DK1497019T3 - Pyrrolo-triazinanilinsammensætninger nyttig som kinasehæmmere - Google Patents

Pyrrolo-triazinanilinsammensætninger nyttig som kinasehæmmere Download PDF

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DK1497019T3
DK1497019T3 DK03724157.7T DK03724157T DK1497019T3 DK 1497019 T3 DK1497019 T3 DK 1497019T3 DK 03724157 T DK03724157 T DK 03724157T DK 1497019 T3 DK1497019 T3 DK 1497019T3
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alkyl
substituted
optionally substituted
phenyl
halogen
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Stephen T Wrobleski
Alaric Dyckman
John Hynes
Katerina Leftheris
Chunjian Liu
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Bristol Myers Squibb Co
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Claims (23)

  1. PYRROLO-TRIAZINANILINSAMMENSÆTNINGER NYTTIG SOM KINASEHÆMMERE PATENTKRAV
    1. Forbindelse med formlen (1 *):
    $*) eller enantiomerer, diastereomerer, salte og solvater deraf, hvor X er udvalgt fra -O-, -0C(=0)-, -S-, -S(=0)-, -S02-, -C(=0)-, -C02-, -NR*-, -NRsC(=0)-, -NR8C(=0)NR9-, -NRsC02-, -NR8S02-, -NRsS02NR9-, -S02NR8-, -C=(0)NR8-, halogen, nitro og cyano, eller X ikke er til stede; Y er -C(=0)NH-; B er eventuelt substitueret cycloalkyl, heterocyclo eller heteroaryl; eller aryl substitueret med én Ru og nul til to Ri2; eller er udvalgt fra -C(=0)Ri3, -C02R13 og -C(=0)NR13R13a; Ri og R5 er uafhængigt udvalgt fra hydrogen, alkyl, substitueret alkyl, -OR14, -SR14, 0C(=0)Ri4, -C02Ri4, -C(=0)NRi4Ri4a, -NRi4Ri4a, -S(=0)Ri4, -S02Ri4, -S02NR|4R|4a, -NRi4S02NRi4aRi4i„ NRi4aS02Ri4, -NRi4C(=0)Ri4a, -NRi4C02Ri4a, -NRi4C(=0)NR14aR14b, halogen, nitro og cyano; R2 er hydrogen eller Ci_4alkyl; R3 er hydrogen, methyl, perfluormethyl, methoxy, halogen, cyano, NH2 eller NH(CH3); R4 er udvalgt fra: (a) hydrogen, forudsat at R4 ikke er hydrogen, hvis X er -S(=0)-, -S02-, -NR8C02-, eller -NR8S02- (b) alkyl, alkenyl, og alkynyl eventuelt substitueret med keto og/eller én til fire R17; (c) aryl og heteroaryl eventuelt substitueret med én til tre R[6 og (d) heterocyclo og cycloalkyl eventuelt substitueret med keto og/eller én til tre R^; eller (e) R4 ikke er til stede, hvis X er halogen, nitro eller cyano; R6 er bundet til et hvilket som helst tilgængeligt carbonatom af phenylring A og er ved hver forekomst uafhængigt udvalgt fra alkyl, halogen, trifluormethoxy, trifluormethyl, hydroxy, alkoxy, alkanoyl, alkanoyloxy, thiol, alkylthio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono, arylsulfonylamin, alkylsulfonylamin, sulfonsyre, allcysulfonyl, sulfonamido, phenyl, benzyl, aryloxy, og benzyloxy, hvor hver R6 gruppe til gengæld kan være yderligere substitueret af én til to R18; Rs og R9 er uafhængigt udvalgt fra hydrogen, alkyl, substitueret alkyl, aryl, cycloalkyl, heterocyclo og heteroaryl; Ru er udvalgt fra eventuelt substitueret cycloalkyl, heterocyclo og heteroaryl; R12 er udvalgt fra alkyl, R17, og C1.4alkyl substitueret med keto (=0) og/eller én til tre R17; Rb og Ri3a er udvalgt fra hydrogen, alkyl og substitueret alkyl; R14, R14a og R14b er uafhængigt udvalgt fra hydrogen, alkyl, substitueret alkyl, aryl, cycloalkyl, heterocyclo og heteroaryl, undtagen når Ri4 er bundet til en sulfonylgruppe som i -S(=0)R14, -S02Ri4 og -NRi4a-S02Ri4, så er Ri4 ikke hydrogen; R16 er udvalgt fra alkyl, Ri7, og Ci_4alkyl substitueret med keto (=0) og/eller én til tre R17; Rn er udvalgt fra halogen, haloalkyl, haloalkoxy, nitro, cyano, -SR23, -OR23, -NR23R24, -NR23S02R25, -S02R25, -S02NR23R24, -C02R23, -C(=0)R23, -C(=0)NR23R24, -0C(=0)R23-0C(=0)NR23R24, -NR23C(=0)R24, -NR23C02R24; aryl eller heteroaryl eventuelt substitueret med én til tre R26; eller cycloalkyl eller heterocyclo eventuelt substitueret med keto (=0) og/eller én til tre R26; Ris og R26 er uafhængigt udvalgt fra C^alkyl, C2_6alkenyl, halogen, haloalkyl, haloalkoxy, cyano, nitro, amino, Ci_4alkylamino, aminoCi_4alkyl, hydroxy, hydroxyCi_4alkyl, alkoxy, Ci-4alkylthio, phenyl, benzyl, phenyloxy og benzyloxy; R23 og R24 er hver uafhængigt udvalgt fra hydrogen, alkyl, alkenyl, substitueret alkyl, substitueret alkenyl, aryl, cycloalkyl, heteroaryl, og heterocyclo; R25 er udvalgt fra alkyl, substitueret alkyl, aryl, heteroaryl, cycloalkyl og heterocyclo; og m er 0, 1, 2 eller 3; hvor begrebet "substitueret alkyl" betyder en alkylgruppe substitueret af én til fire substituenter udvalgt fra halogen, hydroxy, alkoxy, keto (=0), alkanoyl, aryloxy, alkanoyloxy, NRaRb, alkanoylamino, aroylamino, aralkanoylamino, alkanoylamino, arylamino, aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio, alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, -S02NRaRb, nitro, cyano, -C02H, -CONRaRb, alkoxycarbonyl, aryl, guanidino og heteroaryler eller heterocyklusser, hvor Ra og Rb er udvalgt fra hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyklus og heterocyklusalkyl, og hvor substituenten på alkylen eventuelt til gengæld kan være yderligere substitueret, i hvilket tilfælde den vil være substitueret med én eller flere af C|_4alkyl, C2_4alkcnyl, halogen, haloalkyl, haloalkoxy, cyano, nitro, amino, C[.4alkylamino, aminoC[.4alkyl, hydroxy, hydroxyC|_4alkyl, alkoxy, alkylthio, phenyl, benzyl, phenyloxy og/eller benzyloxy; hvor begrebet "substitueret alkenyl" betyder en alkenylgruppe substitueret af én eller to substituenter udvalgt fra de, der er nævnt ovenfor til substituerede alkylgrupper; og hvor begrebet "eventuelt substitueret cycloalkyl" betyder cycloalkyl, der kan have 0 til 3 substituenter udvalgt fra Rc-grupper, og/eller fra keto (hvor det er passende), der til gengæld kan være substitueret med én til tre R(1-grupper, hvor Rc ved hver forekomst er udvalgt fra alkyl, substitueret alkyl, halogen, trifluormethoxy, trifluormethyl, -SR, -OR, -NRR', -NRS02R', -S02R, -S02NRR', -C02R', -C(=0)R', -C(=0)NRR', -0C(=0)R', -0C(=0)NRR', -NRC(=0)R', -NRC02R', phenyl, C3-7cycloalkyl, og fem- til seks-leddet heterocyclo eller heteroaryl, hvor hver R og R' er udvalgt fra hydrogen, alkyl, substitueret alkyl, alkenyl, substitueret alkenyl, phenyl, C3_7cycloalkyl, og fem- til seks-leddet heterocyclo eller heteroaryl, bortset fra i tilfælde af en sulfonylgruppe, så vil R ikke være hydrogen, og hvor Rd er udvalgt fra C^alkyl, C2_6alkenyl, halogen, haloalkyl, haloalkoxy, cyano, nitro, amino, C|_4alkylamino, aminoC|_4alkyl, hydroxy, hydroxyC|_4alkyl, alkoxy, alkylthio, phenyl, benzyl, phenylethyl, phenyloxy og benzyloxy.
  2. 2. Forbindelse ifølge krav 1, eller et farmaceutisk acceptabelt salt, eller et hydrat deraf, hvor: B er en C3.7cycloalkyl eventuelt substitueret med én til to R7, en fem-leddet heteroaryl eventuelt substitueret med én til to R7, en fem- eller seks-leddet heterocyclo eventuelt substitueret med én til to R7, aryl substitueret med én Ru og nul til to R12; eller er udvalgt fra -C(=0)Ri3, -C02Rb og -C(=0)NRi3Ri3a; R7 er bundet til et hvilket som helst tilgængeligt carbon- eller nitrogenatom af ring B og ved hver forekomst er uafhængigt udvalgt fra keto (=0), alkyl, substitueret alkyl, halogen, haloalkoxy, ureido, cyano, -SR20,-OR20, -NR2OR2i, -NR2oS02R2i, -S02Ri9, S02NR2oR2i, -C02R2o, -C(=0)R2o, -C(=0)NR2oR2i; -OC(=O)R20, OC(=O)NR20R2i; -NR20C(=O)R2i, -NR20CO2R2i, aryl, cycloalkyl, heterocyklus og heteroaryl; og/eller når B er cycloalkyl, kan to R7 grupper samles for at danne en eventuelt substitueret carbon-carbon-bro af tre til fire carbonatomer, eller to R7 grupper kan samles for at danne en kondenseret carbocyklisk, heterocyklisk eller heteroarylring, hvilken kondenseret ring til gengæld eventuelt er substitueret med én til tre R22; R20 og R2i er udvalgt fra hydrogen, alkyl, alkenyl, substitueret alkyl, substitueret alkenyl, phenyl, C3.7cycloalkyl, og fem- til seks-leddet heterocyclo eller heteroaryl; og Ri2 og R22 er uafhængigt udvalgt fra Ci.6alkyl, C2_6alkenyl, halogen, haloalkyl, haloalkoxy, cyano, nitro, amino, Q^alkylamino, aminoC^akyl, hydroxy, hydroxyC^alkyl, alkoxy, alkylthio, phenyl, benzyl, phenyloxy og benzyloxy.
  3. 3. Forbindelse ifølge krav 1, med formlen (la),
    da) eller et farmaceutisk acceptabelt salt eller solvat deraf, hvor: R3 er methyl eller -CF3 X er -C(=())-, -NRgC^O)-, eller -C(=())NRS-, hvor R8 er hydrogen eller Q^alkyl; Yer-C(=0)NH-; R4 er hydrogen, C2-6alkyl, C4_4alkyl eventuelt substitueret med én til tre Ri7, cycloalkyl eller heterocyklus eventuelt substitueret med keto (=0) og/eller én til tre R16; eller aryl eller heteroaryl eventuelt substitueret med én til tre R^; R6a og R6h er uafhængigt udvalgt fra hydrogen, C1.6alkyl, substitueret C^alkyl, halogen, trifluormethoxy, trifluormethyl, -OR27, -C(=0)alkyl, -0C(=0)alkyl, -NR27R28, -SR27, -N02, -CN, -C02R27, -CONH2, -S03H, -S(=0)alkyl, -S(=0)aryl, -NHS02-aryl-R27, -S02NHR27, -CONHR27 og -NHC(=0)NHR27; Ri6 er udvalgt fra Ci^alkyl, Ri7, og C4_4alkyl substitueret med keto (=0) og/eller én til to R17; R17 er udvalgt fra halogen, hydroxy, C4_4alkoxy, trifluormethyl, trifluormethoxy, cyano, nitro, phenyl, benzyl, phenyloxy, benzyloxy, NH2, NH(Ci_4alkyl), N(C4_4alkyl)2, C3.7cycloalkyl, eller fem- eller seks-leddet heteroaryl eller heterocyklus; og R27 og R28 er udvalgt fra hydrogen, Ci.4alkyl, phenyl, C3.7cycloalkyl, og fem- til seks-leddet heterocyclo eller heteroaryl.
  4. 4. Forbindelse ifølge krav 1, eller et farmaceutisk acceptabelt salt eller solvat deraf, hvor: ring B er phenyl substitueret med heterocyklus og nul til én Ri2, eller er en cycloalkyl, heteroaryl eller heterocvclorin? udval vt fra:
    hvor E, G, J og K er udvalgt fra O, S, NH og CH2, forudsat at, når q er 0, så er J og K ikke samtidigt udvalgt fra O og S; og M er N eller CH; hvor hvert hydrogenatom af E, G, J, K og M eventuelt kan udskiftes med en R7-gruppe; R7 og Ri2 er uafhængigt udvalgt fra Ci_6alkyl, substitueret C^alkyl, halogen, trifluormethoxy, trifluormethyl, hydroxy, -Cr4alkoxy, -C(=0)alkyl, -0C(=0)alkyl, NH2, NH/C^alkyl), N(Ci-4alkyl)2, -CN, -C02alkyl, -CONH2, -CONH(CH3), -CON(CH3)2, phenyl, benzyl, C3_7cycloalkyl og fem- til seks-leddet heterocyclo eller heteroaryl; n er 0, 1 eller 2; °gP °S ? er udvalgt fra 0, 1, 2, 3 og 4, forudsat at/? og q taget sammen ikke er større end 4.
  5. 5. Forbindelse ifølge krav 4, eller et farmaceutisk acceptabelt salt eller solvat deraf, hvori: X er -C(=0)-, -C(=0)NH- eller -C(=0)N(Cr4alkyl)-; Y er -C(=0)NH-; R4 er hydrogen, C2.6alkyl, C4_4alkyl eventuelt substitueret med én til tre R|7, aryl eller heteroaryl eventuelt substitueret med én til tre R16, eller cycloalkyl eller heterocyklus eventuelt substitueret med keto (=0), og/eller én til tre R16; R16 er udvalgt fra (4_4alkyl, R17 og (4_4alkyl substitueret med keto og/eller én til to R17; og R[7 er udvalgt fra halogen, hydroxy, C4_4alkoxy, trifluormethyl, trifluormethoxy, cyano, nitro, phenyl, benzyl, phenyloxy, benzyloxy, NH2, NI I(C|^alkyl), og N(C1.4alkyl)2.
  6. 6. Forbindelse ifølge krav 1 eller et farmaceutisk acceptabelt salt eller solvat deraf, hvori R| og R5 uafhængigt er hydrogen eller CH3.
  7. 7. Forbindelse ifølge krav 1, eller et farmaceutisk acceptabelt salt eller solvat deraf, hvori R2 er hydrogen.
  8. 8. Forbindelse ifølge krav 1, eller et farmaceutisk acceptabelt salt eller solvat deraf, hvori R3 er methyl eller -CF3.
  9. 9. Forbindelse ifølge krav 1, eller et farmaceutisk acceptabelt salt eller solvat deraf, hvori X er -C(=0)-eller-C(=0)NH-.
  10. 10. Forbindelse ifølge krav 1, eller et farmaceutisk acceptabelt salt eller solvat deraf, hvori X er -C(=0)NH- og R4 er C2-6alkyl, eventuelt substitueret benzyl, eller en heterocyklisk eller heteroarylring udvalgt fra diazepinyl, morpholinyl, piperidinyl og pyrrolidinyl, hvilken heterocyklus eventuelt er substitueret med én til to af C1.4alkyl, hydroxy, C^alkoxy, phenyl og/eller benzyl.
  11. 11. Forbindelse ifølge krav 1, eller et farmaceutisk acceptabelt salt eller solvat deraf, hvori X er -C(=0)- og R4 er phenyl, pyridyl, pyrimidinyl, eller pyrazinyl eventuelt substitueret med én til to Ci.4alkyl, halogen, hydroxy, Ci_4alkoxy, trifluormethyl, trifluormethoxy, cyano, nitro, phenyl, benzyl, phenyloxy, benzyloxy, NH2, NH(Ci_4alkyl), N(Ci.4alkyl)2 og/eller en Ci_4alkyl substitueret med én til to af halogen, hydroxy, Ci_4alkoxy, trifluormethyl, trifluormethoxy, cyano, nitro, phenyl, benzyl, phenyloxy, benzyloxy, NH2, NH(Ci_4 alkyl) og/eller N(C1.4alkyl)2.
  12. 12. Forbindelse ifølge krav 1, eller et farmaceutisk acceptabelt salt eller sol vat deraf, hvori B er cyclopropyl eller cyclobutyl eventuelt substitueret med én til to R7, phenyl substitueret med en fem- eller seks-leddet heterocyklus og nul til to Ri2, eller B er udvalgt fra én af: °g
    R7 og R12 er uafhængigt udvalgt fra C[.4alkyl, trifluormethyl, trifluormethoxy, halogen, cyano, amino, Ci_4alkylalmino, hydroxy, C'|.4alkoxy, phenyl, benzyl, phenyloxy, og benzyloxy; og n er 0, 1 eller 2.
  13. 13. Forbindelse ifølge krav 1 med formlen (3a),
    (3 a) enantiomerer, diastereomerer, salte og solvater deraf, hvor R3 er methyl eller CF3; X er -C(=0)- eller -C(=0)NH-; R4 er lige eller forgrenet C2-6alkyl; cycloalkyl eventuelt substitueret med keto og/eller op til to R16; heterocyklus eller heteroaryl eventuelt substitueret med keto og/eller op til to Ri6; Ci^alkyl substitueret med op til tre of halogen, trifluormethyl, cyano, hydroxy, alkoxy, haloalkyl, haloalkoxy, nitro, phenyl, phenyloxy eller benzyloxy, hvor phenylgruppen eventuelt er substitueret med én til to R26; eller phenyl eventuelt substitueret med nul til to R16; Rga og R6b er udvalgt fra hydrogen C|_4alkyl, halogen, trifluormethoxy, trifluormethyl, hydroxy, C4. 4alkoxy, nitro og cyano; B er en C3.7cycloalkyl eventuelt substitueret med én til to R7, en fem-leddet heteroaryl eventuelt substitueret med én til to R7, en fem- eller seks-leddet heterocyclo eventuelt substitueret med én til to R7, phenyl substitueret med Ru og nul til to Ri2, -C(=0)Ri3,-C02Ri3 og -C(=0)NR13Ri3a; R7 er bundet til et hvilket som helst tilgængeligt carbon- eller nitrogenatom af ring B og ved hver forekomst er uafhængigt udvalgt fra alkyl, substitueret alkyl, halogen, haloalkoxy, ureido, cyano, trifluormethoxy, trifluormethyl, hydroxy, -Q^alkoxy, -C(=0)alkyl, -0C(=0)alkyl, NH2, NI I(Q.4alkyl), N(C|_4aIkyI)2, -CN, -C02alkyl, -CONH2, -CONH(CH3), -CON(CH3)2, phenyl, benzyl, C3-7cycloalkyl, og fem- til seks-leddet heterocyclo eller heteroaryl; og/eller når B er cycloalkyl, kan to R7-grupper samles for at danne en eventuelt substitueret carbon-carbon-bro af tre til fire carbonatomer, eller to R7-grupper kan samles for at danne en kondenseret carbocyklisk, heterocyklisk eller heteroarylring, hvilken kondenseret ring til gengæld eventuelt er substitueret med én til tre R22; Ru er cycloalkyl, heterocyclo, eller heteroaryl eventuelt substitueret med én til to R15; Ri3 og R13aer udvalgt fra hydrogen og Ci_4alkyl; R12, Ris °g Ri6 ved hver forekomst er uafhængigt udvalgt fra hydrogen, alkyl, trifluormethyl, trifluormethoxy, halogen, cyano, nitro, amino, Ci_4alkylamino, aminoQ^alkyl, haloQ^alkyl, hydroxy, hydroxyCi_4alkyl, alkoxy, phenyl, benzyl, phenyloxy og benzyloxy; R20 og R2i er udvalgt fra hydrogen, alkyl, alkenyl, substitueret alkyl, substitueret alkenyl, aryl, cycloalkyl, heteroaryl, og heterocyclo; og R22 og R26 er udvalgt fra Ci_6alkyl, C2.6alkenyl, halogen, haloalkyl, haloalkoxy, cyano, nitro, amino, Ci_4alkylamino, aminoC^alkyl, hydroxy, hydroxyC|_4aIkyI, alkoxy, alkylthio, phenyl, benzyl, phenyloxy og benzyloxy.
  14. 14. Forbindelse ifølge krav 13, eller et farmaceutisk acceptabelt salt eller solvat deraf, hvori B er phenyl substitueret med heterocyclo og én til to R12; cyclopropyl eller cyclobutyl eventuelt substitueret med én til to R7; eller B er udvalgt fra én af:
    Og Ry er C^alkyl, trifluormethyl, trifluormethoxy, halogen, cyano, amino, Ci.4alkylalmino, hydroxy, Ci.4alkoxy, phenyl, benzyl, phenyloxy, eller benzyloxy; og n er 0, 1 eller 2.
  15. 15. Forbindelse ifølge krav 1 med formlen (2a) eller (2b), (2a)
    i (2b) enantiomerer, diastereomerer, salte og solvater deraf, hvor: R3 er methyl eller CF3; R4a er phenyl eller fem- eller seks-leddet heteroaryl eventuelt substitueret med op til to R16; Ru, er lige eller forgrenet C2_6alkyl; cycloalkyl eventuelt substitueret med keto og/eller op til to R16; heterocyklus eventuelt substitueret med keto og/eller op til to Ri6; eller Q.+alkyl substitueret med op til tre of halogen, trifluormethyl, cyano, hydroxy, alkoxy, haloalkyl, haloalkoxy, nitro, phenyl, phenyloxy eller benzyloxy, hvor phenyl- eller benzylgruppen til gengæld er eventuelt substitueret med én til to R26; R6a er Ci^alkyl, halogen, trifluormethoxy, trifluormethyl, hydroxy, C^alkoxy, eller cyano; B er udvalgt fra phenyl substitueret med heterocyclo eller heteroaryl og op til to R12, cyclopropyl eller cyclobutyl, der hver eventuelt kan være substitueret med én til to R7, eller B er udvalgt fra én af: og
    R7 er Q.zjalkyl, trifluormethyl, trifluormethoxy, halogen, cyano, nitro, amino, Ci_4alkylalmino, hydroxy, C^alkoxy, phenyl, benzyl, phenyloxy eller benzyloxy; R12, Ri6 og Rn ved hver forekomst er uafhængigt udvalgt fra hydrogen, alkyl, trilluormethyl, trifluormethoxy, halogen, cyano, nitro, amino, C1.4alkylalmino, hydroxy, alkoxy, phenyl, benzyl, phenyloxy og benzyloxy; R26 er udvalgt fra C1.4alkyl, trifluormethyl, trifluormethoxy, halogen, cyano, amino, Q. 4alkylalmino, hydroxy, alkoxy, phenyl, benzyl, phenyloxy og benzyloxy; n er 0 eller 1.
  16. 16. Forbindelse ifølge krav 15 eller et farmaceutisk acceptabelt salt eller solvat deraf, hvori B er cyclopropyl eventuelt substitueret med én til to R7, eller B er udvalgt fra: °g
  17. 17. Forbindelse ifølge krav 1 udvalgt fra
    eller salte og solvater deraf.
  18. 18. Forbindelse ifølge krav 1 udvalgt fra
    eller enantiomerer, diastereomerer, salte og solvater deraf.
  19. 19. Forbindelse ifølge krav 1, der er
    eller enantiomerer, diastereomerer, salte og solvater deraf.
  20. 20. Forbindelse ifølge krav 1 med formlen
    eller en enantiomer, diastereomer eller et farmaceutisk acceptabelt salt deraf.
  21. 21. Farmaceutisk sammensætning, der mindst omfatter én forbindelse ifølge et hvilket som helst af kravene 1 til 20 og et farmaceutisk acceptabelt bærestof eller fortyndingsmiddel.
  22. 22. Anvendelse af en farmaceutisk sammensætning ifølge krav 21 til fremstilling af et medikament til behandling af en inflammatorisk forstyrrelse hos en patient.
  23. 23. Anvendelse ifølge krav 22, hvor den inflammatoriske forstyrrelse er udvalgt fra astma, adult respiratorisk stresssyndrom, kronisk obstruktiv lungesygdom, kronisk inflammatorisk lungesygdom, diabetes, inflammatorisk tarmsygdom, osteoporose, psoriasis, transplantatafstødning, atherosklerose og arthritis herunder rheumatoid arthritis, psoriatisk arthritis, traumatisk arthritis, rubella arthritis, arthritis urica og osteoarthritis.
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