri tem smo temperaturo vzdrževali pod 25θΟ. Raztopino smo mešali še 4 ure. Viskozno raztopino smo počasi dodali v 150 mL etanola, ki je refluktiral in ki je vseboval 0,50 g kristalnega di-L-lizinium-N,N'-diacetil-Lcistinata. Po tem dodajanju smo raztopino pustili, da se ohladi, in kristale izločili s filtriranjem. Z izpiranjem z etanolom (20 mL) in sušenjem (vakuum, 45θϋ) ki je trajalo 24 ur, smo pridobili 10,0 g (84%) substance iz naslova, kot belo kristalno trdno substanco.
Fizikalni podatki: tališče: 208°C; [ρ(,]25ο=-73θ (c=0,54,
Claims (14)
1. Sol organske baze in Ν,Ν'-diacetil čistina v njegovih posameznih izomerih, tj. D-, L- in mezo- oblikah, kakor tudi njegovih racemskih oblikah (DiNAc), označena s tem, da je njena splošna formula 'OOC -COO'
V^S-S-^ γ 2R
NHCOCH3 NHCOCH3 ali
OOC . /^^COO’ <.' Ύ p?NHCOCHg NHCOCHg kjer sta R+ in R2+ kationa organske baze lizina, etilendiamina, N,N'-dibenziletilendiamina, adamantanamina, Nbenzil-2-feniletilamina ali piperazina.
2. Sol po zahtevku 1, označena s tem, da je sol N,N'-diacetil-L-cistina.
3. Postopek za pripravo soli spojine, ki je definirana v zahtevku 1 ali 2, označen s tem, da se DiNAc tretira z organsko bazo ali soljo, ki vsebuje te katione organske baze, pri tem so reaktanti raztopljeni ali dispergirani v topilu ali zmesi topil, in da se izolira sol, ki je po izbiri lahko v hidratirani ali solvatirani obliki.
4. Postopek za pripravo soli, ki je definirana v zahtevku 1 ali 2, označen s tem, da se sol Nacetilcisteina in organske baze oksidira in da se izolira sol DiNAc, ki je lahko po izbiri v hidratirani ali solvatirani obliki.
5. Farmacevtski sestavek, označen s tem, da vsebuje kot aktivno sestavino sol DiNAc po zahtevku 1 ali 2.
6. Farmacevtski sestavek po zahtevku 5, označen s tem, da se daje s pomočjo inhalatorja z odmerjeno dozo pod pritiskom ali s pomočjo inhalatorja s suhim praškom ali s pomočjo suhega praška uporabljajoč želatinske, plastične ali druge kapsule.
7. Farmacevtski sestavek po zahtevku 5 ali 6, označen s tem, da mu je dodan farmacevtsko sprejemljiv nosilec.
8. Farmacevtski sestavek po zahtevku 5, označen s tem, da je v obliki kapsul ali tablet.
9. Farmacevtski sestavek po zahtevku 8, označen s tem, da vsebuje farmacevtsko sprejemljivega nosilca.
10. Farmacevtski sestavek po zahtevku 5, označen s tem, da se daje v raztopini z nebulizacijo.
11. Sol po zahtevku 1 ali 2, označena s tem, da se uporablja kot terapevtsko aktivna substanca.
12. Sol po zahtevku 1 ali 2, označena s tem, da se uporablja za zdravljenje malignih bolezni.
13. Uporaba soli po zahtevku 1 ali 2, označena s tem, da je namenjena pripravi zdravila, ki kaže imunomodulirajočo aktivnost.
14. Uporaba soli po zahtevku 1 ali 2, označena s tem, da je namenjena pripravi zdravila, ki se rabi za zdravljenje malignih bolezni.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE9103572A SE9103572D0 (sv) | 1991-11-29 | 1991-11-29 | Organic salts of n,n'-diacetyl cystine |
Publications (1)
Publication Number | Publication Date |
---|---|
SI9200351A true SI9200351A (en) | 1993-06-30 |
Family
ID=20384494
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
SI19929200351A SI9200351A (en) | 1991-11-29 | 1992-11-30 | Organic salts of n,n'-diacetyl cystine |
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US (5) | US5385904A (sl) |
EP (1) | EP0621862B1 (sl) |
JP (1) | JP3302018B2 (sl) |
KR (1) | KR100256185B1 (sl) |
CN (1) | CN1039586C (sl) |
AP (1) | AP350A (sl) |
AT (1) | ATE141913T1 (sl) |
AU (1) | AU657827B2 (sl) |
CA (1) | CA2123516A1 (sl) |
CZ (1) | CZ282085B6 (sl) |
DE (1) | DE69213256T2 (sl) |
DK (1) | DK0621862T3 (sl) |
DZ (1) | DZ1637A1 (sl) |
EE (1) | EE03025B1 (sl) |
ES (1) | ES2090713T3 (sl) |
FI (1) | FI942504A (sl) |
GR (1) | GR3021546T3 (sl) |
HK (1) | HK62297A (sl) |
HR (1) | HRP921322B1 (sl) |
HU (1) | HU215390B (sl) |
IL (1) | IL103778A (sl) |
IS (1) | IS1645B (sl) |
LV (1) | LV11949B (sl) |
MA (1) | MA22716A1 (sl) |
MX (1) | MX9206851A (sl) |
MY (1) | MY110523A (sl) |
NO (1) | NO301325B1 (sl) |
NZ (1) | NZ245077A (sl) |
PL (2) | PL171336B1 (sl) |
RU (1) | RU2135468C1 (sl) |
SE (1) | SE9103572D0 (sl) |
SG (1) | SG73962A1 (sl) |
SI (1) | SI9200351A (sl) |
SK (1) | SK281697B6 (sl) |
TN (1) | TNSN92108A1 (sl) |
WO (1) | WO1993011104A1 (sl) |
YU (1) | YU48594B (sl) |
ZA (1) | ZA928739B (sl) |
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-
1991
- 1991-11-29 SE SE9103572A patent/SE9103572D0/xx unknown
-
1992
- 1992-11-10 NZ NZ245077A patent/NZ245077A/en unknown
- 1992-11-12 ZA ZA928739A patent/ZA928739B/xx unknown
- 1992-11-17 IL IL10377892A patent/IL103778A/xx not_active IP Right Cessation
- 1992-11-18 YU YU99092A patent/YU48594B/sh unknown
- 1992-11-20 AP APAP/P/1992/000448A patent/AP350A/en active
- 1992-11-23 HR HR9103572-5A patent/HRP921322B1/xx not_active IP Right Cessation
- 1992-11-23 TN TNTNSN92108A patent/TNSN92108A1/fr unknown
- 1992-11-24 IS IS3949A patent/IS1645B/is unknown
- 1992-11-24 MA MA23006A patent/MA22716A1/fr unknown
- 1992-11-25 AU AU30996/92A patent/AU657827B2/en not_active Ceased
- 1992-11-25 SK SK632-94A patent/SK281697B6/sk unknown
- 1992-11-25 CA CA002123516A patent/CA2123516A1/en not_active Abandoned
- 1992-11-25 SG SG1996004497A patent/SG73962A1/en unknown
- 1992-11-25 DK DK92924975.3T patent/DK0621862T3/da active
- 1992-11-25 CZ CZ941297A patent/CZ282085B6/cs not_active IP Right Cessation
- 1992-11-25 ES ES92924975T patent/ES2090713T3/es not_active Expired - Lifetime
- 1992-11-25 HU HU9401473A patent/HU215390B/hu not_active IP Right Cessation
- 1992-11-25 EP EP92924975A patent/EP0621862B1/en not_active Expired - Lifetime
- 1992-11-25 DZ DZ920148A patent/DZ1637A1/fr active
- 1992-11-25 US US07/981,373 patent/US5385904A/en not_active Expired - Lifetime
- 1992-11-25 JP JP51003993A patent/JP3302018B2/ja not_active Expired - Fee Related
- 1992-11-25 DE DE69213256T patent/DE69213256T2/de not_active Expired - Fee Related
- 1992-11-25 RU RU94027569/04A patent/RU2135468C1/ru not_active IP Right Cessation
- 1992-11-25 WO PCT/SE1992/000807 patent/WO1993011104A1/en active IP Right Grant
- 1992-11-25 AT AT92924975T patent/ATE141913T1/de not_active IP Right Cessation
- 1992-11-25 KR KR1019940701815A patent/KR100256185B1/ko not_active IP Right Cessation
- 1992-11-25 PL PL92314567A patent/PL171336B1/pl unknown
- 1992-11-25 MY MYPI92002155A patent/MY110523A/en unknown
- 1992-11-25 PL PL92303924A patent/PL170787B1/pl unknown
- 1992-11-27 MX MX9206851A patent/MX9206851A/es not_active IP Right Cessation
- 1992-11-28 CN CN92113666A patent/CN1039586C/zh not_active Expired - Fee Related
- 1992-11-30 SI SI19929200351A patent/SI9200351A/sl unknown
-
1994
- 1994-05-26 NO NO941968A patent/NO301325B1/no not_active IP Right Cessation
- 1994-05-27 FI FI942504A patent/FI942504A/fi unknown
- 1994-11-08 US US08/335,941 patent/US5693858A/en not_active Expired - Fee Related
- 1994-11-17 EE EE9400378A patent/EE03025B1/xx not_active IP Right Cessation
-
1995
- 1995-06-07 US US08/477,387 patent/US5804582A/en not_active Expired - Fee Related
- 1995-06-07 US US08/476,218 patent/US5650538A/en not_active Expired - Lifetime
- 1995-06-07 US US08/484,143 patent/US5824681A/en not_active Expired - Fee Related
-
1996
- 1996-11-06 GR GR960402920T patent/GR3021546T3/el unknown
-
1997
- 1997-05-08 HK HK62297A patent/HK62297A/xx not_active IP Right Cessation
- 1997-08-28 LV LVP-97-158A patent/LV11949B/en unknown
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