US20230174520A1 - 3-((Hetero-)Aryl)-Alkyl-8-Amino-2-Oxo-1,3-Diaza-Spiro-[4.5]-Decane Derivatives - Google Patents
3-((Hetero-)Aryl)-Alkyl-8-Amino-2-Oxo-1,3-Diaza-Spiro-[4.5]-Decane Derivatives Download PDFInfo
- Publication number
- US20230174520A1 US20230174520A1 US18/103,180 US202318103180A US2023174520A1 US 20230174520 A1 US20230174520 A1 US 20230174520A1 US 202318103180 A US202318103180 A US 202318103180A US 2023174520 A1 US2023174520 A1 US 2023174520A1
- Authority
- US
- United States
- Prior art keywords
- methyl
- phenyl
- cis
- diazaspiro
- decan
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 125000003118 aryl group Chemical group 0.000 title claims abstract description 12
- 208000002193 Pain Diseases 0.000 claims abstract description 19
- 230000036407 pain Effects 0.000 claims abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 155
- 229920006395 saturated elastomer Polymers 0.000 claims description 122
- -1 2-cyclobutyl Chemical group 0.000 claims description 117
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 114
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 67
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 60
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 59
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 55
- 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims description 48
- 125000006707 (C3-C12) heterocycloalkyl group Chemical group 0.000 claims description 48
- 125000001424 substituent group Chemical group 0.000 claims description 48
- 125000006708 (C5-C14) heteroaryl group Chemical group 0.000 claims description 47
- 125000005915 C6-C14 aryl group Chemical group 0.000 claims description 45
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 35
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 35
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 33
- ZAJNGDIORYACQU-UHFFFAOYSA-N decan-2-one Chemical compound CCCCCCCCC(C)=O ZAJNGDIORYACQU-UHFFFAOYSA-N 0.000 claims description 33
- 238000000034 method Methods 0.000 claims description 27
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 19
- BHNBGYKHHFLUSJ-UHFFFAOYSA-N 8-(dimethylamino)-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound CN(C1(CCC2(CN(C(N2)=O)CC2=CC=C(C=C2)OC)CC1)C1=CC=CC=C1)C BHNBGYKHHFLUSJ-UHFFFAOYSA-N 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 12
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- WRLWEGOEFBBBJN-UHFFFAOYSA-N 1-(cyclobutylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)methyl]-1,3-diazaspiro[4.5]decan-2-one Chemical compound C1(CCC1)CN1C(N(CC11CCC(CC1)(C1=CC(=CC=C1)F)N(C)C)CC1=CC=C(C=C1)OC)=O WRLWEGOEFBBBJN-UHFFFAOYSA-N 0.000 claims description 7
- BGEAEALXBNWGJY-UHFFFAOYSA-N 8-(dimethylamino)-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)methyl]-1,3-diazaspiro[4.5]decan-2-one Chemical compound COc1ccc(CN2CC3(CCC(CC3)(N(C)C)c3cccc(F)c3)NC2=O)cc1 BGEAEALXBNWGJY-UHFFFAOYSA-N 0.000 claims description 7
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 7
- ZLBZEQAPQMBMTC-UHFFFAOYSA-N tert-butyl 2-[8-(dimethylamino)-3-[(4-methoxyphenyl)methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]acetate Chemical compound COc1ccc(CN2CC3(CCC(CC3)(N(C)C)c3ccccc3)N(CC(=O)OC(C)(C)C)C2=O)cc1 ZLBZEQAPQMBMTC-UHFFFAOYSA-N 0.000 claims description 7
- QNBCHHJSUDHSIL-UHFFFAOYSA-N 1-(cyclobutylmethyl)-3-[(3-methoxyphenyl)methyl]-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound C1(CCC1)CN1C(N(CC11CCC(CC1)(C1=CC=CC=C1)NC)CC1=CC(=CC=C1)OC)=O QNBCHHJSUDHSIL-UHFFFAOYSA-N 0.000 claims description 5
- GMXJRLCDFKLCGY-UHFFFAOYSA-N 1-(cyclobutylmethyl)-8-(dimethylamino)-3-[(3-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound C1(CCC1)CN1C(N(CC11CCC(CC1)(C1=CC=CC=C1)N(C)C)CC1=CC(=CC=C1)OC)=O GMXJRLCDFKLCGY-UHFFFAOYSA-N 0.000 claims description 5
- PNGFHKYHCNALQP-UHFFFAOYSA-N 1-(cyclobutylmethyl)-8-(dimethylamino)-3-[(4-hydroxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound CN(C)C1(CCC2(CN(Cc3ccc(O)cc3)C(=O)N2CC2CCC2)CC1)c1ccccc1 PNGFHKYHCNALQP-UHFFFAOYSA-N 0.000 claims description 5
- LTWIXTDRAFZAPF-UHFFFAOYSA-N 1-(cyclobutylmethyl)-8-(dimethylamino)-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound COc1ccc(CN2CC3(CCC(CC3)(N(C)C)c3ccccc3)N(CC3CCC3)C2=O)cc1 LTWIXTDRAFZAPF-UHFFFAOYSA-N 0.000 claims description 5
- VXOYQGDCUZXHBD-UHFFFAOYSA-N 1-(cyclobutylmethyl)-8-(dimethylamino)-8-(3-hydroxyphenyl)-3-[(4-methoxyphenyl)methyl]-1,3-diazaspiro[4.5]decan-2-one Chemical compound COc1ccc(CN2CC3(CCC(CC3)(N(C)C)c3cccc(O)c3)N(CC3CCC3)C2=O)cc1 VXOYQGDCUZXHBD-UHFFFAOYSA-N 0.000 claims description 5
- 125000001425 triazolyl group Chemical group 0.000 claims description 5
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 5
- PEWXZFSEKJFKOF-UHFFFAOYSA-N 1-(cyclobutylmethyl)-3-[(3-methoxyphenyl)methyl]-8-[methyl(propyl)amino]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound C1(CCC1)CN1C(N(CC11CCC(CC1)(C1=CC=CC=C1)N(CCC)C)CC1=CC(=CC=C1)OC)=O PEWXZFSEKJFKOF-UHFFFAOYSA-N 0.000 claims description 4
- HDACKSUZWAPUAP-UHFFFAOYSA-N 1-(cyclobutylmethyl)-3-[(4-methoxyphenyl)methyl]-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound C1(CCC1)CN1C(N(CC11CCC(CC1)(C1=CC=CC=C1)NC)CC1=CC=C(C=C1)OC)=O HDACKSUZWAPUAP-UHFFFAOYSA-N 0.000 claims description 4
- QJAIUODYPSAJPR-UHFFFAOYSA-N 1-(cyclobutylmethyl)-3-[(4-methoxyphenyl)methyl]-8-[methyl(prop-2-enyl)amino]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound COc1ccc(CN2CC3(CCC(CC3)(N(C)CC=C)c3ccccc3)N(CC3CCC3)C2=O)cc1 QJAIUODYPSAJPR-UHFFFAOYSA-N 0.000 claims description 4
- PEPORJMKLNYBKB-UHFFFAOYSA-N 1-(cyclobutylmethyl)-8-(dimethylamino)-3-[(3-methylsulfonylphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound CN(C)C1(CCC2(CN(Cc3cccc(c3)S(C)(=O)=O)C(=O)N2CC2CCC2)CC1)c1ccccc1 PEPORJMKLNYBKB-UHFFFAOYSA-N 0.000 claims description 4
- GFTBNQDZJMFSDP-UHFFFAOYSA-N 1-(cyclobutylmethyl)-8-(dimethylamino)-3-[[4-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]phenyl]methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound COCCOCCOCCOCCOCCOCCOCCOCCOc1ccc(CN2CC3(CCC(CC3)(N(C)C)c3ccccc3)N(CC3CCC3)C2=O)cc1 GFTBNQDZJMFSDP-UHFFFAOYSA-N 0.000 claims description 4
- UYGFTRRNEDTVAD-UHFFFAOYSA-N 1-(cyclobutylmethyl)-8-[2-hydroxyethyl(methyl)amino]-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound COc1ccc(CN2CC3(CCC(CC3)(N(C)CCO)c3ccccc3)N(CC3CCC3)C2=O)cc1 UYGFTRRNEDTVAD-UHFFFAOYSA-N 0.000 claims description 4
- QLCCLFSQGSEYDK-UHFFFAOYSA-N 2-[8-(dimethylamino)-3-[(4-methoxyphenyl)methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-propylacetamide Chemical compound CCCNC(=O)CN1C(=O)N(Cc2ccc(OC)cc2)CC11CCC(CC1)(N(C)C)c1ccccc1 QLCCLFSQGSEYDK-UHFFFAOYSA-N 0.000 claims description 4
- NQNSOTSTQRWEFA-UHFFFAOYSA-N 2-[[1-(cyclobutylmethyl)-3-[(4-methoxyphenyl)methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-8-yl]-methylamino]acetonitrile Chemical compound COc1ccc(CN2CC3(CCC(CC3)(N(C)CC#N)c3ccccc3)N(CC3CCC3)C2=O)cc1 NQNSOTSTQRWEFA-UHFFFAOYSA-N 0.000 claims description 4
- XXZDHFVKLHNUMC-UHFFFAOYSA-N 2-[[8-(dimethylamino)-1-[(1-hydroxycyclobutyl)methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]methyl]benzamide Chemical compound CN(C)C1(CCC2(CN(Cc3ccccc3C(N)=O)C(=O)N2CC2(O)CCC2)CC1)c1ccccc1 XXZDHFVKLHNUMC-UHFFFAOYSA-N 0.000 claims description 4
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 4
- JPPRWNMMGJNQBN-UHFFFAOYSA-N 8-(dimethylamino)-1-(2-hydroxyethyl)-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound CN(C1(CCC2(CN(C(N2CCO)=O)CC2=CC=C(C=C2)OC)CC1)C1=CC=CC=C1)C JPPRWNMMGJNQBN-UHFFFAOYSA-N 0.000 claims description 4
- SFVUCTQOKPNATA-UHFFFAOYSA-N 8-(dimethylamino)-1-(2-methoxy-2-methylpropyl)-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound CN(C1(CCC2(CN(C(N2CC(C)(C)OC)=O)CC2=CC=C(C=C2)OC)CC1)C1=CC=CC=C1)C SFVUCTQOKPNATA-UHFFFAOYSA-N 0.000 claims description 4
- VFVLDDWIJAMRTA-UHFFFAOYSA-N 8-(dimethylamino)-1-[(1-hydroxycyclobutyl)methyl]-8-phenyl-3-(2-phenylethyl)-1,3-diazaspiro[4.5]decan-2-one Chemical compound CN(C)C1(CCC2(CN(CCC3=CC=CC=C3)C(=O)N2CC2(O)CCC2)CC1)C1=CC=CC=C1 VFVLDDWIJAMRTA-UHFFFAOYSA-N 0.000 claims description 4
- QUVDCWLEMFTCQX-UHFFFAOYSA-N 8-(dimethylamino)-1-ethyl-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound CCN1C(=O)N(Cc2ccc(OC)cc2)CC11CCC(CC1)(N(C)C)c1ccccc1 QUVDCWLEMFTCQX-UHFFFAOYSA-N 0.000 claims description 4
- ZFDFQROBUBTCCD-UHFFFAOYSA-N 8-(dimethylamino)-3-[(4-methoxyphenyl)methyl]-1-(2-methylpropyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound COc1ccc(CN2CC3(CCC(CC3)(N(C)C)c3ccccc3)N(CC(C)C)C2=O)cc1 ZFDFQROBUBTCCD-UHFFFAOYSA-N 0.000 claims description 4
- ACPQZFFQLKGWON-UHFFFAOYSA-N 8-(dimethylamino)-3-[(4-methoxyphenyl)methyl]-1-(oxolan-3-ylmethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound COc1ccc(CN2CC3(CCC(CC3)(N(C)C)c3ccccc3)N(CC3CCOC3)C2=O)cc1 ACPQZFFQLKGWON-UHFFFAOYSA-N 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 4
- 229940080818 propionamide Drugs 0.000 claims description 4
- QFCYVANZZZLEKU-UHFFFAOYSA-N 1-(cyclobutylmethyl)-8-(dimethylamino)-8-phenyl-3-(pyridin-3-ylmethyl)-1,3-diazaspiro[4.5]decan-2-one Chemical compound CN(C)C1(CCC2(CN(Cc3cccnc3)C(=O)N2CC2CCC2)CC1)c1ccccc1 QFCYVANZZZLEKU-UHFFFAOYSA-N 0.000 claims description 3
- RABKZFCSZJSVIG-UHFFFAOYSA-N 1-[(1-hydroxycyclobutyl)methyl]-3-[(4-methoxyphenyl)methyl]-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound CNC1(CCC2(CN(Cc3ccc(OC)cc3)C(=O)N2CC2(O)CCC2)CC1)c1ccccc1 RABKZFCSZJSVIG-UHFFFAOYSA-N 0.000 claims description 3
- UGMHTGXNTSNAJX-UHFFFAOYSA-N 3-benzyl-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound CN(C1(CCC2(CN(C(N2)=O)CC2=CC=CC=C2)CC1)C1=CC=CC=C1)C UGMHTGXNTSNAJX-UHFFFAOYSA-N 0.000 claims description 3
- CWNVRGJEWVHJCP-UHFFFAOYSA-N 8-(dimethylamino)-1-(2-hydroxy-2-methylpropyl)-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound COc1ccc(CN2CC3(CCC(CC3)(N(C)C)c3ccccc3)N(CC(C)(C)O)C2=O)cc1 CWNVRGJEWVHJCP-UHFFFAOYSA-N 0.000 claims description 3
- CZVLUFVYJXQKHZ-UHFFFAOYSA-N 8-(dimethylamino)-1-(3-hydroxy-3-methylbutyl)-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound COc1ccc(CN2CC3(CCC(CC3)(N(C)C)c3ccccc3)N(CCC(C)(C)O)C2=O)cc1 CZVLUFVYJXQKHZ-UHFFFAOYSA-N 0.000 claims description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 3
- SGGMATVTIPUWKX-UHFFFAOYSA-N 1-(2-cyclobutylethyl)-8-(dimethylamino)-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound COc1ccc(CN2CC3(CCC(CC3)(N(C)C)c3ccccc3)N(CCC3CCC3)C2=O)cc1 SGGMATVTIPUWKX-UHFFFAOYSA-N 0.000 claims description 2
- BCBRYUWDAGLKPS-UHFFFAOYSA-N 1-(2-cyclohexylethyl)-8-(dimethylamino)-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound COc1ccc(CN2CC3(CCC(CC3)(N(C)C)c3ccccc3)N(CCC3CCCCC3)C2=O)cc1 BCBRYUWDAGLKPS-UHFFFAOYSA-N 0.000 claims description 2
- RQOVYXMPEPGWDI-UHFFFAOYSA-N 1-(cyclobutylmethyl)-3-[[1-(2-hydroxyethyl)triazol-4-yl]methyl]-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound CNC1(CCC2(CN(CC3=CN(CCO)N=N3)C(=O)N2CC2CCC2)CC1)C1=CC=CC=C1 RQOVYXMPEPGWDI-UHFFFAOYSA-N 0.000 claims description 2
- BARLHUVNIVYXMO-UHFFFAOYSA-N 1-(cyclobutylmethyl)-8-(dimethylamino)-3-[(4-methylsulfonylphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound CN(C)C1(CCC2(CN(Cc3ccc(cc3)S(C)(=O)=O)C(=O)N2CC2CCC2)CC1)c1ccccc1 BARLHUVNIVYXMO-UHFFFAOYSA-N 0.000 claims description 2
- VBLSOCKFYRCTFP-UHFFFAOYSA-N 1-(cyclobutylmethyl)-8-(dimethylamino)-3-[[1-(2-hydroxyethyl)triazol-4-yl]methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound CN(C)C1(CCC2(CN(Cc3cn(CCO)nn3)C(=O)N2CC2CCC2)CC1)c1ccccc1 VBLSOCKFYRCTFP-UHFFFAOYSA-N 0.000 claims description 2
- GECAMOXGPHHIKU-UHFFFAOYSA-N 1-(cyclobutylmethyl)-8-(dimethylamino)-3-[[3-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]phenyl]methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound COCCOCCOCCOCCOCCOCCOc1cccc(CN2CC3(CCC(CC3)(N(C)C)c3ccccc3)N(CC3CCC3)C2=O)c1 GECAMOXGPHHIKU-UHFFFAOYSA-N 0.000 claims description 2
- DJFZBCVQEHKNNP-UHFFFAOYSA-N 1-(cyclobutylmethyl)-8-(dimethylamino)-8-(3-methoxyphenyl)-3-[(4-methoxyphenyl)methyl]-1,3-diazaspiro[4.5]decan-2-one Chemical compound COc1ccc(CN2CC3(CCC(CC3)(N(C)C)c3cccc(OC)c3)N(CC3CCC3)C2=O)cc1 DJFZBCVQEHKNNP-UHFFFAOYSA-N 0.000 claims description 2
- ZJSRAQNSQCIMIR-UHFFFAOYSA-N 1-(cyclobutylmethyl)-8-(dimethylamino)-8-(4-fluorophenyl)-3-[(4-methoxyphenyl)methyl]-1,3-diazaspiro[4.5]decan-2-one Chemical compound COc1ccc(CN2CC3(CCC(CC3)(N(C)C)c3ccc(F)cc3)N(CC3CCC3)C2=O)cc1 ZJSRAQNSQCIMIR-UHFFFAOYSA-N 0.000 claims description 2
- YSJKGOYGPSKNGB-UHFFFAOYSA-N 1-(cyclobutylmethyl)-8-(dimethylamino)-8-(4-hydroxyphenyl)-3-[(4-methoxyphenyl)methyl]-1,3-diazaspiro[4.5]decan-2-one Chemical compound COc1ccc(CN2CC3(CCC(CC3)(N(C)C)c3ccc(O)cc3)N(CC3CCC3)C2=O)cc1 YSJKGOYGPSKNGB-UHFFFAOYSA-N 0.000 claims description 2
- IKOPGFJXCMHTLG-UHFFFAOYSA-N 1-(cyclobutylmethyl)-8-(dimethylamino)-8-(4-methoxyphenyl)-3-[(4-methoxyphenyl)methyl]-1,3-diazaspiro[4.5]decan-2-one Chemical compound C1(CCC1)CN1C(N(CC11CCC(CC1)(C1=CC=C(C=C1)OC)N(C)C)CC1=CC=C(C=C1)OC)=O IKOPGFJXCMHTLG-UHFFFAOYSA-N 0.000 claims description 2
- FHIDRVZPWLEQEB-UHFFFAOYSA-N 1-(cyclobutylmethyl)-8-(dimethylamino)-8-phenyl-3-(pyrazin-2-ylmethyl)-1,3-diazaspiro[4.5]decan-2-one Chemical compound CN(C)C1(CCC2(CN(Cc3cnccn3)C(=O)N2CC2CCC2)CC1)c1ccccc1 FHIDRVZPWLEQEB-UHFFFAOYSA-N 0.000 claims description 2
- QNLCVVGGUNWQAS-UHFFFAOYSA-N 1-(cyclobutylmethyl)-8-(dimethylamino)-8-phenyl-3-(pyridin-2-ylmethyl)-1,3-diazaspiro[4.5]decan-2-one Chemical compound CN(C)C1(CCC2(CN(Cc3ccccn3)C(=O)N2CC2CCC2)CC1)c1ccccc1 QNLCVVGGUNWQAS-UHFFFAOYSA-N 0.000 claims description 2
- CAERYDTVNNPWIA-UHFFFAOYSA-N 1-(cyclobutylmethyl)-8-(dimethylamino)-8-phenyl-3-(pyridin-4-ylmethyl)-1,3-diazaspiro[4.5]decan-2-one Chemical compound CN(C)C1(CCC2(CN(Cc3ccncc3)C(=O)N2CC2CCC2)CC1)c1ccccc1 CAERYDTVNNPWIA-UHFFFAOYSA-N 0.000 claims description 2
- LTJOZEQCCDXJDH-UHFFFAOYSA-N 1-(cyclobutylmethyl)-8-(dimethylamino)-8-phenyl-3-[[6-(trifluoromethyl)pyridin-3-yl]methyl]-1,3-diazaspiro[4.5]decan-2-one Chemical compound CN(C)C1(CCC2(CN(Cc3ccc(nc3)C(F)(F)F)C(=O)N2CC2CCC2)CC1)c1ccccc1 LTJOZEQCCDXJDH-UHFFFAOYSA-N 0.000 claims description 2
- PASRXRDOVAGJNP-UHFFFAOYSA-N 1-(cyclobutylmethyl)-8-(methylamino)-8-phenyl-3-(pyridin-3-ylmethyl)-1,3-diazaspiro[4.5]decan-2-one Chemical compound CNC1(CCC2(CN(Cc3cccnc3)C(=O)N2CC2CCC2)CC1)c1ccccc1 PASRXRDOVAGJNP-UHFFFAOYSA-N 0.000 claims description 2
- ODGKMJBDZAKEOJ-UHFFFAOYSA-N 1-(cyclobutylmethyl)-8-[2-methoxyethyl(methyl)amino]-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound COCCN(C)C1(CCC2(CN(Cc3ccc(OC)cc3)C(=O)N2CC2CCC2)CC1)c1ccccc1 ODGKMJBDZAKEOJ-UHFFFAOYSA-N 0.000 claims description 2
- LOYKRVWFMCWRDF-UHFFFAOYSA-N 1-(cyclobutylmethyl)-8-[ethyl(methyl)amino]-3-[(3-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound CCN(C)C1(CCC2(CN(Cc3cccc(OC)c3)C(=O)N2CC2CCC2)CC1)c1ccccc1 LOYKRVWFMCWRDF-UHFFFAOYSA-N 0.000 claims description 2
- NVWJPWMESOJBIQ-UHFFFAOYSA-N 1-(cyclobutylmethyl)-8-[ethyl(methyl)amino]-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one Chemical compound CCN(C)C1(CCC2(CN(Cc3ccc(OC)cc3)C(=O)N2CC2CCC2)CC1)c1ccccc1 NVWJPWMESOJBIQ-UHFFFAOYSA-N 0.000 claims description 2
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- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- DBYQHFPBWKKZAT-UHFFFAOYSA-N lithium;benzene Chemical compound [Li+].C1=CC=[C-]C=C1 DBYQHFPBWKKZAT-UHFFFAOYSA-N 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- YADSQVVJGJHEMZ-UHFFFAOYSA-M magnesium;1-methoxypropane;bromide Chemical compound [Mg+2].[Br-].COCC[CH2-] YADSQVVJGJHEMZ-UHFFFAOYSA-M 0.000 description 1
- BRKADVNLTRCLOW-UHFFFAOYSA-M magnesium;fluorobenzene;bromide Chemical compound [Mg+2].[Br-].FC1=CC=[C-]C=C1 BRKADVNLTRCLOW-UHFFFAOYSA-M 0.000 description 1
- DTKMKZYEOXZPQZ-UHFFFAOYSA-M magnesium;fluorobenzene;bromide Chemical compound [Mg+2].[Br-].FC1=CC=C[C-]=C1 DTKMKZYEOXZPQZ-UHFFFAOYSA-M 0.000 description 1
- FKUUDDGRDRPAQQ-UHFFFAOYSA-M magnesium;methoxybenzene;bromide Chemical compound [Mg+2].[Br-].COC1=CC=C[C-]=C1 FKUUDDGRDRPAQQ-UHFFFAOYSA-M 0.000 description 1
- RBWRWAUAVRMBAC-UHFFFAOYSA-M magnesium;methoxybenzene;bromide Chemical compound [Mg+2].[Br-].COC1=CC=[C-]C=C1 RBWRWAUAVRMBAC-UHFFFAOYSA-M 0.000 description 1
- BCVXHSPFUWZLGQ-UHFFFAOYSA-N mecn acetonitrile Chemical compound CC#N.CC#N BCVXHSPFUWZLGQ-UHFFFAOYSA-N 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- QKASDIPENBEWBU-UHFFFAOYSA-N methyl 2-(bromomethyl)benzoate Chemical compound COC(=O)C1=CC=CC=C1CBr QKASDIPENBEWBU-UHFFFAOYSA-N 0.000 description 1
- CZXGXYBOQYQXQD-UHFFFAOYSA-N methyl benzenesulfonate Chemical compound COS(=O)(=O)C1=CC=CC=C1 CZXGXYBOQYQXQD-UHFFFAOYSA-N 0.000 description 1
- 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 102000051367 mu Opioid Receptors Human genes 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- QKYWADPCTHTJHQ-UHFFFAOYSA-N n,2-dimethylpropan-1-amine Chemical compound CNCC(C)C QKYWADPCTHTJHQ-UHFFFAOYSA-N 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PVWOIHVRPOBWPI-UHFFFAOYSA-N n-propyl iodide Chemical compound CCCI PVWOIHVRPOBWPI-UHFFFAOYSA-N 0.000 description 1
- IHPHPGLJYCDONF-UHFFFAOYSA-N n-propylacetamide Chemical compound CCCNC(C)=O IHPHPGLJYCDONF-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 230000002981 neuropathic effect Effects 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- YNOGYQAEJGADFJ-UHFFFAOYSA-N oxolan-2-ylmethanamine Chemical compound NCC1CCCO1 YNOGYQAEJGADFJ-UHFFFAOYSA-N 0.000 description 1
- GSUBXIVOZXWGKF-UHFFFAOYSA-N oxolane-3-carbaldehyde Chemical compound O=CC1CCOC1 GSUBXIVOZXWGKF-UHFFFAOYSA-N 0.000 description 1
- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 1
- 239000004031 partial agonist Substances 0.000 description 1
- 235000011837 pasties Nutrition 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 102000014187 peptide receptors Human genes 0.000 description 1
- 108010011903 peptide receptors Proteins 0.000 description 1
- 210000005223 peripheral sensory neuron Anatomy 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- YNPNZTXNASCQKK-UHFFFAOYSA-N phenanthrene Chemical compound C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 1
- 239000011505 plaster Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000011809 primate model Methods 0.000 description 1
- 230000002400 pro-nociceptive effect Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- LFILDSDQMSCNBV-LURJTMIESA-N propane-2-sulfinamide Chemical compound CC(C)[S@@](N)=O LFILDSDQMSCNBV-LURJTMIESA-N 0.000 description 1
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
- CPNGPNLZQNNVQM-UHFFFAOYSA-N pteridine Chemical compound N1=CN=CC2=NC=CN=C21 CPNGPNLZQNNVQM-UHFFFAOYSA-N 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 230000003014 reinforcing effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 239000008299 semisolid dosage form Substances 0.000 description 1
- 230000020341 sensory perception of pain Effects 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- RMBAVIFYHOYIFM-UHFFFAOYSA-M sodium methanethiolate Chemical compound [Na+].[S-]C RMBAVIFYHOYIFM-UHFFFAOYSA-M 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 description 1
- ISXSCDLOGDJUNJ-UHFFFAOYSA-N tert-butyl prop-2-enoate Chemical compound CC(C)(C)OC(=O)C=C ISXSCDLOGDJUNJ-UHFFFAOYSA-N 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- ZYXWYDDFNXBTFO-UHFFFAOYSA-N tetrazolidine Chemical compound C1NNNN1 ZYXWYDDFNXBTFO-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- RLTPJVKHGBFGQA-UHFFFAOYSA-N thiadiazolidine Chemical compound C1CSNN1 RLTPJVKHGBFGQA-UHFFFAOYSA-N 0.000 description 1
- CBDKQYKMCICBOF-UHFFFAOYSA-N thiazoline Chemical compound C1CN=CS1 CBDKQYKMCICBOF-UHFFFAOYSA-N 0.000 description 1
- XSROQCDVUIHRSI-UHFFFAOYSA-N thietane Chemical compound C1CSC1 XSROQCDVUIHRSI-UHFFFAOYSA-N 0.000 description 1
- VOVUARRWDCVURC-UHFFFAOYSA-N thiirane Chemical compound C1CS1 VOVUARRWDCVURC-UHFFFAOYSA-N 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- JMXKSZRRTHPKDL-UHFFFAOYSA-N titanium ethoxide Chemical compound [Ti+4].CC[O-].CC[O-].CC[O-].CC[O-] JMXKSZRRTHPKDL-UHFFFAOYSA-N 0.000 description 1
- 238000007070 tosylation reaction Methods 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 1
- 229910001845 yogo sapphire Inorganic materials 0.000 description 1
- 108020001612 μ-opioid receptors Proteins 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Definitions
- the invention relates to 3-((hetero-)aryl)-alkyl-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives, their preparation and use in medicine, particularly in various neurological disorders, including but not limited to pain, neurodegenerative disorders, neuroinflammatory disorders, neuropsychiatric disorders, substance abuse/dependence.
- Opioid receptors are a group of Gi/o protein-coupled receptors which are widely distributed in the human body.
- the opioid receptors are currently subdivided into four major classes, i.e. the three classical opioid receptors mu-opioid (MOP) receptor, kappa-opioid (KOP) receptor, and delta-opioid (DOP) receptor as well as the opioid receptor-like (ORL-1) receptor, which was more recently discovered based on its high homology with said classical opioid receptors.
- MOP mu-opioid
- KOP kappa-opioid
- DOP delta-opioid
- ORL-1 opioid receptor-like receptor
- ORL-1 receptor After identification of the endogenous ligand of the ORL-1 receptor, known as nociceptin/orphanin FQ, a highly basic 17 amino acid peptide isolated from tissue extracts in 1995, the ORL-1 receptor was renamed “nociceptin opioid peptide receptor” and abbreviated as “NOP-receptor”.
- the classical opioid receptors (MOP, KOP and DOP) as well as the NOP receptor are widely distributed/expressed in the human body, including in the brain, the spinal cord, on peripheral sensory neurons and the intestinal tract, wherein the distribution pattern differs between the different receptor classes.
- Nociceptin acts at the molecular and cellular level in very much the same way as opioids. However, its pharmacological effects sometimes differ from, and even oppose those of opioids. NOP-receptor activation translates into a complex pharmacology of pain modulation, which, depending on route of administration, pain model and species involved, leads to either pronociceptive or antinociceptive activity. Furthermore, the NOP receptor system is upregulated under conditions of chronic pain. Systemic administration of selective NOP receptor agonists was found to exert a potent and efficacious analgesia in non-human primate models of acute and inflammatory pain in the absence of side effects.
- NOP receptors The activation of NOP receptors has been demonstrated to be devoid of reinforcing effects but to inhibit opioid-mediated reward in rodents and non-human primates (Review: Schroeder et al, Br J Pharmacol 2014; 171 (16): 3777-3800, and references therein).
- NOP receptor agonists might be useful inter alia in the treatment of neuropsychiatric disorders (Witkin et al, Pharmacology & Therapeutics, 141 (2014) 283-299; Jenck et al., Proc. Natl. Acad. Sci. USA 94, 1997, 14854-14858).
- the DOP receptor is also implicated to modulate not only pain but also neuropsychiatric disorders (Mabrouk et al, 2014; Pradhan et al., 2011).
- MOP receptor agonists show only reduced effectiveness under conditions of chronic and neuropathic pain.
- peripherally restricted opioid receptor ligands that do not easily cross the blood-brain barrier and therefore distribute poorly to the central nervous system (see for instance WO 2015/192039).
- peripherally acting compounds might combine effective analgesia with limited side-effects.
- a further approach has been to provide multi-opioid receptor analgesics that modulate more than one of the opioid receptor subtypes to provide additive or synergistic analgesia and/or reduced side effects like abuse liability or tolerance.
- medicaments which are effective in the treatment of pain and which have advantages compared to the compounds of the prior art.
- medicaments should contain such a small dose of active ingredient that satisfactory pain therapy can be ensured without the occurrence of intolerable treatment-emergent adverse events.
- a first aspect of the invention relates to 3-((hetero-)aryl)-alkyl-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives according to general formula (I)
- —C 1 -C 6 -alkyl linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH 2 , and —O—C 1 -C 6 -alkyl;
- aryl includes but is not limited to phenyl and naphthyl.
- heteroaryl includes but is not limited to -1,2-benzodioxole, -pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl, -thienyl, -imidazolyl, -benzimidazolyl, -thiazolyl, -1,3,4-thiadiazolyl, -benzothiazolyl, -oxazolyl, -benzoxazolyl, -pyrazolyl, -quinolinyl, -isoquinolinyl, -quinazolinyl, -indolyl, -indolinyl, -benzo [c][ 1,2,5]oxadiazolyl, -imidazo[1 ,2-a]pyrazinyl, or -1H-pyrrolo[2,3-b]
- cycloalkyl includes but is not limited to -cyclopropyl, -cyclobutyl, -cyclopentyl and -cyclohexyl.
- heterocycloalkyl includes but is not limited to -aziridinyl, -azetidinyl, -pyrrolidinyl, -piperidinyl, -piperazinyl, -morpholinyl, -sulfamorpholinyl, -oxiridinyl, -oxetanyl, -tetrahydropyranyl, and -pyranyl.
- asymmetric group such as —C( ⁇ O)O— or —C( ⁇ O)O—CH 2 —
- said asymmetric group may be arranged in either direction.
- R 4 when R 4 is connected to the core structure through —C( ⁇ O)O—, the arrangement may be either R 4 —C( ⁇ O)O— core or core —C( ⁇ O)O—R 4 .
- R 7 , R 8 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 independently of one another mean —H, —F, —OH, or —C 1 -C 6 -alkyl; preferably —H.
- R 7 and R 8 together with the carbon atom to which they are attached form a ring and mean —(CH 2 ) 2 — (i.e. form a cyclopropyl ring) or —(CH 2 ) 3 — (i.e. form a cyclobutyl ring).
- R 1 means —H; and R 2 means —C 1 -C 6 -alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
- R 1 means —H and R 2 means —CH 3 .
- R 1 means —CH 3 ; and R 2 means —C 1 -C 6 -alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
- R 1 means —CH 3 and R 2 means —CH 3 .
- R 1 and R 2 together with the nitrogen atom to which they are attached form a ring and mean —(CH 2 ) 3-6 —.
- R 1 and R 2 together with the nitrogen atom to which they are attached form a ring and mean —(CH 2 ) 3 —.
- R 3 means —C 1 -C 6 -alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
- R 3 means —C 1 -C 6 -alkyl, linear or branched, saturated or unsaturated, unsubstituted or monosubstituted with —OCH 3 .
- R 3 means a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted, optionally connected through —C 1 -C 6 -alkylene-, linear or branched, saturated or unsaturated, unsubstituted.
- R 3 means -phenyl unsubstituted, mono- or polysubstituted.
- R 3 means -phenyl unsubstituted, mono- or disubstituted with —F, —CH 3 , —CF 3 , —OH, —OCH 3 , —OCF 3 or —OCH 2 OCH 3 , preferably —F.
- R 3 means -benzyl unsubstituted, mono- or polysubstituted. More preferably, R 3 means -benzyl unsubstituted, mono- or disubstituted with —F, —Cl, —CH 3 , —CF 3 , —OH, —OCH 3 , —OCF 3 or —OCH 2 OCH 3 , preferably —F.
- R 3 means a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted.
- R 3 means -thienyl or -pyridinyl, in each case unsubstituted, mono- or polysubstituted. More preferably, R 3 means -thienyl, -pyridinyl, -imidazolyl or benzimidazolyl, in each case unsubstituted or monosubstituted with —F, —Cl or —CH 3 .
- R 4 means —H.
- R 4 means —C 1 -C 6 -alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
- R 4 means —C 1 -C 6 -alkyl, linear or branched, saturated or unsaturated, unsubstituted or monosubstituted with a substituent selected from the group consisting of —F, —Cl, —Br, —I, —CN, —CF 3 , —OH, —OCF 3 , —O—(CH 2 CH 2 —O) 1-30 —H, —O—(CH 2 CH 2 —O) 1-30 —CH 3 , —C( ⁇ O)C 1 -C 4 -alkyl, —C( ⁇ O)OH, —C( ⁇ O)O—C( ⁇ O)NH 2 , —C( ⁇ O)NHC 1 -C 4
- R 4 means —C 1 -C 6 -alkyl, linear or branched, saturated or unsaturated, unsubstituted or monosubstituted with —O—C 1 -C 4 -alkyl or —C( ⁇ O)N(C 1 -C 4 -alkyl) 2 .
- R 4 means a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein the 3-12-membered cycloalkyl moiety is connected through —C 1 -C 6 -alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
- R 4 means a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl moiety is connected through —CH 2 — or —CH 2 CH 2 —.
- R 4 means a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —C 1 -C 4 -alkyl, —O—C 1 -C 4 -alkyl, —C( ⁇ O)OH, —C( ⁇ O)OC 1 -C 4 -alkyl, —C( ⁇ O)NH 2 , —C( ⁇ O)NHC 1 -C 4 -alkyl, —C( ⁇ O)N(C 1 -C 4 -alkyl) 2 , —S( ⁇ O)C 1 -C 4 -alkyl and —S( ⁇ O) 2 C 1 -C 4 -alkyl; wherein said 3-12-membered cycloalkyl mo
- R 4 means a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is connected through —C 1 -C 6 -alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
- R 4 means a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is connected through —CH 2 — or —CH 2 CH 2 —.
- R 4 means -oxetanyl, -tetrahydrofuranyl or -tetrahydropyranyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —C 1 -C 4 -alkyl, —C( ⁇ O)OH, —C( ⁇ O)OC 1 -C 4 -alkyl, —C( ⁇ O)NH 2 , —C( ⁇ O)NHC 1 -C 4 -alkyl, —C( ⁇ O)N(C 1 -C 4 -alkyl) 2 , —S( ⁇ O)C 1 -C 4 -alkyl and —S( ⁇ O) 2 C 1 -C 4 -alkyl; wherein said -oxetanyl, -tetrahydrofuranyl,
- R 4 means a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is connected through —C 1 -C 6 -alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
- R 4 means -phenyl, unsubstituted, mono- or polysubstituted; wherein said -phenyl is connected through —CH 2 — or —CH 2 CH 2 —.
- R 4 means -phenyl, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —C 1 -C 4 -alkyl, —O—C 1 -C 4 -alkyl, —C( ⁇ O)OH, —C( ⁇ O)OC 1 -C 4 -alkyl, —C( ⁇ O)NH 2 , —C( ⁇ O)NHC 1 -C 4 -alkyl, —C( ⁇ O)N(C 1 -C 4 -alkyl) 2 , —S( ⁇ O)C 1 -C 4 -alkyl and —S( ⁇ O) 2 C 1 -C 4 -alkyl; wherein said -phenyl is connected through —CH 2 — or —CH 2 CH 2 —.
- R 4 means a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is connected through —C 1 -C 6 -alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
- R 4 means a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said -phenyl is connected through —CH 2 — or —CH 2 CH 2 —.
- R 4 means -pyridinyl, -pyrimidinyl, -pyrazinyl, or -pyrazolinyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —C 1 -C 4 -alkyl, —O—C 1 -C 4 -alkyl, —C( ⁇ O)OH, —C( ⁇ O)OC 1 -C 4 -alkyl, —C( ⁇ O)NH 2 , —C( ⁇ O)NHC 1 -C 4 -alkyl, —C( ⁇ O)N(C 1 -C 4 -alkyl) 2 , —S( ⁇ O)C 1 -C 4 -alkyl and —S( ⁇ O) 2 C 1 -C 4 -alkyl; wherein
- n means 1 or 2.
- n means 1.
- R 5 means -phenyl, unsubstituted, mono- or polysubstituted.
- R 5 means -phenyl unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F; —Cl; —Br; —I; —CN; —OH; —CF 3 ; -3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; preferably -cyclopropyl, saturated, unsubstituted; -3-12-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; preferably -pyrrolidinyl, -piperidinyl, -morpholinyl, -piperazinyl, -thiomorpholinyl, or -thio
- R 5 means -pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl, -thienyl, -imidazolyl, triazolyl, or -1,3-benzodioxolyl, in each case unsubstituted, mono- or polysubstituted.
- R 5 means -pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl, -thienyl, -imidazolyl, triazolyl, or -1,3-benzodioxolyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F; —Cl; —Br; —I; —CN; —OH; —C 1 -C 4 -alkyl, —CF 3 ; —C 1 -C 4 -alkyl-C( ⁇ O)NH 2 ; -3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; preferably -cyclopropyl, saturated, unsubstituted; -3-12-membered heterocycloalkyl, saturated or unsaturated
- the compound according to the invention has a structure according to any of general formulas (II-A) to (VIII-C):
- R 5 is selected from the group consisting of:
- R 5 means -phenyl, -pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl, -thienyl, -imidazolyl, triazolyl, or -1,3-benzodioxolyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F; —Cl; —Br; —I; —CN; —OH; —C 1 -C 4 -alkyl; —CF 3 ; alkyl-OH; —C 1 -C 4 -alkyl-C 1 -C 4 -alkyl-C( ⁇ O)NH 2 ; -3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; preferably -cyclopropyl, saturated, unsubstitute
- R 7 , R 8 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 mean —H.
- the compound according to the invention is selected from the group consisting of
- —C 1 -C 4 -alkyl can be linear or branched, saturated or unsaturated.
- Linear saturated alkyl includes methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl.
- branched saturated alkyl include but are not limited to iso-propyl, sec-butyl, and tert-butyl.
- linear unsaturated alkyl include but are not limited to vinyl, propenyl, allyl, and propargyl.
- —C 1 -C 4 -alkyl can be unsubstituted, mono- or polysubstituted.
- substituted alkyl examples include but are not limited to —CH 2 CH 2 OH, —CH 2 CH 2 OCH 3 , —CH 2 CH 2 CH 2 OCH 3 , —CH 2 CH 2 S( ⁇ O) 2 CH 3 , —CH 2 C( ⁇ O)NH 2 , —C(CH 3 ) 2 C( ⁇ O)NH 2 , —CH 2 C(CH 3 ) 2 C( ⁇ O)NH 2 , and —CH 2 CH 2 C( ⁇ O)N(CH 3 ) 2 .
- —C 1 -C 6 -alkylene- can be unsubstituted, mono- or polysubstituted.
- saturated alkylene examples include but are not limited to —CH 2 —, —CH(CH 3 )—, —C(CH 3 ) 2 —, —CH 2 CH 2 —, —CH(CH 3 )CH 2 —, —CH 2 CH(CH 3 )—, —CH(CH 3 )—CH(CH 3 )—, —C(CH 3 ) 2 CH 2 —, —CH 2 C(CH 3 ) 2 —, —CH(CH 3 )C(CH 3 ) 2 —, —C(CH 3 ) 2 CH(CH 3 )—, C(CH 3 ) 2 C(CH 3 ) 2 —, —CH 2 CH 2 CH 2 —, and —C(CH 3 ) 2 CH 2 CH 2 —.
- unsaturated alkylene examples include but are not limited to —CH ⁇ CH—, —C ⁇ —, —C(CH 3 ) ⁇ CH—, —CH ⁇ C(CH 3 )—, —C(CH 3 ) ⁇ C(CH 3 )—, —CH 2 CH ⁇ CH—, —CH ⁇ CHCH 2 —, —CH ⁇ CH—CH ⁇ CH—, and —CH ⁇ CH—C ⁇ C—.
- —C 1 -C 6 -alkylene- can be unsubstituted, mono- or polysubstituted.
- substituted —C 1 -C 6 -alkylene- include but are not limited to —CHF—, —CF 2 —, —CHOH— and —C( ⁇ O)—.
- moieties may be connected through —C 1 -C 6 -alkylene-, i.e. the moieties may not be directly bound to the core structure of compound according to general formula (I), but may be connected to the core structure of compound according to general formula (I) or its periphery through a —C 1 -C 6 -alkylene- linker.
- 3-12-membered cycloalkyl moiety means a non-aromatic, monocyclic, bicyclic or tricyclic moiety comprising 3 to 12 ring carbon atoms but no heteroatoms in the ring.
- preferred saturated 3-12-membered cycloalkyl moieties according to the invention include but are not limited to cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, hydrindane, and decaline.
- Examples of preferred unsaturated 3 membered cycloalkyl moiety moieties according to the invention include but are not limited to cyclopropene, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, 1,3-cyclohexadiene, and 1,4-cyclohexadiene.
- the 3-12-membered cycloalkyl moiety which is bonded to the compound according to the invention, in its periphery may optionally be condensed with a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; and/or with a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; and/or with a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted.
- the ring atoms of the condensed moieties are not included in the 3 to 12 ring atoms of the 3-12-membered cycloalkyl moiety.
- 3-12-membered cycloalkyl moieties condensed with 3-12-membered heterocycloalkyl moieties include but are not limited to octahydro-1H-indol, decahydroquinoline, decahydroisoquinoline, octahydro-2H-benzo[b][1,4]oxazin, and decahydro-quinoxalin, which in each case are connected through the 3-12-membered cycloalkyl moiety.
- 3-12-membered cycloalkyl moieties condensed with 6-14-membered aryl moieties include but are not limited to 2,3-dihydro-1H-indene and tetraline, which in each case are connected through the 3-12-membered cycloalkyl moiety.
- 3-12-membered cycloalkyl moieties condensed with 5-14-membered heteroaryl moieties include but are not limited to 5,6,7,8-tetrahydroquinoline and 5,6,7,8-tetrahydroquinazoline, which in each case are connected through the 3-12-membered cycloalkyl moiety.
- the 3-12-membered cycloalkyl moiety may optionally be connected through —C 1 -C 6 -alkylene-, i.e. the 3-12-membered cycloalkyl moiety may not be directly bound to the compound according to general formula (I) but may be connected thereto through a —C 1 -C 6 -alkylene- linker.
- Examples include but are not limited to —CH 2 -cyclopropyl, —CH 2 -cyclobutyl, —CH 2 -cyclopentyl, —CH 2 -cyclohexyl, —CH 2 CH 2 -cyclopropyl, —CH 2 CH 2 -cyclobutyl, —CH 2 CH 2 -cyclopentyl, and —CH 2 CH 2 -cyclohexyl.
- the 3-12-membered cycloalkyl moiety can be unsubstituted, mono- or polysubstituted.
- substituted 3-12-membered cycloalkyl moieties include but are not limited to —CH 2 -1-hydroxy-cyclobutyl.
- “3-12-membered heterocycloalkyl moiety” means a non-aromatic, monocyclic, bicyclic or tricyclic moiety comprising 3 to 12 ring atoms, wherein each cycle comprises independently of one another 1, 2, 3, 4 or more heteroatoms independently of one another selected from the group consisting of nitrogen, oxygen and sulfur, whereas sulfur may be oxidized (S( ⁇ O) or (S( ⁇ O) 2 ), whereas the remaining ring atoms are carbon atoms, and whereas bicyclic or tricyclic systems may share common heteroatom(s).
- Examples of preferred saturated 3-12-membered heterocycloalkyl moieties according to the invention include but are not limited to aziridin, azetidine, pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, triazolidine, tetrazolidine, oxiran, oxetane, tetrahydrofurane, tetrahydropyrane, thiirane, thietane, tetra-hydrothiophene, diazepane, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine, morpholine, thiomorpholine.
- Examples of preferred unsaturated 3-12-membered heterocycloalkyl moiety moieties according to the invention include but are not limited to oxazoline, pyrazoline, imidazoline, isoxazoline, thiazoline, isothiazoline, and dihydropyran.
- the 3-12-membered heterocycloalkyl moiety which is bonded to the compound according to the invention, in its periphery may optionally be condensed with a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; and/or with a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; and/or with a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted.
- the ring atoms of the condensed moieties are not included in the 3 to 12 ring atoms of the 3-12-membered heterocycloalkyl moieties.
- 3-12-membered heterocycloalkyl moieties condensed with 3-12-membered cycloalkyl moieties include but are not limited to octahydro-1H-indol, decahydroquinoline, decahydroisoquinoline, octahydro-2H-benzo[b][1,4]oxazin, and decahydro-quinoxalin, which in each case are connected through the 3-12-membered heterocycloalkyl moiety.
- An examples of a 3-12-membered heterocycloalkyl moiety condensed with a 6-14-membered aryl moiety includes but is not limited to 1,2,3,4-tetrahydroquinoline, which is connected through the 3-12-membered heterocycloalkyl moiety.
- An example of a 3-12-membered heterocycloalkyl moiety condensed with a 5-14-membered heteroaryl moieties includes but is not limited to 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, which is connected through the 3-12-membered heterocycloalkyl moiety.
- the 3-12-membered heterocycloalkyl moiety may optionally be connected through —C 1 -C 6 -alkylene-, i.e. the 3-12-membered heterocycloalkyl moiety may not be directly bound to the compound according to general formula (I) but may be connected thereto through a —C 1 -C 6 -alkylene- linker.
- Said linker may be connected to a carbon ring atom or to a hetero ring atom of the 3-12-membered heterocycloalkyl moiety.
- Examples include but are not limited to —CH 2 -oxetane, —CH 2 -pyrrolidine, —CH 2 -piperidine, —CH 2 -morpholine, —CH 2 CH 2 -oxetane, —CH 2 CH 2 -pyrrolidine, —CH 2 CH 2 -piperidine, and —CH 2 CH 2 -morpholine.
- the 3-12-membered heterocycloalkyl moiety can be unsubstituted, mono- or polysubstituted.
- substituted 3-12-membered heterocycloalkyl moieties include but are not limited to 2-carboxamido-N-pyrrolidinyl-, 3,4-dihydroxy-N-pyrrolidinyl, 3-hydroxy-N-pyrimidinyl, 3,4-dihydroxy-N-pyrimidinyl, 3-oxo-N-piperazinyl, -tetrahydro-2H-thiopyranyl dioxide and thiomorpholinyl dioxide.
- 6-14-membered aryl moiety means an aromatic, monocyclic, bicyclic or tricyclic moiety comprising 6 to 14 ring carbon atoms but no heteroatoms in the ring.
- 6-14-membered aryl moieties according to the invention include but are not limited to benzene, naphthalene, anthracen, and phenanthren.
- the 6-14-membered aryl moiety, which is bonded to the compound according to the invention, in its periphery may optionally be condensed with a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; and/or with a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; and/or with a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted.
- the ring atoms of the condensed moieties are not included in the 6 to 14 ring carbon atoms of the 6-14-membered heterocycloalkyl moieties.
- 6-14-membered aryl moieties condensed with 3-12-membered cycloalkyl moieties include but are not limited to 2,3-dihydro-1H-indene and tetraline, which in each case are connected through the 6-14-membered aryl moiety.
- 6-14-membered aryl moiety condensed with a 3-12-membered heterocycloalkyl moiety includes but is not limited to 1,2,3,4-tetrahydroquinoline, which is connected through the 6-14-membered aryl moiety.
- 6-14-membered aryl moieties condensed with 5-14-membered heteroaryl moieties include but are not limited to quinoline, isoquinoline, phenazine and phenoxacine, which in each case are connected through the 6-14-membered aryl moiety.
- the 6-14-membered aryl moiety may optionally be connected through —C 1 -C 6 -alkylene-, i.e. the 6-14-membered aryl moiety may not be directly bound to the compound according to general formula (I) but may be connected thereto through a —C 1 -C 6 -alkylene-linker.
- Said linker may be connected to a carbon ring atom or to a hetero ring atom of the 6-14-membered aryl moiety. Examples include but are not limited to —CH 2 -C 6 H 5 , —CH 2 CH 2 -C 6 H 5 and —CH ⁇ CH—C 6 H 5 .
- the 6-14-membered aryl moiety can be unsubstituted, mono- or polysubstituted.
- substituted 6-14-membered aryl moieties include but are not limited to 2-fluorophenyl, 3-fluorophenyl, 2-methoxyphenyl and 3-methoxyphenyl.
- “5-14-membered heteroaryl moiety” means an aromatic, monocyclic, bicyclic or tricyclic moiety comprising 6 to 14 ring atoms, wherein each cycle comprises independently of one another 1, 2, 3, 4 or more heteroatoms independently of one another selected from the group consisting of nitrogen, oxygen and sulfur, whereas the remaining ring atoms are carbon atoms, and whereas bicyclic or tricyclic systems may share common heteroatom(s).
- Examples of preferred 5-14-membered heteroaryl moieties according to the invention include but are not limited to pyrrole, pyrazole, imidazole, triazole, tetrazole, furane, thiophene, oxazole, isoxazole, thiazole, isothiazole, pyridine, pyridazine, pyrimidine, pyrazine, indolicine, 9H-chinolicine, 1,8-naphthyridine, purine, imidazo[1,2-a]pyrazine, and pteridine.
- the 5-14-membered heteroaryl moiety which is bonded to the compound according to the invention, in its periphery may optionally be condensed with a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; and/or with a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; and/or with a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted.
- the ring atoms of the condensed moieties are not included in the 6 to 14 ring carbon atoms of the 6-14-membered heterocycloalkyl moieties.
- 5-14-membered heteroaryl moieties condensed with 3-12-membered cycloalkyl moieties include but are not limited to 5,6,7,8-tetrahydroquinoline and 5,6,7,8-tetrahydroquinazoline, which in each case are connected through the 5-14-membered heteroaryl moiety.
- 5-14-membered heteroaryl moiety condensed with a 3-12-membered heterocycloalkyl moiety includes but is not limited to 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, which is connected through the 5-14-membered heteroaryl moiety.
- 5-14-membered heteroaryl moieties condensed with 6-14-membered aryl moieties include but are not limited to quinoline, isoquinoline, phenazine and phenoxacine, which in each case are connected through the 5-14-membered heteroaryl moiety.
- the 5-14-membered heteroaryl moiety may optionally be connected through —C 1 -C 6 -alkylene-, i.e. the 5-14-membered heteroaryl moiety may not be directly bound to the compound according to general formula (I) but may be connected thereto through a —C 1 -C 6 -alkylene- linker.
- Said linker may be connected to a carbon ring atom or to a hetero ring atom of the 5-14-membered heteroaryl moiety.
- Examples include but are not limited to —CH 2 -oxazole, —CH 2 -isoxazole, —CH 2 -imidazole, —CH 2 -pyridine, —CH 2 -pyrimidine, —CH 2 -pyridazine, —CH 2 CH 2 -oxazole, —CH 2 CH 2 -isoxazole, —CH 2 CH 2 -imidazole, —CH 2 CH 2 -pyridine, —CH 2 CH 2 -pyrimidine, and —CH 2 CH 2 -pyridazine.
- the 5-14-membered heteroaryl moiety can be unsubstituted, mono- or polysubstituted.
- 5-14-membered heteroaryl moieties include but are not limited to 2-methoxy-4-pyridinyl, 2-methoxy-5-pyridinyl, 3-methoxy-4-pyridinyl, 3-methoxy-6-pyridinyl, 4-methoxy-2-pyridinyl, 2-methylsulfonyl-5-pyridinyl, 3-methylsulfonyl-6-pyridinyl, 3-methoxy-6-pyridazinyl, 2-nitrilo-5-pyrimidinyl, 4-hydroxy-2-pyrimidinyl, 4-methoxy-pyrimidinyl, and 2-methoxy-6-pyrazinyl.
- the compounds according to the invention have a structure according to general formula (I′)
- R 1 to R 5 , R 7 , R 8 , R 10 to R 20 and n are defined as above, or a physiologically acceptable salt thereof.
- the excess of the cis-isomer so designated is at least 50% de, more preferably at least 75% de, yet more preferably at least 90% de, most preferably at least 95% de and in particular at least 99% de.
- the compound according to the invention has a structure according to general formula (IX)
- R 5 is selected from -phenyl, -pyridyl, pyrimidinyl, or -triazolyl, in each case unsubstituted, mono- or polysubstituted.
- the compounds according to the invention are in the form of the free bases.
- the compounds according to the invention are in the form of the physiologically acceptable salts.
- salt is to be understood as being any form of the compound in which it assumes an ionic form or is charged and is coupled with a counter-ion (a cation or anion) or is in solution.
- the term is also to be understood as meaning complexes of the compound with other molecules and ions, in particular complexes which are associated via ionic interactions.
- Preferred salts are physiologically acceptable, in particular physiologically acceptable salts with anions or acids or also a salt formed with a physiologically acceptable acid.
- Physiologically acceptable salts with anions or acids are salts of the particular compound in question with inorganic or organic acids which are physiologically acceptable, in particular when used in humans and/or mammals.
- physiologically acceptable salts of particular acids include but are not limited to salts of hydrochloric acid, sulfuric acid, and acetic acid.
- the invention also includes isotopic isomers of a compound according to the invention, wherein at least one atom of the compound is replaced by an isotope of the respective atom which is different from the naturally predominantly occurring isotope, as well as any mixtures of isotopic isomers of such a compound.
- Preferred isotopes are 2 H (deuterium), 3 H (tritium), 13 C and 14 C.
- Certain compounds according to the invention are useful for modulating a pharmacodynamic response from one or more opioid receptors (mu, delta, kappa, NOP/ORL-1) either centrally or peripherally, or both.
- the pharmacodynamic response may be attributed to the compound either stimulating (agonizing) or inhibiting (antagonizing) the one or more receptors.
- Certain compounds according to the invention may antagonize one opioid receptor, while also agonizing one or more other receptors.
- Compounds according to the invention having agonist activity may be either full agonists or partial agonists.
- agonists compounds that bind to receptors and mimic the regulatory effects of endogenous ligands are defined as “agonists”.
- antagonists Compounds that bind to a receptor but produce no regulatory effect, but rather block the binding of ligands to the receptor, are defined as “antagonists”.
- the compounds according to the invention are agonists at the mu opioid (MOP) and/or kappa opioid (KOP) and/or delta opioid (DOP) and/or nociceptin opioid (NOP/ORL-1) receptors.
- MOP mu opioid
- KOP kappa opioid
- DOP delta opioid
- NOP/ORL-1 nociceptin opioid
- the compounds according to the invention potently bind to the MOP and/or KOP and/or DOP and/or NOP receptors.
- the compounds according to the invention can be modulators at the MOP and/or KOP and/or DOP and/or NOP receptors, and therefore the compounds according to the invention can be used/administered to treat, ameliorate, or prevent pain.
- the compounds according to the invention are agonists of one or more opioid receptors. In some embodiments, the compounds according to the invention are agonists of the MOP and/or KOP and/or DOP and/or NOP receptors.
- the compounds according to the invention are antagonists of one or more opioid receptors. In some embodiments, the compounds according to the invention are antagonists of the MOP and/or KOP and/or DOP and/or NOP receptors.
- the compounds according to the invention have both, (i) agonist activity at the NOP receptor; and (ii) agonist activity at one or more of the MOP, KOP, and DOP receptors.
- the compounds according to the invention have both, (i) agonist activity at the NOP receptor; and (ii) antagonist activity at one or more of the MOP, KOP, and DOP receptors.
- the compounds according to the invention have both, (i) antagonist activity at the NOP receptor; and (ii) agonist activity at one or more of the MOP, KOP, and DOP receptors.
- the compounds according to the invention have both, (i) antagonist activity at the NOP receptor; and (ii) antagonist activity at one or more of the MOP, KOP, and DOP receptors.
- the compounds according to the invention have selective agonist activity at the NOP receptor. In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention
- the compounds according to the invention have balanced agonist activity at the NOP receptor as well as at the MOP receptor. In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention
- the compounds according to the invention have balanced agonist activity at the NOP receptor as well as at the KOP receptor. In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention
- the compounds according to the invention have balanced agonist activity at the NOP receptor as well as at the DOP receptor. In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention
- the compounds according to the invention have selective agonist activity at the KOP receptor. In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention
- the compounds according to the invention have agonist activity at the MOP receptor, agonist activity at the KOP receptor, and antagonist activity at the DOP receptor. In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention
- the compounds according to the invention have selective agonist activity at the NOP receptor. In some embodiments, preferably with respect to receptors of the central nervous system, the compounds according to the invention
- the compounds according to the invention have selective antagonist activity at the NOP receptor. In some embodiments, preferably with respect to receptors of the central nervous system, the compounds according to the invention
- the compounds according to the invention have antagonist activity at the NOP receptor as well as agonist activity at the DOP receptor. In some embodiments, preferably with respect to receptors of the central nervous system, the compounds according to the invention
- no significant activity means that the activity (agonist/antagonist) of the given compound at this receptor is lower by a factor of 1000 or more compared to its activity (agonist/antagonist) at one or more of the other opioid receptors.
- a further aspect of the invention relates to the compounds according to the invention as medicaments.
- a further aspect of the invention relates to the compounds according to the invention for use in the treatment of pain.
- a further aspect of the invention relates to a method of treating pain comprising the administration of a pain alleviating amount of a compound according to the invention to a subject in need thereof, preferably to a human.
- the pain is preferably acute or chronic.
- the pain is preferably nociceptive or neuropathic.
- a further aspect of the invention relates to the compounds according to the invention for use in the treatment of neurodegenerative disorders, neuroinflammatory disorders, neuropsychiatric disorders, and substance abuse/dependence.
- a further aspect of the invention relates to a method of treating any one of the aforementioned disorders, diseases or conditions comprising the administration of a therapeutically effective amount of a compound according to the invention to a subject in need thereof, preferably to a human.
- Another aspect of the invention relates to a pharmaceutical composition which contains a physiologically acceptable carrier and at least one compound according to the invention.
- the composition according to the invention is solid, liquid or pasty; and/or contains the compound according to the invention in an amount of from 0.001 to 99 wt. %, preferably from 1.0 to 70 wt. %, based on the total weight of the composition.
- composition according to the invention can optionally contain suitable additives and/or auxiliary substances and/or optionally further active ingredients.
- physiologically acceptable carriers examples include fillers, solvents, diluents, colorings and/or binders. These substances are known to the person skilled in the art (see H. P. Fiedler, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik and angrenzende füre, Editio Cantor Aulendoff).
- the pharmaceutical composition according to the invention contains the compound according to the invention in an amount of preferably from 0.001 to 99 wt. %, more preferably from 0.1 to 90 wt. %, yet more preferably from 0.5 to 80 wt. %, most preferably from 1.0 to 70 wt. % and in particular from 2.5 to 60 wt. %, based on the total weight of the pharmaceutical composition.
- the pharmaceutical composition according to the invention is preferably for systemic, topical or local administration, preferably for oral administration.
- Another aspect of the invention relates to a pharmaceutical dosage form which contains the pharmaceutical composition according to the invention.
- the pharmaceutical dosage form according to the invention is produced for administration twice daily, for administration once daily or for administration less frequently than once daily.
- Administration is preferably systemic, in particular oral.
- the pharmaceutical dosage form according to the invention can be administered, for example, as a liquid dosage form in the form of injection solutions, drops or juices, or as a semi-solid dosage form in the form of granules, tablets, pellets, patches, capsules, plasters/spray-on plasters or aerosols.
- auxiliary substances etc. and the amounts thereof to be used depend on whether the form of administration is to be administered orally, perorally, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or locally, for example to the skin, the mucosa or into the eyes.
- compositions in the form of tablets, dragees, capsules, granules, drops, juices and syrups are suitable for oral administration, and solutions, suspensions, readily reconstitutable dry preparations and also sprays are suitable for parenteral, topical and inhalatory administration.
- the amount of the compounds according to the invention to be administered to the patient varies in dependence on the weight of the patient, on the type of administration, on the indication and on the severity of the disease. Usually, from 0.00005 mg/kg to 50 mg/kg, preferably from 0.001 mg/kg to 10 mg/kg, of at least one compound according to the invention is administered.
- Another aspect of the invention relates to a process for the preparation of the compounds according to the invention. Suitable processes for the synthesis of the compounds according to the invention are known in principle to the person skilled in the art.
- the compounds according to the invention can be obtained via different synthesis routes. Depending on the synthesis route, different intermediates are prepared and subsequently further reacted.
- the synthesis of the compounds according to the invention proceeds via a synthesis route which comprises the preparation of an intermediate according to general formula (IIIa):
- R 1 , R 2 and R 3 are defined as above.
- the synthesis of the compounds according to the invention proceeds via a synthesis route which comprises the preparation of an intermediate according to general formula (IIIb):
- R 1 , R 2 and R 3 are defined as above and PG is a protecting group.
- the protecting group is -p-methoxybenzyl. Therefore, in another preferred embodiment, the synthesis of the compounds according to the invention proceeds via a synthesis route which comprises the preparation of an intermediate according to general formula (IIIc):
- R 1 , R 2 and R 3 are defined as above.
- the -p-methoxybenzyl moiety represents a protecting group which can be cleaved in the course of the synthesis route.
- the synthesis of the compounds according to the invention proceeds via a synthesis route which comprises the preparation of
- RT room temperature (23 7° C.)
- M are indications of concentration in mol/l
- aq.” means aqueous
- sat.” means saturated
- sol.” means solution
- conc.” means concentrated.
- the mixing ratios of solvents or eluents for chromatography are specified in v/v.
- CIS refers to the relative configuration of compounds described herein, in which both nitrogen atoms are drawn on the same face of the cyclohexane ring as described in the following exemplary structure. Two depictions are possible:
- TRANS refers to compounds, in which both nitrogen atoms are on opposite faces of the cyclohexane ring as described in the following exemplary structure. Two depictions are possible:
- Step 1 CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decane-2,4-dione
- Step 2 CIS-8-Dimethylamino-8-phenyl-3-(2-phenyl-ethyl)-1,3-diazaspiro[4.5]decane-2,4-dione
- Step 3 CIS-8-Dimethylamino-8-phenyl-3-(2-phenyl-ethyl)-1,3-diazaspiro[4.5]decan-2-one
- Step 1 CIS-1-((1-(benzyloxy)cyclobutyl)methyl)-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
- Step 2 CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
- Step 1 1-((CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarbonitrile
- Step 2 1-((CIS-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarboxamide
- Step 3 1-((cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutane carbonitrile
- Step 1 1-Cyclobutylmethyl-3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.4.2]tetradecan-2-one
- Step 2 1-Cyclobutylmethyl-3-(4-methoxy-benzyl)-1,3-diaza-spiro[4.5]decane-2,8-dione
- Step 3 1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-meth oxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile
- Step 4 CIS-1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
- Step 5 CIS-1-(cyclobutyl-methyl)-8-(methyl-(2-methyl-propyl)-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
- Step 1 Ethyl 5-cyano-2-oxo-5-(pyridin-2-yl)cyclohexanecarboxylate
- KOtBu (57.0 g, 508.4 mmol) was added to the solution of 2-(pyridin-2-yl)acetonitrile (50.0 g, 423.7 mmol) and ethyl acrylate (89.0 g, 889.8 mmol) in THF (500 mL) at 0° C. and stirred for 16 h at RT. The reaction mixture was quenched with sat. aq. NH 4 Cl and extracted with EtOAc (2 ⁇ 500 mL).
- Step 2 4-Oxo-1-pyridin-2-yl-cyclohexane-1-carbonitrile
- Step 1 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile
- Step 2 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carboxamide
- Step 3 methyl 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ylcarbamate
- Step 4 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-amine
- Step 5 4-Dimethylamino-4-pyridin-2-yl-cyclohexan-1-one
- Step 1 8-(Dimethylamino)-1,4-dioxaspiro[4.5]decane-8-carbonitrile
- Dimethylamine hydrochloride 52 g, 0.645 mol was added to the solution of 1,4-dioxaspiro-[4.5]-decan-8-one (35g, 0.224 mmol) in MeOH (35 mL) at RT under argon atmosphere. The solution was stirred for 10 min and 40wt % aq. dimethylamine (280 mL, 2.5 mol) and KCN (32 g, 0.492 mol) were sequentially added. The reaction mixture was stirred for 48 h at RT, then diluted with water (100mL) and extracted with EtOAc (2 ⁇ 200 mL).
- Step 2 N,N-dimethyl-8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine
- Step 3 4-(dimethylamino)-4-phenylcyclohexanone
- Step 1 9,12-Dioxa-2,4-diazadispiro[4.2.4 ⁇ circumflex over ( ) ⁇ 8 ⁇ .2 ⁇ circumflex over ( ) ⁇ 5 ⁇ ]tetradecane-1,3-dione
- Step 2 2-[(4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4 ⁇ circumflex over ( ) ⁇ 8 ⁇ .2 ⁇ circumflex over ( ) ⁇ 5 ⁇ ]tetradecane-1,3-dione
- Step 3 2-[(4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4 ⁇ circumflex over ( ) ⁇ 8 ⁇ .2 ⁇ circumflex over ( ) ⁇ 5 ⁇ ]tetradecan-3-one
- Step 4 3-[(4-Methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decane-2,8-dione
- Step 1 8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decane-2,4-dione
- Step 2 8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decan-2-one
- Step 3 CIS-8-Dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
- Step 1 CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetic acid tert-butyl ester
- Step 2 cis-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-acetic acid trifluoroacetic acid salt
- CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetic acid tert-butyl ester 200 mg, 0.4 mmol was dissolved in TFA (5 mL) and heated to reflux overnight. After cooling to RT all volatiles are removed in vacuo. The residue was taken up in THF (1 mL) and added dropwise to diethyl ether (20 mL).
- CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-acetic acid (INT-977) trifluoroacetic acid salt (119 mg, 0.35 mmol) was dissolved in DCM (5 mL). Triethylamine (0.21 mL, 1.6 mmol), dimethylamine (0.54 mL, 1.1 mmol) and T3P (0.63 mL, 1.1 mmol) were sequentially added. The reaction mixture was stirred at RT overnight, then diluted with 1 M aq. Na 2 CO 3 (5 mL).
- Step 1 CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-1-((1-methylcyclobutyl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
- Step 2 CIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
- Step 1 CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
- CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-975) was converted into CIS -8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one.
- Step 2 CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
- step 2 CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one was converted into CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-984).
- Step 1 CIS-3-benzyl-1-(cyclobutylmethyl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
- N-Iodosuccinimide (3.11 g, 13.92 mmol) was added to the solution of CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[phenyl-methyl]-1,3-diazaspiro[4.5]decan-2-one (INT-950) (4 g, 9.28 mmol) in a mixture of acetonitrile and THF (1:1 v/v, 80 mL) and the resulting mixture was stirred at RT for 16 h. The reaction mixture was basified with 2N aq. NaOH to pH-10 and the organic product was extracted with DCM (3 ⁇ 10 mL).
- Step 2 CIS-3-benzyl-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
- Step 3 CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-986)
- step 2 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one (INT-952) was converted into CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-987).
- Step 1 CIS-8-(dimethylamino)-1-[2-(1-methoxycyclobutyl)ethyl]-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
- Step 2 CIS-8-(dimethylamino)-1-(2-(1-methoxycyclobutyl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-988)
- Step 1 and step 2 ethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-amine hydrochloride (INT-1004)
- Step 3 4-ethylamino-4-phenyl-cyclohexanone (INT-1005)
- Step 4 cis and trans mixture of 8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (INT-1006 and INT-1007)
- Step 5 CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (INT-1006)
- Step 6 CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (INT-1008)
- CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976) (5.0 g, 18.31 mmol, 1.0 eq.) in dry THF (500 ml) was added t-BuOK (3.07 g, 27.46 mmol, 1.5 eq.) and the reaction mixture was stirred at RT for 15 min.
- 3-Bromo-propyne (3.24 g, 13.18 mmol, 1.2 eq., 80% in toluene) was added and stirring was continued at RT for 18 h.
- the reaction mixture was poured into ice-water and extracted with DCM (800 ml).
- CIS-2-(4-((8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)methyl)-1H-1,2,3-triazol-1-yl)acetate (INT-1011) (2.0 g, 4.54 mmol, 1.0 eq.) in DMSO (30 ml) was added NaOH (727 mg, 18.18 mmol, 4.0 eq.) at RT and the reaction mixture was heated to 70° C. for 30 min.
- Step 1 CIS-3-benzyl-8-(dimethylamino)-1-(2-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one.
- Step 2 CIS-8-(dimethylamino)-1-(2-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1021)
- CIS-8-(dimethylamino)-1-(2-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one was reacted with N-iodosuccinimide to be converted into CIS-1-(2-methoxybenzyl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1022).
- Step 1 synthesis of CIS-1-amino-4-(dimethylamino)-4-phenylcyclohexanecarboxylic acid
- Step 2 synthesis of CIS-1-(tert-butoxycarbonylamino)-4-(dimethylamino)-4-phenylcyclohexanecarboxylic acid (INT-1023)
- CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-8-phenyl-1-tosyl-1,3-diazaspiro[4.5]decan-2-one (SC-2147) was treated with TFA to be converted into CIS-8-(dimethylamino)-8-phenyl-1-tosyl-1,3-diazaspiro[4.5]decan-2-one (INT-1028).
- Step 1 2-methyl-N-(1,4-dioxaspiro[4.5]decan-8-ylidene)propane-2-sulfinamide
- Titaniumethoxide (58.45 g, 256.4 mmol) was added to a solution of 1,4-dioxaspiro[4.5]decan-8-one (20 g, 128.20 mmol) and 2-methylpropane-2-sulfinamide (15.51 g, 128.20 mmol) in THF (200 mL) at RT and the reaction mixture was stirred at RT for 18 h. The reaction mixture was cooled to 0° C. and quenched by dropwise addition of sat. aq. NaHCO 3 (500 mL) over a period of 30 min. The organic product was extracted with EtOAc (3 ⁇ 100 mL).
- Step 2 2-methyl-N-(8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)propane-2-sulfinamide
- Phenylmagnesium bromide (1M in THF, 116 mL, 116 mmol) was added dropwise to a solution of 2-methyl-N-(1,4-dioxaspiro[4.5]decan-8-ylidene)prop ane-2-sulfinamide (10 g, 38.61 mmol) in THF (500 mL) at ⁇ 10° C. under argon atmosphere. The reaction mixture was stirred for 2 h at ⁇ 10° C. to 0° C. The reaction completion was monitored by TLC. The reaction mixture was quenched with sat. aq. NH 4 Cl (50 mL) at 0° C. and the organic product was extracted with EtOAc (3 ⁇ 100 mL).
- Step 3 8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine hydrochloride
- Step 4 8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine
- Step 5 N-methyl-8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine)
- Step 6 4-(methyl((tetrahydrofuran-3-yl)methyl)amino)-4-phenylcyclohexanone
- Step 7 8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione
- Step 8 CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione
- Diastereomeric mixture of 8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione (1.0 g) was separated by reverse phase preparative HPLC to afford 400 mg of isomer 1 (CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione) and 60 mg of isomer 2 (TRANS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione) and 300 mg of mixture of both isomers.
- Reverse phase preparative HPLC conditions mobile phase: 10 mM ammonium bicarbonate in H 2 O/acetonitrile, column: X-BRIDGE-C18 (150*30), Sum, gradient (T/B %): 0/35, 8/55, 8.1/98, 10/98, 10.1/35, 13/35, flow rate: 25 ml/min, diluent: mobile phase+THF.
- Step 9 CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1026)
- Step 1 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one
- Step 2 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one
- Step 1 9,12-dioxa-2,4-diazadispiro[4.2.4 ⁇ circumflex over ( ) ⁇ 8 ⁇ .2 ⁇ circumflex over ( ) ⁇ 5 ⁇ ]tetradecan-3-one
- Lithiumaluminiumhydride (2.2 equiv., 292 mmol) was suspended in THF (400 mL) and the suspension was cooled to 0° C.
- 8-(Dimethylamino)-8-(m-tolyl)-1,3-diazaspiro[4.5]decan-2-one (B, 75 mg, 0.261 mmol) (step 1 of INT-965) was added portionwise at 0° C.
- the reaction mixture was stirred 1.5 h at 0° C., then overnight at RT and then 2 h at 40° C.
- the reaction mixture was cooled down to 0° C., quenched carefully with sat. aq.
- Step 2 1,3-diazaspiro[4.5]decane-2,8-dione
- Step 3 8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile (INT-1037)
- Step 1 CIS-1-acetyl-8-(dimethylamino)-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
- Step 2 CIS-1-acetyl-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1064)
- Step 1 TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione
- Step 2 TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1059)
- TRANS-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione was treated with LiAlH 4 to be converted into TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1059). Mass: m/z 274.2 (M+H) + .
- Step 1 CIS-1-acetyl-3-((2-chloropyridin-4-yl)methyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
- CIS-1-acetyl-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1064) (1 g, 3.17 mmol) in DMF (37 mL) was added sodium hydride (60 wt % in mineral oil, 1.25 equiv., 3.96 mmol, 159 mg) portionwise at 0° C.
- the reaction mixture was stirred for 15 min at 0° C. and 2-chloro-4-(chloromethyl)pyridine (1.25 equiv., 3.96 mmol, 0.485 mL) was added.
- Step 2 CIS-3-((2-chloropyridin-4-yl)methyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1065)
- Step 1 1-amino-4-dimethylamino-4-phenyl-cyclohexanecarbonitrile
- Step 2 N-(1-cyano-4-dimethylamino-4-phenyl-cyclohexyl)-2,2,2-tritluoroacetamide
- Step 3 1-aminomethyl-N′,N′-dimethyl-4-phenyl-N-(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine
- Step 4 CIS- and TRANS-8-dimethylamino-8-phenyl-1-(2,2,2-trifluoro-ethyl)-1,3-diaza-spiro[4.5]decan-2-one (INT-1068 and INT-1069)
- HPLC: 98.53%, Column: Xbridge C-18 (100 ⁇ 4.6), 5 ⁇ , Diluent: MeOH, Mobile phase: A) 0.05% TFA in water; B) ACN flow rate: 1 ml/min, R t 5.17 min.
- reaction completion was monitored by TLC.
- the reaction mixture was quenched with sat. aq. NH 4 Cl and the organic product was extracted with EtOAc (2 ⁇ 10mL). The combined organic extracts were dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
- Step 1 8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile
- Dimethylamine hydrochloride (76.36 g, 936.39 mmol) was added to a solution of 3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decane-2,8-dione INT-966 (90 g, 312.13 mmol) in MeOH (180 mL) at RT under argon atmosphere. The solution was stirred for 15 min and 40% aq. dimethylamine (780 mL) and KCN (48.76 g, 749.11 mmol) were sequentially added. The reaction mixture was stirred for 48 h while being monitored by NMR. The reaction mixture was diluted with water (1.0 L) and the organic product was extracted with EtOAc (2 ⁇ 2.0 L).
- Step 2 CIS-8-Dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one
- Step 1 CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
- CIS-8-dimethylamino-8-[3-(methoxymethyloxy)-phenyl]-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one (INT-968) was converted into CIS-1-(cyclobutylmethyl)-8-(dimethylamino)-3-(4-methoxybenzyl)-8-(3-(methoxymethoxy)phenyl)-1,3-diazaspiro[4.5]decan-2-one.
- Step 2 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-hydroxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one
- KOtBu (411 mg, 3.66 mmol) was added to a solution of CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-987) (250 mg, 0.73 mmol) in THF (6 mL) under nitrogen atmosphere and the reaction mixture was stirred at RT for 30 min. After cooling to 0° C. 3-(chloromethyl)pyridine hydrochloride (180 mg, 1.10 mmol) was added and the reaction mixture was stirred at 0° C. for 30 min and then at RT for 3 days.
- N-Iodosuccinimide (437 mg, 1.95 mmol) was added to a suspension of CIS-1-(cyclobutyl-methyl)-8-dimethylamino-3-[(3-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_2002) (600 mg, 1.30 mmol) in a mixture of acetonitrile and THF (1:1 v/v, 20 mL) at RT and the resulting mixture was stirred at RT for 16 h. The reaction mixture was basified with 2N aq. NaOH to pH ⁇ 10 and the organic product was extracted with DCM (3 ⁇ 10 mL).
- the reaction mixture was allowed to stir at RT for 16 h and then diluted with water (15 mL).
- the organic product was extracted with ethyl acetate (3 ⁇ 25mL).
- the combined organic extracts were dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
- the residue was dissolved in THF (8 mL) and cooled to 0° C.
- a 1M TBAF solution in THF (1.8 mL, 1.81 mmol) was added at 0° C.
- the reaction mixture was allowed to stir at RT for 2 h.
- the reaction mixture was diluted with water (10 mL), the organic product was extracted with DCM (3 ⁇ 25mL).
- the combined organic extracts were washed with sat. aq.
- Powdered sodium hydroxide (21 mg, 0.5 mmol) was dissolved in 0.2 mL of dry DMSO. After stirring at RT for 30 min CIS-1-(cyclobutyl-methyl)-8-dimethylamino-3-[(4-hydroxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_2089) (60 mg, 0.13 mmol) was added and the resulting mixture was stirred for another 30 min.
- N-Iodosuccinimide (233 mg, 1.035 mmol) was added to a solution of CIS-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[(4-methoxyphenyl)-methyl]-8-methylamino-8-phenyl-1,3-diazaspiro [4.5]decan-2-one (SC_2026) (320 mg, 0.690 mmol) in a mixture of acetonitrile and THF (1:1 v/v, 30 mL) at 0° C. and the resulting mixture was stirred for 5 h at RT. The reaction mixture was cooled to 0° C.
- N-Iodosuccinimide 233 mg, 1.035 mmol
- the reaction mixture was allowed to warm up to RT and was stirred for further 11 h.
- the reaction mixture was basified with 2N aq. NaOH to pH-10 and the organic product was extracted with ethyl acetate (3 ⁇ 30mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure.
- the reaction mixture was diluted with sat. aq. NaHCO 3 (20 mL) and the organic product was extracted with EtOAc (4 ⁇ 50mL). The combined organic layer was dried over anhydr. Na 2 SO 4 and concentrated in vacuo.
- the crude product was purified by column chromatography (using 230-400 mesh silica gel and 2-5% MeOH in DCM as eluent) to afford 250 mg of product which was further purified by prep.
- CIS-8-dimethylamino-8-phenyl-3-prop-2-ynyl-1,3-diaza-spiro[4.5]decan-2-one (INT-1010) (1.0 g, 3.21 mmol, 1.0 eq.) in dioxane/MeOH (50 ml, 9:1) were added sodium azide (418 mg, 6.42 mmol, 2.0 eq.) and cuprous chloride (32 mg, 0.32 mmol, 0.1 eq.) at RT.
- the reaction mixture was stirred at 80° C. for 18 h, then quenched with water and concentrated under reduced pressure.
- the resulting residue was purified by column chromatography (silica gel neutralized with aq.
- Step 1 Synthesis of tert-butyl CIS-4-(dimethylamino)-4-phenyl-1-(2-phenylpropan-2-ylcarbamoyl)cyclohexylcarbamate
- Step 2 Synthesis of CIS-1-amino-4-(dimethylamino)-4-phenyl-N-(2-phenylpropan-2-yl)cyclohexanecarboxamide hydrochloride
- Step 3 Synthesis of CIS-N,N-dimethyl-1-phenyl-4-((2-phenylpropan-2-ylamino)methyl)cyclohexane-1,4-diamine
- Step 3 Synthesis of CIS-8-(dimethylamino)-8-phenyl-3-(2-phenylpropan-2-yl)-1,3-diazaspiro[4.5]decan-2-one SC_2170
- 1,1′-Carbonyldiimidazole (0.90 g, 5.58 mmol) was added to a solution of CIS-N,N-dimethyl-1-phenyl-4-((2-phenylpropan-2-ylamino)methyl)cyclohexane-1,4-diamine (1.7 g, 4.65 mmol) in DMF (20 mL) at RT. The reaction mixture was stirred at RT for 16 h.
- Step 1 synthesis of CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-8-phenyl-1-tosyl-1,3-diazaspiro[4.5]decan-2-one
- CIS-8-(dimethylamino)-8-phenyl-1-(p-tolylsulfonyl)-1,3-diazaspiro[4.5]decan-2-one (INT-1028) (200 mg, 0.47 mmol, 1 equiv.) was dissolved in DMF (3.6 mL) under argon atmosphere and the solution was cooled down to 0° C.
- Sodium hydride 60 wt % in mineral oil, 2.1 equiv., 0.98 mmol, 39 mg
- 4-(Bromomethyl)pyridine hydrobromide (1.05 equiv., 0.49 mmol, 124 mg) was added at 0° C.
- Step 2 Synthesis of CIS-8-(dimethylamino)-8-phenyl-3-(pyridin-4-ylmethyl)-1,3-diazaspiro[4.5]decan-2-one (SC_2180)
- CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-8-phenyl-1-tosyl-1,3-diazaspiro[4.5]decan-2-one (110 mg, 0.212 mmol, 1 equiv.) was dissolved in THF (2 mL) and MeOH (4.4 mL) under argon atmosphere. Magnesium turnings (103 mg, 4.24 mmol, 20 equiv.) were added and the resulting mixture was stirred at RT for 18 h. The reaction mixture was diluted with DCM (30 mL) and water (10 mL), stirred at RT for 1.5 h, filtered through celite and the solid residue was washed with DCM (3 ⁇ ).
- SC_2159 CIS-2-[4-[[1-(Cyclobutyl- INT-1030 ammonia SC_2145 1HNMR (DMSO-d6, 400 MHz), ⁇ (ppm) 480.1 methyl)-8-dimethylamino-2-oxo- 7.86 (s, 1H), 7.66 (s, 1H), 7.23-7.33 (m, 6H), 8-phenyl-1,3- 5.00 (s, 2H), 4.30 (s, 2H), 3.09(s, 2H), 3.04 (s, diazaspiro[4.5]decan-3-yl]- 2H), 2.61-2.64 (m, 2H), 1.95-2.02 (m, 11H), methyl]-1H-[1,2,3]triazol-1-yl]- 1.69-1.78 (m, 4H), 1.28-1.33 (m, 4H).
- SC_2165 CIS-8-Dimethylamino-3-[2-(1H- SC_2154 step 3 of 1H NMR (CDCl3): ⁇ 7.45 (s, 1H), 7.38-7.34 368.2 imidazol-1-yl)-ethyl]-8-phenyl- INT-795 (m, 2H), 7.31-7.21 (m, 3H), 7.04 (s, 1H), 6.92 1,3-diazaspiro[4.5]decan-2-one (s, 1H), 4.95 (br s, 1H), 4.12-4.09 (t, 2H), 3.45- 3.43 (t, 2H), 2.67 (s, 2H), 2.03-1.96 (s, 8H), 1.84-1.68 (m, 4H),1.38-1.29 (m, 2H).
- SC_2174 CIS-8-Dimethylamino-1-[(1- SC_2170 (1-(tert-butyldi- INT-799 1H NMR (DMSO-d6): ⁇ 7.36-7.14 (m, 10H), 476.3 hydroxy-cyclobutyl)-methyl]-3- methylsilyloxy) (step 1) 5.88 (m, 1H), 3.33 (s, 2H), 3.03 (s, 2H), 2.68- (1-methyl-1-phenyl-ethyl)-8- cyclobutyl)methyl- 2.64 (m, 2H), 2.09-1.95 (m, 10H), 1.89-1.81 phenyl-1,3-diazaspiro[4.5] 4-methyl- (m, 2H), 1.61-1.56 (m, 7H), 1.48-1.28 (m, 5H).
- SC_2176 CIS-3-(1,3-Benzodioxo1-4-yl- INT-976 4-(bromomethyl)- SC_2097 1H NMR (600 MHz, DMSO) ⁇ 7.37-7.27 (m, 408.2 methyl)-8-dimethylamino-8- 1,3-benzodioxole 4H), 7.27-7.20 (m, 1H), 6.88 (s, 1H), 6.83- phenyl-1,3-diazaspiro[4.5] 6.76 (m, 2H), 6.67 (dd, 1H), 5.96 (s, 2H), 4.18 decan-2-one (s, 2H), 2.95 (s, 2H), 2.30-2.26 (m, 2H), 1.93 (s, 6H),1.84-1.63 (m, 4H), 1.33 (t, 2H).
- SC_2177 CIS-8-Dimethylamino-1-[(1- SC_2171 (1-(tert-butyldi- INT-799 1H NMR (DMSO-d6): ⁇ 7.34-7.17 (m, 8H), 474.2 hydroxy-cyclobutyl)-methyl]-8- methylsilyloxy) (step 1) 7.15-7.13 (m, 2H), 5.89 (s, 1H), 3.29 (s, 2H), phenyl-3-(1-phenyl-cyclopropyl)- cyclobutyl)methyl- 3.09 (s, 2H), 2.64-2.61 (m, 2H), 2.08-2.03 (m, 1,3-diazaspiro[4.5]decan-2-one 4-methylbenzene- 4H), 1.96 (s, 6H), 1.91-1.84 (m, 2H), 1.64-1.61 sulfonate (m, 1H), 1.42-1.29 (m, 5H), 1.29-1.26 (m,
- SC_2184 CIS-8-Dimethylamino-8-phenyl- INT-1065 piperidine SC_2183 1H NMR (600 MHz, CDCl3) ⁇ 8.09 (d, 1H), 448.3 3-[(2-piperidin-1-yl-pyridin-4- 7.38 (dd, 2H), 7.30 (d, 3H), 6.48 (s, 1H), 6.42 yl)-methyl]-1,3- (dd, 1H), 5.47 (s, 1H), 4.23 (s, 2H), 3.54-3.46 diazaspiro[4.5]decan-2-one (m, 4H), 2.96 (s, 2H), 2.20-2.15 (m, 4H) 2.07 (s, 6H), 1.92-1.84 (m, 2H), 1.66-1.60 (m, 6H), 1.47-1.39 (m, 2H).
- hMOP human mu-opioid receptor
- hKOP human kappa-opioid receptor
- hDOP human delta-opioid receptor
- hNOP human nociceptin/orphanin FQ peptide receptor
- the hMOP receptor binding assay was performed as homogeneous SPA-assay (scintillation proximity assay) using the assay buffer 50 mM TRIS-HCl (pH 7.4) supplemented with 0.052 mg/ml bovine serum albumin (Sigma-Aldrich Co.. St. Louis. Mo.).
- the final assay volume 250 ⁇ l/well included 1 nM of [N-allyl-2.3- 3 H]naloxone as ligand (PerkinElmer Life Sciences. Inc. Boston. Mass. USA). and either test compound in dilution series or 25 ⁇ M unlabelled naloxone for determination of unspecific binding.
- the test compound was diluted with 25% DMSO in H 2 O to yield a final 0.5% DMSO concentration. which also served as a respective vehicle control.
- the assay was started by adding wheat germ agglutinin coated SPA beads (GE Healthcare UK Ltd.. Buckinghamshire. UK) which had been preloaded with hMOP receptor membranes (PerkinElmer Life Sciences. Inc. Boston. Mass. USA). After incubation for 90 minutes at RT and centrifugation for 20 minutes at 500 rpm the signal rate was measured by means of a 1450 Microbeta Trilux B-counter (PerkinElmer Life Sciences/Wallac. Turku. Finland). Half-maximal inhibitory concentration (IC50) values reflecting 50% displacement of [ 3 H]naloxone-specific receptor binding were calculated by nonlinear regression analysis and Ki values were calculated by using the Cheng-Prusoff equation. (Cheng and Prusoff. 1973).
- the hKOP receptor binding assay is run as homogeneous SPA-assay (scintillation proximity assay) using the assay buffer 50 mM TRIS-HCl (pH 7.4) supplemented with 0.076 mg BSA/ml.
- the final assay volume of 250 ⁇ l per well includes 2 nM of [ 3 H]U69,593 as ligand, and either test compound in dilution series or 100 ⁇ M unlabelled naloxone for determination of unspecific binding.
- the test compound is diluted with 25% DMSO in H 2 O to yield a final 0.5% DMSO concentration which serves as respective vehicle control, as well.
- the assays are started by the addition of wheat germ agglutinin coated SPA beads (1 mg SPA beads/250 ⁇ l final assay volume per well) which has been preloaded for 15 minutes at room temperature with hKOP receptor membranes (14.8 ⁇ g/250 ⁇ l final assay volume per well). After short mixing on a mini-shaker, the microtiter plates are covered with a lid and the assay plates are incubated for 90 minutes at room temperature. After this incubation, the microtiter plates are sealed with a topseal and centrifuged for 20 minutes at 500 rpm.
- the signal rate is measured after a short delay of 5 minutes by means of a 1450 Microbeta Trilux B-counter (PerkinElmer Life Sciences/Wallac, Turku, Finland).
- Half-maximal inhibitory concentration (IC50) values reflecting 50% displacement of [ 3 H]U69.593-specific receptor binding are calculated by nonlinear regression analysis and K values are calculated by using the Cheng-Prusoff equation, (Cheng and Prusoff, 1973).
- the hDOP receptor binding assay is performed as homogeneous SPA-assay using the assay buffer 50 mM TRIS-HCl, 5 mM MgCl 2 (pH 7.4).
- the final assay volume (250 ⁇ l/well) includes 1 nM of [Tyrosyl-3,5- 3 H]2-D-Ala-deltorphin II as ligand, and either test compound in dilution series or 10 ⁇ M unlabelled naloxone for determination of unspecific binding.
- the test compound is diluted with 25% DMSO in H 2 O to yield a final 0.5% DMSO concentration which serves as respective vehicle control, as well.
- the assays are started by the addition of wheat germ agglutinin coated SPA beads (1 mg SPA beads/250 ⁇ l final assay volume per well) which has been preloaded for 15 minutes at room temperature with hDOP receptor membranes (15.2 ⁇ g/250 ⁇ l final assay volume per well). After short mixing on a mini-shaker, the microtiter plates are covered with a lid and the assay plates are incubated for 120 minutes at room temperature and centrifuged for 20 minutes at 500 rpm. The signal rate is measured by means of a 1450 Microbeta Trilux B-counter (PerkinElmer Life Sciences/Wallac, Turku, Finland).
- IC50 Half-maximal inhibitory concentration
- the hNOP receptor binding assay was performed as homogeneous SPA-assay (scintillation proximity assay) using the assay buffer 50 mM TRIS-HCl. 10 mM MgCl 2 . 1 mM EDTA (pH 7.4).
- the final assay volume (250 ⁇ l/well) included 0.5 nM of [leucyl- 3 H]nociceptin as ligand (PerkinElmer Life Sciences. Inc. Boston. Mass. USA). and either test compound in dilution series or 1 ⁇ M unlabelled nociceptin for determination of unspecific binding.
- the test compound was diluted with 25% DMSO in H 2 O to yield a final 0.5% DMSO concentration. which also served as a respective vehicle control.
- the assay was started by adding wheat germ agglutinin coated SPA beads (GE Healthcare UK Ltd.. Buckinghamshire. UK) which had been preloaded with hMOP receptor membranes (PerkinElmer Life Sciences. Inc. Boston. Mass. USA). After incubation for 60 minutes at RT and centrifugation for 20 minutes at 500 rpm the signal rate was measured by means of a 1450 Microbeta Trilux B-counter (PerkinElmer Life Sciences/Wallac. Turku. Finland). Half-maximal inhibitory concentration (IC50) values reflecting 50% displacement of [ 3 H]nociceptin-specific receptor binding were calculated by nonlinear regression analysis and Ki values were calculated by using the Cheng-Prusoff equation. (Cheng and Prusoff. 1973).
- the [ 35 S]GTP ⁇ S assays are carried out essentially as described by Gillen et al (2000). They are run as homogeneous scintillation proximity (SPA) assays in microtiter luminescence plates, where each well contains 1.5 mg of WGA-coated SPA-beads.
- SPA scintillation proximity
- hNOP hMOP
- hDOP hKOP receptor expressing cell membranes from CHO-K1 or HEK293 cells
- 10 or 5 ⁇ g membrane protein per assay are incubated with 0.4 nM [ 35 S]GTP ⁇ S and serial concentrations of receptor-specific agonists in buffer containing 20 mM HEPES pH 7.4, 100 mM NaCl, 10 mM MgCl2, 1 mM EDTA, 1 mM dithiothreitol, 1.28 mM NaN 3 , and 10 ⁇ M GDP for 45 min at room temperature.
- microtiter plates are then centrifuged for 10 min at 830 to sediment the SPA beads.
- the microtiter plates are sealed and the bound radioactivity [cpm] is determined after a delay of 15 min by means of a 1450 Microbeta Trilux (PerkinElmer, Waltham, Mass.).
- the unstimulated basal binding activity (UBS obs [cpm]) is determined from 12 unstimulated incubates and is set as 100% basal binding.
- the arithmetic mean of the observed total [ 35 S]GTP ⁇ S binding (TB obs [cpm]) of all incubates (duplicates) stimulated by the receptor-specific agonists i.e. N/OFQ, SNC80, DAMGO, or U69,593
- TB obs [%] percent total binding relative to the basal binding activity (i.e. 100% binding).
- the potency (EC 50 ) of the respective agonist and its maximal achievable total [ 35 S]GTP ⁇ S binding (TB calc [%]) above its calculated basal binding (UBS calc [%]) are determined from its transformed data (TB obs [%]) by means of nonlinear regression analysis with XLfit for each individual concentration series. Then the difference between the calculated unstimulated [ 35 S]GTP ⁇ S binding (UBS calc [%]) and the maximal achievable total [ 35 S]GTP ⁇ S binding (TB calc [%]) by each tested agonist is determined (i.e. B1 calc [%]).
- the percentage efficacies of test compounds at the hDOP, hMOP, or hKOP receptor are determined versus the calculated maximal enhancement of [ 35 S]GTP ⁇ S binding by the full agonists SNC80 (B1 calc-SNC80 [%]), DAMGO (B1 calc-DAMGO [%]) and U69,593 (B1 calc-U69,593 [%]) which are set as 100% relative efficacy at each receptor, respectively.
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Abstract
The invention relates to 3-((hetero-)aryl)-alkyl-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives, their preparation and their use in medicine, particularly in the treatment of pain.
Description
- This application is a continuation of U.S. Nonprovisional patent application Ser. No. 17/188,743, filed Mar. 1, 2021, which is a continuation of U.S. Non-Provisional patent application Ser. No. 17/007,258, filed Aug. 31, 2020, now abandoned, which is a continuation of U.S. Nonprovisional patent application Ser. No. 16/265,080, filed Feb, 1, 2019, now U.S. Pat. No. 10,829,480, which is a continuation of U.S. Nonprovisional patent application Ser. No. 15/984,919, filed May 21, 2018, abandoned, which is a continuation of U.S. Nonprovisional patent application Ser. No. 15/405,896, filed Jan. 13, 2017, abandoned, which claims foreign priority benefit under 35 U.S.C. § 119 of European Patent Application No. 16 151 013.6, filed Jan. 13, 2016, the disclosures of which are incorporated herein by reference.
- The invention relates to 3-((hetero-)aryl)-alkyl-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives, their preparation and use in medicine, particularly in various neurological disorders, including but not limited to pain, neurodegenerative disorders, neuroinflammatory disorders, neuropsychiatric disorders, substance abuse/dependence.
- Opioid receptors are a group of Gi/o protein-coupled receptors which are widely distributed in the human body. The opioid receptors are currently subdivided into four major classes, i.e. the three classical opioid receptors mu-opioid (MOP) receptor, kappa-opioid (KOP) receptor, and delta-opioid (DOP) receptor as well as the opioid receptor-like (ORL-1) receptor, which was more recently discovered based on its high homology with said classical opioid receptors. After identification of the endogenous ligand of the ORL-1 receptor, known as nociceptin/orphanin FQ, a highly basic 17 amino acid peptide isolated from tissue extracts in 1995, the ORL-1 receptor was renamed “nociceptin opioid peptide receptor” and abbreviated as “NOP-receptor”.
- The classical opioid receptors (MOP, KOP and DOP) as well as the NOP receptor are widely distributed/expressed in the human body, including in the brain, the spinal cord, on peripheral sensory neurons and the intestinal tract, wherein the distribution pattern differs between the different receptor classes.
- Nociceptin acts at the molecular and cellular level in very much the same way as opioids. However, its pharmacological effects sometimes differ from, and even oppose those of opioids. NOP-receptor activation translates into a complex pharmacology of pain modulation, which, depending on route of administration, pain model and species involved, leads to either pronociceptive or antinociceptive activity. Furthermore, the NOP receptor system is upregulated under conditions of chronic pain. Systemic administration of selective NOP receptor agonists was found to exert a potent and efficacious analgesia in non-human primate models of acute and inflammatory pain in the absence of side effects. The activation of NOP receptors has been demonstrated to be devoid of reinforcing effects but to inhibit opioid-mediated reward in rodents and non-human primates (Review: Schroeder et al, Br J Pharmacol 2014; 171 (16): 3777-3800, and references therein).
- Besides the involvement of the NOP receptor in nociception, results from preclinical experiments suggest that NOP receptor agonists might be useful inter alia in the treatment of neuropsychiatric disorders (Witkin et al, Pharmacology & Therapeutics, 141 (2014) 283-299; Jenck et al., Proc. Natl. Acad. Sci. USA 94, 1997, 14854-14858). Remarkably, the DOP receptor is also implicated to modulate not only pain but also neuropsychiatric disorders (Mabrouk et al, 2014; Pradhan et al., 2011).
- Strong opioids acting at the MOP receptor site are widely used to treat moderate to severe acute and chronic pain. However, the therapeutic window of strong opioids is limited by severe side effects such as nausea and vomiting, constipation, dizziness, somnolence, respiratory depression, physical dependence and abuse. Furthermore, it is known that MOP receptor agonists show only reduced effectiveness under conditions of chronic and neuropathic pain.
- It is known that some of the above mentioned side-effects of strong opioids are mediated by activation of classic opioid-receptors within the central nervous system. Furthermore, peripheral opioid receptors, when activated, can inhibit transmission of nociceptive signals shown in both, clinical and animal studies (Gupta et al., 2001; Kalso et al., 2002; Stein et al., 2003;Zollner et al., 2008).
- Thus, to avoid CNS-mediated adverse effects after systemic administration, one approach has been to provide peripherally restricted opioid receptor ligands that do not easily cross the blood-brain barrier and therefore distribute poorly to the central nervous system (see for instance WO 2015/192039). Such peripherally acting compounds might combine effective analgesia with limited side-effects.
- Another approach has been to provide compounds which interact with both the NOP receptor and the MOP receptor. Such compounds have for instance been described in WO 2004/043967, WO 2012/013343 and WO 2009/118168.
- A further approach has been to provide multi-opioid receptor analgesics that modulate more than one of the opioid receptor subtypes to provide additive or synergistic analgesia and/or reduced side effects like abuse liability or tolerance.
- On the one hand, it would be desirable to provide analgesics that selectively act on the NOP receptor system but less pronounced on the classic opioid receptor system, especially MOP receptor system, whereas it would be desirable to distinguish between central nervous activity and peripheral nervous activity. On the other hand, it would be desirable to provide analgesics that act on the NOP receptor system and also to a balanced degree on the MOP receptor system, whereas it would be desirable to distinguish between central nervous activity and peripheral nervous activity.
- There is a need for medicaments which are effective in the treatment of pain and which have advantages compared to the compounds of the prior art. Where possible, such medicaments should contain such a small dose of active ingredient that satisfactory pain therapy can be ensured without the occurrence of intolerable treatment-emergent adverse events.
- It is an object of the invention to provide pharmacologically active compounds, preferably analgesics that have advantages compared to the prior art.
- This object has been achieved by the subject-matter of the patent claims.
- A first aspect of the invention relates to 3-((hetero-)aryl)-alkyl-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives according to general formula (I)
-
- wherein
- n means 1, 2 or 3;
- R1 and R2 independently of one another mean
- —H;
- —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —OH, —OCH3, —CN and —CO2CH3;
- a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —OH, —OCH3, —CN and —CO2CH3; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted; or
- a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —OH, —OCH3, —CN and —CO2CH3; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted; or
- R1 and R2 together with the nitrogen atom to which they are attached form a ring and mean —(CH2)3-6—; —(CH2)2—O—(CH2)2—; or —(CH2)2—NRA—(CH2)2—, wherein RA means —H or —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br and —I;
- preferably with the proviso that R1 and R2 do not simultaneously mean —H;
- R3 means
- —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted;
- a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted;
- a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted;
- a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6 membered aryl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or
- a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5 membered heteroaryl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted;
- R4 means
- —H;
- —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said —C1-C6-alkyl is optionally connected through —C(═O)—, —C(═O)O—, or —S(═O)2—;
- a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH2—, or —S(═O)2—;
- a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH2—, or —S(═O)2—;
- a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or wherein said 6-14-membered aryl moiety is optionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH2—, or —S(═O)2—; or
- a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or wherein said 5-14-membered heteroaryl moiety is optionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH2—, or —S(═O)2—;
- R5 means
- a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; or
- a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted;
- R7, R8, R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20 independently of one another mean —H, —F, —Cl, —Br, —I, —OH, or —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted;
- or wherein R7 and R8 together with the carbon atom to which they are attached form a ring and mean —(CH2)2— or —(CH2)3—;
- wherein “mono- or polysubstituted” means that one or more hydrogen atoms are replaced by a substituent independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —R21, —C(═O)R21, —C(═O)OR21, —C(═O)NR21R22, —O—(CH2CH2—O)1-30—H, —O—(CH2CH2—O)1-30—CH3, ═O, —OR21, —OC(═O)R21, —OC(═O)OR21, —OC(═O)NR21R22, —NO2, —NR21—(CH2)1-6—C(═O)R22, —NR21—(CH2)1-6—C(═O)OR22, —NR23—(CH2)1-6—C(═O)NR21R22, —NR21C(═O)R22, —NR21C(═O)—OR22, —NR23C(═O)NR21R22, —NR21S(═O)2R22, —SR21, —S(═O)R21, —S(═O)2R21, —S(═O)2OR21, and —S(═O)2NR21R22;
- wherein
- R21, R22 and R23 independently of one another mean
- —H;
- —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH2, and —O—C1-C6-alkyl;
-
- a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH2, —C1-C6-alkyl and —O—C1-C6-alkyl;
- a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH2, —C1-C6-alkyl and —O—C1-C6-alkyl;
- a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6 membered aryl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH2, —C1-C6-alkyl and —O—C1-C6-alkyl;
- a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5 membered heteroaryl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH2, —C1-C6-alkyl and —O—C -C6-alkyl;
- or R21 and R22 within —C(═O)NR21R22, —OC(═O)NR21R22, —NR21R22, —NR23—(CH2)1-6—C(═O)NR21R22, —NR23C(═O)NR21R22, or —S(═O)2NR21R22 together with the nitrogen atom to which they are attached form a ring and mean —(CH2)3-6—; —(CH2)2—O—(CH2)2—; or —(CH2)2—NRB—(CH2)2—, wherein RB means —H or —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br and —I;
- or a physiologically acceptable salt thereof.
- Preferably, aryl includes but is not limited to phenyl and naphthyl. Preferably, heteroaryl includes but is not limited to -1,2-benzodioxole, -pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl, -thienyl, -imidazolyl, -benzimidazolyl, -thiazolyl, -1,3,4-thiadiazolyl, -benzothiazolyl, -oxazolyl, -benzoxazolyl, -pyrazolyl, -quinolinyl, -isoquinolinyl, -quinazolinyl, -indolyl, -indolinyl, -benzo [c][ 1,2,5]oxadiazolyl, -imidazo[1 ,2-a]pyrazinyl, or -1H-pyrrolo[2,3-b]pyridinyl. Preferably, cycloalkyl includes but is not limited to -cyclopropyl, -cyclobutyl, -cyclopentyl and -cyclohexyl. Preferably, heterocycloalkyl includes but is not limited to -aziridinyl, -azetidinyl, -pyrrolidinyl, -piperidinyl, -piperazinyl, -morpholinyl, -sulfamorpholinyl, -oxiridinyl, -oxetanyl, -tetrahydropyranyl, and -pyranyl.
- When a moiety is connected through an asymmetric group such as —C(═O)O— or —C(═O)O—CH2—, said asymmetric group may be arranged in either direction. For example, when R4 is connected to the core structure through —C(═O)O—, the arrangement may be either R4—C(═O)O— core or core —C(═O)O—R4.
- In preferred embodiments of the compound according to the invention, R7, R8, R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20 independently of one another mean —H, —F, —OH, or —C1-C6-alkyl; preferably —H.
- In preferred embodiments of the compound according to the invention, R7 and R8 together with the carbon atom to which they are attached form a ring and mean —(CH2)2— (i.e. form a cyclopropyl ring) or —(CH2)3— (i.e. form a cyclobutyl ring).
- In a preferred embodiment of the compound according to the invention, R1 means —H; and R2 means —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R1 means —H and R2 means —CH3.
- In another preferred embodiment of the compound according to the invention, R1 means —CH3; and R2 means —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R1 means —CH3 and R2 means —CH3.
- In still another preferred embodiment of the compound according to the invention, R1 and R2 together with the nitrogen atom to which they are attached form a ring and mean —(CH2)3-6—. Preferably, R1 and R2 together with the nitrogen atom to which they are attached form a ring and mean —(CH2)3—.
- In yet another preferred embodiment,
-
- R1 means —H or —CH3; and
- R2 means a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted; wherein said 3-12-membered cycloalkyl moiety is connected through —CH2—, unsubstituted; preferably —CH2-cycloalkyl, —CH2-cyclobutyl or —CH2-cyclopentyl; or R2 means a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted; wherein said 3-12-membered heterocycloalkyl moiety is connected through —CH2—, unsubstituted; preferably —CH2-oxetanyl or —CH2-tetrahydrofuranyl.
- In a preferred embodiment of the compound according to the invention, R3 means —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R3 means —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted or monosubstituted with —OCH3.
- In another preferred embodiment of the compound according to the invention, R3 means a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted, optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted. In a preferred embodiment, R3 means -phenyl unsubstituted, mono- or polysubstituted. More preferably, R3 means -phenyl unsubstituted, mono- or disubstituted with —F, —CH3, —CF3, —OH, —OCH3, —OCF3 or —OCH2OCH3, preferably —F. In another preferred embodiment, R3 means -benzyl unsubstituted, mono- or polysubstituted. More preferably, R3 means -benzyl unsubstituted, mono- or disubstituted with —F, —Cl, —CH3, —CF3, —OH, —OCH3, —OCF3 or —OCH2OCH3, preferably —F.
- In still another preferred embodiment of the compound according to the invention, R3 means a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted. Preferably, R3 means -thienyl or -pyridinyl, in each case unsubstituted, mono- or polysubstituted. More preferably, R3 means -thienyl, -pyridinyl, -imidazolyl or benzimidazolyl, in each case unsubstituted or monosubstituted with —F, —Cl or —CH3.
- In a preferred embodiment of the compound according to the invention, R4 means —H.
- In another preferred embodiment of the compound according to the invention, R4 means —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R4 means —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted or monosubstituted with a substituent selected from the group consisting of —F, —Cl, —Br, —I, —CN, —CF3, —OH, —OCF3, —O—(CH2CH2—O)1-30—H, —O—(CH2CH2—O)1-30—CH3, —C(═O)C1-C4-alkyl, —C(═O)OH, —C(═O)O—C(═O)NH2, —C(═O)NHC1-C4-alkyl, —C(═O)NHC1-C4-alkylene—CN, —C(═O)NHC1-C4-alkylene-O—C1-C4-alkyl, —C(═O)N(C1-C4-alkyl)2; —S(═O)C1-C4-alkyl, and —S(═O)2C1-C4-alkyl; or with —C(═O)NR21R22 wherein R21 and R22 together with the nitrogen atom to which they are attached form a ring and mean —(CH2)3-6—, —(CH2)2—O—(CH2)2—, or —(CH2)2—NRB—(CH2)2—, wherein RB means —H or —C1-C6-alkyl; or with —C(═O)NH-3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted or monosubstituted with —F, —Cl, —Br, —I, —CN, or —OH; or with —C(═O)NH-3-12-membered heterocycloalkyl, saturated or unsaturated, unsubstituted or monosubstituted with —F, —Cl, —Br, —I, —CN, or —OH. More preferably, R4 means —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted or monosubstituted with —O—C1-C4-alkyl or —C(═O)N(C1-C4-alkyl)2.
- In still another preferred embodiment of the compound according to the invention, R4 means a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein the 3-12-membered cycloalkyl moiety is connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R4 means a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl moiety is connected through —CH2— or —CH2CH2—. More preferably, R4 means a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —C1-C4-alkyl, —O—C1-C4-alkyl, —C(═O)OH, —C(═O)OC1-C4-alkyl, —C(═O)NH2, —C(═O)NHC1-C4-alkyl, —C(═O)N(C1-C4-alkyl)2, —S(═O)C1-C4-alkyl and —S(═O)2C1-C4-alkyl; wherein said 3-12-membered cycloalkyl moiety is connected through —CH2— or —CH2CH2—.
- In a preferred embodiment of the compound according to the invention, R4 means a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R4 means a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is connected through —CH2— or —CH2CH2—. More preferably, R4 means -oxetanyl, -tetrahydrofuranyl or -tetrahydropyranyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —C1-C4-alkyl, —C(═O)OH, —C(═O)OC1-C4-alkyl, —C(═O)NH2, —C(═O)NHC1-C4-alkyl, —C(═O)N(C1-C4-alkyl)2, —S(═O)C1-C4-alkyl and —S(═O)2C1-C4-alkyl; wherein said -oxetanyl, -tetrahydrofuranyl or -tetrahydropyranyl is connected through —CH2— or —CH2CH2—.
- In yet another preferred embodiment of the compound according to the invention, R4 means a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R4 means -phenyl, unsubstituted, mono- or polysubstituted; wherein said -phenyl is connected through —CH2— or —CH2CH2—. More preferably, R4 means -phenyl, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —C1-C4-alkyl, —O—C1-C4-alkyl, —C(═O)OH, —C(═O)OC1-C4-alkyl, —C(═O)NH2, —C(═O)NHC1-C4-alkyl, —C(═O)N(C1-C4-alkyl)2, —S(═O)C1-C4-alkyl and —S(═O)2C1-C4-alkyl; wherein said -phenyl is connected through —CH2— or —CH2CH2—.
- In a further preferred embodiment of the compound according to the invention, R4 means a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R4 means a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said -phenyl is connected through —CH2— or —CH2CH2—. More preferably, R4 means -pyridinyl, -pyrimidinyl, -pyrazinyl, or -pyrazolinyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —C1-C4-alkyl, —O—C1-C4-alkyl, —C(═O)OH, —C(═O)OC1-C4-alkyl, —C(═O)NH2, —C(═O)NHC1-C4-alkyl, —C(═O)N(C1-C4-alkyl)2, —S(═O)C1-C4-alkyl and —S(═O)2C1-C4-alkyl; wherein said -pyridinyl, -pyrimidinyl, -pyrazinyl, or -pyrazolinyl is connected through —CH2— or —CH2CH2—.
- In a preferred embodiment of the compound according to the invention, n means 1 or 2. Preferably, n means 1.
- In a preferred embodiment of the compound according to the invention, R5 means -phenyl, unsubstituted, mono- or polysubstituted. Preferably, R5 means -phenyl unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F; —Cl; —Br; —I; —CN; —OH; —CF3; -3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; preferably -cyclopropyl, saturated, unsubstituted; -3-12-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; preferably -pyrrolidinyl, -piperidinyl, -morpholinyl, -piperazinyl, -thiomorpholinyl, or -thiomorpholinyl dioxide, in each case saturated, unsubstituted or monosubstituted with —C1-C4-alkyl; —O—CH2—O— (such that it is condensed with a dioxolanyl ring); —O—C1-C4-alkyl; —O—(CH2CH2—O)1-30—H; —O—(CH2CH2—O)1-30—CH3; —C(═O)OH; —C(—O)OC1-C4-alkyl; —C(═O)NH2; —C(═O)NHC1-C4-alkyl; —C(═O)N(C1-C4-alkyl)2; —S(═O)C1-C4-alkyl and —S(═O)2C1-C4-alkyl.
- In another preferred embodiment of the compound according to the invention, R5 means -pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl, -thienyl, -imidazolyl, triazolyl, or -1,3-benzodioxolyl, in each case unsubstituted, mono- or polysubstituted. Preferably, R5 means -pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl, -thienyl, -imidazolyl, triazolyl, or -1,3-benzodioxolyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F; —Cl; —Br; —I; —CN; —OH; —C1-C4-alkyl, —CF3; —C1-C4-alkyl-C(═O)NH2; -3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; preferably -cyclopropyl, saturated, unsubstituted; -3-12-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; preferably -pyrrolidinyl, -piperidinyl, -morpholinyl, -piperazinyl, -thiomorpholinyl, or -thiomorpholinyl dioxide, in each case saturated, unsubstituted or monosubstituted with —C1-C4-alkyl; —O—CH2—O— (such that it is condensed with a dioxolanyl ring); —O—C1-C4-alkyl; —O—(CH2CH2—O)1-30—H; —O—(CH2CH2—O)1-30—CH3; —C(═O)OH; —C(═O)OC1-C4-alkyl; —C(═O)NH2; —C(═O)NHC1-C4-alkyl; —C(═O)N(C1-C4-alkyl)2; —SC1-C4-alkyl; —S(═O)C1-C4-alkyl and —S(═O)2C1-C4-alkyl.
- In preferred embodiments, the compound according to the invention has a structure according to any of general formulas (II-A) to (VIII-C):
-
- wherein in each case
- R1, R2, R3, R4, and R5 are defined as above,
- RC means —H, —OH, —F, —CN or —C1-C4-alkyl; preferably —H or —OH;
- RD means —H or —F;
- or a physiologically acceptable salt thereof.
- Preferably, in the compounds according to general formula (I) or any of the compounds according to general formulas (II-A) to (VIII-C), R5 is selected from the group consisting of:
- In a particularly preferred embodiment of the compound according to the invention,
-
- n means 1 or 2;
- R1 means —H or —CH3;
- R2 means —H or —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted or monosubstituted with —OH, —OCH3, —C(═O)OCH3, or —CN;
- R3 means
- —C1-C4-alkyl, optionally monosubstituted with —OCH3;
- -phenyl, -thienyl or -pyridinyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —CN, —CH3, —CH2CH3, —CH2F, —CHF2, —CF3, —OCF3, —OH, —OCH3, —O—CH2—O—CH3, —C(═O)NH2, C(═O)NHCH3, —C(═O)N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —NHC(═O)CH3, —CH2OH, SOCH3 and SO2CH3; or
- R4 means
- —H;
- —C1-C6-alkyl, linear or branched, saturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, ═O, —OH, —CO2H, —C(═O)O—C1-C4-alkyl, —C(═O)NH2, —C(═O)NH—C1-C4-alkyl, —C(═O)N(C1-C4-alkyl)2, —C(═O)NH—C1-C4-alkyl-CN, —C(═O)NCH3—C1-C4-alkyl-CN, —C(═O)NH-cyclopropyl-CN, —C(═O)NCH3-cyclopropyl-CN, —C(═O)NH—C1-C4-alkyl-OH, —C(═O)NCH3—C1-C4-alkyl-OH, —C(═O)NH—C1-C4-alkyl-OCH3, —C(═O)NCH3—C1-C4-alkyl-OCH3, —C(═O)NRR′ wherein R and R′ together with the nitrogen atom to which they are attached form a ring and mean —(CH2)2-4—;
- 3-6-membered cycloalkyl, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, and —O—C1-C4-alkyl, wherein said 3-6-membered cycloalkyl is connected through —C1-C6-alkylene;
- 3-6-membered heterocycloalkyl, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —CO2H, —C(═O)O—C1-C4-alkyl, —OH, and —O—C1-C4-alkyl, wherein said 3-6-membered heterocycloalkyl is connected through —C1-C6-alkylene;
- 6-14-membered aryl, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —CO2H, —C(═O)O—C1-C4-alkyl, —OH, and —O—C1-C4-alkyl; wherein said 6-14-membered aryl is connected through —C1-C6-alkylene- or —S(═O)2—;
- 5-14-membered heteroaryl, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —CO2H, —C(═O)O—C1-C4-alkyl, —OH, and —O—C1-C4-alkyl; wherein said 5-14-membered heteroaryl is connected through —C1-C6-alkylene- or —S(═O)2—;
- R5 means -phenyl, -pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl, -thienyl, -imidazolyl, triazolyl, or -1,3-benzodioxolyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F; —Cl; —Br; —I; —CN; —OH; —C1-C4-alkyl; —CF3; alkyl-OH; —C1-C4-alkyl-C1-C4-alkyl-C(═O)NH2; -3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; preferably -cyclopropyl, saturated, unsubstituted; -3-12-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; —O—CH2—O—; —O—(CH2CH2—O)1-30—H; (CH2CH2—O)1-30—CH3; —C(═O)OH; —C(═O)OC1-C4-alkyl; —C(═O)NH2; —C(═O)NHC1-C4-alkyl; —C(═O)N(C1-C4-alkyl)2; —SC1-C4-alkyl; —S(═O)C1-C4-alkyl and —S(═O)2C1-C4-alkyl; and
- R7, R8, R11, R12, R13, R14, R15, R16 , R17, R18 , R19, and R20 mean —H.
- In a particularly preferred embodiment of the compound according to the invention,
-
- n means 1 or 2; and/or
- R1 means —H or —CH3; and/or
- R2 means —C1-C6-alkyl, linear or branched, saturated, unsubstituted; preferably, R2 means —CH3 or —CH2CH3; more preferably, R1 and R2 both mean —CH3; and/or
- R3 means -phenyl, -thienyl or -pyridinyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —CN, —CH3, —CH2CH3, —CH2F, —CHF2, —CF3, —OH, —OCH3, —C(═O)NH2, C(═O)NHCH3, —C(═O)N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —NHC(═O)CH3, —CH2OH, SOCH3 and SO2CH3; preferably R3 means -phenyl, -thienyl or -pyridinyl, in each case unsubstituted or substituted with —F; more preferably, R3 means phenyl, unsubstituted; and/or
- R4 means
- —H;
- —C1-C6-alkyl, linear or branched, saturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, and —O—C1-C4-alkyl; or
- 3-6-membered cycloalkyl, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, and —O—C1-C4-alkyl, wherein said 3-6-membered cycloalkyl is connected through —C1-C6-alkylene; preferably R4 means 3-6-membered cycloalkyl, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, and —O—C1-C4-alkyl, wherein said 3-6-membered cycloalkyl is connected through —CH2— or —CH2CH2—; more preferably, R4 means -cyclobutyl, unsubstituted or monosubstituted with —OH, wherein said -cyclobutyl is connected through —CH2—; and/or
- R5 means -phenyl, -pyridazinyl, -pyridinyl, or -pyrimidinyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F; —Cl; —Br; —I; —CN; —OH; —CF3; -3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; preferably -cyclopropyl, saturated, unsubstituted; -3-12-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; preferably -pyrrolidinyl, -piperidinyl, -morpholinyl, -piperazinyl, -thiomorpholinyl, or -thiomorpholinyl dioxide, in each case saturated, unsubstituted or monosubstituted with —C1-C4-alkyl; —O—CH2—O— (such that it is condensed with a dioxolanyl ring); —O—C1-C4-alkyl; —O—(CH2CH2—O)1-30—H; —O—(CH2CH2—O)1-30—CH3; —C(═O)OH; —C(═O)OC1-C4-alkyl; —C(═O)NH2; —C(═O)NHC1-C4-alkyl; —C(═O)N(C1-C4-alkyl)2; —S(═O)C1-C4-alkyl and —S(═O)2C1-C4-alkyl; and/or
- R7, R8, R11, R12, R13, R14, R15, R16 , R17, R18, R19, and R20 mean —H.
- In preferred embodiments, the compound according to the invention is selected from the group consisting of
-
SC_2001 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[(4- methylsulfonyl-phenyl)-methyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2002 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[(3- methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan- 2-one SC_2003 CIS-8-Dimethylamino-1-isopropyl-3-[(4-methoxyphenyl)- methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2004 CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[(4- methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan- 2-one SC_2005 CIS-1-(Cyclobutyl-methyl)-3-[(4-methoxyphenyl)-methyl]-8- [methyl-(2-methyl-propyl)-amino]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2006 CIS-2-[[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzamide SC_2007 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3- (pyrazin-2-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one SC_2008 CIS-8-(Allyl-methyl-amino)-1-(cyclobutyl-methyl)-3-[(4- methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan- 2-one SC_2009 CIS-4-[[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzamide SC_2010 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3- fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3- diazaspiro[4.5]decan-2-one SC_2011 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(4- fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3- diazaspiro[4.5]decan-2-one SC_2012 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3- methoxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3- diazaspiro[4.5]decan-2-one SC_2013 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(4- methoxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3- diazaspiro[4.5]decan-2-one SC_2014 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-(2- methyl-propyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2015 CIS-1-Butyl-8-dimethylamino-3-[(4-methoxyphenyl)- methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2016 CIS-8-Dimethylamino-8-(4-fluorophenyl)-3-[(4- methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one SC_2017 CIS-8-Dimethylamino-8-(3-fluorophenyl)-3-[(4- methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one SC_2018 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3- hydroxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3- diazaspiro[4.5]decan-2-one SC_2019 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3- (pyridin-3-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one SC_2020 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[[3-[2-[2-[2- [2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]- ethoxy]-phenyl]-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan- 2-one SC_2021 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(4- hydroxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3- diazaspiro[4.5]decan-2-one hydrochloride SC_2022 CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3- [(3-methoxyphenyl)-methyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2023 CIS-1-(Cyclopentyl-methyl)-8-dimethylamino-3-[(4- methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan- 2-one SC_2024 CIS-8-Dimethylamino-1-(2-hydroxy-2-methyl-propyl)-3-[(4- methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan- 2-one SC_2025 CIS-8-Dimethylamino-1-(2-methoxy-2-methyl-propyl)-3-[(4- methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan- 2-one SC_2026 CIS-1-(Cyclobutyl-methyl)-3-[(3-methoxyphenyl)-methyl]-8- methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2027 CIS-3-[[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2- oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]- benzonitrile SC_2028 CIS-1-(Cyclobutyl-methyl)-3-[(3-methoxyphenyl)-methyl]-8- (methyl-propyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2- one SC_2029 CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-3-[(3- methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan- 2-one SC_2030 CIS-3-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2- oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-propionitrile SC_2031 CIS-1-(Cyclobutyl-methyl)-8-methylamino-8-phenyl-3- (pyridin-3-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one SC_2032 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1- (oxetan-3-yl-methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2- one SC_2033 CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl- 3-(pyridin-3-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one SC_2034 CIS-8-Dimethylamino-1-(2-hydroxy-ethyl)-3-[(4- methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan- 2-one SC_2035 CIS-8-Dimethylamino-1-(2,2-dimethyl-propyl)-3-[(4- methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan- 2-one SC_2036 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-(3- methyl-butyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2037 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8- phenyl-1-[3-(trifluoromethyloxy)-propyl]-1,3- diazaspiro[4.5]decan-2-one SC_2038 CIS-1-(2-Cyclobutyl-ethyl)-8-dimethylamino-3-[(4- methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan- 2-one SC_2039 CIS-1-[(3,3-Difluoro-cyclobutyl)-methyl]-8-dimethylamino- 3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2040 CIS-2-[[1-(Cyclobutyl-methyl)-3-[(4-methoxyphenyl)- methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-8-yl]- methyl-amino]-acetonitrile SC_2041 CIS-1-(Cyclobutyl-methyl)-8-[(2-methoxy-ethyl)-methyl- amino]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2042 CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2- oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetic acid tert- butyl ester SC_2043 CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2- oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetic acid; 2,2,2-trifluoro-acetic acid salt SC_2044 CIS-1-(Cyclobutyl-methyl)-3-[(4-methoxyphenyl)-methyl]-8- methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2045 CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2- oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetic acid methyl ester SC_2046 CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2- oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetamide SC_2047 CIS-1-Benzyl-8-dimethylamino-3-[(4-methoxyphenyl)- methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2048 CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2- oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-methyl- acetamide SC_2049 CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2- oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-propyl- acetamide SC_2050 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-(3- methoxy-propyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2051 CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3- [(4-methoxyphenyl)-methyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2052 CIS-8-Dimethylamino-1-(2-methoxy-ethyl)-3-[(4- methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan- 2-one SC_2053 CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2- oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetonitrile SC_2054 CIS-8-Dimethylamino-1-hexyl-3-[(4-methoxyphenyl)- methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2055 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8- phenyl-1-(tetrahydro-pyran-4-yl-methyl)-1,3- diazaspiro[4.5]decan-2-one SC_2056 CIS-1-(Cyclohexyl-methyl)-8-dimethylamino-3-[(4- methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan- 2-one SC_2057 CIS-N-(Cyano-methyl)-2-[8-dimethylamino-3-[(4- methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-1-yl]-acetamide SC_2058 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8- phenyl-1-(pyridin-3-yl-methyl)-1,3-diazaspiro[4.5]decan-2- one SC_2059 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-(3- methoxy-propyl)-1,3-diazaspiro[4.5]decan-2-one SC_2060 CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2- oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-(2-methoxy- ethyl)-acetamide SC_2062 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-(2- oxo-2-pyrrolidin-1-yl-ethyl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2063 CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2- oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N,N-dimethyl- acetamide SC_2064 CIS-N-(1-Cyano-cyclopropyl)-2-[8-dimethyl amino-3-[(4- methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-1-yl]-acetamide SC_2065 CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2- oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-methyl-N- propyl-acetamide SC_2066 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[(4- methoxyphenyl)-methyl]-8-(3-methoxy-propyl)-1,3- diazaspiro[4. 5]decan-2-one SC_2067 CIS-8-Dimethylamino-1-(3-hydroxy-propyl)-3-[(4- methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan- 2-one SC_2068 CIS-8-Dimethylamino-1-(4-methoxy-butyl)-3-[(4- methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan- 2-one SC_2069 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-[(1- methyl-cyclobutyl)-methyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2070 CIS-8-Dimethylamino-1-[(1-hydroxy-cyclohexyl)-methyl]-3- [(4-methoxyphenyl)-methyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2071 CIS-5-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2- oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-pentanenitrile SC_2072 CIS-3-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2- oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-propionamide SC_2073 CIS-1-(Cyclobutyl-methyl)-8-[(2-hydroxy-ethyl)-methyl- amino]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2074 CIS-1-[[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2- oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-methyl]- cyclobutane-1-carbonitrile SC_2075 CIS-8-Dimethylamino-1-[(1-hydroxy-cyclopentyl)-methyl]-3- [(4-methoxyphenyl)-methyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2076 CIS-3-[(2-Bromophenyl)-methyl]-1-(cyclobutyl-methyl)-8- dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2077 CIS-3-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2- oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-methyl- propionamide SC_2078 CIS-3-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2- oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-propyl- propionamide SC_2079 CIS-8-Dimethylamino-1-[(1-fluoro-cyclobutyl)-methyl]-3- [(4-methoxyphenyl)-methyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2080 CIS-1-(2-Cyclohexyl-ethyl)-8-dimethylamino-3-[(4- methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan- 2-one SC_2081 CIS-3-[[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzonitrile SC_2082 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1- methyl-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2083 CIS-8-Dimethylamino-1-[2-[2-[2-[2-[2-[2-[2-(2-methoxy- ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]- ethyl]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2084 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8- phenyl-1-(2-tetrahydro-pyran-4-yl-ethyl)-1,3- diazaspiro[4.5]decan-2-one SC_2085 CIS-4-[[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzonitrile SC_2086 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[[6- (trifluoromethyl)-pyridin-3-yl]-methyl]-1,3- diazaspiro[4.5]decan-2-one SC_2087 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[[4-[2-[2-[2- [2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]- ethoxy]-ethoxy]-ethoxy]-ethoxy]-phenyl]-methyl]-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one SC_2088 CIS-3-[[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzamide SC_2089 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[(4- hydroxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan- 2-one SC_2090 CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-3-[(4- methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan- 2-one SC_2091 CIS-8-Dimethylamino-1-[(1-methoxy-cyclobutyl)-methyl]-3- [(4-methoxyphenyl)-methyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2092 CIS-2-[[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzonitrile SC_2093 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[(3- methylsulfonyl-phenyl)-methyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2094 CIS-8-Dimethylamino-1-ethyl-3-[(4-methoxyphenyl)- methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2095 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8- phenyl-1-propyl-1,3-diazaspiro[4.5]decan-2-one SC_2096 CIS-3-Benzyl-1-(cyclobutyl-methyl)-8-dimethylamino-8- phenyl-1,3-diazaspiro[4.5]deccn-2-one SC_2097 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2099 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8- phenyl-1-(pyrimidin-4-yl-methyl)-1,3-diazaspiro[4.5]decan- 2-one SC_2100 CIS-3-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2- oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-2,2-dimethyl- propionitrile SC_2101 CIS-2-[[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2- oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-methyl]-benzoic acid methyl ester SC_2102 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3- (pyridin-2-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one SC_2103 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3- (pyridin-4-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one SC_2104 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8- phenyl-1-(tetrahydro-furan-3-yl-methyl)-1,3- diazaspiro[4.5]decan-2-one SC_2105 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3- (pyrimidin-2-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one SC_2106 CIS-3-[[1-[(5-Cyano-2-methoxy-phenyl)-methyl]-8- dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3- yl]-methyl]-4-methoxy-benzonitrile SC_2107 CIS-8-Dimethylamino-1-(3-hydroxy-3-methyl-butyl)-3-[(4- methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan- 2-one SC_2108 CIS-8-Dimethylamino-1-(3-methoxy-3-methyl-butyl)-3-[(4- methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan- 2-one SC_2109 CIS-2-[[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)- methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- methyl]-benzamide SC_2110 CIS-3-[[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)- methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- methyl]-benzamide SC_2111 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-(2- methyl sulfonyl-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2- one SC_2112 CIS-1-[(1-Hydroxy-cyclobutyl)-methyl]-3-[(4- methoxyphenyl)-methyl]-8-methylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2113 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8- phenyl-1-(tetrahydro-furan-2-yl-methyl)-1,3- diazaspiro[4.5]decan-2-one SC_2114 CIS-3-Benzyl-8-dimethylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2115 CIS-3-Benzyl-8-dimethylamino-1-ethyl-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2117 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-[2- (methylsulfinyl)-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2- one SC_2118 CIS-8-Dimethylamino-1-[(2R)-2-hydroxy-propyl]-3-[(4- methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan- 2-one SC_2119 CIS-8-Dimethylamino-1-[(2S)-2-hydroxy-propyl]-3-[(4- methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan- 2-one SC_2120 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8- phenyl-1-(tetrahydro-furan-3-yl-methyl)-1,3- diazaspiro[4.5]decan-2-one SC_2122 CIS-8-Dimethylamino-1-ethyl-3-[(4-methoxyphenyl)- methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2123 CIS-8-Amino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[(4- methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan- 2-one SC_2124 CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8- phenyl-3-(2-phenyl-ethyl)-1,3-diazaspiro[4.5]decan-2-one SC_2125 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[(4- methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one SC_2126 CIS-3-[[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)- methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- methyl]-4-methoxy-benzonitrile SC_2127 CIS-8-Dimethylamino-1-ethyl-8-phenyl-3-(pyridin-3-yl- methyl)-1,3-diazaspiro[4.5]decan-2-one SC_2129 CIS-8-Dimethylamino-1-[2-(1-methoxy-cyclobutyl)-ethyl]-3- [(4-methoxyphenyl)-methyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2130 CIS-8-Dimethylamino-8-[3-(methoxymethyloxy)-phenyl]-3- [(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one SC_2131 CIS-8-Dimethylamino-8-[4-(methoxymethyloxy)-phenyl]-3- [(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one SC_2132 CIS-3-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2- oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-propionic acid SC_2133 CIS-3-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2- oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-propionic acid tert-butyl ester SC_2134 CIS-2-[[1-(Cyclobutyl-methyl)-3-[(4-methoxyphenyl)- methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-8-yl]- methyl-amino]-acetic acid methyl ester SC_2135 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-(3- methyl-but-2-enyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2136 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[(3- methylsulfanyl-phenyl)-methyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2137 CIS-3-[(3-Bromophenyl)-methyl]-1-(cyclobutyl-methyl)-8- dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2138 CIS-2-((8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)- 2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3- yl)methyl)benzonitrile SC_2139 CIS-8-Dimethylamino-8-(3-methoxyphenyl)-3-[(4- methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one SC_2140 CIS-8-Dimethylamino-8-(4-methoxyphenyl)-3-[(4- methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one SC_2141 CIS-3-((8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)- 2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3- yl)methyl)benzonitrile SC_2142 CIS-3-((8-(dimethylamino)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl)methyl)-4-methoxybenzonitrile SC_2143 CIS-8-Dimethylamino-8-phenyl-3-(1H-[1,2,3]triazol-4-yl- methyl)-1,3-diazaspiro[4.5]decan-2-one SC_2144 CIS-8-Dimethylamino-3-[[1-(2-hydroxy-ethyl)-1H- [1,2,3]triazol-4-yl]-methyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2145 CIS-2-[4-[(8-Dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl)-methyl]-1H-[1,2,3]triazol-1-yl]- acetamide SC_2146 CIS-8-Methylamino-8-phenyl-3-(1H-[1,2,3]triazol-4-yl- methyl)-1,3-diazaspiro[4.5]decan-2-one SC_2147 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8- phenyl-1-(p-tolylsulfonyl)-1,3-diazaspiro[4.5]decan-2-one SC_2148 CIS-2-[4-[(8-Methylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl)-methyl]-1H-[1,2,3]triazol-1-yl]- acetamide SC_2149 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo- 8-phenyl-1,3-diazaspiro[4.5]decane-1-carboxylic acid benzyl ester SC_2150 CIS-3-[[1-(2-Hydroxy-ethyl)-1H-[1,2,3]triazol-4-yl]-methyl]- 8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2152 CIS-8-Dimethylamino-8-phenyl-3-(2-pyridin-2-yl-ethyl)-1,3- diazaspiro[4.5]decan-2-one SC_2153 CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3- [[1-(2-hydroxy-ethyl)-1H-[1,2,3]triazol-4-yl]-methyl]-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2155 CIS-2-[4-[[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)- methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- methyl]-1H-[1,2,3]triazol-1-yl]-acetamide SC_2156 CIS-1-[(1-Hydroxy-cyclobutyl)-methyl]-3-[[1-(2-hydroxy- ethyl)-1H-[1,2,3]triazol-4-yl]-methyl]-8-methylamino-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2159 CIS-2-[4-[[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-1H- [1,2,3]triazol-1-yl]-acetamide SC_2160 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[[1-(2- hydroxy-ethyl)-1H-[1,2,3]triazol-4-yl]-methyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2161 CIS-2-[4-[[1-[(1-Hydroxy-cyclobutyl)-methyl]-8- methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- methyl]-1H-[1,2,3]triazol-1-yl]-acetamide SC_2162 CIS-1-(Cyclobutyl-methyl)-3-[[1-(2-hydroxy-ethyl)-1H- [1,2,3]triazol-4-yl]-methyl]-8-methylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2163 CIS-2-[4-[[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-1H- [1,2,3]triazol-1-yl]-acetamide SC_2164 CIS-8-Dimethylamino-8-phenyl-3-(2-pyridin-3-yl-ethyl)-1,3- diazaspiro[4.5]decan-2-one SC_2165 CIS-8-Dimethylamino-3-[2-(1H-imidazol-1-yl)-ethyl]-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2166 CIS-8-Dimethylamino-8-phenyl-3-(2-pyridin-4-yl-ethyl)-1,3- diazaspiro[4.5]decan-2-one SC_2167 CIS-8-Dimethylamino-8-phenyl-3-(2-pyrimidin-2-yl-ethyl)- 1,3 -diazaspiro[4.5]decan-2-one SC_2168 CIS-8-Dimethylamino-8-phenyl-3-(2-pyrimidin-5-yl-ethyl)- 1,3-diazaspiro[4.5]decan-2-one SC_2169 CIS-8-Dimethylamino-1-ethyl-3-[(4-methylsulfonyl-phenyl)- methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2170 CIS-8-Dimethylamino-3-(1-methyl-1-phenyl-ethyl)-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one SC_2171 CIS-8-Dimethylamino-8-phenyl-3-(1-phenyl-cyclopropyl)- 1,3-diazaspiro[4.5]decan-2-one SC_2172 CIS-8-Dimethylamino-1,3-bis[(2-methoxyphenyl)-methyl]-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2173 CIS-8-Dimethylamino-3-[(3-methylsulfonyl-phenyl)-methyl]- 8-phenyl-1,3-chazaspiro[4.5]decan-2-one SC_2174 CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3- (1-methyl-1-phenyl-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan- 2-one SC_2175 CIS-3-[(3-Cyclopropyl-phenyl)-methyl]-8-dimethylamino-8- phenyl-1,3-chazaspiro[4.5]decan-2-one SC_2176 CIS-3-(1,3-Benzodioxo1-4-yl-methyl)-8-dimethylamino-8- phenyl-1,3-chazaspiro[4.5]decan-2-one SC_2177 CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8- phenyl-3-(1-phenyl-cyclopropyl)-1,3-diazaspiro[4.5]decan-2- one SC_2178 CIS-4-[[8-Dimethylamino-3-[(2-methoxyphenyl)-methyl]-2- oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-methyl]- benzonitrile SC_2179 CIS-8-Dimethylamino-3-[(2-methoxyphenyl)-methyl]-8- phenyl-1,3-chazaspiro[4.5]decan-2-one SC_2180 CIS-8-Dimethylamino-8-phenyl-3-(pyridin-4-yl-methyl)-1,3- diazaspiro[4.5]decan-2-one SC_2181 CIS-8-Dimethylamino-8-phenyl-3-(pyridin-2-yl-methyl)-1,3- diazaspiro[4.5]decan-2-one SC_2182 CIS-8-Dimethylamino-8-phenyl-3-(pyridin-3-yl-methyl)-1,3- diazaspiro[4.5]decan-2-one SC_2183 CIS-8-Dimethylamino-3-[[2-(4-methyl-piperazin-1-yl)- pyridin-4-yl]-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2- one SC_2184 CIS-8-Dimethylamino-8-phenyl-3-[(2-piperidin-1-yl-pyridin- 4-yl)-methyl]-1,3-chazaspiro[4.5]decan-2-one SC_2185 CIS-8-Dimethylamino-3-[(2-morpholin-4-yl-pyridin-4-yl)- methyl]-8-phenyl-1,3-chazaspiro[4.5]decan-2-one SC_2186 CIS-8-Dimethylamino-8-phenyl-3-[(2-piperazin-1-yl-pyridin- 4-yl)-methyl]-1,3-chazaspiro[4.5]decan-2-one
and the physiologically acceptable salts thereof. - According to the invention, unless expressly stated otherwise, “—C1-C4-alkyl”, “—C1-C6-alkyl” and any other alkyl residues can be linear or branched, saturated or unsaturated. Linear saturated alkyl includes methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl. Examples of branched saturated alkyl include but are not limited to iso-propyl, sec-butyl, and tert-butyl. Examples of linear unsaturated alkyl include but are not limited to vinyl, propenyl, allyl, and propargyl.
- According to the invention, unless expressly stated otherwise, “—C1-C4-alkyl”, “—C1-C6-alkyl” and any other alkyl residues can be unsubstituted, mono- or polysubstituted. Examples of substituted alkyl include but are not limited to —CH2CH2OH, —CH2CH2OCH3, —CH2CH2CH2OCH3, —CH2CH2S(═O)2CH3, —CH2C(═O)NH2, —C(CH3)2C(═O)NH2, —CH2C(CH3)2C(═O)NH2, and —CH2CH2C(═O)N(CH3)2.
- According to the invention, unless expressly stated otherwise, “—C1-C6-alkylene-”, “—C1-C4-alkylene” and any other alkylene residue can be unsubstituted, mono- or polysubstituted. Examples of saturated alkylene include but are not limited to —CH2—, —CH(CH3)—, —C(CH3)2—, —CH2CH2—, —CH(CH3)CH2—, —CH2CH(CH3)—, —CH(CH3)—CH(CH3)—, —C(CH3)2CH2—, —CH2C(CH3)2—, —CH(CH3)C(CH3)2—, —C(CH3)2CH(CH3)—, C(CH3)2C(CH3)2—, —CH2CH2CH2—, and —C(CH3)2CH2CH2—. Examples of unsaturated alkylene include but are not limited to —CH═CH—, —C≡—, —C(CH3)═CH—, —CH═C(CH3)—, —C(CH3)═C(CH3)—, —CH2CH═CH—, —CH═CHCH2—, —CH═CH—CH═CH—, and —CH═CH—C≡C—.
- According to the invention, unless expressly stated otherwise, “—C1-C6-alkylene-”, “—C1-C4-alkylene” and any other alkylene residue can be unsubstituted, mono- or polysubstituted. Examples of substituted —C1-C6-alkylene- include but are not limited to —CHF—, —CF2—, —CHOH— and —C(═O)—.
- According to the invention, moieties may be connected through —C1-C6-alkylene-, i.e. the moieties may not be directly bound to the core structure of compound according to general formula (I), but may be connected to the core structure of compound according to general formula (I) or its periphery through a —C1-C6-alkylene- linker.
- According to the invention, “3-12-membered cycloalkyl moiety” means a non-aromatic, monocyclic, bicyclic or tricyclic moiety comprising 3 to 12 ring carbon atoms but no heteroatoms in the ring. Examples of preferred saturated 3-12-membered cycloalkyl moieties according to the invention include but are not limited to cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, hydrindane, and decaline. Examples of preferred unsaturated 3 membered cycloalkyl moiety moieties according to the invention include but are not limited to cyclopropene, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, 1,3-cyclohexadiene, and 1,4-cyclohexadiene. The 3-12-membered cycloalkyl moiety, which is bonded to the compound according to the invention, in its periphery may optionally be condensed with a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; and/or with a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; and/or with a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted. Under these circumstances, the ring atoms of the condensed moieties are not included in the 3 to 12 ring atoms of the 3-12-membered cycloalkyl moiety. Examples of 3-12-membered cycloalkyl moieties condensed with 3-12-membered heterocycloalkyl moieties include but are not limited to octahydro-1H-indol, decahydroquinoline, decahydroisoquinoline, octahydro-2H-benzo[b][1,4]oxazin, and decahydro-quinoxalin, which in each case are connected through the 3-12-membered cycloalkyl moiety. Examples of 3-12-membered cycloalkyl moieties condensed with 6-14-membered aryl moieties include but are not limited to 2,3-dihydro-1H-indene and tetraline, which in each case are connected through the 3-12-membered cycloalkyl moiety. Examples of 3-12-membered cycloalkyl moieties condensed with 5-14-membered heteroaryl moieties include but are not limited to 5,6,7,8-tetrahydroquinoline and 5,6,7,8-tetrahydroquinazoline, which in each case are connected through the 3-12-membered cycloalkyl moiety.
- According to the invention, the 3-12-membered cycloalkyl moiety may optionally be connected through —C1-C6-alkylene-, i.e. the 3-12-membered cycloalkyl moiety may not be directly bound to the compound according to general formula (I) but may be connected thereto through a —C1-C6-alkylene- linker. Examples include but are not limited to —CH2-cyclopropyl, —CH2-cyclobutyl, —CH2-cyclopentyl, —CH2-cyclohexyl, —CH2CH2-cyclopropyl, —CH2CH2-cyclobutyl, —CH2CH2-cyclopentyl, and —CH2CH2-cyclohexyl.
- According to the invention, unless expressly stated otherwise, the 3-12-membered cycloalkyl moiety can be unsubstituted, mono- or polysubstituted. Examples of substituted 3-12-membered cycloalkyl moieties include but are not limited to —CH2-1-hydroxy-cyclobutyl.
- According to the invention, “3-12-membered heterocycloalkyl moiety” means a non-aromatic, monocyclic, bicyclic or tricyclic moiety comprising 3 to 12 ring atoms, wherein each cycle comprises independently of one another 1, 2, 3, 4 or more heteroatoms independently of one another selected from the group consisting of nitrogen, oxygen and sulfur, whereas sulfur may be oxidized (S(═O) or (S(═O)2), whereas the remaining ring atoms are carbon atoms, and whereas bicyclic or tricyclic systems may share common heteroatom(s). Examples of preferred saturated 3-12-membered heterocycloalkyl moieties according to the invention include but are not limited to aziridin, azetidine, pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, triazolidine, tetrazolidine, oxiran, oxetane, tetrahydrofurane, tetrahydropyrane, thiirane, thietane, tetra-hydrothiophene, diazepane, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine, morpholine, thiomorpholine. Examples of preferred unsaturated 3-12-membered heterocycloalkyl moiety moieties according to the invention include but are not limited to oxazoline, pyrazoline, imidazoline, isoxazoline, thiazoline, isothiazoline, and dihydropyran. The 3-12-membered heterocycloalkyl moiety, which is bonded to the compound according to the invention, in its periphery may optionally be condensed with a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; and/or with a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; and/or with a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted. Under these circumstances, the ring atoms of the condensed moieties are not included in the 3 to 12 ring atoms of the 3-12-membered heterocycloalkyl moieties. Examples of 3-12-membered heterocycloalkyl moieties condensed with 3-12-membered cycloalkyl moieties include but are not limited to octahydro-1H-indol, decahydroquinoline, decahydroisoquinoline, octahydro-2H-benzo[b][1,4]oxazin, and decahydro-quinoxalin, which in each case are connected through the 3-12-membered heterocycloalkyl moiety. An examples of a 3-12-membered heterocycloalkyl moiety condensed with a 6-14-membered aryl moiety includes but is not limited to 1,2,3,4-tetrahydroquinoline, which is connected through the 3-12-membered heterocycloalkyl moiety. An example of a 3-12-membered heterocycloalkyl moiety condensed with a 5-14-membered heteroaryl moieties includes but is not limited to 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, which is connected through the 3-12-membered heterocycloalkyl moiety.
- According to the invention, the 3-12-membered heterocycloalkyl moiety may optionally be connected through —C1-C6-alkylene-, i.e. the 3-12-membered heterocycloalkyl moiety may not be directly bound to the compound according to general formula (I) but may be connected thereto through a —C1-C6-alkylene- linker. Said linker may be connected to a carbon ring atom or to a hetero ring atom of the 3-12-membered heterocycloalkyl moiety. Examples include but are not limited to —CH2-oxetane, —CH2-pyrrolidine, —CH2-piperidine, —CH2-morpholine, —CH2CH2-oxetane, —CH2CH2-pyrrolidine, —CH2CH2-piperidine, and —CH2CH2-morpholine.
- According to the invention, unless expressly stated otherwise, the 3-12-membered heterocycloalkyl moiety can be unsubstituted, mono- or polysubstituted. Examples of substituted 3-12-membered heterocycloalkyl moieties include but are not limited to 2-carboxamido-N-pyrrolidinyl-, 3,4-dihydroxy-N-pyrrolidinyl, 3-hydroxy-N-pyrimidinyl, 3,4-dihydroxy-N-pyrimidinyl, 3-oxo-N-piperazinyl, -tetrahydro-2H-thiopyranyl dioxide and thiomorpholinyl dioxide.
- According to the invention, “6-14-membered aryl moiety” means an aromatic, monocyclic, bicyclic or tricyclic moiety comprising 6 to 14 ring carbon atoms but no heteroatoms in the ring. Examples of preferred 6-14-membered aryl moieties according to the invention include but are not limited to benzene, naphthalene, anthracen, and phenanthren. The 6-14-membered aryl moiety, which is bonded to the compound according to the invention, in its periphery may optionally be condensed with a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; and/or with a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; and/or with a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted. Under these circumstances, the ring atoms of the condensed moieties are not included in the 6 to 14 ring carbon atoms of the 6-14-membered heterocycloalkyl moieties. Examples of 6-14-membered aryl moieties condensed with 3-12-membered cycloalkyl moieties include but are not limited to 2,3-dihydro-1H-indene and tetraline, which in each case are connected through the 6-14-membered aryl moiety. An example of a 6-14-membered aryl moiety condensed with a 3-12-membered heterocycloalkyl moiety includes but is not limited to 1,2,3,4-tetrahydroquinoline, which is connected through the 6-14-membered aryl moiety. Examples of 6-14-membered aryl moieties condensed with 5-14-membered heteroaryl moieties include but are not limited to quinoline, isoquinoline, phenazine and phenoxacine, which in each case are connected through the 6-14-membered aryl moiety.
- According to the invention, the 6-14-membered aryl moiety may optionally be connected through —C1-C6-alkylene-, i.e. the 6-14-membered aryl moiety may not be directly bound to the compound according to general formula (I) but may be connected thereto through a —C1-C6-alkylene-linker. Said linker may be connected to a carbon ring atom or to a hetero ring atom of the 6-14-membered aryl moiety. Examples include but are not limited to —CH2-C6H5, —CH2CH2-C6H5 and —CH═CH—C6H5.
- According to the invention, unless expressly stated otherwise, the 6-14-membered aryl moiety can be unsubstituted, mono- or polysubstituted. Examples of substituted 6-14-membered aryl moieties include but are not limited to 2-fluorophenyl, 3-fluorophenyl, 2-methoxyphenyl and 3-methoxyphenyl.
- According to the invention, “5-14-membered heteroaryl moiety” means an aromatic, monocyclic, bicyclic or tricyclic moiety comprising 6 to 14 ring atoms, wherein each cycle comprises independently of one another 1, 2, 3, 4 or more heteroatoms independently of one another selected from the group consisting of nitrogen, oxygen and sulfur, whereas the remaining ring atoms are carbon atoms, and whereas bicyclic or tricyclic systems may share common heteroatom(s). Examples of preferred 5-14-membered heteroaryl moieties according to the invention include but are not limited to pyrrole, pyrazole, imidazole, triazole, tetrazole, furane, thiophene, oxazole, isoxazole, thiazole, isothiazole, pyridine, pyridazine, pyrimidine, pyrazine, indolicine, 9H-chinolicine, 1,8-naphthyridine, purine, imidazo[1,2-a]pyrazine, and pteridine. The 5-14-membered heteroaryl moiety, which is bonded to the compound according to the invention, in its periphery may optionally be condensed with a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; and/or with a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; and/or with a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted. Under these circumstances, the ring atoms of the condensed moieties are not included in the 6 to 14 ring carbon atoms of the 6-14-membered heterocycloalkyl moieties. Examples of 5-14-membered heteroaryl moieties condensed with 3-12-membered cycloalkyl moieties include but are not limited to 5,6,7,8-tetrahydroquinoline and 5,6,7,8-tetrahydroquinazoline, which in each case are connected through the 5-14-membered heteroaryl moiety. An examples of a 5-14-membered heteroaryl moiety condensed with a 3-12-membered heterocycloalkyl moiety includes but is not limited to 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, which is connected through the 5-14-membered heteroaryl moiety. Examples of 5-14-membered heteroaryl moieties condensed with 6-14-membered aryl moieties include but are not limited to quinoline, isoquinoline, phenazine and phenoxacine, which in each case are connected through the 5-14-membered heteroaryl moiety.
- According to the invention, the 5-14-membered heteroaryl moiety may optionally be connected through —C1-C6-alkylene-, i.e. the 5-14-membered heteroaryl moiety may not be directly bound to the compound according to general formula (I) but may be connected thereto through a —C1-C6-alkylene- linker. Said linker may be connected to a carbon ring atom or to a hetero ring atom of the 5-14-membered heteroaryl moiety. Examples include but are not limited to —CH2-oxazole, —CH2-isoxazole, —CH2-imidazole, —CH2-pyridine, —CH2-pyrimidine, —CH2-pyridazine, —CH2CH2-oxazole, —CH2CH2-isoxazole, —CH2CH2-imidazole, —CH2CH2-pyridine, —CH2CH2-pyrimidine, and —CH2CH2-pyridazine.
- According to the invention, unless expressly stated otherwise, the 5-14-membered heteroaryl moiety can be unsubstituted, mono- or polysubstituted. Examples of 5-14-membered heteroaryl moieties include but are not limited to 2-methoxy-4-pyridinyl, 2-methoxy-5-pyridinyl, 3-methoxy-4-pyridinyl, 3-methoxy-6-pyridinyl, 4-methoxy-2-pyridinyl, 2-methylsulfonyl-5-pyridinyl, 3-methylsulfonyl-6-pyridinyl, 3-methoxy-6-pyridazinyl, 2-nitrilo-5-pyrimidinyl, 4-hydroxy-2-pyrimidinyl, 4-methoxy-pyrimidinyl, and 2-methoxy-6-pyrazinyl.
- Preferably, the compounds according to the invention have a structure according to general formula (I′)
- wherein R1 to R5, R7, R8, R10 to R20 and n are defined as above, or a physiologically acceptable salt thereof.
- In one preferred embodiment, the excess of the cis-isomer so designated is at least 50% de, more preferably at least 75% de, yet more preferably at least 90% de, most preferably at least 95% de and in particular at least 99% de.
- In a preferred embodiment, the compound according to the invention has a structure according to general formula (IX)
-
- wherein
- RC means —H or —OH;
- R3 means -phenyl or -3-fluorophenyl; and
- R5 means
- 6-14-membered aryl, unsubstituted, mono- or polysubstituted; or
- 5-14-membered heteroaryl, unsubstituted, mono- or polysubstituted;
- or a physiologically acceptable salt thereof.
- Preferably, R5 is selected from -phenyl, -pyridyl, pyrimidinyl, or -triazolyl, in each case unsubstituted, mono- or polysubstituted.
- In a preferred embodiment, the compounds according to the invention are in the form of the free bases.
- In another preferred embodiment, the compounds according to the invention are in the form of the physiologically acceptable salts.
- For the purposes of the description, a “salt” is to be understood as being any form of the compound in which it assumes an ionic form or is charged and is coupled with a counter-ion (a cation or anion) or is in solution. The term is also to be understood as meaning complexes of the compound with other molecules and ions, in particular complexes which are associated via ionic interactions. Preferred salts are physiologically acceptable, in particular physiologically acceptable salts with anions or acids or also a salt formed with a physiologically acceptable acid.
- Physiologically acceptable salts with anions or acids are salts of the particular compound in question with inorganic or organic acids which are physiologically acceptable, in particular when used in humans and/or mammals. Examples of physiologically acceptable salts of particular acids include but are not limited to salts of hydrochloric acid, sulfuric acid, and acetic acid.
- The invention also includes isotopic isomers of a compound according to the invention, wherein at least one atom of the compound is replaced by an isotope of the respective atom which is different from the naturally predominantly occurring isotope, as well as any mixtures of isotopic isomers of such a compound. Preferred isotopes are 2H (deuterium), 3H (tritium), 13C and 14C.
- Certain compounds according to the invention are useful for modulating a pharmacodynamic response from one or more opioid receptors (mu, delta, kappa, NOP/ORL-1) either centrally or peripherally, or both. The pharmacodynamic response may be attributed to the compound either stimulating (agonizing) or inhibiting (antagonizing) the one or more receptors. Certain compounds according to the invention may antagonize one opioid receptor, while also agonizing one or more other receptors. Compounds according to the invention having agonist activity may be either full agonists or partial agonists.
- As used herein, compounds that bind to receptors and mimic the regulatory effects of endogenous ligands are defined as “agonists”. Compounds that bind to a receptor but produce no regulatory effect, but rather block the binding of ligands to the receptor, are defined as “antagonists”.
- In certain embodiments, the compounds according to the invention are agonists at the mu opioid (MOP) and/or kappa opioid (KOP) and/or delta opioid (DOP) and/or nociceptin opioid (NOP/ORL-1) receptors.
- The compounds according to the invention potently bind to the MOP and/or KOP and/or DOP and/or NOP receptors.
- The compounds according to the invention can be modulators at the MOP and/or KOP and/or DOP and/or NOP receptors, and therefore the compounds according to the invention can be used/administered to treat, ameliorate, or prevent pain.
- In some embodiments, the compounds according to the invention are agonists of one or more opioid receptors. In some embodiments, the compounds according to the invention are agonists of the MOP and/or KOP and/or DOP and/or NOP receptors.
- In some embodiments, the compounds according to the invention are antagonists of one or more opioid receptors. In some embodiments, the compounds according to the invention are antagonists of the MOP and/or KOP and/or DOP and/or NOP receptors.
- In some embodiments, the compounds according to the invention have both, (i) agonist activity at the NOP receptor; and (ii) agonist activity at one or more of the MOP, KOP, and DOP receptors.
- In some embodiments, the compounds according to the invention have both, (i) agonist activity at the NOP receptor; and (ii) antagonist activity at one or more of the MOP, KOP, and DOP receptors.
- In some embodiments, the compounds according to the invention have both, (i) antagonist activity at the NOP receptor; and (ii) agonist activity at one or more of the MOP, KOP, and DOP receptors.
- In some embodiments, the compounds according to the invention have both, (i) antagonist activity at the NOP receptor; and (ii) antagonist activity at one or more of the MOP, KOP, and DOP receptors.
- In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention have selective agonist activity at the NOP receptor. In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention
-
- have agonist activity at the NOP receptor, but no significant activity at the MOP receptor;
- have agonist activity at the NOP receptor, but no significant activity at the KOP receptor;
- have agonist activity at the NOP receptor, but no significant activity at the DOP receptor;
- have agonist activity at the NOP receptor, but no significant activity at the MOP receptor as well as no significant activity at the KOP receptor;
- have agonist activity at the NOP receptor, but no significant activity at the MOP receptor as well as no significant activity at the DOP receptor; or
- have agonist activity at the NOP receptor, but no significant activity at the MOP receptor as well as no significant activity at the KOP receptor as well as no significant activity at the DOP receptor.
- In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention have balanced agonist activity at the NOP receptor as well as at the MOP receptor. In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention
-
- have agonist activity at the NOP receptor as well as agonist activity at the MOP receptor;
- have agonist activity at the NOP receptor as well as agonist activity at the MOP receptor as well as agonist activity at the KOP receptor;
- have agonist activity at the NOP receptor as well as agonist activity at the MOP receptor as well as agonist activity at the DOP receptor;
- can be regarded as opioid pan agonists, i.e. have agonist activity at the NOP receptor as well as agonist activity at the MOP receptor as well as agonist activity at the KOP receptor as well as agonist activity at the DOP receptor;
- have agonist activity at the NOP receptor as well as agonist activity at the MOP receptor, but no significant activity at the KOP receptor;
- have agonist activity at the NOP receptor as well as agonist activity at the MOP receptor, but no significant activity at the DOP receptor; or
- have agonist activity at the NOP receptor as well as agonist activity at the MOP receptor, but no significant activity at the KOP receptor as well as no significant activity at the DOP receptor.
- In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention have balanced agonist activity at the NOP receptor as well as at the KOP receptor. In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention
-
- have agonist activity at the NOP receptor as well as agonist activity at the KOP receptor;
- have agonist activity at the NOP receptor as well as agonist activity at the KOP receptor as well as agonist activity at the MOP receptor;
- have agonist activity at the NOP receptor as well as agonist activity at the KOP receptor as well as agonist activity at the DOP receptor;
- have agonist activity at the NOP receptor as well as agonist activity at the KOP receptor, but no significant activity at the MOP receptor;
- have agonist activity at the NOP receptor as well as agonist activity at the KOP receptor, but no significant activity at the DOP receptor; or
- have agonist activity at the NOP receptor as well as agonist activity at the KOP receptor, but no significant activity at the MOP receptor as well as no significant activity at the DOP receptor.
- In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention have balanced agonist activity at the NOP receptor as well as at the DOP receptor. In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention
-
- have agonist activity at the NOP receptor as well as agonist activity at the DOP receptor;
- have agonist activity at the NOP receptor as well as agonist activity at the DOP receptor, but no significant activity at the MOP receptor;
- have agonist activity at the NOP receptor as well as agonist activity at the DOP receptor, but no significant activity at the KOP receptor; or
- have agonist activity at the NOP receptor as well as agonist activity at the DOP receptor, but no significant activity at the MOP receptor as well as no significant activity at the KOP receptor.
- In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention have selective agonist activity at the KOP receptor. In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention
-
- have agonist activity at the KOP receptor, but no significant activity at the MOP receptor;
- have agonist activity at the KOP receptor, but no significant activity at the NOP receptor;
- have agonist activity at the KOP receptor, but no significant activity at the DOP receptor;
- have agonist activity at the KOP receptor, but no significant activity at the MOP receptor as well as no significant activity at the NOP receptor;
- have agonist activity at the KOP receptor, but no significant activity at the MOP receptor as well as no significant activity at the DOP receptor; or
- have agonist activity at the KOP receptor, but no significant activity at the MOP receptor as well as no significant activity at the NOP receptor as well as no significant activity at the DOP receptor.
- In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention have agonist activity at the MOP receptor, agonist activity at the KOP receptor, and antagonist activity at the DOP receptor. In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention
-
- have agonist activity at the MOP receptor as well as agonist activity at the KOP receptor as well as antagonist activity at the DOP receptor;
- have agonist activity at the MOP receptor as well as agonist activity at the KOP receptor as well as antagonist activity at the DOP receptor as well as agonist activity at the NOP receptor;
- have agonist activity at the MOP receptor as well as agonist activity at the KOP receptor as well as antagonist activity at the DOP receptor as well as antagonist activity at the NOP receptor; or
- have agonist activity at the MOP receptor as well as agonist activity at the KOP receptor as well as antagonist activity at the DOP receptor, no significant activity at the NOP receptor.
- In some embodiments, preferably with respect to receptors of the central nervous system, the compounds according to the invention have selective agonist activity at the NOP receptor. In some embodiments, preferably with respect to receptors of the central nervous system, the compounds according to the invention
-
- have agonist activity at the NOP receptor, but no significant activity at the MOP receptor;
- have agonist activity at the NOP receptor, but no significant activity at the KOP receptor;
- have agonist activity at the NOP receptor, but no significant activity at the DOP receptor;
- have agonist activity at the NOP receptor, but no significant activity at the MOP receptor as well as no significant activity at the KOP receptor;
- have agonist activity at the NOP receptor, but no significant activity at the MOP receptor as well as no significant activity at the DOP receptor; or
- have agonist activity at the NOP receptor, but no significant activity at the MOP receptor as well as no significant activity at the KOP receptor as well as no significant activity at the DOP receptor.
- In some embodiments, preferably with respect to receptors of the central nervous system, the compounds according to the invention have selective antagonist activity at the NOP receptor. In some embodiments, preferably with respect to receptors of the central nervous system, the compounds according to the invention
-
- have antagonist activity at the NOP receptor, but no significant activity at the MOP receptor;
- have antagonist activity at the NOP receptor, but no significant activity at the KOP receptor;
- have antagonist activity at the NOP receptor, but no significant activity at the DOP receptor;
- have antagonist activity at the NOP receptor, but no significant activity at the MOP receptor as well as no significant activity at the KOP receptor;
- have antagonist activity at the NOP receptor, but no significant activity at the MOP receptor as well as no significant activity at the DOP receptor; or
- have antagonist activity at the NOP receptor, but no significant activity at the MOP receptor as well as no significant activity at the KOP receptor as well as no significant activity at the DOP receptor.
- In some embodiments, preferably with respect to receptors of the central nervous system, the compounds according to the invention have antagonist activity at the NOP receptor as well as agonist activity at the DOP receptor. In some embodiments, preferably with respect to receptors of the central nervous system, the compounds according to the invention
-
- have antagonist activity at the NOP receptor as well as agonist activity at the DOP receptor;
- have antagonist activity at the NOP receptor as well as agonist activity at the DOP receptor, but no significant activity at the MOP receptor;
- have antagonist activity at the NOP receptor as well as agonist activity at the DOP receptor, but no significant activity at the KOP receptor; or
- have antagonist activity at the NOP receptor as well as agonist activity at the DOP receptor, but no significant activity at the MOP receptor as well as no significant activity at the KOP receptor.
- For the purpose of the specification, “no significant activity” means that the activity (agonist/antagonist) of the given compound at this receptor is lower by a factor of 1000 or more compared to its activity (agonist/antagonist) at one or more of the other opioid receptors.
- A further aspect of the invention relates to the compounds according to the invention as medicaments.
- A further aspect of the invention relates to the compounds according to the invention for use in the treatment of pain. A further aspect of the invention relates to a method of treating pain comprising the administration of a pain alleviating amount of a compound according to the invention to a subject in need thereof, preferably to a human. The pain is preferably acute or chronic. The pain is preferably nociceptive or neuropathic.
- A further aspect of the invention relates to the compounds according to the invention for use in the treatment of neurodegenerative disorders, neuroinflammatory disorders, neuropsychiatric disorders, and substance abuse/dependence. A further aspect of the invention relates to a method of treating any one of the aforementioned disorders, diseases or conditions comprising the administration of a therapeutically effective amount of a compound according to the invention to a subject in need thereof, preferably to a human.
- Another aspect of the invention relates to a pharmaceutical composition which contains a physiologically acceptable carrier and at least one compound according to the invention.
- Preferably, the composition according to the invention is solid, liquid or pasty; and/or contains the compound according to the invention in an amount of from 0.001 to 99 wt. %, preferably from 1.0 to 70 wt. %, based on the total weight of the composition.
- The pharmaceutical composition according to the invention can optionally contain suitable additives and/or auxiliary substances and/or optionally further active ingredients.
- Examples of suitable physiologically acceptable carriers, additives and/or auxiliary substances are fillers, solvents, diluents, colorings and/or binders. These substances are known to the person skilled in the art (see H. P. Fiedler, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik and angrenzende Gebiete, Editio Cantor Aulendoff).
- The pharmaceutical composition according to the invention contains the compound according to the invention in an amount of preferably from 0.001 to 99 wt. %, more preferably from 0.1 to 90 wt. %, yet more preferably from 0.5 to 80 wt. %, most preferably from 1.0 to 70 wt. % and in particular from 2.5 to 60 wt. %, based on the total weight of the pharmaceutical composition.
- The pharmaceutical composition according to the invention is preferably for systemic, topical or local administration, preferably for oral administration.
- Another aspect of the invention relates to a pharmaceutical dosage form which contains the pharmaceutical composition according to the invention.
- In one preferred embodiment, the pharmaceutical dosage form according to the invention is produced for administration twice daily, for administration once daily or for administration less frequently than once daily. Administration is preferably systemic, in particular oral.
- The pharmaceutical dosage form according to the invention can be administered, for example, as a liquid dosage form in the form of injection solutions, drops or juices, or as a semi-solid dosage form in the form of granules, tablets, pellets, patches, capsules, plasters/spray-on plasters or aerosols. The choice of auxiliary substances etc. and the amounts thereof to be used depend on whether the form of administration is to be administered orally, perorally, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or locally, for example to the skin, the mucosa or into the eyes.
- Pharmaceutical dosage forms in the form of tablets, dragees, capsules, granules, drops, juices and syrups are suitable for oral administration, and solutions, suspensions, readily reconstitutable dry preparations and also sprays are suitable for parenteral, topical and inhalatory administration. Compounds according to the invention in a depot, in dissolved form or in a plaster, optionally with the addition of agents promoting penetration through the skin, are suitable percutaneous administration preparations.
- The amount of the compounds according to the invention to be administered to the patient varies in dependence on the weight of the patient, on the type of administration, on the indication and on the severity of the disease. Usually, from 0.00005 mg/kg to 50 mg/kg, preferably from 0.001 mg/kg to 10 mg/kg, of at least one compound according to the invention is administered.
- Another aspect of the invention relates to a process for the preparation of the compounds according to the invention. Suitable processes for the synthesis of the compounds according to the invention are known in principle to the person skilled in the art.
- Preferred synthesis routes are described below:
- The compounds according to the invention can be obtained via different synthesis routes. Depending on the synthesis route, different intermediates are prepared and subsequently further reacted.
- In a preferred embodiment, the synthesis of the compounds according to the invention proceeds via a synthesis route which comprises the preparation of an intermediate according to general formula (IIIa):
- wherein R1, R2 and R3 are defined as above.
- In another preferred embodiment, the synthesis of the compounds according to the invention proceeds via a synthesis route which comprises the preparation of an intermediate according to general formula (IIIb):
- wherein R1, R2 and R3 are defined as above and PG is a protecting group.
- Preferably the protecting group is -p-methoxybenzyl. Therefore, in another preferred embodiment, the synthesis of the compounds according to the invention proceeds via a synthesis route which comprises the preparation of an intermediate according to general formula (IIIc):
- wherein R1, R2 and R3 are defined as above.
- As already indicated, in general formula (IIIc), the -p-methoxybenzyl moiety represents a protecting group which can be cleaved in the course of the synthesis route.
- In yet another preferred embodiment, the synthesis of the compounds according to the invention proceeds via a synthesis route which comprises the preparation of
-
- an intermediate according to general formula (IIIa) and according to general formula (IIIb); or
- an intermediate according to general formula (IIIa) and according to general formula (IIIc); or
- an intermediate according to general formula (IIIb) and according to general formula (IIIc); or
- an intermediate according to general formula (IIIa), according to general formula (IIIb) and according to general formula (IIIc).
- The following examples further illustrate the invention but are not to be construed as limiting its scope.
- “RT” means room temperature (23 7° C.), “M” are indications of concentration in mol/l, “aq.” means aqueous, “sat.” means saturated, “sol.” means solution, “conc.” means concentrated.
- Further abbreviations:
- brine saturated aqueous sodium chloride solution
- CC column chromatography
- cHex cyclohexane
- DCM dichloromethane
- DIPEA N,N-diisopropylethylamine
- DMF N,N-dimethylformamide
- Et Ethyl
- ether diethyl ether
- EE ethyl acetate
- EtOAc ethyl acetate
- EtOH ethanol
- h hour(s)
- H2O water
- HATU O-(7-aza-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate
- LDA Lithium-di-isoproyl-amid
- Me Methyl
- m/z mass-to-charge ratio
- MeOH methanol
- MeCN acetonitrile
- min minutes
- MS mass spectrometry
- NBS N-bromo-succinimide
- NEt3 triethylamine
- PE Petrol Ether (60-80° C.)
- RM reaction mixture
- RT room temperature
- T3P 2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide
- tBME tert-.butyl methyl ether
- THF tetrahydrofuran
- v/v volume to volume
- w/w weight to weight
- The yields of the compounds prepared were not optimised. All temperatures are uncorrected.
- All starting materials, which are not explicitly described, were either commercially available (the details of suppliers such as for example Acros, Aldrich, Bachem, Butt park, Enamine, Fluka, Lancaster, Maybridge, Merck, Sigma, TCI, Oakwood, etc. can be found in the Symyx® Available Chemicals Database of MDL, San Ramon, US or the SciFinder® Database of the ACS, Washington DC, US, respectively, for example) or the synthesis thereof has already been described precisely in the specialist literature (experimental guidelines can be found in the Reaxys® Database of Elsevier, Amsterdam, NL or the SciFinder® Database of the ACS, Washington DC, US, repspectively, for example) or can be prepared using the conventional methods known to the person skilled in the art.
- The mixing ratios of solvents or eluents for chromatography are specified in v/v.
- All the intermediate products and exemplary compounds were analytically characterised by mass spectrometry (MS, m/z for [M+H]+). In addition 1H-NMR and 13C spectroscopy was carried out for all the exemplary compounds and selected intermediate products.
- Remark Regarding Stereochemistry
- CIS refers to the relative configuration of compounds described herein, in which both nitrogen atoms are drawn on the same face of the cyclohexane ring as described in the following exemplary structure. Two depictions are possible:
- TRANS refers to compounds, in which both nitrogen atoms are on opposite faces of the cyclohexane ring as described in the following exemplary structure. Two depictions are possible:
- Synthesis of Intermediates
- Synthesis of INT-795: CIS-8-Dimethylamino-8-phenyl-3-(2-phenyl-ethyl)-1,3-diazaspiro[4.5]decan-2-one
- A diastereomeric mixture of 8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione (20 g) (INT-976 step 1) was suspended in methanol (200 mL) and was heated to 80° C. for 1 h. The resulting suspension was filtered hot and the precipitate was washed with methanol (100 mL). Solid obtained was dried under reduced pressure to afford major isomer CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decane-2,4-dione (15 g) as an off-white solid. Chiral HPLC purity 98.93%, HPLC purity 98.61%.
- Cs2CO3 (3.9 g, 10.98 mmol) was added to the solution of CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decane-2,4-dione (1.5 g, 5.49 mmol) in MeCN (20 mL) under argon atmosphere and the reaction mixture was stirred for 30 min. (2-Bromoethyl)benzene (1.5 g, 8.24 mmol) was added and the reaction mixture was stirred under reflux for 16 h. The reaction completion was monitored by TLC. The reaction mixture was quenched with water (25 mL) and the organic product was extracted with DCM (2×150 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (230-400 mesh) (5-10% methanol in DCM) further by washing with pentane yielded 1.6 g (78%) of CIS-8-dimethylamino-8-phenyl-3-(2-phenyl-ethyl)-1,3-diazaspiro[4.5]decane-2,4-dione as white solid. (TLC system: 10% MeOH in DCM; Rf: 0.4).
- Anhydrous AlCl3 (1.27 g, 9.59 mmol) was added to the solution of LiAlH4 (1M in THF) (7.6 mL, 7.67 mmol) in THF at 0° C. under argon atmosphere. The reaction was stirred at RT for 1 h. CIS-8-(Dimethylamino)-3-phenethyl-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione (1.5 g, 4.60 mmol) was added to the reaction mixture at 0° C. and stirred at RT for 16 h. The reaction completion was monitored by TLC. The mixture was cooled to 0° C.; quenched with sat. aq. Na2SO4 (10 mL) and filtered through celite. The filtrate was dried over anhydrous Na2SO4 and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (230-400 mesh) (5-10% methanol in DCM) and further by washing with pentane yielded 1 g (69%) of CIS-8-dimethylamino-8-phenyl-3-(2-phenyl-ethyl)-1,3-diazaspiro[4.5]decan-2-one (INT-795) as a white solid. (TLC system: 10% MeOH in DCM; Rf: 0.3). [M+H]+378.
-
- NaOH (1.42 g, 35.5 mmol) was added to a solution of CIS-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-794) (3 g, 7.09 mmol) in DMSO (90 mL) under argon atmosphere and the reaction mixture was stirred at 80° C. for 30 min. ((1-(Bromomethyl)cyclobutoxy)methyl)benzene (5.4 g, 21.3 mmol) was added and stirring was continued for 2 days at 80° C. The reaction completion was monitored by TLC. The reaction mixture was diluted with water (500 mL) and extracted with diethyl ether (4×300 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (230-400mesh silica gel; 65-70% EtOAc in petroleumether as eluent) to afford 2.5 g (59%) of CIS-1-((1-(benzyloxy)cyclobutyl)methyl)-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (TLC system: 10% MeOH in DCM; Rf: 0.8).
- TFA (12 mL) was added to CIS-1-((1-(benzyloxy)cyclobutyl)methyl)-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (2.5 g, 4.18 mmol) at 0° C. and the resulting mixture was stirred at 70° C. for 6 h. The reaction completion was monitored by LCMS. The reaction mixture was concentrated under reduced pressure. To the residue sat. aq. NaHCO3 was added (until pH 10) and the organic product was extracted with DCM (3×150mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (230-400mesh silica gel; 5% MeOH in DCM as eluent) to afford 500 mg (33%) of CIS-8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-799) (TLC system: 10% MeOH in DCM; Rf: 0.5). [M+H]+358.2
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- NaH (50% in mineral oil) (2.44 g, 50.89 mmol) was added to a solution of CIS dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-975) (5 g, 12.72 mmol) in DMF (100 mL) at 0° C. portionwise over 10 min. 1-(Bromomethyl)cyclobutanecarbonitrile (4.4 g, 25.44 mmol) was added dropwise over 10 minutes at 0° C. The reaction mixture was allowed to stir at RT for 3 h, then quenched with water and the organic product was extracted with ethyl acetate (3×200mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 5 g (crude) of 1-((CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutane-carbonitrile as gummy brown liquid. The material was used for the next step without further purification.
- TFA (100 mL) was added to 1-((CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarbonitrile (5 g, 10.28 mmol) at 0° C. and the reaction mixture at mixture was stirred at RT for 2 days. The reaction mixture was concentrated in vacuo. To the residue sat. aq. NaHCO3 was added (until pH 10) and the organic product was extracted with dichloromethane (3×150mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 3.5 g (crude) of 1-((CIS-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl) cyclobutanecarboxamide. The material was used for the next step without further purification.
- Thionyl chloride (35 mL) was added to 1-((cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarboxamide (3.5 g, 9.11 mmol) at RT and the resulting mixture was stirred at reflux for 2 h. The reaction mixture was concentrated in vacuo. To the residue sat. aq. NaHCO3 was added (until pH 10) and the organic product was extracted with dichloromethane (3×150mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography to afford 1.3 g (34% after three steps) of CIS-1-[(8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-methyl]-cyclobutane-1-carbonitrile (INT-951). [M+H]+367.2.
-
- To a stirred solution of 3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.4.2]tetradecan-2-one (4 g, 12.04 mmol) in anhydrous DMF (60 ml) was added NaH (1.38 g, 60% dispersion in oil, 36.14 mmol) at RT. The reaction mixture was stirred for 10 min, bromomethylcyclobutane (3 ml, 26.5 mmol) was added dropwise and stirring was continued for 50 h. TLC analysis showed complete consumption of the starting material. The reaction mixture was quenched with sat. aq. NH4Cl (50 ml) and extracted with EtOAc (3×200 ml). The combined organic phase was dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified column chromatography (neutral aluminum oxide, EtOAc—petroleumether (2:8)) to give 1-cyclobutylmethyl-3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.4.2]tetradecan-2-one (2.4 g, 50%, white solid). TLC system: EtOAc—pet ether (6:4); Rf=0.48.
- To a stirred solution of 1-cyclobutylmethyl-3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.4.2]tetradecan-2-one (1 g, 2.5 mmol) in MeOH (7 ml) was added 10% aq. HCl (8 ml) at 0° C. The reaction mixture was warmed up to RT and stirred for 16 h. TLC analysis showed complete consumption of the starting material. The reaction mixture was quenched with sat. aq. NaHCO3 (30 ml) and extracted with EtOAc (3×50 ml). The combined organic phase was dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, 230-400 mesh, EtOAc—pet ether (1:3)→(3:7)) to give 1-cyclobutylmethyl-3-(4-methoxy-benzyl)-1,3-diaza-spiro[4.5]decane-2,8-dione (650 mg, 73%, colorless viscous oil). TLC system: EtOAc—pet ether (6:4); Rf=0.40.
- To a stirred solution of N-isobutyl-N-methylamine (1.34 ml, 11.23 mmol) and MeOH/H2O (8 ml, 1:1, v/v) was added 4N aq. HCl (1.5 ml) and the reaction mixture was stirred for 10 min at 0° C. (ice bath). A solution of 1-cyclobutylmethyl-3-(4-methoxy-benzyl)-1,3-diaza-spiro[4.5]decane-2,8-dione (1 g, 2.80 mmol) in MeOH (7 ml) and KCN (548 mg, 8.42 mmol) were added and the reaction mixture was stirred at 45° C. for 20 h. TLC analysis showed complete consumption of the starting material. The reaction mixture was diluted with water (30 ml), extracted with EtOAc (3×30 ml), the combined organic phase was dried over Na2SO4 and concentrated under reduced pressure to give 1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile (1.3 g, viscous yellow oil). TLC system: EtOAc—pet ether (1:1); Rf=0.45. The product was used for the next step without additional purification.
- A round bottom flask containing 1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile (1.3 g, 2.81 mmol) was cooled in an ice bath (˜0° C.) and a solution of phenylmagnesium bromide (26 ml, ˜2M in THF) was added slowly at 0° C.-5° C. The ice bath was removed and the reaction mixture was stirred for 30 min, then diluted with sat. aq. NH4Cl (25 ml) and extracted with EtOAc (4×30 ml). The combined organic phase was dried over Na2SO4 and concentrated under reduced pressure to give pale yellow viscous oil. This residue was purified by column chromatography (silica gel, 230-400 mesh, eluent: EtOAc—pet ether (15:85)→*(2:4)) to give CIS-1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (135 mg, 10%, white solid). TLC system: EtOAc—pet ether (1:1); Rf=0.6
- A round bottom flask containing CIS-1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (130 mg, 0.25 mmol) was cooled in an ice bath and a mixture of TFA/CH2Cl2 (2.6 ml, 1:1, v/v) was added slowly at 0° C.-5° C. The reaction mixture was warmed to RT and stirred for 20 h, then quenched with methanolic NH3 (10 ml, ˜10% in MeOH) and concentrated under reduced pressure to give pale yellow viscous oil. This residue was purified twice by column chromatography (silica gel, 230-400 mesh, eluent: MeOH—CHCl3 (1:99)→(2:98)) to give CIS-1-(cyclobutyl-methyl)-8-(methyl-(2-methyl-propyl)-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-953) (65 mg, 66%, white solid). TLC system: MeOH—CHCl3 (5:95); Rf=0.25; [M+H]+384.3
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- KOtBu (57.0 g, 508.4 mmol) was added to the solution of 2-(pyridin-2-yl)acetonitrile (50.0 g, 423.7 mmol) and ethyl acrylate (89.0 g, 889.8 mmol) in THF (500 mL) at 0° C. and stirred for 16 h at RT. The reaction mixture was quenched with sat. aq. NH4Cl and extracted with EtOAc (2×500 mL). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford 68.0 g (60%; crude) of ethyl 5-cyano-2-oxo-5-(pyridin-2-yl)cyclohexanecarboxylate as a brown liquid (TLC system: 50% ethyl acetate in petroleumether ; Rf: 0.65).
- A solution of ethyl 5-cyano-2-oxo-5-(pyridin-2-yl)cyclohexanecarboxylate (68.0 g, 250.0 mmol) was added to a mixture of conc. aq. HCl and glacial acetic acid (170 mL/510 mL) at 0° C. The reaction mixture was heated to 100° C. for 16 h. All volatiles were evaporated under reduced pressure. The residue was diluted with sat. aq. NaHCO3 and extracted with ethyl acetate (3×300 mL). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford 44.0 g (88%) of 4-oxo-1-pyridin-2-yl-cyclohexane-1-carbonitrile INT-958 as a brown solid (TLC system: 50% ethyl acetate in pet ether; Rf: 0.45). [M+H]+201.1
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- A solution of 4-oxo-1-pyridin-2-yl-cyclohexane-1-carbonitrile (INT-958) (44.0 g, 220.0 mmol), ethylene glycol (27.0 g, 440.0 mmol) and PTSA (4.2 g, 22.0 mmol) in toluene (450 mL) was heated to 120° C. for 16 h using Dean Stark apparatus. All volatiles were evaporated under reduced pressure. The residue was diluted with sat. aq. NaHCO3 and extracted with ethyl acetate (3×300 mL). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford 45.0 g (85%) of 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile as a light brown solid (TLC system: 50% ethyl acetate in petroleumether; Rf: 0.55).
- Potassium carbonate (50.0 g, 368.84 mmol) and 30% aq. H2O2 (210.0 mL, 1844.2 mmol) were added to the solution of 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (45.0 g, 184.42 mmol) in DMSO (450 mL) at 0° C. and the resulting mixture was stirred at RT for 14 h. The reaction mixture was diluted with water (1.5 L) and stirred for 1 h. The precipitated solid was separated by filtration, washed with water, petroleumether and dried under reduced pressure to get 32.0 g (66%) of 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carboxamide as a white solid. (TLC system: 10% MeOH in DCM Rf: 0.35).
- A mixture of 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carboxamide (25.0 g, 95.41 mmol), sodium hypochlorite (5wt % aq. solution, 700 mL, 477.09 mmol) and KF-Al2O3 (125.0 g) in methanol (500 mL) was heated to 80° C. for 16 h. The reaction mixture was filtered through celite and the solid residue was washed with methanol. The combined filtrate was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (3×500mL). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford 18.0 g (66%) of methyl 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ylcarbamate as a light brown solid. (TLC system: 5% MeOH in DCM Rf: 0.52.)
- A suspension of methyl 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ylcarbamate (18.0 g, 61.64 mmol) in 10 wt % aq. NaOH (200 mL) was heated to 100° C. for 24 h. The reaction mixture was filtered through celite pad, the solid residue was washed with water and the combined filtrate was extracted with EtOAc (4×200 mL). The combined organic layer washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford 12.5 g (88%) of 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-amine as a light brown semi-solid. (TLC system: 5% MeOH in DCM Rf: 0.22.).
- Sodium cyanoborohydride (13.7 g, 0.213 mol) was added portionwise to a solution of 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-amine (12.5 g, 53.418 mmol) and 35 wt %aq. formaldehyde (45 mL, 0.534 mol) in acetonitrile (130 mL) at 0° C. The reaction mixture was warmed up to room temperature and stirred for 16 h. The reaction mixture was quenched with sat. aq. NH4Cl and concentrated under reduced pressure. The residue was dissolved in water and extracted with EtOAc (3×200 mL). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford 10.5 g (72%) of 4-dimethylamino-4-pyridin-2-yl-cyclohexan-1-one (INT-961) as a light brown solid. (TLC system: 5% MeOH in DCM Rf: 0.32.). [M+H]+219.1
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- Dimethylamine hydrochloride (52 g, 0.645 mol) was added to the solution of 1,4-dioxaspiro-[4.5]-decan-8-one (35g, 0.224 mmol) in MeOH (35 mL) at RT under argon atmosphere. The solution was stirred for 10 min and 40wt % aq. dimethylamine (280 mL, 2.5 mol) and KCN (32 g, 0.492 mol) were sequentially added. The reaction mixture was stirred for 48 h at RT, then diluted with water (100mL) and extracted with EtOAc (2×200 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 44 g of 8-(dimethylamino)-1,4-dioxaspiro-[4.5]-decane-8-carbonitrile (93%) as a white solid.
- 8-(Dimethylamino)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (35 g, 0.167 mol) in THF (350 mL) was added to the solution of 3M phenylmagnesium bromide in diethyl ether (556 mL, 1.67 mol) dropwise at −10° C. under argon atmosphere. The reaction mixture was stirred for 4 h at −10° C. to 0° C. and then at RT for 18 h. The reaction completion was monitored by TLC. The reaction mixture was cooled to 0° C., diluted with sat. aq. NH4Cl (1 L) and extracted with EtOAc (2×600 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 60 g of, N N-dimethyl-8-phenyl-1, 4-dioxaspiro-[4.5]-decan-8-amine as a liquid.
- A solution of N,N-dimethyl-8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine (32 g, 0.123 mol) in 6N aq. HCl (320 mL) was stirred at 0° C. for 2 h and then at RT for 18 h. The reaction completion was monitored by TLC. The reaction mixture was extracted with DCM (2×150 mL). The aqueous layer was basified to pH 10 with solid NaOH and extracted with ethyl acetate (2×200mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The solid residue was washed with hexane and dried in vacuo to afford 7 g of 4-dimethylamino-4-phenyl-cyclohexan-1-one (INT-965) (25% over 2 steps) as a brown solid. [M+H]+218.1
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- KCN (93.8 g, 1441.6 mmol) and (NH4)2CO3 (271.8 g, 1729.9 mmol) were added to the solution of 1,4-dioxaspiro[4.5]decan-8-one (150 g, 961 mmol) in MeOH:H2O (1:1 v/v) (1.92 L) at RT under argon atmosphere. The reaction mixture was stirred at 60° C. for 16 h. The reaction completion was monitored by TLC. The reaction mixture was cooled to 0° C., the precipitated solid was filtered off and dried in vacuo to afford 120 g (55%) of 9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}.2{circumflex over ( )}{5}]tetradecane-1,3-dione. The filtrate was extracted with DCM (2×1.5 L). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford additional 30 g (14%) of 9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}.2{circumflex over ( )}{5}]tetradecane-1,3-dione (TLC system: 10% Methanol in DCM; Rf: 0.4).
- Cs2CO3 (258.7 g, 796.1 mmol) was added to the solution of 73a (150 g, 663.4 mmol) in MeCN (1.5 L) under argon atmosphere and the reaction mixture was stirred for 30 min. A solution of p-methoxybenzyl bromide (96 mL, 663.4 mmol) was added. The reaction mixture was stirred at RT for 48 h. The reaction completion was monitored by TLC. The reaction mixture was quenched with sat. aq. NH4Cl (1.0 L) and the organic product was extracted with EtOAc (2×1.5 L). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was washed with diethyl ether and pentane and dried under reduced pressure to afford 151 g (65%) of 2-[4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}.2{circumflex over ( )}{5}]tetradecane-1,3-dione as an off white solid (TLC system: 10% MeOH in DCM; Rf: 0.6).
- AlCl3 (144.3 g, 1082.6 mmol) was added to a solution of LiAlH4 (2M in THF) (433 mL, 866.10 mmol) in THF (4.5 L) at 0° C. under argon atmosphere and the resulting mixture was stirred at RT for 1 h. 2-[4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}.2{circumflex over ( )}{5}]tetradecane-1,3-dione (150 g, 433.05 mmol) was added at 0° C. The reaction mixture was stirred at RT for 16 h. The reaction completion was monitored by TLC. The reaction mixture was cooled to 0° C., quenched with sat. aq. NaHCO3 (500 mL) and filtered through celite pad. The filtrate was extracted with EtOAc (2×2.0 L). The combined organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to afford 120 g (84%) of 2-[(4-methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}.2{circumflex over ( )}{5}]tetradecan-3-one as an off-white solid. (TLC system: 10% MeOH in DCM, Rf: 0.5).
- A solution of 2-[(4-methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}.2{circumflex over ( )}{5}]tetradecan-3-one (120 g, 361.03 mmol) in 6N aq. HCl (2.4 L) was stirred at 0° C. for 2 h and then at RT for 18 h. The reaction completion was monitored by TLC. The reaction mixture was extracted with DCM (2×2.0L). The aqueous layer was basified to pH 10 with 50% aq. NaOH and then extracted with DCM (2×2.0 L). Combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The solid residue was washed with hexane and dried in vacuo to afford 90 g of 3-[4-Methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decane-2,8-dione (INT-966) as an off-white solid (TLC system: 10% MeOH in DCM; Rf: 0.4) [M+H]+289.11.
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- KOtBu (1M in THF) (29.30 mL, 29.30 mmol) was added to the solution of CIS-8-Dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 (8.0 g, 29.30 mmol) in THF (160 mL) under argon atmosphere and the reaction mixture was stirred for 30 min. 4-Methoxybenzyl bromide (4.23 mL, 29.30 mmol) was added and stirring was continued at RT for 4 h. The reaction completion was monitored by TLC. The reaction mixture was diluted with sat. aq. NH4Cl (150 mL) and the organic product was extracted with EtOAc (2×150 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The reaction was carried out in 2 batches (8 g×2) and the batches were combined for purification. Purification of the crude product by flash column chromatography on silica gel (0-10% methanol in DCM) and subsequently by washing with pentane yielded 11 g (47%) of CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-975) as a white solid. [M+H]+394.2
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- In a sealed tube 4-dimethylamino-4-phenyl-cyclohexan-1-one (INT-965) (2 g, 9.22 mmol) was suspended in 40 mL EtOH/H2O (1:1 v/v) at RT under argon atmosphere. (NH4)2CO3 (3.62 g, 23.04 mmol) and KCN (0.6 g, 9.22 mmol) were added. The reaction mixture was stirred at 60° C. for 18 h. The reaction mixture was cooled to 0° C. and diluted with ice-water and filtered through a glass filter. The solid residue was dried under reduced pressure to afford 8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decane-2,4-dione (1.8 g, 86%) as an off white crystalline solid (TLC: 80% EtOAc in hexane; Rf : 0.25).
- LiAlH4 (2M in THF) (70 mL, 139.4 mmol) was added to the solution of 8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decane-2,4-dione (10 g, 34.8 mmol) in THF/Et2O (2:1 v/v) (400 mL) at 0° C. under argon atmosphere. The reaction mixture was stirred for 4 h at 60° C. The reaction completion was monitored by TLC. The reaction mixture was cooled to 0° C., quenched with saturated Na2SO4 solution (100 mL) and filtered through Celite pad. The filtrate was dried over anhydrous Na2SO4 and concentrated in vacuo to afford 5.7 g (59%) of 8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decan-2-one as an off white solid. (TLC system: 10% MeOH in DCM, Rf: 0.3).
- A mixture of CIS- and TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decan-2-one (8 g, 29.30 mmol) was purified by preparative chiral SFC (column: Chiralcel AS-H, 60% CO2, 40% (0.5% DEA in MeOH)) to get 5 g of CIS-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976) as a white solid. [M+H]+274.2.
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- A solution of CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-975) (5.0 g, 12.7 mmol) in THF (18 mL) was cooled to 0° C. and treated with LDA solution (2M in THF/heptane/ether, 25.4 mL, 50.8 mmol). The resulting mixture was was allowed to warm up to RT over 30 min. The solution was then cooled to 0° C. again and tert-butyl-bromoacetate (5.63 mL, 38.1 mmol) was added. The reaction mixture was stirred at RT for 16 h, quenched with water and extracted with DCM (3×). The combinded organic layers were dried over Na2SO4, filtered and concentrated inder reduced pressure. Purification of the residue by column chromatography on silica gel provided CIS-2-[8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetic acid tert-butyl ester (4.4 g).
- CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetic acid tert-butyl ester (200 mg, 0.4 mmol) was dissolved in TFA (5 mL) and heated to reflux overnight. After cooling to RT all volatiles are removed in vacuo. The residue was taken up in THF (1 mL) and added dropwise to diethyl ether (20 mL). The resulting precipitate was filtered off and dried under reduced pressure to give CIS-2-(8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-acetic acid; 2,2,2-trifluoro-acetic acid salt (INT-977) (119 mg) as a white solid. [M+H]+332.2
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- CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-acetic acid (INT-977) trifluoroacetic acid salt (119 mg, 0.35 mmol) was dissolved in DCM (5 mL). Triethylamine (0.21 mL, 1.6 mmol), dimethylamine (0.54 mL, 1.1 mmol) and T3P (0.63 mL, 1.1 mmol) were sequentially added. The reaction mixture was stirred at RT overnight, then diluted with 1 M aq. Na2CO3 (5 mL). The aqueous layer was extracted with DCM (3×5mL), the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to yield CIS-2-(8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-N,N-dimethyl-acetamide (INT-978) (39 mg) as a white solid. [M+H]+359.2
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- A solution of NaOH (2.85 g, 71.2 mmol) in DMSO (25 mL) was stirred at RT for 10 min. CIS -8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-975) (7.00 g, 17.8 mmol) was added and stirring was continued for 15 min. 1-(Bromo-methyl)-1-methyl-cyclobutane (8.7 g, 53.4 mmol) was added at 0° C. The reaction mixture was heated to 60° C. for 16 h. After cooling down to RT, water (100 mL) was added and the mixture was extracted with DCM (3×150 mL). The combined organic layers were washed with water (70 mL), brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification of the residueby column chromatography on silica gel provided CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-1-((1-methylcyclobutyl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (6.5 g) as a light yellow solid.
- To the solution of CIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (6.66 g, 14.0 mmol) in DCM (65 mL) was added TFA (65 mL) and the resulting mixture was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was taken up in DCM (100 mL) and water (60 mL) and basified with 2M aq. NaOH to pH 10. The organic layer was separated and washed with brine (40 mL), dried over MgSO4, filtered and concentrated under reduced pressure. Crystallization of the residue from EtOAc provided CIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-982) (3.41 g) as an off-white solid. [M+H]+356.3
-
- In analogy to the method described for INT-951 step 1 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-975) was converted into CIS -8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one.
- In analogy to the method described for INT-982 step 2 CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one was converted into CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-984).
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- N-Iodosuccinimide (3.11 g, 13.92 mmol) was added to the solution of CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[phenyl-methyl]-1,3-diazaspiro[4.5]decan-2-one (INT-950) (4 g, 9.28 mmol) in a mixture of acetonitrile and THF (1:1 v/v, 80 mL) and the resulting mixture was stirred at RT for 16 h. The reaction mixture was basified with 2N aq. NaOH to pH-10 and the organic product was extracted with DCM (3×10 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was stirred vigorously with a mixture of 10 wt % aq. citric acid (5 mL) and DCM (10 mL) at RT for 10 min. The reaction mixture was basified with 5N aq. NaOH to pH-10 and extracted with DCM (3×10 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to give 3.5 g (crude) of CIS-3-benzyl-1-(cyclobutylmethyl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one as semi solid (TLC system: 10% MeOH in DCM; Rf: 0.60.).
- Sodium cyanoborohydride (1.56 g, 25.17 mmol, 3 equiv.) was added to the solution of CIS-3-benzyl-1-(cyclobutylmethyl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (3.5 g, 8.39 mmol), acetaldehyde (738 mg, 16.78 mmol, 2 equiv.) and acetic acid (0.5 mL) in methanol (20 mL). The reaction mixture was stirred at RT for 3 h, then quenched with sat. aq. NaHCO3 and the organic product was extracted with DCM (3×50 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (230-400 mesh) (20-25% ethyl acetate in petroleum ether) yielded 2.3 g (62%) of CIS-3-benzyl-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one as a solid. (TLC system: 50% EtOAc in Pet. Ether; Rf: 0.65).
- Sodium metal (1.18 g, 51.68 mmol, 10 equiv.) was added to liquid ammonia (˜25 mL) at −78° C. The resulting mixture was stirred for 10 min at −78° C. A solution of CIS-3-benzyl-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (2.3 g, 5.16 mmol) in THF (25 mL) was added at −78° C. The reaction mixture was stirred for 15 min, then quenched with sat. aq. NH4Cl, warmed to RT and stirred for 1 h. The organic product was extracted with DCM (3×50 mL). The combined organic layer was washed with water, brine and concentrated under reduced pressure to afford 1.30 g (72%) of CIS-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-986) as an off-white solid. (TLC system: 10% MeOH in DCM Rf: 0.15.). [M+H]+356.3
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- In analogy to the method as described for INT-982 step 2 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one (INT-952) was converted into CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-987).
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- Sodium hydroxide (78.06 mg, 4.0 equiv.) was suspended in DMSO (3.5 mL), stirred for 10 minutes, 8-(dimethylamino)-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-975) (192.0 mg, 1.0 equiv.) was added, the reaction mixture was stirred for 5 min followed by addition of 2-(1-methoxycyclobutyl)ethyl 4-methylbenzenesulfonate (416.2 mg, 3.0 equiv.) in DMSO (1.5 mL). The resulting mixture was stirred overnight at 50° C. The reaction mixture was quenched with water and extracted with DCM (3×20 mL). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue (283 mg yellow oil) was purified by column chromatography on silica gel (eluent DCM/EtOH 98/2 to 96/4) to give 8-(dimethylamino)-1-[2-(1-methoxycyclobutyl)ethyl]-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one 163 mg (66%).
- In analogy to the method described for INT-982 step 2 CIS-8-(dimethylamino)-1-[2-(1-methoxycyclobutyl)ethyl]-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one was converted into CIS-8-(dimethylamino)-1-(2-(1-methoxycyclobutyl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-988). Mass: m/z 386.3 (M+H)+.
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- A mixture of 1,4-dioxa-spiro[4.5]decan-8-one (25.0 g, 160.25 mmol, 1.0 eq.) and 2M solution of EtNH2 in THF (200 ml, 2.5 eq. 400.64 mmol) in EtOH (30 ml) was stirred at RT for 48 h. The reaction mixture was concentrated under argon atmosphere and the residue was diluted with ether (60 ml), and a freshly prepared PhLi solution was added [prepared by addition of 2.5 Mn—BuLi in THF (70.5 ml, 1.1 eq. 176.27 mmol) to a solution of bromobenzene (27.675 g, 1.1 eq. 176.275 mmol) in ether (100 ml) at −30° C. and stirred at RT for 1 h). The reaction mixture was stirred at RT for 1.5 h, quenched with saturated NH4Cl solution (100 ml) at 0° C. and extracted with ethyl acetate (2×750 ml). The combined organic layer was washed with water (3×350 ml), brine (300 ml), dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was dissolved in ethyl methyl ketone (100 ml) and trimethylsilyl chloride (37.5 ml) was added at 0° C. The resulting mixture was stirred at RT for 16 h. The precipitated solid was filtered off and washed with acetone followed by THF to get ethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-amine hydrochloride as an off white solid. This reaction was done in 2 batches of 25 g scale and the yield is given for 2 combined batches. Yield: 18% (17.1 g, 57.575 mmol). LCMS: m/z 262.2 (M+H)+.
- To a solution of ethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-amine hydrochloride (10.1 g, 34.0 mmol, 1 eq.) in water (37.5 ml) was added conc. aq. HCl (62.5 ml) at 0° C. and the resulting mixture was stirred at RT for 16 h. The reaction mixture was basified with aq. NaOH (pH ˜14) at 0° C. and extracted with DCM (2×750 ml). Organic layer was washed with water (400 ml), brine (400 ml), dried over Na2SO4 and concentrated under reduced pressure to yield 4-ethylamino-4-phenyl-cyclohexanone which was used in the next step without further purification. This reaction was carried out in another batch of 15.1 g scale and the yield is given for 2 combined batches. Yield: 92% (17.0 g, 78.34 mmol).
- To a solution of 4-ethylamino-4-phenyl-cyclohexanone (17 g, 78.341 mmol, 1.0 eq.) in EtOH (250 ml) and water (200 ml) was added (NH4)2CO3 (18.8 g, 195.85 mmol, 2.5 eq.) and the reaction mixture was stirred at RT for 15 min. KCN (5.09 g, 78.341 mmol, 1.0 eq.) was added and stirring was continued at 60° C. for 18 h. The reaction mixture was cooled down to RT. The precipitated solid was filtered off, washed with water (250 ml), EtOH (300 ml), hexane (200 ml) and dried under reduced pressure to yield cis and trans mixture of 8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (13.0 g, 45.29 mmol, 58%) as a white solid. Yield: 58% (13 g, 45.296 mmol). LC-MS: m/z [M+1]+=288.2.
- To a solution of cis and trans mixture of 8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (12 g) in MeOH-DCM (1:1, 960 ml) was added a solution of L-tartaric acid in MeOH (25 ml) and the resulting mixture stirred at RT for 2 h and then kept in refrigerator for 16 h. The precipitated solid was filtered off and washed with MeOH-DCM (1:5, 50 ml) to get tartrate salt of 8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (7.5 g) as a white solid. To this solid sat. aq. NaHCO3 was added (pH ˜8) and the resulting mixture was extracted with 25% MeOH-DCM (2×800 ml). Combined organic layer was washed with water (300 ml), brine (300 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was triturated with 20% DCM-hexane and the resulting solid was dried under reduced pressure to afford CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione as white solid. This step was done in 2 batches (12 g & 2.4 g) and the yield is given for 2 combined batches. Yield: 31.2% (5.0 g, 17.421 mmol). LC-MS: m/z [M+1]+=288.0.
- To a slurry of LiAlH4 (793 mg, 20.91 mmol, 3.0 eq.) in THF (15 ml) was added a suspension of CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (2.0 g, 6.97 mmol, 1.0 eq.) in THF (60 ml) at 0° C. and the reaction mixture was heated to 65° C. for 16 h. The reaction mixture was cooled to 0° C., quenched with sat. aq. Na2SO4 (20 ml), stirred at RT for 1 h and filtered through celite pad. The residue was washed with 15% MeOH-DCM (500 ml). The combined filtrate was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give crude product which was triturated with 15% DCM-Hexane to afford CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (INT-1008) (1.6 g, 5.86 mmol, 84%) as a white solid. Yield: 84% (1.6 g, 5.86 mmol). LC-MS: m/z [M+1]+=274.2.
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- To a solution of CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976) (5.0 g, 18.31 mmol, 1.0 eq.) in dry THF (500 ml) was added t-BuOK (3.07 g, 27.46 mmol, 1.5 eq.) and the reaction mixture was stirred at RT for 15 min. 3-Bromo-propyne (3.24 g, 13.18 mmol, 1.2 eq., 80% in toluene) was added and stirring was continued at RT for 18 h. The reaction mixture was poured into ice-water and extracted with DCM (800 ml). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (neutral alumina; 1% MeOH/Hexane) to yield CIS-8-(dimethylamino)-8-phenyl-3-(prop-2-yn-1-yl)-1,3-diazaspiro[4.5]decan-2-one (INT-1010) (3.0 g, 9.64 mmol, 52%) as an off white solid. Yield: 52% (3.0 g, 9.64 mmol). Mass: m/z 312.3 (M+H)+.
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- To a suspension of CIS-8-dimethylamino-8-phenyl-3-prop-2-ynyl-1,3-diaza-spiro[4.5]decan-2-one (INT-1010) (1.0 g, 3.21 mmol, 1.0 eq.) and azidoacetic acid ethyl ester (0.37 ml, 3.21 mmol, 1.0 eq.) in t-BuOH:H2O (1:1, 18 ml) and 1M aq. CuSO4 (0.19 ml) was added sodium ascorbate (191 mg, 0.963 mmol, 0.3 eq.). The reaction mixturewas stirred at RT for 18 h, then quenched with water and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel neutralized with TEA; 10% MeOH/DCM) to yield ethyl CIS-2-(4-((8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)methyl)-1H-1,2,3-triazol-1-yl)acetate (INT-1011) (1.0 g, 2.27 mmol, 70%) as an off white solid. Yield: 70% (1.0 g, 2.27 mmol). Mass: m/z 441.4 (M+H)+.
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- To a solution of CIS-2-(4-((8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)methyl)-1H-1,2,3-triazol-1-yl)acetate (INT-1011) (2.0 g, 4.54 mmol, 1.0 eq.) in DMSO (30 ml) was added NaOH (727 mg, 18.18 mmol, 4.0 eq.) at RT and the reaction mixture was heated to 70° C. for 30 min. The resulting mixture was cooled down to RT and a solution of 1-oxa-spiro[2.3]hexane (953 mg, 11.35 mmol, 2.5 eq.) in DMSO (5 ml) was added. The reaction mixture was stirred at 50° C. for 16 h, then cooled down to RT and diluted with MeOH (40 ml). Thionyl chloride (1.32 ml, 18.18 mmol, 4.0 eq.) was added at 0° C. and stirring was continued at RT for 16 h. The reaction mixture was concentrated under reduced pressure, then diluted with DCM (300 ml), sat. NaHCO3 solution (200 ml) was added slowly at 0° C. and the resulting mixture was stirred at RT for 1 h. The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; 4% MeOH/DCM) to yield methyl CIS-2-(4-((8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)methyl)-1H-1,2,3-triazol-1-yl)acetate (INT-1012) (950 mg, 1.86 mmol, 41%) as brown sticky solid. After purification, isolated compound was ˜60% pure and was used in the next steps without further purification. Yield: 41% (950 mg, 1.86 mmol). Mass: m/z 509.4 (M+H)+.
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- NaH (0.15 g, 3.30 mmol) was added to a solution of CIS-3-benzyl-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-963) (0.4 g, 1.10 mmol) in DMF (8 mL) at 0° C. over 15 min. The reaction mixture was stirred for 5 min, 1-(bromomethyl)-2-methoxybenzene (0.33 g, 1.65 mmol) was added portionwise, ice bath was removed and stirring was continued at RT for 3 h. The resulting mixture was quenched with cold water (precipitation observed), the precipitate was filtered off and dried under reduced pressure to give 450 mg (84%) of CIS-3-benzyl-8-(dimethylamino)-1-(2-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one. The crude material was used in the next step without further purification. (TLC system: 10% MeOH in DCM; Rf: 0.7).
- CIS-3-benzyl-8-(dimethylamino)-1-(2-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (0.45 g, 0.93 mmol) in THF (10mL) was added to sodium metal (0.21g, 9.316 mmol) in liquid ammonia (10 mL) at −78° C. The reaction mixture was stirred at −78° C. for 15 min, quenched with sat. aq. NH4Cl and the organic product was extracted with EtOAc (2×20mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. Purification of the residue by preparative TLC using 2% methanol in DCM as eluent gave 170 mg of solid material, which was washed with pentane to give 150 mg (40%) of CIS-8-(dimethylamino)-1-(2-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1021) as an off white solid. (TLC system: 10% MeOH in DCM; Rf: 0.3). 1H NMR (DMSO-d6): δ 7.34-7.18 (m, 7H), 6.96 (d, 1H), 6.90 (t, 1H), 6.33 (s, 1H), 4.19 (s, 2H), 3.83 (s, 3H), 3.20 (s, 2H), 2.59-2.55 (m, 2H), 1.98-1.90 (m, 8H), 1.37-1.30 (m, 4H). Mass: m/z 394.3 [M+H]+
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- In analogy to the method described for INT-986 (step 1) CIS-8-(dimethylamino)-1-(2-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one was reacted with N-iodosuccinimide to be converted into CIS-1-(2-methoxybenzyl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1022). 1H NMR (DMSO-d6): δ 7.39 (d, 2H), 7.29 (t, 2H), 7.23-7.15 (m, 3H), 6.96 (d, 1H), 6.89 (t, 1H), 6.36 (s, 1H), 4.21 (s, 2H), 3.84 (s, 3H), 3.25 (s, 2H), 2.13 (m, 1H), 2.03-1.98 (m, 2H), 1.82-1.80 (m, 5H), 1.64-1.58 (m, 2H), 1.34-1.31 (m, 2H). Mass: m/z 380.2 [M+H]+
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- Ba(OH)2x8H2O (36.87 g, 117.07 mmol) was added to the solution of CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione (12 g, 41.81 mmol) in water (450 mL) at RT. The reaction mixture was stirred at 150° C. for 8 h. The resulting mixture was cooled down to RT and (NH4)2CO3 (22.97 g, 146.34 mmol) was added. The reaction mixture was stirred at 65° C. for 8 h, then filtered through celite and the precipitate was washed with water. The combined filtrate was concentrated in vacuo to afford 6.5 g of crude CIS-1-amino-4-(dimethylamino)-4-phenylcyclohexanecarboxylic acid. The product was used in the next step without further purification. (TLC system: 10% MeOH in DCM; Rf: 0.1).
- K2CO3 (4.74 g, 34.34 mmol) was added to a solution of CIS-1-amino-4-(dimethylamino)-4-phenylcyclohexanecarboxylic acid (3.0 g, 11.4 mmol) in water-THF (40 mL, 1:1 v/v) at RT. After 15 min, Boc2O (3.24 g, 14.85 mmol) was added and the reaction mixture was stirred at RT for 16 h. The resulting mixture was diluted with water, acidified with glacial acetic acid (pH ˜4) and extracted with 10% MeOH in DCM (2×150mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (neutral alumina, 10% methanol in DCM as eluent) and further purified by washing with pentane to give 1.0 g (24%) of CIS-1-(tert-butoxycarbonylamino)-4-(dimethylamino)-4-phenylcyclohexanecarboxylic acid (INT-1023) as a white solid. (TLC system: 10% MeOH in DCM; Rf: 0.10). Mass: m/z 361.2 (M−H)−.
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- In analogy to the method described for INT-982 step 2 CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-8-phenyl-1-tosyl-1,3-diazaspiro[4.5]decan-2-one (SC-2147) was treated with TFA to be converted into CIS-8-(dimethylamino)-8-phenyl-1-tosyl-1,3-diazaspiro[4.5]decan-2-one (INT-1028).
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- Titaniumethoxide (58.45 g, 256.4 mmol) was added to a solution of 1,4-dioxaspiro[4.5]decan-8-one (20 g, 128.20 mmol) and 2-methylpropane-2-sulfinamide (15.51 g, 128.20 mmol) in THF (200 mL) at RT and the reaction mixture was stirred at RT for 18 h. The reaction mixture was cooled to 0° C. and quenched by dropwise addition of sat. aq. NaHCO3 (500 mL) over a period of 30 min. The organic product was extracted with EtOAc (3×100 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo to afford 10 g (crude) of 2-methyl-N-(1,4-dioxaspiro[4.5]decan-8-ylidene)propane-2-sulfinamide as a white solid (TLC system: 30% Ethyl acetate in hexane; Rf: 0.30).
- Phenylmagnesium bromide (1M in THF, 116 mL, 116 mmol) was added dropwise to a solution of 2-methyl-N-(1,4-dioxaspiro[4.5]decan-8-ylidene)prop ane-2-sulfinamide (10 g, 38.61 mmol) in THF (500 mL) at −10° C. under argon atmosphere. The reaction mixture was stirred for 2 h at −10° C. to 0° C. The reaction completion was monitored by TLC. The reaction mixture was quenched with sat. aq. NH4Cl (50 mL) at 0° C. and the organic product was extracted with EtOAc (3×100 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel 230-400 mesh; 40-60% ethyl acetate in hexane) to yield 6.0 g (46%) of 2-methyl-N-(8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)propane-2-sulfinamide as a liquid (TLC system: 70% Ethyl acetate in hexane; Rf: 0.30).
- 2N solution of HCl in diethyl ether (17.80 mL, 35.60 mmol) was added to a solution of 2-methyl-N-(8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)propane-2-sulfinamide (6.0g, 17.80 mmol) in DCM (60 mL) at 0° C. The reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated in vacuo. The residue was washed with diethyl ether to yield 3 g (crude) of 8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine hydrochloride as a brown solid (TLC system: 5% MeOH in DCM; Rf: 0.10).
- Sodium cyanoborohydride (2.17 g, 33.45 mmol) was added to a solution of 8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine hydrochloride (3.0 g, 11.15 mmol) and tetrahydrofuran-3-carbaldehyde (4.46 mL, 22.30 mmol) and acetic acid (0.05 mL) in methanol (30 mL) at 0° C. The reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated in vacuo at 30° C. and to the residue sat. aq. NaHCO3 was added. The organic product was extracted with DCM (3×30 mL). The combined organic extracts were dried over anhydrous Na2SO4 and solvent was concentrated under reduced pressure to get 3 g (crude) of 8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine as a semi-solid (TLC system: 10% MeOH in DCM; Rf: 0.22).
- Sodium cyanoborohydride (1.76 g, 28.39 mmol) was added to a solution of 8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine (3.0 g, 9.46 mmol), 37% formaldehyde in water (7.70 mL, 94.60 mmol) and acetic acid (0.05 mL) in methanol (30 mL) at 0° C. The reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated in vacuo and to the residue sat. aq. NaHCO3 was added. The organic product was extracted with DCM (3×30 mL). The combined organic extracts were dried over anhydrous Na2SO4 and solvent was concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel 230-400 mesh; 5-6% MeOH in DCM) to yield 2.50 g (83%) of N-methyl-8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine as a semi solid (TLC system: 10% MeOH in DCM; Rf: 0.25).
- 5% sulfuric acid in water (25 mL) was added to N-methyl-8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine (2.50 g, 7.55 mmol) at 0° C. and the resulting mixture was stirred at RT for 24 h. The reaction mixture was quenched with sat. aq. NaHCO3 and the organic product was extracted with DCM (2×50 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo to afford 2.0 g (crude) of 4-(methyl((tetrahydrofuran-3-yl)methyl)amino)-4-phenylcyclohexanone as a thick liquid (TLC system: 10% MeOH in DCM, Rf: 0.20).
- 4-(methyl((tetrahydrofuran-3-yl)methyl)amino)-4-phenylcyclohexanone (1.50 g, 5.22 mmol) was suspended in 30 mL of EtOH:H2O (1:1 v/v) at RT under argon atmosphere. (NH4)2CO3 (1.9 g, 13.05 mmol) and KCN (0.34 g, 5.22 mmol) were added. The reaction mixture was heated to 70° C. for 16 h. The reaction mixture was diluted with ice-water and the organic product was extracted with DCM (2×50 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to give 1.0 g (crude) of 8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione as a solid (TLC system: 70% Ethyl acetate in hexane; Rf: 0.18).
- Diastereomeric mixture of 8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione (1.0 g) was separated by reverse phase preparative HPLC to afford 400 mg of isomer 1 (CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione) and 60 mg of isomer 2 (TRANS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione) and 300 mg of mixture of both isomers. Reverse phase preparative HPLC conditions: mobile phase: 10 mM ammonium bicarbonate in H2O/acetonitrile, column: X-BRIDGE-C18 (150*30), Sum, gradient (T/B %): 0/35, 8/55, 8.1/98, 10/98, 10.1/35, 13/35, flow rate: 25 ml/min, diluent: mobile phase+THF.
- LiAlH4 (1M in THF) (4.48 mL, 4.48 mmol) was added to a solution of CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione (isomer-1) (0.4 g, 1.12 mmol) in THF:Et2O (2:1 v/v, 15 mL) at 0° C. under argon atmosphere .The reaction mixture was stirred at 65° C. for 16 h. The mixture was cooled to 0° C., quenched with sat. aq. Na2SO4 (1000 mL) and filtered through celite pad. The filtrate was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel 230-400 mesh; 5-6% MeOH in DCM) to yield 0.3 g (78%) of CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1026) as an off white solid. (TLC system: 10% MeOH in DCM, Rf: 0.2). LC-MS: m/z [M+1]+=344.2.
-
- In analogy to the method described for INT-952 CIS-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one (INT-974) was converted into CIS-1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one.
- In analogy to the method described for INT-982 step 2 1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one was converted into 1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one (INT-1031).
-
- Lithiumaluminiumhydride (2.2 equiv., 292 mmol) was suspended in THF (400 mL) and the suspension was cooled to 0° C. 8-(Dimethylamino)-8-(m-tolyl)-1,3-diazaspiro[4.5]decan-2-one (B, 75 mg, 0.261 mmol) (step 1 of INT-965) was added portionwise at 0° C. The reaction mixture was stirred 1.5 h at 0° C., then overnight at RT and then 2 h at 40° C. The reaction mixture was cooled down to 0° C., quenched carefully with sat. aq. Na2SO4, EtOAc (400 mL) was added and the resulting mixture was stirred for 2 h and then left without stirring for 2 h at RT. The precipitate was filtered off and washed with EtOAc and MeOH. The resulting solid residue was suspended in methanol and stirred at RT overnight. The precipitate was filtered off and disposed. The filtrate was concentrated under reduced pressure, the residue was suspended thoroughly in water (50 mL) at 40° C., the precipitate was filtered off and dried under reduced pressure to yield 9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}.2{circumflex over ( )}{5}]tetradecan-3-one (11.4 g, 41%). Mass: m/z 213.2 (M+H)+.
- In analogy to the method described for INT-1003 step 3 9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}.2{circumflex over ( )}{5}]tetradecan-3-one was treated with conc. aq. HCl to be converted into 1,3-diazaspiro[4.5]decane-2,8-dione. Mass: m/z 169.1 (M+H)+.
- In analogy to the method described for INT-965 step 1 1,3-diazaspiro[4.5]decane-2,8-dione was treated with dimethyl amine and potassium cyanide to be converted into 8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile (INT-1037). Mass: m/z 223.2 (M+H)+.
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- To the suspension of 8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile (200 mg, 0.90 mmol) in THF (4 mL) at RT was added dropwise 1M bromo(m-tolyl)magnesium in THF (4 equiv., 3.6 mmol, 3.6 mL) and the reaction mixture was stirred for 1 h at RT. Additional portion of 1M bromo(m-tolyl)magnesium in THF (1 equiv., 0.8 mL) was added. The reaction mixture was stirred at RT overnight, then quenched with methanol/water. Solid NH4Cl and DCM were added to the resulting mixture and the precipitate was filtered off. The organic phase of the filtrate was separated and the aqueous phase was extracted with DCM (3×). The combined organic phases were dried over anhydr. Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (DCM/MeOH, 100/0 to 65/35) to yield CIS-8-(dimethylamino)-8-(m-tolyl)-1,3-diazaspiro[4.5]decan-2-one (INT-1038) (81 mg, 31%). Mass: m/z 288.2 (M+H)+.
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- To a solution of CIS-8-dimethylamino-3-(4-methoxy-benzyl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (INT-975) (19.5 g, 49.6 mmol, 1.0 eq.) in THF (180 ml) was added 2.5M solution of n-BuLi in hexane (39.7 ml, 99.23 mmol, 2.0 eq.) at 0° C. and the resulting mixture was stirred for 1 h. A solution of acetyl chloride (7.7 g, 99.23 mmol, 2.0 eq.) in THF (20 ml) was added dropwise at 0° C. The cooling bath was removed, the reaction mixture was stirred at RT for 16 h, then cooled down to 0° C. again, quenched with water and extracted with ethyl acetate (2×200 ml). The combined organic extracts were washed with brine (250 ml), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; 30% EtOAc/Hexane) to yield CIS-1-acetyl-8-dimethylamino-3-(4-methoxy-benzyl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (6.1 g, 14.02 mmol, 28%) as a light yellow sticky solid. Mass: m/z 436.3 [M+H]+
- To a solution of CIS-1-acetyl-8-dimethylamino-3-(4-methoxy-benzyl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (5.0 g, 11.5 mmol, 1.0 eq.) in acetonitrile (60 ml) was added a solution cerium(IV) ammonium nitrate (18.98 g, 34.5 mmol, 3.0 eq.) in water (60 ml) at 0° C. and the reaction mixture was stirred at RT for 2 h. The reaction mixture was quenched with aq. NaHCO3 solution (50 ml) and extracted with ethyl acetate (2×100 ml). The combined organic layer was washed with brine (2×100 ml), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel neutralized with TEA; 2/3 v/v EtOAc/Hexane) to yield CIS-1-acetyl-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (INT-1064) as an off white solid. Yield: 61% (4.9 g, 15.55 mmol). 1HNMR (DMSO-d6, 400 MHz), δ (ppm)=7.57 (s, 1H), 7.33-7.23 (m, 5H), 3.21 (s, 2H), 3.03 (t, 2H, J=12.78 Hz), 2.60 (d, 2H, J=13.32 Hz), 2.32 (s, 3H), 1.89 (s, 6H), 1.37-1.32 (m, 4H). Mass: m/z 316.2 [M+H]+
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- To a stirred solution of 4-dimethylamino-4-phenyl-cyclohexanone (250.0 g, 1.15 mol, 1.0 eq.) in EtOH (2.5 L) and water (2.1 L) was added (NH4)2CO3 (276.2 g, 2.87 mol, 2.5 eq.) and the reaction mixture was stirred at RT for 15 min. KCN (74.92 g, 1.15 mol, 1.0 eq.) was added. The reaction mixture was stirred at 60° C. for 18 h and then filtered in hot condition to get white solid which was washed with water (2.5 L), ethanol (1 L) and hexane (2.5 L). The resulting solid was dried under reduced pressure to get CIS-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (223 g, 0.776 mol, 65%) as a white solid. The filtrate was collected from multiple batches (˜450 g) which contained a mixture of cis and trans isomers. The filtrate was concentrated under reduced pressure and solid obtained was filtered and washed with water (1 L) and hexane (1 L). Solid material was dried under reduced pressure to get ˜100 g of a mixture of cis and trans (major) isomers. Crude material was partially dissolved in hot MeOH (600 mL) and cooled to RT, filtered through sintered funnel, washed with MeOH (200 mL) followed by ether (150 mL) and dried to get TRANS-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (50 g, 0.174 mmol, ˜9-10%).
- In analogy to the method described for INT-976 step 2 TRANS-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione was treated with LiAlH4 to be converted into TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1059). Mass: m/z 274.2 (M+H)+.
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- To a solution of CIS-1-acetyl-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1064) (1 g, 3.17 mmol) in DMF (37 mL) was added sodium hydride (60 wt % in mineral oil, 1.25 equiv., 3.96 mmol, 159 mg) portionwise at 0° C. The reaction mixture was stirred for 15 min at 0° C. and 2-chloro-4-(chloromethyl)pyridine (1.25 equiv., 3.96 mmol, 0.485 mL) was added. The reaction mixture was stirred at RT for 2 h, then cooled down to 0° C., quenched with sat. aq. NaHCO3 (10 mL), water (10 mL) and extracted with EtOAc (2×50 mL). Combined organic phase was washed with brine, dried over anhydr. Na2SO4 and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel (eluent MeCN/DCM 98/2) to yield 1215 mg (87%) of CIS-1-acetyl-342-chloropyridin-4-yl)methyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one. Mass: m/z 441.2 (M+H)+.
- To a solution of CIS-1-acetyl-3-((2-chloropyridin-4-yl)methyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (1140 mg, 2.59 mmol) in THF/MeOH (2:1 v/v, 15 mL) was added 3M aq. NaOH (26 mL). The reaction mixture was stirred for 1.5 h at RT and then extracted with EtOAc (2×50 mL). The combined organic phase was dried over anhydr. Na2SO4 and concentrated under reduced pressure to yield 932 mg (90%) of CIS-3-((2-chloropyridin-4-yl)methyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1065) which was used in the next steps without additional purification. Mass: m/z 399.2 (M+H)+.
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- To a stirred solution of 4-dimethylamino-4-phenyl-cyclohexanone (50 g, 230.096 mmol) in MeOH (400 mL) was added NH4Cl (24.6 g, 460.8 mmol) followed by NH4OH (400 mL) at RT and the reaction mixture was stirred for 15 min. NaCN (22.5 g, 460.83 mmol) was added and the resulting mixture was stirred for 16 h at RT. The reaction mixture was extracted with DCM (3×750 mL). Combined organic layer was washed with water (750 mL), brine (750 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was triturated with DCM/hexane to get crude 1-amino-4-dimethylamino-4-phenyl-cyclohexanecarbonitrile (50 g, 90%) as an off white solid which was used in next step without further purification. LC-MS: m/z [M+H]+=244.2 (MW calc. 244.09).
- To a solution of 1-amino-4-dimethylamino-4-phenyl-cyclohexanecarbonitrile (5.0 g, 20.57 mmol, 1.0 eq.) in THF (100 ml) were added DIPEA (10.72 ml, 61.71 mmol, 3.0 eq), trifluoroacetic acid (1.89 ml, 24.69 mmol, 1.2 eq) and T3P (18.2 ml, 30.85 mmol, 1.5 eq) at 0° C. The reaction mixture was stirred at RT for 16 h, then diluted with water (100 ml) and extracted with 10% MeOH in DCM (2×250 mL). Combined organic layer was washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to get crude N-(1-cyano-4-dimethylamino-4-phenyl-cyclohexyl)-2,2,2-trifluoroacetamide as a light yellow sticky material which was used in the next step without further purification. LC-MS: m/z [M+1]+=339.9 (MW calc. 339.36).
- To suspension of LiAlH4 (4.03 g, 106.19 mmol, 6.0 eq.) in dry THF (40 mL) was added N-(1-cyano-4-dimethylamino-4-phenyl-cyclohexyl)-2,2,2-trifluoro-acetamide (6.0 g, 17.69 mmol, 1.0 eq.) in dry THF (100 mL) dropwise at 0° C. The reaction mixture was stirred at RT for 16 h, then quenched with sat. aq. Na2SO4 at 0° C., excess THF was added and the resulting mixture was stirred at RT for 2 h. The resulting suspension was filtered through celite and the filter cake was washed with 10% MeOH in DCM (150 mL). Combined filtrate was concentrated under reduced pressure to yield crude 1-aminomethyl-N′,N′-dimethyl-4-phenyl-N-(2,2,2-trifluoro-ethyl)-cyclohexane-1,4-diamine (4.2 g, crude) as a light yellow sticky material which was directly used in the next step without further purification. LC-MS: m/z [M+1]+=330.0 (MW calc. 329.40).
- To a solution of 1-aminomethyl-N′,N′-dimethyl-4-phenyl-N-(2,2,2-trifluoro-ethyl)-cyclohexane-1,4-diamine (4.2 g, 12.76 mmol, 1.0 eq.) in toluene (60 ml) was added KOH (4.29 g, 76.56 mmol, 6.0 eq.) in water (120 ml) at 0° C. followed by addition of COCl2 (15.6 ml, 44.66 mmol, 3.5 eq., 20% in toluene) at 0° C. and stirred at RT for 16 h. Reaction mixture was basified with sat NaHCO3 solution and extracted with DCM (2×200 ml). Combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to get crude product which was purified by prep HPLC to get CIS-8-dimethylamino-8-phenyl-1-(2,2,2-trifluoro-ethyl)-1,3-diaza-spiro[4.5]decan-2-one (INT-1068) (1.5 g) (major isomer, polar spot on TLC) and TRANS-8-dimethylamino-8-phenyl-1-(2,2,2-trifluoro-ethyl)-1,3-diaza-spiro[4.5]decan-2-one (INT-1069) as minor isomer (non-polar spot on TLC) (120 mg, 92.93% by HPLC) as off-white solids. CIS-isomer: LC-MS: m/z [M+1]+=356.2 (MW calc.=355.40). HPLC: 98.53%, Column: Xbridge C-18 (100×4.6), 5 μ, Diluent: MeOH, Mobile phase: A) 0.05% TFA in water; B) ACN flow rate: 1 ml/min, Rt=5.17 min. 1HNMR (DMSO-d6, 400 MHz), δ (ppm)=7.43-7.27 (m, 5H), 6.84 (s, 1H), 3.30-3.25 (m, 4H), 2.66-2.63 (d, 2H, J=12.72 Hz), 1.89 (s, 6H), 1.58-1.51 (m, 2H), 1.46-1.43 (m, 2H), 1.33-1.23 (m, 2H).
- For further intermediates the synthesis in analogy to previously described methods is given in the following table. The syntheses of the building blocks and intermediates have either been described previously within this application or can be performed in analogy to the herein described methods or by methods known to the person, skilled in the art. Such a person will also know which building blocks and intermediates need to be chosen for synthesis of each exemplary compound.
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Inter- in analogy m/z mediate Chemical Name to method [M + H]+ INT-794 CIS-3-(3,4-dimethoxybenzyl)- 8-(dimethylamino)-8-phenyl- 1,3-diazaspiro[4.5]decan- 2-one SC_2097 424.3 INT-796 CIS-8-Dimethylamino-3-[(4- methoxyphenyl)-methyl]-8-(3- methoxy-propyl)-1,3- diazaspiro[4.5]decan-2-one SC_2017 390.3 INT-797 CIS-8-(Ethyl-methyl-amino)- 8-phenyl-1,3-diazaspiro[4.5] decan-2-one INT-976 288.2 INT-798 CIS-3-[[8-(Ethyl-methyl- amino)-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan- 3-yl]-methyl]-benzonitrile SC_2097 403.3 INT-949 CIS-8-Dimethylamino-1- ethyl-8-phenyl-1,3- diazaspiro[4.5]decan- 2-one INT-984 302.2 INT-950 CIS-1-(Cyclobutyl-methyl)- 8-dimethylamino-8-phenyl- 3-[phenyl-methyl]- 1,3-diazaspiro[4.5]decan- 2-one SC_2125 432.3 INT-954 4-Dimethylamino-4-(5- methyl-thiophen-2-yl)- cyclohexan-1-one INT-965 238.1 INT-955 1-one 4-Dimethylamino-4- thiophen-2-yl-cyclohexan- 1-one INT-965 224.1 INT-956 1-(1-Methyl-1H-pyrazol-3- yl)-4-oxo-cyclohexane-1- carbonitrile INT-958 204.1 INT-957 4-Oxo-1-pyrazin-2-yl- cyclohexane-1-carbonitrile INT-958 202.1 INT-959 4-Dimethylamino-4-(1- methyl-1H-pyrazol-3-yl)- cyclohexan-1-one INT-961 222.2 INT-960 4-Dimethylamino-4-pyrazin- 2-yl-cyclohexan-1-one INT-961 220.1 INT-962 4-Dimethylamino-4-(3- methoxyphenyl)-cyclohexan- 1-one INT-965 248.2 INT-963 CIS-3-Benzyl-8- dimethylamino-8-phenyl- 1,3-diazaspiro[4.5]decan- 2-one INT-975 364.2 INT-964 4-(Ethyl-methyl-amino)-4- phenyl-cyclohexan-1-one INT-965 232.2 INT-967 CIS-8-Dimethylamino-8-[4- (methoxymethyloxy)-phenyl]- 3-[(4-methoxyphenyl)- methyl]-1,3-diazaspiro[4.5] decan-2-one SC_2017 454.3 INT-968 CIS-8-Dimethylamino-8-[3- (methoxymethyloxy)-phenyl]- 3-[(4-methoxyphenyl)- methyl]-1,3-diazaspiro[4.5] decan-2-one SC_2017 454.3 INT-969 CIS-1-(Cyclobutyl-methyl)- 8-dimethylamino-8-(4- hydroxyphenyl)-3-[(4- methoxyphenyl)-methyl]- 1,3-diazaspiro[4.5]decan- 2-one SC_2018 478.3 INT-970 CIS-8-Dimethylamino-8-(4- methoxyphenyl)-3-[(4- methoxyphenyl)-methyl]- 1,3-diazaspiro[4.5]decan- 2-one SC_2017 424.3 INT-972 CIS-8-Dimethylamino-8-(3- methoxyphenyl)-3-[(4- methoxyphenyl)-methyl]- 1,3-diazaspiro[4.5]decan- 2-one SC_2017 424.3 INT-979 CIS-8-Dimethylamino-1-(3- methoxy-propyl)-8-phenyl- 1,3-diazaspiro[4.5]decan- 2-one INT-984 346.2 INT-980 CIS-8-Dimethylamino-1-(2- methoxy-ethyl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one INT-984 332.2 INT-981 CIS-8-Dimethylamino-8- phenyl-1-propyl-1,3- diazaspiro[4.5]decan-2- one INT-984 316.2 INT-983 CIS-1-(Cyclopropyl-methyl)- 8-dimethylamino-8-phenyl- 1,3-diazaspiro[4.5]decan- 2-one INT-984 328.2 INT-985 CIS-1-(Cyclobutyl-methyl)- 8-(methyl-propyl-amino)-8- phenyl-1,3-diazaspiro[4.5] decan-2-one INT-986 370.3 INT-993 4-benzyl-4-(dimethylamino) cyclohexanone INT-965 232.3 INT-994 CIS-8-benzyl-8- (dimethylamino)-1,3- diazaspiro[4.5]decan-2-one INT-976 288.2 INT-995 TRANS-8-benzyl-8- (dimethylamino)-1,3- diazaspiro[4.5]decan-2-one INT-976 288.2 INT-997 CIS-8-(dimethylamino)-8- (thiophen-2-yl)-1,3- diazaspiro[4.5]decan-2-one INT-976 280.1 INT-998 TRANS-8-(dimethylamino)- 8-(thiophen-2-yl)-1,3- diazaspiro[4.5]decan-2-one INT-976 280.1 INT-999 4-(dimethylamino)-4-(1- methyl-1H-benzo[d] imidazol-2-yl) cyclohexanone INT-965 272.2 INT-1000 CIS-8-(dimethylamino)-8-(1- methyl-1H-benzo[d]imidazol- 2-yl)-1,3-diazaspiro[4.5] decan-2-one INT-976 328.2 INT-1001 TRANS-8-(dimethylamino)- 8-(1-methyl-1H-benzo[d] imidazol-2-yl)-1,3-diazaspiro [4.5]decan-2-one INT-976 328.2 INT-1009 TRANS-8-ethylamino-8- phenyl-1,3-diaza-spiro [4.5]decan-2-one INT-1008 274.2 INT-1024 CIS-8-(dimethylamino)-8-(3- fluorophenyl)-1,3-diazaspiro [4.5]decan-2-one INT-977 (step 2) 292.2 INT-1025 CIS-8-(dimethylamino)-8-(4- fluorophenyl)-1,3-diazaspiro [4.5]decan-2-one INT-974, INT-977 (step 2) 292.2 INT-1029 CIS-1-(cyclobutylmethyl)-8- (dimethylamino)-8-phenyl- 3-(prop-2-yn-1-yl)-1,3- diazaspiro[4.5]decan-2-one INT-1010 380.3 INT-1030 ethyl CIS-2-(4-((1- (cyclobutylmethyl)-8- (dimethylamino)-2-oxo-8- phenyl-1,3-diazaspiro[4.5] decan-3-yl)methyl)-1H- 1,2,3-triazol-1-yl)acetate INT-1011 509.3 INT-1039 CIS-8-(dimethylamino)-8-(3- (trifluoromethoxy)phenyl)- 1,3-diazaspiro[4.5]decan- 2-one INT-1038 358.2 INT-1040 (CIS)-8-(dimethyl amino)-8- (3-(trifluoromethyl)phenyl)- 1,3-diazaspiro[4.5]decan- 2-one INT-1038 342.2 INT-1041 (CIS)-8-(dimethylamino)-8- (3-methoxyphenyl)-1,3- diazaspiro[4.5]decan-2-one INT-1038 304.2 INT-1042 (CIS)-8-(5-chlorothiophen-2- yl)-8-(dimethylamino)-1,3- diazaspiro[4.5]decan-2-one INT-1038 314.1 INT-1043 (CIS)-8-(dimethylamino)-8- (3-fluoro-5-methylphenyl)- 1,3-diazaspiro[4.5]decan- 2-one INT-1038 306.2 INT-1044 (CIS)-8-(3-chlorophenyl)-8- (dimethylamino)-1,3- diazaspiro[4.5]decan-2-one INT-1038 308.2 INT-1047 (CIS)-8-(methyl(oxetan-3- ylmethyl)amino)-8-phenyl- 1,3-diazaspiro[4.5]decan- 2-one INT-1026 330.5 INT-1061 TRANS-1-(cyclopropyl- methyl)-8-dimethylamino- 8-phenyl-1,3-diazaspiro [4.5]decan-2-one INT-984 328.2 INT-1063 CIS-1-(cyclopropylmethyl)- 8-(dimethylamino)-8-(3- fluorophenyl)-1,3- diazaspiro[4.5]decan-2-one INT-1031 346.2 INT-1066 TRANS-1- (cyclobutylmethyl)-8- (dimethylamino)-8-phenyl- 1,3-diazaspiro[4.5]decan- 2-one INT-987 342.3 INT-1070 CIS-8-(dimethylamino)-8- phenyl-1-(3,3,3- trifluoropropyl)-1,3- diazaspiro[4.5]decan-2-one INT-1068 360.2 INT-1074 CIS-8-(dimethylamino)-8- (3-fluorophenyl)-1-((1- hydroxycyclobutyl)methyl)- 1,3-diazaspiro[4.5]decan- 2-one INT-1031 376.2 - Synthesis of Exemplary Compounds
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- NaH (60% in mineral oil) (70 mg, 2.93 mmol) and 1-(bromomethyl)-3-methoxy-benzene (58 mg, 0.29 mmol) were sequentially added to a suspension of CIS-1-(cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-987 (100 mg, 0.29 mmol) in DMF (3 mL) at 0° C. and the reaction mixture was stirred at RT for 30 min. The reaction completion was monitored by TLC. The reaction mixture was quenched with sat. aq. NH4Cl solution and the organic product was extracted with EtOAc (2×12mL). The combined organic layer was dried over anhydrous MgSO4 and concentrated in vacuo. Purification of the residue by flash column chromatography over silica gel (230-400 mesh) using 30-35% ethyl acetate in petroleumether as eluent yielded 42 mg of CIS-1-(cyclobutyl-methyl)-8-dimethylamino-3-[(3-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2002 as solid. [M+H]+462.3
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- To the solution of CIS-1-(cyclobutyl-methyl)-3-[(4-methoxyphenyl)-methyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2044 (70 mg, 0.16 mmol) in MeCN (1 mL) was added potassium carbonate (216 mg, 1.56 mmol). The reaction mixture was stirred for 15 min, 3-bromo-prop-1-ene (41 μL, 0.47 mmol) was added and stirring was continued at RT for 3 days. The mixture was then diluted with DCM, filter through celite and the filtrate was concentrated in vacuo. Purification of the residue by flash column chromatography provided 44 mg of CIS-8-(allyl-methyl-amino)-1-(cyclobutyl-methyl)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2008 as a solid. [M+H]+488.3.
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- CIS-8-Dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one (SC_2017) (0.2 g, 0.48 mmol) was added to the solution of NaH (60% in mineral oil) (0.08 g, 1.94 mmol) in DMF (5 mL) and the reaction mixture was stirred at RT for 1 h. The reaction mixture was cooled to 0° C., (bromomethyl)cyclobutane (0.21 mL, 1.94 mmol) was added dropwise and stirring was continued for 30 min at 0° C. and then for 2 days at RT. The reaction completion was monitored by TLC. The reaction mixture was quenched with sat. aq. NH4Cl and the organic product was extracted with EtOAc (2×10mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (100-200 mesh) using 0-50% EtOAc in petroleumether as eluent gave 0.1 g of product which was further purified by preparative TLC using 30% EtOAc in petroleumether as mobile phase to give 65 mg (28%) of CIS-1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one (SC_2010) as an off white solid. (TLC system: 30% EtOAc in petroleumether; Rf: 0.6). [M+H]+480.3
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- A solution of NaOH (81 mg, 2.0 mmol) in DMSO (1 mL) was stirred at RT for 10 min. CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_2097) (200 mg, 1.52 mmol) was added and stirring was continued for 15 min. Isobutyl-bromide (20 mg, 1.52 mmol) was added and the reaction mixture was heated to 60° C. for 16 h. After cooling to RT, water (100 mL) was added and the resulting mixture was extracted with DCM (3×150 mL). The combined organic layers were washed with water (70 mL) and brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification of the residue by column chromatography provided CIS-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-(2-methyl-propyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2014 (72 mg) as a solid. [M+H]+450.3
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- Dimethylamine hydrochloride (76.36 g, 936.39 mmol) was added to a solution of 3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decane-2,8-dione INT-966 (90 g, 312.13 mmol) in MeOH (180 mL) at RT under argon atmosphere. The solution was stirred for 15 min and 40% aq. dimethylamine (780 mL) and KCN (48.76 g, 749.11 mmol) were sequentially added. The reaction mixture was stirred for 48 h while being monitored by NMR. The reaction mixture was diluted with water (1.0 L) and the organic product was extracted with EtOAc (2×2.0 L). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 90 g (85%) of 8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile as an off white solid (TLC system: TLC system: 10% MeOH in DCM; Rf: 0.35, 0.30).
- 3-Fluorophenylmagnesium bromide (1M in THF) (220 mL, 219.17 mmol) was added dropwise to a solution of 8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile (15 g, 43.83 mmol) in THF (300 mL) at 0° C. under argon atmosphere. The reaction mixture was stirred for 16 h at RT. The reaction completion was monitored by TLC. The reaction mixture was cooled to 0° C., quenched with sat. aq. NH4Cl (200 mL) and the organic product was extracted with EtOAc (2×200 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The reaction was carried out in 4 batches (15 g×2 and 5 g×2) and the batches were purified together. Purification of the residue by flash column chromatography over silica gel (230-400 mesh) (2 times) by using 0-20% methanol in DCM as eluent and further purified by washing with pentane yielded 5.6 g (11%) of CIS-8-Dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one SC_2017 as off-white solid. (TLC system: 5% MeOH in DCM in presence of ammonia; Rf: 0.1). [M+H]+412.2
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- In analogy to the method described for INT-951 step 1 CIS-8-dimethylamino-8-[3-(methoxymethyloxy)-phenyl]-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one (INT-968) was converted into CIS-1-(cyclobutylmethyl)-8-(dimethylamino)-3-(4-methoxybenzyl)-8-(3-(methoxymethoxy)phenyl)-1,3-diazaspiro[4.5]decan-2-one.
- TFA (0.2 mL) was added to a solution of CIS-1-(cyclobutylmethyl)-8-(dimethylamino)-3-(4-methoxybenzyl)-8-(3-methoxyphenyl)-1,3-diazaspiro[4.5]decan-2-one (300 mg, 0.57 mmol) in DCM (1.5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 3 h. The reaction completion was monitored by TLC. The reaction mixture was quenched with sat. aq. NaHCO3 and the organic product was extracted with DCM (3×10mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification of the residue by preparative TLC using 3% MeOH in DCM as a mobile phase yielded 50 mg (18%) of CIS (cyclobutyl-methyl)-8-dimethylamino-8-(3-hydroxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one (SC_2018) as an off white solid. (TLC system: 10% MeOH in DCM; Rf: 0.20) [M+H]+478.3
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- KOtBu (411 mg, 3.66 mmol) was added to a solution of CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-987) (250 mg, 0.73 mmol) in THF (6 mL) under nitrogen atmosphere and the reaction mixture was stirred at RT for 30 min. After cooling to 0° C. 3-(chloromethyl)pyridine hydrochloride (180 mg, 1.10 mmol) was added and the reaction mixture was stirred at 0° C. for 30 min and then at RT for 3 days. The resulting mixture was diluted with water, extracted with DCM (3×), the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. Purification of the residue by flash column chromatography provided 208 mg of CIS-1-(cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(pyridin-3-yl-methyl)-1,3-di-azaspiro[4.5]decan-2-one (SC_2019). [M+H]+433.3
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- CIS-8-Dimethylamino-1-(2-hydroxy-2-methyl-propyl)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2024 (0.2 g, 0.42 mmol) was added to a solution of NaH (60% in mineral oil) (0.01 g, 0.42 mmol) in DMF (5 mL) at RT. The reaction mixture was stirred at RT for 30 min, then cooled to 0° C. and methyl iodide (0.08 g, 1.28 mmol) was added dropwise. the resulting mixture was stirred for 30 min at 0° C. and then for 16 h at RT. The reaction completion was monitored by TLC. The reaction mixture was quenched with sat. aq. NH4Cl and the organic product was extracted with EtOAc (2×10 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC using 30% EtOAc in petroleumether as a mobile phase to give 40 mg (20%) of CIS-8-dimethylamino-1-(2-methoxy-2-methyl-propyl)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_2025) as an off white solid. (TLC system: 30% EtOAc in Pet. Ether; Rf: 0.6). [M+H]+480.3.
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- N-Iodosuccinimide (437 mg, 1.95 mmol) was added to a suspension of CIS-1-(cyclobutyl-methyl)-8-dimethylamino-3-[(3-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_2002) (600 mg, 1.30 mmol) in a mixture of acetonitrile and THF (1:1 v/v, 20 mL) at RT and the resulting mixture was stirred at RT for 16 h. The reaction mixture was basified with 2N aq. NaOH to pH˜10 and the organic product was extracted with DCM (3×10 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was stirred vigorously with a mixture of 10% aqueous citric acid solution (5 mL) and DCM (10 mL) at RT for 10 min. The resulting mixture was basified with 5N aq. NaOH to pH˜10 and extracted with DCM (3×10 mL). The combined organic layer was dried over anhydrous sodium sulfate and was concentrated in vacuo. The residue was purified by preparative reverse phase HPLC [Column: KINETEX C-18(150*21.2)5 μ and mobile phase: 10 mM ammonium bicarbonate-acetonitrile] to give 120 mg (20%) of CIS-1-(Cyclobutyl-methyl)-3-[(3-methoxyphenyl)-methyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_2026) as semi solid (TLC system: 10% MeOH in DCM; Rf: 0.20.). [M+H]+448.3
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- Sodium cyanoborohydride (20 mg, 0.33 mmol) was added to a solution of CIS-1-(cyclobutyl-methyl)-3-[(3-methoxyphenyl)-methyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_2026) (60 mg, 0.13 mmol), propionaldehyde (19 mg, 0.33 mmol) and acetic acid (0.05 mL) in methanol (5 mL) at RT. The reaction mixture was stirred at RT for 3 h. The reaction mixture was quenched with sat. aq. NaHCO3 and the organic product was extracted with DCM (10 mL3). The combined organic extracts were dried over anhydr. Na2SO4 and concentrated under reduced pressure. A second batch of this reaction was carried out starting from 100 mg of CIS-1-(Cyclobutyl-methyl)-3-[(3-methoxyphenyl)-methyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2026 in a similar manner. Both batches were combined and purified by preparative TLC to give 45 mg (25%) of CIS-1-(cyclobutyl-methyl)-3-[(3-methoxyphenyl)-methyl]-8-(methyl-propyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_2028) as semi solid (TLC system: 10% MeOH in DCM; Rf: 0.25). [M+H]+490.3
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- NaH (55% in mineral oil) (0.26 g, 6.10 mmol) was added to a solution of CIS-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_2097) (0.4 g, 1.02 mmol) in DMF (10 mL) at 0° C. The reaction mixture was stirred at 0° C. for 15 min. To the reaction mixture (2-bromoethoxy)(tert-butyl)dimethylsilane (1.45g, 6.10 mmol) was added dropwise over 5 min at 0° C. The reaction mixture was allowed to stir at RT for 16 h and then diluted with water (15 mL). The organic product was extracted with ethyl acetate (3×25mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was dissolved in THF (8 mL) and cooled to 0° C. Then a 1M TBAF solution in THF (1.8 mL, 1.81 mmol) was added at 0° C. The reaction mixture was allowed to stir at RT for 2 h. The reaction mixture was diluted with water (10 mL), the organic product was extracted with DCM (3×25mL). The combined organic extracts were washed with sat. aq. NaHCO3, water and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification by prep HPLC using 10 Mm ammonium bicarbonate-acetonitrile as mobile phase yielded 93 mg of compound which was further washed with n-pentane (5 mL) to give 85 mg (19% after two steps) of CIS-8-dimethyl-amino-1-(2-hydroxy-ethyl)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_2034) as off white solid. (TLC system: 5% MeOH in DCM Rf: 0.30). [M+H]+438.3
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- NaH (50% in mineral oil) (24 mg, 0.6 mmol) was added to a stirred solution of CIS-1-(cyclobutyl-methyl)-3-[(4-methoxyphenyl)-methyl]-8-methylamino-8-phenyl-1,3-diazaspiro [4.5]decan-2-one (SC_2044) (134 mg, 0.3 mmol) in DMF (1 mL) at 0° C. Then iodoacetonitrile (0.11 mL, 1.5 mmol) was added dropwise at 0° C. over a period of 10 min. The reaction mixture was allowed to stir at RT for 16 h. The reaction mixture was quenched with water and the organic product was extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Purification of the residue by flash column chromatography provided 13 mg of CIS-2-[[1-(cyclobutyl-methyl)-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-8-yl]-methyl-amino]-acetonitrile (SC_2040). [M+H]+487.3
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- CIS-8-D imethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2097 (500 mg, 1.3 mmol) was dissolved in 1.7 mL THF and LDA (2M solution in THF, 2.5 mL) was added at 0° C. The reaction mixture was stirred at RT for 30 min, then cooled to 0° C. and tert-butylbromoacetate (0.5 mL, 3.8 mmol) was added. The reaction was stirred for 18 h, then diluted with water and extracted with DCM (3×10 ml). The combined organic layers were dried over Na2SO4, concentrated in vacuo and the residue was purified by flash chromatography to yield CIS-2-[8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-hacetic acid tert-butyl ester (SC_2042) (470 mg) as a white solid. [M+H]+508.3
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- CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetic acid tert-butyl ester SC_2042 (200 mg, 0.4 mmol) was dissolved in trifluoroacetic acid (5 mL) and stirred at RT for 30 min. All volatiles are removed in vacuo to yield CIS-2-[8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]acetic acid 2,2,2-trifluoro-acetic acid salt SC_2043 (190 mg) as a solid. [M+H]+452.3
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- To a mixture of CIS-2-[8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetic acid 2,2,2-trifluoro-acetic acid salt (SC_2043) (60 mg, 0.11 mmol), n-propylamine (35 μL, 0.43 mmol) and DIPEA (109 μL, 0.64 mmol) in DMF (1 ml) was added HATU (60 mg, 0.16 mmol) and the reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched with a 1M aq. NaHCO3, diluted with water and extracted with DCM (3×). The combined organic layers were washed with water (3 mL), brine (3 ml), dried over Na2SO4, filtered and concentrated in vacuo. Flash column chromatography of the residue provided CIS-2-[8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-propyl-acetamide (SC_2049) (20 mg). [M+H]+493.3
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- CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]acetamide (SC_2046) (37 mg, 0.083 mmol) was dissolved in EtOAc (1 mL) and triethylamine (23 μL, 0.166 mmol) and T3P (59 μL, 0.099 mmol) were sequentially added. The reaction mixture was stirred at RT for 16 h and then heated at reflux for another 3 h. After cooling to RT the reaction mixture was partitioned between water and DCM. The organic layer was separated and the aqueous layers was extracted twice with DCM. The combined organic layers were dried over MgSO4, concentrated in vacuo and the residue was purified by flash chromatography to yield CIS-2-[8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetonitrile (SC_2053) (31 mg) as a solid. [M+H]+433.3
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- To a solution of CIS-2-[[1-(cyclobutyl-methyl)-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-8-yl]-methyl-amino]-acetic acid methyl ester (SC_2134) (125 mg, 0.24 mmol) in THF (1 mL) was added lithium borohydride (2M in THF, 0.36 mL, 0.72 mmol) at RT. The reaction mixture was stirred at RT for 16 h followed by addition of another portion of lithium borohydride (2M in THF, 0.36 mL, 0.72 mmol). After stirring at RT for 16 h, the reaction mixture was quenched with water. The organic layer was separated, washed with a 1M aq. NaOH and water, dried over MgSO4, filtered and concentrated in vacuo. Purification of the residue by flash chromatography provided 37 mg of CIS-1-(cyclobutyl-methyl)-8-[(2-hydroxy-ethyl)-methyl-amino]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_2073). [M+H]+492.3
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- Powdered sodium hydroxide (21 mg, 0.5 mmol) was dissolved in 0.2 mL of dry DMSO. After stirring at RT for 30 min CIS-1-(cyclobutyl-methyl)-8-dimethylamino-3-[(4-hydroxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_2089) (60 mg, 0.13 mmol) was added and the resulting mixture was stirred for another 30 min. Then 2,5,8,11,14,17,20,23-octaoxapentacosan-25-yl 4-methylbenzenesulfonate (prepared via tosylation of 2,5,8,11,14,17,20,23-octaoxapentacosan-25-ol following standard procedures) (216 mg, 0.4 mmol) was added. The reaction mixture was stirred at at 60° C. for 16 h. The reaction mixture was quenched with water and the organic product was extracted with DCM (2×20mL). The combined organic extracts were dried over anhydrous Na2SO4, concentrated in vacuo and the residue was purified by flash chromatography to yield CIS-1-(cyclobutyl-methyl)-8-dimethylamino-3-[[4-[2-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-phenyl]-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_2087) (25 mg) as a white solid. [M+H]+814.5
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- CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_2125) (153 mg, 0.33 mmol) was dissolved in DCM (7 mL) and boron tribromide (1M solution in DCM, 1.3 mL) was added at 0° C. The reaction was stirred for 18 h, then water and methanol (1:1 mixture, 6 mL) was added. The reaction mixture was extracted with DCM (3×10 ml). The combined organic layers were dried over Na2SO4, concentrated in vacuo and the residue was purified by flash chromatography to yield CIS-1-(cyclobutyl-methyl)-8-dimethylamino-3-[(4-hydroxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_2089) (21 mg) as a white solid. [M+H]+448.3
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- CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[(3-methylsulfanyl-phenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_2136) (109 mg) was dissolved in methanol (3 mL) and water (2 mL) and oxone (105 mg) was added at RT. The reaction mixture was stirred for 24 h, another portion of oxone (105 mg) was added, the reaction mixture was stirred for 12 h at RT, then diluted with water and extracted with DCM (3×10 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography to yield CIS-1-(cyclobutyl-methyl)-8-dimethylamino-3-[(3-methylsulfonyl-phenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_2093) as a white solid. [M+H]+510.3
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- KOtBu (1M in THF) (29.30 mL, 29.30 mmol) was added to the solution of CIS-8-Dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 (8.0 g, 29.30 mmol) in THF (160 mL) under argon atmosphere and the reaction mixture was stirred for 30 min. 4-Methoxybenzyl bromide (4.23 mL, 29.30 mmol) was added and stirring was continued at RT for 4 h. The reaction completion was monitored by TLC. The reaction mixture was diluted with sat. aq. NH4Cl (150 mL) and the organic product was extracted with EtOAc (2×150 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The reaction was carried out in 2 batches (8 g×2) and the batches were combined for purification. Purification of the crude product by flash column chromatography on silica gel (0-10% methanol in DCM) and subsequently by washing with pentane yielded 11 g (47%) of CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_2097) as a white solid. [M+H]+394.2
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- 50 wt % aq. sulphuric acid (0.57 mL) was added to the solution of CIS-8-dimethylamino [(4-methoxyphenyl)-methyl]-1-(3-methyl-but-2-enyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_2135) (0.25 g, 0.54 mmol) in 1,4-dioxane (5.75 mL) at RT and the reaction mixture was stirred for 3 h at RT. The reaction mixture was quenched with sat. aq. NaHCO3 and the organic product was extracted with ethyl acetate (2×10mL). The combined organic extracts were dried over anhydr. Na2SO4 and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC to give 0.04 g (15%) of CIS-8-dimethylamino-1-(3-hydroxy-3-methyl-butyl)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-on (SC_2107) as an off white solid. (TLC system: 10% MeOH in DCM; Rf: 0.4). [M+H]+480.3
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- 30% aq. H2O2 (0.3 mL, 2.54 mmol) was added to a solution of CIS-2-((8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)methyl)benzonitrile (SC_2138) (0.4 g, 0.85 mmol) in DMSO (8 mL) at 0° C. A solution of potassium hydroxide (0.23 g, 4.23 mmol) in water (0.5 mL) was added dropwise. The reaction mixture was allowed to warm up to RT and stirred for 30 min and then quenched with cold water (20 mL). The precipitated product was filtered off and washed with water. Purification by preparative TLC using 5% methanol in DCM as mobile phase yielded 78 mg of target compound which was further washed with n-pentane (5 mL) to give 70 mg (17%) of CIS-2-[[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]methyl]-benzamide (SC_2109) as an off-white solid. (TLC system: 10% MeOH in DCM Rf: 0.4). [M+H]+491.3
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- N-Iodosuccinimide (233 mg, 1.035 mmol) was added to a solution of CIS-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[(4-methoxyphenyl)-methyl]-8-methylamino-8-phenyl-1,3-diazaspiro [4.5]decan-2-one (SC_2026) (320 mg, 0.690 mmol) in a mixture of acetonitrile and THF (1:1 v/v, 30 mL) at 0° C. and the resulting mixture was stirred for 5 h at RT. The reaction mixture was cooled to 0° C. and another portion of N-Iodosuccinimide (233 mg, 1.035 mmol) was added. The reaction mixture was allowed to warm up to RT and was stirred for further 11 h. The reaction mixture was basified with 2N aq. NaOH to pH-10 and the organic product was extracted with ethyl acetate (3×30mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC by using 3% methanol in DCM as a mobile phase to give 100 mg of target compound which was further purified by preparative reverse phase HPLC to give 65 mg (21%) of CIS-8-amino-1-((1-hydroxycyclobutyl)methyl)-3-(4-methoxybenzyl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (SC_2123) as an off-white solid (TLC system: 5% MeOH in DCM; Rf: 0.40.). [M+H]+450.3
-
- NaOH (0.53 g, 13.26 mmol) was added to a solution of CIS-8-dimethylamino-8-phenyl-3-(2-phenyl-ethyl)-1,3-diazaspiro[4.5]decan-2-one INT-795 (1 g, 2.65 mmol) in DMSO (50 mL) under argon atmosphere at RT and the reaction mixture was stirred at 70° C. for 30 min. (1-(Tert-butyldimethylsilyloxy)cyclobutyl)methyl-4-methylbenzenesulfonate (2.94 g, 7.95 mmol) was added and stirring was continued for 2 days at 70° C. The reaction completion was monitored by TLC. The reaction mixture was diluted with sat. aq. NaHCO3 (20 mL) and the organic product was extracted with EtOAc (4×50mL). The combined organic layer was dried over anhydr. Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (using 230-400 mesh silica gel and 2-5% MeOH in DCM as eluent) to afford 250 mg of product which was further purified by prep. TLC (4% MeOH: DCM as an eluent) followed by washing with pentane to yield 133 mg (11%) of CIS-8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-(2-phenyl-ethyl)-1,3-diazaspiro[4.5]decan-2-one (SC_2124) as an off-white solid. (TLC system: 10% MeOH in DCM; Rf: 0.8). [M+H]+462.3
-
- To a solution of CIS-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_2097) (10 g, 25 mmol) in 500 mL THF was added KOtBu (7.1 g, 63 mmol) at 50° C. The reaction mixture was heated up to reflux and cyclobutylmethylbromide (11.3 g, 76 mmol) was added quickly in one portion. After 12 h new portions of KOtBu (7.1 g) and cyclobutylmethylbromide (11.3 g) were added and the reaction mixture was allowed to stir for 2 h at reflux and was then cooled to RT. Water (150 mL) was added and the organic layer separated. The aqueous layer was extracted with ethyl acetate (3×300 mL). The combined organic layers were dried over Na2SO4 and then concentrated in vacuo. The residue was filtered through a pad of silica gel using DCM/MeOH (19/1 v/v). The filtrate was concentrated in vacuo and the resulting solid was recrystallized from hot ethanol to yield 7.8 g of CIS-1-(cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one (SC_2125). [M+H]+461.3
-
- CIS-3-[(3-Bromophenyl)-methyl]-1-(cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (SC_2137) (100 mg, 0.2 mmol), sodium thiomethoxide (20 mg, 0.3 mmol), Pd2(dba)3 (8 mg, 0.02 mmol) and 9,9-dimethyl-4,5-bis(diphenyl-phosphino)xanthene (10 mg, 0.02 mmol) were placed in an oven dried flask. After three vacuum/nitrogen purge cycles, toluene (2 mL) and DIPEA (66 μL, 0.4 mmol) were added and the resulting suspension was heated to 100° C. for 24 h. The reaction mixture was cooled to RT, water was added and the mixture was extracted with DCM (3×5mL). The combined organic layers were dried over Na2SO4, concentrated in vacuo and the residue was purified by flash chromatography to yield CIS-1-(cyclobutyl-methyl)-8-dimethylamino-3-[(3-methylsulfanyl-phenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_2136) as a white solid. [M+H]+478.3
- Synthesis of SC_2143: CIS-3-((1H-1,2,3-triazol-4-yl)methyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
- To a solution of CIS-8-dimethylamino-8-phenyl-3-prop-2-ynyl-1,3-diaza-spiro[4.5]decan-2-one (INT-1010) (1.0 g, 3.21 mmol, 1.0 eq.) in dioxane/MeOH (50 ml, 9:1) were added sodium azide (418 mg, 6.42 mmol, 2.0 eq.) and cuprous chloride (32 mg, 0.32 mmol, 0.1 eq.) at RT. The reaction mixture was stirred at 80° C. for 18 h, then quenched with water and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel neutralized with aq. NH3; 0.5% aq NH3 in 10% MeOH/DCM) to yield CIS-341H-1,2,3-triazol-4-yl)methyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_2143) (600 mg, 1.69 mmol, 52%) as an off white solid. Yield: 52% (600 mg, 1.69 mmol). 1HNMR (DMSO-d6, 400 MHz), δ (ppm)=14.84 (bs, 1H), 7.65 (s, 1H), 7.32-7.24 (m, 5H), 6.93 (bs, 1H), 4.27 (s, 2H), 2.98 (s, 2H), 2.28 (bs, 2H), 1.92 (s, 6H), 1.76 (bs, 4H), 1.31 (bs, 2H). Mass: m/z 355.0 (M+H)+.
-
- To a suspension of LiAlH4 (207 mg, 5.45 mmol, 3.0 eq.) in dry THF (20 ml) was added ethyl CIS -2-(4-((8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)methyl)-1H-1,2,3-triazol-1-yl)acetate (INT-1011) (800 mg, 1.82 mmol, 1.0 eq.) in dry THF (20 ml) dropwise at 0° C. and the resulting mixture was stirred at RT for 1 h. The reaction mixture was quenched with sat. aq. Na2SO4, excess THF was added and the resulting mixture was stirred at RT for 1 h. The reaction mixture was filtered through celite and washed with THF. The filtrate was concentrated under reduced pressure to get crude product which was purified by column chromatography (silica gel, neutralized with aq. NH3; 1% aq NH3 in 20% MeOH/DCM) to yield CIS-8-(dimethylamino)-3-((1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_2144) (450 mg, 1.13 mmol, 62%) as a white solid. Yield: 62% (450 mg, 1.13 mmol). 1HNMR (DMSO-d6, 400 MHz), δ (ppm)=7.86 (s, 1H), 7.36-7.22 (m, 5H), 6.89 (bs, 1H), 4.97 (t, 1H, J=5.3 Hz), 4.34 (t, 2H, J=5.42 Hz), 4.24 (s, 2H), 3.72 (q, 2H, J=5.32 Hz), 3.01 (s, 2H), 2.30 (bs, 2H), 1.91 (s, 6H), 1.77-1.75 (m, 4H), 1.33-1.31 (m, 2H). Mass: m/z 399.1 (M+H)+.
-
- To a solution of CIS-2-(4-((8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)methyl)-1H-1,2,3-triazol-1-yl)acetate (INT-1011) (300 mg, 0.68 mmol, 1.0 eq.) in MeOH (6 ml) was added 7 M NH3 solution in MeOH (2 ml) at RT and the reaction mixture was stirred at 80° C. in a sealed tube for 18 h. The reaction mixture was cooled down to RT and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, neutralized with TEA; 2% aq. NH3 in 20% MeOH/DCM) to yield CIS-2-(4-((8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)methyl)-1H-1,2,3-triazol-1-yl)acetamide (SC_2145) (220 mg, 0.54 mmol, 78%) as an off white solid. Yield: 78% (220 mg, 0.54 mmol). 1HNMR (DMSO-d6, 400 MHz), δ (ppm)=7.85 (s, 1H), 7.67 (s, 1H), 7.34-7.22 (m, 6H), 6.93 (bs, 1H), 5.00 (s, 2H), 4.25 (s, 2H), 3.01 (s, 2H), 2.30 (bs, 2H), 1.92 (s, 6H), 1.76 (bs, 4H), 1.31 (bs, 2H). Mass: m/z 412.3 (M+H)+.
-
- CIS-8-(dimethylamino)-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_2097) (500 mg, 1.271 mmol) was dissolved in THF (8 mL) under nitrogen atmosphere and the solution was cooled down to −78° C. [Bis(trimethylsilyl)amino]lithium (1M in THF, 1.5 equiv., 1.906 mmol, 1.9 mL) was added dropwise and the reaction mixture was stirred at −78° C. for 30 min, then at 0° C. for 30 min. The reaction mixture was cooled down to −78° C. again and the solution of p-toluenesulfonyl chloride (1.5 equiv., 1.906 mmol) in THF (5 mL) was added. The reaction mixture was stirred further 2.5 h at −78° C. and then the temperature was allowed to increase to RT overnight. The reaction mixture was quenched by the addition of sat. aq. NaHCO3 (20 mL). The aqueous phase was extracted with EtOAc (3×40 mL). The combined organic extracts were washed with brine (30 mL), dried over MgSO4 and concentrated under reduced pressure. Purification by flash chromatography on silica gel (elution with gradient DCM/EtOH 100/0 to 97/3) yielded 281 mg (40%) of CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-8-phenyl-1-tosyl-1,3-diazaspiro[4.5]decan-2-one (SC_2147). 1H NMR (600 MHz, DMSO) δ 7.90-7.84 (m, 2H), 7.47-7.40 (m, 2H), 7.42-7.27 (m, 4H), 7.27-7.22 (m, 1H), 7.15-7.06 (m, 2H), 6.92-6.83 (m, 2H), 4.16 (s, 2H), 3.72 (s, 3H), 3.24 (s, 2H), 2.99 (ddd, 2H), 2.70-2.62 (m, 2H), 2.42 (s, 3H), 2.01 (s, 6H), 1.56-1.49 (m, 2H), 1.31 (td, 2H). Mass: m/z 548.3 (M+H)+.
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- To a stirred solution of CIS-1-(tert-butoxycarbonylamino)-4-(dimethylamino)-4-phenylcyclohexanecarboxylic acid (INT-1023) (1 g, 2.76 mmol) in DMF (15 mL) were added diisopropylethyl amine (1.78 g, 13.81 mmol) and HATU (2.09 g, 5.52 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 45 min and then 2-phenylpropan-2-amine (0.74 g, 5.52 mmol) was added. The reaction mixture was warmed to RT and stirred for 16 h. The reaction mixture was quenched with sat. aq. NaHCO3 and the organic product was extracted with EtOAc (3×25mL). The combined organic extracts were dried over anhydr. Na2SO4 and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel 230-400 mesh) using 5-8% methanol in DCM as eluent gave 0.7 g (52%) of tert-butyl CIS (dimethylamino)-4-phenyl-1-(2-phenylpropan-2-ylcarbamoyl)cyclohexylcarbamate as a liquid. (TLC system: 10% MeOH in DCM a Rf: 0.30).
- 4N HCl in dioxane (15 mL) was added to a stirred solution of tert-butyl CIS-4-(dimethylamino)-4-phenyl-1-(2-phenylpropan-2-ylcarbamoyl)cyclohexylcarbamate (0.7 g, 1.46 mmol) in DCM (15 mL) at 0° C. The reaction mixture was stirred at RT for 2 h and then concentrated under reduced pressure to afford 0.7 g of CIS-1-amino-4-(dimethylamino)-4-phenyl-N-(2-phenylpropan-2-yl)cyclohexanecarboxamide hydrochloride as an off-white solid. The product was used in the next step without additional purification. (TLC system: 10% MeOH in DCM a Rf: 0.20).
- A solution of CIS-1-amino-4-(dimethylamino)-4-phenyl-N-(2-phenylpropan-2-yl)cyclohexanecarboxamide (0.7 g, 1.84 mmol) in THF (10 mL) was added to BH3xTHF solution (1M in THF, 18 mL, 18.46 mmol) at RT. The resulting mixture was refluxed for 2 h. The reaction mixture was cooled to 0° C. and slowly quenched with 6N HCl (20 mL). The aqueous layer was extracted with EtOAc and then basified (pH˜10) with 20% aq. NaOH. The organic product was extracted with 10% MeOH/DCM (20mL×4). The combined organic layer was washed with brine, dried over anhydr. Na2SO4 and concentrated in vacuo to give 0.3 g of CIS-N,N-dimethyl-1-phenyl-4-((2-phenylpropan-2-ylamino)methyl)cyclohexane-1,4-diamine as a liquid. The product was used in the next step without additional purification. (TLC system: 10 vol % methanol in DCM, Rf: 0.10).
- 1,1′-Carbonyldiimidazole (0.90 g, 5.58 mmol) was added to a solution of CIS-N,N-dimethyl-1-phenyl-4-((2-phenylpropan-2-ylamino)methyl)cyclohexane-1,4-diamine (1.7 g, 4.65 mmol) in DMF (20 mL) at RT. The reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched with cold water, the precipitated solid was filtered off and dried under reduced pressure to give the product which was further purified by preparative HPLC (column: Column: Kinetex-C18 (150*21.2 mm) 5 μm, mobile phase: 0.1% formic acid in water (A): Acetonitrile(B), gradient: T/%B: 0/20, 7/50, 7.1/98, 9/98, 9.1/20, 12/20, flow rate: 18 ml/min, diluent: mobile phase+THF) to yield 0.83 g (55%) of CIS-8-(dimethylamino)-8-phenyl-3-(2-phenylpropan-2-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_2170) as a white solid. (TLC system: 10% MeOH in DCM Rf: 0.30). 1H NMR (DMSO-d6): δ 7.36-7.22 (m, 9H), 7.16-7.13 (m, 1H), 6.64 (s, 1H), 3.10 (s, 2H), 2.28 (m, 2H), 1.93-1.79 (m, 10H), 1.52 (s, 6H), 1.37 (m, 2H). Mass: m/z 392.2 [M+H]+.
-
- CIS-8-(dimethylamino)-8-phenyl-1-(p-tolylsulfonyl)-1,3-diazaspiro[4.5]decan-2-one (INT-1028) (200 mg, 0.47 mmol, 1 equiv.) was dissolved in DMF (3.6 mL) under argon atmosphere and the solution was cooled down to 0° C. Sodium hydride (60 wt % in mineral oil, 2.1 equiv., 0.98 mmol, 39 mg) was added and the reaction mixture was stirred at RT for 15 min. 4-(Bromomethyl)pyridine hydrobromide (1.05 equiv., 0.49 mmol, 124 mg) was added at 0° C. The reaction mixture was stirred overnight at RT, then quenched with sat. aq. NaHCO3 (2 mL) and water (2 mL) and extracted with EtOAc (2×15 mL). The combined organic extract was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (100% acetonitrile) to yield CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-8-phenyl-1-tosyl-1,3-diazaspiro[4.5]decan-2-one (112 mg, 46%). Mass: m/z 519.2 [M+H]+.
- CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-8-phenyl-1-tosyl-1,3-diazaspiro[4.5]decan-2-one (110 mg, 0.212 mmol, 1 equiv.) was dissolved in THF (2 mL) and MeOH (4.4 mL) under argon atmosphere. Magnesium turnings (103 mg, 4.24 mmol, 20 equiv.) were added and the resulting mixture was stirred at RT for 18 h. The reaction mixture was diluted with DCM (30 mL) and water (10 mL), stirred at RT for 1.5 h, filtered through celite and the solid residue was washed with DCM (3×). The organic phase of the filtrate was separated and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (EtOH 100% to EtOH/MeOH 70/30) to yield 33 mg (43%) of CIS-8-(dimethylamino)-8-phenyl-3-(pyridin-4-ylmethyl)-1,3-diazaspiro[4.5]decan-2-one (SC_2180). 1H NMR (600 MHz, DMSO-d6) δ 8.52-8.47 (m, 2H), 7.36-7.28 (m, 4H), 7.25-7.21 (m, 1H), 7.21-7.17 (m, 2H), 7.01 (s, 1H), 4.23 (s, 2H), 2.98 (s, 2H), 2.37-2.22 (m, 2H), 1.93 (s, 6H), 1.87-1.61 (m, 4H), 1.42-1.29 (m, 2H). Mass: m/z 365.2 [M+H]+.
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- A mixture of 3-[(2-chloro-4-pyridyl)methyl]-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1065) (100 mg, 0.251 mmol), 1-methylpiperazine (50 equiv., 12.54 mmol, 1.39 mL) and DIPEA (5 equiv., 1.25 mmol, 0.22 mL) was stirred at 140° C. under microwave irradiation until complete conversion of INT-1065 (LCMS control). The reaction mixture was diluted with 2 N aq. NaOH and EtOAc, the organic phase was separated, washed with brine, dried over anhydr. Na2SO4 and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel (eluent gradient 0.2 N NH3 in MeOH/EtOH/DCM 10/40/50 to 25/25/50 v/v/v) to yield CIS-8-(dimethylamino)-3-((2-(4-methylpiperazin-1-yl)pyridin-4-yl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_2183) (87 mg, 75%). 1H NMR (600 MHz, DMSO) δ 8.02 (d, 1H), 7.36-7.30 (m, 2H), 7.31-7.26 (m, 2H), 7.23 (td, 1H), 6.94 (s, 1H), 6.58 (s, 1H), 6.45 (dd, 1H), 4.12 (s, 2H), 3.45-3.39 (m, 4H), 2.94 (s, 2H), 2.36 (t, 4H), 2.33-2.22 (m, 2H), 2.19 (s, 3H), 1.92 (s, 6H), 1.86-1.62 (m, 4H), 1.34 (t, 2H). Mass: m/z 463.3 (M+H)+.
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- A mixture of 3-[(2-chloro-4-pyridyl)methyl]-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1065) (100 mg, 0.251 mmol), piperazine (1.5 equiv., 0.38 mmol, 32 mg), DIPEA (5 equiv., 1.25 mmol, 0.22 mL) and n-butanol (1 mL) was stirred 4 h at 140° C. under microwave irradiation. A new portion of piperazine (4.5 equiv, 1.13 mmol, 97 mg) was added and the reaction mixture was stirred further 16 h at 140° C. under microwave irradiation. The resulting mixture was concentrated under reduced pressure, taken in water/EtOAc, organic phase separated, aqueous phase extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydr. Na2SO4 and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel (eluent gradient 0.2 N NH3 in MeOH/EtOH/DCM 0/20/80 to 30/0/70 v/v/v) to yield CIS-8-(dimethylamino)-8-phenyl-3-((2-(piperazin-1-yl)pyridin-4-yl)methyl)-1,3-diazaspiro[4.5]decan-2-one (SC_2186) (48 mg, 43%). 1H NMR (600 MHz, CDCl3) δ 8.13-8.09 (m, 1H), 7.37 (t, 2H), 7.31-7.24 (m, 3H), 6.49 (d, 2H), 5.20-5.16 (m, 1H), 4.25 (s, 2H), 3.51-3.46 (m, 4H), 3.01-2.95 (m, 6H), 2.18-2.09 (m, 2H), 2.05 (s, 6H), 2.03-1.92 (m, 2H), 1.92-1.84 (m, 2H), 1.50-1.42 (m, 2H). Mass: m/z 449.3 (M+H)+.
- For further exemplary compounds the last synthesis step in analogy to previously described methods is given in the following table. The syntheses of the building blocks and intermediates have either been described previously within this application or can be performed in analogy to the herein described methods or by methods known to the person, skilled in the art. Such a person will also know which building blocks and intermediates need to be chosen for synthesis of each exemplary compound.
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in analogy m/z Example Chemical Name Reactant I Reactant II to method [M + H]+ SC_2001 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[(4- SC_2136 — SC_2093 510.3 methylsulfonyl-phenyl)-methyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2003 CIS-8-Dimethylamino-1-isopropyl-3-[(4-methoxyphenyl)- SC_2097 2-bromo-propane SC_2014 436.3 methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2004 CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[(4- SC_2097 cyclopropyl-methylbromide SC_2125 448.3 methoxyphenyl)-methyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2005 CIS-1-(Cyclobutyl-methyl)-3-[(4-methoxyphenyl)-methyl]- SC_2026 Isobutyraldehyde SC_2028 504.4 8-[methyl-(2-methyl-propyl)-amino]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2006 CIS-2-[[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- SC_2092 — SC_2109 475.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzamide SC_2007 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3- INT-987 2-(bromomethyl)pyrazine SC_2002 434.3 (pyrazin-2-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one SC_2009 CIS-4-[[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- SC_2085 — SC_2109 475.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzamide SC_2011 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(4- SC_2016 (bromomethyl)cyclobutan SC_2010 480.3 fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3- diazaspiro[4.5]decan-2-one SC_2012 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3- SC_2139 (bromomethyl)cyclobutan SC_2010 492.3 methoxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3- diazaspiro[4.5]decan-2-one SC_2013 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(4- SC_2140 (bromomethyl)cyclobutan SC_2010 492.3 methoxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3- diazaspiro[4.5]decan-2-one SC_2015 CIS-1-Butyl-8-dimethylamino-3-[(4-methoxyphenyl)- SC_2097 1-bromobutane SC_2010 450.3 methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2016 CIS-8-Dimethylamino-8-(4-fluorophenyl)-3-[(4- INT-966 dimethylamine/KCN SC_2017 412.2 methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one 4-fluorophenylmagnesium bromide SC_2020 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[[3-[2-[2-[2- SC_2089 2,5,8,11,14,17-hexaoxanonadecan- SC_2089 726.5 [2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]- 19-ol ethoxy]-phenyl]-methyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2021 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(4- INT-967 — SC_2018 478.3 hydroxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3- diazaspiro[4.5]decan-2-one hydrochloride SC_2022 CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]- INT-799 1-(bromomethyl)-3-methoxybenzene SC_2019 478.3 3-[(3-methoxyphenyl)-methyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2023 CIS-1-(Cyclopentyl-methyl)-8-dimethylamino-3-[(4- SC_2097 (bromomethyl)cyclopentane SC_2010 476.3 methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan- 2-one SC_2024 CIS-8-Dimethylamino-1-(2-hydroxy-2-methyl-propyl)-3- SC_2097 2,2-dimethyl-oxirane SC_2010 466.3 [(4-methoxyphenyl)-methyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2027 CIS-3-[[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2- INT-798 (bromomethyl)cyclobutan SC_2010 471.3 oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]- benzonitrile SC_2029 CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-3-[(3- SC_2026 acetaldehyde SC_2028 476.3 methoxyphenyl)-methyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2030 CIS-3-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2- SC_2097 3-bromopropanenitrile SC_2010 447.3 oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-propionitrile SC_2031 CIS-1-(Cyclobutyl-methyl)-8-methylamino-8-phenyl-3- SC_2019 — SC_2026 419.3 (pyridin-3-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one SC_2032 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1- SC_2097 3-(bromomethyl)oxetane SC_2014 464.3 (oxetan-3-yl-methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2- one SC_2033 CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8- INT-986 bromomethylpyridine SC_2002 447.3 phenyl-3-(pyridin-3-yl-methyl)-1,3-diazaspiro[4.5]decan-2- hydrobromide one SC_2035 CIS-8-Dimethylamino-1-(2,2-dimethyl-propyl)-3-[(4- SC_2097 1-bromo-2,2-dimethylpropane SC_2014 464.3 methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan- 2-one SC_2036 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-(3- SC_2097 1-bromo-3-methylbutane SC_2010 464.3 methyl-butyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2037 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8- SC_2097 1-bromo-3-(trifluoro- SC_2010 520.3 phenyl-1-[3-(trifluoromethyloxy)-propyl]-1,3- methoxy)propane diazaspiro[4.5]decan-2-one SC_2038 CIS-1-(2-Cyclobutyl-ethyl)-8-dimethylamino-3-[(4- SC_2097 2-cyclobutylethyl 4- SC_2010 476.3 methoxyphenyl)-methyl]-8-phenyl-1,3- methylbenzenesulfonate diazaspiro[4.5]decan-2-one SC_2039 CIS-1-[(3,3-Difluoro-cyclobutyl)-methyl]-8-dimethylamino- SC_2097 3-(bromomethyl)-1,1- SC_2010 498.3 3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3- difluorocyclobutane diazaspiro[4.5]decan-2-one SC_2041 CIS-1-(Cyclobutyl-methyl)-8-[(2-methoxy-ethyl)-methyl- SC_2044 1-bromo-2-methoxyethane SC_2008 506.3 amino]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2044 CIS-1-(Cyclobutyl-methyl)-3-[(4-methoxyphenyl)-methyl]- SC_2125 — SC_2026 448.3 8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2045 CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2- SC_2097 methyl 2-bromoacetate SC_2010 466.3 oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetic acid methyl ester SC_2046 CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2- SC_2043 NH4Cl SC_2049 451.3 oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetamide SC_2047 CIS-1-Benzyl-8-dimethylamino-3-[(4-methoxyphenyl)- SC_2097 (bromomethyl)benzene SC_2010 484.3 methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2048 CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2- SC_2043 methylamine SC_2049 465.3 oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-methyl- acetamide SC_2050 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-(3- SC_2097 1-bromo-3-methoxypropane SC_2010 466.3 methoxy-propyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2051 CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]- SC_799 1-(bromomethyl)-4-methoxybenzene SC_2019 478.3 3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2052 CIS-8-Dimethylamino-1-(2-methoxy-ethyl)-3-[(4- SC_2097 1-bromo-2-methoxyethane SC_2014 452.3 methoxyphenyl)-methyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2054 CIS-8-Dimethylamino-1-hexyl-3-[(4-methoxyphenyl)- SC_2097 1-bromohexane SC_2014 478.3 methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2055 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8- SC_2097 4-(bromomethyl)tetrahydro-2H- SC_2014 492.3 phenyl-1-(tetrahydro-pyran-4-yl-methyl)-1,3- pyran diazaspiro[4.5]decan-2-one SC_2056 CIS-1-(Cyclohexyl-methyl)-8-dimethylamino-3-[(4- SC_2097 (bromomethyl)cyclohexane SC_2014 490.3 methoxyphenyl)-methyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2057 CIS-N-(Cyano-methyl)-2-[8-dimethylamino-3-[(4- SC_2043 2-aminoacetonitrile SC_2049 490.3 methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-1-yl]-acetamide SC_2058 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8- SC_2097 3-(bromomethyl)pyridine SC_2014 485.3 phenyl-1-(pyridin-3-yl-methyl)-1,3-diazaspiro[4.5]decan-2- one SC_2059 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-(3- INT-966 dimethylamine/KCN SC_2017 390.3 methoxy-propyl)-1,3-diazaspiro[4.5]decan-2-one 3-methoxypropyl magnesium bromide SC_2060 CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2- SC_2043 2-methoxyethanamine SC_2049 509.3 oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-(2-methoxy- ethyl)-acetamide SC_2062 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-(2- SC_2043 pyrrolidine SC_2049 505.3 oxo-2-pyrrolidin-1-yl-ethyl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2063 CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2- SC_2043 dimethylamine SC_2049 479.3 oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N,N-dimethyl- acetamide SC_2064 CIS-N-(1-Cyano-cyclopropyl)-2-[8-dimethylamino-3-[(4- SC_2043 1-aminocyclopropanecarbonitrile SC_2049 516.3 methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-1-yl]-acetamide SC_2065 CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2- SC_2043 N-methylpropan-1-amine SC_2049 507.3 oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-methyl-N- propyl-acetamide SC_2066 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[(4- SC_2059 (bromomethyl)cyclobutane SC_2125 458.3 methoxyphenyl)-methyl]-8-(3-methoxy-propyl)-1,3- diazaspiro[4.5]decan-2-one SC_2067 CIS-8-Dimethylamino-1-(3-hydroxy-propyl)-3-[(4- SC_2097 (3-bromopropoxy)(tert- SC_2034 452.3 methoxyphenyl)-methyl]-8-phenyl-1,3- butyl)dimethylsilane diazaspiro[4.5]decan-2-one SC_2068 CIS-8-Dimethylamino-1-(4-methoxy-butyl)-3-[(4- SC_2097 1-bromo-4-methoxybutane SC_2014 480.3 methoxyphenyl)-methyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2069 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-[(1- SC_2097 1-(bromo-methyl)-1-methyl- INT-982 476.3 methyl-cyclobutyl)-methyl]-8-phenyl-1,3- cyclobutane step 1 diazaspiro[4.5]decan-2-one SC_2070 CIS-8-Dimethylamino-1-[(1-hydroxy-cyclohexyl)-methyl]- SC_2097 O-tert-butyldimethylsilyl-1-(4- SC_2124 506.3 3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3- methylbenzenesulfon- diazaspiro[4.5]decan-2-one oxymethyl)cyclohexanol SC_2071 CIS-5-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2- SC_2097 5-aminopentanenitrile SC_2014 475.3 oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-pentanenitrile SC_2072 CIS-3-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2- SC_2132 NH4Cl SC_2049 465.3 oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-propionamide SC_2074 CIS-1-[[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2- SC_2097 1-(aminomethyl)cyclobutane- SC_2014 487.3 oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-methyl]- carbonitrile cyclobutane-1-carbonitrile SC_2075 CIS-8-Dimethylamino-1-[(1-hydroxy-cyclopentyl)-methyl]- SC_2097 O-tert-butyldimethylsilyl-1-(4- SC_2124 492.3 3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3- methylbenzenesulfon- diazaspiro[4.5]decan-2-one oxymethyl)cyclopentanol SC_2076 CIS-3-[(2-Bromophenyl)-methyl]-1-(cyclobutyl-methyl)-8- INT-987 1-bromo-2-(bromomethyl)benzene SC_2002 510.2 dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2077 CIS-3-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2- SC_2132 methylamine SC_2049 479.3 oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-methyl- propionamide SC_2078 CIS-3-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2- SC_2132 propan-1-amine SC_2049 507.3 oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-propyl- propionamide SC_2079 CIS-8-Dimethylamino-1-[(1-fluoro-cyclobutyl)-methyl]-3- SC_2097 1-(bromomethyl)-1- SC_2014 480.3 [(4-methoxyphenyl)-methyl]-8-phenyl-1,3- fluorocyclobutane diazaspiro[4.5]decan-2-one SC_2080 CIS-1-(2-Cyclohexyl-ethyl)-8-dimethylamino-3-[(4- SC_2097 2-cyclohexylethanamine SC_2014 504.4 methoxyphenyl)-methyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2081 CIS-3-[[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- 3-(aminomethyl)benzonitrile SC_2002 457.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzonitrile SC_2082 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1- SC_2097 Iodo-methane SC_2010 408.3 methyl-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2083 CIS-8-Dimethylamino-1-[2-[2-[2-[2-[2-[2-[2-(2-methoxy- SC_2097 25-bromo-2,5,8,11,14,17,20,23- SC_2014 760.5 ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]- octaoxapentacosane ethyl]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2084 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8- SC_2097 4-(2-bromoethyl)tetrahydro-2H- SC_2014 506.3 phenyl-1-(2-tetrahydro-pyran-4-yl-ethyl)-1,3- pyran diazaspiro[4.5]decan-2-one SC_2085 CIS-4-[[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- INT-987 4-(bromomethyl)benzonitrile SC_2002 457.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzonitrile SC_2086 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3- INT-987 5-(bromomethyl)-2- SC_2002 501.3 [[6-(trifluoromethyl)-pyridin-3-yl]-methyl]-1,3- (trifluoromethyl)pyridine diazaspiro[4.5]decan-2-one SC_2088 CIS-3-[[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- SC_2081 — SC_2109 475.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzamide SC_2090 CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-3-[(4- SC_2044 acetaldehyde SC_2028 476.3 methoxyphenyl)-methyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2091 CIS-8-Dimethylamino-1-[(1-methoxy-cyclobutyl)-methyl]- SC_2075 methyliodide SC_2025 492.3 3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2092 CIS-2-[[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- INT-987 2-(aminomethyl)benzonitrile SC_2002 457.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzonitrile SC_2094 CIS-8-Dimethylamino-1-ethyl-3- [(4-methoxyphenyl)- SC_2097 1-iodo-ethane SC_2010 422.3 methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2095 CIS-8-Dimethylamino-3- [(4-methoxyphenyl)-methyl]-8- SC-2097 1-iodopropane SC_2010 436.3 phenyl-1-propyl-1,3-diazaspiro[4.5]decan-2-one SC_2096 CIS-3-Benzyl-1-(cyclobutyl-methyl)-8-dimethylamino-8- INT-963 cyclobutyl-methylbromide SC_2014 432.3 phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2099 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8- SC_2097 4-(bromomethyl)pyrimidine SC_2010 486.3 phenyl-1-(pyrimidin-4-yl-methyl)-1,3-diazaspiro[4.5]decan- 2-one SC_2100 CIS-3-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2- SC_2097 3-amino-2,2-dimethylpropanenitrile SC_2014 475.3 oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-2,2-dimethyl- propionitrile SC_2101 CIS-2-[[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2- SC_2097 methyl 2-(bromomethyl)benzoate SC_2125 542.3 oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-methyl]- benzoic acid methyl ester SC_2102 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3- INT-987 2-(bromomethyl)pyridine SC_2002 433.3 (pyridin-2-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one SC_2103 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3- INT-987 4-(bromomethyl)pyridine SC_2002 433.3 (pyridin-4-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one SC_2104 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8- SC_2097 3-(bromomethyl)tetrahydrofuran SC_2014 478.3 phenyl-1-(tetrahydro-furan-3-yl-methyl)-1,3- diazaspiro[4.5]decan-2-one SC_2105 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3- INT-987 2-(bromomethyl)pyrimidine SC_2002 434.3 (pyrimidin-2-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one SC_2106 CIS-3-[[1-[(5-Cyano-2-methoxy-phenyl)-methyl]-8- SC_2142 3-(bromomethyl)-4- SC_2125 564.3 dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3- methoxybenzonitrile yl]-methyl]-4-methoxy-benzonitrile SC_2108 CIS-8-Dimethylamino-1-(3-methoxy-3-methyl-butyl)-3-[(4- SC_2107 Methyliodide SC_2025 494.3 methoxyphenyl)-methyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2110 CIS-3-[[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)- SC_2141 — SC_2109 491.3 methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- methyl]-benzamide SC_2111 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-(2- SC_2097 1-bromo-2-(methylsulfonyl)ethane SC_2010 500.3 methylsulfonyl-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2- one SC_2112 CIS-1-[(1-Hydroxy-cyclobutyl)-methyl]-3-[(4- SC_2051 — SC_2026 464.3 methoxyphenyl)-methyl]-8-methylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2113 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8- SC_2097 (tetrahydrofuran-2-yl)methanamine SC_2014 478.3 phenyl-1-(tetrahydro-furan-2-yl-methyl)-1,3- diazaspiro[4.5]decan-2-one SC_2114 CIS-3-Benzyl-8-dimethylamino-8-phenyl-1,3- INT-976 (bromomethyl)benzene SC_2097 364.2 diazaspiro[4.5]decan-2-one SC_2115 CIS-3-Benzyl-8-dimethylamino-1-ethyl-8-phenyl-1,3- SC_2114 1-bromoethane SC_2010 392.3 diazaspiro[4.5]decan-2-one SC_2117 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-[2- SC_2097 1-chloro-2-(methylsulfinyl)ethane SC_2010 484.3 (methylsulfinyl)-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan- 2-one SC_2118 CIS-8-Dimethylamino-1-[(2R)-2-hydroxy-propyl]-3-[(4- SC_2087 (R)-propylene oxide SC_2010 452.3 methoxyphenyl)-methyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2119 CIS-8-Dimethylamino-1-[(2S)-2-hydroxy-propyl]-3-[(4- (S)-propylene oxide SC_2010 452.3 methoxyphenyl)-methyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2120 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8- SC_2097 3-(bromomethyl)tetrahydrofuran SC_2010 478.3 phenyl-1-(tetrahydro-furan-3-yl-methyl)-1,3- diazaspiro[4.5]decan-2-one SC_2122 CIS-8-Dimethylamino-1-ethyl-3-[(4-methoxyphenyl)- SC_2097 1-bromoethane SC_2010 422.3 methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2126 CIS-3-[[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)- SC_2142 (1-(tert-butyldimethylsilyloxy)- SC_2124 503.3 methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- cyclobutyl)methyl-4- methyl]-4-methoxy-benzonitrile methylbenzenesulfonate SC_2127 CIS-8-Dimethylamino-1-ethyl-8-phenyl-3-(pyridin-3-yl- INT-949 3-(bromomethyl)pyridine SC_2019 393.3 methyl)-1,3-diazaspiro[4.5]decan-2-one SC_2129 CIS-8-Dimethylamino-1-[2-(1-methoxy-cyclobutyl)-ethyl]- SC_2097 3-(bromomethyl)pyridine SC_2014 506.3 3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_2130 CIS-8-Dimethylamino-8-[3-(methoxymethyloxy)-phenyl]-3- INT-966 dimethylamine/KCN SC_2017 454.3 [(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2- 3-methoxymethoxy-phenyl- one magnesium bromide SC_2131 CIS-8-Dimethylamino-8-[4-(methoxymethyloxy)-phenyl]-3- INT-966 dimethylamine/KCN SC_2017 454.3 [(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2- 4-methoxymethoxy-phenyl- one magnesium bromide SC_2132 CIS-3-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2- SC_2133 — SC_2043 466.3 oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-propionic acid SC_2133 CIS-3-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2- SC_2097 tert-butyl acrylate SC_2042 522.3 oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-propionic acid tert-butyl ester SC_2134 CIS-2-[[1-(Cyclobutyl-methyl)-3-[(4-methoxyphenyl)- SC_2044 methyl 2-bromoacetate SC_2040 520.3 methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-8-yl]- methyl-aminol-acetic acid methyl ester SC_2135 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-(3- SC_2097 1-bromo-3-methylbut-2-ene SC_2010 462.3 methyl-but-2-enyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2- one SC_2137 CIS-3-[(3-Bromophenyl)-methyl]-1-(cyclobutyl-methyl)-8- INT-987 1-bromo-3-(bromomethyl)benzene SC_2002 510.2 dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2138 CIS-2-((8-(dimethylamino)-1-((1- INT-987 2-(bromomethyl)benzonitrile SC_2019 473.3 hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl)methyl)benzonitrile SC_2139 CIS-8-Dimethylamino-8-(3-methoxyphenyl)-3-[(4- INT-966 dimethylamine/KCN SC_2017 424.3 methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one 3-methoxy-phenylmagnesium bromide SC_2140 CIS-8-Dimethylamino-8-(4-methoxyphenyl)-3-[(4- INT-966 dimethylamine/KCN SC_2017 424.3 methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one 4-methoxy-phenylmagnesium bromide SC_2141 CIS-3-((8-(dimethylamino)-1-((1- INT-987 3-(bromomethyl)benzonitrile SC_2019 473.3 hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl)methyl)benzonitrile SC_2142 CIS-3-((8-(dimethylamino)-2-oxo-8-phenyl-1,3- INT-976 3-(bromomethyl)-4- SC_2097 419.2 diazaspiro[4.5]decan-3-yl)methyl)-4-methoxybenzonitrile methoxybenzonitrile -
in m/z Chemical analogy (M + Example name Reactant I Reactant II to method 1H NMR data H)+ SC_2146 CIS-8- SC_2143 SC_2026 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 341.4 Methylamino-8-phenyl- 14.33 (bs, 1H), 7.67 (s, 1H), 7.38 (d, 2H, J = 3-(1H-[1,2,3]triazol-4- 7.4 Hz), 7.29 (t, 2H, J = 7.56 Hz), 7.17 yl-menthyl)-1,3- (t, 1H, J = 7.12 Hz), 6.65 (s, 1H), 4.30 (s, 2H), diazaspiro 3.10 (s, 2H), 1.92 (t, 2H, J = 11.86 Hz), [4.5]decan-2-one 1.83-1.78 (m, 5H), 1.63 (t, 2H, J = 11.76 Hz), 1.36 (d, 2H, J = 12.12 Hz). SC_2148 CIS-2-[4-[(8-Methylamino- SC_2145 SC_2026 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 398.2 2-oxo-8-phenyl-1,3- 7.87 (s, 1H), 7.67 (bs, 1H), 7.41-7.27 (m, 5H), diazaspiro[4.5]decan-3-yl)- 7.17 (t, 1H, J = 7.16 Hz), 6.64 (bs, 1H), 5.02 (s, methyl]-1H-[1,2,3] 2H), 4.28 (s, 2H), 3.13 (s, 2H), 1.95-1.79 (m, triazol-1-yl]-acetamide 8H, J = 11.32 Hz), 1.66-1.60 (m, 2H), 1.37 (d, 2H, J = 12.16 Hz). SC_2149 CIS-8-Dimethylamino-3-[(4- SC_2097 benzyl SC_2147 1H NMR (600 MHz, DMSO) δ 7.52-7.45 (m, 528.3 methoxyphenyl)-methyl]-2-oxo- carbono- 2H), 7.44-7.37 (m, 2H), 7.38-7.29 (m, 3H), 8-phenyl-1,3- chloridate 7.30-7.24 (m, 2H), 7.26-7.19 (m, 1H), 7.21- diazaspiro[4.5]decane-1- 7.15 (m, 2H), 6.93-6.86 (m, 2H), 5.23 (s, carboxylic acid benzyl ester 2H, 4.28 (s, 2H), 3.73 (s, 3H), 3.19 (s, 2H), 2.84 (ddd, 2H), 2.63-2.56 (m, 2H), 1.88 (s, 6H), 1.37-1.23 (m, 4H) SC_2150 CIS-3-[[1-(2-Hydroxy-ethyl)- SC_2144 SC_2026 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 385.2 1H-[1,2,3]triazol-4-yl]-methyl]- 7.88 (s, 1H), 7.39 (d, 2H, J = 7.0 Hz), 7.29 (t, 8-methylamino-8-phenyl-1,3- 2H, J = 7.38 Hz), 7.19-7.17 (m, 1H), 6.64 (bs, diazaspiro[4.5]decan-2-one 1H), 4.99 (t, 1H, J = 5.24 Hz), 4.35 (t, 2H, 5.32 Hz), 4.27 (s, 2H), 3.75-3.73 (m, 2H), 3.12 (s, 2H), 1.94-1.79 (m, 7H), 1.64 (m, 2H), 1.36 (d, 2H, J = 12.2 Hz). SC_2151* CIS-8-Dimethylamino-8-phenyl- INT-795 2-(2- step 2 1H NMR (DMSO-d6): δ 8.64 (br s, 1H), 8.42- 393.3 3-(2-pyridin-2-yl-ethyl)-1,3- step1 bromoethyl) of 8.41 (m, 1H), 7.67-7.63 (m, 1H),7.40-7.37 (m, diazaspiro[4.5]decane-2,4-dione pyridine INT-795 2H), 7.32-7.26 (m, 3H), 7.19-7.16 (m, 2H), 3.63-3.61 (t, 2H), 2.92-2.90 (t, 2H), 2.46-2.45 (m, 2H),1.91 (m, 8H), 1.51 (m, 2H), 1.45-1.42 (m, 2H). SC_2152 CIS-8-Dimethylamino-8-phenyl- SC_2151 step 3 1H NMR (DMSO-d6): δ 8.45-8.44 (d, 1H), 379.3 3-(2-pyridin-2-yl-ethyl)-1,3- of 7.69-7.65 (m, 1H), 7.37-7.30 (m, 4H), 7.26- diazaspiro[4.5]decan-2-one INT-795 7.16 (m, 3H), 6.65 (br s ,1H), 3.37-3.32 (m, 2H), 2.99 (s, 2H), 2.86-2.82 (t, 2H), 2.28 (m, 2H), 1.91 (m, 6H), 1.72-1.71 (m, 4H), 1.28- 1.26 (m, 2H). SC_2153 CIS-8-Dimethylamino-1-[(1- INT-1012 SC_2144 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 483.2 hydroxy-cyclobutyl)- 7.92 (s, 1H), 7.36-7.24 (m, 5H), 6.00 (s, 1H) methyl]-3-[[1-(2-hydroxy-ethyl)- 4.97 (t, 1H, J = 5.32 Hz), 4.36-4.34 (m, 4H) 1H-[1,2,3]triazol-4-yl]- 3.73 (q, 2H, J = 5.36 Hz), 3.24 (s, 2H), 3.11 (s, methyl]-8-phenyl-1,3- 2H), 2.62 (d, 2H, J = 14.0 Hz), 2.08-1.84 (m, diazaspiro[4.5]decan-2-one 12H), 1.64-1.61 (m, 1H), 1.38-1.28 (m, 5H). SC_2154* CIS-8-Dimethylamino-3-[2-(1H INT-795 1-(2-bromethyl)- step 2 1H NMR (DMSO-d6); δ 8.71 (br s, 1H), 7.42- 382.3 imidiazol-l-yl)-ethyl]-8-phenyl- step1 1H-imidazole of 7.37 (m, 3H), 7.32-7.26 (m, 3H), 7.00 (s, 1H), 1,3-diazaspiro[4.5]decane-2,4- hydrobromide INT-795 6.79 (s, 1H), 4.15-4.12 (t, 2H), 3.65-3.62 (t, dione 2H), 2.46 (m, 2H), 1.91 (s, 8H), 1.47-1.37 (m, 4H). SC_2155 CIS-2-[4-[[8-Dimethylamino-1- INT-1012 SC_2145 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 496.3 [(1-hydroxy-cyclobutyl)-menthyl]- 7.91 (s, 1H), 7.67 (s, 1H), 7.34-7.24 (m, 6H), 2-oxo-8-phenyl-1,3- 5.99 (s, 1H), 5.01 (s, 2H), 4.36 (s, 2H), 3.25 (s, diazaspiro[4.5]decan-3-yl]- 2H), 3.11 (s, 2H), 2.62-2.65 (m, 2H), 2.08-1.86 methyl]-1H-[1,2,3]triazol-1-yl]- (m, 12H), 1.64-1.61 (m, 1H), 1.38-1.18 (m, acetamide 5H). SC_2156 CIS-1-[(1-Hydroxy-cyclobutyl)- SC_2153 SC_2026 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 469.3 methyl]-3-[[1-(2-hydroxy-ethyl)- 7.93 (s, 1H), 7.44-7.17 (m, 5H), 6.03 (s, 1H), 1H-[1,2,3]triazol-4-yl]-methyl]- 4.98 (t, 1H), 4.36 (s, 4H), 3.73-3.75 (q, 2H, J = 8-methylamino-8-phenyl-1,3- 5.48 Hz), 3.27 (s, 2H), 3.20 (s, 2H), 2.11-2.03 diazaspiro[4.5]decan-2-one (m, 4H), 1.86 (bs, 7H), 1.62-1.33 (m, 7H). SC_2157* CIS-8-Dimethylamino-8-phenyl- INT-795 3-(2- step 2 of 1H NMR (DMSO-d6): δ 8.65 (br s, 1H), 8.38- 393.3 3-(2-pyridin-3-yl-ethyl)-1,3- step1 bromoethyl) INT-795 8.37 (m, 1H), 8.28 (d, 1H), 7.54 (d, 1H), 7.40- diazaspiro[4.5]decane-2,4-dione pyridine 7.36 (m, 2H), 7.31-7.24 (m, 4H), 3.56 (t, 2H), 2.83 (t, 2H), 2.44-2.41 (m, 2H), 1.95-1.90 (m, 8H), 1.42-1.35 (m, 4H). SC_2158* CIS-8-Dimethylamino-8-phenyl- INT-795 4-(2- step 2 of 1H NMR (DMSO-d6): δ 8.67 (br s, 1H), 8.42- 393.3 3-(2-pyridin-4-yl-ethyl)-1,3- step1 bromoethyl) INT-795 8.40 (d, 2H), 7.40-7.36 (m, 2H), 7.31-7.25 (m, diazaspiro[4.5]decane-2,4-dione pyridine 3H), 7.14-7.12 (d, 2H), 3.60-3.56 (t, 2H), 2.85- 2.82 (t, 2H), 2.45-2.41 (m, 2H), 1.95-1.85 (m, 8H), 1.44-1.35 (m, 4H). SC_2159 CIS-2-[4-[[1-(Cyclobutyl- INT-1030 ammonia SC_2145 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 480.1 methyl)-8-dimethylamino-2-oxo- 7.86 (s, 1H), 7.66 (s, 1H), 7.23-7.33 (m, 6H), 8-phenyl-1,3- 5.00 (s, 2H), 4.30 (s, 2H), 3.09(s, 2H), 3.04 (s, diazaspiro[4.5]decan-3-yl]- 2H), 2.61-2.64 (m, 2H), 1.95-2.02 (m, 11H), methyl]-1H-[1,2,3]triazol-1-yl]- 1.69-1.78 (m, 4H), 1.28-1.33 (m, 4H). acetamide SC_2160 CIS-1-(Cyclobutyl-methyl)-8- INT-1030 SC_2144 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 467.0 dimethylamino-3-[[1-(2-hydroxy- 7.87 (s, 1H), 7.23-7.35 (m, 5H), 4.97 (t, 1H, J = ethyl)-1H-[1,2,3]triazol-4-yl]- 5.28 Hz), 4.34 (t, 2H, J = 5.34 Hz), 4.29 (s, methyl]-8-phenyl-1,3- 2H), 3.71-3.75 (q, 2H), 3.09 (s, 2H), 3.04-3.05 diazaspiro[4.5]decan-2-one (d, 2H, J = 7.2 Hz), 1.95-2.05 (m, 11H), 1.67- 1.85 (m, 4H), 1.25-1.33 (bs, 4H). SC_2161 CIS-2-[4-[[1-[(1-Hydroxy- SC_2155 SC_2026 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 482.3 cyclobutyl)-menthyl]-8- 7.91 (s, 1H), 7.68 (s, 1H), 7.44-7.42 (m, 2H), methylamino-2-oxo-8-phenyl- 7.35-7.28 (m, 3H), 7.19-7.16 (m, 1H), 6.03 (s, 1,3-diazaspiro[4.5]decan-3-yl]- 1H), 5.02 (s, 2H), 4.37 (s, 2H), 3.28 (s, 2H), methyl]-1H-[1,2,3]triazol-1-yl]- 3.20 (s, 2H), 2.14-2.01 (m, 4H), 1.90-1.84 (m, acetamide 7H), 1.62-1.56 (m, 3H), 1.46.133 (m, 3H). SC_2162 CIS-1-(Cyclobutyl-methyl)-3- SC_2160 SC_2026 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 453.1 [[1-(2-hydroxy-ethyl)-1H- 7.87 (s, 1H), 7.40-7.42 (d, 2H, J = 7.64 Hz), [1,2,3]triazol-4-yl]-methyl]-8- 7.29 (t, 2H, J = 7.48 Hz), 7.17 (t, 1H, J = 7.18 methylamino-8-phenyl-1,3- Hz), 4.98 (t, 1H, J = 5.32 Hz), 4.35 (t, 2H, J = diazaspiro[4.5]decan-2-one 5.44 Hz), 4.31 (s, 2H), 3.71-3.75 (q, 2H), 3.13 (s, 2H), 3.07-3.09 (d, 2H, J = 7.36 Hz), 2.53- 2.57 (m, 1H), 2.05-2.32 (m, 3H), 1.93-197 (m, 2H), 1.67-1.86 (m, 8H), 1.53-1.60 (m, 2H), 1.22-1.25 (m, 2H). SC_2163 CIS-2-[4-[[1-(Cyc1obutyl- SC_2159 SC_2026 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 466.3 methyl)-8-methylamino-2-oxo-8- 7.86 (s, 1H), 7.68 (s, 1H), 7.27-7.37 (m, 5H), phenyl-1,3-diazaspiro[4.5]decan- 7.17 (t, 1H, J = 7.10 Hz), 5.02 (s, 2H), 4.32 (s, 3-yl]-methyl]-1H-[1,2,3]triazol- 2H), 3.07-3.13 (m, 4H), 2.26 (bs, 1H), 2.05- 1-yl]-acetamide 2.11 (m, 2H), 1.95 (bs, 2H), 1.67-1.86 (m, 8H), 1.57-1.60 (m, 2H), 1.22-1.25 (m, 2H). SC_2164 CIS-8-Dimethylamino-8-phenyl- SC_2157 step 3 of 1H NMR (DMSO-d6): δ 8.39-8.37 (m, 2H), 379.3 3-(2-pyridin-3-yl-ethyl)-1,3- INT-795 7.61-7.60 (m, 1H), 7.38-7.23 (m, 6H), 6.67 (br diazaspiro[4.5]decan-2-one s, 1H), 3.26 (t, 2H), 3.01 (s, 2H), 2.72 (t, 2H), 2.27 (m, 2H), 1.91 (s, 6H), 1.73-1.71 (m, 4H), 1.28-1.24 (m, 2H). SC_2165 CIS-8-Dimethylamino-3-[2-(1H- SC_2154 step 3 of 1H NMR (CDCl3): δ 7.45 (s, 1H), 7.38-7.34 368.2 imidazol-1-yl)-ethyl]-8-phenyl- INT-795 (m, 2H), 7.31-7.21 (m, 3H), 7.04 (s, 1H), 6.92 1,3-diazaspiro[4.5]decan-2-one (s, 1H), 4.95 (br s, 1H), 4.12-4.09 (t, 2H), 3.45- 3.43 (t, 2H), 2.67 (s, 2H), 2.03-1.96 (s, 8H), 1.84-1.68 (m, 4H),1.38-1.29 (m, 2H). SC_2166 CIS-8-Dimethylamino-8-phenyl- SC_2158 step 3 of 1H NMR (DMSO-d6): δ 8.50-8.48 (m, 2H), 379.2 3-(2-pyridin-4-yl-ethyl)-1,3- INT-795 7.39-7.35 (m, 2H), 7.30-7.27 (m, 3H), 7.14- diazaspiro[4.5]decan-2-one 7.12 (d, 2H), 4.62 (br s, 1H), 3.46-3.43 (t, 2H), 2.95 (s, 2H), 2.82-2.78 (t, 2H), 2.17-2.02 (m, 10H), 1.85-1.75 (m, 2H), 1.41-1.29 (m, 2H). SC_2167 CIS-8-Dimethylamino-8-phenyl- INT-976 2-(2- SC_2097 1H NMR (DMSO-d6): δ 8.70 (d, 2H), 7.38- 380.3 3-(2-pyrimidin-2-yl-ethyl)-1,3- bromoethyl) 7.23 (m, 6H), 6.65 (br s, 1H), 3.45 (t, 2H), diazaspiro[4.5]decan-2-one pyrimidine 3.00-2.49 (m, 4H), 2.28 (br m, 2H), 1.91 (s, 6H), 1.73-1.71 (m, 4H), 1.29-1.27 (m, 2H). SC_2168 CIS-8-Dimethylamino-8-phenyl- INT-976 5-(2- SC_2097 1H NMR (DMSO-d6): δ 9.00 (s, 1H), 8.64 (s, 380.2 3-(2-pyrimidin-5-yl-ethyl)-1,3- chloroethyl) 2H), 7.38-7.31 (m, 4H), 7.26-7.23 (m, 1H), diazaspiro[4.5]decan-2-one pyrimidine 6.69 (br s, 1H), 3.26 (m, 2H), 3.05 (s, 2H), 2.74 (t, 2H), 2.27 (br m, 2H), 1.92-1.69 (m, 10H), 1.28-1.24 (m, 2H). SC_2169 CIS-8-Dimethylamino-1-ethyl-3- INT-976 1-(chloromethyl)-4- SC_2097 1H NMR (600 MHz, DMSO) δ 7.92-7.86 (m, 470.3 [(4-methylsulfonyl-phenyl)- methylsulfonyl- (for step 1), 2H), 7.50-7.46 (m, 2H), 7.38-7.28 (m, 4H), methyl]-8-phenyl-1,3- benzene (step 1), SC_2010 7.27-7.19 (m, 1H), 4.37 (s, 2H), 3.19 (s, 3H), diazaspiro[4.5]decan-2-one bromoethane (for step 2) 3.15-3.03 (m, 4H), 2.69-2.60 (m, 2H), 2.15- (step 2) 2.06 (m, 2H), 1.97 (s, 6H), 1.38-1.27 (m, 4H), 1.14 (t, 3H). SC_2171 CIS-8-Dimethylamino-8-phenyl- INT-1023 1-phenyl- SC_2170 1H NMR (DMSO-d6): δ 7.36-7.14 (m, 8H), 390.2 3-(1-phenyl-cyclopropyl)-1,3- cyclopropanamine 7.08 (d, 2H), 6.77 (br s, 1H), 3.08 (s, 2H), 2.29 diazaspiro[4.5]decan-2-one (step 1) (m, 2H), 1.92 (s, 6H), 1.79-1.77 (m, 4H), 1.35- 1.33 (m, 2H), 1.23-1.21(m, 2H), 1.09-1.06 (m, 2H). SC_2172 CIS-8-Dimethylamino-1,3- INT-976 1- SC_2097 1H NMR (DMSO-d6): δ 7.32-7.14 (m, 9H), 514.2 bis[(2-methoxyphenyl)-methyl]- (bromomethyl)- 6.99-6.90 (m, 4H), 4.32-4.27 (m, 4H), 3.84- 8-phenyl-1,3- 2- 3.77 (m, 6H), 3.14 (s, 2H), 2.58-2.54 (m, 2H), diazaspiro[4.5]decan-2-one methoxybenzene 2.03-1.97 (m, 2H), 1.89 (s, 6H), 1.29-1.22 (m, 4H). SC_2173 CIS-8-Dimethylamino-3-[(3- INT-976 1-(bromomethyl)- SC_2097 1H NMR (600 MHz, DMSO) δ 7.84-7.79 (m, 442.2 methylsulfonyl-phenyl)-methyl]- 3-methylsulfonyl- 1H), 7.74 (d, 1H), 7.62 (t, 1H), 7.55 (d, 1H), 8-phenyl-1,3- benzene 7.36-7.27 (m, 4H), 7.23 (t, 1H), 6.99 (br s, diazaspiro[4.5]decan-2-one 1H), 4.33 (s, 2H), 3.19 (s, 2H), 2.97 (s, 2H), 2.35-2.24 (m, 2H), 1.93 (d, 6H), 1.85-1.66 (m, 4H), 1.38-1.31 (m, 2H). SC_2174 CIS-8-Dimethylamino-1-[(1- SC_2170 (1-(tert-butyldi- INT-799 1H NMR (DMSO-d6): δ 7.36-7.14 (m, 10H), 476.3 hydroxy-cyclobutyl)-methyl]-3- methylsilyloxy) (step 1) 5.88 (m, 1H), 3.33 (s, 2H), 3.03 (s, 2H), 2.68- (1-methyl-1-phenyl-ethyl)-8- cyclobutyl)methyl- 2.64 (m, 2H), 2.09-1.95 (m, 10H), 1.89-1.81 phenyl-1,3-diazaspiro[4.5] 4-methyl- (m, 2H), 1.61-1.56 (m, 7H), 1.48-1.28 (m, 5H). decan-2-one benzenesulfonate SC_2175 CIS-3-(3-Cyclopropyl-phenyl)- INT-976 1-(bromomethyl)- SC_2097 1H NMR (600 MHz, DMSO) δ 8.17 (s, 1H), 403.3 methyl1-8-dimethylamino-8- 3-cyclopropyl- 7.41-7.29 (m, 4H), 7.30-7.20 (m, 1H), 7.18 phenyl-1,3-diazaspiro[4.5] benzene (t, 1H), 6.98-6.89 (m, 3H), 6.87 (t, 1H), 4.15 decan-2-one (s, 2H), 2.89 (s, 2H), 2.28 (s, 2H), 1.97 (s, 6H), 1.91-1.83 (m, 1H), 1.80-1.75 (m, 3H), 1.34- 1.27 (m, 2H), 0.96-0.88 (m, 2H), 0.65- 0.57 (m, 2H). SC_2176 CIS-3-(1,3-Benzodioxo1-4-yl- INT-976 4-(bromomethyl)- SC_2097 1H NMR (600 MHz, DMSO) δ 7.37-7.27 (m, 408.2 methyl)-8-dimethylamino-8- 1,3-benzodioxole 4H), 7.27-7.20 (m, 1H), 6.88 (s, 1H), 6.83- phenyl-1,3-diazaspiro[4.5] 6.76 (m, 2H), 6.67 (dd, 1H), 5.96 (s, 2H), 4.18 decan-2-one (s, 2H), 2.95 (s, 2H), 2.30-2.26 (m, 2H), 1.93 (s, 6H),1.84-1.63 (m, 4H), 1.33 (t, 2H). SC_2177 CIS-8-Dimethylamino-1-[(1- SC_2171 (1-(tert-butyldi- INT-799 1H NMR (DMSO-d6): δ 7.34-7.17 (m, 8H), 474.2 hydroxy-cyclobutyl)-methyl]-8- methylsilyloxy) (step 1) 7.15-7.13 (m, 2H), 5.89 (s, 1H), 3.29 (s, 2H), phenyl-3-(1-phenyl-cyclopropyl)- cyclobutyl)methyl- 3.09 (s, 2H), 2.64-2.61 (m, 2H), 2.08-2.03 (m, 1,3-diazaspiro[4.5]decan-2-one 4-methylbenzene- 4H), 1.96 (s, 6H), 1.91-1.84 (m, 2H), 1.64-1.61 sulfonate (m, 1H), 1.42-1.29 (m, 5H), 1.29-1.26 (m, 2H), 1.13-1.01 (m, 2H) SC_2178 CIS-4-[[8-Dimethylamino-3-[(2- SC_2179 4- SC_2097 1H NMR (DMSO-d6): δ 7.81 (d, 2H), 7.53 (d, 509.2 methoxyphenyl)-methyl]-2-oxo- (bromomethyl) 2H), 7.32-7.21 (m, 6H), 7.15-7.13 (m, 1H), 8-phenyl-1,3- benzonitrile 6.99-6.92 (m, 2H), 4.38-4.31 (m, 4H), 3.77 (s, diazaspiro[4.5]decan-1-yl]- 3H), 3.16 (s, 2H), 2.58-2.55 (m, 2H), 2.00-1.89 methyl]-benzonitrile (m, 8H), 1.29-1.23 (m, 4H). SC_2179 CIS-8-Dimethylamino-3-[(2- INT-976 1-(bromomethyl)- SC_2097 1H NMR (600 MHz, DMSO) δ 7.37-7.27 (m, 394.3 methoxyphenyl)-methyl]-8- 2-methoxybenzene 4H), 7.27-7.19 (m, 2H), 7.08 (dd, 1H), 6.96 phenyl-1,3-diazaspiro[4.5] (dd, 1H), 6.91 (td, 1H), 6.85 (s, 1H), 4.19 (s, decan-2-one 2H), 3.75 (s, 3H), 2.96 (s, 2H), 2.30 (d, 2H), 1.93 (s, 6H), 1.86-1.69 (m, 4H), 1.38-1.32 (m, 2H). SC_2181 CIS-8-Dimethylamino-8-phenyl- INT-1028 2- SC_2180 1H NMR (600 MHz, DMSO) δ 8.48 (ddd, 1H), 365.2 3-(pyridin-2-yl-methyl)-1,3- (bromomethyl)- 7.76 (td, 1H), 7.37-7.27 (m, 4H), 7.29-7.17 diazaspiro[4.5]decan-2-one pyridine (m, 3H), 6.93 (s, 1H), 4.30 (s, 2H), 3.05 (s, hydrobromide 2H), 2.36-2.21 (m, 2H), 1.93 (s, 6H), 1.88- (step 1) 1.58 (m, 4H), 1.41-1.31 (m, 2H). SC_2182 CIS-8-Dimethylamino-8-phenyl- INT-1028 3- SC_2180 1H NMR (600 MHz, DMSO) δ 8.46 (dd, 1H), 365.2 3-(pyridin-3-yl-methyl)-1,3- (bromomethyl)- 8.42 (dd, 1H), 7.60 (dt, 1H), 7.38-7.30 (m, diazaspiro[4.5]decan-2-one pyridine 3H), 7.31-7.26 (m, 2H), 7.26-7.20 (m, 1H), hydrobromide 6.97-6.93 (m, 1H), 4.24 (s, 2H), 2.95 (s, 2H), (step 1) 2.33-2.20 (m, 2H), 1.92 (s, 6H), 1.84-1.60 (m, 4H), 1.35-1.29 (m, 2H). SC_2184 CIS-8-Dimethylamino-8-phenyl- INT-1065 piperidine SC_2183 1H NMR (600 MHz, CDCl3) δ 8.09 (d, 1H), 448.3 3-[(2-piperidin-1-yl-pyridin-4- 7.38 (dd, 2H), 7.30 (d, 3H), 6.48 (s, 1H), 6.42 yl)-methyl]-1,3- (dd, 1H), 5.47 (s, 1H), 4.23 (s, 2H), 3.54-3.46 diazaspiro[4.5]decan-2-one (m, 4H), 2.96 (s, 2H), 2.20-2.15 (m, 4H) 2.07 (s, 6H), 1.92-1.84 (m, 2H), 1.66-1.60 (m, 6H), 1.47-1.39 (m, 2H). SC_2185 CIS-8-Dimethylamino-3-[(2- INT-1065 morpholine SC_2183 1H NMR (600 MHz, DMSO) δ 8.05 (d, 1H), 450.3 morpholin-4-yl-pyridin-4-yl)- 7.37-7.27 (m, 4H), 7.26-7.20 (m, 1H), 6.94 methyl]-8-phenyl-1,3- (s, 1H), 6.59 (s, 1H), 6.50 (dd, 1H), 4.13 (s, diazaspiro[4.5]decan-2-one 2H), 3.68 (t, 4H), 3.41-3.36 (m, 4H), 2.96 (s, 2H), 2.37-2.22 (m, 2H), 1.93 (s, 6H), 1.86- 1.62 (m, 4H), 1.42-1.29 (m, 2H). (*Comparative Example) - Chemical Structure of All Examples
- Pharmacological Investigations
- Functional investigation on the human mu-opioid receptor (hMOP), human kappa-opioid receptor (hKOP), human delta-opioid receptor (hDOP), and human nociceptin/orphanin FQ peptide receptor (hNOP)
- Human Mu-Opioid Peptide (hMOP) Receptor Binding Assay
- The hMOP receptor binding assay was performed as homogeneous SPA-assay (scintillation proximity assay) using the assay buffer 50 mM TRIS-HCl (pH 7.4) supplemented with 0.052 mg/ml bovine serum albumin (Sigma-Aldrich Co.. St. Louis. Mo.). The final assay volume (250 μl/well) included 1 nM of [N-allyl-2.3-3H]naloxone as ligand (PerkinElmer Life Sciences. Inc. Boston. Mass. USA). and either test compound in dilution series or 25 μM unlabelled naloxone for determination of unspecific binding. The test compound was diluted with 25% DMSO in H2O to yield a final 0.5% DMSO concentration. which also served as a respective vehicle control. The assay was started by adding wheat germ agglutinin coated SPA beads (GE Healthcare UK Ltd.. Buckinghamshire. UK) which had been preloaded with hMOP receptor membranes (PerkinElmer Life Sciences. Inc. Boston. Mass. USA). After incubation for 90 minutes at RT and centrifugation for 20 minutes at 500 rpm the signal rate was measured by means of a 1450 Microbeta Trilux B-counter (PerkinElmer Life Sciences/Wallac. Turku. Finland). Half-maximal inhibitory concentration (IC50) values reflecting 50% displacement of [3H]naloxone-specific receptor binding were calculated by nonlinear regression analysis and Ki values were calculated by using the Cheng-Prusoff equation. (Cheng and Prusoff. 1973).
- Human Kappa-Opioid Peptide (hKOP) Receptor Binding Assay
- The hKOP receptor binding assay is run as homogeneous SPA-assay (scintillation proximity assay) using the assay buffer 50 mM TRIS-HCl (pH 7.4) supplemented with 0.076 mg BSA/ml. The final assay volume of 250 μl per well includes 2 nM of [3H]U69,593 as ligand, and either test compound in dilution series or 100 μM unlabelled naloxone for determination of unspecific binding. The test compound is diluted with 25% DMSO in H2O to yield a final 0.5% DMSO concentration which serves as respective vehicle control, as well. The assays are started by the addition of wheat germ agglutinin coated SPA beads (1 mg SPA beads/250 μl final assay volume per well) which has been preloaded for 15 minutes at room temperature with hKOP receptor membranes (14.8 μg/250 μl final assay volume per well). After short mixing on a mini-shaker, the microtiter plates are covered with a lid and the assay plates are incubated for 90 minutes at room temperature. After this incubation, the microtiter plates are sealed with a topseal and centrifuged for 20 minutes at 500 rpm. The signal rate is measured after a short delay of 5 minutes by means of a 1450 Microbeta Trilux B-counter (PerkinElmer Life Sciences/Wallac, Turku, Finland). Half-maximal inhibitory concentration (IC50) values reflecting 50% displacement of [3H]U69.593-specific receptor binding are calculated by nonlinear regression analysis and K values are calculated by using the Cheng-Prusoff equation, (Cheng and Prusoff, 1973).
- Human Delta-Opioid Peptide (hDOP) Receptor Binding Assay
- The hDOP receptor binding assay is performed as homogeneous SPA-assay using the assay buffer 50 mM TRIS-HCl, 5 mM MgCl2 (pH 7.4). The final assay volume (250 μl/well) includes 1 nM of [Tyrosyl-3,5-3H]2-D-Ala-deltorphin II as ligand, and either test compound in dilution series or 10 μM unlabelled naloxone for determination of unspecific binding. The test compound is diluted with 25% DMSO in H2O to yield a final 0.5% DMSO concentration which serves as respective vehicle control, as well. The assays are started by the addition of wheat germ agglutinin coated SPA beads (1 mg SPA beads/250 μl final assay volume per well) which has been preloaded for 15 minutes at room temperature with hDOP receptor membranes (15.2 μg/250 μl final assay volume per well). After short mixing on a mini-shaker, the microtiter plates are covered with a lid and the assay plates are incubated for 120 minutes at room temperature and centrifuged for 20 minutes at 500 rpm. The signal rate is measured by means of a 1450 Microbeta Trilux B-counter (PerkinElmer Life Sciences/Wallac, Turku, Finland). Half-maximal inhibitory concentration (IC50) values reflecting 50% displacement of [Tyrosyl-3,5-3H]2-D-Ala-deltorphin II-specific receptor binding are calculated by nonlinear regression analysis and Ki values are calculated by using the Cheng-Prusoff equation, (Cheng and Prusoff, 1973).
- Human Nociceptin/Orphanin FQ Peptide (hNOP) Receptor Binding Assay
- The hNOP receptor binding assay was performed as homogeneous SPA-assay (scintillation proximity assay) using the assay buffer 50 mM TRIS-HCl. 10 mM MgCl2. 1 mM EDTA (pH 7.4). The final assay volume (250 μl/well) included 0.5 nM of [leucyl-3H]nociceptin as ligand (PerkinElmer Life Sciences. Inc. Boston. Mass. USA). and either test compound in dilution series or 1 μM unlabelled nociceptin for determination of unspecific binding. The test compound was diluted with 25% DMSO in H2O to yield a final 0.5% DMSO concentration. which also served as a respective vehicle control. The assay was started by adding wheat germ agglutinin coated SPA beads (GE Healthcare UK Ltd.. Buckinghamshire. UK) which had been preloaded with hMOP receptor membranes (PerkinElmer Life Sciences. Inc. Boston. Mass. USA). After incubation for 60 minutes at RT and centrifugation for 20 minutes at 500 rpm the signal rate was measured by means of a 1450 Microbeta Trilux B-counter (PerkinElmer Life Sciences/Wallac. Turku. Finland). Half-maximal inhibitory concentration (IC50) values reflecting 50% displacement of [3H]nociceptin-specific receptor binding were calculated by nonlinear regression analysis and Ki values were calculated by using the Cheng-Prusoff equation. (Cheng and Prusoff. 1973).
-
hNOP Ki hMOP Ki [nM] or % [nM] or % inhibition inhibition Example @ 1 μM @ 1 μM SC_2001 2.7 245 SC_2002 4.3 965 SC_2003 585 5875 SC_2004 21.5 1310 SC_2005 12% @ 1 μM — SC_2006 0.8 43 SC_2007 1.1 43.5 SC_2008 690 not determined SC_2009 17.6 385 SC_2010 88.5 not determined SC_2011 50.5 880 SC_2012 50 1350 SC_2013 125 18.4 SC_2014 23.5 470 SC_2015 6.4 162.5 SC_2017 80 5460 SC_2018 70.8 66.8 SC_2019 0.8 50.8 SC_2020 15.5 305 SC_2021 1200 4615 SC_2022 5.4 420 SC_2023 3.8 180 SC_2024 48 1450 SC_2025 49.5 920 SC_2026 11 255 SC_2027 12 1415 SC_2028 135 3260 SC_2029 50 2150 SC_2030 96.5 1260 SC_2031 4.6 139.5 SC_2032 36 1035 SC_2033 27 855 SC_2034 490 4025 SC_2035 39 1240 SC_2036 3.1 215 SC_2037 19.5 160 SC_2038 13.5 380 SC_2039 2.8 54.5 SC_2040 34 705 SC_2041 195 1925 SC_2042 16.5 1275 SC_2043 530 20% @ 1 μM SC_2044 10.8 275 SC_2045 21 1035 SC_2046 38% @ 1 μM 23% @ 1 μM SC_2047 85.5 600 SC_2048 390 3430 SC_2049 24 1570 SC_2050 11.5 310 SC_2051 9 515 SC_2052 26.2 996.7 SC_2053 220 1385 SC_2054 43.5 340 SC_2055 96.5 2780 SC_2056 31 545 SC_2057 330 5475 SC_2058 49.5 195 SC_2059 4% @ 1 μM 26% @ 1 μM SC_2060 45 1035 SC_2061 0.5 86.5 SC_2062 20.5 1750 SC_2063 18 3430 SC_2064 41 2000 SC_2065 27 650 SC_2066 455 90 SC_2067 217.5 4700 SC_2068 34.5 230 SC_2069 14 675 SC_2070 18.5 5875 SC_2071 40 860 SC_2072 620 19% @ 1 μM SC_2073 200 3440 SC_2074 3.4 310 SC_2075 9.1 480 SC_2076 51.5 925 SC_2077 325 3460 SC_2078 170 563.3 SC_2079 19.3 710 SC_2080 87.5 625 SC_2081 1.2 147 SC_2082 180 2390 SC_2083 405 5250 SC_2084 34 880 SC_2085 3.8 230 SC_2086 3.5 150 SC_2087 47 1365 SC_2088 1.9 110 SC_2089 1.8 73 SC_2090 106 3185 SC_2091 26 1620 SC_2092 5.6 380 SC_2093 0.8 53.7 SC_2094 19 50.5 SC_2095 11.2 575 SC_2096 1.3 81 SC_2097 91 2645 SC_2099 215 5135 SC_2100 11.8 1320 SC_2101 135 1170 SC_2102 3.3 84.5 SC_2103 1.5 54 SC_2104 22.5 1000 SC_2105 2.4 45 SC_2106 16.5 1540 SC_2107 57 1700 SC_2108 10.1 195 SC_2109 17 260 SC_2110 16.5 134 SC_2111 159 1675 SC_2112 135 925 SC_2113 4 310 SC_2114 300 3045 SC_2115 720 2480 SC_2117 630 not determined SC_2118 195 995 SC_2119 85 90 SC_2120 19 1000 SC_2122 310 830 SC_2123 not determined 3840 SC_2124 4 43 SC_2125 3.4 120 SC_2143 405 5290 SC_2144 715 5180 SC_2145 340 4940 SC_2146 2% 9% SC_2147 14% 10% SC_2148 8% 0% SC_2149 160 250 SC_2150 6% 4% SC_2152 175 2475 SC_2153 22 130 SC_2155 12.5 98 SC_2156 130 330 SC_2159 2.35 40.5 SC_2160 4 39 SC_2161 100.5 295 SC_2162 31 82.5 SC_2163 13 93.5 SC_2164 130 2765 SC_2165 255 2000 SC_2166 106.5 3690 SC_2168 240 13% SC_2169 785 790 SC_2170 325 not determined SC_2171 49.25 362.5 SC_2172 50 630 SC_2173 145 5245 SC_2174 8.15 235 SC_2175 90.5 1830 SC_2176 110 3090 SC_2177 18 99.5 SC_2178 390 1050 SC_2179 108.5 2660 SC_2180 240 4085 SC_2181 190 19% SC_2182 250 13% SC_2183 63 3580 SC_2184 25 845 SC_2185 115 6980 SC_2186 40 2775 - Protocol for [35S]GTPγS Functional NOP/MOP/KOP/DOP Assays
- Cell membrane preparations of CHO-K1 cells transfected with the human MOP receptor (Art.-No. RBHOMM) or the human DOP receptor (Art.-No.RBHODM), and HEK293 cells transfected with the human NOP receptor (Art.-No.RBHORLM) or the human KOP receptor (Art.-No. 6110558) are available from PerkinElmer (Waltham, Mass.). Membranes from CHO-K1 cells transfected with the human nociceptin/orphanin FQ peptide (hNOP) receptor (Art.-No. 93-0264C2, DiscoveRx Corporation, Freemont, Calif.) are also used. [35S]GTPγS (Art.-No. NEGO30H; Lot-No. #0112, #0913, #1113 calibrated to 46.25 TBq/mmol) is available from PerkinElmer (Waltham, Mass.).
- The [35S]GTPγS assays are carried out essentially as described by Gillen et al (2000). They are run as homogeneous scintillation proximity (SPA) assays in microtiter luminescence plates, where each well contains 1.5 mg of WGA-coated SPA-beads. To test the agonistic activity of test compounds on recombinant hNOP, hMOP, hDOP, and hKOP receptor expressing cell membranes from CHO-K1 or HEK293 cells, 10 or 5 μg membrane protein per assay are incubated with 0.4 nM [35S]GTPγS and serial concentrations of receptor-specific agonists in buffer containing 20 mM HEPES pH 7.4, 100 mM NaCl, 10 mM MgCl2, 1 mM EDTA, 1 mM dithiothreitol, 1.28 mM NaN3, and 10 μM GDP for 45 min at room temperature. The microtiter plates are then centrifuged for 10 min at 830 to sediment the SPA beads. The microtiter plates are sealed and the bound radioactivity [cpm] is determined after a delay of 15 min by means of a 1450 Microbeta Trilux (PerkinElmer, Waltham, Mass.).
- The unstimulated basal binding activity (UBSobs [cpm]) is determined from 12 unstimulated incubates and is set as 100% basal binding. For determination of the potency and the efficacy, the arithmetic mean of the observed total [35S]GTPγS binding (TBobs [cpm]) of all incubates (duplicates) stimulated by the receptor-specific agonists (i.e. N/OFQ, SNC80, DAMGO, or U69,593) are transformed in percent total binding (TBobs [%]) relative to the basal binding activity (i.e. 100% binding). The potency (EC50) of the respective agonist and its maximal achievable total [35S]GTPγS binding (TBcalc [%]) above its calculated basal binding (UBScalc [%]) are determined from its transformed data (TBobs [%]) by means of nonlinear regression analysis with XLfit for each individual concentration series. Then the difference between the calculated unstimulated [35S]GTPγS binding (UBScalc [%]) and the maximal achievable total [35S]GTPγS binding (TBcalc [%]) by each tested agonist is determined (i.e. B1calc [%]). This difference (B1calc [%]) as a measure of the maximal achievable enhancement of [35S]GTPγS binding by a given agonist is used to calculate the relative efficacy of test compounds versus the maximal achievable enhancement by a receptor-specific full agonist, e.g. N/OFQ (B1calc-N/OFQ [%]) which is set as 100% relative efficacy for the hNOP receptor. Likewise, the percentage efficacies of test compounds at the hDOP, hMOP, or hKOP receptor are determined versus the calculated maximal enhancement of [35S]GTPγS binding by the full agonists SNC80 (B1calc-SNC80 [%]), DAMGO (B1calc-DAMGO [%]) and U69,593 (B1calc-U69,593 [%]) which are set as 100% relative efficacy at each receptor, respectively.
- The foregoing description and examples have been set forth merely to illustrate the invention and are not intended to be limiting. Since modifications of the described embodiments incorporating the spirit and substance of the invention may occur to persons skilled in the art, the invention should be construed broadly to include all variations within the scope of the appended claims and equivalents thereof.
Claims (28)
1. A compound according to general formula (I)
wherein
n means 1, 2 or 3;
R1 and R2 independently of one another mean
—H;
—C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —OH, —OCH3, —CN and —CO2CH3;
a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —OH, -OCH3, —CN and —CO2CH3; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted; or
a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —OH, -OCH3, —CN and —CO2CH3; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted; or
R1 and R2 together with the nitrogen atom to which they are attached form a ring and mean —(CH2)3-6—; —(CH2)2—O—(CH2)2—; or —(CH2)2—NRA—(CH2)2—, wherein RA means —H or —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br and —I;
R3 means
—C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted;
a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted;
a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted;
a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or
a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted;
R4 means
—H;
—C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said —C1-C6-alkyl is optionally connected through —C(═O)—, —C(═O)O—, or —S(═O)2—;
a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH2—, or —S(═O)2—;
a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH2—, or —S(═O)2—;
a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6 membered aryl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or wherein said 6-14-membered aryl moiety is optionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH2—, or —S(═O)2—; or
a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or wherein said 5-14-membered heteroaryl moiety is optionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH2—, or —S(═O)2—;
R5 means
a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; or
a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted;
R7, R8, R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20 independently of one another mean —H, —F, —Cl, —Br, —I, —OH, or —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted;
or wherein R7 and R8 together with the carbon atom to which they are attached form a ring and mean —(CH2)2— or —(CH2)3—;
wherein “mono- or polysubstituted” means that one or more hydrogen atoms are replaced by a substituent independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —R21, —C(═O)R21, —C(═O)OR21, —C(═O)NR21R22, —O—(CH2CH2—O)1-30—H, —O—(CH2CH2—O)1-30—CH3, ═O, —OR21, —OC(═O)R21, —OC(═O)OR21, —OC(═O)NR21R22, —NO2, —NR21R22, —NR21—(CH2)1-6—C(═O)R22, —NR21—(CH2)1-6—C(═O)OR22, —NR23—(CH2)1-6—C(═O)NR21R22, —NR21C(═O)R22, —NR21C(═O)—OR22, —NR23C(═O)NR21R22, —NR21S(═O)2R22, —SR21, —S(═O)R21, —S(═O)2R21, —S(═O)2OR21, and —S(═O)2NR21R22; wherein
R21, R22 and R23 independently of one another mean
—H;
—C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH2, and —O—C1-C6-alkyl;
a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH2, —C1-C6-alkyl and —O—C1-C6-alkyl;
a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH2, —C1-C6-alkyl and —O—C1-C6-alkyl;
a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, -I, —CN, —OH, —NH2, —C1-C6-alkyl and —O—C1-C6-alkyl;
a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH2, —C1-C6-alkyl and —O—C1-C6-alkyl;
or R21 and R22 within —C(═O)NR21R22, —OC(═O)NR21R22, NR21R22, —NR23—(CH2)1-6—C(═O)NR21R22, —NR23C(═O)NR21R22, or —S(═O)2NR21R22 together with the nitrogen atom to which they are attached form a ring and mean —(CH2)3-6—; —(CH2)2—O—(CH2)2—; or —(CH2)2—NRB—(CH2)2—, wherein RB means —H or —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br and —I;
or a physiologically acceptable salt thereof.
2. The compound according to claim 1 , wherein R7, R8, R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20 independently of one another mean —H, —F, —OH, or —C1-C6-alkyl; or R7 and R8 together with the carbon atom to which they are attached form a ring and mean —(CH2)2—.
3. The compound according to claim 1 , wherein R1 means —H; and R2 means —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
4. The compound according to claim 1 , wherein R1 means —CH3; and R2 means —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
5. The compound according to claim 1 , wherein R1 means —H or —CH3; and wherein R2 means —CH2-cycloalkyl, —CH2-cyclobutyl, —CH2-cyclopentyl, —CH2-oxetanyl or —CH2-tetrahydrofuranyl.
6. The compound according to claim 1 , wherein R1 and R2 together with the nitrogen atom to which they are attached form a ring and mean —(CH2)3-6—.
7. The compound according to claim 1 , wherein R3 means —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
8. The compound according to claim 1 , wherein R3 means a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted.
9. The compound according to claim 1 , wherein R3 means a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted.
10. The compound according to claim 1 , wherein R4 means —H.
11. The compound according to claim 1 , wherein R4 means —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
12. The compound according to claim 1 , wherein R4 means a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein the 3-12-membered cycloalkyl moiety is connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
13. The compound according to claim 1 , wherein R4 means a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
14. The compound according to claim 1 , wherein R4 means a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
15. The compound according to claim 1 , wherein R4 means a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
16. The compound according to claim 1 , wherein n means 1 or 2.
17. The compound according to claim 1 , wherein R5 means -phenyl, unsubstituted, mono- or polysubstituted.
18. The compound according to claim 1 , wherein R5 means -pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl, -thienyl, -imidazolyl, triazolyl, or -1,3-benzodioxolyl in each case unsubstituted, mono- or polysubstituted.
21. The compound according to claim 1 , wherein
n means 1 or 2;
R1 means —H or —CH3;
R2 means —H or —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted or monosubstituted with —OH, —OCH3, —C(═O)OCH3, or —CN;
R3 means
—C1-C4-alkyl, optionally monosubstituted with —OCH3;
-phenyl, -thienyl or -pyridinyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —CN, —CH3, —CH2CH3, —CH2F, —CHF2, —CF3, —OCF3, —OH, —OCH3, —O—CH2—O—CH3, —C(═O)NH2, C(═O)NHCH3, —C(═O)N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —NHC(═O)CH3, —CH2OH, SOCH3 and SO2CH3; or
R4 means
—H;
—C1-C6-alkyl, linear or branched, saturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, ═O, —OH, —CO2H, —C(═O)O—C1-C4-alkyl, —C(═O)NH2, —C(═O)NH—C1-C4-alkyl, —C(═O)N(C1-C4-alkyl)2, —C(═O)NH—C1-C4-alkyl-CN, —C(═O)NCH3—C1-C4-alkyl-CN, —C(═O)NH-cyclopropyl-CN, —C(═O)NCH3-cyclopropyl-CN, —C(═O)NH—C1-C4-alkyl-OH, —C (═O)NCH3—C1-C4-alkyl-OH, —C(═O)NH—C1-C4-alkyl-OCH3, —C(═O)NCH3—C1-C4-alkyl-OCH3, —C(═O)NRR′ wherein R and R′ together with the nitrogen atom to which they are attached form a ring and mean —(CH2)2-4—;
3-6-membered cycloalkyl, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, and —O—C1-C4-alkyl, wherein said 3-6-membered cycloalkyl is connected through —C1-C6-alkylene;
3-6-membered heterocycloalkyl, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —CO2H, —C(═O)O—C1-C4-alkyl, —OH, and —O—C1-C4-alkyl, wherein said 3-6-membered heterocycloalkyl is connected through —C1-C6-alkylene;
6-14-membered aryl, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —CO2H, —C(═O)O—C1-C4-alkyl, —OH, and —O—C1-C4-alkyl; wherein said 6-14-membered aryl is connected through —C1-C6-alkylene- or —S(═O)2—;
5-14-membered heteroaryl, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —CO2H, —C(═O)O—C1-C4-alkyl, —OH, and —O—C1-C4-alkyl; wherein said 5-14-membered heteroaryl is connected through —C1-C6-alkylene- or —S(═O)2—;
R5 means -phenyl, -pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl, -thienyl, -imidazolyl, triazolyl, or -1,3-benzodioxolyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F; —Cl; —Br; —I; —CN; —OH; —CF3; —C1-C4-alkyl-C(═O)NH2; -3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; preferably -cyclopropyl, saturated, unsubstituted; -3-12-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; —O—CH2—O—; —O—(CH2CH2—O)1-30—H; —O—(CH2CH2—O)1-30—CH3; —C(═O)OH; —C(═O)OC1-C4-alkyl; —C(═O)NH2; —C(═O)NHC1-C4-alkyl; —C(═O)N(C1-C4-alkyl)2; —SC1-C4-alkyl; —S(═O)C1-C4-alkyl and —S(═O)2C1-C4-alkyl; and
R7, R8, R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20 mean —H.
23. The compound according to claim 1 , which has a structure according to general formula (IX)
24. The compound according to claim 23 , wherein R5 is selected from -phenyl, -pyridyl, pyrimidinyl, or -triazolyl, in each case unsubstituted, mono- or polysubstituted.
25. The compound according to claim 1 , which is selected from the group consisting of
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[(4-methylsulfonyl-phenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[(3-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-1-isopropyl-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclobutyl-methyl)-3-[(4-methoxyphenyl)-methyl]-8-[methyl-(2-methyl-propyl)-amino]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-2-[[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzamide;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(pyrazin-2-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-(Allyl-methyl-amino)-1-(cyclobutyl-methyl)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-4-[[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzamide;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(4-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-methoxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(4-methoxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-(2-methyl-propyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-Butyl-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-8-(4-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-hydroxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(pyridin-3-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[[3-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-phenyl]-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(4-hydroxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one hydrochloride;
CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[(3-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclopentyl-methyl)-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-1-(2-hydroxy-2-methyl-propyl)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-1-(2-methoxy-2-methyl-propyl)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclobutyl-methyl)-3-[(3-methoxyphenyl)-methyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-3-[[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzonitrile;
CIS-1-(Cyclobutyl-methyl)-3-[(3-methoxyphenyl)-methyl]-8-(methyl-propyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-3-[(3-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-3-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-propionitrile;
CIS-1-(Cyclobutyl-methyl)-8-methylamino-8-phenyl-3-(pyridin-3-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-(oxetan-3-yl-methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-3-(pyridin-3-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-1-(2-hydroxy-ethyl)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-1-(2,2-dimethyl-propyl)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-(3-methyl-butyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1-[3-(trifluoromethyloxy)-propyl]-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(2-Cyclobutyl-ethyl)-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-[(3,3-Difluoro-cyclobutyl)-methyl]-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-2-[[1-(Cyclobutyl-methyl)-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-8-yl]-methyl-amino]-acetonitrile;
CIS-1-(Cyclobutyl-methyl)-8-[(2-methoxy-ethyl)-methyl-amino]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]acetic acid tert-butyl ester;
CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]acetic acid; 2,2,2-trifluoro-acetic acid salt;
CIS-1-(Cyclobutyl-methyl)-3-[(4-methoxyphenyl)-methyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]acetic acid methyl ester;
CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5 ]decan-1-yl]-acetamide;
CIS-1-Benzyl-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5 ]decan-2-one;
CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5 ]decan-1-yl]-N-methyl-acetamide;
CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5 ]decan-1-yl]-N-propyl-acetamide;
CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-(3-methoxy-propyl)-8-phenyl-1,3-diazaspiro[4.5 ]decan-2-one;
CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro [4. 5]decan-2-one;
CIS-8-Dimethylamino-1-(2-methoxy-ethyl)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5 ]decan-2-one;
CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5 ]decan-1-yl]-acetonitrile;
CIS-8-Dimethylamino-1-hexyl-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5 ]decan-2-one;
CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1-(tetrahydro-pyran-4-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclohexyl-methyl)-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5 ]decan-2-one;
CIS-N-(Cyano-methyl)-2-[8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5 ]decan-1-yl]-acetamide;
CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1-(pyridin-3-yl-methyl)-1,3-diazaspiro [4.5]decan-2-one;
CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-(3-methoxy-propyl)-1,3-diazaspiro[4.5]decan-2-one;
CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5 ]decan-1-yl]-N-(2-methoxy-ethyl)-acetamide;
CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-(2-oxo-2-pyrrolidin-1-yl-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N,N-dimethyl-acetamide;
CIS-N-(1-Cyano-cyclopropyl)-2-[8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetamide;
CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-methyl-N-propyl-acetamide;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-(3-methoxy-propyl)-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-1-(3-hydroxy-propyl)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-1-(4-methoxy-butyl)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-1-[(1-hydroxy-cyclohexyl)-methyl]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-5-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-pentanenitrile;
CIS-3-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-propionamide;
CIS-1-(Cyclobutyl-methyl)-8-[(2-hydroxy-ethyl)-methyl-amino]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-[[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-methyl]-cyclobutane-1-carbonitrile;
CIS-8-Dimethylamino-1-[(1-hydroxy-cyclopentyl)-methyl]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-3-[(2-Bromophenyl)-methyl]-1-(cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-3-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-methyl-propionamide;
CIS-3-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-propyl-propionamide;
CIS-8-Dimethylamino-1-[(1-fluoro-cyclobutyl)-methyl]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(2-Cyclohexyl-ethyl)-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-3-[[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzonitrile;
CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-methyl-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-1-[2-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1-(2-tetrahydro-pyran-4-yl-ethyl)-1,3-diazaspiro[4.5]decan-2-one;
CIS-4-[[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzonitrile;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[[6-(trifluoromethyl)-pyridin-3-yl]-methyl]-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[[4-[2-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]- ethoxy]-ethoxy]-ethoxy]-phenyl]-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-3-[[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzamide;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[(4-hydroxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-1-[(1-methoxy-cyclobutyl)-methyl]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-2-[[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzonitrile;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[(3-methylsulfonyl-phenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-1-ethyl-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-3-Benzyl-1-(cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1-(pyrimidin-4-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one;
CIS-3-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-2,2-dimethyl-propionitrile;
CIS-2-[[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-methyl]-benzoic acid methyl ester;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(pyridin-2-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(pyridin-4-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1-(tetrahydro-furan-3-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(pyrimidin-2-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one;
CIS-3-[[1-[(5-Cyano-2-methoxy-phenyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-4-methoxy-benzonitrile;
CIS-8-Dimethylamino-1-(3-hydroxy-3-methyl-butyl)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-1-(3-methoxy-3-methyl-butyl)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-2-[[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzamide;
CIS-3-[[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzamide;
CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-(2-methylsulfonyl-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-[(1-Hydroxy-cyclobutyl)-methyl]-3-[(4-methoxyphenyl)-methyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1-(tetrahydro-furan-2-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one;
CIS-3-Benzyl-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-3-Benzyl-8-dimethylamino-1-ethyl-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-[2-(methylsulfinyl)-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-1-[(2R)-2-hydroxy-propyl]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-1-[(2S)-2-hydroxy-propyl]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1-(tetrahydro-furan-3-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-1-ethyl-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Amino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-(2-phenyl-ethyl)-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one;
CIS-3-[[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-4-methoxy-benzonitrile;
CIS-8-Dimethylamino-1-ethyl-8-phenyl-3-(pyridin-3-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-1-[2-(1-methoxy-cyclobutyl)-ethyl]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-8-[3-(methoxymethyloxy)-phenyl]-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-8-[4-(methoxymethyloxy)-phenyl]-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one;
CIS-3-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-propionic acid;
CIS-3-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-propionic acid tert-butyl ester;
CIS-2-[[1-(Cyclobutyl-methyl)-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-8-yl]-methyl-amino]-acetic acid methyl ester;
CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-(3-methyl-but-2-enyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[(3-methylsulfanyl-phenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-3-[(3-Bromophenyl)-methyl]-1-(cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-2-((8-(dimethylamino)-1-((l-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)methyl)benzonitrile;
CIS-8-Dimethylamino-8-(3-methoxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-8-(4-methoxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one;
CIS-3-((8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)methyl)benzonitrile;
CIS-3-((8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)methyl)-4-methoxybenzonitrile;
CIS-8-Dimethylamino-8-phenyl-3-(1H-[1,2,3]triazol-4-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-3-[[1-(2-hydroxy-ethyl)-1H-[1,2,3]triazol-4-yl]-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-2-[4-[(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-methyl]-1H-[1,2,3]triazol-1-yl]-acetamide;
CIS-8-Methylamino-8-phenyl-3-(1H-[1,2,3]triazol-4-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1-(p-tolylsulfonyl)-1,3-diazaspiro[4.5]decan-2-one;
CIS-2-[4-[(8-Methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-methyl]-1H-[1,2,3]triazol-1-yl]-acetamide;
CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decane-1-carboxylic acid benzyl ester;
CIS-3-[[1-(2-Hydroxy-ethyl)-1H-[1,2,3]triazol-4-yl]-methyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-8-phenyl-3-(2-pyridin-2-yl-ethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
CIS-8-Dimethylamino-8-phenyl-3-(2-pyridin-2-yl-ethyl)-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[[1-(2-hydroxy-ethyl)-1H-[1,2,3]triazol-4-yl]-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-3-[2-(1H-imidazol-1-yl)-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione;
CIS-2-[4-[[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-1H-[1,2,3]triazol-1-yl]-acetamide;
CIS-1-[(1-Hydroxy-cyclobutyl)-methyl]-3-[[1-(2-hydroxy-ethyl)-1H-[1,2,3]triazol-4-yl]-methyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-8-phenyl-3-(2-pyridin-3-yl-ethyl)-1,3-diazaspiro [4.5]decane-2,4-dione;
CIS-8-Dimethylamino-8-phenyl-3-(2-pyridin-4-yl-ethyl)-1,3-diazaspiro [4.5]decane-2,4-dione;
CIS-2-[4-[[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-1H-[1,2,3 ]triazol-1-yl]-acetamide;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[[1-(2-hydroxy-ethyl)-1H-[1,2,3]triazol-4-yl]-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-2-[4-[[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-1H-[1,2,3 ]triazol-1-yl]-acetamide;
CIS-1-(Cyclobutyl-methyl)-3-[[1-(2-hydroxy-ethyl)-1H-[1,2,3]triazol-4-yl]-methyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-2-[4-[[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-1H-[1,2,3 ]triazol-1-yl]-acetamide;
CIS-8-Dimethylamino-8-phenyl-3-(2-pyridin-3-yl-ethyl)-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-3-[2-(1H-imidazol-1-yl)-ethyl]-8-phenyl-1,3-diazaspiro [4.5 ]decan-2-one;
CIS-8-Dimethylamino-8-phenyl-3-(2-pyridin-4-yl-ethyl)-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-8-phenyl-3-(2-pyrimidin-2-yl-ethyl)-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-8-phenyl-3-(2-pyrimidin-5-yl-ethyl)-1,3-diazaspiro [4.5]decan-2-one;
CIS-8-Dimethylamino-1-ethyl-3-[(4-methylsulfonyl-phenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-3-(1-methyl-1-phenyl-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-8-phenyl-3-(1-phenyl-cyclopropyl)-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-1,3-bis[(2-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-3-[(3-methylsulfonyl-phenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(1-methyl-1-phenyl-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-3-[(3-Cyclopropyl-phenyl)-methyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-3-(1,3-Benzodioxol-4-yl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-(1-phenyl-cyclopropyl)-1,3-diazaspiro[4.5]decan-2-one;
CIS-4-[[8-Dimethylamino-3-[(2-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-methyl]-benzonitrile;
CIS-8-Dimethylamino-3-[(2-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-8-phenyl-3-(pyridin-4-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-8-phenyl-3-(pyridin-2-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-8-phenyl-3-(pyridin-3-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-3-[[2-(4-methyl-piperazin-1-yl)-pyridin-4-yl]-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-8-phenyl-3-[(2-piperidin-1-yl-pyridin-4-yl)-methyl]-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-3-[(2-morpholin-4-yl-pyridin-4-yl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-8-phenyl-3-[(2-piperazin-1-yl-pyridin-4-yl)-methyl]-1,3-diazaspiro[4.5]decan-2-one;
and the physiologically acceptable salts thereof.
26. The compound according to claim 1 for use in the treatment of pain.
27. A medicament comprising a compound according to claim 1 .
28. A method of treating pain in a patient in need thereof, said method comprising administering to said patient an effective amount therefor of at least one compound according to claim 1 .
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US15/405,896 US20170197947A1 (en) | 2016-01-13 | 2017-01-13 | 3-((Hetero-)Aryl)-Alkyl-8-Amino-2-Oxo-1,3-Diaza-Spiro-[4.5]-Decane Derivatives |
US15/984,919 US20180327392A1 (en) | 2016-01-13 | 2018-05-21 | 3-((hetero-)aryl)-alkyl-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives |
US16/265,080 US10829480B2 (en) | 2016-01-13 | 2019-02-01 | 3-((hetero-)aryl)-alkyl-8-amino-2-oxo-l,3-diaza-spiro-[4.5]-decane derivatives |
US17/007,258 US20200399252A1 (en) | 2016-01-13 | 2020-08-31 | 3-((hetero-)aryl)-alkyl-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives |
US17/188,743 US20210179592A1 (en) | 2016-01-13 | 2021-03-01 | 3-((hetero-)aryl)-alkyl-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives |
US18/103,180 US20230174520A1 (en) | 2016-01-13 | 2023-01-30 | 3-((Hetero-)Aryl)-Alkyl-8-Amino-2-Oxo-1,3-Diaza-Spiro-[4.5]-Decane Derivatives |
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US15/984,919 Abandoned US20180327392A1 (en) | 2016-01-13 | 2018-05-21 | 3-((hetero-)aryl)-alkyl-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives |
US16/265,080 Active US10829480B2 (en) | 2016-01-13 | 2019-02-01 | 3-((hetero-)aryl)-alkyl-8-amino-2-oxo-l,3-diaza-spiro-[4.5]-decane derivatives |
US17/007,258 Abandoned US20200399252A1 (en) | 2016-01-13 | 2020-08-31 | 3-((hetero-)aryl)-alkyl-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives |
US17/188,743 Abandoned US20210179592A1 (en) | 2016-01-13 | 2021-03-01 | 3-((hetero-)aryl)-alkyl-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives |
US18/103,180 Pending US20230174520A1 (en) | 2016-01-13 | 2023-01-30 | 3-((Hetero-)Aryl)-Alkyl-8-Amino-2-Oxo-1,3-Diaza-Spiro-[4.5]-Decane Derivatives |
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US15/984,919 Abandoned US20180327392A1 (en) | 2016-01-13 | 2018-05-21 | 3-((hetero-)aryl)-alkyl-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives |
US16/265,080 Active US10829480B2 (en) | 2016-01-13 | 2019-02-01 | 3-((hetero-)aryl)-alkyl-8-amino-2-oxo-l,3-diaza-spiro-[4.5]-decane derivatives |
US17/007,258 Abandoned US20200399252A1 (en) | 2016-01-13 | 2020-08-31 | 3-((hetero-)aryl)-alkyl-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives |
US17/188,743 Abandoned US20210179592A1 (en) | 2016-01-13 | 2021-03-01 | 3-((hetero-)aryl)-alkyl-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives |
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EA037649B1 (en) | 2016-01-13 | 2021-04-27 | Грюненталь Гмбх | 3-(carboxyethyl)-8-amino-2-oxo-1,3-diaza-spiro[4.5]decane derivatives |
EA037598B1 (en) * | 2016-01-13 | 2021-04-20 | Грюненталь Гмбх | 3-((hetero)aryl)-8-amino-2-oxo-1,3-diaza-spiro[4.5]decane derivatives |
JP6917379B2 (en) | 2016-01-13 | 2021-08-11 | グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング | 8-Amino-2-oxo-1,3-diaza-spiro- [4.5] -decane derivative |
JP6854823B2 (en) | 2016-01-13 | 2021-04-07 | グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング | 3- (Carboxymethyl) -8-amino-2-oxo-1,3-diaza-spiro- [4.5] -decane derivative |
ES2797904T3 (en) | 2016-01-13 | 2020-12-04 | Gruenenthal Gmbh | 3 - ((hetero) aryl) alkyl-8-amino-2-oxo-1,3-diazaspiro- [4.5] -decane derivatives |
IL278013B2 (en) | 2018-04-18 | 2024-01-01 | Constellation Pharmaceuticals Inc | Modulators of methyl modifying enzymes, compositions and uses thereof |
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