DK2953943T3 - Substituerede bicykliske dihydropyrimidinoner og anvendelse deraf som inhi-bitorer af neutrofil elastaseaktivitet - Google Patents

Substituerede bicykliske dihydropyrimidinoner og anvendelse deraf som inhi-bitorer af neutrofil elastaseaktivitet Download PDF

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DK2953943T3
DK2953943T3 DK14705723.6T DK14705723T DK2953943T3 DK 2953943 T3 DK2953943 T3 DK 2953943T3 DK 14705723 T DK14705723 T DK 14705723T DK 2953943 T3 DK2953943 T3 DK 2953943T3
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Christian Gnamm
Thorsten Oost
Stefan Peters
Holger Hoesch
Uwe Jörg Ries
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Boehringer Ingelheim Int
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Claims (15)

1. Forbindelse med formlen 1
hvor R1 er phenyl eller en fem- eller seksleddet heteroaryl, hvor et, to eller tre elementer er erstattet med et element uafhængigt udvalgt fra gruppen bestående af N, O eller S; hver ring er eventuelt substitueret med en, to eller tre substituenter uafhængigt udvalgt fra gruppen bestående af halogen, O2N-, NC-, H2N-, HO-, R11, R^O-, R1·2, R1,3S-, R13(0)s- og R13(0)2S-; R1·1 er uafhængigt udvalgt fra gruppen bestående af Ci-6-alkyl-, C3-6-cykloalkyl-, Ci-s-haloalkyl- og C3-6-halocykloalkyl; R1·2 er HO-Ci-6-alkyl- eller R1 ^-O-Ci-e-alkyl-; R1·3 er uafhængigt udvalgt fra gruppen bestående af H, HO-, R1·1 og R1·2; R2 er phenyl eller en fem- eller seksleddet heteroaryl, hvor et eller to elementer er erstattet af et element uafhængigt udvalgt fra gruppen bestående af N, O eller S; hver ring er eventuelt substitueret med en substituent uafhængigt udvalgt fra gruppen bestående af halogen, Ci-4-alkyl-, Ci-4-haloalkyl- og Ci-4-alkyl-0-; R3 er en rest uafhængigt udvalgt fra gruppen bestående af • R31 -; • R32(0)C-; • R320(0)C-; • R320(0)C-A-; • R32S-; R3-2(0)S-; R32(0)2S-; • (R3 2)2N(0)C og • (R3-2)2N(0)C-A-; R31 er uafhængigt udvalgt fra gruppen bestående af H, R3 3, R3·4, C1.6-alkyl-C3.6-cykloalkyl- og C3-6-cykloalkyl-Ci-6-alkyl-, hver især eventuel substitueret med en eller to substituenter udvalgt blandt R3·1·1-; R311 er udvalgt fra gruppen bestående af HO-, halogen, NC-, R330-, R3 5, R3-5og R3·7 eller R311 betegner en ring uafhængigt udvalgt blandt phenyl og en firleddet heterocyklisk ring indeholdende ét element uafhængigt udvalgt blandt N, O, S, S(O) og S(0)2; R311 betegner en fem- eller seksleddet heterocyklisk ring eller heteroarylring indeholdende ét, to eller tre elementer uafhængigt udvalgt blandt N, O, S, S(O) og S(0)2; hver af ringene er eventuelt substitueret med én eller to substituenter uafhængigt udvalgt blandt HO-, 0=, halogen, NC-, R33, R330-, R3 3-(0)C-, R3 4, R3·5, R3·6 og R3·7, eller to substituenter danner tilsammen R3·8; R3·2 er uafhængigt udvalgt blandt R31, phenyl og en fem- eller seksleddet heterocyklisk ring eller heteroarylring indeholdende ét, to eller tre elementer uafhængigt udvalgt blandt N, O, S, S(O) og S(0)2; hver ring er eventuelt substitueret med en eller to substituenter uafhængigt udvalgt blandt HO-, 0=, NC-, halogen, R33, R330-, R33-(0)C-, R3·4, R3·5, R3·6 og R3 7, eller to substituenter danner tilsammen R3·8; eller to R3 2 danner tilsammen en tre-, fir-, fem- eller seksleddet monocyklisk eller en seks-, syv-, otte-, ni- eller tileddet bicyklisk heterocyklisk ring eller heteroarylring eventuelt indeholdende, ud over nitrogenet, ét eller to elementer uafhængigt udvalgt blandt N, O, S, S(O) og S(0)2; eventuelt substitueret med én eller to substituenter, uafhængigt udvalgt blandt HO-, F, 0=, NC-, R33, R3-30-, R3 3- (O)C-, R3 4, R3 5, R3 6, R3 7, phenyl og en fem- eller seksleddet heterocyklisk ring eller heteroarylring indeholdende ét, to eller tre elementer uafhængigt udvalgt blandt N, O, S, S(O) og S(0)2; eller to substituenter danner tilsammen R3 8; R3 3 er uafhængigt udvalgt fra gruppen bestående af Ci-6-alkyl-, C3-e-cykloalkyl-, Ci- 6-haloalkyl- og C3-6-halocykloalkyl; R34 er HO-Ci-6-alkyl- eller R3 3-0-Ci-6-alkyl-, R3 5 er uafhængigt udvalgt fra gruppen bestående af H2N-, R3 3-HN-, (R3 3)2N-, R3 3- (O)C-HN- og R3 3-(0)C-(R3 3)N-; R3 6 er uafhængigt udvalgt fra gruppen bestående af R3 3 (0)S-, R3 3-(0)2S-, R3 3(HN)S-, R33(HN)(0)S-, R3-3(R33N)S-, R3 3(R33N)(0)S-, R33(R34N)S-, R3 3(R3 4N)(0)S-; R3 3(NC-N)S og R33(NC-N)(0)S-; R3 7 er uafhængigt udvalgt fra gruppen bestående af H0(0)C-, H2N(0)C-, R3 3-0- (O)C-, R33 -NH-(0)C- og (R3 3)2N-(0)C-; R3 8 er uafhængigt udvalgt fra gruppen bestående af Ci-6-alkylen og Ci-6-haloalkylen, hvor eventuelt én eller to CH2-grupper er erstattet med -HN-, -(R3-3)N-, -(R3-4)N-, -(R3-3(0)C-)N-; -(R3 4(0)C-)N-, -O-, -S-, -S(O) - eller -S(0)2-; A er -CH2-, -CH2-CH2- eller -CH2-CH2-CH2-; eventuelt substitueret med én eller to substituenter uafhængigt udvalgt fra gruppen bestående af halogen, R3·3, R3 30- og R3·4, eller to substituenter danner tilsammen R3·8; R4 er uafhængigt udvalgt fra gruppen bestående af halogen, Ci-6-alkyl-, C3-6-cykloalkyl-, Ci-6-haloalkyl- og C3-6-halocykloalkyl; eller to R4 danner tilsammen Ci-5-alkylen eller Ci-6-haloalkylen; m er 0, 1 eller 2; eller et salt deraf.
2. Forbindelse med formlen 1 ifølge krav 1, hvor R1 er Rlc, og Rlc er phenyl eller pyridinyl; hver ring er eventuelt substitueret med en, to eller tre rester uafhængigt udvalgt fra gruppen bestående af F, Cl, Br-, NC-, R11, R13(0)S- og R13(0)2S-; R11 er uafhængigt udvalgt fra gruppen bestående af Ci-e-alkyl-, C3-6-cykloalkyl-, Ci-6-haloalkyl- og C3-6-halocykloalkyl; R1·2 er HO-Ci-e-alkyl- eller R1 ^-O-Ci-e-alkyl-; R13 er uafhængigt udvalgt fra gruppen bestående af H, HO-, R11 og R12; eller et salt deraf.
3. Forbindelse med formlen 1 ifølge krav 1, hvor R1 er Rl e, og Rl e er phenyl eller pyridinyl; hver ring er eventuelt substitueret med én eller to rester uafhængigt udvalgt fra gruppen bestående af NC-, Me(0)S-, Me(0)2S og Et(0)2S; eller et salt deraf.
4. Forbindelse med formlen 1 ifølge et af kravene 1 til 3, hvor R2 er R2b, og R2 b er phenyl eller en seksleddet heteroaryl; hvor ét eller to elementer er erstattet med N; hver ring er eventuelt substitueret med en substituent uafhængigt udvalgt fra gruppen bestående af halogen, Ci-4-alkyl- og Ci-4-haloalkyl-; eller et salt deraf.
5. Forbindelse med formlen 1 ifølge et af kravene 1 til 3, hvor R2 er R2 f, og R2 f er pyridinyl, eventuelt substitueret med en substituent uafhængigt udvalgt fra gruppen bestående af F3C- og F2HC-, eller et salt deraf.
6. Forbindelse med formlen 1 ifølge et af kravene 1 til 5, hvor A er Ab, og Ab er -CH2-, eventuelt substitueret med én eller to substituenter uafhængigt udvalgt fra gruppen bestående af F, Me, Et, i-Pr, MeO, EtO, FIOCFI2O- og MeOCH2-; eller et salt deraf.
7. Forbindelse med formlen 1 ifølge et af kravene 1 til 6, hvor R4 er R4a, og R4a er udvalgt fra gruppen bestående af halogen, Ci-s-alkyl-, C3-s-cykloalkyl-, Ci-6-haloalkyl- og C3-6-halocykloalkyl; eller et salt deraf.
8. Forbindelse med formlen 1 ifølge et af kravene 1 til 7, hvor R3 er en rest uafhængigt udvalgt fra gruppen bestående af . R3Λ-; • R3 20(0)C- eller R3 20(0)C-CH2-; • R3 2(0)2S- og • (R3 2)2N(0)C- eller (R32)2N(0)C-CH2-; R31 er uafhængigt udvalgt fra gruppen bestående af H, R3 3, R3 4, Ci-6-alkyl-C3-e-cykloalkyl- og C3-6-cykloalkyl-Ci 6-alkyl-, hver især eventuel substitueret med en eller to substituenter udvalgt blandt R3·1·1-; R311 er udvalgt fra gruppen bestående af HO-, halogen, NC-, R3 30-, R3·5, R3 6 og R3·7, eller R311 er udvalgt fra gruppen bestående af en ring uafhængigt udvalgt blandt phenyl og en fir-leddet heterocyklisk ring indeholdende ét element uafhængigt udvalgt blandt N, O, S, S(O) og S(0)2; eller R311 betegner en fem- eller seksleddet heterocyklisk ring eller heteroarylring indeholdende ét, to eller tre elementer uafhængigt udvalgt blandt N, O, S, S(O) og S(0)2; hver af ringene er eventuelt substitueret med én eller to substituenter uafhængigt udvalgt blandt HO-, 0=, halogen, R3 3, R3 30-, R3 3-(0)C-, R3 4, R3·5, R3·6, og R3 7 eller to substituenter danner tilsammen R3 8; R3·2 er uafhængigt udvalgt blandt R3·1, phenyl eller en fem- eller seksleddet heterocyklisk ring eller heteroarylring indeholdende ét, to eller tre elementer uafhængigt udvalgt blandt N, O, S, S(O) og S(0)2; hver ring er eventuelt substitueret med en eller to substituenter uafhængigt udvalgt blandt HO-, 0=, NC-, halogen, R3 3, R3 30-, R3 3(0)C-, R3 4, R3 5, R3 6, og R3 7 eller to substituenter danner tilsammen R3 8; eller to R3 2 danner tilsammen en fem- eller seksleddet monocyklisk eller en otte-, ni- eller ti-leddet bicyklisk heterocyklisk ring eller heteroarylring eventuelt indeholdende, ud over nitrogenet, ét eller to elementer uafhængigt udvalgt blandt N, O, S, S(O) og S(0)2; eventuelt substitueret med én eller to substituenter, uafhængigt udvalgt blandt HO-, F, 0=, R3 3, R3 30-, R3 3-(0)C-, R3 4, R3 5, R3·7, og R3 5 eller to substituenter danner tilsammen R3 8; R3 3 er uafhængigt udvalgt fra gruppen bestående af Ci-6-alkyl-, C3-6-cykloalkyl-, Ci-6-haloalkyl- og C3-6-halocykloalkyl; R3·4 er HO-Ci-e-alkyl- eller R3 3-0-Ci-6-alkyl-; R3 5 er uafhængigt udvalgt fra gruppen bestående af H2n-, R3 3-HN-, (R3 3)2N- og R33-(0)C-HN-; R3 6 er uafhængigt udvalgt fra gruppen bestående af R3 3-(0)S-, R3 3-(0)2S-, R33(HN)S-, R3 3(HN)(0)S-, R3 3(R33N)S-, R3 3(R3 3N)(0)S-, R3 3(R34N)S- og R33(R34N)(0)S-; R3 7 er uafhængigt udvalgt fra gruppen bestående af H0(0)C-, H2N(0)C-, R3 3-0- (O)C-, R3 3 -NH-(0)C- og (R3 3)2N-(0)C-; R3 8 er uafhængigt udvalgt fra gruppen bestående af Ci-6-alkylen eller Ci-6-haloalkylen, hvor eventuelt én eller to CH2-grupper er erstattet med -HN-, -(R3 3)N-, -(R3-4)N-, -(R3-3(0)C-)N-, -(R3-4(0)C-)N-, -O-, -S-, -S(O)- og-S(0)2-; eller et salt deraf.
9. Forbindelse med formlen 1 ifølge et af kravene 1 til 7, hvor R3 er uafhængigt udvalgt fra gruppen bestående af H0(0)C-H2C-, MeO(0)C-H2C-, H2N(0)C-H2C-, MeHN(0)C-H2C-, Me2N(0)C-H2C-, morpholinyl-(0)C-H2C-, azetidinyl-(0)C-H2C-, pyrrolidinyl-(0)C-H2C-, MeHN(0)C-, EtHN(0)C-, H0(CH2)2HN(0)C-, H0(CMe2)(CH2)HN(0)C-, H0(CH2)3HN(0)C-, Me(0)S(CH2)2HN(0)C-f Me(0)2S(CH2)2HN(0)C-, Et(0)2S- og Me(0)2S-; eller et salt deraf.
10. Forbindelse med formlen I.a til I.s ifølge krav 1
eller et salt deraf.
11. Forbindelse ifølge et af kravene 1 til 10, hvor konfigurationen af formel 1 er formel 1'
eller et salt deraf.
12. Forbindelse med formlen 1 ifølge et hvilket som helst af kravene 1 til 11 til anvendelse som lægemiddel.
13. Forbindelse med formlen 1 ifølge et hvilket som helst af kravene 1 til 11 til anvendelse som lægemiddel til behandling af astma- og allergisygdomme, mave-tarm-inflammatoriske sygdomme, eosinofile sygdomme, kronisk obstruktiv lungesygdom, alfa-1-antitrypsin-mangel, infektion med patogene mikrober og rheumatoid arthrit.
14. Farmaceutisk sammensætning, kendetegnet ved, at den indeholder en eller flere forbindelser med formlen 1 ifølge et hvilket som helst af kravene 1 til 11 eller et farmaceutisk virksomt salt deraf.
15. Farmaceutisk sammensætning omfattende, ud overen forbindelse med formlen 1 ifølge et hvilket som helst af kravene 1 til 11, en farmaceutisk virksom forbindelse udvalgt fra gruppen bestående af betamimetika, anticholinergica, corticosteroider, PDE4-hæmmere, LTD4-antagonister, EGFR-hæmmere, cathepsin C-hæmmere, CRTH2-hæmmere, 5-LO-hæmmere, histaminreceptorantagonister og SYK-hæmmere, men også kombinationer af to eller tre aktive stoffer.
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