DK2847190T3 - Bicyklisk substituerde uraciler og anvendelse heraf - Google Patents

Bicyklisk substituerde uraciler og anvendelse heraf Download PDF

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DK2847190T3
DK2847190T3 DK13720407.9T DK13720407T DK2847190T3 DK 2847190 T3 DK2847190 T3 DK 2847190T3 DK 13720407 T DK13720407 T DK 13720407T DK 2847190 T3 DK2847190 T3 DK 2847190T3
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hydrogen
trifluoromethyl
alkyl
mmol
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Chantal Fürstner
Alexander Straub
Heinrich Meier
Hanna Tinel
Katja Zimmermann
Adrian Tersteegen
Raimund Kast
Martina Schäfer
Kirsten Börngen
Jens Ackerstaff
Dmitry Zubov
Jens Schamberger
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Bayer Pharma AG
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Claims (17)

1. Forbindelse med formel (I)
(T), hvor R1 står for hydrogen eller (C1-C4)-alkyl, R2 står for en gruppe med formel
idet * står for forbindelsesstedet til uracil-nitrogenatomet, A står for -CH2-, -CH2-CH2-, -0-CH2-## eller oxygen, hvor ## står for forbindelsesstedet til phenyl-ringen, m står for et tal 0, 1 eller 2, R4 står for halogen, difluormethyl, trifluormethyl, (C1-C4)- alkyl, difluormethoxy, trifluormethoxy eller (C1-C4)-alkoxy, R5a står for hydrogen eller deuterium, R5b står for hydrogen, deuterium eller (C1-C4)-alkyl, R6 står for hydrogen eller fluor, R7 står for hydrogen eller fluor, R8 står for halogen, difluormethyl, trifluormethyl, (C1-C4)- alkyl eller nitro, R9 står for hydrogen, halogen, difluormethyl, trifluormethyl, (C1-C4)-alkyl, nitro eller (C1-C4) -alkylthio, R3 står for en gruppe med formel
idet # står for forbindelsesstedet til uracil-nitrogenatomet, ringen Q står for 5- til 7-leddet heterocyclyl eller 5- eller 6-leddet heteroaryl, hvor 5- til 7-leddet heterocyclyl og 5- eller 6-leddet heteroaryl kan være substitueret med 1 til 4 substituenter uafhængigt af hinanden udvalgt af gruppen halogen, difluormethyl, trifluormethyl, trideuteromethyl, (Ci-Cg)-alkyl, (C3-C7)-cycloalkyl, oxo, hydroxy, (C1-C4)-alkylcarbonyl, (Ci — C4)-alkoxycarbonyl, aminocarbonyl og (C1-C4)-alkylsulfonyl, hvor (C1-C6) -alkyl og (C3-C7) -cycloalkyl for deres vedkommende kan være substitueret med 1 til 3 substituenter uafhængigt af hinanden udvalgt af gruppen halogen, cyano, trifluormethyl, (C3-C7)-cycloalkyl, hydroxy, (C1-C4) -alkoxy og 4- til 7-leddet heterocyclyl, og hvor to til et carbonatom af 5- til 7-leddet heterocyclyl og 5- eller 6-leddet heteroaryl bundne (Ci-Cg)-alkyl-grupper sammen med det carbonatom, som de er bundet til, kan danne en 3- til 6-leddet carbocyklus, R24 står for halogen, (C1-C4)-alkyl eller (C1-C4)-alkoxy, n står for et tal 0, 1, 2 eller 3 samt deres salte, solvater og solvater af saltene.
2. Forbindelse med formel (I) ifølge krav 1, hvor R1 står for hydrogen, methyl eller ethyl, R2 står for en gruppe med formel
idet * står for forbindelsesstedet til uracil-nitrogenatomet, A står for -CH2-, -CH2-CH2-, -0-CH2-## eller oxygen, hvor ## står for forbindelsesstedet til phenyl-ringen, R4a står for hydrogen, fluor, chlor, trifluormethyl eller methyl, R4b står for hydrogen, fluor, chlor, trifluormethyl eller methyl, på den betingelse at i det mindste en af grupperne R4A og R er forskellrg fra hydrogen, R5a står for hydrogen, R5b står for hydrogen, R6 står for hydrogen, R7 står for hydrogen, R8 står for fluor, chlor, difluormethyl, trifluormethyl eller methyl, R9 står for fluor, chlor, difluormethyl, trifluormethyl eller methyl, R3 står for en gruppe med formel
hvor # står for forbindelsesstedet til uracil-nitrogenatomet, E1 står for CR11 eller N, hvor R11 står for hydrogen, (C1-C4)-alkyl, (C3-C7) -cycloalkyl eller aminocarbonyl, E2 står for CR12 eller N, hvor R12 står for hydrogen, (C1-C4)-alkyl eller (C3-C7)-cycloalkyl, E3 står for NR14 eller S, hvor R14 står for hydrogen, (C1-C4)-alkyl eller (C3-C7)-cycloalkyl, G1 står for C=0 eller SO2, G2 står for CR16AR16B, NR17, 0 eller S, hvor R16a står for hydrogen, fluor, (C1-C4) -alkyl eller hydroxy, R16b står for hydrogen, fluor, chlor, (C1-C4) -alkyl eller trifluormethyl, eller R16a og R16b sammen med det carbonatom, som de er bundet til, danner en 3- til 6-leddet carbocyklus, R17 står for hydrogen, (C1-C6) -alkyl, (C3-C7) -cycloalkyl eller (C1-C4) -alkoxycarbonyl, hvor (C1-C6) -alkyl kan være substitueret med 1 til 3 substituenter uafhængigt af hinanden udvalgt af gruppen fluor, trifluormethyl, cyano, (C3-C7)-cycloalkyl, hydroxy, trifluormethoxy, (C1-C4)-alkoxy, azetidinyl, oxetanyl, tetrahydrofuranyl og pyrrolidinyl, G3 står for CR18AR18B, NR19, 0 eller S, hvor R18a står for hydrogen, fluor, (C1-C4) -alkyl eller hydroxy, R18b står for hydrogen, fluor, chlor, (C1-C4) -alkyl eller trifluormethyl, eller R og R sammen med det carbonatom, som de er bundet til, danner en 3- til 6-leddet carbocyklus, R19 står for hydrogen, (Ci-C6) -alkyl, (C3-C7) -cycloalkyl eller (C1-C4) -alkoxycarbonyl, hvor (C1-C6) -alkyl kan være substitueret med 1 til 3 substituenter uafhængigt af hinanden udvalgt af gruppen fluor, trifluormethyl, cyano, (C3-C7)-cycloalkyl, hydroxy, trifluormethoxy, (C1-C4)-alkoxy, azetidinyl, oxetanyl, tetrahydrofuranyl og pyrrolidinyl, G4 står for CH2, C=0 eller S02, K1 står for CH2 eller 0, K2 står for CH2 eller 0, på den betingelse, at kun en af gruppen K1 og K2 står for 0, D1, D2, D3 og D4 uafhængigt af hinanden står for CR23 eller N, hvor R23 står for hydrogen, halogen, (C1-C6) -alkyl eller (C3-C7) -cycloalkyl, på den betingelse at maksimalt 2 af grupperne D1, D2, D3 og D4 står for N, R24 står for fluor eller methyl, n står for et tal 0 eller 1, R10 står for (C1-C4)-alkyl eller (C3-C7)-cycloalkyl, hvor (C1-C4)-alkyl kan være substitueret med 1 eller 2 substituenter uafhængigt af hinanden udvalgt af gruppen fluor, trifluormethyl, cyclopropyl, cyclobutyl, hydroxy, methoxy, ethoxy, azetidinyl, oxetanyl, tetrahydrofuranyl og pyrrolidiny1, R13 står for hydrogen, (C1-C4)-alkyl eller (C3-C7)-cycloalkyl, R15 står for hydrogen, (Οχ-Οε) -alkyl eller (C3-C7) -cycloalkyl, hvor (C1-C6)-alkyl kan være substitueret med 1 eller 2 substituenter uafhængigt af hinanden udvalgt af gruppen fluor, trifluormethyl, cyclopropyl, cyclobutyl, hydroxy, methoxy, ethoxy, azetidinyl, oxetanyl, tetrahydrofuranyl og pyrrolidiny1, R20 står for hydrogen, (Ci-C6) -alkyl, (C3-C7) -cycloalkyl eller (C1-C4)-alkylcarbonyl, hvor (Ci-C6)-alkyl kan være substitueret med 1 eller 2 substituenter uafhængigt af hinanden udvalgt af gruppen fluor, trifluormethyl, cyclopropyl, cyclobutyl, hydroxy, methoxy, ethoxy, azetidinyl, oxetanyl, tetrahydrofuranyl og pyrrolidinyl, R21 står for hydrogen, (Ci-C6) -alkyl, (C3-C7) -cycloalkyl eller (C1-C4) -alkylsulfonyl, R22a står for hydrogen eller (C1-C4)-alkyl, R22b står for hydrogen eller (C1-C4)-alkyl, eller R og R sammen med det carbonatom, som de er bundet til, danner en carbonylgruppe, samt deres salte, solvater og solvater af saltene.
3. Forbindelse med formel (I) ifølge krav 1 eller 2, hvor R1 står for hydrogen, R2 står
for en gruppe med formel hvor * står for forbindelsesstedet til uracil-nitrogenatomet, A står for -CH2-, R4a står for chlor eller trifluormethyl, R4b står for hydrogen, R3 står for en
gruppe med formel idet # står for forbindelsesstedet til uracil-nitrogenatomet, E1 står for CR11, hvor R11 står for hydrogen, E2 står for N, G1 står for C=0, G2 står for CR16AR16B, NR17, 0 eller S, hvor R16a står for hydrogen, fluor, methyl eller hydroxy, R16b står for hydrogen, fluor, methyl eller trif luormethyl, eller R16a og R16b sammen med det carbonatom, som de er bundet til, danner en cyclopropyl-ring, R17 står for hydrogen, (C1-C4)-alkyl eller (C3-C5) -cycloalkyl, hvor (C1-C4) -alkyl kan være substitueret med 1 til 3 substituenter uafhængigt af hinanden udvalgt af gruppen fluor, trifluormethyl, cyano, cyclopropyl, cyclobutyl, hydroxy, trifluormethoxy, methoxy, ethoxy, azetidinyl, oxetanyl, tetrahydrofuranyl og pyrrolidinyl, R24 står for hydrogen eller fluor, R10 står for (C1C4)-alkyl, R15 står for hydrogen, methyl eller ethyl, hvor methyl og ethyl kan være substitueret med 1 substituent udvalgt af gruppen fluor, trifluormethyl og cyclopropyl, samt deres salte, solvater og solvater af saltene.
4. Forbindelse med formel (I) ifølge krav 1 eller 2, hvor R1 står for hydrogen, R2 står
for en gruppe med formel idet * står for forbindelsesstedet til uracil-nitrogenatomet, R5a står for hydrogen, R5b står for hydrogen, R6 står for hydrogen, R7 står for hydrogen, R8 står for fluor, chlor eller trifluormethyl, R9 står for fluor, chlor, trifluormethyl eller methyl, R3 står for en
gruppe med formel idet # står for forbindelsesstedet til uracil-nitrogenatomet, E1 står for CR11, hvor R11 står for hydrogen, E2 står for N, G1 står for C=0, G2 står for CR16AR16B, NR17, 0 eller S, hvor R16a står for hydrogen, fluor, methyl eller hydroxy, R16b står for hydrogen, fluor, methyl eller trif luormethyl, eller R16a og R16b sammen med det carbonatom, som de er bundet til, danner en cyclopropyl-ring, R17 står for hydrogen, (C1-C4)-alkyl eller (C3-C5) -cycloalkyl, hvor (C1-C4) -alkyl kan være substitueret med 1 til 3 substituenter uafhængigt af hinanden udvalgt af gruppen fluor, trifluormethyl, cyano, cyclopropyl, cyclobutyl, hydroxy, trifluormethoxy, methoxy, ethoxy, azetidinyl, oxetanyl, tetrahydrofuranyl og pyrrolidinyl, R24 står for hydrogen eller fluor, R10 står for (C1-C4)-alkyl, R15 står for hydrogen, methyl eller ethyl, hvor methyl og ethyl kan være substitueret med 1 substituent udvalgt af gruppen fluor, trifluormethyl og cyclopropyl, samt deres salte, solvater og solvater af saltene.
5. Forbindelse med formel (I) ifølge krav 1 med det systematiske navn 1-(1,3-dimethyl-2-oxo-2,3-dihydro-lH- benzimidazol-5-yl)-2,4-dioxo-3-[(IR)-4-(trifluormethyl)-2,3-dihydro-lH-inden-l-yl]-1,2,3,4-tetrahydropyrimidin-5-carboxylsyre (R-enantiomer) og strukturformel
6. Forbindelse med formel (I) ifølge krav 1 med det systematiske navn 1-(6-fluor-1,3-dimethyl-2-oxo-2,3-dihydro-lH-benzimidazol-5-yl)-2,4-dioxo-3-[(IR)-4-(trifluormethyl)- 2,3-dihydro-lH-inden-l-yl]-1,2,3,4-tetrahydropyrimidin-5-carboxylsure (R-enantiomer) og strukturformel
7. Forbindelse med formel (I) ifølge krav 1 med det systematiske navn 1-(3-methyl-2-oxo-2,3-dihydro-l,3- benzoxazol-6-yl)-2,4-dioxo-3-[(IR)-4-(trifluormethyl)-2,3-dihydro-lH-inden-l-yl]-1,2,3,4-tetrahydropyrimidin-5-carboxylsyre (R-enantiomer) og strukturformel
8. Forbindelse med formel (I) ifølge krav 1 med det systematiske navn 2,4-dioxo-3-[(IR)-4-(trifluormethyl)-2,3-dihydro-lH-inden-l-yl]-1-(1,3,3-trimethyl-2-oxo-2,3-dihydro-lH-indol-5-yl)-1,2,3,4-tetrahydropyrimidin-5-carboxylsyre (R-enantiomer) og strukturformel
9. Forbindelse med formel (I) ifølge krav 1 med det systematiske navn 1-(1'-methyl-2'-oxo-1' , 2'- dihydrospiro[cyclopropan-1,3'-indol]-5'-yl) -2,4-dioxo-3-[ (IR)-4-(trifluormethyl)-2,3-dihydro-lH-inden-l-yl]-1,2,3,4-tetrahydropyrimidin-5-carboxylsyre (R-enantiomer) og strukturformel
10. Forbindelse med formel (I) ifølge krav 1 med det systematiske navn 1-(3-methyl-2-oxo-2,3-dihydro-l,3- benzothiazol-6-yl)-2,4-dioxo-3-[(IR)-4-(trifluormethyl)-2,3-dihydro-lH-inden-l-yl]-1,2,3,4-tetrahydropyrimidin-5- carboxylsyre (R-enantiomer) og strukturformel
11. Forbindelse med formel (I) ifølge krav 1 med det systematiske navn ethyl-1-(3-methyl-2-oxo-2,3-dihydro-l, 3-benzoxazol-6-yl)-2,4-dioxo-3-[(IR)-4-(trifluormethyl)-2,3-dihydro-lH-inden-l-yl]-1,2,3,4-tetrahydropyrimidin-5-carboxvlat (R-enantiomer) og strukturformel
12. Fremgangsmåde til fremstilling af forbindelser med formel (I), hvor [A] en forbindelse med formel (II)
(Π), hvor R1a står for (C1-C4)-alkyl, T1 står for (C1-C4)-alkyl, T2 står for (Ci-C4)-alkyl, Omsættes i et inert opløsningsmiddel i givet fald i nærvær af en egnet base med en forbindelse med formel (III) H2N-R3 (III), hvor R3 har den i krav 1 til 4 anførte betegnelse, til en forbindelse med formel (IV)
(TV), ΊΑ g hvor R og R hver rsær har de ovenfor anførte betegnelser, denne efterfølgende omsættes i et inert opløsningsmiddel i nærvær af en egnet base med en forbindelse med formel (V) X1-R2 V), hvor R2 har den i krav 1 til 4 anførte betegnelse, og X1 står for hydroxy eller en egnet fraspaltelig gruppe, navnlig chlor, brom eller rod, til en forbindelse med formel (I—1)
Ί A 9 g hvor R , R og R hver især har de ovenfor anførte betegnelser, eller ΓΒ1 en forbindelse med formel (VI)
(VI), Ί A 1 hvor R og T hver især har de ovenfor anførte betegnelser, og T3 står for (C1-C4)-alkyl, omdannes i et inert opløsningsmiddel eller også uden opløsningsmiddel med forbindelse med formel (III) til en forbindelse med formel (VII)
(VTT), Ί A g g hvor R , R og T hver især har de ovenfor anførte betegnelser, denne i det følgende omsættes i et inert opløsningsmiddel med chlorsulfonylisocyanat til en forbindelse med formel (IV), og denne efterfølgende omdannes analogt med fremgangsmåde [A] til en forbindelse med formel (I — 1), eller [C] en forbindelse med formel (VIII)
(VITI), hvor R2 har den i krav 1 til 4 nævnte betegnelser, omsættes i et inertooløsningsmiddel med en forbindelse med formel (IX)
(IX) , hvor R og T hver rsær har de ovenfor anførte betegnelser, og T5 står for (C1-C4)-alkyl, og cykliseres i nærvær af en egnet base til en forbindelse med formel (X)
(X) , hvor R1a og R2 hver især har de ovenfor anførte betegnelser, og denne efterfølgende omsættes i et inert opløsningsmiddel i nærvær af en egnet katalysator og en egnet base med en forbindelse med formel (XI)
(XI), hvor R3 har den ovenfor anførte betegnelse, og T6 står for hydrogen, (C1-C4)-alkyl, eller de to grupper T6 tilsammen danner en -C (CH3) 2_C (CH3) 2_bro, til en forbindelse med formel (I — 1), eller [D] en forbindelse med formel (I — 1) forsæbes i et inert opløsningsmiddel i nærvær af en egnet syre eller base til en forbindelse med formel (1-2)
(1-2), hvor R2 og R3 hver især har de i krav 1 til 4 nævnte betegnelser, og R1b står for hydrogen, eksisterende beskyttelsesgrupper i givet fald fraspaltes og/eller forbindelserne med formler (I — 1) og (1-2) i givet fald omdannes med de tilsvarende (i) opløsningsmidler og/eller (ii) baser eller syre til deres solvater, salte og/eller solvater af saltene.
13. Forbindelse som defineret i et af kravene 1 til 11 til anvendelse ved behandlingen og profylaksen af sygdomme.
14. Forbindelse som defineret i et af kravene 1 til 11 til anvendelse i en fremgangsmåde til behandling og/eller profylakse af hjerteinsufficiens, pulmonal hypertension, kronisk-obstruktiv lungesygdom, astma, nyreinsufficiens, nefropatier, fibrotiske sygdomme i de indre organer og dermatologiske fibroser.
15. Lægemiddel indeholdende en forbindelse som defineret i et af kravene 1 til 11 i kombination med et eller flere inerte, ikke-toksiske, farmaceutisk egnede hjælpestoffer.
16. Lægemiddel indeholdende en forbindelse som defineret i et af kravene 1 til 11 i kombination med et eller flere yderligere aktivstoffer udvalgt af gruppen bestående af calcium-antagonister, angiotensin AII-antagonister, ACE-hæmmere, vasopeptidase-hæmmere, endothelin-antagonister, renin-hæmmere, alpha-receptor-blokkere, beta-receptor- blokkere, mineralocorti-coid-receptor-antagonister, rho- kinase-hæmmere, diuretika, kinase-hæmmere, matrixmetaloprotease-hæmmere, stimulatorer og aktivatorer i den opløselige guanylatcyclase og phosphodiesterase-hæmmere.
17. Lægemiddel ifølge krav 15 eller 16 til anvendelse ved behandling og/eller profylakse af hjerteinsufficiens, pulmonal hypertension, kronisk-obstruktiv lungesygdom, astma, nyreinsufficiens, nefropatier, fibrotiske sygdomme i de indre organer og dermatologiske fibroser.
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