NZ621894B2 - Ethynyl derivatives as mglur5 allosteric modulators - Google Patents
Ethynyl derivatives as mglur5 allosteric modulators Download PDFInfo
- Publication number
- NZ621894B2 NZ621894B2 NZ621894A NZ62189412A NZ621894B2 NZ 621894 B2 NZ621894 B2 NZ 621894B2 NZ 621894 A NZ621894 A NZ 621894A NZ 62189412 A NZ62189412 A NZ 62189412A NZ 621894 B2 NZ621894 B2 NZ 621894B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- phenylethynyl
- pyridinyl
- lower alkyl
- hydrogen
- trimethyl
- Prior art date
Links
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 title claims abstract description 15
- 230000000051 modifying Effects 0.000 title description 16
- 230000003281 allosteric Effects 0.000 title description 14
- -1 1-[6-(4-Fluoro-phenylethynyl)-pyridin-3-yl]-3,4,4-trimethyl-imidazolidin-2-one 1-[6-(3-Fluoro-phenylethynyl)-pyridin-3-yl]-3,4,4-trimethyl-imidazolidin-2-one Chemical compound 0.000 claims abstract description 104
- 150000001875 compounds Chemical class 0.000 claims abstract description 84
- 150000003839 salts Chemical class 0.000 claims abstract description 30
- 239000011780 sodium chloride Substances 0.000 claims abstract description 30
- 239000000203 mixture Substances 0.000 claims abstract description 27
- 238000007792 addition Methods 0.000 claims abstract description 18
- 239000002253 acid Substances 0.000 claims abstract description 16
- 230000000875 corresponding Effects 0.000 claims abstract description 16
- 230000003287 optical Effects 0.000 claims abstract description 13
- 230000002265 prevention Effects 0.000 claims abstract description 9
- 201000000980 schizophrenia Diseases 0.000 claims abstract description 9
- 206010003805 Autism Diseases 0.000 claims abstract description 8
- 201000002055 autistic disease Diseases 0.000 claims abstract description 8
- 208000001914 Fragile X Syndrome Diseases 0.000 claims abstract description 7
- 108009000484 Fragile X Syndrome Proteins 0.000 claims abstract description 7
- 206010057668 Cognitive disease Diseases 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 65
- 229910052739 hydrogen Inorganic materials 0.000 claims description 54
- 239000001257 hydrogen Substances 0.000 claims description 54
- 125000003545 alkoxy group Chemical group 0.000 claims description 45
- 150000002431 hydrogen Chemical group 0.000 claims description 34
- 229910052736 halogen Inorganic materials 0.000 claims description 22
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 19
- 150000002367 halogens Chemical group 0.000 claims description 16
- 229910052799 carbon Inorganic materials 0.000 claims description 15
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- WRBSLLOTRGATJI-UHFFFAOYSA-N 6,6-dimethyl-3-[6-(2-phenylethynyl)pyridin-3-yl]-1,3-oxazinan-2-one Chemical compound O=C1OC(C)(C)CCN1C1=CC=C(C#CC=2C=CC=CC=2)N=C1 WRBSLLOTRGATJI-UHFFFAOYSA-N 0.000 abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 31
- 239000007787 solid Substances 0.000 description 24
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 16
- 102000005962 receptors Human genes 0.000 description 14
- 108020003175 receptors Proteins 0.000 description 14
- 235000019439 ethyl acetate Nutrition 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 210000004027 cells Anatomy 0.000 description 9
- 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 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 229960001866 silicon dioxide Drugs 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 8
- 239000000969 carrier Substances 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 108010010914 Metabotropic Glutamate Receptors Proteins 0.000 description 6
- 102000016193 Metabotropic Glutamate Receptors Human genes 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 230000027455 binding Effects 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 238000003818 flash chromatography Methods 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 125000005843 halogen group Chemical group 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- RODTWUBQTXSTLJ-UHFFFAOYSA-N 2-(2-phenylethynyl)pyridine Chemical compound C1=CC=CC=C1C#CC1=CC=CC=N1 RODTWUBQTXSTLJ-UHFFFAOYSA-N 0.000 description 5
- UEXCJVNBTNXOEH-UHFFFAOYSA-N Phenylacetylene Chemical group C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- PTRUTZFCVFUTMW-UHFFFAOYSA-N 1-ethynyl-3-fluorobenzene Chemical group FC1=CC=CC(C#C)=C1 PTRUTZFCVFUTMW-UHFFFAOYSA-N 0.000 description 4
- NHUBNHMFXQNNMV-UHFFFAOYSA-N 2-ethynylpyridine Chemical compound C#CC1=CC=CC=N1 NHUBNHMFXQNNMV-UHFFFAOYSA-N 0.000 description 4
- HSNBRDZXJMPDGH-UHFFFAOYSA-N 5-bromo-2-iodopyridine Chemical compound BrC1=CC=C(I)N=C1 HSNBRDZXJMPDGH-UHFFFAOYSA-N 0.000 description 4
- YNHIGQDRGKUECZ-UHFFFAOYSA-L Bis(triphenylphosphine)palladium(II) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 4
- 210000003169 Central Nervous System Anatomy 0.000 description 4
- LSXDOTMGLUJQCM-UHFFFAOYSA-M Copper(I) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 4
- 239000001828 Gelatine Substances 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000000556 agonist Substances 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000000825 pharmaceutical preparation Substances 0.000 description 4
- 229920005862 polyol Polymers 0.000 description 4
- 150000003077 polyols Chemical class 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Chemical compound [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 230000004936 stimulating Effects 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- FZBHCYSESMFQJL-UHFFFAOYSA-N 2-bromo-3-iodopyridine Chemical class BrC1=NC=CC=C1I FZBHCYSESMFQJL-UHFFFAOYSA-N 0.000 description 3
- IRLLLHYGMMQKFU-UHFFFAOYSA-N 4,4-dimethylimidazolidin-2-one Chemical compound CC1(C)CNC(=O)N1 IRLLLHYGMMQKFU-UHFFFAOYSA-N 0.000 description 3
- HGVPKAGCVCGRDQ-UHFFFAOYSA-N 4,4-dimethylpyrrolidin-2-one Chemical compound CC1(C)CNC(=O)C1 HGVPKAGCVCGRDQ-UHFFFAOYSA-N 0.000 description 3
- OIHVPJNMIRGQSV-UHFFFAOYSA-N 6,6-dimethyl-1,3-oxazinan-2-one Chemical compound CC1(C)CCNC(=O)O1 OIHVPJNMIRGQSV-UHFFFAOYSA-N 0.000 description 3
- 206010001897 Alzheimer's disease Diseases 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N Methyl iodide Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 208000002193 Pain Diseases 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 230000001270 agonistic Effects 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N (E)-but-2-enedioate;hydron Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N 1-[(1S,2R,3R,4S,5R,6R)-3-carbamimidamido-6-{[(2R,3R,4R,5S)-3-{[(2S,3S,4S,5R,6S)-4,5-dihydroxy-6-(hydroxymethyl)-3-(methylamino)oxan-2-yl]oxy}-4-formyl-4-hydroxy-5-methyloxolan-2-yl]oxy}-2,4,5-trihydroxycyclohexyl]guanidine Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- IPEJYDSOKWOWDS-UHFFFAOYSA-N 2-bromo-4-iodopyrimidine Chemical compound BrC1=NC=CC(I)=N1 IPEJYDSOKWOWDS-UHFFFAOYSA-N 0.000 description 2
- LKUGAEKNPIPMED-UHFFFAOYSA-N 2-ethynyl-1,4-difluorobenzene Chemical group FC1=CC=C(F)C(C#C)=C1 LKUGAEKNPIPMED-UHFFFAOYSA-N 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N 289-95-2 Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- BEUWBSAVSYYTEI-UHFFFAOYSA-N 5,5-dimethylpyrazolidin-3-one Chemical compound CC1(C)CC(=O)NN1 BEUWBSAVSYYTEI-UHFFFAOYSA-N 0.000 description 2
- 206010002855 Anxiety Diseases 0.000 description 2
- 206010057666 Anxiety disease Diseases 0.000 description 2
- 210000004556 Brain Anatomy 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L Caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 102100006612 GRM5 Human genes 0.000 description 2
- 101700027086 GRM5 Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 201000001971 Huntington's disease Diseases 0.000 description 2
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 102100001279 PAM Human genes 0.000 description 2
- 208000003715 Parkinsonian Disorders Diseases 0.000 description 2
- 206010034010 Parkinsonism Diseases 0.000 description 2
- 238000003477 Sonogashira cross-coupling reaction Methods 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N Triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 230000001154 acute Effects 0.000 description 2
- 230000036506 anxiety Effects 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- 238000004166 bioassay Methods 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 230000001684 chronic Effects 0.000 description 2
- 230000019771 cognition Effects 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000003925 fat Substances 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 150000003951 lactams Chemical class 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 238000011068 load Methods 0.000 description 2
- 239000012160 loading buffer Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- 239000002858 neurotransmitter agent Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229920002401 polyacrylamide Polymers 0.000 description 2
- 239000001184 potassium carbonate Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- NDGRWYRVNANFNB-UHFFFAOYSA-N pyrazolidin-3-one Chemical class O=C1CCNN1 NDGRWYRVNANFNB-UHFFFAOYSA-N 0.000 description 2
- 238000009738 saturating Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 230000001225 therapeutic Effects 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- QXSWHQGIEKUBAS-UHFFFAOYSA-N 1-ethynyl-4-fluorobenzene Chemical group FC1=CC=C(C#C)C=C1 QXSWHQGIEKUBAS-UHFFFAOYSA-N 0.000 description 1
- IMRWILPUOVGIMU-UHFFFAOYSA-N 2-bromopyridine Chemical compound BrC1=CC=CC=N1 IMRWILPUOVGIMU-UHFFFAOYSA-N 0.000 description 1
- PGFIHORVILKHIA-UHFFFAOYSA-N 2-bromopyrimidine Chemical class BrC1=NC=CC=N1 PGFIHORVILKHIA-UHFFFAOYSA-N 0.000 description 1
- CLRPXACRDTXENY-UHFFFAOYSA-N 3-ethynylpyridine Chemical compound C#CC1=CC=CN=C1 CLRPXACRDTXENY-UHFFFAOYSA-N 0.000 description 1
- AHJURMYTAVIGPC-UHFFFAOYSA-N 4,4-dimethyl-1-[2-(2-phenylethynyl)pyrimidin-5-yl]imidazolidin-2-one Chemical compound O=C1NC(C)(C)CN1C1=CN=C(C#CC=2C=CC=CC=2)N=C1 AHJURMYTAVIGPC-UHFFFAOYSA-N 0.000 description 1
- VGLAJERHBBEPQP-UHFFFAOYSA-N 5-bromo-2-ethynylpyridine Chemical compound BrC1=CC=C(C#C)N=C1 VGLAJERHBBEPQP-UHFFFAOYSA-N 0.000 description 1
- 206010000565 Acquired immunodeficiency syndrome Diseases 0.000 description 1
- 208000005298 Acute Pain Diseases 0.000 description 1
- 206010002026 Amyotrophic lateral sclerosis Diseases 0.000 description 1
- 108009000433 Amyotrophic lateral sclerosis (ALS) Proteins 0.000 description 1
- 229940064005 Antibiotic throat preparations Drugs 0.000 description 1
- 229940083879 Antibiotics FOR TREATMENT OF HEMORRHOIDS AND ANAL FISSURES FOR TOPICAL USE Drugs 0.000 description 1
- 229940042052 Antibiotics for systemic use Drugs 0.000 description 1
- 229940042786 Antitubercular Antibiotics Drugs 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 206010007515 Cardiac arrest Diseases 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- 229920002676 Complementary DNA Polymers 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 208000008208 Craniocerebral Trauma Diseases 0.000 description 1
- KDXKERNSBIXSRK-RXMQYKEDSA-N D-lysine Chemical compound NCCCC[C@@H](N)C(O)=O KDXKERNSBIXSRK-RXMQYKEDSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- 206010012378 Depression Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 208000001187 Dyskinesias Diseases 0.000 description 1
- 206010015037 Epilepsy Diseases 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N Ethyl iodide Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- XEHVFKKSDRMODV-UHFFFAOYSA-N Ethynyl radical Chemical class C#[C] XEHVFKKSDRMODV-UHFFFAOYSA-N 0.000 description 1
- 208000010167 Eye Injury Diseases 0.000 description 1
- 102000003688 G-protein coupled receptors Human genes 0.000 description 1
- 108090000045 G-protein coupled receptors Proteins 0.000 description 1
- 102100004351 GRM1 Human genes 0.000 description 1
- 102100006616 GRM2 Human genes 0.000 description 1
- 102100006614 GRM3 Human genes 0.000 description 1
- 102100006613 GRM4 Human genes 0.000 description 1
- 102100002039 GRM6 Human genes 0.000 description 1
- 101700022058 GRM6 Proteins 0.000 description 1
- 102100002041 GRM7 Human genes 0.000 description 1
- 102100002037 GRM8 Human genes 0.000 description 1
- 101700067982 GRM8 Proteins 0.000 description 1
- 229940093922 Gynecological Antibiotics Drugs 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N HEPES Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 208000010496 Heart Arrest Diseases 0.000 description 1
- 206010020993 Hypoglycaemia Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- 108090000862 Ion Channels Proteins 0.000 description 1
- 206010061255 Ischaemia Diseases 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 102100014726 MECP2 Human genes 0.000 description 1
- 101700029603 MECP2 Proteins 0.000 description 1
- 206010027175 Memory impairment Diseases 0.000 description 1
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 1
- 206010027599 Migraine Diseases 0.000 description 1
- 208000008085 Migraine Disorders Diseases 0.000 description 1
- 206010028334 Muscle spasms Diseases 0.000 description 1
- 208000009025 Nervous System Disease Diseases 0.000 description 1
- 208000003019 Neurofibromatosis 1 Diseases 0.000 description 1
- 206010029305 Neurological disorder Diseases 0.000 description 1
- 206010057852 Nicotine dependence Diseases 0.000 description 1
- 230000035536 Oral bioavailability Effects 0.000 description 1
- 206010061536 Parkinson's disease Diseases 0.000 description 1
- 229940049954 Penicillin Drugs 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 206010037175 Psychiatric disease Diseases 0.000 description 1
- 206010061920 Psychotic disease Diseases 0.000 description 1
- 229940083082 Pyrimidine derivatives acting on arteriolar smooth muscle Drugs 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- 206010038932 Retinopathy Diseases 0.000 description 1
- 208000006289 Rett Syndrome Diseases 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 210000002265 Sensory Receptor Cells Anatomy 0.000 description 1
- 210000002966 Serum Anatomy 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 208000008513 Spinal Cord Injury Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229960005322 Streptomycin Drugs 0.000 description 1
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 description 1
- 210000000225 Synapses Anatomy 0.000 description 1
- 229940024982 Topical Antifungal Antibiotics Drugs 0.000 description 1
- 208000009999 Tuberous Sclerosis Diseases 0.000 description 1
- 206010046543 Urinary incontinence Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- AVFUHBJCUUTGCD-UHFFFAOYSA-M [Br-].[Mg+]C Chemical compound [Br-].[Mg+]C AVFUHBJCUUTGCD-UHFFFAOYSA-M 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000000240 adjuvant Effects 0.000 description 1
- 230000001058 adult Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000111 anti-oxidant Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000004429 atoms Chemical group 0.000 description 1
- 229960000626 benzylpenicillin Drugs 0.000 description 1
- 230000003115 biocidal Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 230000004641 brain development Effects 0.000 description 1
- 230000003925 brain function Effects 0.000 description 1
- 239000012578 cell culture reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- LNAMMBFJMYMQTO-FNEBRGMMSA-N chloroform;(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].ClC(Cl)Cl.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 LNAMMBFJMYMQTO-FNEBRGMMSA-N 0.000 description 1
- LKYXEULZVGJVTG-UHFFFAOYSA-N chloromethane Chemical compound Cl[CH] LKYXEULZVGJVTG-UHFFFAOYSA-N 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- VMQMZMRVKUZKQL-UHFFFAOYSA-N cu+ Chemical compound [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000003412 degenerative Effects 0.000 description 1
- 230000001419 dependent Effects 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000007877 drug screening Methods 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002708 enhancing Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000002964 excitative Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000001146 hypoxic Effects 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229940079866 intestinal antibiotics Drugs 0.000 description 1
- 230000003834 intracellular Effects 0.000 description 1
- 229960004903 invert sugar Drugs 0.000 description 1
- 230000001057 ionotropic Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 230000000873 masking Effects 0.000 description 1
- 230000001404 mediated 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
- 108010038449 metabotropic glutamate receptor 7 Proteins 0.000 description 1
- 108010014719 metabotropic glutamate receptor type 1 Proteins 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- LWSYHFSVQUXZJI-UHFFFAOYSA-N methyl 3-(phenylmethoxycarbonylamino)propanoate Chemical compound COC(=O)CCNC(=O)OCC1=CC=CC=C1 LWSYHFSVQUXZJI-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 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
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 201000004931 neurofibromatosis Diseases 0.000 description 1
- 210000002569 neurons Anatomy 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 229940005935 ophthalmologic Antibiotics Drugs 0.000 description 1
- 230000036220 oral bioavailability Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000003204 osmotic Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000003389 potentiating Effects 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 230000002335 preservative Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 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
- 239000001384 succinic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000003765 sweetening agent Substances 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
- 229960001367 tartaric acid Drugs 0.000 description 1
- AYEKOFBPNLCAJY-UHFFFAOYSA-O thiamine pyrophosphate Chemical compound CC1=C(CCOP(O)(=O)OP(O)(O)=O)SC=[N+]1CC1=CN=C(C)N=C1N AYEKOFBPNLCAJY-UHFFFAOYSA-O 0.000 description 1
- 235000008170 thiamine pyrophosphate Nutrition 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 230000000472 traumatic Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 230000001960 triggered Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
-
- 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
- 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
Abstract
The disclosure relates to ethynyl derivatives of formula (I) wherein the unspecified moieties are disclosed within the specification, or a pharmaceutically acceptable acid addition salt, to a racemic mixture, or to its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof. The disclose also relates to their use in the treatment of or prevention of schizophrenia, cognitive diseases, fragile X syndrome or autism. Example compounds include: 1-[6-(4-Fluoro-phenylethynyl)-pyridin-3-yl]-3,4,4-trimethyl-imidazolidin-2-one 1-[6-(3-Fluoro-phenylethynyl)-pyridin-3-yl]-3,4,4-trimethyl-imidazolidin-2-one 2-[6-(3-Fluoro-phenylethynyl)-pyridin-3-yl]-1,5,5-trimethyl-5 pyrazolidin-3-one 2-[6-(2,5-Difluoro-phenylethynyl)-pyridin-3-yl]-1,5,5-trimethyl-pyrazolidin-3-one 4,4-Dimethyl-1-(6-phenylethynyl-pyridin-3-yl)-pyrrolidin-2-one 6,6-Dimethyl-3-(6-phenylethynyl-pyridin-3-yl)-[1,3]oxazinan-2-one. isclose also relates to their use in the treatment of or prevention of schizophrenia, cognitive diseases, fragile X syndrome or autism. Example compounds include: 1-[6-(4-Fluoro-phenylethynyl)-pyridin-3-yl]-3,4,4-trimethyl-imidazolidin-2-one 1-[6-(3-Fluoro-phenylethynyl)-pyridin-3-yl]-3,4,4-trimethyl-imidazolidin-2-one 2-[6-(3-Fluoro-phenylethynyl)-pyridin-3-yl]-1,5,5-trimethyl-5 pyrazolidin-3-one 2-[6-(2,5-Difluoro-phenylethynyl)-pyridin-3-yl]-1,5,5-trimethyl-pyrazolidin-3-one 4,4-Dimethyl-1-(6-phenylethynyl-pyridin-3-yl)-pyrrolidin-2-one 6,6-Dimethyl-3-(6-phenylethynyl-pyridin-3-yl)-[1,3]oxazinan-2-one.
Description
Case 30647
ETHYNYL DERIVATIVES AS MGLUR5 ALLOSTERIC MODULATORS
The present invention relates to ethynyl derivatives of formula I
wherein
U is N or CH,
R is hydrogen, halogen, lower alkyl or lower alkoxy;
4 5 5’
Y is –N(R )-, -O- or –C(R R )-;
4 5 5’
wherein R is hydrogen or lower alkyl and R /R are independently hydrogen, hydroxy,
lower alkyl or lower alkoxy;
6 7 7’
V is –N(R )- or –C(R R ),
6 7 7’
wherein R is hydrogen or lower alkyl and R /R are independently from each other
hydrogen, lower alkyl, CH -lower alkoxy or may form together with the carbon atom to
which they are attached a C -C -cycloalkyl;
R is phenyl or heteroaryl, which are optionally substituted by halogen, lower alkyl or lower
alkoxy;
m is 0 or 1; in case m is 1,
3 3’
R /R are independently from each other hydrogen, lower alkyl, CH -lower alkoxy or may form
together with the carbon atom to which they are attached a C -C -cycloalkyl;
n is 0 or 1; in case n is 1,
2 2’
R /R are independently from each other hydrogen, lower alkyl, CH -lower alkoxy or may form
together with the carbon atom to which they are attached a C -C -cycloalkyl;
or if m is 1 and n is 0, R and R may form together with the carbon atoms to which they are
attached a C -cycloalkyl;
2 3 3 7
or if m is 1 and n is 1, R and R or R and R may form together with the carbon atoms to
which they are attached a C -cycloalkyl;
Pop/11.07.2012
or to a pharmaceutically acceptable acid addition salt, to a racemic mixture, or to its
corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.
It has now surprisingly been found that the compounds of general formula I are
allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGluR5).
In the central nervous system (CNS) 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.
At present, eight different members of these mGluR are known and of these some even
have sub-types. According to their sequence homology, signal transduction mechanisms and
agonist selectivity, these eight receptors can be sub-divided into three sub-groups:
mGluR1 and mGluR5 belong to group I, mGluR2 and mGluR3 belong to group II and
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.
Other 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.
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)).
A new avenue for developing selective modulators is to identify compounds which act
through allosteric mechanism, modulating the receptor by binding to a site different from the
highly conserved orthosteric binding site. Allosteric modulators of mGluR5 have emerged
recently as novel pharmaceutical entities offering this attractive alternative. Allosteric
modulators have been described, for example in WO2008/151184, WO2006/048771,
WO2006/129199 and WO2005/044797 and in Molecular Pharmacology, 40, 333 – 336, 1991;
The Journal of Pharmacology and Experimental Therapeutics, Vol 313, No. 1, 199-206, 2005;
In recent years there have been significant advantages in understanding the
pathophysiology of several disorders of brain development, suggesting that protein synthesis at
synapses is triggered by activation of group I metabotropic glutamate receptors. Such 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.
Therefore, there remains a need for compounds that overcome these deficiencies and that
effectively provide selective allosteric modulators for the mGluR5 receptor.
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 their use for the
manufacture of medicaments for the treatment or prevention of disorders, relating to allosteric
modulators for the mGluR5 receptor, selected from schizophrenia, cognition, fragile X syndrome
and autism, and to pharmaceutical compositions containing the compounds of formula I.
The following definitions of the general terms used in the present description apply
irrespective of whether the terms in question appear alone or in combination.
As used herein, the term "lower alkyl" denotes a saturated, i.e. aliphatic hydrocarbon group
including a straight or branched carbon chain with 1 – 4 carbon atoms. Examples for “alkyl” are
methyl, ethyl, n-propyl, and isopropyl.
The term “alkoxy” denotes a group -O-R’ wherein R’ is lower alkyl as defined above.
The term “ethynyl” denotes the group −C≡C-.
The term “cycloalkyl” denotes a saturated carbon ring, containing from 3 to 6 carbon ring
atoms, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
The term “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.
The term "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.
One embodiment of the invention are compounds of formula
3' 2
I-1
wherein
U is N or CH;
R is hydrogen;
Y is CH , O, -N(CH )- or -N(CH CH )-
2 3 2 3 ;
V is CH , -NH- or -N(CH )-;
R is phenyl or pyridinyl, which are optionally substituted by halogen;
m is 0 or 1; in case m is 1,
3 3’
R /R are independently from each other hydrogen or lower alkyl,
n is 1;
2 2’
R /R are independently from each other hydrogen or lower alkyl;
or a pharmaceutically acceptable acid addition salt, a racemic mixture, or its corresponding
enantiomer and/or optical isomer and/or stereoisomer thereof, for example the following
compounds
4,4-Dimethyl(6-phenylethynyl-pyridinyl)-pyrrolidinone
6,6-Dimethyl(6-phenylethynyl-pyridinyl)-[1,3]oxazinanone
3,4,4-Trimethyl(6-phenylethynyl-pyridinyl)-imidazolidinone
1-[6-(4-Fluoro-phenylethynyl)-pyridinyl]-3,4,4-trimethyl-imidazolidinone
1-[6-(3-Fluoro-phenylethynyl)-pyridinyl]-3,4,4-trimethyl-imidazolidinone
3,4,4-Trimethyl(6-pyridinylethynyl-pyridinyl)-imidazolidinone
1-[6-(3-Fluoro-phenylethynyl)-pyridinyl]-4,4-dimethyl-pyrrolidinone
,5-Dimethyl(6-phenylethynyl-pyridinyl)-pyrazolidinone
4,4-Dimethyl(6-phenylethynyl-pyrimidinyl)-pyrrolidinone
3,4,4-Trimethyl(2-phenylethynyl-pyrimidinyl)-imidazolidinone
3-Ethyl-4,4-dimethyl(2-phenylethynyl-pyrimidinyl)-imidazolidinone
1,5,5-Trimethyl(6-phenylethynyl-pyridinyl)-pyrazolidinone
2-[6-(3-Fluoro-phenylethynyl)-pyridinyl]-1,5,5-trimethyl-pyrazolidinone
2-[6-(2,5-Difluoro-phenylethynyl)-pyridinyl]-1,5,5-trimethyl-pyrazolidinone
2-[6-(3-Fluoro-phenylethynyl)-pyridinyl]-5,5-dimethyl-pyrazolidinone or
2-[6-(2,5-Difluoro-phenylethynyl)-pyridinyl]-5,5-dimethyl-pyrazolidinone.
One further embodiment of the invention are compounds of formula
wherein
U is N or CH,
R is hydrogen, halogen, lower alkyl or lower alkoxy;
4 5 5 ’
Y is –N(R )-, O or -C(R R )- ;
4 5 5’
wherein R is hydrogen or lower alkyl and R /R are independently hydrogen, hydroxy,
lower alkyl or lower alkoxy;
R is phenyl or heteroaryl, which are optionally substituted by halogen, lower alkyl or lower
alkoxy;
2 2’
R /R are independently from each other hydrogen, lower alkyl, CH -lower alkoxy or may form
together with the carbon atom to which they are attached a C -C -cycloalkyl;
or a pharmaceutically acceptable acid addition salt, a racemic mixture, or its corresponding
enantiomer and/or optical isomer and/or stereoisomer thereof.
Examples of compounds of formula IA are the followings:
4,4-dimethyl(6-phenylethynyl-pyridinyl)-pyrrolidinone
3,4,4-trimethyl(6-phenylethynyl-pyridinyl)-imidazolidinone
1-[6-(4-fluoro-phenylethynyl)-pyridinyl]-3,4,4-trimethyl-imidazolidinone
1-[6-(3-fluoro-phenylethynyl)-pyridinyl]-3,4,4-trimethyl-imidazolidinone
3,4,4-trimethyl(6-pyridinylethynyl-pyridinyl)-imidazolidinone
1-[6-(3-fluoro-phenylethynyl)-pyridinyl]-4,4-dimethyl-pyrrolidinone
4,4-dimethyl(6-phenylethynyl-pyrimidinyl)-pyrrolidinone
3,4,4-Trimethyl(2-phenylethynyl-pyrimidinyl)-imidazolidinone or
3-Ethyl-4,4-dimethyl(2-phenylethynyl-pyrimidinyl)-imidazolidinone.
A further embodiment of the invention are compounds of formula
IB
wherein
U is N or CH,
R is hydrogen, halogen, lower alkyl or lower alkoxy;
4 5 5’
Y is –N(R )-, O or –C(R R )-;
4 5 5’
wherein R is hydrogen or lower alkyl and R /R are independently hydrogen, hydroxy,
lower alkyl or lower alkoxy;
R is phenyl or heteroaryl, which are optionally substituted by halogen, lower alkyl or lower
alkoxy;
2 2’
R /R are independently from each other hydrogen, lower alkyl, CH -lower alkoxy or may form
together with the carbon atom to which they are attached a C -C -cycloalkyl;
or a pharmaceutically acceptable acid addition salt, a racemic mixture, or its corresponding
enantiomer and/or optical isomer and/or stereoisomer thereof.
Specific examples from compounds of formula IB is the following:
6,6-dimethyl(6-phenylethynyl-pyridinyl)-[1,3]oxazinanone.
A further embodiment of the invention are compounds of formula
IC
wherein
U is N or CH,
R is hydrogen, halogen, lower alkyl or lower alkoxy;
4 5 5 ’
Y is –N(R )-, O or –C(R R )- ;
4 5 5’
wherein R is hydrogen or lower alkyl and R /R are independently hydrogen, hydroxy,
lower alkyl or lower alkoxy;
R is phenyl or heteroaryl, which are optionally substituted by halogen, lower alkyl or lower
alkoxy;
2 2’
R /R are independently from each other hydrogen, lower alkyl, CH -lower alkoxy or may form
together with the carbon atom to which they are attached a C -C -cycloalkyl;
or a pharmaceutically acceptable acid addition salt, a racemic mixture, or its corresponding
enantiomer and/or optical isomer and/or stereoisomer thereof.
Examples from compounds of formula IC is the following:
5,5-dimethyl(6-phenylethynyl-pyridinyl)-pyrazolidinone.
One further embodiment of the invention are compounds of formula
wherein
U is N or CH,
R is hydrogen, halogen, lower alkyl or lower alkoxy;
4 5 5’
Y is –N(R )-, -O- or –C(R R )-;
4 5 5’
wherein R is hydrogen or lower alkyl and R /R are independently hydrogen, hydroxy,
lower alkyl or lower alkoxy;
R is hydrogen or lower alkyl
R is phenyl or heteroaryl, which are optionally substituted by halogen, lower alkyl or lower
alkoxy;
2 2’
R /R are independently from each other hydrogen, lower alkyl, CH -lower alkoxy or may form
together with the carbon atom to which they are attached a C -C -cycloalkyl;
or a pharmaceutically acceptable acid addition salt, a racemic mixture, or its corresponding
enantiomer and/or optical isomer and/or stereoisomer thereof.
Examples of compounds of formula I-D are
1,5,5-Trimethyl(6-phenylethynyl-pyridinyl)-pyrazolidinone
2-[6-(3-Fluoro-phenylethynyl)-pyridinyl]-1,5,5-trimethyl-pyrazolidinone
2-[6-(2,5-Difluoro-phenylethynyl)-pyridinyl]-1,5,5-trimethyl-pyrazolidinone
2-[6-(3-Fluoro-phenylethynyl)-pyridinyl]-5,5-dimethyl-pyrazolidinone or
2-[6-(2,5-Difluoro-phenylethynyl)-pyridinyl]-5,5-dimethyl-pyrazolidinone.
The preparation of compounds of formula I of the present invention may be carried out in
sequential or convergent synthetic routes. Syntheses of the compounds of the invention are
shown in the following schemes 1 and 2. The skills required for carrying out the reaction and
purification of the resulting products are known to those skilled in the art. The substituents and
indices used in the following description of the processes have the significance given herein
before.
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.
The present compounds of formula I and their pharmaceutically acceptable salts may be
prepared by methods, known in the art, for example by the process variant described below,
which process comprises
a) reacting a compound of formula
Br U
with a suitable aryl-acetylene of formula
2
to a compound of formula
wherein the substituents are described above, or
b) reacting a compound of formula
3' 2
4
with a suitable compound of formula
to a compound of formula
3' 2
wherein the substituents are described above, and,
if desired, converting the compounds obtained into pharmaceutically acceptable acid addition
salts.
The preparation of compounds of formula I is further described in more detail in schemes 1 and
2 and in examples 1 – 16.
Scheme 1
3' 2'
1. Bis-(tpp)-Pd(II)Cl R
Et N, CuI, THF
Br 2
3 ()
N V ()
16h 60°C n
8 R HN
I U R 1
3' 3
2. K CO , Cu(I)I
N,N´-dimethylethylenediamine V
dioxane, 16h, 100°C
An ethynyl-pyridine or ethynyl-pyrimidine compound of formula I can be obtained for
example by Sonogashira coupling of an appropriate 5-bromoiodo-pyridine or pyrimidine 1
with an appropriately substituted arylacetylene 2 to yield the corresponding 5-bromo
ethynylpyridine or pyrimidine derivatives 3. Substitution of 3 with an appropriate lactam, cyclic
carbamate, cyclic urea or pyrazolidinone derivative 4 in presence of a base such as potassium
carbonate and using copper(I)iodide and N,N´-dimethylethylenediamine in a solvent like dioxane
yields the desired ethynyl-pyridine or ethynyl-pyrimidine compound of formula I.
Scheme 2
1. Cs CO xantphos
R 2 3, 3' 3
Pd (dba) , toluene
N V () R
1h 90°C
V ()
HN Y
Br U R
Br U R
3' 3
2. Bis-(tpp)-Pd(II)Cl
Et N, TPP, CuI
DMF, 2h, 70°C
An ethynyl-pyridine or ethynyl-pyrimidine compound of formula I can be obtained for
example by substitution of 2-bromoiodo-pyridine or pyrimidine 5 with an appropriate lactam,
cyclic carbamate, cyclic urea or pyrazolidinone derivative 4 in presence of a base such as
cesium carbonate and using xantphos and Pd (dba) in a solvent like toluene yielding the desired
2-bromo-pyridine or pyrimidine derivatives 6. Sonogashira coupling of 6 with an appropriately
substituted arylacetylene 2 yields ethynyl-pyridine or ethynyl-pyrimidine compound of formula
I.
List of Examples:
Ex. Structure Name EC50 (nM) Eff. (%)
mGlu5PAM
4,4-Dimethyl(6-
1 phenylethynyl-pyridin 49 75
yl)-pyrrolidinone
6,6-Dimethyl(6-
2 O phenylethynyl-pyridin 96 85
yl)-[1,3]oxazinanone
3,4,4-Trimethyl(6-
3 phenylethynyl-pyridin 15 45
yl)-imidazolidinone
1-[6-(4-Fluoro-
phenylethynyl)-pyridin
4 O 50 44
yl]-3,4,4-trimethyl-
imidazolidinone
1-[6-(3-Fluoro-
phenylethynyl)-pyridin
O 19 42
yl]-3,4,4-trimethyl-
imidazolidinone
3,4,4-Trimethyl(6-
pyridinylethynyl-
6 241 36
pyridinyl)-imidazolidin-
2-one
1-[6-(3-Fluoro-
phenylethynyl)-pyridin
7 39 62
yl]-4,4-dimethyl-
pyrrolidinone
,5-Dimethyl(6-
8 phenylethynyl-pyridin 62 56
yl)-pyrazolidinone
4,4-Dimethyl(6-
9 phenylethynyl-pyrimidin- 36 39
3-yl)-pyrrolidinone
3,4,4-Trimethyl(2-
phenylethynyl-pyrimidin- - -
-yl)-imidazolidinone
3-Ethyl-4,4-dimethyl(2-
11 phenylethynyl-pyrimidin- 79 52
-yl)-imidazolidinone
1,5,5-Trimethyl(6-
12 phenylethynyl-pyridin 40 66
yl)-pyrazolidinone
2-[6-(3-Fluoro-
phenylethynyl)-pyridin
13 38 63
yl]-1,5,5-trimethyl-
pyrazolidinone
2-[6-(2,5-Difluoro-
phenylethynyl)-pyridin
14 O 53 57
yl]-1,5,5-trimethyl-
pyrazolidinone
2-[6-(3-Fluoro-
phenylethynyl)-pyridin
68 38
yl]-5,5-dimethyl-
pyrazolidinone
2-[6-(2,5-Difluoro-
phenylethynyl)-pyridin
16 O 40 41
yl]-5,5-dimethyl-
pyrazolidinone
Experimental Section:
Example 1
4,4-Dimethyl(6-phenylethynyl-pyridinyl)-pyrrolidinone
Step 1: 5-Bromophenylethynyl-pyridine
Bis-(triphenylphosphine)-palladium(II)dichloride (62 mg, 0.088 mmol, 0.05 equiv.) was
dissolved in 5 ml THF. (500 mg, 1.76 mmol) 5-Bromoiodopyridine and phenylacetylene (216
mg, 2.11 mmol, 1.2 equiv.) were added at room temperature. Triethylamine (0.74 ml, 5.28 mmol,
3 equiv.) and copper(I)iodide (10 mg, 0.053 mmol, 0.03 equiv.) were added and the mixture was
stirred for 16 hours at 60°C. The reaction mixture was evaporated to dryness and loaded directly
to a silica gel column. The crude product was purified by flash chromatography on a silica gel
column eluting with a heptane:ethyl acetate gradient 100:0 to 90:10. The desired 5-bromo
phenylethynyl-pyridine (354 mg, 78 % yield) was obtained as a light yellow solid, MS: m/e =
258.0/259.9 (M+H ).
Step 2: 4,4-Dimethyl(6-phenylethynyl-pyridinyl)-pyrrolidinone
To a suspension of 5-bromophenylethynyl-pyridine (Example 1, step 1) (40 mg, 0.155 mmol),
4,4-dimethylpyrrolidineone (21 mg, 0.186 mmol, 1.2 equiv.), potassium carbonate (64 mg,
0.465 mmol, 3 equiv.) and N,N´-dimethylethylenediamine (1.4 mg, 0.015 mmol, 0.1 equiv.) in
1ml of dioxane was added under argon atmosphere copper(I)iodide (3 mg, 0.015 mmol, 0.1
equiv.). The mixture was stirred overnight at 100°C. The reaction mixture was cooled and
extracted with saturated NaHCO solution and two times with ethyl acetate. The organic layers
were extracted with brine, combined, dried over sodium sulfate and evaporated to dryness. The
crude product was purified by flash chromatography on a silica gel column eluting with a
heptane:ethyl acetate gradient 100:0 to 30:70. The desired 4,4-dimethyl(6-phenylethynyl-
pyridinyl)-pyrrolidinone (30 mg, 67 % yield) was obtained as a white solid, MS: m/e =
291.1 (M+H ).
Example 2
6,6-Dimethyl(6-phenylethynyl-pyridinyl)-[1,3]oxazinanone
Step 1: (3-Hydroxymethyl-butyl)-carbamic acid benzyl ester
O N O
(10 g, 42.1 mmol) Methyl 3-(benzyloxycarbonylamino)propanoate (CAS 547550) was
dissolved in THF (150 ml) and cooled to 0-5 °C. 3N Methylmagnesium bromide in THF (56.2
ml, 120 mmol, 4 equiv.) was added drop wise and the mixture stirred for 1 hour at 0-5 °C. The
reaction mixture was extracted with saturated NH Cl solution and two times with EtOAc. The
organic layers were dried over Na SO and evaporated to dryness. The desired (3-hydroxy
methyl-butyl)-carbamic acid benzyl ester (11.6 g, quant.) was obtained as a colorless oil, MS:
m/e = 238.1 (M+H ) and used in the next step without further purification.
Step 2: 6,6-dimethyl-[1,3]oxazinanone
(11.6 g, 48.9 mmol) (3-Hydroxymethyl-butyl)-carbamic acid benzyl ester (Example 72, step1)
was dissolved in THF (250 ml) and sodium hydride (60%, 5.2 g, 108 mmol, 2.2 equiv.) was
added in portions. The mixture was stirred for 3 hours at room temperature. 5ml saturated
NaHCO solution was added carefully and the mixture was evaporated with isolute to dryness.
The crude product was purified by flash chromatography by directly loading the residue onto a
silica gel column and eluting with an ethyl acetate:methanol gradient 100:0 to 90:10. The desired
6,6-dimethyl-[1,3]oxazinanone (3.2 g, 51 % yield) was obtained as a yellow solid, MS: m/e =
130.1 (M+H ).
Step 3: 6,6-Dimethyl(6-phenylethynyl-pyridinyl)-[1,3]oxazinanone
The title compound was obtained as a white solid, MS: m/e = 307.2 (M+H ), using chemistry
similar to that described in Example 1, step 2 from 5-bromophenylethynyl-pyridine (Example
1, step 1) and 6,6-dimethyl-[1,3]oxazinanone (Example 2, step 2).
Example 3
3,4,4-Trimethyl(6-phenylethynyl-pyridinyl)-imidazolidinone
Step 1: 1-(6-Bromo-pyridinyl)-4,4-dimethyl-imidazolidinone
To a suspension of 2-bromoiodopyridine (1.0 g, 3.52 mmol), 4,4-dimethyl-imidazolidinone
(CAS 245726) (400 mg, 3.52 mmol, 1.0 equiv.), cesium carbonate (1.72 g, 5.28 mmol, 1.5
equiv.), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos) (82 mg, 0.141 mmol,
0.04 equiv.) in 10ml of toluene was added under argon atmosphere
tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (Pd (dba) *CHCl ) (73 mg, 0.07
2 3 3
mmol, 0.02 equiv.). The mixture was stirred for 1 hour at 100°C. The mixture was directly
loaded on a 50 g silicagel column and was eluted with an heptan:ethyl acetate gradient 100:0 to
0:100 and an ethyl acetate:methanol gradient 100:0 to 80:20. The desired 1-(6-bromo-pyridin
yl)-4,4-dimethyl-imidazolidinone (810 mg, 85 % yield) was obtained as a light yellow solid,
MS: m/e = 207.1/272.1 (M+H ).
Step 2: 1-(6-Bromo-pyridinyl)-3,4,4-trimethyl-imidazolidinone
(810 mg, 3.0 mmol) 1-(6-Bromo-pyridinyl)-4,4-dimethyl-imidazolidinone (Example 3,
step 1) was dissolved in DMF (8 ml) and cooled to 0-5°C. Iodomethane (640 mg, 280 µl, 4.5
mmol, 1.5 equiv.) and NaH (60%) (156 mg, 3.9 mmol, 1.3 equiv.) were added and the mixture
was stirred for 2 hours at 0-5°C. The reaction mixture was treated with sat. NaHCO solution and
extracted two times with EtOAc. The organic layers were extracted with water and brine, dried
over Na SO and evaporated to dryness. The crude product was purified by flash
chromatography on a silica gel column eluting with a heptane:ethyl acetate gradient 100:0 to
0:100. The desired 1-(6-bromo-pyridinyl)-3,4,4-trimethyl-imidazolidinone (800 mg, 94 %
yield) was obtained as a yellow solid, MS: m/e = 284.1/286.0 (M+H ).
Step 3: 3,4,4-Trimethyl(6-phenylethynyl-pyridinyl)-imidazolidinone
Bis-(triphenylphosphine)-palladium(II)dichloride (6 mg, 8.5 µmol, 0.03 equiv.) was dissolved in
1 ml DMF. (80 mg, 282 µmol) 1-(6-Bromo-pyridinyl)-3,4,4-trimethyl-imidazolidinone
(Example 3, step 2) and phenylacetylene (58 mg, 563 µmol, 2 equiv.) were added at room
temperature. Triethylamine (118 µl, 0.845 mmol, 3 equiv.), triphenylphosphine (4.4 mg, 16.9
µmol, 0.06 equiv.) and copper(I)iodide (1.6 mg, 8.45 µmol, 0.03 equiv.) were added and the
mixture was stirred for 4 hours at 90°C. The reaction mixture was evaporated to dryness with
isolute® and the crude product was purified by flash chromatography by directly loading the
solid onto a silica gel column and eluting with an ethyl acetate:heptane gradient 0:100 to 100:0.
The desired 3,4,4-trimethyl(6-phenylethynyl-pyridinyl)-imidazolidinone (52 mg, 61 %
yield) was obtained as a yellow solid, MS: m/e = 306.2 (M+H ).
Example 4
1-[6-(4-Fluoro-phenylethynyl)-pyridinyl]-3,4,4-trimethyl-imidazolidinone
The title compound was obtained as a yellow solid, MS: m/e = 324.2 (M+H ), using chemistry
similar to that described in Example 3, step 3 from 1-(6-bromo-pyridinyl)-3,4,4-trimethyl-
imidazolidinone (Example 3, step 2) and 4-fluorophenylacetylene.
Example 5
1-[6-(3-Fluoro-phenylethynyl)-pyridinyl]-3,4,4-trimethyl-imidazolidinone
The title compound was obtained as a yellow solid, MS: m/e = 324.2 (M+H ), using chemistry
similar to that described in Example 3, step 3 from 1-(6-bromo-pyridinyl)-3,4,4-trimethyl-
imidazolidinone (Example 3, step 2) and 3-fluorophenylacetylene.
Example 6
3,4,4-Trimethyl(6-pyridinylethynyl-pyridinyl)-imidazolidinone
Step 1: 5-Bromopyridinylethynyl-pyridine
The title compound was obtained as a yellow solid, MS: m/e = 259.0/260.9 (M+H ), using
chemistry similar to that described in Example 1, step 1 from 5-bromoiodopyridine and 3-
ethynylpyridine.
Step 2: 4,4-Dimethyl(6-pyridinylethynyl-pyridinyl)-imidazolidinone
The title compound was obtained as a white solid, MS: m/e = 293.1 (M+H ), using chemistry
similar to that described in Example 1, step 2 from 5-bromopyridinylethynyl-pyridine
(Example 6, step 1) and 4,4-dimethyl-imidazolidinone (CAS 245726).
Step 3: 3,4,4-Trimethyl(6-pyridinylethynyl-pyridinyl)-imidazolidinone
The title compound was obtained as a white solid, MS: m/e = 307.2 (M+H ), using chemistry
similar to that described in Example 3, step 2 from 4,4-Dimethyl(6-pyridinylethynyl-
pyridinyl)-imidazolidinone (Example 6, step 2) and iodomethane.
Example 7
1-[6-(3-Fluoro-phenylethynyl)-pyridinyl]-4,4-dimethyl-pyrrolidinone
The title compound was obtained as a white solid, MS: m/e = 309.1 (M+H ), using chemistry
similar to that described in Example 1, step 1 and step 2 from 5-bromoiodopyridine, 3-
fluorophenylacetylene and 4,4-dimethylpyrrolidineone.
Example 8
,5-Dimethyl(6-phenylethynyl-pyridinyl)-pyrazolidinone
The title compound was obtained as a white solid, MS: m/e = 292.1 (M+H ), using chemistry
similar to that described in Example 1, step 2 from 5-bromophenylethynyl-pyridine (Example
1, step 1) and 5,5-dimethyl-pyrazolidinone (CAS 429532).
Example 9
4,4-Dimethyl(6-phenylethynyl-pyrimidinyl)-pyrrolidinone
Step 1: 1-(2-Bromo-pyrimidinyl)-4,4-dimethyl-pyrrolidinone
Br N
The title compound was obtained as a light yellow solid, MS: m/e = 270.1/272.1 (M+H ), using
chemistry similar to that described in Example 3, step 1 from 2-bromoiodopyrimidine and
4,4-dimethylpyrrolidineone.
Step 2: 4,4-Dimethyl(6-phenylethynyl-pyrimidinyl)-pyrrolidinone
The title compound was obtained as a light brown solid, MS: m/e = 292.3 (M+H ), using
chemistry similar to that described in Example 1, step 3 from 1-(2-bromo-pyrimidinyl)-4,4-
dimethyl-pyrrolidinone (Example 9, step 1) and phenylacetylene.
Example 10
3,4,4-Trimethyl(2-phenylethynyl-pyrimidinyl)-imidazolidinone
Step 1: 1-(2-Bromo-pyrimidinyl)-4,4-dimethyl-imidazolidinone
Br N
The title compound was obtained as a white solid, MS: m/e = 271.2/273.1 (M+H ), using
chemistry similar to that described in Example 3, step 1 from 2-bromoiodopyrimidine and
4,4-dimethyl-imidazolidinone (CAS 245726).
Step 2: 4,4-Dimethyl(2-phenylethynyl-pyrimidinyl)-imidazolidinone
The title compound was obtained as a white solid, MS: m/e = 293.0 (M+H ), using chemistry
similar to that described in Example 3, step 3 from 1-(2-bromo-pyrimidinyl)-4,4-dimethyl-
imidazolidinone (Example 10, step 1) and phenylacetylene.
Step 2: 3,4,4-Trimethyl(2-phenylethynyl-pyrimidinyl)-imidazolidinone
The title compound was obtained as a white solid, MS: m/e = 307.2 (M+H ), using chemistry
similar to that described in Example 3, step 2 from 4,4-dimethyl(2-phenylethynyl-pyrimidin-
5-yl)-imidazolidinone (Example 10, step 2) and iodomethane.
Example 11
3-Ethyl-4,4-dimethyl(2-phenylethynyl-pyrimidinyl)-imidazolidinone
The title compound was obtained as a light yellow solid, MS: m/e = 321.4 (M+H ), using
chemistry similar to that described in Example 3, step 2 from 4,4-dimethyl(2-phenylethynyl-
pyrimidinyl)-imidazolidinone (Example 10, step 2) and iodoethane.
Example 12
1,5,5-Trimethyl(6-phenylethynyl-pyridinyl)-pyrazolidinone
Step 1: 2-(6-Bromo-pyridinyl)-5,5-dimethyl-pyrazolidinone
The title compound was obtained as a yellow oil, MS: m/e = 270.3/272.3 (M+H ), using
chemistry similar to that described in Example 3, step 1 from 2-bromoiodopyridine and 5,5-
dimethyl-pyrazolidinone (CAS 429532) by using dioxane instead of toluene as solvent.
Step 2: 2-(6-Bromo-pyridinyl)-1,5,5-trimethyl-pyrazolidinone
A suspension of 2-(6-bromo-pyridinyl)-5,5-dimethyl-pyrazolidinone (Example 12, step 1)
(800 mg, 2.96 mmol) and formic acid (0.57 ml, 14.8 mmol, 5 equiv.) in water (8 ml) was heated
to 100°C. At this temperature formaldehyde (36% in water) (1.13 ml, 14.8 mmol, 5 equiv.) was
added drop wise. The mixture was stirred overnight at 100°C. The reaction mixture was cooled
and basified carefully with 2N NaOH and extracted two times with a small amount of
dichloromethane. The organic layers were loaded directly on a silica gel column and the crude
product was purified by flash chromatography eluting with a heptane:ethyl acetate gradient
100:0 to 0:100. The desired 2-(6-bromo-pyridinyl)-1,5,5-trimethyl-pyrazolidinone (380 mg,
45 % yield) was obtained as a colorless oil, MS: m/e = 284.3/286.3 (M+H ).
Step 3: 1,5,5-Trimethyl(6-phenylethynyl-pyridinyl)-pyrazolidinone
The title compound was obtained as a yellow oil, MS: m/e = 306.5 (M+H ), using chemistry
similar to that described in Example 3, step 3 from 2-(6-bromo-pyridinyl)-1,5,5-trimethyl-
pyrazolidinone (Example 12, step 2) and phenylacetylene.
Example 13
2-[6-(3-Fluoro-phenylethynyl)-pyridinyl]-1,5,5-trimethyl-pyrazolidinone
The title compound was obtained as a yellow oil, MS: m/e = 324.4 (M+H ), using chemistry
similar to that described in Example 3, step 3 from 2-(6-bromo-pyridinyl)-1,5,5-trimethyl-
pyrazolidinone (Example 12, step 2) and 3-fluorophenylacetylene.
Example 14
2-[6-(2,5-Difluoro-phenylethynyl)-pyridinyl]-1,5,5-trimethyl-pyrazolidinone
The title compound was obtained as a yellow solid, MS: m/e = 342.4 (M+H ), using chemistry
similar to that described in Example 3, step 3 from 2-(6-bromo-pyridinyl)-1,5,5-trimethyl-
pyrazolidinone (Example 12, step 2) and 2,5-difluorophenylacetylene.
Example 15
2-[6-(3-Fluoro-phenylethynyl)-pyridinyl]-5,5-dimethyl-pyrazolidinone
The title compound was obtained as a brown oil, MS: m/e = 310.4 (M+H ), using chemistry
similar to that described in Example 3, step 3 from 2-(6-bromo-pyridinyl)-5,5-dimethyl-
pyrazolidinone (Example 12, step 1) and 3-fluorophenylacetylene.
Example 16
2-[6-(2,5-Difluoro-phenylethynyl)-pyridinyl]-5,5-dimethyl-pyrazolidinone
The title compound was obtained as a light yellow solid, MS: m/e = 328.4 (M+H ), using
chemistry similar to that described in Example 3, step 3 from 2-(6-bromo-pyridinyl)-5,5-
dimethyl-pyrazolidinone (Example 12, step 1) and 2,5-difluorophenylacetylene.
Biological Assay and Data:
Intracellular Ca 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. 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 μg/ml hygromycin and 15 μg/ml blasticidin (all cell culture
reagents and antibiotics from Invitrogen, Basel, Switzerland).
About 24 hrs before an experiment, 5x10 cells/well were seeded in poly-D-lysine coated,
black/clear-bottomed 96-well plates. The cells were loaded with 2.5 µM Fluo-4AM in loading
buffer (1xHBSS, 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. Following this pre-
incubation step, the agonist L-glutamate was added to the cells at a concentration corresponding
to EC (typically around 80 μM) with on-line recording of fluorescence; in order to account for
day-to-day variations in the responsiveness of cells, the EC of glutamate was determined
immediately ahead of each experiment by recording of a full dose-response curve of glutamate.
Responses were measured as peak increase in fluorescence minus basal (i.e. fluorescence
without addition of L-glutamate), normalized to the maximal stimulatory effect obtained with
saturating concentrations of L-glutamate. Graphs were plotted with the % maximal stimulatory
using XLfit, a curve fitting program that iteratively plots the data using Levenburg Marquardt
algorithm. The single site competition analysis equation used was y = A + ((B-A)/(1+((x/C)D))),
where y is the % maximal stimulatory effect, A is the minimum y, B is the maximum y, C is the
EC , x is the log10 of the concentration of the competing compound and D is the slope of the
curve (the Hill Coefficient). From these curves the EC (concentration at which half maximal
stimulation was achieved), the Hill coefficient as well as the maximal response in % of the
maximal stimulatory effect obtained with saturating concentrations of L-glutamate were
calculated.
Positive signals obtained during the pre-incubation with the PAM test compounds (i.e. before
application of an EC concentration of L-glutamate) were indicative of an agonistic activity, the
absence of such signals were demonstrating the lack of agonistic activities. A depression of the
signal observed after addition of the EC concentration of L-glutamate was indicative of an
inhibitory activity of the test compound.
In the list of examples above are shown the corresponding results for compounds which all have
EC < 250 nM..
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, dragées, hard and soft
gelatine capsules, solutions, emulsions or suspensions. However, the administration can also be
effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection
solutions.
The compounds of formula (I) and pharmaceutically acceptable salts thereof can be
processed with pharmaceutically inert, inorganic or organic carriers for the production of
pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its
salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragées
and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable
oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active
substance no carriers are, however, usually required in the case of soft gelatine capsules. 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.
In addition, 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.
As mentioned earlier, medicaments containing a compound of formula (I) or
pharmaceutically acceptable salts thereof and a therapeutically inert excipient are also an aspect
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.
As further mentioned earlier, 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
aspect 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. In general, 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. The daily dosage for an adult human being
weighing 70 kg accordingly lies between 0.7-1400 mg per day, preferably between 7 and 700 mg
per day.
Pharmaceutical compositions comprising compounds of the invention:
Tablets of the following composition are produced in a conventional manner:
mg/Tablet
Active ingredient 100
Powdered. lactose 95
White corn starch 35
Polyvinylpyrrolidone 8
Na carboxymethylstarch 10
Magnesium stearate 2
Tablet weight 250
Claims (20)
1. Ethynyl derivatives of formula I 5 wherein U is N or CH, R is hydrogen, halogen, lower alkyl or lower alkoxy; 4 5 5’ Y is –N(R )-, -O- or –C(R R )-; 4 5 5’ wherein R is hydrogen or lower alkyl and R /R are independently hydrogen, hydroxy, 10 lower alkyl or lower alkoxy; 6 7 7’ V is –N(R )- or –C(R R ), 6 7 7’ wherein R is hydrogen or lower alkyl and R /R are independently from each other hydrogen, lower alkyl, CH -lower alkoxy or may form together with the carbon atom to which they are attached a C -C -cycloalkyl; 15 R is phenyl or heteroaryl, which are optionally substituted by halogen, lower alkyl or lower alkoxy; m is 0 or 1; in case m is 1, 3 3’ R /R are independently from each other hydrogen, lower alkyl, CH -lower alkoxy or may form together with the carbon atom to which they are attached a C -C -cycloalkyl; 20 n is 0 or 1; in case n is 1, 2 2’ R /R are independently from each other hydrogen, lower alkyl, CH -lower alkoxy or may form together with the carbon atom to which they are attached a C -C -cycloalkyl; or if m is 1 and n is 0, R and R may form together with the carbon atoms to which they are attached a C -cycloalkyl; 2 3 3 7 25 or if m is 1 and n is 1, R and R or R and R may form together with the carbon atoms to which they are attached a C -cycloalkyl; or to a pharmaceutically acceptable acid addition salt, to a racemic mixture, or to its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.
2. Ethynyl derivatives of formula I-1according to claim 1 5 wherein U is N or CH; R is hydrogen; Y is CH , O, -N(CH )- or -N(CH CH )- 2 3 2 3 ; V is CH , -NH- or -N(CH )-; 10 R is phenyl or pyridinyl, which are optionally substituted by halogen; m is 0 or 1; in case m is 1, 3 3’ R /R are independently from each other hydrogen or lower alkyl, n is 1; 2 2’ R /R are independently from each other hydrogen or lower alkyl; 15 or a pharmaceutically acceptable acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.
3. Ethynyl derivatives of formula I-1according to claim 1 or claim 2, which compounds 20 4,4-Dimethyl(6-phenylethynyl-pyridinyl)-pyrrolidinone 6,6-Dimethyl(6-phenylethynyl-pyridinyl)-[1,3]oxazinanone 3,4,4-Trimethyl(6-phenylethynyl-pyridinyl)-imidazolidinone 1-[6-(4-Fluoro-phenylethynyl)-pyridinyl]-3,4,4-trimethyl-imidazolidinone 1-[6-(3-Fluoro-phenylethynyl)-pyridinyl]-3,4,4-trimethyl-imidazolidinone 25 3,4,4-Trimethyl(6-pyridinylethynyl-pyridinyl)-imidazolidinone 1-[6-(3-Fluoro-phenylethynyl)-pyridinyl]-4,4-dimethyl-pyrrolidinone 5,5-Dimethyl(6-phenylethynyl-pyridinyl)-pyrazolidinone 4,4-Dimethyl(6-phenylethynyl-pyrimidinyl)-pyrrolidinone 3,4,4-Trimethyl(2-phenylethynyl-pyrimidinyl)-imidazolidinone 3-Ethyl-4,4-dimethyl(2-phenylethynyl-pyrimidinyl)-imidazolidinone 1,5,5-Trimethyl(6-phenylethynyl-pyridinyl)-pyrazolidinone 2-[6-(3-Fluoro-phenylethynyl)-pyridinyl]-1,5,5-trimethyl-pyrazolidinone 5 2-[6-(2,5-Difluoro-phenylethynyl)-pyridinyl]-1,5,5-trimethyl-pyrazolidinone 2-[6-(3-Fluoro-phenylethynyl)-pyridinyl]-5,5-dimethyl-pyrazolidinone or 2-[6-(2,5-Difluoro-phenylethynyl)-pyridinyl]-5,5-dimethyl-pyrazolidinone.
4. Ethynyl derivatives of formula IA according to claim 1, 10 IA wherein U is N or CH, R is hydrogen, halogen, lower alkyl or lower alkoxy; 4 5 5 ’ Y is –N(R )-, O or -C(R R )- ; 4 5 5’ 15 wherein R is hydrogen or lower alkyl and R /R are independently hydrogen, hydroxy, lower alkyl or lower alkoxy; R is phenyl or heteroaryl, which are optionally substituted by halogen, lower alkyl or lower alkoxy; 2 2’ R /R are independently from each other hydrogen, lower alkyl, CH -lower alkoxy or may form 20 together with the carbon atom to which they are attached a C -C -cycloalkyl; or a pharmaceutically acceptable acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.
5. Ethynyl derivatives of formula IA according to claim 1 or claim 4, which compounds 25 are: 4,4-dimethyl(6-phenylethynyl-pyridinyl)-pyrrolidinone 3,4,4-trimethyl(6-phenylethynyl-pyridinyl)-imidazolidinone 1-[6-(4-fluoro-phenylethynyl)-pyridinyl]-3,4,4-trimethyl-imidazolidinone 1-[6-(3-fluoro-phenylethynyl)-pyridinyl]-3,4,4-trimethyl-imidazolidinone 30 3,4,4-trimethyl(6-pyridinylethynyl-pyridinyl)-imidazolidinone 1-[6-(3-fluoro-phenylethynyl)-pyridinyl]-4,4-dimethyl-pyrrolidinone 4,4-dimethyl(6-phenylethynyl-pyrimidinyl)-pyrrolidinone 3,4,4-Trimethyl(2-phenylethynyl-pyrimidinyl)-imidazolidinone or 3-Ethyl-4,4-dimethyl(2-phenylethynyl-pyrimidinyl)-imidazolidinone.
6. Ethynyl derivatives of formula according to claim 1, wherein U is N or CH, 10 R is hydrogen, halogen, lower alkyl or lower alkoxy; 4 5 5’ Y is –N(R )-, O or –C(R R )-; 4 5 5’ wherein R is hydrogen or lower alkyl and R /R are independently hydrogen, hydroxy, lower alkyl or lower alkoxy; R is phenyl or heteroaryl, which are optionally substituted by halogen, lower alkyl or lower 15 alkoxy; 2 2’ R /R are independently from each other hydrogen, lower alkyl, CH -lower alkoxy or may form together with the carbon atom to which they are attached a C -C -cycloalkyl; or a pharmaceutically acceptable acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.
7. Ethynyl derivatives of formula IB according to claim 1 or claim 6, which compound is 6,6-dimethyl(6-phenylethynyl-pyridinyl)-[1,3]oxazinanone.
8. Ethynyl derivatives of formula IC according to claim 1, 25 IC wherein U is N or CH, R is hydrogen, halogen, lower alkyl or lower alkoxy; 4 5 5 ’ Y is –N(R )-, O or –C(R R )- ; 4 5 5’ wherein R is hydrogen or lower alkyl and R /R are independently hydrogen, hydroxy, 5 lower alkyl or lower alkoxy; R is phenyl or heteroaryl, which are optionally substituted by halogen, lower alkyl or lower alkoxy; 2 2’ R /R are independently from each other hydrogen, lower alkyl, CH -lower alkoxy or may form together with the carbon atom to which they are attached a C -C -cycloalkyl; 10 or a pharmaceutically acceptable acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.
9. Ethynyl derivatives of formula IC according to claim 1 or claim 8, which compound is 5,5-dimethyl(6-phenylethynyl-pyridinyl)-pyrazolidinone.
10. Ethynyl derivatives of formula ID according to claim 1, wherein U is N or CH, 20 R is hydrogen, halogen, lower alkyl or lower alkoxy; 4 5 5’ Y is –N(R )-, -O- or –C(R R )-; 4 5 5’ wherein R is hydrogen or lower alkyl and R /R are independently hydrogen, hydroxy, lower alkyl or lower alkoxy; R is hydrogen or lower alkyl 25 R is phenyl or heteroaryl, which are optionally substituted by halogen, lower alkyl or lower alkoxy; 2 2’ R /R are independently from each other hydrogen, lower alkyl, CH -lower alkoxy or may form together with the carbon atom to which they are attached a C -C -cycloalkyl; or a pharmaceutically acceptable acid addition salt, a racemic mixture, or its corresponding 30 enantiomer and/or optical isomer and/or stereoisomer thereof.
11. Ethynyl derivatives of formula ID according to claim 1 or claim 10, wherein the compounds are 1,5,5-Trimethyl(6-phenylethynyl-pyridinyl)-pyrazolidinone 5 2-[6-(3-Fluoro-phenylethynyl)-pyridinyl]-1,5,5-trimethyl-pyrazolidinone 2-[6-(2,5-Difluoro-phenylethynyl)-pyridinyl]-1,5,5-trimethyl-pyrazolidinone 2-[6-(3-Fluoro-phenylethynyl)-pyridinyl]-5,5-dimethyl-pyrazolidinone or 2-[6-(2,5-Difluoro-phenylethynyl)-pyridinyl]-5,5-dimethyl-pyrazolidinone. 10
12. A process for preparation of a compound of formula I as described in claim 1, comprising the variants a) reacting a compound of formula Br U with a suitable aryl-acetylene of formula 15 2 to a compound of formula wherein the substituents are described in claim 1, or b) reacting a compound of formula 3' 2 20 4 with a suitable compound of formula to a compound of formula 3' 2 5 wherein the substituents are described in claim 1, and, if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts.
13. A compound according to any one of claims 1 to 11 for use as therapeutically active substance. 10
14. A pharmaceutical composition comprising at least one of the compounds according to any one of claims 1 to 11 as well as its pharmaceutically acceptable salt.
15. A compound of any one of claims 1 –11, when applicable as mixtures of enantiomers, diastereomers, or in enantiomerically pure form; as well as its pharmaceutically acceptable salt, for use as a medicament. 15
16. The use of a compound according to any one of claims 1 to 11 as well as its pharmaceutically acceptable salt for the manufacture of a medicament for the treatment or prevention of schizophrenia, cognitive diseases, fragile X syndrome or autism.
17. The use of a compound according to claim 16 for the treatment or prevention of schizophrenia, cognitive diseases, fragile X syndrome or autism. 20
18. A compound according to any one of claims 1 to 11 for use in the treatment or prevention of schizophrenia, cognitive diseases, fragile X syndrome or autism.
19. A process according to claim 12 for the preparation of a compound of formula I substantially as herein described with reference to any example thereof.
20. A pharmaceutical composition according to claim 14 substantially as herein described with reference to any example thereof.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP11184331.4 | 2011-10-07 | ||
EP11184331 | 2011-10-07 | ||
PCT/EP2012/069599 WO2013050454A1 (en) | 2011-10-07 | 2012-10-04 | Ethynyl derivatives as mglur5 allosteric modulators |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ621894A NZ621894A (en) | 2016-03-31 |
NZ621894B2 true NZ621894B2 (en) | 2016-07-01 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP2763977B1 (en) | Ethynyl derivatives as mglur5 allosteric modulators | |
KR101431367B1 (en) | Arylethynyl derivatives | |
EP2493856A1 (en) | Positive allosteric modulators (pam) | |
EP2702051B1 (en) | Ethynyl derivatives as positive allosteric modulators of the mglur5 | |
EP2699547B1 (en) | 5-(phenyl/pyridinyl-ethinyl)-2-pyridine/2-pyrimidine-carborxamides as mglur5 modulators | |
EP2702050B1 (en) | Pyrazolidin-3-one derivatives | |
WO2013050460A1 (en) | Ethynyl derivatives as metabotropic glutamate receptor modulators | |
NZ621894B2 (en) | Ethynyl derivatives as mglur5 allosteric modulators | |
AU2012320509B8 (en) | Ethynyl derivatives as metabotropic glutamate receptor modulators | |
AU2012247654B2 (en) | Pyrazolidin-3-one derivatives | |
NZ614883B2 (en) | Pyrazolidin-3-one derivatives | |
NZ613070B2 (en) | 5-(phenyl/pyridinyl-ethinyl)-2-pyridine/2-pyrimidine-carborxamides as mglur5 modulators | |
NZ621583B2 (en) | Ethynyl derivatives as metabotropic glutamate receptor modulators |