SI9520044B - Inhibitorji Xa faktorja - Google Patents

Inhibitorji Xa faktorja Download PDF

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SI9520044B
SI9520044B SI9520044A SI9520044A SI9520044B SI 9520044 B SI9520044 B SI 9520044B SI 9520044 A SI9520044 A SI 9520044A SI 9520044 A SI9520044 A SI 9520044A SI 9520044 B SI9520044 B SI 9520044B
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chg
arg
paph
leu
pro
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SI9520044A
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Fahad Al-Obeidi
Michal Lebd
A. James Ostrem
Pavel Safar
Alena Stierandova
Peter Strop
Armin Wasler
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Aventis Pharmaceuticals Inc.
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Claims (18)

1 Patentni zahtevki 1. Spojina, ki specifično zavira aktivnost Xa faktorja, s splošno formulo X,-R1-R2-R3-X2 kjer je Xi H, acil, alkil ali arilalkil; R1 je Tyr; R2 je Ile; R3 je Arg; in je X2 izbran iz skupine, ki jo sestavljajo modificirana C-terminalna skupina, ena ali več karboksi zaščitnih skupin in ena ali več amino kislin ali druga substituenta, kjer je modificirana C-terminalna skupina modificiran^ z redukcijo C-konČne karboksi skupine v alkohol ali aldehid ali s tvorbo oralnega estra ali s substitucijo karboksi skupine s substituento, vključno njene farmacevtsko sprejemljive soli.
2. Spojina, ki specifično zavira aktivnost Xa faktorja, s splošno formulo A1-A2-A3-B kjer je Al Tyr, F(pNH2) mAph, pAph ali Nal (2), ki vsebuje 0 ali 1 amino zaščitno skupino; A2 je Ile ali Chg; A3 je Arg, PalMe (3), Dab (Ny-C3H7N), Dap (NP-C3H7N) ali Om (N3-C3H7N); in je B -H, -OH, -NH2, ena do pet amino kislin ali karboksi zaščitna skupina; 2 vključno njene farmacevtsko sprejemljive soli.
3. Spojina po zahtevku 1 ali 2, kjer je amino zaščitna skupina izbrana iz skupine, ki jo sestavljajo formil, acetil, pikoloil, terc-butilacetil, terc-butiloksikarbonil, benziloksikarbonil, 2-aril-2-0-benziloksim, aminoacil, benzoil, tožil, 3-fenoksiproprionična, 5-benzimidazolkarboksi, CClF2-CO, CF2H-CO, CF3-CF2CO, CH3-CHCI-CO, CH3-O-CO, CH3-SO2, ch3ch2-o-co, Cl2CHCO, C1CH2C0, (pOH)C6H4-CH2CH(OH)-CO, (pOH)C6H4-CH2CHOH-CO, (pOHjOsH,-OCH(CH3)CO, (pOH)C6H4-OCH2CO, 4-MeO-C6H4-CO, N-morfolinil-CO, Ph-C(NOCH2Ph)-CO, Ph-CH=CH-CO, Ph-CH2CH2CH2-CO, Ph-CH2CH2CO, trifluoroacetil, ali je substitucija N-končne amino skupine s ciklopentilkarboksi, izokinolilkarboksi ali pirazinkarboksi skupino.
4. Spojina po zahtevkih 1 do 3, kjer je farmacevtsko sprejemljiva sol kislinska adicijska sol.
5. Spojina po zahtevku 4, kjer je kislinska adicijska sol sol, tvorjena z anorgansko kislino, izbrano iz skupine, ki jo sestavljajo klorovodikova kislina, bromovodikova kislina, fosforjeva kislina, žveplova kislina ali perklorova kislina, ali je sol, tvorjena z organsko kislino, izbrano iz skupine, ki jo sestavljajo ocetna kislina, oksalna kislina, maleinska kislina, jabolčna kislina, vinska kislina, citronska kislina, jantarjeva kislina ali malonska kislina.
6. Spojina po zahtevkih 1 do 5, kjer je farmacevtsko sprejemljiva sol izbrana iz skupine, ki jo sestavljajo anorganski nitrat, sulfat, acetat, malat, format, laktat, tatrat, sukcinat, citrat in p-toluensulfonat.
7. Spojina po zahtevku 6, kjer je farmacevtsko sprejemljiva sol p-toluensulfonat. 3
8. Spojina po zahtevkih 1 in 3 do 7, kjer je Xi izbran iz skupine, ki jo sestavljajo metil, etil, n-propil, izopropil, sek-butil, 1-metilbutil, 2,2-dimetilbutil, 2-metilpentil, 2,2-dimetilpropil, n-pentil, n-heksil, ciklopentil, cikloheksil, metil-cikoheksil in ciklopropil-metilen, formil, acetil, benzoil, benzil, pikolil.
9. Spojina po zahtevkih 1 in 3 do 7, kjer je oralni ester izbran iz skupine, ki jo sestavljajo alkoksimetilne skupine, a-(Ci do C4)alkoksietilne skupine, 2-okso-l,3-dioksolen-4-ilmetilne skupine, C! do C3alkiltiometilne skupine, aciloksimetilne skupine, α-aciloksi-a-substituirane metilne skupine, l-(Ci do C4) alkiloksikarboniloksi)et-l-ilne skupine in l-(Ci do C4 alkilaminokarboniloksi)et-l-ilne skupine.
10. Spojina po zahtevku 9, kjer je oralni ester izbran iz skupine, ki jo sestavljajo metoksimetil, etoksimetil, izo-propoksimetil, metoksietil, etoksietil, propoksietil, izopropoksietil, 5-metil-2-okso-l,3-dioksolen-4-ilmetil, 5-fenil-2-okso-l,3-dioksolen-4-ilmetil, metiltiometil, etiltiometil, izopropiltiometil, pivaloiloksimetil, a-acetoksimetil, etoksikarbonil-1-metil, α-acetoksietil, 3-ftalidil, 5,6-dimetilftalidil, 1-(etoksikarboniloksi)et-1 -il in 1 -(metilaminokarboniloksi)et-1 -il.
11. Spojina po zahtevkih 1 do 10, izbrana iz skupine, ki jo sestavljajo CF3C (O) - (iBu) Phe (NH2) -Chg-Arg-Leu-Pro-NH2; Ac-pAph-Ile-Arg-Leu-Pro-NH2; CF3C(0) - (iBu)Nal (2) -Chg-Arg-Leu-Pro-NH2; Ac-Phe (31,4NH2) -Chg-Arg-Leu-Pro-NH2; 4 CF3Č,(0) -Tyr-Chg- Arg-Leu-Pro-NH2; (5 -benzimidazoii. j -Phe (NH2) -Chg - Ar g - Leu - Pr o - NH2 ; CF3C(0) - (iBu)Tyr-Ile-Arg~Leu-Pro-NH2; Ac- (Chx-CHa) Tvr-Ile-Arg-Leu-Pro-NHj; D - Tyx - Chg - Arg-Leu - Pr o - NH2 ; Ac - Trp - Chg-Arg- Leu- Pro-NH2 ; Ac -pAph - Chg - Arg - Leu - Pro - NH2 ; Ac -pAph - Chg - Arg - Gla - Pro -NHa ; Ac - (iBu)Nal (2) -Ghg-Arg-Leu-Pro-NH2; Ac-Phe (p-CONHa) -Chg-Arg-Leu-Pro-NHa; Ac -pAph- Ile-Arg-heu-Pro-NHj; Ac-Phe (pNHa) -Chg-Arg- (Me) Leu-Pro-NH2; Ac- (Chx-CHs)Tyr-Chg-Arg-Leu-Pro-NHa; Ac-pAph-Chg-Pal (3) Me-Leu-Pro-NR, ; (benzoil)- Phe (pNH,) -Chg-Arg~Leu-Pro-NH2; Ac- (2-metilpentanil) - Tyx -1 le - Arg - Leu -Pro- NH2 ; Ac- (2-metilbutil) Tyr-Ile-Arg-Leu-Pxo-NH2; Ac - Phe (pNHj) - Chg - Arg - Leu - Pro - NH2 ; Ac-Tyx-Chg-Arg-Leu-Pro-NH2 ; Ac-(iBu)-Phe(pNHj)-Chg-Arg-Leu-Pro-NH2; Ac- (Chx-CHa) -Tyr-Ile-Arg-Leu-Pro-NH2.; (2-benzofuroil)- pAph-Chg-Pal (3) Me-NH2; Ac- (iBu)Phe (pNH2) -Chg-Arg-NH2; Ac -pAph- Chg - Arg - NH2 / CF3C{0) - (iBu) Phe (pNH2) - Chg-Arg-NH2; Ac - pAph- Chg - Arg - NH2 ; Ac -pAph- Chg - Pal (3) Me -NH2 ; CF3C (O) (iBu) -Tyr-Ile-Arg-NH2; Ac-pAph-Chg-PalMe (3) -NH-CHa-Chx; Ac-pAph-Chg-PalMe(3)-NH-2CMT; Ac-pAph-Chg-PalMe(3)-NH-Chx; Ac-F(pNH2) -Chg-Dah(NV-C3NH7) -L-P-NHa; Bz-F (pNH2) -Chg-R-L-P-NH2; 5 TOS-FipNHa) -Chg-R-Ii-P-NH^; Ac-Y(3-1) -Chg-R-1,-P-NH2; y-Chg-R-L-NH^· Ac-F(pNH2)-Chg-R-ol; ciklopentil -CO-pAph-Chg-PalMe (3) -NRj,; 3-Xqc-pAph-Chg-PalMe {3)-NK,; Bzf-pAph-Chg-PalMe (3) -NH2; 3-Igc-F(pNH2) -Chg-R-L-P-NH2; Ac-F(pNH2) -Chg-R-HH-2~ tiazolil 2-furoil- 1-pAph-Chg-PalMe (3) -NH2; 5-Me-2- nienil .-CO-pAph-Chg-PalMe(3) -NH2; Ac -Nal (2} -Chg-R-NH-2-tiazolil; 2-Bzf ~F(pNH2) -Chg-R-L-P-NH2; Ac-pAph-Chg-Dab ΟΤ^Ή-,Ν) -L-P-NH2; Ac- (iBu)pAph-Chg-R-L-P-NH2; Ac-pAph-Chg-R-Gla-P-NHj,; Ac-pAph-Chg-R-Pen (CH2COOH) -P-NH*; Ac-pAph-Chg-R-L-P-NH2; Ac-F (pNH2) -Chg-R- (Me)L-P-NH2; Ac-F(pNH2)-Chg-R-OEt; · . Ac-FlpNHj) -Chg-Om (N*-C3H7N.) -L-P-NH2; Ac-F (pNH2) -Chg-R-L-P-NH2; Ac-Nal (2) -Chg-R-L-P-NHj ; Ac-pAph-Chg-Dab (NY-C3H7N) -NH2; Ac-pAph-Chg-PalMe(3) -NH2; Ac-pAph-Chg-PalMe (3) -L-P-NH2; Ac - pAph- Chg - R -NH2 ; Ac-pAph-Chg-R-OH; DIPA- (m)pAph-Chg-R-L-P-NH2? DIPA- (m) F (pNH2) -Chg-R-Ii-P-NB^; Isn-F(pNH2) -Chg-R-L-P-NH2; Pza-F (pNH2) -Chg-R-L-P-NH2; Tfa- (iBu)Y-Chg-R-L-P-NH2; 6 Tfa-(iBu) Y-I-0:m(I^-C2H7N)-L-P-NHj,* Ac-pAph-Chg-PalMe (3) -NH-CH,-Chx; Ac-pAph-Chg-PalMe (3) -NH-Chx; Bzf-pAph-Chg-PalMe (3) -NHj; Ac-pAph-Chg-PalMe (3) -L-P-NH2; Ac -pAph- Chg- PalMe (3) -NH2 ; ciklopentil -CO-pAph-Chg-PalMe(3) -NH2; 3 -lqc-pAph-Chg-PalMe (3}-NH2; 2-furoil- pAph- Chg- PalMe {3) -NH2 ; 5-Me -tienil- -CO-pAph-Chg-PalMe{3)-NK^; Ac-pAph-Chg-PalMe (3)-ol; Ac - Tyr-Ile-Arg-Leu-Ala-NH2, Ac-Tyr-Ile-Arg-Leu-Pro-NH2, Ac- (iBu) Tyr-Ile-Arg-Leu-Pro-NH2, Ac-Tyr-Ile-Arg-N(CH3) 0(CH3) , Ac-iyr- {¥{CH2NH) }-Ile-Arg-Leu-Pro-£[H2i Ac-Tyx-lle-Arg-NH-CH2 (4-piridil), Ac-Tyr-Ile- {Ψ (CH2NH) } -Arg-Leu-Pro-NH2, Ac-Tyr-Chg-Arg(NO.,) -{Ψ(CHjNH) J-Leu-NIij, Ac-Tyr-Ile-Arg-{y (COCH2)} -Gly-Pro-NH2, . . Αο-ΤγΓ-ΙΙθ-ΟΒίιίΝ^^ΗτΝ) -Leu-Ala-NH2, Ac-Tyr-Ile-PalMe (3) Tyr-Ile-Arg-NH2, D - Tyr -11 e - Ar g - Leu ~ Pr o - NH 2, Ac-(Bzl)Gly-(Chx)Gly- (3-gvanidopropil); Gly-NH2, Cyclo(Gly-Tyr-Ile~Arg-Gly) , Tfa- (iBu) Tyr-Chg-Arg-Leu-Pro-NH2, Ac -pAph- Chg - Ar g- Leu - Pro -NH2, Ac-Nal (2) -Chg-Arg-Leu-Pro-NH2, Ac-pAph - Chg-PalMe-NHj ( Ac-P-pAph-Chg-Pal (Me) -Leu-Pro-NH2, Ac-D-pAph-Chg-Pal (Me) -NH2, and Ac-Phe(pNH2) -Chg-Arg-Leu-Pro-NHj.
12. Farmacevtski sestavek, ki vsebuje spojino po zahtevkih 1 do 11. 7
13. Farmacevtski sestavek po zahtevku 12, ki nadalje obsega farmacevtsko sprejemljiv nosilec.
14. Uporaba spojine po kateremkoli od zahtevkov 1 do 11 za pripravo farmacevtskega sestavka za specifično inhibiranje aktivnosti faktorja Xa.
15. Uporaba po zahtevku 14, kjer je farmacevtski pripravek za zdravljenje kardiovaskularne motnje, izbrane iz skupine, ki jo sestavljajo restenoza po angioplastiji, sindrom respiratorne stiske odraslega, multi-organska odpoved, kap in motnja razsejanega intravaskulamega koagulacijskega strjevanja.
16. Uporaba po zahtevku 14, kjer je farmacevtski pripravek za zdravljenje komplikacij, povezanih s kirurškimi ukrepi, ki so izbrane iz skupine, ki jo sestavljata globoka venska in proksimalna venska tromboza.
17. Uporaba v zahtevku 14, kjer je farmacevtski pripravek za zmanjšanje ali zaviranje strjevanja krvi.
18. Uporaba spojine po kateremkoli od zahtevkov 1 do 11 kot antikoagulant za preprečevanje koagulacije krvnega vzorca.
SI9520044A 1994-04-26 1995-04-25 Inhibitorji Xa faktorja SI9520044B (sl)

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