WO2011128279A1 - Arylethynyl derivatives - Google Patents
Arylethynyl derivatives Download PDFInfo
- Publication number
- WO2011128279A1 WO2011128279A1 PCT/EP2011/055585 EP2011055585W WO2011128279A1 WO 2011128279 A1 WO2011128279 A1 WO 2011128279A1 EP 2011055585 W EP2011055585 W EP 2011055585W WO 2011128279 A1 WO2011128279 A1 WO 2011128279A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pyridin
- phenylethynyl
- dimethyl
- fluoro
- pyrimidin
- Prior art date
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- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims abstract description 26
- 230000003281 allosteric effect Effects 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims description 341
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 91
- 125000003545 alkoxy group Chemical group 0.000 claims description 84
- 125000000217 alkyl group Chemical group 0.000 claims description 79
- 239000000203 mixture Substances 0.000 claims description 78
- 239000001257 hydrogen Substances 0.000 claims description 76
- 229910052739 hydrogen Inorganic materials 0.000 claims description 76
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 76
- 229910052799 carbon Inorganic materials 0.000 claims description 71
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 46
- 238000000034 method Methods 0.000 claims description 46
- 125000004432 carbon atom Chemical group C* 0.000 claims description 40
- 150000003839 salts Chemical class 0.000 claims description 37
- 229910052736 halogen Chemical group 0.000 claims description 33
- 150000002367 halogens Chemical group 0.000 claims description 33
- 229910052757 nitrogen Inorganic materials 0.000 claims description 31
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 25
- 239000002253 acid Substances 0.000 claims description 21
- 125000001072 heteroaryl group Chemical group 0.000 claims description 19
- 125000001424 substituent group Chemical group 0.000 claims description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
- 230000003287 optical effect Effects 0.000 claims description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 12
- -1 (RS)-5-hydroxy-6,6-dimethyl-3-(5-phenylethynyl-pyridin-2-yl)-[ 1 ,3]oxazinan-2-one (4aRS,7aSR)-3-(5-phenylethynyl-pyridin-2-yl)-hexahydro-cyclopenta[e] [ 1 ,3]oxazin-2-one Chemical compound 0.000 claims description 11
- 102000005962 receptors Human genes 0.000 claims description 10
- 108020003175 receptors Proteins 0.000 claims description 10
- 230000002265 prevention Effects 0.000 claims description 9
- 201000000980 schizophrenia Diseases 0.000 claims description 9
- 206010003805 Autism Diseases 0.000 claims description 7
- 208000020706 Autistic disease Diseases 0.000 claims description 7
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 7
- YAMHXTCMCPHKLN-UHFFFAOYSA-N imidazolidin-2-one Chemical compound O=C1NCCN1 YAMHXTCMCPHKLN-UHFFFAOYSA-N 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 7
- VILLJTFEJYBCOM-UHFFFAOYSA-N 3-[5-[2-(5-fluoropyridin-3-yl)ethynyl]pyridin-2-yl]-5,5-dimethyl-1,3-oxazolidin-2-one Chemical compound O=C1OC(C)(C)CN1C1=CC=C(C#CC=2C=C(F)C=NC=2)C=N1 VILLJTFEJYBCOM-UHFFFAOYSA-N 0.000 claims description 6
- XYVMOLOUBJBNBF-UHFFFAOYSA-N 3h-1,3-oxazol-2-one Chemical compound OC1=NC=CO1 XYVMOLOUBJBNBF-UHFFFAOYSA-N 0.000 claims description 6
- TUQKPEKCBXAHHP-UHFFFAOYSA-N 4,4-dimethyl-1-[5-(2-phenylethynyl)pyridin-2-yl]imidazolidin-2-one Chemical compound O=C1NC(C)(C)CN1C1=CC=C(C#CC=2C=CC=CC=2)C=N1 TUQKPEKCBXAHHP-UHFFFAOYSA-N 0.000 claims description 6
- 208000001914 Fragile X syndrome Diseases 0.000 claims description 6
- 102000016193 Metabotropic glutamate receptors Human genes 0.000 claims description 6
- 108010010914 Metabotropic glutamate receptors Proteins 0.000 claims description 6
- 208000010877 cognitive disease Diseases 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- WKHRJQZGUZXFRC-UHFFFAOYSA-N 5,5-dimethyl-1-[5-(2-phenylethynyl)pyridin-2-yl]-1,3-diazinan-2-one Chemical compound C1C(C)(C)CNC(=O)N1C1=CC=C(C#CC=2C=CC=CC=2)C=N1 WKHRJQZGUZXFRC-UHFFFAOYSA-N 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- CVAQGQQKWMAYLM-UHFFFAOYSA-N 1-[5-[2-(3-fluorophenyl)ethynyl]pyrimidin-2-yl]-3-methoxy-4,4-dimethylpyrrolidin-2-one Chemical compound C1C(C)(C)C(OC)C(=O)N1C1=NC=C(C#CC=2C=C(F)C=CC=2)C=N1 CVAQGQQKWMAYLM-UHFFFAOYSA-N 0.000 claims description 4
- ZWQRBPIGEGXFCU-UHFFFAOYSA-N 3,4,4-trimethyl-1-[5-(2-phenylethynyl)pyridin-2-yl]imidazolidin-2-one Chemical compound C1C(C)(C)N(C)C(=O)N1C1=CC=C(C#CC=2C=CC=CC=2)C=N1 ZWQRBPIGEGXFCU-UHFFFAOYSA-N 0.000 claims description 4
- MELDBDQYIOJFIA-UHFFFAOYSA-N 3-[3-fluoro-5-(2-phenylethynyl)pyridin-2-yl]-5,5-dimethyl-1,3-oxazolidin-2-one Chemical compound O=C1OC(C)(C)CN1C1=NC=C(C#CC=2C=CC=CC=2)C=C1F MELDBDQYIOJFIA-UHFFFAOYSA-N 0.000 claims description 4
- CXSRRWDESYDWAM-UHFFFAOYSA-N 3-[5-[2-(3-fluorophenyl)ethynyl]pyridin-2-yl]-1-methyl-4,5,6,6a-tetrahydro-3ah-cyclopenta[d]imidazol-2-one Chemical compound O=C1N(C)C2CCCC2N1C(N=C1)=CC=C1C#CC1=CC=CC(F)=C1 CXSRRWDESYDWAM-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- WOANZEXNQOLHHD-UHFFFAOYSA-N 3,4,4-trimethyl-1-[5-(2-phenylethynyl)pyridin-2-yl]-1,3-diazinan-2-one Chemical compound C1CC(C)(C)N(C)C(=O)N1C1=CC=C(C#CC=2C=CC=CC=2)C=N1 WOANZEXNQOLHHD-UHFFFAOYSA-N 0.000 claims description 3
- HJBIGZGKFHWYTD-UHFFFAOYSA-N 3,4,4-trimethyl-1-[5-(2-phenylethynyl)pyrimidin-2-yl]-1,3-diazinan-2-one Chemical compound C1CC(C)(C)N(C)C(=O)N1C1=NC=C(C#CC=2C=CC=CC=2)C=N1 HJBIGZGKFHWYTD-UHFFFAOYSA-N 0.000 claims description 3
- FLHDXOQHAPPNKO-UHFFFAOYSA-N 3,4,4-trimethyl-1-[5-(2-pyridazin-4-ylethynyl)pyridin-2-yl]imidazolidin-2-one Chemical compound C1C(C)(C)N(C)C(=O)N1C1=CC=C(C#CC=2C=NN=CC=2)C=N1 FLHDXOQHAPPNKO-UHFFFAOYSA-N 0.000 claims description 3
- SATNCABEKXHUKZ-UHFFFAOYSA-N 3-[5-(2-phenylethynyl)pyridin-2-yl]-4,4a,5,6,7,7a-hexahydrocyclopenta[e][1,3]oxazin-2-one Chemical compound O=C1OC2CCCC2CN1C(N=C1)=CC=C1C#CC1=CC=CC=C1 SATNCABEKXHUKZ-UHFFFAOYSA-N 0.000 claims description 3
- PIMKOAXNBYUHBS-UHFFFAOYSA-N 3-[5-[2-(3,4-difluorophenyl)ethynyl]pyridin-2-yl]-6,6-dimethyl-1,3-oxazinan-2-one Chemical compound O=C1OC(C)(C)CCN1C1=CC=C(C#CC=2C=C(F)C(F)=CC=2)C=N1 PIMKOAXNBYUHBS-UHFFFAOYSA-N 0.000 claims description 3
- FHSFDLQSTNGRAJ-UHFFFAOYSA-N 4,4-dimethyl-1-[5-(2-phenylethynyl)pyrazin-2-yl]piperidin-2-one Chemical compound O=C1CC(C)(C)CCN1C1=CN=C(C#CC=2C=CC=CC=2)C=N1 FHSFDLQSTNGRAJ-UHFFFAOYSA-N 0.000 claims description 3
- VSMZMGWIFUANEM-UHFFFAOYSA-N 4,4-dimethyl-1-[5-(2-pyridin-3-ylethynyl)pyrazin-2-yl]piperidin-2-one Chemical compound O=C1CC(C)(C)CCN1C1=CN=C(C#CC=2C=NC=CC=2)C=N1 VSMZMGWIFUANEM-UHFFFAOYSA-N 0.000 claims description 3
- LDPYGSGCEMTKOA-UHFFFAOYSA-N 4,4-dimethyl-1-[6-(2-phenylethynyl)pyridazin-3-yl]pyrrolidin-2-one Chemical compound O=C1CC(C)(C)CN1C1=CC=C(C#CC=2C=CC=CC=2)N=N1 LDPYGSGCEMTKOA-UHFFFAOYSA-N 0.000 claims description 3
- YZHZQNRGXOPPNW-UHFFFAOYSA-N 4-methyl-6-[5-(2-phenylethynyl)pyridin-2-yl]-4,6-diazaspiro[2.4]heptan-5-one Chemical compound CN1C(=O)N(C=2N=CC(=CC=2)C#CC=2C=CC=CC=2)CC11CC1 YZHZQNRGXOPPNW-UHFFFAOYSA-N 0.000 claims description 3
- PIHMCLNCOGXHBT-UHFFFAOYSA-N 5,5-dimethyl-3-[5-(2-phenylethynyl)pyridin-2-yl]-1,3-oxazinan-2-one Chemical compound C1C(C)(C)COC(=O)N1C1=CC=C(C#CC=2C=CC=CC=2)C=N1 PIHMCLNCOGXHBT-UHFFFAOYSA-N 0.000 claims description 3
- TUSSXAVLJHYIML-UHFFFAOYSA-N 5,5-dimethyl-3-[6-(2-phenylethynyl)pyridazin-3-yl]-1,3-oxazolidin-2-one Chemical compound O=C1OC(C)(C)CN1C1=CC=C(C#CC=2C=CC=CC=2)N=N1 TUSSXAVLJHYIML-UHFFFAOYSA-N 0.000 claims description 3
- OXFJFOLEFXYRTF-UHFFFAOYSA-N 6,6-dimethyl-4-[5-(2-phenylethynyl)pyridin-2-yl]morpholin-3-one Chemical compound O=C1COC(C)(C)CN1C1=CC=C(C#CC=2C=CC=CC=2)C=N1 OXFJFOLEFXYRTF-UHFFFAOYSA-N 0.000 claims description 3
- LCVAMCWKYDWEFZ-UHFFFAOYSA-N 6-methyl-4-[5-(2-phenylethynyl)pyridin-2-yl]morpholin-3-one Chemical compound O=C1COC(C)CN1C1=CC=C(C#CC=2C=CC=CC=2)C=N1 LCVAMCWKYDWEFZ-UHFFFAOYSA-N 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- 239000013543 active substance Substances 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- CEGIJZFEIDUTNC-UHFFFAOYSA-N 1,1-dioxo-4-[5-(2-phenylethynyl)pyridin-2-yl]-1,4-thiazinan-3-one Chemical compound O=C1CS(=O)(=O)CCN1C1=CC=C(C#CC=2C=CC=CC=2)C=N1 CEGIJZFEIDUTNC-UHFFFAOYSA-N 0.000 claims description 2
- WCSCMCRCRMPYSU-UHFFFAOYSA-N 1-[5-[2-(5-fluoropyridin-3-yl)ethynyl]pyridin-2-yl]-4,4-dimethylpyrrolidin-2-one Chemical compound O=C1CC(C)(C)CN1C1=CC=C(C#CC=2C=C(F)C=NC=2)C=N1 WCSCMCRCRMPYSU-UHFFFAOYSA-N 0.000 claims description 2
- YHBYGMGQXNUERN-UHFFFAOYSA-N 3,4,4-trimethyl-1-[5-(2-pyridin-3-ylethynyl)pyridin-2-yl]imidazolidin-2-one Chemical compound C1C(C)(C)N(C)C(=O)N1C1=CC=C(C#CC=2C=NC=CC=2)C=N1 YHBYGMGQXNUERN-UHFFFAOYSA-N 0.000 claims description 2
- OZKBWEDVSNOMJW-UHFFFAOYSA-N 3-[5-(2-phenylethynyl)pyridin-2-yl]-1-oxa-3-azaspiro[4.5]decan-2-one Chemical compound C1N(C=2N=CC(=CC=2)C#CC=2C=CC=CC=2)C(=O)OC21CCCCC2 OZKBWEDVSNOMJW-UHFFFAOYSA-N 0.000 claims description 2
- VEMQMLIJJSSQEM-UHFFFAOYSA-N 3-ethyl-4,4-dimethyl-1-[5-(2-phenylethynyl)pyridin-2-yl]imidazolidin-2-one Chemical compound C1C(C)(C)N(CC)C(=O)N1C1=CC=C(C#CC=2C=CC=CC=2)C=N1 VEMQMLIJJSSQEM-UHFFFAOYSA-N 0.000 claims description 2
- SDXSBFPZQBICAJ-UHFFFAOYSA-N 3-methoxy-4,4-dimethyl-1-[5-[2-(3-methylphenyl)ethynyl]pyridin-2-yl]pyrrolidin-2-one Chemical compound C1C(C)(C)C(OC)C(=O)N1C1=CC=C(C#CC=2C=C(C)C=CC=2)C=N1 SDXSBFPZQBICAJ-UHFFFAOYSA-N 0.000 claims description 2
- AJZOJMKFJGGDFM-UHFFFAOYSA-N 4,4-dimethyl-1-[5-(2-pyridin-3-ylethynyl)pyridin-2-yl]pyrrolidin-2-one Chemical compound O=C1CC(C)(C)CN1C1=CC=C(C#CC=2C=NC=CC=2)C=N1 AJZOJMKFJGGDFM-UHFFFAOYSA-N 0.000 claims description 2
- KKEQIIHBKBKUNL-UHFFFAOYSA-N 4,4-dimethyl-1-[6-(2-phenylethynyl)pyridazin-3-yl]piperidin-2-one Chemical compound O=C1CC(C)(C)CCN1C1=CC=C(C#CC=2C=CC=CC=2)N=N1 KKEQIIHBKBKUNL-UHFFFAOYSA-N 0.000 claims description 2
- NVTOYEYPMUMDHQ-UHFFFAOYSA-N 4-cyclopropyl-3-methyl-1-[5-(2-phenylethynyl)pyridin-2-yl]imidazolidin-2-one Chemical compound O=C1N(C)C(C2CC2)CN1C(N=C1)=CC=C1C#CC1=CC=CC=C1 NVTOYEYPMUMDHQ-UHFFFAOYSA-N 0.000 claims description 2
- REXQQZHWUKJAGZ-UHFFFAOYSA-N 5,5-dimethyl-1-[5-(2-phenylethynyl)pyridin-2-yl]piperidin-2-one Chemical compound C1C(C)(C)CCC(=O)N1C1=CC=C(C#CC=2C=CC=CC=2)C=N1 REXQQZHWUKJAGZ-UHFFFAOYSA-N 0.000 claims description 2
- XKMKSEYOGDIPRN-UHFFFAOYSA-N 5,5-dimethyl-3-[5-(2-phenylethynyl)pyridin-2-yl]-1,3-oxazolidin-2-one Chemical compound O=C1OC(C)(C)CN1C1=CC=C(C#CC=2C=CC=CC=2)C=N1 XKMKSEYOGDIPRN-UHFFFAOYSA-N 0.000 claims description 2
- WGWLYPWXRZSIOO-UHFFFAOYSA-N 6,6-dimethyl-3-[5-[2-(3-methylphenyl)ethynyl]pyridin-2-yl]-1,3-oxazinan-2-one Chemical compound CC1=CC=CC(C#CC=2C=NC(=CC=2)N2C(OC(C)(C)CC2)=O)=C1 WGWLYPWXRZSIOO-UHFFFAOYSA-N 0.000 claims description 2
- ZXRANHVDPNPSDO-UHFFFAOYSA-N 6-[5-(2-pyridin-3-ylethynyl)pyridin-2-yl]-4-oxa-6-azaspiro[2.4]heptan-5-one Chemical compound C1N(C=2N=CC(=CC=2)C#CC=2C=NC=CC=2)C(=O)OC21CC2 ZXRANHVDPNPSDO-UHFFFAOYSA-N 0.000 claims description 2
- JJBRQDXGLZTCID-UHFFFAOYSA-N 6-[5-(2-pyridin-3-ylethynyl)pyridin-2-yl]-6-azabicyclo[3.2.0]heptan-7-one Chemical compound O=C1C2CCCC2N1C(N=C1)=CC=C1C#CC1=CC=CN=C1 JJBRQDXGLZTCID-UHFFFAOYSA-N 0.000 claims description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 2
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- NVKBRZCXPYSEQB-UHFFFAOYSA-N 1-[3-fluoro-5-(2-phenylethynyl)pyridin-2-yl]-4,4-dimethylpyrrolidin-2-one Chemical compound O=C1CC(C)(C)CN1C1=NC=C(C#CC=2C=CC=CC=2)C=C1F NVKBRZCXPYSEQB-UHFFFAOYSA-N 0.000 claims 1
- DPZBOPXKAJUVNN-UHFFFAOYSA-N 1-methyl-3-[5-(2-phenylethynyl)pyridin-2-yl]-1,3-diazaspiro[4.4]nonan-2-one Chemical compound CN1C(=O)N(C=2N=CC(=CC=2)C#CC=2C=CC=CC=2)CC11CCCC1 DPZBOPXKAJUVNN-UHFFFAOYSA-N 0.000 claims 1
- XOUVHFBEGYPDIX-UHFFFAOYSA-N 3-[5-[2-(2,5-difluorophenyl)ethynyl]pyridin-2-yl]-5,5-dimethyl-1,3-oxazolidin-2-one Chemical compound O=C1OC(C)(C)CN1C1=CC=C(C#CC=2C(=CC=C(F)C=2)F)C=N1 XOUVHFBEGYPDIX-UHFFFAOYSA-N 0.000 claims 1
- OJCOYBZMMKWFAI-UHFFFAOYSA-N 3-methoxy-4,4-dimethyl-1-[5-(2-phenylethynyl)pyridin-2-yl]pyrrolidin-2-one 2-[5-(2-phenylethynyl)pyridin-2-yl]-2-azaspiro[4.4]nonan-3-one Chemical compound COC1C(N(CC1(C)C)C1=NC=C(C=C1)C#CC1=CC=CC=C1)=O.C1(=CC=CC=C1)C#CC=1C=CC(=NC1)N1CC2(CC1=O)CCCC2 OJCOYBZMMKWFAI-UHFFFAOYSA-N 0.000 claims 1
- ZHWOCDWCIUNDPX-UHFFFAOYSA-N 4,4-dimethyl-1-[5-(2-phenylethynyl)pyridin-2-yl]piperidin-2-one 7-[5-(2-phenylethynyl)pyridin-2-yl]-2-oxa-7-azaspiro[3.4]octan-6-one Chemical compound CC1(CC(N(CC1)C1=NC=C(C=C1)C#CC1=CC=CC=C1)=O)C.C1(=CC=CC=C1)C#CC=1C=CC(=NC1)N1CC2(COC2)CC1=O ZHWOCDWCIUNDPX-UHFFFAOYSA-N 0.000 claims 1
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- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 1
- YVPJCJLMRRTDMQ-UHFFFAOYSA-N ethyl diazoacetate Chemical compound CCOC(=O)C=[N+]=[N-] YVPJCJLMRRTDMQ-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000002964 excitative effect Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 229940028332 halog Drugs 0.000 description 1
- 231100000234 hepatic damage Toxicity 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 229960004903 invert sugar Drugs 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 230000001057 ionotropic effect Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 230000008818 liver damage Effects 0.000 description 1
- 208000007903 liver failure Diseases 0.000 description 1
- 231100000835 liver failure Toxicity 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 108010038421 metabotropic glutamate receptor 2 Proteins 0.000 description 1
- 108010038445 metabotropic glutamate receptor 3 Proteins 0.000 description 1
- 108010038422 metabotropic glutamate receptor 4 Proteins 0.000 description 1
- 108010038450 metabotropic glutamate receptor 6 Proteins 0.000 description 1
- 108010038449 metabotropic glutamate receptor 7 Proteins 0.000 description 1
- 108010038448 metabotropic glutamate receptor 8 Proteins 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- FRQPMIDWJDBNJL-UHFFFAOYSA-N methyl 2-hydroxy-3-(phenylmethoxycarbonylamino)propanoate Chemical compound COC(=O)C(O)CNC(=O)OCC1=CC=CC=C1 FRQPMIDWJDBNJL-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- VUPQHSHTKBZVML-UHFFFAOYSA-J rhodium(3+);tetraacetate Chemical compound [Rh+3].[Rh+3].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O VUPQHSHTKBZVML-UHFFFAOYSA-J 0.000 description 1
- XIIOFHFUYBLOLW-UHFFFAOYSA-N selpercatinib Chemical compound OC(COC=1C=C(C=2N(C=1)N=CC=2C#N)C=1C=NC(=CC=1)N1CC2N(C(C1)C2)CC=1C=NC(=CC=1)OC)(C)C XIIOFHFUYBLOLW-UHFFFAOYSA-N 0.000 description 1
- 210000002265 sensory receptor cell Anatomy 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- KVGHRGZLASNXMA-UHFFFAOYSA-N tert-butyl 1-methyl-2-oxo-4,5,6,6a-tetrahydro-3ah-cyclopenta[d]imidazole-3-carboxylate Chemical compound C1CCC2N(C(=O)OC(C)(C)C)C(=O)N(C)C21 KVGHRGZLASNXMA-UHFFFAOYSA-N 0.000 description 1
- WONFZQLPWSGYJI-UHFFFAOYSA-N tert-butyl 2-oxo-1,3a,4,5,6,6a-hexahydrocyclopenta[d]imidazole-3-carboxylate Chemical compound C1CCC2NC(=O)N(C(=O)OC(C)(C)C)C21 WONFZQLPWSGYJI-UHFFFAOYSA-N 0.000 description 1
- YEVUZCQMURNMQB-UHFFFAOYSA-N tert-butyl n-(3-amino-3-methylbutyl)carbamate;hydrochloride Chemical compound Cl.CC(C)(N)CCNC(=O)OC(C)(C)C YEVUZCQMURNMQB-UHFFFAOYSA-N 0.000 description 1
- JXPGHMMHNMMAFH-UHFFFAOYSA-N tert-butyl n-[4-[(5-iodopyridin-2-yl)amino]-2-methylbutan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)NC(C)(C)CCNC1=CC=C(I)C=N1 JXPGHMMHNMMAFH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- HBDDRESWUAFAHY-UHFFFAOYSA-N thiomorpholin-3-one Chemical compound O=C1CSCCN1 HBDDRESWUAFAHY-UHFFFAOYSA-N 0.000 description 1
- PXMBRPRXSVLVLQ-UHFFFAOYSA-N thiomorpholine-2,3,6-trione Chemical compound O=C1CNC(=O)C(=O)S1 PXMBRPRXSVLVLQ-UHFFFAOYSA-N 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
-
- 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
- C07D401/14—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 three or more hetero rings
-
- 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
- C07D403/04—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 directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
Definitions
- the present invention relates to thynyl derivatives of formula I
- R 5 is hydrogen, methyl or halogen
- Y is -N(R 6 )-, -0-, -C(R 7' )(R 7 )-, -CH 2 0- or -CH 2 S(0) 2 -;
- R 6 is hydrogen or lower alkyl and R 7 /R 7 are independently from each other hydrogen, hydroxy, lower alkyl or lower alkoxy;
- R 1 is phenyl or heteroaryl, which are optionally substituted by one or two substituents, selected from halogen, lower alkyl or lower alkoxy;
- R 2 /R 2' are independently from each other hydrogen, lower alkyl, hydroxy, lower alkoxy, C3-C6- cycloalkyl, CH 2 -lower alkoxy, or may form together with the carbon atom to which they are attached a C3-C6-cycloalkyl or a ring containing -CH 2 OCH 2 -;
- n 0, 1 or 2;
- R 3 /R 3' are independently from each other hydrogen, lower alkyl, CH 2 -lower alkoxy or may form together with the carbon atom to which they are attached a C3-C6-cycloalkyl; or R 3 and R 2 may form together with the carbon atom to which they are attached a C 3 _6- cycloalkyl or a ring containing -(CH 2 ) 2 OCH 2 -; n is 0 or 1 ;
- R 4 /R 4 are independently from each other hydrogen, lower alkyl, CH 2 -lower alkoxy or may form together with the carbon atom to which they are attached a C3-C6-cycloalkyl; R 4 and R 2 may form together with the carbon atom to which they are attached a
- R 6 and R 2 may form together with the carbon atom and the nitrogen atom to which they are attached a C3_6-cycloalkyl;
- R 2 and R 7 may form together with the carbon atoms to which they are attached a C3_6-cycloalkyl
- the compounds of general formula I are allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGluR5).
- the transmission of stimuli takes place by the interaction of a neurotransmitter, which is sent out by a neuron, with a neuroreceptor.
- Glutamate is the major excitatory neurotransmitter in the brain and plays a unique role in a variety of central nervous system (CNS) functions.
- the glutamate-dependent stimulus receptors are divided into two main groups.
- the first main group namely the ionotropic receptors, forms ligand-controlled ion channels.
- the metabotropic glutamate receptors (mGluR) belong to the second main group and, furthermore, belong to the family of G-protein coupled receptors.
- these eight receptors can be sub-divided into three sub-groups:
- mGluRl and mGluR5 belong to group I
- mGluR2 and mGluR3 belong to group II
- mGluR4 mGluR6, mGluR7 and mGluR8 belong to group III.
- Ligands of metabotropic glutamate receptors belonging to the first group can be used for the treatment or prevention of acute and/or chronic neurological disorders such as psychosis, epilepsy, schizophrenia, Alzheimer's disease, cognitive disorders and memory deficits, as well as chronic and acute pain.
- acute and/or chronic neurological disorders such as psychosis, epilepsy, schizophrenia, Alzheimer's disease, cognitive disorders and memory deficits, as well as chronic and acute pain.
- treatable indications in this connection are restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia.
- Further treatable indications are ischemia, Huntington's chorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficiency functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, opiate addiction, anxiety, vomiting, dyskinesia and depressions.
- ALS amyotrophic lateral sclerosis
- Disorders mediated full or in part by mGluR5 are for example acute, traumatic and chronic degenerative processes of the nervous system, such as Alzheimer's disease, senile dementia, Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis and multiple sclerosis, psychiatric diseases such as schizophrenia and anxiety, depression, pain and drug dependency (Expert Opin. Ther. Patents (2002), 12, (12)).
- disorders include fragile X syndrome, autism, idiopatic autism, tuberous sclerosis complex disorder, neurofibromatosis type 1 or Rett syndrome (Annu. Rev. Med., 2011, 62, 31.1 - 31.19 and Neuroscience 156, 2008, 203-215).
- Described in the prior art are positive allosteric modulators. They are compounds that do not directly activate receptors by themselves, but markedly potentiate agonist-stimulated responses, increase potency and maximum of efficacy. The binding of these compounds increases the affinity of a glutamate-site agonist at its extracellular N-terminal binding site. Allosteric modulation is thus an attractive mechanism for enhancing appropriate physiological receptor activation. There is a scarcity of selective allosteric modulators for the mGluR5 receptor. Conventional mGluR5 receptor modulators typically lack satisfactory aqueous solubility and exhibit poor oral bioavailability.
- Compounds of formula I are distinguished by having valuable therapeutic properties. They can be used in the treatment or prevention of disorders, relating to allosteric modulators for the mGluR5 receptor.
- the most preferred indications for compounds which are allosteric modulators are schizophrenia and cognition.
- the present invention relates to compounds of formula I and to their pharmaceutically acceptable salts, in cases where this applies to mixtures of enantiomers or diastereomers or their enantiomerically or diastereomerically pure forms, to these compounds as pharmaceutically active substances, to the processes for their production as well as to the use in the treatment or prevention of disorders, relating to allosteric modulators for the mGluR5 receptor, such as schizophrenia, cognition, fragile X syndrome or autism, and to pharmaceutical compositions containing the compounds of formula I..
- lower alkyl denotes a saturated, i.e. aliphatic hydrocarbon group including a straight or branched carbon chain with 1 - 4 carbon atoms.
- alkyl examples are methyl, ethyl, n-propyl, and isopropyl.
- alkoxy denotes a group -O-R' wherein R' is lower alkyl as defined above.
- ethynyl denotes the group -C ⁇ C-.
- cycloalkyl denotes a saturated carbon ring, containing from 3 to 6 carbon ring atoms, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
- heteroaryl denotes a 5 or 6-membered aromatic ring, containing at least one
- N, O or S-heteroatom for example pyridinyl, pyrimidinyl, pyrazolyl, pyridazinyl, imidazolyl, triazolyl, thienyl or pyrazinyl.
- pharmaceutically acceptable salt or “pharmaceutically acceptable acid addition salt” embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like.
- hydrochloric acid such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like.
- One embodiment of the invention are compounds of formula
- R 5 is hydrogen, methyl or halogen
- R 1 is phenyl or heteroaryl, which are optionally substituted by one or two substituents, selected from halogen, lower alkyl or lower alkoxy;
- R 2 /R 2' are independently from each other hydrogen, lower alkyl, hydroxy, lower alkoxy, C3-C6- cycloalkyl, CH 2 -lower alkoxy, or may form together with the carbon atom to which they are attached a C3-C6-cycloalkyl or a ring containing -CH 2 OCH 2 -;
- R 3 /R 3' are independently from each other hydrogen, lower alkyl, CH 2 -lower alkoxy or may form together with the carbon atom to which they are attached a C3-C6-cycloalkyl;
- R 3 and R 2 may form together with the carbon atom to which they are attached a C 3 _6- cycloalkyl or a ring containing -(CH 2 ) 2 OCH 2 -;
- R 5 is hydrogen, methyl or halogen
- R 1 is phenyl or heteroaryl, which are optionally substituted by one or two substituents, selected from halogen, lower alkyl or lower alkoxy;
- R 2 /R 2' are independently from each other hydrogen, lower alkyl, hydroxy, lower alkoxy, C3-C6- cycloalkyl, CH 2 -lower alkoxy, or may form together with the carbon atom to which they are attached a C3-C6-cycloalkyl or a ring containing -CH 2 OCH 2 -;
- R 3 and R 2 may form together with the carbon atom to which they are attached a C 3 _6- cycloalkyl or a ring containing -(CH 2 ) 2 OCH 2 -;
- R 5 is hydrogen, methyl or halogen
- R 6 is hydrogen or lower alkyl
- R 1 is phenyl or heteroaryl, which are optionally substituted by one or two substituents, selected from halogen, lower alkyl or lower alkoxy;
- R 2 /R 2' are independently from each other hydrogen, lower alkyl, hydroxy, lower alkoxy, C3-C6- cycloalkyl, CH 2 -lower alkoxy, or may form together with the carbon atom to which they are attached a C3-C6-cycloalkyl or a ring containing -CH 2 OCH 2 -;
- R 3 and R 2 may form together with the carbon atom to which they are attached a C 3 _6- cycloalkyl or a ring containing -(CH 2 ) 2 OCH 2 -;
- R 6 and R 2 may form together with the carbon atom and the nitrogen atom to which they are attached a C 3 _6-cycloalkyl;
- R 5 is hydrogen, methyl or halogen
- R 1 is phenyl or heteroaryl, which are optionally substituted by one or two substituents, selected from halogen, lower alkyl or lower alkoxy;
- R 2 /R 2' are independently from each other hydrogen, lower alkyl, hydroxy, lower alkoxy, C 3 -C 6 - cycloalkyl, CH 2 -lower alkoxy, or may form together with the carbon atom to which they are attached a C 3 -C 6 -cycloalkyl or a ring containing -CH 2 OCH 2 -;
- R 3 and R 2 may form together with the carbon atom to which they are attached a C 3 _6- cycloalkyl or a ring containing -(CH 2 ) 2 OCH 2 -;
- R 4 /R 4 are independently from each other hydrogen, lower alkyl, CH 2 -lower alkoxy or may form together with the carbon atom to which they are attached a C 3 -C 6 -cycloalkyl;
- R 4 and R 2 may form together with the carbon atom to which they are attached a
- R 5 is hydrogen, methyl or halogen
- R 1 is phenyl or heteroaryl, which are optionally substituted by one or two substituents, selected from halogen, lower alkyl or lower alkoxy;
- R 2 /R 2' are independently from each other hydrogen, lower alkyl, hydroxy, lower alkoxy, C 3 -C 6 - cycloalkyl, CH 2 -lower alkoxy, or may form together with the carbon atom to which they are attached a C 3 -C 6 -cycloalkyl or a ring containing -CH 2 OCH 2 -;
- R 3 and R 2 may form together with the carbon atom to which they are attached a C 3 _6- cycloalkyl or a ring containing -(CH 2 ) 2 OCH 2 -;
- R 4 /R 4 are independently from each other hydrogen, lower alkyl, CH 2 -lower alkoxy or may form together with the carbon atom to which they are attached a C 3 -C 6 -cycloalkyl;
- R 4 and R 2 may form together with the carbon atom to which they are attached a
- R 5 is hydrogen, methyl or halogen
- R 6 is hydrogen or lower alkyl
- R 1 is phenyl or heteroaryl, which are optionally substituted by one or two substituents, selected from halogen, lower alkyl or lower alkoxy;
- R 2 /R 2' are independently from each other hydrogen, lower alkyl, hydroxy, lower alkoxy, C3-C6- cycloalkyl, CH 2 -lower alkoxy, or may form together with the carbon atom to which they are attached a C3-C6-cycloalkyl or a ring containing -CH 2 OCH 2 -;
- R 3 and R 2 may form together with the carbon atom to which they are attached a C 3 _6- cycloalkyl or a ring containing -(CH 2 ) 2 OCH 2 -;
- R 4 /R 4 are independently from each other hydrogen, lower alkyl, CH 2 -lower alkoxy or may form together with the carbon atom to which they are attached a C 3 -C6-cycloalkyl;
- R 4 and R 2 may form together with the carbon atom to which they are attached a
- R 5 is hydrogen, methyl or halogen
- Y is -N(R 6 )-, -0-, -C(R 7' )(R 7 )-, -CH 2 0- or -CH 2 S(0) 2 -;
- R 6 is hydrogen or lower alkyl and R 7 /R 7 are independently from each other hydrogen, hydroxy, lower alkyl or lower alkoxy;
- R is phenyl or heteroaryl, which are optionally substituted by one or two substituents, selected from halogen, lower alkyl or lower alkoxy;
- R 2 /R 2' are independently from each other hydrogen, lower alkyl, hydroxy, lower alkoxy, C3-C6- cycloalkyl, CH 2 -lower alkoxy, or may form together with the carbon atom to which they are attached a C3-C6-cycloalkyl or a ring containing -CH 2 OCH 2 -;
- a further object of the invention are compounds of formula I, wherein Y is -CH 2 0- , for example
- a further object of the invention are compounds of formula I, wherein Y is -CH 2 S(0) 2 -, for example
- a further object of the invention are compounds of formula I, wherein m is 2, for example
- One object of the invention are eth nyl derivatives of formula I
- X is N or C-R 5 ,
- R 5 is hydrogen or halog Y is N-R 6 , O or CHR 7 ,
- R 6 is hydrogen or lower alkyl and R 7 is hydrogen, hydroxy, lower alkyl or lower alkoxy;
- R 1 is phenyl or heteroaryl, which are optionally substituted by halogen, lower alkyl or lower alkoxy;
- R 2 /R 2' are independently from each other hydrogen, lower alkyl, CH 2 -lower alkoxy or may form together with the carbon atom to which they are attached a C3-C6-cycloalkyl;
- n 0 or 1 ; in case m is 1 ,
- n is 0 or 1 ; in case n is 1 ,
- R 4 /R 4 are independently from each other hydrogen, lower alkyl, CH 2 -lower alkoxy or may form together with the carbon atom to which they are attached a C3-C6-cycloalkyl; or if m is 1 and n is 0, R 3 and R 2 may form together with the carbon atoms to which they are attached a C3_6-cycloalkyl;
- R 4 and R 2 may form together with the carbon atoms to which they are attached a C3_6-cycloalkyl;
- the compounds of formula I can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art.
- the reaction sequence is not limited to the one displayed in the schemes, however, depending on the starting materials and their respective reactivity the sequence of reaction steps can be freely altered. Starting materials are either commercially available or can be prepared by methods analogous to the methods given below, by methods described in references cited in the description or in the examples, or by methods known in the art.
- X is a suitable leaving group which can be substituted by an acetylene moiety such as, for example a bromine or iodine atom, a trialkylstannyl group, a boronic acid or boronic ester group
- a ethynyl-pyridine, ethynyl-pyrimidine, ethynyl-pyrazine or ethynyl-pyridazine compound of formula I-A can be obtained by substitution of an appropriate 5-iodo-2-fluoro- pyridine, 5-iodo-2-fluoro-pyrimidine, 2-chloro-5-iodopyridazine or 2-bromo-5-iodopyrazine 1 or the like and an appropriate aminoalcohol 2 with a base such as pyridine, triethylamine, or cesium carbonate in a solvent such as NMP, pyridine, or dioxane to yield the corresponding 5-iodo-2- aminoalkoxy- adducts of formula 3, which are treated with phosgene or a phosgene equivalent such as triphosgene in presence of base such as pyridine in a solvent like dichloromethane to give the corresponding cycl
- An ethynyl-pyridine, ethynyl-pyrimidine, ethynyl-pyrazine or ethynyl-pyridazine compound of formula I-B can be obtained by reacting an appropriate 5-iodo-2-amino-pyridine- or 5-iodo-2-amino-pyrimidine-, 5-iodo-2-amino-pyrazine, or 5-iodo-2-amino-pyridazine derivative 6 or the like with an appropriately substituted anhydride 7 in a solvent such as DMF to yield the corresponding imide derivative 8, which is reduced with a reducing agent such as sodium borohydride in a solvent such as THF and/or MeOH to give the corresponding alcohol derivative 9.
- An ethynyl-pyridine, ethynyl-pyrimidine, ethynyl-pyrazine or ethynyl-pyridazine compound of formula I-C can be obtained by substitution of an appropriate 5-iodo-2-fluoro- pyridine, 5-iodo-2-fluoro-pyrimidine, 2-chloro-5-iodopyridazine or 2-bromo-5-iodopyrazine 1 or the like (1) wherein Y is a suitable leaving group which can be displaced via nucleophillic substitution by an amine such as a fluorine, chlorine, or bromine atom or an alkysulfonyl group with an appropriate diaminoalkyl derivative 11 in presence of a base such as pyridine or cesium carbonate in a solvent like NMP, pyridine, or dioxane to yield the corresponding N-heteroaryl derivative 12, which is cyclized with phosgene or
- An ethynyl-pyridine or ethynyl-pyrimidine compound of formula I can be obtained for example by Sonogashira coupling of a 2-bromo-5-iodo-pyridine, 2-bromo-5-iodo-pyrimidine, 2- bromo-5-iodopyridazine or 2-bromo-5-iodopyrazine 1 or the like with ethynyltrimethylsilane 15 to yield the 2-bromo-5-trimethylsilanylethynyl-substituted heteroaryl derivatives 16.
- sequence of steps used to synthesize the compounds of formula I can also be modified in certain cases, for example by first running the Sonogashira coupling with an appropriately substituted aryl- or heteroaryl-ethynyl derivative followed by the introduction of a lactam-, cyclic carbamate- or cyclic urea using procedures similar to those described in schemes 1 to 4. (scheme 6)
- the compound of formula I as described herein as well as its pharmaceutically acceptable salt is used in the treatment or prevention of psychosis, epilepsy, schizophrenia, Alzheimer's disease, cognitive disorders and memory deficits, chronic and acute pain, restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia, ischemia, Huntington's chorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments, muscle spasms, convulsions, migraine, urinary incontinence, gastrointestinal reflux disorder, liver damage or failure whether drug or disease induced, Fragile-X syndrom, Down syndrom, autism, nicotine addiction, opiate addiction, anxiety, vomiting, dyskinesia, eating disorders, in particular bulimia or anorexia nervosa, and depressions, particularly for the treatment and prevention of acute and/or
- the preferred indications are schizophrenia and cognitive disorders.
- Present invention further relates to the use of a compound of formula I as described herein, as well as its pharmaceutically acceptable salt, for the manufacture of a medicament, preferably for the treatment and prevention of the above-mentioned disorders.
- Intracellular Ca 2+ mobilization assay A monoclonal HEK-293 cell line stably transfected with a cDNA encoding for the human mGlu5a receptor was generated; for the work with mGlu5 Positive Allosteric Modulators (PAMs), a cell line with low receptor expression levels and low constitutive receptor activity was selected to allow the differentiation of agonistic versus PAM activity.
- PAMs mGlu5 Positive Allosteric Modulators
- Cells were cultured according to standard protocols (Freshney, 2000) in Dulbecco's Modified Eagle Medium with high glucose supplemented with 1 mM glutamine, 10% (vol/vol) heat-inactivated bovine calf serum, Penicillin/Streptomycin, 50 ⁇ g/ml hygromycin and 15 ⁇ g/ml blasticidin (all cell culture reagents and antibiotics from Invitrogen, Basel, Switzerland). About 24 firs before an experiment, 5x10 4 cells/well were seeded in poly-D-lysine coated, black/clear-bottomed 96-well plates.
- the cells were loaded with 2.5 ⁇ Fluo-4AM in loading buffer (lxHBSS, 20 mM HEPES) for 1 hr at 37°C and washed five times with loading buffer.
- the cells were transferred into a Functional Drug Screening System 7000 (Hamamatsu, Paris, France), and 11 half logarithmic serial dilutions of test compound at 37°C were added and the cells were incubated for 10-30 min. with on-line recording of fluorescence.
- the compounds of formula (I) and pharmaceutically acceptable salts thereof can be used as medicaments, e.g. in the form of pharmaceutical preparations.
- the pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions.
- the administration can also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
- Suitable carriers for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like.
- Adjuvants such as alcohols, polyols, glycerol, vegetable oils and the like, can be used for aqueous injection solutions of water-soluble salts of compounds of formula (I), but as a rule are not necessary.
- Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
- the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
- pharmaceutically acceptable salts thereof and a therapeutically inert excipient are also an object of the present invention, as is a process for the production of such medicaments which comprises bringing one or more compounds of formula I or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical dosage form together with one or more therapeutically inert carriers.
- the use of the compounds of formula (I) for the preparation of medicaments useful in the prevention and/or the treatment of the above recited diseases is also an object of the present invention.
- the dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case.
- the effective dosage for oral or parenteral administration is between 0.01-20 mg/kg/day, with a dosage of 0.1-10 mg/ kg/day being preferred for all of the indications described.
- compositions comprising compounds of the invention: Tablets of the following composition are produced in a conventional manner: mg/T ablet
- 2,3-Difluoro-5-iodopyridine 500 mg, 2.07 mmol was dissolved in NMP (500 ⁇ ) and pyridine (201 ⁇ , 2.49 mmol, 1.2 equiv.) and l-amino-2-methylpropan-2-ol (555 mg, 6.22 mmol, 3 equiv.) were added at room temperature. The mixture was stirred for 16 hours at 100 °C. The reaction mixture was cooled and extracted with saturated NaHCOs solution and two times with a small volume of dichloromethane.
- Example 1 (580 mg, 1.87 mmol) l-(3-Fluoro-5-iodopyridin-2-ylamino)-2-methylpropan-2-ol (Example 1, step 1) was dissolved in dichloromethane (10 ml) and pyridine (300 ⁇ , 3.74 mmol, 2 equiv.) was added at room temperature. The mixture was cooled to 0-5°C and phosgene (20% in toluene) (1.19 ml, 2.24 mmol, 1.2 equiv.) was added dropwise over a period of 15min at 0-5°C. The mixture was stirred for 1 hour at 0-5 °C.
- the reaction mixture was extracted with saturated NaHCC"3 solution and two times with a small volume of dichloromethane.
- the crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a silica gel column and eluting with a heptane:ethyl acetate gradient 100:0 to 50:50.
- Triethylamine (108 mg, 149 ⁇ , 1.07 mmol, 3 equiv.), triphenylphosphine (2.81 mg, 10.7 ⁇ , 0.03 equiv.) and copper(I)iodide (2.04 mg, 10.7 ⁇ , 0.03 equiv.) were added and the mixture was stirred for 3 hours at 70°C.
- the reaction mixture was cooled and extracted with saturated NaHCOs solution and two times with a small volume of dichloromethane.
- the crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a silica gel column and eluting with an ethyl acetate:heptane gradient 0: 100 to 40:60.
- the crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a amino-silica gel column and eluting with a ethyl acetate/heptane gradient, 0: 100 to 100:0.
- Step 3 (4RS)-4-(tert-Butyl-diphenyl-silanyloxy)-l-(5-iodo-pyridin-2-yl)-3,3-dimethyl- rro lidine-2 , 5 -dione
- Step 4 (3RS,5RS)-3-(tert-Butyl-diphenyl-silanyloxy)-5-hydroxy-l-(5-iodo-pyridin-2-yl)-4,4- dimeth l-pyrro lidin-2-one
- Step 5 (3RS)-3-(tert-Butyl-diphenyl-silanyloxy)- 1 -(5-iodo-pyridin-2-yl)-4,4-dimethyl- pyrrolidin-2-one
- Example 15 (Example 15, step 3) was dissolved in DMF (0.5 ml) and cooled to 0-5°C. NaH (55%) (19.8 mg, 453 ⁇ , 1.2 equiv.) was added and the mixture was stirred for 30min at 0-5°C. lodomethane (35.3 ⁇ , 566 ⁇ , 1.5 equiv.) was added and the mixture was stirred for 30 min at 0-5 °C. The reaction mixture was treated with sat. NaHC0 3 solution and extracted twice with a small volume of CH 2 CI 2 .
- step 1 (1.6 g, 5.4 mmol) l-Dibenzylamino-3,3-dimethyl-butan-2-one (Example 19, step 1) was dissolved in diethylether (20 ml) and cooled to 0-5°C. Methylmagnesium bromide (3M in diethylether) (2.2 ml, 6.5 mmol, 1.2 equiv.) was added drop wise at 0-5°C and the mixture was stirred for 72 hours at room temperature. The reaction mixture was extracted with sat. NH 4 C1- solution and two times EtOAc. The organic layers were extracted with water, dryed over Na 2 S0 4 , filtered and evaporated to dryness.
- Methylmagnesium bromide 3M in diethylether
- EtOAc EtOAc
- Step 6 (5RS)-5-tert-Butyl-5-methyl-3-(5-phenylethynyl-pyridin-2-yl)-oxazolidin-2-one
- Step 1 3-(5-Iodo-pyridin-2-yl)-5,5-dimethyl-[l,3]oxazinan-2-one
- ethynyltrimethylsilane 950 mg, 1.34 ml, 9.6 mmol, 1.1 equiv.
- triethylamine (1.78 g, 2.44 ml, 17.6 mmol, 3 equiv.)
- copper(I)iodide 84 mg, 440 ⁇ , 0.05 equiv.
- the crude product was purified by flash chromatography on silica gel, eluting with an ethyl acetate: heptane gradient 0: 100 to 15:85.
- Step 2 4 ⁇ -Dimethyl-l-(5-trimethylsilanylethynyl-pyridin-2-yl)-pyrrolidin-2-one
- Example 41
- the BOC protecting group is removed by reacting ⁇ l-[(5-iodo-pyridin-2-ylamino)-methyl]- cyclopentyl ⁇ -carbamic acid tert-butyl ester (Example 44, step 1) with 4N HCl in dioxane for 1 hour at room temperature.
- Step 3 3-(5-Iodo-pyridin-2-yl)-l,3-diaza-spiro[4.4]nonan-2-one
- Step 2 (RS)-l-[5-(5-Chloro-pyridin-3-ylethynyl)-pyridin-2-yl]-3-methoxy-4,4-dimethyl- rrolidin-2-one
- the BOC protecting group is removed by reacting [3-(5-iodo-pyridin-2-ylamino)- 1 , 1 -dimethyl- propyl] -carbamic acid tert-butyl ester (Example 67, step 1) with 4N HCl in dioxane for 4 hours at room temperature.
- Ste 3 l-(5-Iodo-pyridin-2-yl)-4,4-dimethyl-tetrahydro-pyrimidin-2-one
- Step 4 1 -(5-Iodo-pyridin-2-yl)-3 ,4,4-trimethyl-tetrahydro-pyrimidin-2-one
- MS: m/e 346.0 (M+H + )
- chemistry similar to that described in Example 16 from l-(5-iodo-pyridin-2-yl)-4,4-dimethyl-tetrahydro- pyrimidin-2-one (Example 67, step 3) and iodomethane.
- Step 1 3 A4-Trimethyl-l-(5-trimethylsilanyleth ⁇
- Step 1 (3-Hydroxy-3-methyl-butyl)-carbamic acid benzyl ester
- Step 1 3-(5-Iodo-pyridin-2-yl)-6,6-dimethyl-[l,3]oxazinan-2-one
- MS: m/e 333.1 (M+H + )
- step 2 from 2-fluoro-5-iodopyridine and 4- amino -2-methy l-butan-2-o 1 hydro chloride .
- Ste 2 6,6-Dimethyl-3-(5-pyridin-3-ylethynyl-pyridin-2-yl)-[l,3]oxazinan-2-one
- Step 3 (3aSR,7aRS)-(3aRS,7aRS)- 1 -(5-Iodo-pyridin-2-yl)-3-methyl-octahydro-benzoimidazol- 2-one
- Ste 1 4 ⁇ -Dimethyl-5'-trimethylsilanylethynyl-3,4,5,6-tetrahydro-[l,2']bipyridinyl-2-one
- Step 2 7 -Dimethyl-3-(5-phenylethynyl-pyridin-2-yl)-[l,3]oxazepan-2-one
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BR112012026004A BR112012026004A2 (en) | 2010-04-13 | 2011-04-11 | arylethynyl derivatives |
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KR1020127029579A KR101431367B1 (en) | 2010-04-13 | 2011-04-11 | Arylethynyl derivatives |
JP2013504215A JP5559418B2 (en) | 2010-04-13 | 2011-04-11 | Arylethynyl derivatives |
SG2012066759A SG183974A1 (en) | 2010-04-13 | 2011-04-11 | Arylethynyl derivatives |
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