LV12755A - C-21 modified epothilones - Google Patents

C-21 modified epothilones Download PDF

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Publication number
LV12755A
LV12755A LV010126A LV010126A LV12755A LV 12755 A LV12755 A LV 12755A LV 010126 A LV010126 A LV 010126A LV 010126 A LV010126 A LV 010126A LV 12755 A LV12755 A LV 12755A
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Prior art keywords
dihydroxy
dione
thiazolyl
dioxabicyclo
methyl
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LV010126A
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LV12755B (lv
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Gerhard Hoefle
Nicole Glaser
Thomas Leibold
Gregory Vite
Soong-Hoon Kim
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Biotechnolog Forschung Gmbh
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Priority claimed from DE1999107588 external-priority patent/DE19907588A1/de
Priority claimed from DE1999130111 external-priority patent/DE19930111A1/de
Application filed by Biotechnolog Forschung Gmbh filed Critical Biotechnolog Forschung Gmbh
Publication of LV12755A publication Critical patent/LV12755A/lv
Publication of LV12755B publication Critical patent/LV12755B/lv

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Saccharide Compounds (AREA)

Claims (30)

  1. LV 12755 Izgudrojuma formula 1. Savienojums ar formulu (I)
    kurā: P-Q ir C=C divkāršā saite vai epoksīdgrupa; G ir S R1 N vai
    R ir ņemts no rindas: ūdeņraža atoms, alkilgrupa, aizvietota alkilgrupa; R1 ir ņemts no rindas: G1 G2 G3 R2
    ir ņemts no rindas: ūdeņraža atoms, halogēna atoms, ciāngrupa, alkilgrupa un aizvietota alkilgrupa; ir ņemts no rindas: ūdeņraža atoms, alkilgrupa un aizvietota alkilgrupa: ir ņemts no rindas: 0, S un NZ1; 1 G4 ir ņemts no rindas: ūdeņraža atoms, alkilgrupa, aizvietota alkilgrupa, OZ1, NZ1Z3, Z1C=0, Z4S01 un neobligāti aizvietota glikozilgrupa; G5 ir ņemts no rindas: halogēna atoms, N3, NCS, SH, CN, NC, N(Z1)3+ un heteroarilgrupa; G6 ir ņemts no rindas: ūdeņraža atoms, alkilgrupa, aizvietota alkilgrupa, trifluormetilgrupa, OZ5, SZ5 un NZ5Z6; G7 ir CZ7 vai N; G8 ir ņemts no rindas: ūdeņraža atoms, halogēna atoms, alkilgrupa, aizvietota alkilgrupa, OZ10, SZ10 un NZ10Z11; G9 ir ņemts no rindas: 0, S, -NH-NH- un -N=N-; G10 ir N vai CZ12; G11 ir ņemts no rindas: aminogrupa, aizvietota aminogrupa, alkilgrupa, aizvietota alkilgrupa, arilgrupa un aizvietota arilgrupa; Z1, Z6, Z9 un Z11, neatkarīgi viens no otra, ņemti no rindas: ūdeņraža atoms, alkilgrupa, aizvietota alkilgrupa, acilgrupa un aizvietota acilgrupa; Z1 ir ņemts no rindas: ūdeņraža atoms, alkilgrupa, aizvietota alkilgrupa, arilgrupa, aizvietota arilgrupa un heterocikliska grupa; Z3, Z5, Z8 un Z10, neatkarīgi viens no otra, ir ņemti no rindas: ūdeņraža atoms, alkilgrupa, aizvietota alkilgrupa, acilgrupa, aizvietota acilgrupa, arilgrupa un aizvietota arilgrupa; Z4 ir ņemts no rindas: alkilgrupa, aizvietota alkilgrupa, arilgrupa, aizvietota arilgrupa un heterocikliska grupa; Z7 ir ņemts no rindas: ūdeņraža atoms, halogēna atoms, alkilgrupa, aizvietota alkilgrupa, arilgrupa, aizvietota arilgrupa, OZ8, SZ8 un NZ8Z9; Z12 ir ņemts no rindas: ūdeņraža atoms,halogēna atoms, alkilgrupa, aizvietota alkilgrupa, arilgrupa un aizvietota arilgrupa; ar noteikumu, ka tad, kad R1 ir
    G1, G1, G3 un G4 nevar vienlaikus būt: G1un G1=H, G3=0, G4=H vai Z1C=0, kur Z1 ir alkilgrupa.
  2. R
    O OH O kurā: P-Q ir C=C divkāršā saite vai epoksīdgrupa; R ir ūdeņraža atoms vai metilgrupa; G1 ir ņemts no rindas: ūdeņraža atoms, halogēna atoms, alkilgrupa un aizvietota alkilgrupa; 2 1 Savienojums pēc 1. punkta ar formulu (la) LV 12755 G2 ir ņemts no rindas: ūdeņraža atoms, alkilgrupa un aizvietota alkilgrupa; G3 ir ņemts no rindas: O, S un NZ1, kur Z1 ir ņemts no rindas: ūdeņraža atoms, alkilgrupa, aizvietota alkilgrupa, acilgrupa un aizvietota acilgrupa; G4 ir ņemts no rindas: ūdeņraža atoms, alkilgrupa, aizvietota alkilgrupa, OZ2, NZ2Z3, Z2C=0, Z4S02 un neobligāti aizvietota glikozilgrupa, kur Z2 ir ņemts no rindas: ūdeņraža atoms, alkilgrupa, aizvietota alkilgrupa, arilgrupa, aizvietota arilgrupa un heterocikliska grupa; Z3 ir ņemts no rindas: ūdeņraža atoms, alkilgrupa, aizvietota alkilgrupa, acilgrupa un aizvietota acilgrupa; Z4 ir ņemts no rindas: alkilgrupa, aizvietota alkilgrupa, arilgrupa, aizvietota arilgrupa un heterocikliska grupa; ar noteikumu, ka G1, G2, G3 un G4 nevar vienlaikus būt: G1un G2=H, G3=0, G4=H vai Z2C=0, kur Z2 ir alkilgrupa.
  3. 3. Savienojums pēc 2. punkta, kurā G3 ir skābekļa atoms.
  4. 4. Savienojums pēc 2. punkta, kurā G3 ir sēra atoms.
  5. 5. Savienojums pēc 2. punkta, kurā G3 ir NZ1.
  6. 6. Savienojums pēc 1. punkta ar formulu (Ib) R
    kurā: P-Q ir C=C divkāršā saite vai epoksīdgrupa; R ir ūdeņraža atoms vai metilgrupa; G1 ir ņemts no rindas: ūdeņraža atoms, halogēna atoms, alkilgrupa un aizvietota alkilgrupa; G2 ir ņemts no rindas: ūdeņraža atoms, alkilgrupa un aizvietota alkilgrupa; G5 ir ņemts no rindas: halogēna atoms, N3, NCS, SH, CN, NC un heterocikliska grupa.
  7. 7. Savienojums pēc 6. punkta, kurā G5 ir N3 grupa.
  8. 8. Savienojums pēc 6. punkta, kurā G5 ir NCS grupa.
  9. 9 vispirms aktivē un pēc tam pakļauj savienojumu ar formulu [7] nukleolīlai aizvietošanai, lai iegūtu R
    p. P-Q= i , = R = H, CH3 pēc tam iegūto savienojumu ar formulu [7] reducējot par savienojumu ar formulu [9], kurā: P-Q = CH=CH vai CH...C, kur... ir vienkāršā C-C saite ar epoksīda 0 tiltiņu, R = ūdeņraža atoms vai metilgrupa, X = N3.
    9. Savienojums pēc 6. punkta, kurā G5 ir SH grupa.
  10. 10. Savienojums pēc 6. punkta, kurā G5 ir CN grupa. 3
  11. 11. Savienojums pēc 6. punkta, kurā G5 ir NC grupa.
  12. 12. Savienojums pēc 6. punkta, kurā G5 ir heterocikliska grupa.
  13. 13. Savienojums pēc 1. punkta ar formulu (lla)
    kurā: P-Q ir C=C divkāršā saite vai epoksTdgrupa; R ir ūdeņraža atoms vai metilgrupa; G6 ir ņemts no rindas: ūdeņraža atoms, alkilgrupa, aizvietota alkilgrupa, trifluormetiigrupa, OZ5, SZ5 un NZSZ6, kur Z5 ir ņemts no rindas: ūdeņraža atoms, alkilgrupa, aizvietota alkilgrupa, acilgrupa un aizvietota acilgrupa; Z6 ir ūdeņraža atoms, alkilgrupa vai aizvietota alkilgrupa; G7 ir CZ7 vai N, kur Z7 ir ņemts no rindas: ūdeņraža atoms, halogēna atoms, alkilgrupa, aizvietota alkilgrupa, arilgrupa, aizvietota arilgrupa, OZ8, SZ8 un NZ8Z9, kur Z8 ir ņemts no rindas: ūdeņraža atoms, alkilgrupa, aizvietota alkilgrupa, acilgrupa un aizvietota acilgrupa, un Z9 ir ūdeņraža atoms, alkilgrupa vai aizvietota alkilgrupa; G8 ir ņemts no rindas: ūdeņraža atoms, halogēna atoms, alkilgrupa, aizvietota alkilgrupa, OZ10, SZ10 un NZ10Z11, kur Z10 ir ņemts no rindas: ūdeņraža atoms, alkilgrupa, aizvietota alkilgrupa, acilgrupa, aizvietota acilgrupa, arilgrupa un aizvietota arilgrupa, Z11 ir ņemts no rindas: ūdeņraža atoms, alkilgrupa, aizvietota alkilgrupa, acilgrupa un aizvietota acilgrupa.
  14. 14. Savienojums pēc 1. punkta ar formulu (llb)
    kurā: P-Q ir C=C divkāršā saite vai epoksTdgrupa; 4 LV 12755 R ir ūdeņraža atoms vai metilgrupa; G6 ir ņemts no rindas: ūdeņraža atoms, alkilgrupa, aizvietota alkilgrupa, trifluormetilgrupa, OZ5, SZ5 un NZ5Z®, kur Z5 ir ņemts no rindas: ūdeņraža atoms, alkilgrupa, aizvietota alkilgrupa, acilgrupa un aizvietota acilgrupa; Z6 ir ūdeņraža atoms, alkilgrupa vai aizvietota alkilgrupa; G9 ir O vai S atoms vai -N=N- grupa.
  15. 15. Savienojums pēc 14. punkta, kurā G9 ir O atoms.
  16. 16. Savienojums pēc 1. punkta ar formulu (III) R
    kurā: P-Q ir C=C divkāršā saite vai epoksīdgrupa; R ir ūdeņraža atoms vai metilgrupa; G10 ir N vai CZ12, kur Z12 ir ņemts no rindas: ūdeņraža atoms,halogēna atoms, alkilgrupa, aizvietota alkilgrupa, arilgrupa un aizvietota ariigrupa.
  17. 17. Savienojums pēc 16. punkta, kurā G10 ir N atoms.
  18. 18. Savienojums pēc 16. punkta, kurā G10 ir CZ12 grupa.
  19. 19. Savienojums pēc 1. punkta ar formulu (IV)
    kurā: P-Q ir C=C divkāršā saite vai epoksīdgrupa; R ir ūdeņraža atoms vai metilgrupa; G11 ir ņemts no rindas: aminogrupa, aizvietota aminogrupa, alkilgrupa, aizvietota alkilgrupa, arilgrupa un aizvietota arilgrupa. 5
  20. 20. Savienojums, kas ņemts no rindas: [1 S-[1 R*, 3R*(E), 7R*. 10S*, 11R*, 12R*, 16S*]]-3-[2-(2-azidometil-4-tiazolil)-1-metiletenil]-7,11-dihidroksi-8,8,10,12,16-pentametil-4,17-dioksabiciklo- [14.1.0] -heptadekān-5,9-dions; [1 S-[1 R*. 3R*(E), 7R*, 10S*, 11R*, 12R*, 16S*]]-3-[2-(2-aminometil-4-tiazolil)-1 -metiletenil]-7,11-dihidroksi-8,8,10,12,16-pentametil-4,17-dioksabiciklo- [14.1.0] -heptadekān-5,9-dions; [1S-[1 R*, 3R*(E), 7R*, 10S*, 11R*, 12R*, 16S*j]-3-[2-[2-[(1,1 -dīmetiletoksi)-karbonil]amino]metil]-4-tiazolil)-1 -metiletenil]-7,11 -dihidroksi-8,8,10,12,16-pentametil-4,17-dioksabiciklo-[14.1.0]-heptadekān-5,9-dions; [4S-[4R*, 7S*, 8R*. 9R*, 15R*(E)]-16-[2-[[[(1,1-dimetiletoksi)karbonil]amino]-metil]-4-tiazolil)-1-metiletenil]-4,8-dihidroksi-5, 5, 7, 9, 13-pentametil-1-oksa-13(Z)-cikloheksadecēn-2,6-dions; [4S-[4R*, 7S*. 8R*. 9R*. 15R*(E)]-16-[2-(2-aminometil-4-tiazolil)-1-metiletenil]-4,8-dihidroksi-5, 5, 7, 9, 13-pentametil-1-oksa-13(Z)-cikloheksadecēn-2,6-dions; [1S-[1R*, 3R*(E), 7R*. 10S*, 11R*. 12R*, 16S*]]-7,11-dihidroksi-8,8,10,12-tetrametiI-3-[1 -metil-2-[2-(pentanoiloksimetil)-4-tiazolii)etenil]-4,17-dioksa-biciklo-{14.1.0]-heptadekān-5,9-dions; [1 S-[1 R*. 3R*(E), 7R*. 10S*, 11R*, 12R*, 16S1J-7,11-dihidroksi-8,8,10,12-tetrametil-3-[1-metil-2-[2-(naftoiloksimetil)-4-tiazolil)etenil]-4,17-dioksabiciklo- [14.1.0] -heptadekān-5,9-dions; [1S-[1 R*. 3R*(E), 7R*. 10S*, 11R*, 12R*, 16S*]]-7,11-dihidroksi-8,8,10,12- tetrametil-3-[2-[2-[[(2-metoksietoksi)acetiloksi]metil]-1-metH-4-tiazolil)etenil]- 4,17-dioksabiciklo-[14.1.0]-heptadekān-5,9-dions; [1 S-[1 R*, 3R*(E), 7R*. 10S*, 11R*, 12R*, 16S*]]-7,11-dīhidroksi-8,8,10,12- tetrametil-3-[1-metil-2-[2-[[(N-propionilamino)metii]-4-tiazolil)etenil]-4,17- dioksabiciklo-[14.1.0]-heptadekān-5,9-dions; [1 S-[1 R*, 3R*(E), 7R*. 10S*, 11R*, 12R*, 16S*]]-3-[2-[3-acetil-2,3-dihidro-2-metilēn^-tiazoliO-l-metiletenilļ^.H-dihidroksi-S.S.IO.IZ-tetrametiM,^-dioksabiciklo-[14.1.0]-heptadekān-5,9-diona N-oksīds; [1S-[1 R*. 3R*(E), 7R*, 10S*, 11R*, 12R*, 16S*]]-7,11-dihidroksi-3-[2-[2-(metoksimetil)-4-tiazolil)-1-metiletenil]-8,8,10,12-tetrametil-4,17-dioksabiciklo- [14.1.0] -heptadekān-5,9-dions; [1 S-[1 R*. 3R*(E), 7R*. 10S*, 11R*, 12R*, 16S*]]-7,11-dihidroksi-8,8.10,12,16-pentametil-3-[1-metii-2-(2-fenoksimetil)-4-tiazolil]etenil]-4,17-dioksabicikIo- [14.1.0] -heptadekān-5,9-dions; 6 LV 12755 [1 S-[1 R*, 3R*(E), 7R*. 10S*, 11R*, 12R*, 16S*]]-3-[2-[2-(etiltiometil)-4-tiazolil]-1-metiletenil]-7I11-dihidroksi-8I8f10,12I16-pentametil-4,17-dioksabiciklo- [14.1.0] -heptadekān-5,9-dions; [1 S-[1 R*, 3R*(E), 7R*. 10S*, 11R*, 12R*, 16S*]]-3-[2-[2-(etoksimetil)-4-tiazolil]-1 -metiletenil]-7,11 -dihidroksi-8,8,10,12,16-tetrametil-4,17-dioksabiciklo-[14.1.0]-heptadekān-5,9-dions; [1 S-[1 R*. 3R*(E), 7R*. 10S*, 11R*, 12R*, 16S*]]-7,11 -dihidroksi-8,8,10,12-tetrametil-3-[1-metil-2-[2-(2,3,4,6-tetraacetil-alfa-glikoziloksi)metil-4-tiazolil)-etenil]- 4,17-dioksabiciklo-[14.1.0]-heptadekān-5,9-dions; [1 S-[1 R*. 3R*(E), 7R*, 10S*, 11R*. 12R*, 16S*]]-7,11 -dihidroksi-8,8,10,12-tetrametil-3-[1-metil-2-[2-(2,,3’,4’,6,-tetraacetil-beta-glikoziloksi)metil-4-tiazolil)-etenil]-4,17-dioksabiciklo-[14.1.0]-heptadekān-5,9-dions; [1 S-[1 R*. 3R*(E), 7R*. 10S*, 11R*, 12R*, 16S*]]-7,11 -dihidroksi-8,8,10,12-tetrametil-3-[1 -rnetil-2-[2-{6’-acetil-alfa-glikoziloksi)rnetil-4-tiazolil)etenil]-4,17-dioksabiciklo-[14.1.0]-heptadekān-5,9-dions; [1 S-[1 R*. 3R*(E), 7R*. 10S*, 11R*, 12R*, 16S*]]-7,11 -dihidroksi-8,8,10.12,16-pentametil-3-[1-metil-2-[2-[(p-toluolsulfonil)oksi]metil]-4-tiazolīI]etenil]—4,17-dioksabiciklo-[14.1.0]-heptadekān-5,9-dions; [1 S-[1 R*. 3R*(E), 7R*. 10S*, 11R*, 12R*, 16S*]]-3-[2-[2-brommetil-4-tiazolil]-1-metiletenil]-7,11-dihidroksi-8,8,10,12-tetrametil-4,17-dioksabiciklo-[14.1.0]-heptadekān-5,9-dions; [1 S-[1R*. 3R*(E), 7R*. 10S*, 11R*, 12R*, 16S*]]-3-[2-[5-brom-2-metil-4-tiazolil]-1-metiietenii]-7,11-dihidroksi-8,8,10,12-tetrametil-4,17-dioksabiciklo- [14.1.0] -heptadekān-5,9-dions; [1 S-[1 R*, 3R*(E), 7R*. 10S*, 11R*, 12R*, 16S*]]-3-[2-[2-ciānmetil-4-tiazolil]-1-metiletenil]-7,11 -dihidroksi-8,8,10,12,16-pentametil-4,17-dioksabiciklo- [14.1.0] -heptadekān-5,9-dions; [4S-[4R*, 7S*. 8R*, 9R*, 15R*(E)]-16-[2-(2-ciānmetil-4-tiazolil)-1-metiletenil]-4,8-dihidroksi-5,5,7,9,13-pentametil-1-oksa-13(Z)-cikIoheksadecēn-2,6-dions; [1 S-[1 R*. 3R*(E), 7R*. 10S*, 11R*, 12R*, 16S*]]-7,11 -dihidroksi-3-[2-[2-(1 H-imidazol-1 -ilmetil)-4-tiazolil]-1 -metiletenil]-8,8,10,12,16-pentametil-4,17-dioksabiciklo-[14.1,0]-heptadekān-5,9-dions; [1S-[1R*, 3R*(E), 7R*. 10S*, 11R*, 12R*, 16S*]]-3-[2-(2-formil-4-tiazolil]-1-metiletenil]-7,11-dihidroksi-8,8,10,12-tetrametil-4,17-dioksabiciklo-[14.1.0]-heptadekān-5,9-dions; [1 S-[1 R*, 3R*(E), 7R*, 10S*, 11R*, 12R*, 16S*]]-3-[2-(2-formil-4-tiazolil]-1-metiletenil]-7,11-dihidroksi-8,8,10,12,16-pentametil-4,17-dioksabiciklo- [14.1.0] -heptadekān-5,9-dions; 7 [1 S-[1 R*. 3R*(E), 7R*. 10S*. 11R*. 12R*, 16S*]]-3-[2-(2-etenil-4-tiazolil)-1-metiletenilļ-7,11 -dihidroksi-8,8,10,12-tetrametil-4,17-dioksabiciklo-[14.1.0]-heptadekān-5,9-dions; [1S-[1R*, 3R*(E), 7R*. 10S*, 11R*. 12R*, 16S*]]-7,11-dihidroksi-3-[2-(2-metoksiimino-4-tiazolil)-1-metiletenil]-8,8,10,12-tetrametil-4,17-dioksabiciklo- [14.1.0] -heptadekān-5,9-dions; [1 S-[1 R*, 3R*(E), 7R*. 10S*, 11R*, 12R*, 16S*]]-7,11 -dihidroksi-8,8,10,12-tetrametil-3-[1 -metil-2-(2-fenilmetil)imino]metil]-4-tiazolii)etenil]-4,17-dioksabiciklo-[14.1.0]-heptadekān-5,9-dions; [1 S-[1 R*, 3R*(E), 7R*, 10S*, 11R*, 12R*, 16S*]]-3-[2-(2-acetil-4-tiazolil)-1-metiletenil]-7,11 -dihidroksi-8,8,10,12-tetrametil-4,17-dioksabiciklo-[14.1.0]-heptadekān-5,9-dions; [1 S-[1 R*. 3R*(E), 7R*. 10S*, 11R*, 12R*, 16S*]]-7,11 -dihidroksi-8,8,10,12-tetrametil-3-[1-metil-2-(2-oksiranil-4-tiazolil)etenil]-4,17-dioksabiciklo-[14.1.0]-heptadekān-5,9-dions; [1S-[1 R*. 3R*(E), 7R*, 10S*, 11R*, 12R*, 16S*]]-7,11 -dihidroksi-3-[2-[2-(2-jodetenil )-4-tiazol il]-1 -metileten il]-8,8,10,12-tetra metil-4,17 -d io ksa bici klo- [14.1.0] -heptadekān-5,9-dions; [1 S-[1 R*, 3R*(E), 7R*, 10S*, 11R*, 12R*, 16S*]]-3-[2-(2-etinil-4-tiazolil)-1-metiletenil]-7,11 -dihidroksi-8,8,10,12-tetrametiI-4,17-dioksabiciklo-[14.1.0]-heptadekān-5,9-dions; [1S-[1 R*, 3R*(E), 7R*, 10S*, 11R*. 12R*, 16S*]]-7,11 -dihidroksi-8,8,10,12,16-pentametil-3-[1-metil-2-(2-metilaminometil-4-tiazolil)etenil]-4,17-dioksabiciklo- [14.1.0] -heptadekān-5,9-dions; [1 S-[1 R*. 3R*(E), 7R*, 10S*, 11R*. 12R*, 16S*]]-3-[2-[2-[2-(dimetilaminoetil)-amino]metil-4-tiazolil]-1 -metiletenil]-7,11 -dihidroksi-8,8,10,12,16-pentametil-4,17-dioksabiciklo-[14.1.0]-heptadekān-5,9-dions; [1 S-[1 R*. 3R*(E), 7R*. 10S*, 11R*, 12R*, 16S*]]-3-[2-[2-[(dimetilamino)metil]-4-tiazolil]-1 -metiletenil]-7,11 -dihidroksi-8,8,10,12,16-pentametil-4,17-dioksabiciklo[14.1.0]heptadekan-5,9-dions; [1 S-[1 R*. 3R*(E), 7R*, 10S*, 11R*, 12R*, 16S*]]-3-[2-[2-[bis(2- metoksietil)amino]metil]-4-tiazolil]-1 -metiietenil]-7,11 -dihidroksi-8,8,10,12,16-pentametil-4,17-dioksabiciklo-[14.1.0]-heptadekān-5,9-d ions; [1S-[1 R*, 3R*(E), 7R*. 10S*, 11R*, 12R*, 16S*]]-7,11-dihidroksi-8,8,10,12,16-pentametii-3-[1 -metil-2-[2-[(4-metil-1 -piperazinil)metil]-4-tiazolii]etenil]-4,17-dioksabiciklo-[14.1.0]-heptadekān-5,9-dions; 8 LV 12755 [1 S-[1 R*. 3R*(E), 7R*. 10S*. 11R*, 12R*, 16S*]]-4-[2-(7,11-dihidroksi- 8.8.10.12- tetrametil-5,9-diokso-4,17-dioksabiciklo-[14.1.0]-heptadekan-3-il)-1 -propenil]-2-tiazolkarbonskābe; [1 S-[1 R*. 3R*(E), 7R*, 10S*. 11R*. 12R*, 16S*]]-4-[2-(7.11-dihidroksi- 8.8.10.12- tetrametil-5,9-diokso-4,17-dioksabiciklo-[14.1.0]-heptadekan-3-il)-1-propenil]-2-tiazolkarbonskābes metilesteris, tā farmaceitiski pieņemamās sālis, solvāti un hidrāti.
  21. 21. Paņēmiens savienojuma ar formulu [9], R I
    kas atbilst savienojumam ar formulu (la), kurā G1 un G2 ir ūdeņraža atoms, G3 ir NZ1 un Z1 un G4 ir ūdeņraža atoms, iegūšanai, saskaņā ar kuru savienojumu ar formulu [4] vai [5] R
    R
  22. 22. Paņēmiens pēc 21. punkta, kurā: (i) aktivēšanu veic ar TosHal (Hal = Cl, Br vai I) un piridīnu, bet nukleofilo aizvietošanu ar NaN3 vai (ii) aktivēšanu un nukleofflo aizvietošanu veic ar diazabicikloundecēnu (DBU) un difenilfosforilazīdu (DPPA).
  23. 23. Paņēmiens pēc 21. punkta, kurā reducēšanu veic: (i) hidrogenējot ar Lindlara katalizatoru vai (ii) ar fosfīnu.
  24. 24. Farmaceitiskā kompozīcija, kas ietver kā darbīgo sastāvdaļu vismaz vienu savienojumu no rindas: savienojums ar 1. punktā minēto kopējo formulu, savienojums ar formulu (la) pēc 2. punkta, savienojums ar formulu (Ib) pēc 6. punkta, savienojums ar formulu (lla) pēc 13. punkta, savienojums ar formulu (llb) pēc 14. punkta, savienojums ar formulu (III) pēc 16. punkta un savienojums ar formulu (IV) pēc 19. punkta, vai tā farmaceitiski pieņemamo sāli un vienu vai vairākus farmaceitiski pieņemamus nesējus, pildvielas vai atšķaidītājus.
  25. 25. Farmaceitiskā kompozīcija pēc 24. punkta, kas ietver kā darbīgo sastāvdaļu vismaz vienu savienojumu ar pretvēža vai citotoksisku aktivitāti.
  26. 26. Farmaceitiskā kompozīcija pēc 25. punkta, kurā savienojums ar pretvēža vai citotoksisko aktivitāti ir ņemts no rindas: [1S-[1R*, 3R*(E), 7R*, 10S*, 11R*, 12R*, 16S*]]-3-[2-(2-azidometil-4-tiazolil)-1 -metiletenil]-7,11-dihidroksi-8,8,10,12,16-pentametil-4,17-dioksabiciklo-[14.1.0]-heptadekān-5,9-dions; 10 LV 12755 [1 S-[1 R*. 3R*(E), 7R*. 10S*, 11R*, 12R*, 16S*]]-3-[2-(2-aminometil-4-tiazolil)-1-metiletenil]-7,11-dihidroksi-8,8,10,12,16-pentametil-4,17-dioksabiciklo- [14.1.0] -heptadekān-5,9-dions; [1S-[1R*, 3R*(E), 7R*, 10S*, 11R*, 12R*, 16S*]]-3-[2-[[(1,1-dimetiletoksi)-karbonil]amino]metil]-4-tiazolil)-1-metiletenil]-7,11 -dihidroksi-8,8,10,12,16-pentametil-4,17-dioksabiciklo-[14.1.0]-heptadekān-5,9-dions; [4S-[4R*, 7S*, 8R*. 9R*. 15R*(E)]-16-[2-[[[(1,1-dimetiletoksi)karbonil]amino]-metil]-4-tiazolil)-1-metiletenil]-4,8-dihidroksi-5, 5, 7, 9, 13-pentametil-1-oksa-13(Z)-cikloheksadecēn-2,6-dions; [4S-[4R*, 7S*. 8R*. 9R*. 15R*(E)]-16-[2-(2-aminometil-4-tiazolil)-1 -metiletenil]-4,8-dihidroksi-5, 5, 7, 9, 13-pentametil-1-oksa-13(Z)-cikloheksadecēn-2,6-dions; [1S-[1R*, 3R*(E), 7R*, 10S*, 11R*. 12R*, 16S*]]-7,11-dihidroksi-8,8,10,12-tetrametil-3-[1 -metil-2-[2-(pentanoiloksimetil)-4-tiazolii)etenil]-4,17-dioksa-biciklo-[14.1.0]-heptadekān-5,9-dions; [1 S-[1 R*, 3R*(E), 7R*. 10S*, 11R*, 12R*, 16S*]]-7,11 -dihidroksi-8,8,10,12-tetrametil-3-[1 -metil-2-[2-(naftoiioksimetil)-4-tia20lil)eteniI]-4,17-dioksabiciklo- [14.1.0] -heptadekān-5,9-dions; [1 S-[1 R*, 3R*(E), 7R*. 10S*, 11R*, 12R*, 16S*]]-7,11-dihidroksi-8,8,10,12- tetrametil-3-[2-[2-[[(2-metoksietoksi)acetiloksi]metil]-1-metil-4-tiazolil)etenil]- 4,17-dioksabiciklo-[14.1.0]-heptadekān-5,9-dions; [1S-[1R*, 3R*(E), 7R*, 10S*. 11R*, 12R*, 16S*]]-7,11 -dihidroksi-8,8,10,12-tetrametil-3-[1 -metil-2-[2-[[(N-propionilamino)metil]-4-tiazolil)etenil]-4,17-dioksabiciklo-[14.1.0]-heptadekān-5,9-dions; [1 S-[1 R*. 3R*(E), 7R*, 10S*, 11R*, 12R*, 16S*]]-3-[2-[3-acetil-2,3-dihidro-2-metilēn-4-tiazolil)-1 -metiletenil]-7,11 -dihidroksi-8,8,10,12-tetrametil-4,17-dioksabiciklo-[14.1.0]-heptadekān-5,9-diona N-oksīds; [1 S-[1 R*. 3R*(E), 7R*. 10S*, 11R*, 12R*, 16S*]]-7,11-dihidroksi-3-[2-[2-(metoksimetil)-4-tiazolil)-1-metiletenil]-8,8,10,12-tetrametil-4,17-dioksabiciklo- [14.1.0] -heptadekān-5,9-dions; [1 S-[1 R*. 3R*(E), 7R*, 10S*, 11R*. 12R*, 16S*]]-7,11 -dihidroksi-8,8,10,12,16-pentametil-3-[1-metil-2-(2-fenoksimetil)-4-tiazolil]etenil]-4,17-dioksabiciklo- [14.1.0] -heptadekān-5,9-dions; [1 S-[1 R*. 3R*(E), 7R*, 10S*. 11R*, 12R*, 16S*]]-3-[2-[2-(etiltiometil)-4-tiazolil]-1-metiletenil]-7,11-dihidroksi-8,8,10,12,16-pentametil-4,17-dioksabiciklo- [14.1.0] -heptadekān-5,9-dions; 11 [1 S-[1 R*. 3R*(E), 7R*, 10S*. 11R*, 12R*, 16S*]]-3-[2-[2-(etoksimetil)-4-tiazolil]-1-metiIetenil]-7,11-dihidroksi-8,8,10,12-tetrametil-4,17-dioksabiciklo- [14.1.0] -heptadekān-5,9-dions; [1S-[1R*, 3R*(E), 7R*. 10S*, 11R*, 12R*, 16S*]]-7,11 -dihidroksi-8,8,10,12-tetrametil-3-[1-metil-2-[2-(2,3,4,6-tetraacetil-alfa-glikoziloksi)metil-4-tiazoliI)-etenil]- 4,17-dioksabiciklo-[14.1.0]-heptadekān-5,9-dions; [1S-[1R*, 3R*(E), 7R*, 10S*, 11R*, 12R*, 16S*]]-7,11-dihidroksi-8,8,10,12-tetrametil-3-[1-metil-2-[2-(2’,3’,4’,6,-tetraacetil-beta-glikoziloksi)metil-4-tiazolil)-etenil]-4,17-dioksabiciklo-[14.1.0]-heptadekān-5,9-dions; [1S-[1 R*, 3R*(E), 7R*. 10S*, 11R*, 12R*, 16S*]]-7,11 -dihidroksi-8,8,10,12-tetrametil-3-[1 -metil-2-[2-(6’-acetil-alfa-glikoziloksi)metil-4-tiazolil)etenil]-4,17-dioksabiciklo-[14.1.0]-heptadekān-5,9-dions; [1S-[1R*t 3R*(E), 7R*. 10S*, 11R*, 12R*, 16S*]]-7,11 -dihidroksī-8.8,10,12,16-pentametil-3-[1 -metil-2-[2-[(p-toluolsulfonil)oksi]metil]-4-tiazolil]etenil]-4,17-dioksabiciklo-[14.1.0]-heptadekān-5,9-dions; [1S-[1R*, 3R*(E), 7R*. 10S*, 11R*, 12R*, 16S*]]-3-[2-[2-brommetil-4-tiazolil]-1 -metiletenil]-7,11 -dihidroksi-8,8,10,12-tetrametil-4,17-dioksabiciklo-[14.1.0]-heptadekān-5,9-dions; [1 S-[1 R*, 3R*(E), 7R*, 10S*, 11R*, 12R*, 16S*]]-3-[2-[5-brom-2-meti1-4-tiazolil]-1 -metiletenil]-7,11-dihidroksi-8,8,10,12-tetrametil-4,17-dioksabiciklo- [14.1.0] -heptadekān-5,9-dions; [1S-[1R*, 3R*(E), 7R*. 10S*, 11R*, 12R*, 16S*]]-3-[2-[2-ciānmetil-4-tiazolii]-1 -metiletenil]-7,11 -dihidroksi-8,8,10,12,16-pentametil-4,17-dioksabiciklo- [14.1.0] -heptadekān-5,9-dions; [4S-[4R*, 7S*. 8R*, 9R*, 15R*(E)]-16-[2-(2-ciānmetii-4-tiazolil)-1 -metiletenil]-4,8-dihidroksi-5,5I7,9,13-pentametil-1-oksa-13(Z)-cikloheksadecēn-2,6-dions; [1S-[1R*, 3R*(E), 7R*. 10S*, 11R*, 12R*, 16S*]]-7,11-dihidroksi-3-[2-[2-(1H- imidazol-l-ilmetiiH-tiazolilļ-l-metiletenilļ-S.S.IO.^.ie-pentametiM,^- dioksabiciklo-[14.1.0]-heptadekān-5,9-dions; [1S-[1 R*, 3R*(E), 7R*. 10S*, 11R*, 12R*, 16S*]]-3-[2-(2-formil-4-tiazolil]-1-metiietenil]-7,11 -dihidroksi-8,8,10,12-tetrametil-4,17-dioksabiciklo-[14.1.0]-heptadekān-5,9-dions; [1S-[1R*, 3R*(E), 7R*, 10S*, 11R*, 12R*, 16S*]]-3-[2-(2-formil-4-tiazolii]-1-metiletenii]-7,11-dihidroksi-8,8,10,12,16-pentametil-4,17-dioksabiciklo- [14.1.0] -heptadekān-5,9-dions; [1 S-[1 R*. 3R*(E), 7R*. 10S*, 11R*, 12R*. 16S*]]-3-[2-(etenil-4-tiazolil)-1- metiletenil]-7,11-dihidroksi-8,8,10,12-tetrametil-4,17-dioksabiciklo-[14.1.0]- heptadekān-5,9-dions; 12 LV 12755 [1 S-[1 R*, 3R*(E), 7R*, 10S*. 11R*, 12R*, 16S*]]-7,11-dihidroksi-3-[2-(2-metoksiimino-4-tiazolil)-1 -metiletenil]-8,8,10,12-tetrametil-4,17-dioksabiciklo- [14.1.0] -heptadekān-5,9-dions; [1 S-[1 R*. 3R*(E), 7R*, 10S*, 11R*, 12R*, 16S*]]-7,11 -dihidroksi-8,8,10,12-tetrametil-3-[1 -metil-2-(2-feniliminometil-4-tiazolil)etenil]-4,17-dioksabiciklo- [14.1.0] -heptadekān-5,9-dions; [1 S-[1 R*. 3R*(E), 7R*, 10S*, 11R*, 12R*, 16S*]]-3-[2-(2-acetil-4-tiazolil)-1-metiieten il]-7,11-dihidroksi-8,8,10,12-tetrametil-4,17-dioksabiciklo-[14.1.0]-heptadekān-5,9-dions; [1S-[1R*, 3R*(E), 7R*. 10S*, 11R*. 12R*, 16S*]]-7,11 -dihidroksi-8,8,10,12- tetrametil-3-[1-metil-2-(2-oksiranil-4-tiazolil)etenil]-4,17-dioksabiciklo-[14.1.0]- heptadekān-5,9-dions; [1S-[1R*, 3R*(E), 7R*. 10S*, 11R*, 12R*, 16S*]]-7,11-dihidroksi-3-[2-[2-(2-jodetenil)-4-tiazolii]-1-metiletenil]-8,8,10,12-tetrametil-4,17-dioksabiciklo- [14.1.0] -heptadekān-5,9-dions; [1 S-[1 R*, 3R*(E), 7R*. 10S*, 11R*, 12R*, 16S*]]-3-[2-(2-etinil-4-tiazolil)-1- metiietenilļ^.H-dihidroksi-e.e.lO.^-tetrametiM.^-dioksabiciklo-tM.I.O]- heptadekān-5,9-dions; [1S-[1R*. 3R*(E), 7R*, 10S*. 11R*, 12R*, 16S*]]-7,11-dihidroksi-8,8,10,12,16-pentametil-3-[1 -metil-2-(2-metilaminometil-4-tiazolil)etenii]-4,17-dioksabiciklo- [14.1.0] -heptadekān-5,9-dions; [1S-[1R*, 3R*(E), 7R*, 10S*. 11R*, 12R*, 16S*]]-3-[2-[2-[2-(dimetilaminoetil)-amino]metil-4-tiazolil]-1 -metiletenil]-7,11 -dihidroksi-8,8,10,12,16-pentametil-4,17-dioksabiciklo-[14.1.0]-heptadekān-5,9-dions; [1S-[1R*, 3R*(E), 7R*, 10S*, 11R*, 12R*, 16S*]]-3-[2-[2-[(dimetilaminometil)-4-tiazolil]-1-metiletenil]-7,11 -dihidroksi-8,8,10,12,16-pentametil-4,17-dioksabiciklo-[14.1.0]-heptadekān-5,9-dions; [1 S-[1 R*. 3R*(E), 7R*. 10S*, 11R*, 12R*, 16S*]]-3-[2-[2-[bis(2- metoksietil)amino]metii]-4-tiazolil]-1-metiletenil]-7,11-dihidroksi-8,8,10,12,16-pentametil-4,17-dioksabiciklo-[14.1.0]-heptadekān-5,9-dions; [1 S-[1 R*. 3R*(E), 7R‘, 10S*. 11R*, 12R*. 16S*]]-7,11-dihidroksi-8,8,10,12,16-pentametil-3-[1 -metil-2-[2-[(4-metil-1 -piperazinil)metil]-4-tiazolil]etenil]-4,17-dioksabiciklo-[14.1.0]-heptadekān-5,9-dions; [1S-[1R*, 3R*(E), 7R*, 10S*, 11R*. 12R*, 16S*]]-4-[2-(7,11-dihidroksi-8,8,10,12-tetrametil-5,9-diokso-4,17-dioksabiciklo-[14.1.0]-heptadekan-3-il)-1-propenil]-2-tiazolkarbonskābe; 13 [1S-[1R*, 3R*(E), 7R*, 10S*, 11R*. 12R*. 16S*]]-4-[2-(7f 11-dihidroksi-8,8,10,12-tetrametil-5,9-diokso-4,17-dioksabiciklo-[14.1.0]-heptadekan-3-il)-1-propenil]-2-tiazolkarbonskābes metilesteris, to farmaceitiski pieņemamās sālīs, solvāti un hidrāti.
  27. 27. Farmaceitiskās kompozīcijas pēc 24. punkta pielietojums vēža un citu proliferatīvo slimību ārstēšanai.
  28. 28. Farmaceitiskās angioģenēzes inhibēšanai. kompozīcijas pēc 24. punkta pielietojums
  29. 29. Farmaceitiskās kompozīcijas pēc 24. punkta pielietojums apoptozes inducēšanai.
  30. 30. Farmaceitiskās kompozīcijas pielietojums pēc 27. punkta vēža vai citu proliferatīvo slimību ārstēšanai vienlaikus vai secīgi ar citu ārstniecības līdzekli, kas ir derīgs vēža vai citu proliferatīvo slimību ārstēšanai. 14
LV010126A 1999-02-22 2001-08-23 Pie c-21 modificetie epotiloni LV12755B (lv)

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