DK2771329T3 - Nye disubstituerede 3,4-diamino-3-cyclobuten-1,2-dion-forbindelser til anvendelse i behandlingen af chemokin-formidlede sygdomme - Google Patents

Nye disubstituerede 3,4-diamino-3-cyclobuten-1,2-dion-forbindelser til anvendelse i behandlingen af chemokin-formidlede sygdomme Download PDF

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DK2771329T3
DK2771329T3 DK12791825.8T DK12791825T DK2771329T3 DK 2771329 T3 DK2771329 T3 DK 2771329T3 DK 12791825 T DK12791825 T DK 12791825T DK 2771329 T3 DK2771329 T3 DK 2771329T3
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methyl
radical
amino
atom
enylamino
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Laurence Clary
Patricia Rossio
Marlène Schuppli-Nollet
Branislav Musicki
Jean-Guy Boiteau
Jérã´Me Aubert
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Claims (9)

  1. (1) hvor R5 og X har den efterfølgende angivne betydning, R3 står for en heteroaromatisk cyklus, som svarer til den følgende formel (d):
    id) hvor R7, Y og Z har den efterfølgende angivne betydning, hvor det præciseres, at cyklus (d) eventuelt kan bære flere R7-grupper, identiske eller forskellige, hvor det samlede antal for sådanne R7-grupper højst er lig med antallet af atomer, der kan substitueres fra cyklussen; R4 står for en aromatisk cyklus, der svarer til den følgende formel (t):
    (t) hvor R8, R9, R10, R11 og R12 harden efterfølgende angivne betydning, R5 står for et hydrogenatom, et fluoratom, et alkylradikal med 1 til 5 carbona-tomer eller et fluor- eller perfluoralkylradikal med 1 til 5 carbonatomer, R6 står for et hydrogenatom, et -COOtBu- eller -COOBn-radikal, R7 står foret halogenatom, et R16-, -CF3-, -COR16-, -OR16-, -NR16R17-, -N02-, -CN-, -S02R16-, -S02NR16R17-, -NR16COR17-, -CONR16R17-, -NR16C02R17- eller -C02R16-radikal, R8 står for et hydrogenatom, et -OH-, -SH-, -CONHOR16-, -C0NR160H-, -NR16R17-, -S03H-, -OCOR16-, -NHS02R16-, -S02NR16R17-, -NHCOR16-, -CONR16R17-,-NR16C02R17-, -NHS02NR16R17-, -C02R16-, pyrrolyl-, imidazolyl-, triazolyl eller tetrazolylradikal, R9, R10, R11 og R12 er identiske eller forskellige og er uafhængigt udvalgt i gruppen bestående af et hydrogenatom, et halogenatom, et alkyl-, alkoxy- -CF3-, -OCF3-, - OH-, -N02-, -CN-, -S02R16-, -S02NR16R17-, - NR16COR17-, -NR16C02R17-, -CONR16R17-, -C0R16- eller -C02R16-radikal, eller også når to af radikalerne R9, R10, R11 og R12 befinder sig i ortho-position på den aromatiske cyklus (t), så kan de sammen med den forbindelse, som forbinder dem, danne en aryl-, heteroaryl-, cycloalkyl- eller heterocy-cloalkylcyklus R15 står for et hydrogenatom, et -OH-, -S02R16-, -COR16-, -C02R16-, aryl-, heteroaryl-, arylalkyl-, heteroarylalkyl-, alkyl-, cycloalkyl eller cycloalkylalkyl-radikal, R16 og R17 er identiske eller forskellige og er uafhængigt udvalgt i gruppen bestående af et hydrogenatom, et aryl-, heteroaryl-, arylalkyl-, heteroarylalkyl-, alkyl-, fluoral kyl radikal, som har fra 1 til 5 carbonatomer, cycloalkyl- eller cy cl oal kyl al kyl rad i kal, en -CH2COOR18-gruppe, hvor R18 står for et alkylra-dikal med 1 til 5 carbonatomer, eller også når R16 og R17 er bundet til det samme nitrogenatom, danner de en heterocyklus med mellem 3 og 7 led og omfatter eventuelt et eller to hete-roatomer, der er udvalgt blandt oxygen, svovl og nitrogen ud over det fælles nitrogenatom, til hvilket de er bundet, hvor heterocyklussen kan substitueres med en alkylgruppe med 1 til 5 carbonatomer eller en -COOR18-gruppe, hvor R18 står for et alkylradikal med 1 til 5 carbonatomer; X står for et oxygenatom, et svovlatom eller et nitrogenatom, der er substitueret med et radikal R6, Y står for et oxygenatom, et svovlatom eller et nitrogenatom, der er substitueret med et radikal R15, og Z står for et carbon- eller nitrogenatom.
    (1) (2) (3) hvor R5, R7a, X og X' har den efterfølgende angivne betydning, R3 står for en aromatisk eller heteroaromatisk cyklus, der er udvalgt i gruppen bestående af de cyklusser, som svarer til de følgende formler (a), (b) og (riY
    hvor R7, R7a, Y og Z har den efterfølgende angivne betydning, hvor det præciseres, at cyklusserne (a), (b) og (d) eventuelt kan bære forskellige R7- grupper, identiske eller forskellige, hvor det samlede antal for sådanne R7-grupper højst er lig med antallet af atomer, der kan substitueres fra cyklussen; R4 står for en aromatisk eller heteroaromatisk cyklus, der er udvalgt i gruppen bestående af de cyklusser, som svarer til de følgende formler (p), (q), (t), (z), (ad), (ag) og (ah): <p> <q)
    (t) {z)
    (ad) (ag) (ah) hvor R8, R9, R10, R11, R12, R13 og R15 står for en aromatisk eller heteroaromatisk cyklus, der er udvalgt i gruppen bestående af de cyklusser, som svarer til de følgende formler, R5 står for et hydrogenatom, et fluoratom, et alkylradikal med 1 til 5 carbona-tomer eller et fluor- eller perfluoralkylradikal med 1 til 5 carbonatomer, R6 står for et hydrogenatom, et -COOtBu- eller -COOBn-radikal, R7 står for halogen, et R16-, -CF3-, -COR16-, -OR16-, -NR16R17-, -N02-, -CN, -S02R16-, -S02NR16R17-, -NR16COR17-, -CONR16R17-, - NR16C02R17- eller -C02R16-radikal, R7a står for et hydrogen- eller alkylradikal med 1 til 5 carbonatomer, R8 står for et hydrogenatom, et -OH-, -SH-, -CONHOR16-, -C0NR160H-, -NR16R17-, -S03H-, -OCOR16-, -NHS02R16-, -S02NR16R17-, -NHCOR16-, -CONR16R17-, -NR16C02R17-, -NHS02NR16R17-, -C02R16-, pyrrolyl-, imidazolyl-, triazolyl- eller tetrazolylradikal, R9, R10, R11 og R12 er identiske eller forskellige og er uafhængigt udvalgt i gruppen bestående af et hydrogenatom, et halogenatom, et alkyl-, alkoxy- -CF3-, -OCF3-, - OH-, -N02-, -CN-, -S02R16-, -S02NR16R17-, - NR16COR17-, -NR16C02R17-, -CONR16R17-, -C0R16- eller -C02R16-radikal, eller også når to af radikalerne R9, R10, R11 og R12 befinder sig i ortho-position på en aromatisk eller heteroaromatisk cyklus, der er udvalgt i gruppen bestående af de cyklusser, der svarer til formlerne (p), (q), (t), (z), (ad), (ag) og (ah) ovenfor, så kan de sammen med den forbindelse, som forbinder dem, danne en aryl-, heteroaryl-, cycloalkyl- eller heterocycloalkylcyklus, R13 er udvalgt fra gruppen bestående af et hydrogenatom, et halogenatom, et alkyl-, -CF3-, -OCF3-, -OH-, -SH-, -CN-, -S02R16-, -S02NR16R17-, -NHS02NR16R17-, -NR16R17-, -NR16CONR16R17-, -NR16COR17-, -NR16C02R17-, -CONR16R17-, -COR16- eller -C02R16-radikal, R15 står for et hydrogenatom, et -OH-, -S02R16-, -COR16-, -C02R16-, aryl-, heteroaryl-, arylalkyl-, heteroarylalkyl-, alkyl-, cycloalkyl eller cycloalkylalkyl-radikal, R16 og R17 er identiske eller forskellige og er uafhængigt udvalgt i gruppen bestående af et hydrogenatom, et aryl-, heteroaryl-, arylalkyl-, heteroarylalkyl-, arylalkyl-, heteroarylalkyl-, alkyl-, f I uo ral kyl rad i kal, som har fra 1 til 5 car-bonatomer, cycloalkyl- eller cycloalkylalkylradikal, en -CH2COOR18-gruppe, hvor R18 står for et alkylradikal med 1 til 5 carbonatomer, eller også når R16 og R17 er bundet til det samme nitrogenatom, danner de en heterocyklus med mellem 3 og 7 led og omfatter eventuelt et eller to hete-roatomer, der er udvalgt blandt oxygen, svovl og nitrogen ud over det fælles nitrogenatom, til hvilket de er bundet, hvor heterocyklussen kan substitueres med en alkylgruppe med 1 til 5 carbonatomer eller en -COOR18-gruppe, hvor R18 står for et alkylradikal med 1 til 5 carbonatomer; X og X', identiske eller forskellige, står for et oxygenatom, et svovlatom eller et nitrogenatom, der er substitueret med et radikal R6, Y står for et oxygenatom, et svovlatom eller et nitrogenatom, der er substitueret med et radikal R15, og Z står for et carbon- eller nitrogenatom.
    (1) (2) (3) (4) hvor R5, R7a, X og X' har den efterfølgende angivne betydning, R3 står for en aromatisk eller heteroaromatisk cyklus, der er udvalgt i gruppen bestående af de cyklusser, som svarer til de følgende formler (a) til (o):
    ti) (k). (0 (m)
    (π) (ο) hvor R7, R7a, Υ og Ζ har den efterfølgende angivne betydning, idet det skal præciseres, at cyklusserne (a) til (o) kan eventuelt bære flere identiske eller forskellige R7-grupper, hvor det samlede antal af sådanne R7-grupper er højst lige med antallet af atomer, som kan substitueres med cyklussen; R4 står for en aromatisk eller heteroaromatisk cyklus, der er udvalgt i gruppen bestående af de cyklusser, som svarer til de følgende formler (p) til (z) og (aa) til (ak):
    (ag) (ah) (aj) (aj) (a^ hvor R7, R8, R9, R10, R11, R12, R13, R14 og R15 har den efterfølgende angivne betydning, R5 står for et hydrogenatom, et fluoratom, et alkylradikal med 1 til 5 carbona-tomer eller et fluor- eller perfluoralkylradikal med 1 til 5 carbonatomer, R6 står for et hydrogenatom, et -COOtBu- eller -COOBn-radikal, R7 står for et halogen, et -R16-, -CF3-, -COR16-, -OR16-, -NR16R17-, -N02-, -CN-, - S02R16-, -S02NR16R17-, -NR16COR17-, -CONR16R17-, -NR16C02R17- eller -C02R16-radikal, - R7a står for hydrogenradikal eller et alkylradikal med 1 til 5 carbonatomer, R8 står for et hydrogenatom, et halogenatom, et -OH-radikal, et -SH-, -CONHOR16-, -CONR160H-, -NR16R17-, -S03H-, -OCOR16-, -NHS02R16-, -S02NR16R17-, -NHCOR16-, -CONR16R17-, -NR16C02R17-, - NHS02NR16R17-, -C02R16-, pyrrolyl-, imidazolyl-, triazolyl- eller tetrazolyl-radikal, R9, R10, R11 og R12 er identiske eller forskellige og er uafhængigt udvalgt fra gruppen bestående af hydrogen, et halogenatom, et alkyl-, alkoxy-, -CF3-, -OCF3-, -OH-, -N02-, -CN-, -S02R16-, -S02NR16R17-, -NR16COR17-, -NR16C02R17-, -CONR16R17-, -COR16- eller -C02R16-radikal, eller også når to af radikalerne R9, R10, R11 og R12 befinder sig i ortho-position på en aromatisk eller heteroaromatisk cyklus, der er udvalgt i gruppen bestående af de cyklusser, der svarer til formlerne (p) til (z) og (aa) til (ak) ovenfor, så kan de sammen med den forbindelse, som forbinder dem, danne en aryl-, heteroaryl-, cycloalkyl- eller heterocycloalkylcyklus, R13 og R14 er identiske eller forskellige og er uafhængigt udvalgt i gruppen bestående af et hydrogenatom, et halogenatom, et alkyl-, -CF3-, -OCF3-, -OH-, -SH-, -CN-, -S02R16-, -S02NR16R17-, -NHS02NR16R17-, -NR16R17-, -NR16CONR16R17-, -NR16COR17-, -NR16C02R17-, - CONR16R17-, -COR16- eller -C02R16-radikal, R15 står for et hydrogenatom, et -OH-, -S02R16-, -COR16-, -C02R16-, aryl-, heteroaryl-, arylalkyl-, heteroarylalkyl-, alkyl-, cycloalkyl- eller cycloalkylalkyl-radikal, R16 og R17 er identiske eller forskellige og er uafhængigt udvalgt i gruppen bestående af et hydrogenatom, et aryl-, heteroaryl-, arylalkyl-, heteroarylal-kyl-, arylalkyl-, heteroarylalkyl-, alkyl-, f I uo ral kyl rad i kal, som har fra 1 til 5 car-bonatomer, cycloalkyl- eller cycloalkylalkylradikal, en -CH2COOR18-gruppe, hvor R18 står for et alkylradikal med 1 til 5 carbonatomer, eller også når R16 og R17 er bundet til det samme nitrogenatom, danner de en heterocyklus med mellem 3 og 7 led og omfatter eventuelt et eller to hete-roatomer, der er udvalgt blandt oxygen, svovl og nitrogen ud over det fælles nitrogenatom, til hvilket de er bundet, hvor heterocyklussen kan substitueres med en alkylgruppe med 1 til 5 carbonatomer eller en -COOR18-gruppe, hvor R18 står for et alkylradikal med 1 til 5 carbonatomer; X og X', identiske eller forskellige, står for et oxygenatom, et svovlatom eller et nitrogenatom, der er substitueret med et radikal R6, Y står for et oxygenatom, et svovlatom eller et nitrogenatom, der er substitueret med et radikal R15, og Z står for et carbon- eller nitrogenatom.
    1. Disubstituerede 3,4-diamino-3-cyclobuten-1,2-dion-forbindelse, som svarer til den følgende almene formel (I) eller et af sine farmaceutisk acceptable salte eller solvater:
    (i) hvor R1 står for et hydrogenatom eller en methyl, R2 står for en cyklus med fem atomer, der er udvalgt blandt de følgende strukturer (1), (2), (3) og (4):
  2. 2. Forbindelser ifølge krav 1, kendetegnet ved, at i den ovennævnte formel (I): R1 står for et hydrogenatom, R2 står for en cyklus med fem led, der er udvalgt blandt de følgende strukturer (1), (2) og (3):
  3. 3. Forbindelse ifølge krav 1 eller 2, kendetegnet ved, at i den førnævnte formel (I): R1 står for et hydrogenatom, R2 står for en cyklus med fem atomer med den følgende struktur (1):
  4. 4. Farmaceutisk sammensætning, omfattende en virksom mængde af en forbindelse eller et farmaceutisk acceptabelt salt af forbindelsen ifølge krav 1 i kombination med et farmaceutisk acceptabelt opløsningsmiddel eller en farmaceutisk acceptabel bærer.
  5. 5. Forbindelse ifølge krav 1 eller farmaceutisk sammensætning ifølge krav 4 til anvendelse som lægemiddel.
  6. 6. Forbindelse ifølge krav 1 eller farmaceutisk sammensætning ifølge krav 4 til anvendelse i behandlingen af sygdomme, som formidles af a-chimiokiner, der er udvalgt blandt sygdommene af gruppen, som omfatter neutrophile dermatoser, der er udvalgt blandt psoriasis, atopiske dermatider, akne, rosacea, astma, kronisk-obstruktive lungesygdomme, luftvejssygdomme hos voksne, artritis, inflammatoriske tarmsygdomme, Crohns sygdom, transplantatafstødning, cystisk fibrose og hudkræftstyper.
  7. 7. Forbindelse eller farmaceutisk sammensætning ifølge krav 6 til anvendelse i behandlingen af dermatologiske sygdomme, omfattende neutrophile dermatoser, der er udvalgt blandt psoriasis, atopiske dermatider, akne og rosacea.
  8. 8.
  9. Forbindelse ifølge krav 1, der er udvalgt fra listen, som omfatter: 1/- 2-hydroxy-N,N-dimethyl-3-(2-{[(5-methyl-furan-2-yl)-(2-methyl- tetrahydrofuran-2-yl)-methyl]-amino}-3,4-dioxo-cyclobut-1-enylamino)- benzamid 2/-2-hydroxy-/V,A/-dimethyl-3-(2-{[(5-methyl-furan-2-yl)-(tetrahydro-thiophen- 2-yl)-methyl]-amino}-3,4-dioxo-cyclobut-1-enylamino)-benzamid 3/- (S)-1-[2-fluoro-3-(2-{[(5-methyl-furan-2-yl)-(tetrahydro-thiophen-2-yl)- methyl]-amino}-3,4-dioxo-cyclobut-1-enylamino)-benzoyl]-pyrrolidine-2- carbonsyremethylester 4/- (S)-1-[2-fluoro-3-(2-{[(5-methyl-furan-2-yl)-(tetrahydro-thiophen-2-yl)- methyl]-amino}-3,4-dioxo-cyclobut-1-enylamino)-benzoyl]-pyrrolidin-2- carbonsyreisopropylester 5/- (S)-1-[2-fluoro-3-(2-{[(5-methyl-furan-2-yl)-(tetrahydro-thiophen-2-yl)- methyl]-amino}-3,4-dioxo-cyclobut-1-enylamino)-benzoyl]-pyrrolidin-2- carbonsyreethylester 6/- (R)-1-[2-hydroxy-3-(2-{[(5-methyl-furan-2-yl)-(tetrahydro-thiophen-2-yl)- methyl]-amino}-3,4-dioxo-cyclobut-1-enylamino)-benzoyl]-pyrrolidin-2- carbonsyremethylester 7/- (S)-1-[2-hydroxy-3-(2-{[(5-methyl-furan-2-yl)-(tetrahydro-thiophen-2-yl)- methyl]-amino}-3,4-dioxo-cyclobut-1-enylamino)-benzoyl]-pyrrolidin-2- carbonsyremethylester 8/- 2-hydroxy-N-methyl-3-(2-{[(S)-(5-methyl-furan-2-yl)-tetrahydro-thiophen-2- yl-methyl]-amino}-3,4-dioxo-cyclobut-1-enylamino)-N-(2,2,2-trifluoro-ethyl)- benzamid 9/- {[2-hydroxy-3-(2-{[(5-methyl-furan-2-yl)-(tetrahydro-thiophen-2-yl)-methyl]- amino}-3,4-dioxo-cyclobut-1-enylamino)-benzoyl]-methyl-amino}- eddikesyremethylester 10/- 6-chloro-2-hydroxy-N,N-dimethyl-3-(2-{[(5-methyl-furan-2-yl)-(tetrahydro- thiophen-2-yl)-methyl]-amino}-3,4-dioxo-cyclobut-1-enylamino)- benzolsulfonamid 11/-2-hydroxy-N,N-dimethyl-3-(2-{[(R)-(5-methyl-furan-2-yl)-tetrahydro-furan- 2-yl-methyl]-amino}-3,4-dioxo-cyclobut-1-enylamino)-benzamid 12/- 2-hydroxy-N,N-dimethyl-3-(2-{[(S)-(5-methyl-furan-2-yl)-tetrahydro-furan- 2- yl-methyl]-amino}-3,4-dioxo-cyclobut-1-enylamino)-benzamid 13/- 3-(3,4-dioxo-2-{[phenyl-(tétrahydrofuran-2-yl)-méthyl]-amino}-cyclobut-1 -enyl-amino)-2-hydroxy-N,N-dimethylbenzamid 14/- 3-(2-{[((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-(5-methyl-furan-2-yl)-methyl]-amino}-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N,N-dimethylbenzamid 15/ (S)-1 -[2-Fluoro-3-(2-{[(5-methyl-furan-2-yl)-(tetrahydro-thiophen-2-yl)-methyl]-amina}-3,4-dioxo-cyclobut-1-enylamino)-benzoyl]-pyrrolidin-2-carbonsyremethylester 16/ 3-(2-hydroxy-pyridin-3-ylamino)-4-{[(5-methyl-furan-2-yl)-(tetrahydro- thiophen-2-yl)-methyl]-amino}-cyclobut-3-en-1,2-dion 17/ 3-{[(5-methyl-furan-2-yl)-(tetrahydro-thiophen-2-yl)-methyl]-amino}-4-(1 - methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino)-cyclobut-3-en-1,2-dion 18/ (-)-2-hydroxy-N-methyl-3-(2-{[(S)-(5-methyl-furan-2-yl)-(tetrahydro- thiophen-2-yl)-methyl]-amino}-3,4-dioxo-cyclobut-1-enylamino)-N-(2,2,2- trifluoro-ethyl)-benzamid 19/(-)-{[2-hydroxy-3-(2-{[(S)-(5-methyl-furan-2-yl)-(tetrahydro-thiophen-2-yl)- methyl]-amino}-3,4-dioxo-cyclobut-1-enylamino)-benzoyl]-methyl-amino}- eddikesyremethylester 20/ (-)-1-[2-hydroxy-3-(2-{[((S)-5-methyl-furan-2-yl)-(tetrahydro-thiophen-2- yl)-methyl]-amino}-3,4-dioxo-cyclobut-1-enylamino)-benzoyl]-pyrrolidin-2-(R)- carbonsyremethylester 21/(-)-6-chloro-2-hydroxy-N,N-dimethyl-3-(2-{[((S)-5-methyl-furan-2-yl)- (tetrahydro-thiophen-2-yl)-methyl]-amino}-3,4-dioxo-cyclobut-1-enylamino)- benzamid 22/(-)-3-[4-chloro-2-hydroxy-3-(4-methyl-piperazin-1-sulfonyl)-phenylamino]-4- {[(5-methyl-furan-2-yl)-(tetrahydro-thiophen-2-yl)-methyl]-amino}-cyclobut- 3- en-1,2-dion
DK12791825.8T 2011-10-28 2012-10-26 Nye disubstituerede 3,4-diamino-3-cyclobuten-1,2-dion-forbindelser til anvendelse i behandlingen af chemokin-formidlede sygdomme DK2771329T3 (da)

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PCT/FR2012/052478 WO2013061004A1 (fr) 2011-10-28 2012-10-26 Nouveaux composés di-substitués de la diamino-3,4-cyclobutène-3-dione-1,2 utiles dans le traitement de pathologies médiées par des chimiokines

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WO2019165315A1 (en) 2018-02-23 2019-08-29 Syntrix Biosystems Inc. Method for treating cancer using chemokine antagonists alone or in combination
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