HRP20010725A2 - 1,4-benzothiazepine-1,1-dioxide derivatives substituted by sugar radicals, methods for the production thereof, medicaments containing these compounds and the use thereof - Google Patents
1,4-benzothiazepine-1,1-dioxide derivatives substituted by sugar radicals, methods for the production thereof, medicaments containing these compounds and the use thereof Download PDFInfo
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- HRP20010725A2 HRP20010725A2 HR20010725A HRP20010725A HRP20010725A2 HR P20010725 A2 HRP20010725 A2 HR P20010725A2 HR 20010725 A HR20010725 A HR 20010725A HR P20010725 A HRP20010725 A HR P20010725A HR P20010725 A2 HRP20010725 A2 HR P20010725A2
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- 150000001875 compounds Chemical class 0.000 title claims description 69
- 235000000346 sugar Nutrition 0.000 title claims description 26
- 239000003814 drug Substances 0.000 title claims description 9
- 238000000034 method Methods 0.000 title claims description 9
- 238000004519 manufacturing process Methods 0.000 title claims description 7
- IVGHNDNOFMTFMK-UHFFFAOYSA-N 1$l^{6},4-benzothiazepine 1,1-dioxide Chemical group O=S1(=O)C=CN=CC2=CC=CC=C12 IVGHNDNOFMTFMK-UHFFFAOYSA-N 0.000 title description 3
- 150000003839 salts Chemical class 0.000 claims description 20
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D281/02—Seven-membered rings
- C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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Description
Izum se odnosi na supstituirane derivate 1,4-benzotiazepin-1,1-dioksida, na njihove fiziološki podnošljive soli i fiziološki funkcionalne derivate.
Već su opisani derivati 1,4-benzotiazepin-1,1-dioksida, te njihova upotreba za liječenje hiperlipidemije kao i arterioskleroze i hiperholesterinemije [usp. PCT patentna prijava br. PCT/GB 95/01884, publikacija br. WO 96/05188].
Zadatak izuma je dati na raspolaganje daljnje spojeve koji razvijaju terapeutski dragocjeno hipolipidemijsko djelovanje. Zadatak se posebno sastoji u tome da se pronađu novi spojevi koji, suprotno spojevima opisanim u stanju tehnike, potiču izlučivanje žučne kiseline već pri nižem doziranju.
Izum se stoga odnosi na spojeve formule I,
[image]
u kojoj
R1 predstavlja metil, etil, propil, butil;
R2 je H, OH;
R3 je šećerni radikal, dišećerni radikal, trišećerni radikal, tetrašećerni radikal, pri čemu je šećerni radikal, dišećerni radikal, trišećerni radikal ili tetrašećerni radikal prema potrebi jednostruko ili višestruko supstituiran sa šećernom zaštitnom skupinom;
Z je -(C=O)n-C0-C16-alkil-, -(C=O)n-C0-C16-alkil-NH-, -(C=O)n-C0-C16-alkil-O-, -(C=O) n-C0-C16-alkil-(C=O)m, kovalentna veza;
n je 0 ili 1;
m je 0 ili 1;
kao i njihove farmaceutski podnošljive soli i njihove fiziološki funkcionalne derivate.
Prednosni su spojevi formule I, u kojoj jedan ili više radikala ima, odnosno imaju slijedeće značenje:
R1 je etil, propil, butil;
R2 je H, OH;
R3 je šećerni radikal, dišećerni radikal, pri čemu šećerni radikal ili dišećerni radikal je prema potrebi jednostruko ili višestruko supstituiran sa šećernom zaštitnom skupinom;
Z je -(C=O)n-C0-C16-alkil-, -(C=O)n-C0-C16-alkil-NH-, -(C=O)n-C0-C16-alkil-O-, -(C=O)n-C0-C16-alkil-(C=O)m, kovalentna veza;
n je 0 ili 1;
m je 0 ili 1;
te njihove farmaceutski podnošljive soli.
Posebno prednosni su spojevi formule I, u kojima jedan ili više radikala ima, odnosno imaju slijedeća značenja:
R1 je radikal etil, butil;
R2 je H, OH;
R3 je šećerni radikal, pri čemu šećerni radikal je prema potrebi jednostruko ili višestruko supstituiran sa šećernom zaštitnom skupinom;
Z je -(C=O)-C0-C4-alkil, kovalentna veza;
kao i njihove farmaceutski podnošljive soli.
Farmaceutski podnošljive soli su zbog njihove više topivosti u vodi, u usporedbi s polaznim odnosno osnovnim spojevima, posebno prikladne za medicinsku primjenu. Te soli moraju imati farmaceutski podnošljiv anion ili kation. Prikladne farmaceutski podnošljive kiselinske adicijske soli spojeva prema izumu su soli anorganskih kiselina, kao što je solna kiselina, bromovodična, fosforna, meta-fosforna, dušična, sulfonska i sumporna kiselina, te soli organskih kiselina, kao što je npr. octena kiselina, benzolsulfonska, benzojeva, limunska, etansulfonska, fumarna, glukonska, glikolna, izotionska, mliječna, laktobionska, maleinska, jabučna, metansulfonska, jantarna, p-toluolsulfonska, vinska i trifluoroctena kiselina. Za medicinsku svrhu s posebnom prednošću se upotrebljava solna kiselina. Prikladne farmaceutski podnošljive bazične soli su amonijeve soli, soli alkalijskih metala (kao natrijeve i kalijeve soli) i soli zemno alkalijskih metaka (kao soli magnezija i kalcija).
Soli s aminom koji nije farmaceutski podnošljiv također spadaju u okvir izuma kao korisni međuproizvodi za proizvodnju ili za čišćenje farmaceutski podnošljivih soli i/ili za ne-terapeutsku upotrebi, na primjer za primjernu in vitro.
Pojam "fiziološki funkcionalni derivat", koji se ovdje upotrebljava, odnosi se na svaki fiziološki podnošljiv derivat spoja prema izumu, npr. ester, koji dat sisavcu, npr. čovjeku, može (izravno ili posredno) dati takav spoj ili aktivan metabolit.
Daljnji predmet ovog izuma su predlijekovi spojeva prema izumu. Takovi predlijekovi mogu se in vivo metabolizirati u spoj prema izumu. Ti predlijekovi sami mogu ili ne moraju biti učinkoviti.
Spojevi prema izumu mogu također postojati u različitim polimorfnim oblicima, npr. kao amorfni i kristalinični polimorfni oblici. Svi polimorfni oblici spojeva prema izumu spadaju u okvir izuma i oni su daljnji predmet izuma.
Nadalje, svi navodi "spoja (spojeva) formule (I)" odnose se na spoj (spojeve) formule (I) kako je gore opisana, kao i na njihove soli, solvate i fiziološki funkcionalne derivate kako su ovdje opisani.
Količina spoja formule (I), koja je potreba da bi se postigao željeni biološki učinak, ovisi o nizu faktora, npr. o odabranom specifičnom spoju, predviđenoj upotrebi, o načinu davanja i o kliničkom stanju pacijenta. Općenito dnevna doza je u području od 0,1 mg do 100 mg (tipično od 0,1 mg i 50 mg) dnevno po kilogramu tjelesne težine, npr. 0,1-10 mg/kg/dnevno. Tablete ili kapsule mogu sadržavati, na primjer, od 0,01 do 100 mg, tipično od 0,02 do 50 mg. U slučaju farmaceutski podnošljivih soli navedeni težinski podaci odnose se na težinu iona benzotiazepina dobivenih od soli. Za profilaksu ili terapiju gore navedenih stanja spojevi formule (I) se mogu upotrijebiti kao čisti spoj, međutim oni se daju ponajprije zajedno s podnošljivim nosačem u obliku farmaceutskog pripravka. Nosač mora naravno biti podnošljiv u takovom smislu da je on kompatibilan s drugim sastojcima pripravka i da ne šteti zdravlju pacijenta. Nosač može biti kruta tvar ili tekućina ili oboje i ponajprije se formulira sa spojem kao pojedinačna doza, na primjer kao tablete koje mogu sadržavati od 0,05% do 95 mas. % aktivne tvari. Također mogu biti prisutne i daljnje farmaceutski aktivne tvari, koje uključuju daljnje spojeve formule (I). Farmaceutski pripravci se mogu proizvesti poznatim farmaceutskim postupcima, koji se uglavnom sastoje u tome da se sastojak pomiješa s farmakološki podnošljivim nosačem i/ili pomoćnim tvarima.
Farmaceutski pripravci prema izumu su oni koji su prikladni za oralnu i peroralnu (npr. suplingvalnu) aplikaciju, pri čemu najpovoljniji način aplikacije ovisi u svakom slučaju o vrsti i težini stanja koje se liječi i o vrsti dotičnog upotrebljenog spoja formule (1) . Formulacije u obliku dražeja i formulacije dražeja za usporeno oslobađanje također spadaju u okvir izuma. Prednosne su formulacije koje su otporne prema kiselinama i želučanom soku. Prikladne prevlake otporne prema želučanom solu obuhvaćaju celulozni acetat ftalat, polivinal acetat ftalat, hidroksipropilmetilcelulozni ftalat i anionske polimere metakrilne kiseline i metil estera metakrilne kiseline.
Prikladni farmaceutski spojevi za oralno davanje mogu biti u posebnim jedinicama, kao što su na primjer kapsule, kapsule od hostije, pastile ili tablete, koje u svakom slučaju sadrže određenu količinu spoja formule (I) ; kao prah ili granulat; kao otopina ili suspenzija u vodenoj ili ne-vodenoj tekućini; ili kao emulzija ulja u vodi ili vode u ulju. Kako je već spomenuto, ti pripravci se mogu proizvesti bilo kojim prikladnim farmaceutskim postupkom koji obuhvaća jedan stupanj, u kojem se aktivna tvar i nosač (koji se može sastojati iz jednog ili više dodatnih sastojaka) dovedu u dodir. Općenito, pripravci se proizvode jednolikim i homogenim miješanjem aktivne tvari s tekućim i/ili fino usitnjenim krutim nosačem, nakon čega se prema potrebi oblikuje proizvod. Tako se, na primjer, tablete mogu proizvesti tako da se prah ili granulat spoja spreša ili oblikuje, prema potrebi s jednim ili više dodatnih sastojaka. Isprešane tablete se mogu proizvesti tabletiranjem spoja u sipkom obliku, na primjer tabletiranjem praha ili granulata, pomiješanog prema potrebi s veznim sredstvom, kliznim sredstvom, s inertnim sredstvom za razrjeđivanje i/ili s jednim ili više površinski aktivnih/disperznih sredstava u prikladnoj mješalici. Oblikovane tablete mogu se proizvesti oblikovanjem praškastog spoja navlaženog s inertnim tekućim sredstvom za razrjeđivanje pomoću odgovarajućeg stroja.
Farmaceutski pripravci koji su prikladni za peroralno (suplingvalno) davanje obuhvaćaju pastile, koje sadrže spoj formule (I) sa sredstvom koje im podaje okus, uobičajeno saharozu i gumu arabiku ili tragant, i pastile koje sadrže spoj u inertnoj osnovi kao što je želatina i glicerin ili saharoza i guma arabika.
Predmet izuma su, nadalje, također i smjese izomera formule I, kao također i čisti stereoizomeri formule I, kao i smjese diastereomera formule I, kao također i čisti diastereomeri. Rastavljanje smjese vrši se kromatografijom.
Prednost se daje racemičnim kao također i enantiomerno čistim spojevima formule I slijedeće strukture:
[image]
Kao šećerni radikali podrazumijevaju se spojevi derivirani od aldoza i ketoza s 3 do 7 ugljikovih atoma, koji mogu pripadati nizu D ili L; tu također spadaju amino šećeri, šećerni alkoholi ili šećerne kiseline. Kao primjeri se navode glukoza, manoza, fruktoza, galaktoza, riboza, eritroza, glicerin aldehid, sedoheptuloza, glukozamin, galaktozamin, glukuronska kiselina, galakturonska kiselina, glukonska kiselina, galaktonska kiselina, manonska kiselina, glukamin, 3-amino-1,2-propandiol, glukarna kiselina i galaktarna kiselina.
Sa dišećerima se misli na saharide koji se sastoje iz dvije šećerne skupine. Di-, tri- ili tetrasaharidi nastaju acetalnim povezivanjem dvaju ili više šećera. Pri tome do povezivanja može doći u α ili u β obliku. Kao primjeri se navode laktoza, maltoza i celobioza.
Ako je šećer supstituiran, tada se supstitucija vrši ponajprije na vodikovom atomu OH skupine šećera.
Za hidroksi skupine šećera kao zaštitne skupine uglavnom dolaze u obzir slijedeće: benzilna, acetilna, benzoilna, pivaloilna, tritilna, terc-butildimetilsililna, benzilidenska, cikloheksilidenska ili izopropilidenska zaštitna skupina.
Spojevi formule I i njihove farmaceutski podnošljive soli i njihovi fiziološki funkcionalni derivati predstavljaju idealan lijek za liječenje poremećaja izmjene lipida, posebno hiperlipidemije. Spojevi formule I prikladni su također za utjecanje na razinu hoelsterola u serumu, te za prevenciju i liječenje arteriosklerotičkih pojava. Spojevi se prema potrebi također mogu dati u kombinaciji sa statinima, kao što su npr. simvastatatin, fluvastatin, pravastatin, cerivastatin, lovastatin ili atorvastin. Slijedeći nalazi potvrđuju farmakološku učinkovitost spojeva prema izumu.
Biološka ispitivanja spojeva prema izumu provedena su pokusima perfuzije. Tim pokusom ispituje se djelovanje spojeva prema izumu na transport žučne kiseline u ileum.
Ispitane su diastereomerne smjese spojeva.
Pokus perfuzije se provodi kako slijedi.
Opis pokusa
Mužjaci Wistar štakora (raspona težine 250-350 g) narkotiziraju se s uretanom (1,5 g/kg i.p.) i žučni kanal se kanulira s polietilenskom cjevčicom. Osam cm proksimalno prema zaklopcu slijepog crijeva zareže se u ileum i za cjevčicu se pričvrsti silikonski adapter. Drugu inciziju s ugradnjom odgovarajućeg silikonskog adaptera izvrši se u slijepom crijevu. Silikonsku cjevčicu se priključi na adapter da bi se perfundiralo ileum s perfuzijskim puferom ortogradno i otvoreno s (ne cirkulirajući) brzinom perfuzije od 1 ml/min.
Perfuzijsku cjevčicu se napuni s puferom za perfuziju (137 mM NaCl, 0,9 mM CaCl2, 0,51 mM MgCl2, 8,1 mM Na2HPO4, 2,7 mM KCl, 1,47 mM KH2PO4) (pH 7,4), 1% (v/v) etanola + 1% DMSO. Pufer za perfuziju sadržavao je ispitne spojeve u navedenim koncentracijama ili vehikl. Pufer je prethodno zagrijan na 37°C. Pufer za perfuziju sadržavao je 3 mM tauroholne kiseline (TCA), koja je bila obilježena s 1000 dpm/μl 3H TCA kao markerom.
Provedba ispitivanja i obrada rezultata
Odabran je eksperimentalni postav koji omogućuje određivanje inhibicije transporta žučne kiseline na pojedinačnoj životinji. Žuč je skupljana u razmacima od 10 minuta tijekom 90 minuta (i tijekom 160 minuta u slučaju priključene faze ispiranja za ispitivanje revezibilnosti). Nakon perfuzije puferske otopine koja je sadržavala vehikl tijekom 40 minuta (prethodna ispitna tvar) slijedila je perfuzuja s perfuzijskim puferom koji je sadržavao ispitni spoj u koncentraciji koju se je željelo ispitati (do 90 min).
Za izračunavanje postotka inhibcije pomoću ispitnog spoja, dpms (dezintegracije po min/raspadanje 3H-TCA po minuti) u žuči od 80-90 min (kraj perfuzije s ispitnom tvari) dovedene su u vezu s periodom skupljanja 30-40 min tijekom prethodne faze, kad je u kontrolnoj fazi izlučivanje 3H-TCA bilo doseglo svoj maksimum i stabiliziralo se. Izračunata je EC50 (= efektivna koncentracija 50) kao učinkovita koncentracija među vrijednostima inhibicije različitih koncentracija, koja maksimalno izlučivanje žučne kiseline inhibira za 50%.
Rezultati
Tablica 1
[image]
Iz mjernih podataka se vidi da spojevi prema izumu formule I, u usporedbi sa spojevima opisanim u stanju tehnike, pokazuju djelovanje koje je bolje za faktore 7 do 100.
Slijedeći primjeri služe za pobliže objašnjenje izuma, pri čemu se izum ne ograničava na proizvode i izvedbene oblike opisane u primjerima.
Primjer 1
[image]
C29H43N3O8S (593,74). MS (M + H)+ = 594.3
Primjer 2
[image]
C29H43N3O9S (609.74), MS (M + H)+ = 610.4
Primjer 3
[image]
C34H54N4O8S (678.89). MS (M + H}+ = 679.4
Primjer 4
[image]
C41H64N4O9S (777,03). MS (M + H)+ = 777.6
Primjer 5
[image]
C31H47N3O8S (621.79). MS (M + H)+ = 622.4
Primjer 6
[image]
C31H47N3O9S (637.79). MS (M + H)+ = 638.5
Primjer 7
[image]
C36H58N4O8S (706.94). MS (M + H)+ = 707.6
Usporedbeni primjer iz WO 96/05188 (primjer br. 20, 2644W94 (Glaxo Wellcome)):
Usporedbeni primjer 1
[image]
Primjeri su proizvedeni kako slijedi:
[image]
[image]
Sinteza spoja 2:
20g (91,6 mmola) 2,5-difluorbenzofenona 1 (Fluka) otopi se u 400 ml DMSO. Pod argonom se doda 7,0 g (150 mmolova) litijevog sulfida (Fluka). Nakon tri sata pri 120°C, pusti se ohladiti na sobnu temperaturu. Promućka se s 200 ml 2 M aq. HCl i 500 ml etil acetata. Organsku fazu se ispere još dva puta s otopinom NaCl, osuši se preko MgSO4, profiltrira i koncentrira. Dobije se 24 g sirovog proizvoda 2 kao crvenkasto ulje. DC (n-heptan/etil acetat 3:1). Rf = 0,3, edukt 1 Rf = 0,4. C13H9FOS (232,28). MS (M+H)+ = 233,1.
Sinteza spoja 4:
7 g sirovog proizvoda 2, 2,5 g (16 mmolova) dibutil-aziridina 3 (R. Gauthier et al., J. Organomet. Chem. 140 (1977) 245 - 255) i 300 mg p-toluolsulfonske kiseline otopi se u 100 ml lutidina. Reakcijsku otopinu se kuha tri sata pod separatorom vode. Nakon toga se koncentrira i ostatak se očisti vakuumskom kromatografijom. Dobije se 3,6 g (61 %) spoja 4 kao bezbojno ulje. DC (n-heptan/etil acetat 9:1). Rf = 0,5. C13H28FNS (369,55). MS (M+H)+ = 370,3.
Sinteza spoja 5:
3,6 g (9,7 mmolova) spoja 4 i 6,0 g NaJO4 suspendira se u 100 ml acetonitrila, 50 ml metilen klorida i 30 ml vode. Nakon dodatka 200 mg RuCla pusti se snažno miješati 2 sata pri sobnoj temperaturi. Otopinu se razrijedi s 200 ml etil acetata i ispere se dva puta s otopinom NaCl. Nakon sušenja preko MgSO4 se koncentrira i očisti vakuumskom kromatografijom. Dobije se 3,47 g (89%) spoja 5 kao amorfnu krutu tvar. DC (n-heptan/etil acetat 4:1). Rf = 0,5, edukt 4 Rf - 0,6. C23H28FNO2S (401,55). MS (M+H)+ = 402,2.
Sinteza spoja 6:
3,47 g (8,6 mmolova) spoja 5 otopi se u 24 ml kiseline za nitriranje (iz 14 ml HN03 i 10 ml H2SO4). Reakcijsku temperaturu se hlađenjem održava pri 20°C. Nakon 30 minuta otopinu se prelije na mješavinu od 700 g leda i 200 ml etil acetata. Vodenu fazu se odvoji i oprezno se 4 puta ispere sa 150 ml zasićene otopine NaHC03. Zatim se osuši preko MgSO4, koncentrira i očisti vakuumskom kromatografijom. Dobije se 3,0 g (78%) spoja 6 kao amorfnu krutu tvar. DC (n-heptan/etil acetat 4:1). Rf = 0,4. C23H27N2O4SF (446,54). MS (M+H)+ = 447,2.
Sinteza spoja 7:
3,0 g (6,7 mmolova) spoja 6 otopi se u 50 ml 33%-tnog HNMe2 u etanolu (Fluka) i miješa se jedan sat pri 50°C. Nakon toga se pusti ohladiti na sobnu temperaturu i nastali proizvod se odfiltrira. Dobije se 2,86 g (90%) spoja 7 kao žućkaste kristale s talištem pri 188°C. DC (n-heptan/etil acetat 2:1). Rf = 0,5, edukt 7 Rf = 0,6. C52H33N3O4S (471,62). MS (M+H)+ = 472,3.
Sinteza spoja 8a/b kao smjese enantiomera:
1,05 g (2,2 mmola) spoja 7 suspendira se u 30 ml toluola i doda se 500 mg platine na aktivnom ugljenu (10%-tne). Hidrira se 30 sati pod tlakom vodika od 150 bara i pri 100°C u vibracijskom autoklavu. Za obradu se filtrira preko silika gela, ispere se sa 100 ml metanola, koncentrira se i ostatak se očisti vakuumskom kromatografijom. Dobije se 495 mg (48%) spoja 8a/b kao amorfnu krutu tvar. DC (n-heptan/etil acetat 1:1). Rf = 0,3. C25H37N3O2S (443,65). MS (M+H)+ = 444,3.
Sinteza spoja 10a/b kao smjese diastereomera:
80 mg (0,18 mmola) spoja 8a/b i 100 mg (0,24 mmola) penta-O-acetil-D-glukonske kiseline (Org. Synth., svezak 5, 887) se otopi u 4 ml DMF-a (dimetilformamida). K tome se uzastopce doda 100 mg (0,3 mmola) TOTU (Fluka), 35 mg (0,24 mmola) oksima (hidroksi-imino-cijanoctena kiselina-etil ester; Fluka) i 0,1 ml (0,78 mmola) NEM-a (4-etil-morfolin). Nakon jednog sata pri sobnoj temperaturi razrijedi se s 20 ml etil acetata i tri puta se ispere s vodom. Organsku fazu se osuši preko MgSO4, profiltrira i koncentrira. Ostatak se očisti vakuumskom kromatografijom (etil acetat/n-heptan 2:1) i dobije se 130 mg (86%) spoja 10a/b kao amorfnu krutu tvar. DC (etil acetat/n-heptan 2:1) Rf = 0,3. Proizvod ima istu retenciju kao edukt 8a/b, ali se drugačije oboji s 2 M sumpornom kiselinom. C41H57N3O13S (131,97). MS (M + H) + = 832,6.
Sinteza spoja 11a/b kao smjese diastereomera:
130 mg (0,16 mmola) spoja 10a/b se otopi u 5 ml metanola. Nakon dodatka 0,2 ml metanolne 1 M otopine natrijevog metanolata, pusti se stajati jedan sat pri sobnoj temperaturi. Zatim se neutralizira s metanolnom otopinom HCl i koncentrira. Ostatak se očisti vakuumskom kromatografijom (metilen klorid/metanol/konc. amonijak 30/10/3), čime se dobije 78 mg (80%) spoja 10a/b kao amorfnu krutu tvar. DC (metilen klorid/metanoi/konc. amonijak 30/10/3). Rf = 0,4. C31H47N3O8S (621,80). MS (M + H)+ = 622,4.
Sinteza spoja 12a/b kao smjese diastereomera:
618 mg (0,74 mmola) spoja 10a/b otopi se u 30 ml metilen klorida i doda se 385 mg (2,23 mmola) 70%-tne m-klorperbenzojeve kiseline (Fluka). Nakon 30 minuta pri sobnoj temperaturi razrijedi se sa 100 ml etil acetata i ispere se tri puta s otopinom NaHCO3. Zatim se osuši s MgSO4 i koncentrira, čime se dobije 700 mg sirovog proizvoda. Taj sirov proizvod se otopi u 28 ml 0,05 M otopine TiCl4/acetonitrila. Nakon dodatka 300 mg krutog NaJ, pusti se miješati 15 minuta. Za obradu se razrijedi sa 150 ml etil acetata i ispere sa 100 ml 2 M otopine natrijevog tiosulfata. Organsku fazu se osuši preko MgSO4, koncentrira i ostatak se očisti vakuumskom kromatografijom. Dobije se 550 mg (87% iz dva stupnja) spoja 12a/b kao amorfnu krutu tvar. DC (n-heptan/etil acetat 1:2). Rf = 0,3. Edukt 10a/b Rf = 0,35. C41H57N3O14S (847,99). MS (M+H)+ = 848,5.
Sinteza spoja 13a/b kao smjese diastereomera:
550 mg (0,65 mmola) spoja 12a/b se otopi u 20 ml metanola. Nakon dodatka 0,3 ml 1 M metanolne otopine natrijevog metanolata, pusti se stajati jedan sat pri sobnoj temperaturi. Zatim se neutralizira s metanolnom otopinom HCl i koncentrira. Ostatak se očisti vakuumskom kromatografijom (metilen klorid/metanol/konc. amonijak 30/10/3), čime se dobije 370 mg (89%) spoja 13a/b kao amorfnu krutu tvar. DC (metilen korid/metanol/konc. amonijak 30/10/3). Rf = 0,4. C31H47N3O9S (637,80). MS (M + H)+ = 638,4.
Sinteza spoja 15a/b kao smjese diastereomera:
719 mg (1,6 mmola) spoja 8a/b otopi se u 30 ml metilen klorida i 2 ml trietilamina. K toj otopini doda se kap po kap 0,5 ml (3,7 mmol) spoja 14 i pusti se stajati 15 minuta pri sobnoj temperaturi. Zatim se otopinu filtrira preko silika gela i ispere sa 100 ml etil acetata. Ostatak nakon koncentriranja se očisti vakuumskom kromatografijom. Dobije se 950 mg (95%) spoja 15a/b kao amorfnu krutu tvar. DC (n-heptan/etil acetat 1:1). Rf = 0,4. C30H44BrN3O3S (606,67). MS (M+H)+ = 607,3.
Sinteza spoja 17a/b kao smjese diastereomera:
897 mg (1,47 mmola) spoja 15a/b otopi se u 20 ml DMF-a. Nakon dodatka 1,3 g (7,1 mmolova) spoja 16 (glukamin, Fluka) grije se dva sata pri 80°C. Zatim se razrijedi s 50 ml etil acetata i ispere se tri puta s vodom. Organsku fazu se osuši preko MgSO4, profiltrira i koncentrira. Ostatak se očisti vakuumskom kromatografijom (metilen klorid/metanol/ konc. amonijak 30/10/3), čime se dobije 700 mg (67%) spoja 17a/b kao amorfnu krutu tvar. DC (metilen klorid/metanol/ konc. amonijak 30/10/3). Rf = 0,4. C36H58N4O8S (706,95). MS (M + H)+ = 707,4.
Sinteza spoja 19:
8,0 g (18,8 mmolova) spoja 9 (klorid penta-O-acetil-D-glukonske kiseline; Org. Synth. Sv. 5, 887) doda se k suspenziji od 8,0 g (40 mmolova) spoja 18 (Fluka) u 150 ml bezvodnog DMF-a. Tu suspenziju se snažno miješa 20 sati pri sobnoj temperaturi. Zatim se doda 500 ml etil acetata i 200 ml vode. Vodenu fazu se još jednom ekstrahira s 250 ml etil acetata. Sjedinjene organske faze se isperu tri puta s otopinom natrijevog klorida, osuše se preko MgSO4, profiltriraju i koncentriraju. Dobije se 9,5 g (86%) spoja 19 kao bezbojno ulje. DC (metilenklorid/metanol/konc. amonijak 30/10/3). Rf - 0,8. C27H43NO13 (589,64). MS (M + H) + = 590,4.
Sinteza spoja 21a/b kao smjese diastereomera:
200 mg (0,34 mmola) spoja 19, 70 mg (0,17 mmola) spoja 20a/b (20a/b je proizveden analogno postupku opisanom za spoj 8a/b, pri čemu se sekvencu reakcije iz sheme formula 1 provodi s 2-butil-2-etil-aziridinom (R. Gauthier et al./ J. Organomet. Chem. 140 (1977) 245 - 255) i sa spojem 1), 240 mg TOTU, 80 mg oksima i 0,3 ml NEM-a reagira u 4 ml DMF-a analogno postupku opisanom za spoj 11a/b. Nakon vakuumske kromatografije (metilen klorid/metanol/konc. amonijak 30/5/1) dobiveno je 60 mg (46%, u dva stupnja) spoja 21a/b kao amorfna kruta tvar. DC (metilen klorid/metanol/konc. amonijak 30/5/1). Rf = 0,2. C40H64N4O9S (777,04). MS (M + H)+ = 777,8.
Claims (11)
1. Spojevi formule I,
[image]
naznačeni time, da
u kojoj
R1 predstavlja metil, etil, propil, butil;
R2 je H, OH;
R3 je šećerni radikal, dišećerni radikal, trišećerni radikal, tetrašećerni radikal, pri čemu je šećerni radikal, dišećerni radikal, trišećerni radikal ili tetrašećerni radikal prema potrebi jednostruko ili višestruko supstituiran sa šećernom zaštitnom skupinom;
Z je -(C=O)n-C0-C16-alkil-, -(C=O)n-C0-C16-alkil-NH-, -(C=O)n-C0-C16-alkil-O-, -(C=O) n-C0-C16-alkil-(C=O)m, kovalentna veza;
n je 0 ili 1;
m je 0 ili 1;
kao i njihove farmaceutski podnošljive soli i njihovi fiziološki funkcionalni derivati.
2. Spojevi formule I, prema zahtjevu 1, naznačeni time, da jedan ili više radikala ima, odnosno imaju slijedeće značenje:
R1 je etil, propil, butil;
R2 je H, OH;
R3 je šećerni radikal, dišećerni radikal, pri čemu šećerni radikal ili dišećerni radikal je prema potrebi jednostruko ili višestruko supstituiran sa šećernom zaštitnom skupinom;
Z je -(C=O)n-C0-C16-alkil-, -(C=O)n-C0-C16-alkil-NH-, -(C=O)n-C0-C16-alkil-O-, -(C=O)n-C0-C16-alkil-(C=O)m, kovalentna veza;
n je 0 ili 1;
m je 0 ili 1;
te njihove farmaceutski podnošljive soli.
3. Spojevi formule I, prema zahtjevu 1 ili 2, naznačeni time, da jedan ili više radikala ima, odnosno imaju slijedeće značenje:
R1 je radikal etil, butil;
R2 je H, OH;
R3 je šećerni radikal, pri čemu šećerni radikal je prema potrebi jednostruko ili višestruko supstituiran sa šećernom zaštitnom skupinom;
Z je -(C=O)-C0-C4-alkil, kovalentna veza;
kao i njihove farmaceutski podnošljive soli.
4. Postupak za proizvodnju spojeva formule I, prema jednom ili više zahtjeva 1 do 3, naznačen time, da po slijedećoj shemi formula
[image]
amin formule II, u kojoj R1, R2 i R3 imaju značenja navedena za formulu I, reagira sa spojem formule III, u kojoj R3 i Z imaju značenja navedena za formulu I, uz odcjepljenje vode, čime se dobije spoj formule I i dobiveni spoj formule I se prema potrebi prevodi u fiziološki podnošljivu sol ili u fiziološki funkcionalan derivat.
5. Lijek, naznačen time, da sadrži jedan ili više spojeva prema jednom ili više zahtjeva 1 do 3.
6. Lijek, naznačen time, da sadrži jedan ili više spojeva prema jednom ili više zahtjeva 1 do 3 i jedan ili više statina.
7. Spoj prema jednom ili više zahtjeva 1 do 3, naznačen time, da se upotrebljava kao lijek za liječenje poremećaja izmjene lipida.
8. Postupak za proizvodnju lijeka koji sadrži jedan ili više spojeva prema jednom ili više zahtjeva 1 do 3, naznačen time, da se aktivnu tvar pomiješa s farmaceutski prikladnim nosačem i tu smjesu se dovede u oblik prikladan za aplikaciju.
9. Upotreba spoja prema jednom ili više zahtjeva 1 do 3, naznačena time, da se on koristi za proizvodnju lijeka za liječenje hiperlipidemije.
10. Upotreba spoja prema jednom ili više zahtjeva 1 do 3, naznačena time, da se on koristi za proizvodnju lijeka koji djeluje na razinu holesterina u serumu.
11. Upotreba spoja prema jednom ili više zahtjeva 1 do 3, naznačena time, da se on koristi za proizvodnju lijeka za prevenciju arteriosklerotičnih pojava.
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| DE19916108A DE19916108C1 (de) | 1999-04-09 | 1999-04-09 | Mit Zuckerresten substituierte 1,4-Benzothiazepin-1,1-dioxidderivate, Verfahren zu deren Herstellung und deren Verwendung |
| PCT/EP2000/002570 WO2000061568A2 (de) | 1999-04-09 | 2000-03-23 | Mit zuckerresten substituierte 1,4-benzothiazepin-1,1-dioxidderivate, verfahren zu deren herstellung, diese verbindungen enthaltende arzneimittel und deren verwendung |
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| DK406686D0 (da) * | 1986-08-26 | 1986-08-26 | Hans Bundgaard | Carboxylsyrederivater |
| GB9203347D0 (en) * | 1992-02-17 | 1992-04-01 | Wellcome Found | Hypolipidaemic compounds |
| IL108634A0 (en) * | 1993-02-15 | 1994-05-30 | Wellcome Found | Hypolipidaemic heterocyclic compounds, their prepatation and pharmaceutical compositions containing them |
| IL108633A (en) * | 1993-02-15 | 1998-07-15 | Wellcome Found | History of Benzothiazepine Hypolipidemic Preparation and Pharmaceutical Preparations Containing Them |
| ZA956647B (en) * | 1994-08-10 | 1997-02-10 | Wellcome Found | Hypolipidaemic compounds. |
| GB9423172D0 (en) * | 1994-11-17 | 1995-01-04 | Wellcom Foundation The Limited | Hypolipidemic benzothiazepines |
| US5723589A (en) * | 1995-12-21 | 1998-03-03 | Icn Pharmaceuticals | Carbohydrate conjugated bio-active compounds |
| PT864582E (pt) * | 1997-03-14 | 2003-10-31 | Aventis Pharma Gmbh | 1,4-benzotiazepina-1,1-dioxidos hipolipidemicos |
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