HRP920923A2 - Dekstrogiri enantiomer metil alfa - (4,5,6,7-tetrahidro-tieno (3,2-c) pirid-5-il)-(2-klorofenil)-acetata, njegove soli i postupak za njegovo dobivanje - Google Patents
Dekstrogiri enantiomer metil alfa - (4,5,6,7-tetrahidro-tieno (3,2-c) pirid-5-il)-(2-klorofenil)-acetata, njegove soli i postupak za njegovo dobivanje Download PDFInfo
- Publication number
- HRP920923A2 HRP920923A2 HRP920923AA HRP920923A HRP920923A2 HR P920923 A2 HRP920923 A2 HR P920923A2 HR P920923A A HRP920923A A HR P920923AA HR P920923 A HRP920923 A HR P920923A HR P920923 A2 HRP920923 A2 HR P920923A2
- Authority
- HR
- Croatia
- Prior art keywords
- thieno
- tetrahydro
- acetate
- chlorophenyl
- enantiomer
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 11
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical class [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 title 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 50
- 150000003839 salts Chemical class 0.000 claims description 34
- 239000002253 acid Substances 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 14
- -1 methyl alpha-(4,5,6,7-tetrahydro-thieno[3,2-c]pyrid-5-yl)-(2-chlorophenyl)-acetate Chemical compound 0.000 claims description 9
- 238000001953 recrystallisation Methods 0.000 claims description 7
- 230000003287 optical effect Effects 0.000 claims description 6
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- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
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- 244000215068 Acacia senegal Species 0.000 description 3
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- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
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- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
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- DTGLZDAWLRGWQN-UHFFFAOYSA-N prasugrel Chemical compound C1CC=2SC(OC(=O)C)=CC=2CN1C(C=1C(=CC=CC=1)F)C(=O)C1CC1 DTGLZDAWLRGWQN-UHFFFAOYSA-N 0.000 description 2
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- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
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- OGUWOLDNYOTRBO-UHFFFAOYSA-N 4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1NCCC2=C1C=CS2 OGUWOLDNYOTRBO-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
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- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
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- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
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- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
- C07J41/0061—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives one of the carbon atoms being part of an amide group
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Description
Područje tehnike
Izum je iz područja kemije organskih spojeva i, bliže, iz područja optički aktivnih spojeva, te njihovog dobivanja iz racemskih smjesa. Znak izuma prema Međunarodnoj klasifikaciji patenata je C 07 D 495/04.
Tehnički problem
Spoj metil α-(4,5,6,7-tetrahidro-tieno[3,2-c]pirid-5-il)-(2-klorofenil)-acetat opisan je u Francu-skom patentu br. 2 530 247, gdje se navodi i njegova primjena kao aktivnog sredstva protiv agregacije krvnih zrnaca (trombocita). Spoj je dobiven u obliku racemske smjese enantiomjera. U istraživanjima koja su dovela do sadašnjeg izuma je, međutim, neočekivano otkriveno da aktivno sredstvo, u stvari predstavlja samo dekstrogiri enantiomjer, dok ljevogiri enantiomjer nema takvo djelovanje. S druge strane, negativni ljevogiri enantiomjer se i podnosi gore od destrogirog. Sadašnjim izumom rješen je tehnički problem osiguranja novog, dekstrogirog enantiomera metil α-(4,5,6,7-tetrahidro-tieno[3,2-c]pirid-5-il)-(2-kloro-fenil)-acetata, kao i postupka za njegovo dobivanje iz racemske smjese izomera.
Stanje tehnike
Postupak za dobivanje racemskog metil α-(4,5,6,7-tetrahidro-tieno[3,2-c]pirid-5-il)-(2-kloro-fenil)-acetata opisan je u Francuskom patentu br. 2 530 247. Prema Primjeru 1 navedenog patenta, otopina 4,5,6,7-tetrahidro-tieno[3.2-c]piridina u dimetilfornamidu tretira se na temperaturi od 90°C metil oklorofenil acetatom u prisustvu kalijevog karbonata.
Opis rješenja tehničkog problema
Novi dekstrogiri enantiomjer prema sadašnjem pronalasku odgovara formuli :
[image]
ukojoj atom c* predstavlja asimetričan ugljikov atom. U stvari, formula predstavlja kako dekstrogiri enantiomjer iz sadašnjeg izuma, tako i ljevogiri enantiomjer ovog spoja. U nastavku teksta dekstrogiri enantiomjer biti će označen kao Id, dok će ljevogiri biti označen kao I.
Rotacija spoja ovisi o otapalu u kojem je otopljen, kao i od koncentracije u toj otopini. Dekstrogiri enantiomjer iz sadašnjeg izuma ima pozitivnu rotaciju kada je otopljen u metanolu.
Izum se također odnosi na adicijske soli spoja formule (Id) sa farmaceutski prihvatljivim mineralnim ili organskim kiselinama.
Spoj formule (Id) je ulje, dok se njegov klorohidrat pojavljuje u obliku bijelog praška. Uljni proizvodi se u načelu teško pročišćavaju, te će se stoga za dobivanje farmaceutskih preparata koristiti kristalni proizvodi, koji se u načelu pročišćavaju rekristalizacijom.
Utemeljeno je da se, u ovom slučaju, izvjesne soli spoja (Id) talože u amorfnom obliku i/ili predstavljaju supstance koje upijaju vlagu, što ih čini nepodobnima za primjenu u industrijskim postupcima. Ako se pipreme soli sa karboksilnim ili sulfatnim kiselinama koje su uobičajene u farmaciji, kao što su octena, benzolova, fumarna, maleinska, limunska, vinska, dioksibenzolova, metansulfatna, etansulfatna, benzolsulfatna i laurilsulfatna kiselina, dobezilat (t.t.70°C), ili sol sa paratoluolsulfatnom kiselinom (t.t.51°C), njihovo će pročišćavanje biti problematično.
Među solima dekstrogirog izomera spoja formule (Id) sa organskim i mineralnim kiselinama posebno su korisne one koje lako kristaliziraju, ne upijaju vlagu i dovoljno su topljive da bi se mogle koristiti kao aktivni sastojci u lijekovima.
Sadašnji izum se odnosi na hidrogenosulfat (adicijska sol sa sumpornom kiselinom), tauroholat i bromhidrat dekstrogirog enantiomjera metil α-(4,5,6,7-tetrahidro-tieno/3.2-c/pirid-5-il)-(2-klorofenil)-acetata.
Ove soli dobivaju se na uobičajeni način, djelovanjem odgovarajuće kiseline na lužinu, u otopini u kojoj dolazi do taloženja kada se doda otapalo u kojem sol nije topljiva.
Dekstrogiri izomer metil α-(4,5,6,7-tetrahidro-tieno/3.2-c/pirid5-il)-acetata dobiva se pretvor-bom racemske smjese ovog spoja u sol sa optički aktivnom kiselinom, u podobnom otapalu, serijom uzastopnih rekristalizacija sve dok se ne dobije proizvod sa konstantnom rotacijom, oslobađanjem dekstrogirog izomera iz soli, njenim tretiranjem sa lužinom i, po potrebi, pretvorbom dekstrogirog izomera u adicijsku sol, reakcijom sa farmaceutski podobnom kiselinom.
Kao optički aktivna kiselina može se koristiti ljevogira 10-kamfosulfonska kiselina.
Preporučuje se da se i za pretvorbu u sol i za kristalizaciju koristi isto otapalo: u ovom slučaju najbolje je koristiti aceton.
Hiralna ljevogira 10-kamfosulfonska kiselina formule (II1) reagira, u inertnom otapalu, sa racemskom smjesom formule (I) prema slijedećoj reakcijskoj shemi:
[image]
Pretvaranje u sol može se vršiti u otapalu kao što je npr. alkohol, keton ili dimetilformamid. Sol se taloži spontano, ili se izolira razblaživanjem ili uparavanjem otapala. Gradi se smjesa dvaju dijastereoizomera formule (IIIa). Tokom uzastopnih rekristalizacija iz otapala kao što je aceton, talog sadrži sve veći postotak soli dekstrogirog izomera spoja formule (I). Nakon svake rekristalizacije mjeri se rotacija /alfa/20/D taloga, na 20°C u metanolu, pri koncentraciji od 1.5 do 2 g/100 ml. Kada se /alfa/20/D prestane mijenjati, iz soli (IIIa) se izolira slobodna lužina formule (Id), reakcijom sa lužinom kao što je natrijev ili kalijev bikarbonat, u vodenoj otopini i na temperaturi od 5 do 20°C.
Uparavanje filtrata nakon prve rekristalizacije (IV) i otklanjanja crastala staložene soli formule (IIIa), daje smjesu s većim postotkom soli enantiomjera (I1). Alkalizacija ove smjese dijastereoizomernih soli sa slabom lužinom, kao što je kalijev ili natrijev bikarbonat, u vodenoj otopini i na temperaturi od 5 do 20°C, daje smjesu dvaju enantiomjera, (Id)+(I1), obogaćenu ljevogirim enantiomjerom (I1).
Smjesa (Id)+(I1), obogaćena enantiomjerom (I1), reagira sa dekstrogirom 10-kamfosulfonska kiselinom koju označavamo sa (IId), u podobnom otapalu, prema slijedećoj reakcijskoj shemi:
[image]
Smjesa kristalnih dijastereoizomernih soli rekristalizira se iz acetona sve dok rotacija /alfa/D ne postane konstantna. Kao i u prethodnom slučaju, nakon svake rekristalizacije mjeri se /alfa/20/D.
Dobivanje slobodnog oblika srereoizomera (I1) vrši se na uobičajeni način, kao i kod spoja (Id).
Ljevogira 10-kamfosulfonska kiselina (II1) dobiva se polazeći od komercijalno dostupnog amonijak 10-kamfosulfata formule (V) prema slijedećoj reakcijskoj shemi:
[image]
Kromatografijom vodene otopine amonijeve soli formule (V) preko smole Amberlite IRN-77 i liofilizacijom eluata, dobiva se 10-kamfosulfonska kiselina formule (II1).
Ukupan postupak je shematski prikazan ovako:
[image]
[image]
Oba enantiomjera (Id) i (I1) mogu se pretvoriti u soli na uobičajeni način: npr. klorohidrati se dobivaju dodatkom otopine klorovodika u dietileteru u dietileterskoj otopini spoja (Id) ili (I1).
Određivanje enantiomerne čistoće dekstrogirog (Id) i ljevogirog (I1) izomera
Koriste se dvije metode:
- protonska NMR spektroskopija sa dodatkom hiralnog lantanida,
- tečna kromatografija pod visokim tlakom (HPLC) sa kiralnom stacionarnom fazom;
a.) protonska NMR spektroskopija sa dodatkom kiralnog lantanida
Enantiomjerna (optička) čistoća odreduje se 1H NMR spektroskopijom na 60 MHz, u prisustvu kiralnog kompleksnog spoja lantanida, po metodi opisanoj od strane G. M. Whitesides-a i suradnika (J. Am. Chem. Soc., 1974, 96, 1038).
U racemskom proizvodu (I), vodik je vezan za centar asimetrije-u alfa-položaju esterske dunkcije-javlja se kao singlet (kemijsko pomicanje delta=4.87 ppm u CDCl3 kao otapalu). Dodatak lantanidskog kompleksa Eu(tfc)/europijum(III) tris(triflorometil3-hidroksimetilen)-d-kamforata/u sondi koja sadrži racemsko otapalo spoja (I) u CDCl3, dovodi do razdvajanja početnog singleta u dva dobro odvojena singleta, koji odgovaraju protonima svakog od izomera (Id) i (I1). Za molarni odnos kompleks lantanida/spoj formule (I)=0.4, razdvajanje dva singleta iznosi 6 Hz.
Sa svakim od dva dobivena izomera (Id) i (I1), ponavlja se procedura kao za racemsku smjesu (I). Manje kemijsko pomicanje odgovara dekstrogirom enantiomjeru (Id), dok veće kemijsko pomicanje odgovara ljevogirom (I1).
Preciznost metode određuje se usporedbom 1H NMR spektara (60 MHz) dobivenih sa ili bez dodatka lantanidskog kompleksa, za svaki od dva enantiomjera (Id) i (I1), i to kako u čistom stanju, tako i u smjesi koja sadrži rastuću količinu jednog enantiomjera u odnosu na drugi. Ustanovljeno je da se jedan enantiomjer može lako otkriti u smjesi s drugim ukoliko mu je količina veća od 5 mas.%.
b.) HPLC uz korištenje hiralne stacionarne faze
Ispitivanje je izvršeno na tečnom kromatografu HP-1084 uz korištenje UV detektora na 215 nm. Stacionarna faza sastojala se od silikagela DEAE (10 mikrona) formiranog sa kiselim 1-alfaglikoproteinom (0.4 x l00mm)(ENANTIOPAC R-LKB). Mobilnu fazu je predstavljala vodena otopina 8mM fosfatnog pufera (NaH2PO4/Na2HPO4) i 0.1M NaCl, namješten na ph 7.4, koji sadrži 15% izopropanola (zapr./zapr.). Protok je namješten na 0.3 ml/min., a temperatura kolone je održavana na 18-20°C. Pod ovim uvjetima dekstrogiri enantiomer (Id) ima retencijsko vrijeme od 45 minuta, dok ljevogiri enantiomer (I1) ima retencijsko vrijeme od 35 minuta.
Preciznost određivanja optičke čistoće dvaju enantiomjera određuje se kromatografiranjem svakog od dva dobivena enantiomjera, kako u čistom obliku, tako i u smjesi koja sadrži rastuću količinu jednog enantiomjera u odnosu na drugi. Ustanovljeno je da se može detektirati:
- 2 mas./mas.% enantiomjera (Id) u enantiomjeru (I1), i
- 4 mas./mas.% enantiomjera (I1) u enantiomjeru (Id);
Pod ovim uvjetima može se utvrditi da optička čistoća dvaju izomera (Id) i (I1), dobivenih u primjerima koji slijede, iznosi najmanje 96% za dekstrogiri enantiomjer (Id), odnosno najmanje 98% za ljevogiri enantiomjer (I1).
Primjeri u nastavku teksta dani su u svrhe ilustriranja sadašnjeg izuma, te ih ne treba shvatiti kao ograničavajuće.
Primjeri
PRIMJER 1 - Soli dekstrogirog metil alfa-(4,5,6,7-tetrahidrotieno/3.2-c/-pirid-5-il)-(2-klorofenil)-acetata
a.) Ljevogira 10-kamfosulfonska kiselina
Pripremljena je kolona smole Amberlite IRN-77 i tretirana je propuštanjem IN klorovodikove kiseline. Ovako zakiseljena smola obilno je isprana vodom. Na prethodno pripremljenu kolonu nanosi se ljevogiri amonijev10-kamfosulfat otopljen u minimalnoj količini vode. Eluiranje se vrši vodom, pa se frakcije eluata koje sadrže kiselinu podvrgavaju liofilizaciji.
Bijeli kristali, t.t. 198°C;/alfa/20/D= -20.53 (C: 2.075 g/100 ml, voda).
b.) Sol L-10-kamfosulfatne kiseline sa metil alfa-(4,5,6,7-tetrahidro-tieno/3.2-c/pirid-5-il)-(2-klorofenil)-acetatom (SR 25990 B)
U 150 ml acetona otopljeno je 32 g (0.0994 mola) racemskog metil alfa-(4,5,6,7-tetrahidro-tieno/3.2-c/pirid-5-il)-(2-klorofenil)-acetata, pa je dodano 9.95 g (0.0397 mola) monohidrata ljevogire 10-kamfosulfatne kiseline. Homogena smjesa stavljena je da stoji na sobnoj temperaturi, pa je nakon 48 sati primijećeno pojavljivanje izvjesne količine kristala. Reakcijska smjesa koncentrirana je do 50 ml, stavljena na sobnu temperaturu na 24 sata, pa su kristali filtrirani, isprani acetonom i sušeni (Doprinos: 55% u odnosu na početnu racemsku smjesu).
Bijeli kristali, t.t. 165°C; /alfa/20D=+24.67 (C=1.58 g/100 ml; metanol).
Dobiveni kristali ponovo su otopljeni u 50 ml kipućeg acetona. Hlađenjem otopine ponovo se talože kristali koji se filtriraju, ispiru acetonom i suše (Doprinos: 88%).
Bijeli kristali, t.t. 165°C;/alfa/20D=+24.75 (C=1.68 g/100 ml; metanol).
c.) Metil alfa-(4,5,6,7-tetrahidro-tieno/3.2-c/pirid-5-il)-(2-klorofenil)-acetat, dekstrogiri
12 g (0.022 mola) proizvoda iz dijela b.) rastvoreno je u minimalnoj količini vode. Nakon hlađenja do 5°C, dobivena vodena otopina alkalizirana je dodatkom zasićene vodene otopine natrijevog bikarbonata. Alkalna vodena faza odvojena (ekstrahirana) je diklorometanom, pa je organski sloj osušen preko bezvodnog natrijevog sulfata. Isparavanje otopine dalo je bezbojno ulje (kvantitativni doprinos).
Ulje, /alfa/20D=+51.52 (C=1.61 g/100 ml; metanol).
d.) Klorohidrat dekstrogirog metil alfa-(4,5,6,7-tetrahidro-tieno-/3.2-c/pirid-5-il)-(2-klorofenil)-acetata (SR 25990 A)
U 100 ml dietil etera otopljeno je 7g (0.0228 mola) dekstrogirog metil alfa-(4,5,6,7-tetrahidro-tieno/3.2-c/pirid-5-il)-(2-klorofenil)-acetata. Ovoj smjesi dodano je 30 ml IN otopine HCl u dietil eteru, pa su dobiveni kristali filtrirani. Kristali su isprani dietil eterom i sušeni (Doprinos: 94%).
Bijeli kristali, t.t. 117°C,/alfa/20D=+62.23 (C=1.82 g/100 ml; metanol).
e.) Adicijska sol dekstrogirog metil alfa-(4,5,6,7-tetrahidro-tieno-/3.2-c/pirid-5-il)-(2-klorofenil)-acetata sa sumpornom kiselinom (SR 25990 C)
U suspenziju 200 g spoja SR 25990 B u 800 ml diklorometana dodano je 800 ml zasićene vodene otopine natrijevog bikarbonata, pa je nakon miješanja organska faza sušena preko bezvodnog natrijevog sulfata i otapalo je isparavano pod smanjenim pritiskom. Ostatak je otopljen u 500 ml acetona, ohlađen na ledu, i u kapima mu je dodano 20.7 ml koncentrirane sumporne kiseline (93.64% -d=1.83). Dobiveni talog je izoliran filtriranjem i ispran sa 1000 ml acetona, te sušen u peći na 50°C.
Dobiveno je 139g bijelih kristala, t.t. analitičkog uzorka 184°C.
Zbrojna formula C16H16ClNO2S•H2SO4;/alfa/20D=+55.10 (c=1.891 g/100 ml; metanol).
f.) Bromohidrat dekstrogirog metil alfa-(4,5,6,7-tetrahidro-tieno-/3.2-c/pirid-5-il)-(2-klorofenil)-acetata (SR 25990 D)
U suspenziju 20g spoja SR 25990 B u 200 ml diklorometana dodano je 150 ml vodene otopine natrijevog bikarbonata. Ostatak, koji je dobiven nakon odvajanja organske faze, sušenja i isparavanja otopine, otopljen je u 150 ml dietil ili diizopropil etera i u kapima mu je dodano 4.4 ml 48 mas/zapr.% vodene otopine bromovodikove kiseline. Dobiveni talog je odvojen, pa je nakon sušenja dao 14.4 g (99%) kristala sa t.t. 111°C.
13.4 g ovih kristala je prekristalizirano iz smjese izopropil etera (100 ml) i izopropanola (150 ml), da bi dobili 10.2g analitički čistog bromohidrata, t.t. 140°C. Zbrojna formula: C16H16ClNO2S•HBr; /alfa/20D=+59.23 (c=2.09 g/100 ml; metanol).
g.) Tauroholat dekstrogirog metil alfa-(4,5,6,7-tetrahidro-tieno-/3.2-c/pirid-5-il)-(2-klorofenil)-acetata (SR 25990 E)
Natrijeva sol tauroholne kiseline je kromatografirana na koloni sa smolom Amberlite IRN, uz eluiranje vodom. Dobivene frakcije su liofilizirane.
3g (0.0054 mola) spoja SR 25990 B alkalizira se otapanjem u 200 ml zasićene vodene otopine natrijevog bikarbonata, pa se eksptrahira diklorometanom. Organska faza suši se preko Na2SO4 i isparava dok se ne osuši. Dobivena slobodna baza otapa se u 30 ml izopropanola, pa se otopini doda otopina 2.8g (0.0054 mola) tauroholne kiseline u 100 ml izopropanola. Smjesa se stavi na sobnu temperaturu, uz miješanje, preko noći, a zatim se isparava dok se ne osuši. Ostatak kristalizira iz etera, da bi dao 3.5g kristala boje mesa. T.t. 120°C; /alfa/20/D=+39.53 (1.791 g/100 ml metanola). C16H16ClNO2S•C26H45NO7S; analitički podaci za C, H i N odgovaraju izračunatim.
PRIMJER 2 - Soli ljevogirog metil alfa-(4,5,6,7-tetrahidro-tieno/3.2-c/pirid-5-il)-(2-klorofenil)-acetata
a.) Sol sa D-10-kamfosulfatnom kiselinom (SR 25989 B)
Vrši se isparavanje acetonske otopine dobivene u Primjeru 1-b, nakon odvajanja spoja SR 25990 B.
Ostatak se preuzima u vodi i dietil eteru. Eterska faza se dekantira. Vodena faza se ohladi do 5°C i alkalizira sa zasićenom vodenom otopinom natrijevog bikarbonata. Bazna vodena faza se ekstrahira dietil eterom, eterski ekstrakti se spoje, i suše se preko anhidriranog natrijevog sulfata.
Isparavanjem se dobiva ulje, koje se pročišćava filtriranjem kroz sloj silikagela (eluent: dietil eter).
Izolirano bezbojno ulje predstavlja smjesu oko 65% ljevogirog enantiomjera i 35% dekstrogirog enantiomjera, pri čemu je proporcija utvrđena H NMR spektroskopijom (60 MHz) uz dodatak kiralnog kompleksnog spoja lantanida.
16.66 g (0.0517 mola) tako dobivene smjese otopi se u 70 ml acetona. Doda se 7.77 g (0.0310 mola) monohidrata dekstrogire 10-kamfosulfatne kiseline. Homogena smjesa ostavlja se preko noći na sobnoj temperaturi. Dobiveni kristali se filtriraju, ispiru acetonom i suše (Doprinos: 44% u odnosu na smjesu).
Dobiveni kristali otapaju se u minimalnoj količini acetona (60 ml) na temperaturi refluksa. Talog dobiven nakon hlađenja do sobne temperature se filtrira, ispire acetonom i suši. Bijeli kristali, t.t. 167°C, /alfa/20D=-24.85 (c=1.79 g/100 ml, metanol).
b.) Ljevogiri metil alfa-(4,5,6,7-tetrahidro-tieno/3.2-c/pirid-5-il)-(2-klorofenil)-acatata
11.3 g (0.0204 mola) 10-kamfosulfata dobivenog u dijelu a.) otapa se u minimalnoj količini vode. Nakon hlađenja do 5°C, dobivena vodena otopina se alkalizira dodatkom zasićene vodene otopine natrijevog bikarbonata. Alkalna vodena faza se ekstrahira diklorometanom, pa se organska faza suši i otapalo isparava. Izolira se bezbojno ulje (kvantitativni doprinos).
Ulje, /alfa/20D=-50.74 (c=1.58 g/100 ml, metanol).
c.) Klorohidrat ljevogirog metil alfa-(4,5,6,7-tetrahidro-tieno/3.2-c/pirid-5-il)-(2-klorofenil)-acetata (SR 25989 A)
Dobiva se prema postupku opisanom u Primjeru 1-d. Doprinos: 94%.
Bijeli kristali, t.t. 117°C, /alfa/20D=-62.56 (c=1.80 g/100 ml, metanol).
d. ) Adicijska sol ljevogirog metil alfa-(4,5,6,7- tetrahidro-tieno/3.2-c/pirid-5-il)-(2-klorofenil)-acetata sa sumpornom kiselinom (SR 25989 C)
Alkalizira se 70 g (0.126 mola) kamfosulfata SR 25989 B, dobivenog u dijelu a.), otapanjem u zasićenoj vodenoj otopini natrijevog bikarbonata sa diklorometanom. Organska faza se dakantira, suši preko natrijevog sulfata i isparava dok se ne osuši.
Ostatak se stavi u 300 ml acetona i u kapima se dodaje 7.2 ml (0.126 mola) koncentrirane sumporne kiseline. Nakon miješanja se dobiveni kristali filtriraju i ispiru acetonom. Dobiva se 47.8 g bijelih kristala.
T.t. 182°C, /alfa/20D=-51.61 (c=2.044 g/100 ml, metanol). Analitički podaci za C, H i N odgovaraju izračunatim.
FARMAKOLOŠKO ISPITIVANJE
Učinak novih spojeva protiv agregacije krvnih zrnca, kao i njihova toksičnost, istraživani su uspoređivanjem s odgovarajućim svojstvima racemske smjese opisane u Francuskom patentu Br. 82,12599 (izd. br. 2 530 247).
U vezi s tim, opisani su rezultati navedenih testova koji upućuju na daljnju prednost sadašnjeg izuma - zaključak da soli dekstrogiorog izomera imaju veću terapeutsku vrijednost od soli racemske smjese; u stvari, ljevogiri izomer nema praktički nikakav učinak na agregaciju krvnih zrnca, a toksičnost mu je bitno veća od toksičnosti njegovog dekstrogirog homologa.
Učinak na agregaciju krvnih zrnca i antitrombogeni učinak ovih spojeva istraživani su kod štakora, na uobičajeni način. Izvršeno je in vivo određivanje učinka na agregaciju krvnih zrnca izazvanu sa ADP ili s kolagenom.
Proizvodi su, etanolskoj otopini (200 mg/ml) razblaženom sa vodom koja sadrži gumiarabiku (5 mas/zapr.%), oralnim putem davani grupama od po 5 ženki štakora vrste CD-COBS težine 250-300 g, u količini od 10 ml suspenzije na kilogram, 2 sata prije uzimanja krvi.
Pripremljeni su uzorci krvi sa 3.8% vodenom otopinom natrijevog citrata (1 volumen na 9 volumena krvi), pri čemu je krv uzeta punktiranjem abdominalne aorte životinja, prethodno anesteziranih dietil eterom. Zatim je, centrifugiranjem pri 200 x g tokom 10 minuta, dobivena plazma bogata krvnim zrncima.
Agregacija se izaziva dodatkom 2 mikrolitra otopine za agregaciju na 400 mikrolitara plazme bogate krvnim zrncima. Korištene otopine za agregaciju bile su slijedeće: vodena otopina ADP koncentracije 500 mikroM, koji prodaje Boehringer Mannheim (finalna koncentracija 2.5 mikroM) i otopina kolagena koji prodaje Sigma (type 1) koncentracije 0.25 g/100 ml octene kiseline, sa koncentracijom 3% (zapr./zapr.) (finalna koncentracija 12.5 mikrograma/ml).
Agregacija zrnca promatrana je metodom koju je opisao G. V. R. Born, Nature, 194, str. 927 (1967), s agregometrom Coultronics R, na 37°C i pri miješanju od 900 okretaja u minuti.
Za agregaciju izazvanu sa ADP, agregometar je dao krivulju koja predstavlja agregaciju pločica mjerenu preko promjene optičke gustoće. Visina krivulje definirana je kao visina agregacije. Postotak agregacije predstavlja izmjerenu visinu agregacije podijeljenu s visinom koja odgovara 100%-tnoj agregaciji, puta 100. Postotak inhibicije odreduje se pomoću slijedeće formule:
(visina agregacije kontrolnog uzorka)-(visina agregacije proizvoda)
-------------------------------------------------------------------------------------------- x 100
(visina agregacije kontrolnog uzorka)
Rezultati dobiveni za agregaciju izazvanu sa ADP za klorohidrat racemske smjese (PCR 4099), adicijske soli sa sumpornom kiselinom dekstrogirog (SR 25990 C) i ljevogirog (SR 25989 C) izomera s jedne strane i PCR 4099 i klorohidrata dekstrogirog (SR 25990 A) izomera s druge strane, prikazani su u Tabeli I; oni pokazuju da je ljevogiri izomer neaktivan, dok je dekstrogiri izomer aktivniji od racemata.
TABELA I
[image]
[image]
* srednja vrijednost rezultata +/- srednja standardna devijacija (SSD)
** studentov test
*** visina agregacije u mm: srednja +/- SSD (n=5)
n.s. nije važan
Za agregaciju sa kolagenom, postotak inhibicije predstavlja razliku nagiba krivulja koje prikazuju promjenu optičke gustoće u funkciji vremena za kontrolni uzorak i za proizvod, podijelj enu nagibom krivulje za kontrolni uzorak i pomnoženu sa 100. Rezultati prikazani u Tabeli II ponovo, uspoređivanjem aktivnosti označenih soli, pokazuje da je aktivan samo dekstrogiri izomer.
TABELA II
[image]
[image]
** studentov test
n.s. nije važno
Također se ispituje antitrombogeni učinak spoja iz sadašnjeg izuma, testom venske tromboze izazvane svrdlom koji je opisao T. Kumada sa suradnicima u Thromb. Res. 18, str. 189 (1980).
Ženke štakora, iste vrste kao i u prethodnom istraživanju, korištene u grupama od po 10, anestezirane su dietil eterom i nakon rezanja abdomena izolirana im je šuplja vena.
Kroz otvor na ovoj veni se, neposredno iznad bubrežnog račvanja i u smjeru slabinskih vena, bez oštećenja zidova, spušta metalno zubarsko svrdlo (borer) dužine 21 mm, nabavljeno od firme Dyna (Francuska), veličina br. 30; svrdlo se implantira dužinom od 19 do 20 mm, 1 mm se ostavlja da viri, a zatim se abdomen ponovo zatvara.
Trombi se formiraju brzo, pa se za najviše 5 sati, pod pentobarbitalskom anestezijom, abdomen ponovo otvara i vena se podvezuje uzvodno i nizvodno od svrdla, koje se odstranjuje nakon uzdužnog rezanja vene. Izolirani tromb se mjeri.
Rezultati iz Tabele III pokazuju da je u ovom testu ljevogiri izomer neaktivan, za razliku od dekstrogirog izomera i racemata.
TABELA III
[image]
* = masa tromba u mg +/- srednja standardna devijacija
P = Kruskal-Wallis-ov test
U toksikološkom ispitivanju, spojevi se daju oralno, kao suspenzija u podjednakoj količini vode koja sadrži 10 mas/zapr.% gumiarabike, grupama od po 10 ženki štakora vrste Sprague Dawley teških 120 do 135g, na tašte.
Broj uginulih životinja bilježi se 14 sati nakon davanja testiranog proizvoda. Smrtonosne doze, izražene kao masa davane soli, navedene su u Tabeli IV; ovi rezultati jednim dijelom pokazuju da je toksičnost racemske smjese slična toksičnosti ljevogirog izomera, dok je dekstrogiri izomer znatno manje toksičan, a drugim dijelom pokazuju da toksičnost ovisi o prirodi kiseline sa kojom se sol sagrađuje.
TABELA IV
[image]
( ) = interval vjerodostojnosti
Izvršena farmakološka istraživanja daju dokaze o zanimljivim svojstvima inhibicije agregacije krvnih zrnca za spoj (Id), te o nedostatku aktivnosti za izomer (I1).
Lijekovi iz sadašnjeg izuma mogu, za oralno davanje, biti u obliku tableta, dražeja, kapsula, kapi, granula ili sirupa. Također mogu biti u obliku suspozitorija za rektalno davanje ili otopine za injekcije za parenteralno davanje.
Svaka pojedinačna doza sadržavati će od 0.001 do 0.1g derivata iz sadašnjeg izuma, a dnevna doza biti će od 0.001 do 0.500g aktivnog sastojka, ovisno od stadija bolesti i ozbiljnosti tretiranog poremećaja.
Slijedi nekoliko neograničavajućih primjera farmaceutskih proizvoda koji sadrže lijek iz sadašnjeg izuma.
1) Tablete
Aktivni sastojak ......... 0.010 g
Ekscipijent: laktoza, kristalni šećer, rižin škrob, alginska kiselina, magnezij stearat
2) Dražeje
Aktivni sastojak ......... 0.005 g
Ekscipijent: magnezij stearat, kukuruzni škrob, gumiarabika, gumilak, bijeli šećer, glukoza,
bijeli vosak, karnuba vosak(1), parafin, novi koksin(2)
3) Kapsule
Aktivni sastojak ......... 0.025 g
Ekscipijent: magnezij stearat, kukuruzni škrob, laktoza
4) Otopina za injekcije
Aktivni sastojak ......... 0.050 g
izotona otopina do 3 ml
5 ) Suspozitoriji
Aktivni sastojak ......... 0.030 g
polusintetički trigliceridi do količine za jedan suspozitorij.
-------------------------------
(1) vosak dobiven sa lišća brazilske karnuba-palme (Copernicia cerifera)- prim. prev.
(2) vrsta crvene prehrambene boje- prim. prev.
Zbog svojih zanimljivih svojstava inhibiraju agregacije krvnih zrnca, preko utjecaja na mehanizam nastanka arterijske i venske tromboze, lijekovi iz sadašnjeg izuma mogu se davati u terapiji ili prevenciji agregacije krvnih zrnca koja se javlja u vantjelesnim cirkulatornim sustavima ili kao posljedica komplikacija ateroma.
Claims (6)
1. Dekstrogiri enantiomjer metil alfa-(4,5,6,7-tetrahidro-tieno[3,2-c]pirid-5-il)-(2-klorofenil)-acetata.
2. Klorohidrat dekstrogirog enantiomjera metil alfa-(4,5,6,7-tetrahidro-tieno[3,2-c]pirid-5-il)-(2-klorofenil)-acetata.
3. Bromohidrat dekstrogirog enantiomjera metil alfa-(4,5,6,7-tetrahidro-tieno[3,2-c]pirid-5-il)-(2-klorofenil)-acetata.
4. Hidrogen sulfat dekstrogirog enantiomjera metil alfa-(4,5,6,7-tetrahidro-tieno[3,2-c]pirid-5-il)-(2-klorofenil)-acetata.
5. Tauroholat dekstrogirog enantiomjera metil alfa-(4,5,6,7- tetrahidro-tieno[3,2-c]pirid-5-il)-(2-klorofenil)-acetata.
6. Postupak za dobivanje dekstrogirog enantiomjera metil alfa-(4,5,6,7-tetrahidro-tieno[3,2-c]pirid-5-il)-(2-klorofenil)-acetata i njegovih farmaceutski prihvatljivih soli, označen time, što se formira sol racemskog metil alfa-(4,5,6,7-tetrahidro-tieno[3,2-c]pirid-5-il)-(2-klorofenil)-acetata s optički aktivnom kiselinom, kao npr. ljevogira kamfor-10-sulfatna kiselina, u otapalu kao što je aceton; vrši se višestruka rekristalizacija, u istom otapalu, sve dok se ne dobije proizvod s konstantnom optičkom rotacijom; dekstrogiri izomer pretvara se u oblik slobodne baze; po potrebi se dobiveni proizvod pretvara u svoju sol sa farmaceutski prihvatljivom kiselinom.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8702025A FR2612929B1 (fr) | 1987-02-17 | 1987-02-17 | Enantiomere dextrogyre de 1a-(tetrahydro- 4,5,6,7 thieno (3,2-c) pyridyl-5) (chloro-2 phenyl)-acetate de methyle, son procede de preparation et les compositions pharmaceutiques le renfermant |
| FR878716516A FR2623810B2 (fr) | 1987-02-17 | 1987-11-27 | Sels de l'alpha-(tetrahydro-4,5,6,7 thieno(3,2-c) pyridyl-5) (chloro-2 phenyl) -acetate de methyle dextrogyre et compositions pharmaceutiques en contenant |
| YU23188A YU46748B (sh) | 1987-02-17 | 1988-02-05 | Dekstrogiri enantiomer metil alfa (4,5,6,7-tetrahidro-tien/,3,2-c/ pirid-5-il)-(2-hlorofenil)-acetata, njegove soli i postupak za dobijanje |
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| HRP920923A2 true HRP920923A2 (hr) | 1994-04-30 |
| HRP920923B1 HRP920923B1 (en) | 2001-12-31 |
Family
ID=26225786
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|---|---|---|---|
| HR920923A HRP920923B1 (en) | 1987-02-17 | 1992-10-02 | Dextrorotatory enantiomer of alpha-(4,5,6,7-tetrahydrothieno/3,2-c/pyrid-5-yl) (2-chlorophenyl)methyl acetate, its salts, and process for its preparation |
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| US (1) | US4847265A (hr) |
| EP (1) | EP0281459B1 (hr) |
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| AT (1) | ATE121745T1 (hr) |
| AU (1) | AU597784B2 (hr) |
| CA (1) | CA1336777C (hr) |
| CS (1) | CS274420B2 (hr) |
| CY (1) | CY2087B1 (hr) |
| DE (2) | DE19875053I2 (hr) |
| DK (1) | DK173636B1 (hr) |
| ES (1) | ES2071621T4 (hr) |
| FI (1) | FI87216C (hr) |
| FR (1) | FR2623810B2 (hr) |
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Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2530247B1 (fr) * | 1982-07-13 | 1986-05-16 | Sanofi Sa | Nouveaux derives de la thieno (3, 2-c) pyridine, leur procede de preparation et leur application therapeutique |
| DE3621413A1 (de) * | 1986-06-26 | 1988-01-07 | Boehringer Ingelheim Kg | Verwendung carbocyclisch und heterocyclisch annelierter dihydropyridine als cardioprotektive mittel sowie neue heterocyclisch und carbocyclisch anellierte dihydropyridine, verfahren zu deren herstellung und zwischenstufen fuer deren herstellung |
| DE3736664A1 (de) * | 1987-10-29 | 1989-05-11 | Boehringer Ingelheim Kg | Tetrahydro-furo- und -thieno(2,3-c)pyridine, ihre verwendung als arzneimittel und verfahren zu ihrer herstellung |
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