DK2897948T3 - Bicykliske aza-forbindelser som muskarin m1-receptoragonister - Google Patents

Bicykliske aza-forbindelser som muskarin m1-receptoragonister Download PDF

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DK2897948T3
DK2897948T3 DK13766641.8T DK13766641T DK2897948T3 DK 2897948 T3 DK2897948 T3 DK 2897948T3 DK 13766641 T DK13766641 T DK 13766641T DK 2897948 T3 DK2897948 T3 DK 2897948T3
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octane
carboxylate
ethyl
azaspiro
carbamoyl
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Giles Albert Brown
Julie Elaine Cansfield
Miles Stuart Congreve
Mark Pickworth
Benjamin Gerald Tehan
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Heptares Therapeutics Ltd
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Claims (15)

1. Forbindelse med formlen (1):
eller et salt deraf, hvor: p er 0, 1 eller 2; og er mættede carbonhydridgrupper, der sammen indeholder i alt fem til ni carbonatomer, og som bindes sammen således, at delen: danner et bicyklisk ringsystem;
er en ikke-aromatisk Ci-io-carbonhydridgruppe, der eventuelt er substitueret med et til seks fluoratomer, og hvor et eller to, men ikke alle, carbonatomer fra carbonhydridgruppen eventuelt kan være erstattet af et heteroatom udvalgt fra O, N og S og oxiderede former deraf; R^ er hydrogen eller en ikke-aromatisk Ci-io-carbonhydridgruppe; eller R^ og R^ sammen med nitrogenatomet, til hvilket de er forbundet, danner en ikke-aromatisk heterocyklisk ring på fire til ni ringdele, hvor den heterocykliske ring eventuelt kan indeholde et andet heteroatom udvalgt fra O, N og S og oxiderede former deraf; og hvor den heterocykliske ring eventuelt kan være substitueret med en til seks substituenter udvalgt fra Ci-2-alkyl; fluor; og cyan; R^ er udvalgt fra hydrogen; halogen; cyan; hydroxy; Ci-3-alkoxy; og en ikke-aromatisk C1-5-carbonhydridgruppe, der eventuelt er substitueret med et til seks fluoratomer og hvor et eller to, men ikke alle, carbonatomer fra carbonhydridgruppen eventuelt kan være erstattet af et heteroatom udvalgt fra O, N og S; R"* er en ikke-aromatisk Ci-e-carbonhydridgruppe, der eventuelt er substitueret med et til seks fluoratomer, og hvor et eller to, men ikke alle, carbonatomer fra carbonhydridgruppen eventuelt kan være erstattet af et heteroatom udvalgt fra O, N og S og oxiderede former deraf; og R^ er fluor.
2. Forbindelse ifølge krav 1, hvor R^ er udvalgt fra: o Ci-6-alkyl eventuelt substitueret med 1 til 6 fiuoratomer; o methoxy-Ci-4-alkyl eventuelt substitueret med 1 til 6 fluoratomer; o Ci-6-alkoxy; o C2-6-alkenyl; o C2-6-alkynyl; o C3-6-cycloalkyl eventuelt substitueret med en eller to methylgrupper; o C4-5-cycloalkyl-CH2-, hvor C4-5-cycloalkyldelen eventuelt er substitueret med en C1-2- 5 alkylgruppe, og hvor et carbonatom fra C4-5-cycloalkyldelen eventuelt kan erstattes af et oxygenatom; o cyclopropyl-Ci-3-alkyl; o cyclopentenyl; og o methyl-bicyclo[2.2.2]octanyl.
3. Forbindelse ifølge krav 1 eller krav 2, hvor er udvalgt fra 2-methylpropyl; 2,2-dimethylpropyl; tert-butyl; 2-methyl-but-2-yl; 2,3-dimethylbut-2-yl; cyclopropylmethyl; cyclobutylmethyl; cyclopentyl; cyclopentylmethyl; 1-methylcyclobutyl; 1-methylcyclopentyl; 1-methylcyclohexyl; 1- methylcyclopentylmethyl; cyclopropyl-prop-2-yl; 1-methylcyclobutylmethyl og 1-ethyl-cyclobutylmethylgrupper. 15
4. Forbindelse ifølge et hvilket som helst af kravene 1 til 3, hvor er udvalgt fra hydrogen, methyl, ethyl og isopropyl.
5. Forbindelse ifølge et hvilket som helst af kravene 1 til 4, hvor R^ er udvalgt fra hydrogen, fluor 20 og methoxy.
6. Forbindelse ifølge et hvilket som helst af kravene 1 til 5, hvor R"* er udvalgt fra methyl, ethyl, ethynyl og 1 -propynyl.
7. Forbindelse ifølge et hvilket som helst af kravene 1 til 6, hvor p er 0.
8. Forbindelse ifølge et hvilket som helst af kravene 1 til 7, hvor det bicykliske ringsystem dannet af delen:
er udvalgt fra: 30 (a) et azabicyclo-oktan- eller azabicyclo-nonanringsystem; (b) et 2-aza-spir[3.4]octan- eller et 6-aza-spiro[3.4]oktanringsystem; og (c) et cyclopentanopyrrolidinringsystem.
9. Forbindelse ifølge krav 8, hvor det bicykliske ringsystem daimet af delen:
er udvalgt fra ringsystemer BA, BB, BC, CA, CB og DA nedenfor:
10. Forbindelse ifølge krav 1, der har formlen (3):
hvor R‘, R^, R"*, R^ og p er som defineret ifølge et hvilket som helst af kravene 1 til 7; s er 0 eller 1, og t er 0 eller 1.
11. Forbindelse ifølge krav 10, hvor s = 0 og t = 1.
12. Forbindelse ifølge krav 1, hvilken forbindelse er udvalgt fra ethyl 3-{4-[(l-methylcyclobutyl)carbamoyl]piperidin-l-yl}-8-azabicyclo[3.2.1 ]oktan-8-carboxylat, ethyl 3-{4-[(l-methylcyclobutyl)carbamoyl]piperidin-l-yl} -9-azabicyclo[3.3.1 ]nonan-9-carboxylat, ethyl 3- {4-[(l -methylcyclobutyl)carbamoyl]piperidin-1 -yl} -6-azabicyclo[3.2.1]oktan-6-carboxylat, ethyl 5- {4-[( 1 -methylcyclobutyl)carbamoyl]piperidin-1 -yl} hexahydrocyclopenta[c]pyrrol-2(lH)-carboxylat, ethyl 2-{4-fiuor-4-[(l-methylcyclobutyl)carbamoyl]piperidin-l-yl}-6-azaspiro[3.4]oktan-6-carboxylat, ethyl 6-{4-[(l-methylcyclobutyl)carbamoyl]piperidin-l-yl}-2-azaspiro[3.4]oktan-2-carboxylat, prop-2-yn-1 -yl 6-{4-[(l-methylcyclobutyl)carbamoyl]piperidin-l-yl}-2-azaspiro[3.4]oktan-2-carboxylat, ethyl 2-{4-[(l-methylcyclobutyl)carbamoyl]piperidin-l-yl}-6-azaspiro[3.4]oktan-6-carboxylat, ethyl (2r,4s)-2-{4-[(l-methylcyclobutyl)carbamoyl]piperidin-l-yl}-6-azaspiro[3.4]oktan-6-carboxylat, ethyl (2s,4r)-2-{4-[(l-methylcyclobutyl)carbamoyl]piperidin-l-yl}-6-azaspiro[3.4]oktan-6-carboxylat, ethyl 2-(4- {[ 1 -(1,1,1 -trideuteromethyl)cyclobutyl]carbamoyl}piperidin-1 -yl)-6-azaspiro [3.4] oktan-6-carboxylat, ethyl (2r,4s)-2-(4- {[1-(1,1,1 -trideuteromethyl)cyclobutyl]carbamoyl}piperidin-1 -yl)-6-azaspiro [3.4] oktan-6-carboxylat, ethyl (2s,4r)-2-(4- {[1-(1,1,1 -trideuteromethyl)cyclobutyl]carbamoyl}piperidin-1 -yl)-6-azaspiro [3.4] oktan-6-carboxylat, ethyl 2-(4-{[1-(1,1,1 -trideuteromethyl)-2,2,3,3,4,4-hexadeuterocyclobutyl]carbamoyl}piperidin-l-yl)-6-azaspiro[3.4]oktan-6-carboxylat, ethyl (2r,4s)-2-(4- {[1 -(1,1,1 -trideuteromethyl)-2,2,3,3,4,4-hexadeuterocyclobutyl]carbamoyl}piperidin-l-yl)-6-azaspiro[3.4]oktan-6-carboxylat, ethyl (2s,4r)-2-(4- {[1 -(1,1,1 -trideuteromethyl)-2,2,3,3,4,4-hexadeuterocyclobutyl]carbamoyl}piperidin-l-yl)-6-azaspiro[3.4]oktan-6-carboxylat, ethyl 2-(4- {[ 1 -(fluormethyl)cyclobutyl]carbamoyl}piperidin-1 -yl)-6-azaspiro[3.4]oktan-6-carboxylat, ethyl (2r,4s)-2-(4-{[1 -(fluormethyl)cyclobutyl]carbamoyl}piperidin-l-yl)-6-azaspiro[3.4]oktan-6-carboxylat, ethyl (2s,4r)-2-(4-{[1 -(fluormethyl)cyclobutyl]carbamoyl}piperidin-l-yl)-6-azaspiro[3.4]oktan-6-carboxylat, (2,2,2-trideutero)ethyl-2-{4-[(l-methylcyclobutyl)carbamoyl]piperidin-l-yl}-6-azaspiro [3.4] oktan-6-carboxylat, (2,2,2-trideutero)ethyl(2r,4s)-2- {4-[(l -methylcyclobutyl)carbamoyl]piperidin-l -yl} -6-azaspiro [3.4] oktan-6-carboxylat, (2,2,2-trideutero)ethyl(2s,4r)-2- {4-[(l -methylcyclobutyl)carbamoyl]piperidin-l -yl} -6-azaspiro [3.4] oktan-6-carboxylat, (2,2,2-trideutero)ethyl 2-(4- {[1 -(1,1,1 -trideuteromethyl)cyclobutyl]carbamoyl}piperidin-l -yl)-6-azaspiro[3.4]oktan-6-carboxylat, (2,2,2-trideutero)ethyl(2r,4s)-2-(4- {[1-(1,1,1 -trideuteromethyl)cyclobutyl]carbamoyl}piperidin-1 -yl)-6-azaspiro[3.4] oktan-6-carboxylat, (2,2,2-trideutero)ethyl(2s,4r)-2-(4- {[1-(1,1,1 -trideuteromethyl)cyclobutyl]carbamoyl}piperidin- 1 -yl)-6-azaspiro[3.4] oktan-6-carboxylat, (2,2,2-trideutero)ethyl2-(4- {[1-(1,1,1 -trideuteromethyl)-2,2,3,3,4,4-hexadeuterocyclobutyl]carbamoyl}piperidin-l-yl)-6-azaspiro[3.4]oktan-6-carboxylat, (2,2,2-trideutero)ethyl(2r,4s)-2-(4-{[1-(1,1,1-trideuteromethyl)-2,2,3,3,4,4-hexadeuterocyclobutyl]carbamoyl}piperidin-l-yl)-6-azaspiro[3.4]oktan-6-carboxylat, (2,2,2-trideutero)ethyl(2s,4r)-2-(4-{[l-(l,l,l-trideuteromethyl)-2,2,3,3,4,4-hexadeuterocyclobutyl]carbamoyl}piperidin-l-yl)-6-azaspiro[3.4]oktan-6-carboxylat, (2,2,2-trideutero)ethyl2-(4- {[1-(1,1,1 -trideuteromethyl)-2,2,3,3,4,4-hexadeuterocyclobutyl]carbamoyl}piperidin-l-yl)-6-azaspiro[3.4]oktan-6-carboxylat, (2,2,2-trideutero)ethyl(2r,4s)-2-(4-{[1-(1,1,1-trideuteromethyl)-2,2,3,3,4,4-hexadeuterocyclobutyl]carbamoyl}piperidin-l-yl)-6-azaspiro[3.4]oktan-6-carboxylat, (2,2,2-trideutero)ethyl2-(4- {[1-(1,1,1 -trideuteromethyl)-2,2,3,3,4,4-hexadeuterocyclobutyl]carbamoyl}piperidin-l-yl)-6-azaspiro[3.4]oktan-6-carboxylat, (2,2,2-trideutero)ethyl 2-(4-{[1-(fluormethyl)cyclobutyl]carbamoyl}piperidin-l-yl)-6-azaspiro [3.4] oktan-6-carboxylat, (2,2,2-trideutero)ethyl(2r,4s)-2-(4-{[l-(fluormethyl)cyclobutyl]carbamoyl}piperidin-lyl)-6-azaspiro [3.4] oktan-6-carboxylat, (2,2,2-trideutero)ethyl(2s,4r)-2-(4-{[l-(fluormethyl)cyclobutyl]carbamoyl}piperidin-lyl)-6-azaspiro [3.4] oktan-6-carboxylat, (1,1,2,2,2-pentadeutero)ethyl 2-{4-[(l-methylcyclobutyl)carbamoyl]piperidin-l -yl}-6-azaspiro [3.4] oktan-6-carboxylat, (1,1,2,2,2-pentadeutero)ethyl(2r,4s)-2- {4-[(l -methylcyclobutyl)carbamoyl]piperidin-1 -yl} -6-azaspiro [3.4] oktan-6-carboxylat, (1,1,2,2,2-pentadeutero)ethyl(2s,4r)-2- {4-[(l -methylcyclobutyl)carbamoyl]piperidin-1 -yl} -6-azaspiro [3.4] oktan-6-carboxylat, (1,1,2,2,2-pentadeutero)ethyl 2-(4- {[ 1 -(1,1,1 -trideuteromethyl)cyclobutyl]carbamoyl}piperidin-1 -yl)-6-azaspiro [3.4] oktan-6-carboxylat, (1,1,2,2,2-pentadeutero)ethyl(2r,4s)-2-(4- {[1-(1,1,1-trideuteromethyl)cyclobutyl]carbamoyl}piperidin-l-yl)-6-azaspiro[3.4]oktan-6-carboxylat, (1,1,2,2,2-pentadeutero)ethyl(2s,4r)-2-(4- {[1-(1,1,1-trideuteromethyl)cyclobutyl]carbamoyl}piperidin-l-yl)-6-azaspiro[3.4]oktan-6-carboxylat, (1,1,2,2,2-pentadeutero)ethyl 2-(4- {[1 -(1,1,1 -trideuteromethyl)-2,2,3,3,4,4-hexadeuterocyclobutyl]carbamoyl}piperidin-l-yl)-6-azaspiro[3.4]oktan-6-carboxylat, (1,1,2,2,2-pentadeutero)ethyl(2r,4s)-2-(4- {[1 -(1,1,1 -trideuteromethyl)-2,2,3,3,4,4-hexadeuterocyclobutyl]carbamoyl}piperidin-l-yl)-6-azaspiro[3.4]oktan-6-carboxylat, (1,1,2,2,2-pentadeutero)ethyl(2s,4r)-2-(4- {[1 -(1,1,1 -trideuteromethyl)-2,2,3,3,4,4-hexadeuterocyclobutyl]carbamoyl}piperidin-l-yl)-6-azaspiro[3.4]oktan-6-carboxylat.
13. Forbindelse ifølge krav 12, hvilken forbindelse er udvalgt fra ethyl (2r,4s)-2-{4-[(l -methylcyclobutyl)carbamoyl]piperidin-l -yl} -6-azaspiro[3.4]oktan-6-carboxylat, ethyl (2r,4s)-2-(4- {[1-(1,1,1 -trideuteromethyl)cyclobutyl]carbamoyl} piperidin-1 -yl)-6-azaspiro [3.4] oktan-6-carboxylat, ethyl (2r,4s)-2-(4- {[1-(1,1,1 -trideuteromethyl)-2,2,3,3,4,4-hexadeuterocyclobutyl]carbamoyl}piperidin-l-yl)-6-azaspiro[3.4]oktan-6-carboxylat, ethyl (2r,4s)-2-(4- {[1 -(fluormethyl)cyclobutyl]carbamoyl} piperidin-1 -yl)-6-azaspiro[3.4] oktan-6-carboxylat, (2,2,2-trideutero)ethyl(2r,4s)-2-{4-[(l-methylcyclobutyl)carbamoyl]piperidin-l-yl}-6-azaspiro [3.4] oktan-6-carboxylat, (2,2,2-trideutero)ethyl(2r,4s)-2-(4- {[1-(1,1,1 -trideuteromethyl)cyclobutyl]carbamoyl} piperidin-1 -yl)-6-azaspiro[3.4] oktan-6-carboxylat, (2,2,2-trideutero)ethyl(2r,4s)-2-(4- {[1-(1,1,1 -trideuteromethyl)-2,2,3,3,4,4-hexadeuterocyclobutyl]carbamoyl}piperidin-l-yl)-6-azaspiro[3.4]oktan-6-carboxylat, (2,2,2-trideutero)ethyl(2r,4s)-2-(4-{[1-(1,1,1-trideuteromethyl)-2,2,3,3,4,4-hexadeuterocyclobutyl]carbamoyl}piperidin-l-yl)-6-azaspiro[3.4]oktan-6-carboxylat, (2,2,2-trideutero)ethyl(2r,4s)-2-(4-{[l-(fluormethyl)cyclobutyl]carbamoyl}piperidin-l-yl)-6-azaspiro [3.4] oktan-6-carboxylat, (1,1,2,2,2-pentadeutero)ethyl(2r,4s)-2- {4- [(1 -methylcyclobutyl)carbamoyl]piperidin-1 -yl} -6-azaspiro [3.4] oktan-6-carboxylat, (1,1,2,2,2-pentadeutero)ethyl(2r,4s)-2-(4- {[1-(1,1,1 -trideuteromethyl)cyclobutyl]carba-moyl} piperidin-1 -yl)-6-azaspiro[3.4] oktan-6-carboxylat, (1,1,2,2,2-pentadeutero)ethyl(2r,4s)-2-(4- {[1 -(1,1,1 -trideuteromethyl)-2,2,3,3,4,4-hexadeuterocyclobutyl]carbamoyl}piperidin-l-yl)-6-azaspiro[3.4]oktan-6-carboxylat.
14. Farmaceutisk sammensætning, der omfatter en forbindelse som defineret ifølge et hvilket som helst af kravene 1 til 13 og en farmaceutisk acceptabel excipiens.
15. Forbindelse ifølge kravs 1 til 13 til anvendelse til behandling af en kognitiv sygdom eller psykotisk sygdom eller til anvendelse til behandling eller reduktion af alvorsgraden af akut, kronisk, neuropatisk eller inflammatorisk smerte.
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