LV11991B - Mazmolekulāri rotamāzes funkciju inhibitori - Google Patents

Mazmolekulāri rotamāzes funkciju inhibitori Download PDF

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LV11991B
LV11991B LVP-97-243A LV970243A LV11991B LV 11991 B LV11991 B LV 11991B LV 970243 A LV970243 A LV 970243A LV 11991 B LV11991 B LV 11991B
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pyrrolidinecarboxylate
propyl
group
dimethyl
dioxopentyl
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LVP-97-243A
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LV11991A (lv
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Gregory S. Hamilton
Joseph P. Steiner
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Guilford Pharmaceuticals Inc.
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Priority claimed from US08/479,436 external-priority patent/US5614547A/en
Application filed by Guilford Pharmaceuticals Inc. filed Critical Guilford Pharmaceuticals Inc.
Publication of LV11991A publication Critical patent/LV11991A/lv
Publication of LV11991B publication Critical patent/LV11991B/lv

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Claims (43)

  1. LV 11991 IZGUDROJUMA FORMULA 1. Neirotrofisks savienojums ar formulu:
    Rl kur Rt ir C,-C9 taisnas vai sazarotas virknes alkil- vai alkenilgrupa, iespējams aizvietota ar C3-C8 cikloalkil-, C3 - vai C5 - cikloalkil-, C5-C7 cikloalkenil- vai Arrgrupu, kur minētās alkil-, alkenil-, cikloalkil- vai cikloalkenilgrupas iespējams aizvietotas ar Cļ-C4 alkil-, CrC4 alkenil- vai oksigrupu un kur Arr grupu izvēlas no grupas, kura sastāv no 1-naftil-; 2-naftil-; 2-indolil-; 3-indolil-; 2-furil-; 3-furil-; 2-tiazolil-; 2-tienil-; 3-tienil-; 2-, 3- vai 4-piridil-vai fenilgrupas, kas satur no viena līdz trim aizvietotājiem, kurus neatkarīgi izvēlas no grupas, kas sastāv no ūdeņraža atoma, halogēna atoma, hidroksil-, nitro-, trifluormetil-, CrC6-taisnas vai sazarotas alkil- vai alkenilgrupas, Ci-C4alkoksi- vai Ci-C4 alkeniloksi-, fenoksi-, benziloksi- un aminogrupām; X ir skābekļa vai sēra atoms; Y ir skābekļa atoms vai NR2 grupa, kur R2 ir ūdeņraža atoms vai CrC6 alkilgrupa; un Z ir C2-C6 taisnas vai sazarotas virknes alkil- vai alkenilgrupa, kur alkilvirkne vienā vai vairākos stāvokļos aizvietota ar Arrgrupu, kā norādīts iepriekš; C3-C8 cikloalkilgrupa, pie kam cikloalkilgrupa savienota ar CrC6 taisnas vai sazarotas virknes alkil- vai alkenilgrupu; vai Ar2-grupu, kur Ar2-grupu izvēlas no grupas, kura sastāv no 2-indolil-, 3-indolil-, 2-furil-, 3-furil-, 2-tiazolil-, 2-tienil-, 3-tienil-, 2-, 3-, vai 4-piridilgrupas; vai fenilgrupu, kura satur no 2 viena līdz trim aizvietotājiem, kurus neatkarīgi izvēlas no grupas, kura sastāv no ūdeņraža atoma, halogēna atoma, hidroksil-, nitro-, trifluormetil-, CrC6 taisnas vai sazarotas alkil- vai alkenilgrupas, C,-C4 alkoksi- vai CrC4 alkeniloksi-, fenoksi-, benziloksi- un aminogrupām; Z var būt ari fragments: :h X—r4 Ra kur R3 izvēlas no grupas, kura sastāv no taisnas vai sazarotas CrC8 alkilgrupas, iespējams aizvietotas ar C3-C8 cikloalkil- vai Arrgrupu, kā norādīts iepriekš; X2 ir skābekļa atoms vai NR5 grupa, kur R5 izvēlas no grupas, kura sastāv no ūdeņraža atoma, taisnas vai sazarotas Cj-C6 alkil- un alkenilgrupām; R4 izvēlas no grupas, kura sastāv no fenil-, benzil-, taisnas vai sazarotas CVC5 alkil- vai alkenilgrupas un taisnas vai sazarotas CrC5 alkil- vai alkenilgrupas aizvietotas ar fenilgrupu; vai tā farmaceitiski pieņemami sāļi vai hidrāti.
  2. 2. Neirotrofisks savienojums saskaņā ar 1. punktu, kam ir afinitāte uz FKBP-tipa imunofilīniem.
  3. 3. Neirotrofisks savienojums saskaņā ar 2. punktu, kas atšķiras ar to, ka FKBP-tipa imunofilīns ir FKBP-12.
  4. 4. Neirotrofisks savienojums saskaņā ar 1. punktu, kas ir spējīgs inhibēt rotamāzes aktivitāti.
  5. 5. Neirotrofisks savienojums saskaņā ar 1. punktu, kas atšķiras ar to, ka Z un Rļ ir lipofīlas grupas. 3 LV 11991
  6. 6. Neirotroflsks savienojums saskaņā ar 1. punktu, kas atšķiras ar to, ka šo savienojumu izvēlas no grupas, kas sastāv no: 3-fenil-1 -propil (2i)-1 -(3,3-dimetil-1,2-dioksopentil)-2-pirolidinkarboksilāta; 3-fenil- l-prop-2-(£)-enil (25)- l-(3,3-dimetil-1,2-dioksopentil)-2-pirolidinkarboksilāta; 3-(3,4,5-trimetoksifenil)-l-propil (25)-1-(3,3-dimetil-l,2-dioksopentil)-2-pirolidinkarboksilāta; 3-(3,4,5-trimetoksifenil)-1 -prop-2-(£)-enil (25)-1 -(3,3-dimetil-1,2-dioksopentil)- 2- pirolidinkarboksilāta; 3- (4,5-dihlorfenil)-1 -propil (25)-1 -(3,3-dimetil-1,2-dioksopentil)-2-pirolidinkarboksilāta; 3-(4,5-dihlorfenil)-l-prop-2-(.£)-enil (25)-1-(3,3-dimetil-l,2-dioksopentil)-2-pirolidinkarboksilāta: 3-(4,5-metilēndioksifenil)-l-propil (25)-1-(3,3-dimetil-l,2-dioksopentil)-2-pirolidinkarboksilāta; 3-(4,5-metilēndioksifenil)-l-prop-2-(£)-enil (25)-1-(3,3-dimetil-l,2-dioksopentil)- 2- pirolidinkarboksilāta; 3- cikloheksil-l-propil (25)-1-(3,3-dimetil-l,2-dioksopentil)-2-pirolidinkarboksilāta; 3-cikloheksil- l-prop-2-(£)-enil (25)-1-(3,3-dimetil-l,2-dioksopentil)-2-pirolidinkarboksilāta; (17?)-1,3-difenil-1 -propil (25)-1-(3,3-dimetil-1,2-dioksopentil)-2-pirolidinkarboksilāta; (17?)-1,3-difenil-1 -prop-2-(Ū)-enil (25)-1-(3,3-dimetil-1,2-dioksopentil)-2-pirolidinkarboksilāta; (1 /?)-1 -cikloheksil-3-fenil-1 -propil (25)-1-(3,3-dimetil-l,2-dioksopentil)-2-pirolidinkarboksilāta; (1R)-1 -cikloheksil-3-fenil-1 -prop-2-(£)-enil (25)-1 -(3,3-dimetil-1,2-dioksopentil)- 2- pirolidinkarboksilāta; (17?)-1 -(4,5-dihlorfenil)-3-fenil-1 -propil (25)-1 -(3,3-dimetil-1,2-dioksopentil)-2-pirolidinkarboksilāta; 3- fenil-1 -propil (25)-1 -(1,2-diokso-2-cikloheksil)etil-2-pirolidinkarboksilāta; 4 3-fenil-1 -propil (25)-l-(l,2-diokso-4-cikloheksil)butil-2-pirolidinkarboksilāta; 3-fenil-l-propil (25)-1-(1,2-diokso-2-[2-fiiranil])etil-2-pirolidinkarboksilāta; 3-fenil-l-propil (25)-l-(l,2-diokso-2-[2-tienil])etil-2-pirolidinkarboksilāta; 3-fenil-l-propil (25)-1-(1,2-diokso-2-[2-tiazolil])etil-2-pirolidinkarboksilāta; 3-fenil-1 -propil (25)-1 -(1,2-diokso-2-fenil])etil-2-pirolidinkarboksilāta; 1,7-difenil-4-heptil (25)-1 -(3,3-dimetil-1,2-dioksopentil)-2-pirolidinkarboksilāta; 3-fenil-l-propil (25)-1-(3,3-dimetil-l,2-diokso-4-oksibutil)-2-pirolidinkarboksilāta; 3-fenil-1 -propil (25)-1 -(3,3-dimetil-1,2-dioksopentil)-2-pirolidinkarboksamīda; 1 - [ 1 -(3,3-dimetil-1,2-dioksopentil)-L-prolīn] -L-fenilalanīna etilesteris; 1 - [ 1 -(3,3 -dimetil-1,2-dioksopentil)-L-prolīn] -L-leicīna etilesteris; l-[l-(3,3-dimetil-l,2-dioksopentil)-L-prolīn]-L-fenilglicīna etilesteris; l-[l-(3,3-dimetil-l,2-dioksopentil)-L-prolīn]-L-fenilalanīna fenilesteris; l-[l-(3,3-dimetil-l,2-dioksopentil)-L-prolīn]-L-fenilalanīna benzilesteris; un l-[l-(3,3-dimetil-l,2-dioksopentil)-L-prolīn]-L-izoleicīna etilesteris.
  7. 7. Farmaceitiska kompozīcija, kurā ietilpst neirotrofiski efektīvs daudzums savienojuma saskaņā ar 1. punktu un farmaceitiski pieņemams nesējs.
  8. 8. Neirotrofiska savienojuma saskaņa ar 1. punktu pielietojums tāda ārstniecības preparāta iegūšanai, kas paredzēts bojātu perifērisko nervu augšanas stimulēšanai.
  9. 9. Neirotrofisks savienojums ar formulu:
    5 LV 11991 kur Rļ ir Cļ-Cg taisnas vai sazarotas virknes alkil- vai alkenilkgrupa, iespējams aizvietota ar C3-C8 cikloalkil-, C3- vai C5-cikloalkil-, C5-C7 cikloalkenil- vai Ar,-grupu, kur minētās alkil-, alkenil-, cikloalkil- vai cikloalkenilgrupas iespējams aizvietotas ar C,-C4 alkil-, C,-C4 alkenil- vai oksigrupu, un kur Ar,-grupu izvēlas no grupas, kura sastāv no 1-naftil-; 2-naftil-; 2-indolil-; 3- indolil-; 2-furil-; 3-furil-; 2-tiazolil-; 2-tienil-; 3-tienil-; 2-, 3- vai 4-piridil-vai fenilgrupas, kas satur no viena līdz trim aizvietotājiem, kurus neatkarīgi izvēlas no grupas, kas sastāv no ūdeņraža atoma, halogēna atoma, hidroksil-, nitro-, trifluormetil-, C,-C6 taisnas vai sazarotas alkil- vai alkenilgrupas, C,-C4 alkoksi- vai C,-C4 alkeniloksi-, fenoksi-, benziloksi- un aminogrupām. Z ir C2-C6 taisnas vai sazarotas virknes alkil- vai alkenilgrupa, kur alkilvirkne vienā vai vairākos stāvokļos aizvietota ar Ar,-grupu, kā norādīts iepriekš; C3-C8 cikloalkilgrupu, pie kam cikloalkilgrupa savienota ar C,-C6 taisnas vai sazarotas virknes alkil- vai alkenilgrupu vai Ar2-grupu, kur Ar2-grupu izvēlas no grupas, kura sastāv no 2-indolil-; 3-indolil-; 2-furil-; 3-furil-; 2-tiazolil-; 2-tienil-; 3-tienil-; 2-, 3- vai 4-piridilgrupas vai fenilgrupu, kura satur no viena līdz trim aizvietotājiem, kurus neatkarīgi izvēlas no grupas, kura sastāv no ūdeņraža atoma, halogēna atoma, hidroksil-, nitro-, trifluormetil-, C,-C6 taisnas vai sazarotas alkil- vai alkenilgrupas, C,-C4 alkoksi- vai C,-C4 alkeniloksi-, fenoksi-, benziloksi un aminogrupām; vai tā farmaceitiski pieņemami sāļi vai hidrāti.
  10. 10. Neirotrofisks savienojums saskaņā ar 9. punktu, kas atšķiras ar to, ka R, izvēlas no grupas, kura sastāv no C,-C9 taisnas vai sazarotas alkilgrupas, 2-cikloheksil-, 4-cikloheksil-, 2-furanil-, 2-tienil-, 2-tiazolil- un 4- oksibutilgrupām.
  11. 11. Neirotrofisks savienojums saskaņā ar 9. punktu, kam ir afinitāte uz FKBP-tipa imunofilīniem. 6
  12. 12. Neirotrofisks savienojums saskaņā ar 11. punktu, kas atšķiras ar to, ka FKBP-tipa imunofilīns ir FKBP-12.
  13. 13. Neirotrofisks savienojums saskaņā ar 9. punktu, kas ir spējīgs inhibēt rotamāzes aktivitāti.
  14. 14. Neirotrofisks savienojums saskaņā ar 9. punktu, kas atšķiras ar to, ka Z un R-! ir lipofīlas grupas.
  15. 15. Farmaceitiska kompozīcija, kurā ietilpst neirotrofiski efektīvs daudzums savienojuma saskaņā ar 9. punktu un farmaceitiski pieņemams nesējs.
  16. 16. Neirotrofisks savienojums ar formulu:
    kur Z ir fragments: O CH- •*2· un R3 izvēlas no grupas, kura sastāv no taisnas vai sazarotas CrC8 alkilgrupas, iespējams aizvietotas ar C3-C8 cikloalkil- vai Arrgrupu, kā norādīts iepriekš, un neaizvietotu Arrgrupu; X2 ir skābekļa atoms vai NR5 grupa, kur R5 izvēlas no grupas, kura sastāv no ūdeņraža atoma, CrC6 taisnas vai sazarotas alkil- un alkenilgrupām; 7 LV 11991 R4 izvēlas no grupas, kura sastāv no fenil-, benzil-, CrC5 taisnas vai sazarotas alkil-vai alkenilgrupas, un CrC5 taisnas vai sazarotas alkil- vai alkenilgrupas, aizvietotas ar fenilgrupu; vai tā farmaceitiski pieņemami sāļi vai hidrāti.
  17. 17. Neirotrofisks savienojums saskaņā ar 16. punktu, kam ir afinitāte uz FKBP-tipa imunofilīniem.
  18. 18. Neirotrofisks savienojums saskaņā ar 17. punktu, kas atšķiras ar to, ka FKBP-tipa imunofilīns ir FKBP-12.
  19. 19. Neirotrofisks savienojums saskaņā ar 16. punktu, kas ir spējīgs inhibēt rotamāzes aktivitāti.
  20. 20. Neirotrofisks savienojums saskaņā ar 16. punktu, kas atšķiras ar to, ka Z ir lipofīla grupa.
  21. 21. Farmaceitiska kompozīcija, kurā ietilpst neirotrofiski efektīvs daudzums savienojuma saskaņā ar 16. punktu un farmaceitiski pieņemams nesējs.
  22. 22. Neirotrofisks savienojums, kam ir afinitāte uz FKBP-tipa imunofilīniem, kas atšķiras ar to, ka imunofilīns uzrāda rotamāzes aktivitāti un neirotrofisks savienojums inhibē imunofilīna rotamāzes aktivitāti.
  23. 23. Neirotrofisks savienojums saskaņā ar 22. punktu, kas atšķiras ar to, ka FKBP-tipa imunofilīns ir FKBP-12.
  24. 24. Imūndepresiju neizraisoša savienojuma, kam ir afinitāte uz FKBP-tipa imunofilīnien, pielietojums tāda ārstniecības preparāta iegūšanā, kas paredzēts dzīvnieku neiroloģisko traucējumu ārstēšanai, kas atšķiras ar to, ka imunofilīns uzrāda rotamāzes aktivitāti un neirotrofisks savienojums inhibē imunofilīna rotamāzes aktivitāti. δ
  25. 25. Pielietojums saskaņā ar 24. punktu, kas atšķiras ar to, ka FKBP-tipa imunofilīns ir FKBP-12.
  26. 26. Pielietojums saskaņā ar 24. punktu, kas atšķiras ar to, ka neiroloģisko traucējumu izvēlas no grupas, kas sastāv no perifēriskās neiropātijas un neiroloģiskām patoloģijām, kas attiecas uz neirodeģenerāciju.
  27. 27. Pielietojums saskaņā ar 24. punktu, kas atšķiras ar to, ka neiroloģisks traucējums ir Alcheimera slimība.
  28. 28. Pielietojums saskaņā ar 24. punktu, kas atšķiras ar to, ka neiroloģisks traucējums ir Parkinsona slimība.
  29. 29. Pielietojums saskaņā ar 24. punktu, kas atšķiras ar to, ka neiroloģisks traucējums ir laterāla amiotrofiska skleroze.
  30. 30. Neirotrofiska savienojuma, kam ir afīnitāte uz FKBP-tipa imunofilīniem, pielietojums tāda ārstniecības preparāta iegūšanā, kas paredzēts zīdītāju neiroreģenerācijas un augšanas stimulēšanai, kas atšķiras ar to, ka imunofilīns uzrāda rotamāzes aktivitāti un neirotrofisks savienojums inhibē imunofilīna rotamāzes aktivitāti.
  31. 31. Pielietojums saskaņā ar 30. punktu, kas atšķiras ar to, ka FKBP-tipa imunofilīns ir FKBP-12.
  32. 32. Savienojuma, kam ir afinitāte uz FKBP-tipa imunofilīniem, pielietojums tāda ārstniecības preparāta iegūšanā, kas paredzēts neiroreģenerācijas profilaksei, kas atšķiras ar to, ka imunofilīns uzrāda rotamāzes aktivitāti un neirotrofisks savienojums inhibē imunofilīna rotamāzes aktivitāti.
  33. 33. Pielietojums saskaņā ar 32. punktu, kas atšķiras ar to, ka FKBP-tipa imunofilīns ir FKBP-12. 9 LV 11991
  34. 34. Neirotrofisks N-glioksilprolilestera savienojums ar formulu:
    kur Rļ ir CrC5 taisnas vai sazarotas virknes alkil- vai alkenilgrupa, iespējams aizvietota ar C3-C6 cikloalkil- vai Arļ-grupu, kur Arrgrupu izvēlas no grupas, kura sastāv no 2-furil-, 2-tienil- vai fenilgrupas; X izvēlas no grupas, kas sastāv no skābekļa un sēra atomiem; Y ir skābekļa atoms; un Z ir taisnas vai sazarotas virknes alkil- vai alkenilgrupa, kur alkilvirkne aizvietota vienā vai vairākos stāvokļos ar Arrgrupu, kā norādīts iepriekš, C3-C6 cikloalkil-, Ar2 - grupu, kur Ar2 - grupu izvēlas no grupas, kas sastāv no 2-, 3- vai 4-piridilgrupas vai fenilgrupu, kas satur no viena līdz trim aizvietotājiem, kurus neatkarīgi izvēlas no grupas, kas sastāv no ūdeņraža atoma un Cļ-C4 alkoksigrupas.
  35. 35. Neirotrofisks N-glioksilprolilestera savienojums saskaņā ar 34. punktu, kas atšķiras ar to, ka Z un Ri ir lipofilas grupas.
  36. 36. Neirotrofisks N-glioksilprolilestera savienojums saskaņā ar 34. punktu, kas atšķiras ar to, ka šo esteri izvēlas no grupas, kas sastāv no: 3-(2,5-dimetoksifenil)- 1-propil (25)-1 -(3,3-dimetil-1,2-dioksopentil)-2-pirolidinkarboksilāta; 3-(2,5-dimetoksifenil)-l-prop-2-(£)-enil (25)-1-(3,3-dimetil-l,2-dioksopentil)-2-pirolidinkarboksilāta; 10 2- (3,4,5-trimetoksifenil)-1 -etil (25)-1-(3,3-dimetil-1,2-dioksopentil)-2-pirolidinkarboksilāta; 3- (3-piridil)-1 -propil (25)- l-(3,3-dimetil-1,2-dioksopentil)-2-pirolidinkarboksilāta; 3-(2-piridil)-l-propil (25)-1-(3,3-dimetil-l,2-dioksopentil)-2-pirolidinkarboksilāta; 3-(4-piridil)-l-propil (25)-l-(3,3-dimetil-l,2-dioksopentil)-2-pirolidinkarboksilāta; 3-fenil-1 -propil (25)-l-(2-terc-butil-1,2-dioksoetil)-2-pirolidinkarboksilāta; 3-fenil-l-propil (25)-l-(2-cikloheksiletil-l,2-dioksoetil)-2-pirolidinkarboksilāta; 3-(3-piridil)-1 -propil (25)-1 -(2-cikloheksiletil-1,2-dioksoetil)-2-pirolidinkarboksilāta; 3-(3-piridil)-l-propil (25)-l-(2-terc-butil-l,2-dioksoetil)-2-pirolidinkarboksilāta; 3.3- difenil-1 -propil (25)-1 -(3,3-dimetil-1,2-dioksopentil)-2-pirolidinkarboksilāta; 3-(3-piridil)-l-propil (25)-l-(2-cikloheksil-l,2-dioksoetil)-2-pirolidinkarboksilāta; 3-(3-piridil)-l-propil (25)-N-([2-tienil]-glioksil) pirolidinkarboksilāta; 3.3- difenil-l-propil (25)-1-(3,3-dimetil-l,2-dioksobutil)-2-pirolidinkarboksilāta; 3.3- difenil-1 -propil (25)-1 -cikloheksilglioksil-2- pirolidinkarboksilāta; 3.3- difenil-l-propil (25)-l-(2-tienilglioksil)-2- pirolidinkarboksilāta;
  37. 37. Farmaceitiska kompozīcija, kurā ietilpst neirotrofiski efektīvs daudzums N-glioksilprolilestera savienojuma saskaņā ar 34. punktu un farmaceitiski pieņemams nesējs.
  38. 38. Neirotrofiska savienojuma N-glioksilprolilestera saskaņā ar 34. punktu, pielietojums tāda ārstniecības līdzekļa iegūšanā, kas paredzēts bojātu perifērisku nervu augšanas stimulēšanai.
  39. 39. Neirotrofiska savienojuma N-glioksilprolilestera, kam ir afinitāte uz FKBP-tipa imunofilīniem, pielietojums tāda ārstniecības līdzekļa iegūšana, kas 11 LV 11991 paredzēts dzīvnieku neiroloģisko traucējumu ārstēšanai, ko izvēlas no grupas, kas sastāv no perifēriskās neiropātijas un neiroloģīskām pataloģijām, kas atšķiras ar to, ka imunofilīns uzrāda rotamāzes aktivitāti un neirotrofisks savienojums inhibē imunofilīna rotamāzes aktivitāti.
  40. 40. Pielietojums saskaņā ar 39. punktu, kas atšķiras ar to, ka FKBP-tipa imunofilīns ir FKBP-12.
  41. 41. Pielietojums saskaņā ar 39. punktu, kas atšķiras ar to, ka neiroloģisks traucējums ir Alcheimera slimība.
  42. 42. Pielietojums saskaņā ar 39. punktu, kas atšķiras ar to, ka neiroloģisks traucējums ir Parkinsona slimība.
  43. 43. Pielietojums saskaņā ar 39. punktu, kas atšķiras ar to, ka neiroloģisks traucējums ir laterāla amiotrofiska skleroze.
LVP-97-243A 1995-06-07 1997-12-03 Mazmolekulāri rotamāzes funkciju inhibitori LV11991B (lv)

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