SI9520044B - Inhibitorji Xa faktorja - Google Patents
Inhibitorji Xa faktorja Download PDFInfo
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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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- paph
- leu
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- C07K14/8107—Endopeptidase (E.C. 3.4.21-99) inhibitors
- C07K14/811—Serine protease (E.C. 3.4.21) inhibitors
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- C07K5/0207—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)4-C(=0), e.g. 'isosters', replacing two amino acids
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- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
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- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
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- C07K5/08—Tripeptides
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- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
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- C07K5/10—Tetrapeptides
- C07K5/1002—Tetrapeptides with the first amino acid being neutral
- C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
- C07K5/101—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
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- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1002—Tetrapeptides with the first amino acid being neutral
- C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/64—Cyclic peptides containing only normal peptide links
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- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/56—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving blood clotting factors, e.g. involving thrombin, thromboplastin, fibrinogen
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US23305494A | 1994-04-26 | 1994-04-26 | |
PCT/US1995/005268 WO1995029189A1 (en) | 1994-04-26 | 1995-04-25 | FACTOR Xa INHIBITORS |
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Publication Number | Publication Date |
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SI9520044A SI9520044A (en) | 1997-10-31 |
SI9520044B true SI9520044B (sl) | 2004-08-31 |
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Application Number | Title | Priority Date | Filing Date |
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SI9520044A SI9520044B (sl) | 1994-04-26 | 1995-04-25 | Inhibitorji Xa faktorja |
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EP (2) | EP0758341B1 (sl) |
JP (1) | JP3655632B2 (sl) |
KR (1) | KR100380124B1 (sl) |
CN (1) | CN1181091C (sl) |
AT (1) | ATE262536T1 (sl) |
AU (1) | AU707653B2 (sl) |
CA (1) | CA2186497C (sl) |
CZ (1) | CZ296439B6 (sl) |
DE (1) | DE69532754T2 (sl) |
DK (1) | DK0758341T3 (sl) |
EE (1) | EE03973B1 (sl) |
ES (1) | ES2214500T3 (sl) |
FI (1) | FI120494B (sl) |
HU (1) | HUT76346A (sl) |
IL (1) | IL113505A (sl) |
LT (1) | LT4218B (sl) |
LV (1) | LV11740B (sl) |
NO (1) | NO318759B1 (sl) |
NZ (1) | NZ284977A (sl) |
PL (1) | PL188132B1 (sl) |
PT (1) | PT758341E (sl) |
RU (1) | RU2152954C1 (sl) |
SI (1) | SI9520044B (sl) |
SK (1) | SK286094B6 (sl) |
TW (1) | TW409129B (sl) |
WO (1) | WO1995029189A1 (sl) |
ZA (1) | ZA953361B (sl) |
Families Citing this family (51)
Publication number | Priority date | Publication date | Assignee | Title |
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EA199700186A1 (ru) * | 1995-02-17 | 1998-02-26 | Басф Акциенгезельшафт | Новые дипептидные амидины, используемые в качестве ингибиторов тромбина |
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