DK2991988T3 - Pyrrolo[2,3-d]pyrimidinderivater som CB2-receptoragonister - Google Patents

Pyrrolo[2,3-d]pyrimidinderivater som CB2-receptoragonister Download PDF

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DK2991988T3
DK2991988T3 DK14720136.2T DK14720136T DK2991988T3 DK 2991988 T3 DK2991988 T3 DK 2991988T3 DK 14720136 T DK14720136 T DK 14720136T DK 2991988 T3 DK2991988 T3 DK 2991988T3
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methyl
tert
pyrrolo
butyl
pyrimidin
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Uwe Grether
Atsushi Kimbara
Matthias Nettekoven
Stephan Roever
Mark Rogers-Evans
Tanja Schulz-Gasch
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Hoffmann La Roche
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Claims (13)

1. Forbindelse med formlen (I)
hvor A er CH2 eller fraværende; R1 og R2 sammen med det nitrogenatom, de er bundet til, danner substitueret pyrrolidinyl eller 2-oxa 6-azaspiro[3.3]heptyl, hvor substitueret pyrrolidinyl er pyrrolidinyl substitueret med en eller to substituentc uafhængigt valgt blandt halogen, hydroxyl og alkylcarbonyloxy; og R3 er halogenphenyl, alkylsulfonylphenyl, halogenalkylphenyl, halogenpyridinyl, alkyloxadiazoly alkyltriazolyl, alkyltetrazolyl, oxolanyl, cycloalkyltetrazolyl eller halogenalkyl-lH-pyrazolyl; eller et fannaceutisk acceptabelt salt eller en farmaceutisk acceptabel ester deraf.
2. Forbindelse ifølge krav 1, hvor A er CH2.
3. Forbindelse ifølge krav 1 eller 2, hvor R1 og R2 sammen med det nitrogenatom, de er bund( til, danner substitueret pyrrolidinyl, hvor substitueret pyrrolidinyl er pyrrolidinyl substitueret med en eller t substituenter uafhængigt valgt blandt halogen og hydroxyl.
4. Forbindelse ifølge et hvilket som helst af kravene 1 til 3, hvor R1 og R2 sammen med d( nitrogenatom, de er bundet til, danner substitueret pyrrolidinyl, hvor substitueret pyrrolidinyl er pyrrolidinj substitueret med en eller to substituenter uafhængigt valgt blandt fluor og hydroxyl.
5. Forbindelse ifølge et hvilket som helst af kravene 1 til 4, hvor R1 og R2 sammen med dt nitrogenatom, de er bundet til, danner difluorpyrrolidinyl eller hydroxypyrrolidinyl.
6. Forbindelse ifølge et hvilket som helst af kravene 1 til 5, hvor R3 er halogenpheny halogenalkylphenyl, alkylsulfonylphenyl, halogenpyridinyl eller alkyloxadiazolyl.
7. Forbindelse ifølge et hvilket som helst af kravene 1 til 6, hvor R3 er dichlorpheny chlorfluorphenyl, trifluormethylphenyl, methylsulfonylphenyl, chlorpyridinyl eller methyloxadiazolyl.
8. Forbindelse ifølge et hvilket som helst af kravene 1 til 7, der er valgt blandt 2-tert-butyl-7-[(2-chlorphenyl)methyl]-4-(3,3-difluorpyrrolidin-l-yl)pyrrolo[2,3-d]pyrimidin; 2-tert-butyl-7- [(2-chlor-4-fluorphenyl)methyl]-4-(3,3-difluorpyrrolidin-l-yl)pyrrolo[2,3-d]pyrimidir 2-tert-butyl-4-(3,3-difluorpyrrolidin-l-yl)-7-[(2-methylsulfonylphenyl)methyl]pyrrolo[2,3- d]pyrimidin; 2-tert-butyl-4-(3,3-difluorpyrrolidin-l-yl)-7-[[2-(trifluormethyl)phenyl]methyl]pyrrolo[2,3- d]pyrimidin; 2-tcrt-butyl-7-[(2,3-dichlorphcnyl)mcthyl]^l-(3,3-difluorpyrrolidin-l -yl)pyrrolo[2,3-d]pyrimidin; 2-tert-butyl-7-[(2-chlorpyridin-3-yl)methyl]-4-(3,3-difhjorpyrrolidm-l-yl)pyrrolo[2,3-d]pyrimidin; 2- tert-butyl-7-[(3-chlorpyridin-2-yl)methyl]-4-(3,3-difluorpyrrolidm-l-yl)pyrrolo[2,3-d]pyrimidin; 5- [[2-tert-butyl-4-(3,3-difluorpyrrolidin-l-yl)pyrrolo[2,3-d]pyrimidin-7-yl]methyl]-3-methyl-l,2,4-oxadiazol; 3- [[2-tert-butyl-4-(3,3-difluorpyrrolidin-l -yl)pynOlo[2,3-d]pyrimidin-7-yl]methyl]-4-methyl-l,2,5-oxadiazol; 2-[[2-tert-butyl-4-(3,3-difluorpyrrolidin-l-yl)pyrrolo[2,3-d]pyrimidin-7-yl]methyl]-5-methyl-l,3,4- oxadiazol; 2-tert-butyl-4-(3,3-difluorpyrrolidm-l-yl)-7-[(4,5-dimethyl-l,2,4-triazol-3-yl)methyl]pyrrolo[2,3- djpyrimidin; 2-tert-butyl-4-(3,3-difluorpyrrolidin-l-yl)-7-[(l-methyltetrazol-5-yl)methyl]pyrrolo[2,3-d]pyrimidin; 2-tert-butyl-7-[(l-cyclopropyltetrazol-5-yl)methyl]-4-(3,3-difluorpyrrolidin-l-yl)pyrrolo[2,3- djpyrimidin; 6- [2-tert-bulyl-7-[(2-chlorphenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]-2-oxa-6-azaspiro[3.3]heptan 6-[2 -tert-butyl-7-[(3 -methyl-1,2,4-oxadiazol-5 -yl)methyl]pyrrolo [2,3 -d]pyrimidin-4-yl] -2 -oxa-6- azaspiro[3.3]heptan; 6-[2-tcrt-butyl-7-[(3S)-oxolan-3-yl]pyrrolo[2,3-d]pyrimidin-4-yl]-2-oxa-6-azaspiro[3.3]hcptan; 6-[2-tert-butyl-7-[(3R)-oxolan-3-yl]pyrrolo[2,3-d]pyrimidin-4-yl]-2-oxa-6-azaspiro[3.3]heptan; 6-[2-tert-butyl-7-[(2-chlor-4-fluorphenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]-2-oxa-6- azaspiro [3.3 ] heptan; 6-[2-tert-butyl-7-[(2-methylsulfonylphenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]-2-oxa-6- azaspiro[3.3]heptan; 6-[2-tert-butyl-7-[(2-chlorpyridin-3-yl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]-2-oxa-6- azaspiro[3.3]heptan; 6-[2-tert-butyl-7-[(2,3-dichlorphenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]-2-oxa-6- azaspiro[3.3]heptan; 6-[2 -tert-butyl-7-[(4-methyl-1,2,5 -oxadiazol-3 -yl)methyl]pyrrolo [2,3 -d]pyrimidin-4-yl] -2 -oxa-6-azaspiro[3.3]heptan; 6-[2-tert-butyl-7-[(5-methyl-l,3,4-oxadiazol-2-yl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]-2-oxa-6- azaspiro[3.3]heptan; l-[2-tert-butyl-7-[(2-chlorphenyl)methyl]pyrrolo[23-d]pyrimidin-4-yl]pyrrolidin-3-ol; l-[2-tert-butyl-7-[(2-chlor-4-fluorphenyl)methyl]pyrrolo[2,3-d]pyrimidm-4-yl]pyrrolidm-3-ol; l-[2-tert-butyl-7-[(2-methylsulfonylphenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-ol; l-[2-tert-butyl-7-[[2-(trifluormethyl)phenyl]methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pynOlidin-3-ol; l-[2-tert-butyl-7-[(2,3-dichlorphenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-ol; l-[2-tert-butyl-7-[(2-chlorpyridin-3-yl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-ol; l-[2-tert-butyl-7-[(3-chlorpyridin-2-yl)methyl]pyrrolo[2,3-d]pyrimidm-4-yl]pyiTolidin-3-ol; 1 -[2 -tert-butyl-7-[(3 -methyl-1,2,4-oxadiazol-5 -yl)methyl]pyrrolo [2,3 -d]pyrimidin-4-yl]pyrrolidin-3 -ol; l-[2-tert-butyl-7-[(4-methyl-l,2,5-oxadiazol-3-yl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3- ol; l-[2-tert-butyl-7-[(5-methyl-l,3,4-oxadiazol-2-yl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3- ol; l-[2-tert-butyl-7-[(l-methyltetrazol-5-yl)methyl]pyrrolo[2,3-d]pyrimidm-4-yl]pyrrolidin-3-ol; [l-[2-tert-butyl-7-[(l-methyltetrazol-5-yl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-yl]aceta [1 -[2-tcrt-butyl-7-[(2,3-dichlorphenyl)incthyl]pyrrolo[2,3-d]pyrimidin^l-yl]pyrrolidin-3-yl]acetat; [l-[2-tert-butyl-7-[(4-methyl-l,2,5-oxadiazol-3-yl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3 yl]acetat; 1 -[2-tcrt-butyl-7-[( 1 -cyclopropyltetrazol-5-yl)mcthyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-ol; l-[2-tert-butyl-7-[(3R)-oxolan-3-yl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-ol; l-[2-tcrt-butyl-7-[[3-(trifluormcthyl)-lH-pyrazoM-yl]mcthyl]pyrrolo[2,3-d]pyrimidin-4- yl]pyrrolidin-3-ol; 2 -tert-buty 1-4-(3,3 -difluorpyrrolidin-1 -yl)-7-[[3 -(trifluormethyl)-1 H-pyrazol-4-yl]methyl]pyrrolo[2,3 djpyrimidin; (3S)-l-[2-tert-butyl-7-[(2,3-dichlorphenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pynolidin-3-ol; (3S)-l-[2-tert-butyl-7-[(2-chlor-4-fluorphenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-ol; (3S)-l-[2-tert-butyl-7-[[2-(trifluormethyl)phenyl]methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3- ol; (3S)-l-[2-tert-butyl-7-[(2-methylsulfonylphenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3- ol; (3S)-l-[2-tert-butyl-7-[(2-chlorpyridin-3-yl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-ol; (3S)-l-[2-tert-butyl-7-[(3-chlorpyridin-2-yl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-ol; (3S)-l-[2-tert-butyl-7-[(4-methyl-l,2,5-oxadiazol-3-yl)methyl]pyrrolo[2,3-d]pyrimidin-4- yl]pyrrolidin-3-ol; 6-[2-tert-butyl-7-[(3-chlorpyridin-2-yl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]-2-oxa-6-azaspiro[3.3]heptan og 6-[2-tert-butyl-7-[(l-methyltetrazol-5-yl)methyl]pyrrolo[2,3-d]pyrimidm-4-yl]-2-oxa-6- azaspiro[3.3]heptan.
9. Forbindelse ifølge et hvilket som helst af kravene 1 til 8, der er valgt blandt 2-tert-butyl-4-(3,3-difluorpyrrolidin-l-yl)-7-[[2-(trifluomiethyl)phenyl]methyl]pyrrolo[2,3- d]pyrimidin; 2- tert-butyl-7-[(3-chlorpyridin-2-yl)mcthyl]-4-(3,3-difluorpyrrolidin-l -yl)pyrrolo[2,3<l]pynrnidin; 3- [[2-tert-butyl-4-(3,3-difluorpyrrolidin-l-yl)pyrrolo[2,3-d]pyrimidin-7-yl]methyl]^l-methyl-l,2,5- oxadiazol; l-[2-tert-butyl-7-[[2-(trifluormethyl)phenyl]methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-ol; l-[2-tert-butyl-7-[(2-chlorpyridin-3-yl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-ol; l-[2-tert-butyl-7-[(3-chlorpyridin-2-yl)methyl]pynOlo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-ol; (3S)-l-[2-tert-butyl-7-[(2,3-dichlorphenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-ol; (3S)-l-[2-tert-butyl-7-[(2-chlor-4-fluorphenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-ol; (3S)-l-[2-tert-butyl-7-[[2-(trifhærmethyl)phenyl]methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3- ol; (3 S)-1 - [2-tert-buty 1-7 - [(2 -methylsulfonylphenyl)methyl]pyrrolo [2,3 -d]pyrimidin-4 -yl]pyrrolidin-3 -ol; (3 S)-1 -[2-tcrt-butyl-7-[(2 -chlorpyridin-3 -yl)mcthyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3 -ol; (3 S)-1 -[2-tert-butyl-7-[(3 -chlorpyridin-2 -yl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3 -ol; (3S)-l-[2-tert-butyl-7-[(4-methyl-l,2,5-oxadiazol-3-yl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]pyrrolidin-3-ol.
10. Fremgangsmåde til fremstilling af en forbindelse ifølge et hvilket som helst af kravene 1 t: 9, hvilken fremgangsmåde omfatter omsætning af en forbindelse med formlen (A)
i nærvær af X-A-R3, hvor X er en fraspaltelig gruppe, og hvor A og R1 til R3 er som defineret i < hvilket som helst af kravene 1 til 7.
11. Forbindelse ifølge et hvilket som helst af kravene 1 til 9 til anvendelse som terapeutisk aktn stof.
12. Farmaceutisk sammensætning, der omfatter en forbindelse ifølge et hvilket som helst s kravene 1 til 9 og en terapeutisk inert bærer.
13. Forbindelse ifølge et hvilket som helst af kravene 1 lil 9 til anvendelse ved behandling elk profylakse af smerter, arteriosklerose, aldersrelateret makuladegeneration, diabetisk retinopati, glaukon retinal veneokklusion, præmaturitetsretinopati, okulært iskæmisk syndrom, geografisk atrofi, diabete mcllitus, inflammation, inflammatorisk tarmsygdom, iskæmi-rcpcrfiisionsskadc,akut leversvigt, leverfibrost lungefibrose, nyrefibrose, systemisk fibrose, akut allotransplantatafstødning, kronis allotransplantationsnefropati, diabetisk nefropati, glomerulonefropati, kardiomyopati, hjertesvig myokardieiskæmi, myokardieinfarkt, systemisk sklerose, termisk skade, forbrænding, hypertrofiske ai keloider, gingivitis pyrexia, levercirrose eller -tumorer, regulering af knoglemassen, amyotrofis lateralsklerose, multipel sklerose, Alzheimers sygdom, Parkinsons sygdom, apopleksi, transitorisk iskæmis attak eller uveitis.
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