CN101341153A - New compounds - Google Patents
New compounds Download PDFInfo
- Publication number
- CN101341153A CN101341153A CNA2006800481946A CN200680048194A CN101341153A CN 101341153 A CN101341153 A CN 101341153A CN A2006800481946 A CNA2006800481946 A CN A2006800481946A CN 200680048194 A CN200680048194 A CN 200680048194A CN 101341153 A CN101341153 A CN 101341153A
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- phenyl
- heterocyclic radical
- optional substituted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000001875 compounds Chemical class 0.000 title claims description 143
- 150000003839 salts Chemical class 0.000 claims abstract description 43
- 239000012453 solvate Substances 0.000 claims abstract description 35
- 238000000034 method Methods 0.000 claims abstract description 34
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 26
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 19
- 208000002193 Pain Diseases 0.000 claims abstract description 18
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 14
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 13
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 13
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 13
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 13
- 239000001257 hydrogen Substances 0.000 claims abstract description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 12
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 12
- 125000000547 substituted alkyl group Chemical group 0.000 claims abstract description 11
- 208000005298 acute pain Diseases 0.000 claims abstract description 8
- 230000004064 dysfunction Effects 0.000 claims abstract description 7
- 230000002232 neuromuscular Effects 0.000 claims abstract description 7
- 210000001635 urinary tract Anatomy 0.000 claims abstract description 7
- 208000000094 Chronic Pain Diseases 0.000 claims abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
- 208000020016 psychiatric disease Diseases 0.000 claims abstract description 6
- 208000012902 Nervous system disease Diseases 0.000 claims abstract description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 66
- 238000002360 preparation method Methods 0.000 claims description 25
- 102000005962 receptors Human genes 0.000 claims description 23
- 108020003175 receptors Proteins 0.000 claims description 23
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims description 22
- 238000011282 treatment Methods 0.000 claims description 17
- 230000001404 mediated effect Effects 0.000 claims description 16
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 11
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 10
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 8
- DBDCNCCRPKTRSD-UHFFFAOYSA-N thieno[3,2-b]pyridine Chemical class C1=CC=C2SC=CC2=N1 DBDCNCCRPKTRSD-UHFFFAOYSA-N 0.000 claims description 8
- 208000035475 disorder Diseases 0.000 claims description 7
- 230000001684 chronic effect Effects 0.000 claims description 6
- 230000008878 coupling Effects 0.000 claims description 6
- 238000010168 coupling process Methods 0.000 claims description 6
- 238000005859 coupling reaction Methods 0.000 claims description 6
- 210000001035 gastrointestinal tract Anatomy 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 241000124008 Mammalia Species 0.000 claims description 3
- NTWSZZFAOBJYDD-UHFFFAOYSA-N (4-fluorophenyl)methyl pyridine-2-carboxylate Chemical compound FC1=CC=C(C=C1)COC(=O)C1=NC=CC=C1 NTWSZZFAOBJYDD-UHFFFAOYSA-N 0.000 claims description 2
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 2
- 108010065028 Metabotropic Glutamate 5 Receptor Proteins 0.000 abstract description 25
- 102000012777 Metabotropic Glutamate 5 Receptor Human genes 0.000 abstract description 25
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 10
- 230000001575 pathological effect Effects 0.000 abstract description 7
- 230000001154 acute effect Effects 0.000 abstract description 5
- 230000008569 process Effects 0.000 abstract description 4
- 230000002265 prevention Effects 0.000 abstract description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 abstract 2
- 208000018522 Gastrointestinal disease Diseases 0.000 abstract 1
- 208000025966 Neurological disease Diseases 0.000 abstract 1
- 235000010290 biphenyl Nutrition 0.000 abstract 1
- 239000004305 biphenyl Substances 0.000 abstract 1
- 150000004677 hydrates Chemical class 0.000 abstract 1
- 239000003446 ligand Substances 0.000 abstract 1
- 238000002560 therapeutic procedure Methods 0.000 abstract 1
- 102000016193 Metabotropic glutamate receptors Human genes 0.000 description 23
- 108010010914 Metabotropic glutamate receptors Proteins 0.000 description 23
- 239000000203 mixture Substances 0.000 description 23
- 102100036834 Metabotropic glutamate receptor 1 Human genes 0.000 description 22
- 108010014719 metabotropic glutamate receptor type 1 Proteins 0.000 description 22
- 239000000370 acceptor Substances 0.000 description 21
- 239000000243 solution Substances 0.000 description 21
- 210000004027 cell Anatomy 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 239000002253 acid Substances 0.000 description 12
- 230000004913 activation Effects 0.000 description 12
- 239000002585 base Substances 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- -1 methoxyl group Chemical group 0.000 description 9
- 239000003826 tablet Substances 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 239000011575 calcium Substances 0.000 description 8
- 238000004113 cell culture Methods 0.000 description 7
- 210000001638 cerebellum Anatomy 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000003708 ampul Substances 0.000 description 6
- 210000003169 central nervous system Anatomy 0.000 description 6
- 239000012153 distilled water Substances 0.000 description 6
- 229960002989 glutamic acid Drugs 0.000 description 6
- 239000008101 lactose Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 230000001537 neural effect Effects 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000000829 suppository Substances 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 238000013016 damping Methods 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 230000005284 excitation Effects 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000012530 fluid Substances 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 210000000478 neocortex Anatomy 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- MTVWFVDWRVYDOR-UHFFFAOYSA-N 3,4-Dihydroxyphenylglycol Chemical compound OCC(O)C1=CC=C(O)C(O)=C1 MTVWFVDWRVYDOR-UHFFFAOYSA-N 0.000 description 4
- 208000019901 Anxiety disease Diseases 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 125000004442 acylamino group Chemical group 0.000 description 4
- 239000000556 agonist Substances 0.000 description 4
- 125000003282 alkyl amino group Chemical group 0.000 description 4
- 125000003368 amide group Chemical group 0.000 description 4
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 4
- 239000005557 antagonist Substances 0.000 description 4
- 230000036506 anxiety Effects 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 229910052791 calcium Inorganic materials 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 125000004093 cyano group Chemical group *C#N 0.000 description 4
- 125000004663 dialkyl amino group Chemical group 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 230000003203 everyday effect Effects 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- 230000036407 pain Effects 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- 206010001497 Agitation Diseases 0.000 description 3
- 208000019695 Migraine disease Diseases 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 101001032838 Rattus norvegicus Metabotropic glutamate receptor 5 Proteins 0.000 description 3
- 229920002125 Sokalan® Polymers 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000000443 aerosol Substances 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 206010015037 epilepsy Diseases 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 230000006698 induction Effects 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 206010027599 migraine Diseases 0.000 description 3
- 210000002569 neuron Anatomy 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 230000001242 postsynaptic effect Effects 0.000 description 3
- 230000003518 presynaptic effect Effects 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 201000000980 schizophrenia Diseases 0.000 description 3
- 239000002175 thienopyridine Substances 0.000 description 3
- 229940125670 thienopyridine Drugs 0.000 description 3
- STDHINPODVHROK-UHFFFAOYSA-N 2-[2-(3-methoxyphenyl)ethynyl]-6-methylpyridine Chemical compound COC1=CC=CC(C#CC=2N=C(C)C=CC=2)=C1 STDHINPODVHROK-UHFFFAOYSA-N 0.000 description 2
- WSBXLJWHCPQREZ-UHFFFAOYSA-N 3-(4-chlorophenyl)-2-(4-chlorophenyl)sulfonyl-7-oxidothieno[2,3-b]pyridin-7-ium Chemical compound S1C=2[N+]([O-])=CC=CC=2C(C=2C=CC(Cl)=CC=2)=C1S(=O)(=O)C1=CC=C(Cl)C=C1 WSBXLJWHCPQREZ-UHFFFAOYSA-N 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-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
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- 206010008190 Cerebrovascular accident Diseases 0.000 description 2
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 2
- HOOWCUZPEFNHDT-UHFFFAOYSA-N DHPG Natural products OC(=O)C(N)C1=CC(O)=CC(O)=C1 HOOWCUZPEFNHDT-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- 206010019196 Head injury Diseases 0.000 description 2
- 101001032845 Homo sapiens Metabotropic glutamate receptor 5 Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 208000013016 Hypoglycemia Diseases 0.000 description 2
- 231100000678 Mycotoxin Toxicity 0.000 description 2
- 150000001204 N-oxides Chemical class 0.000 description 2
- 208000008589 Obesity Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 108091000080 Phosphotransferase Proteins 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 101001071426 Rattus norvegicus Metabotropic glutamate receptor 1 Proteins 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 208000006011 Stroke Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000004479 aerosol dispenser Substances 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 239000001961 anticonvulsive agent Substances 0.000 description 2
- 239000003125 aqueous solvent Substances 0.000 description 2
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000000084 colloidal system Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- ZOOGRGPOEVQQDX-KHLHZJAASA-N cyclic guanosine monophosphate Chemical compound C([C@H]1O2)O[P@](O)(=O)O[C@@H]1[C@H](O)[C@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-KHLHZJAASA-N 0.000 description 2
- 230000001086 cytosolic effect Effects 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000001506 fluorescence spectroscopy Methods 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 229940049906 glutamate Drugs 0.000 description 2
- 229930195712 glutamate Natural products 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 102000052256 human GRM5 Human genes 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- 230000002218 hypoglycaemic effect Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 210000000936 intestine Anatomy 0.000 description 2
- 208000028867 ischemia Diseases 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 230000027939 micturition Effects 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000002636 mycotoxin Substances 0.000 description 2
- WHQSYGRFZMUQGQ-UHFFFAOYSA-N n,n-dimethylformamide;hydrate Chemical compound O.CN(C)C=O WHQSYGRFZMUQGQ-UHFFFAOYSA-N 0.000 description 2
- 230000000324 neuroprotective effect Effects 0.000 description 2
- 239000002858 neurotransmitter agent Substances 0.000 description 2
- 230000009871 nonspecific binding Effects 0.000 description 2
- 235000020824 obesity Nutrition 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 150000003906 phosphoinositides Chemical class 0.000 description 2
- 102000020233 phosphotransferase Human genes 0.000 description 2
- 230000035479 physiological effects, processes and functions Effects 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 229960003081 probenecid Drugs 0.000 description 2
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical compound [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 description 2
- 239000002287 radioligand Substances 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000008174 sterile solution Substances 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- MEIRRNXMZYDVDW-MQQKCMAXSA-N (2E,4E)-2,4-hexadien-1-ol Chemical compound C\C=C\C=C\CO MEIRRNXMZYDVDW-MQQKCMAXSA-N 0.000 description 1
- YHDUQRGEHNIMJY-DFWYDOINSA-N (2s)-2-aminopentanedioic acid;2-oxopropanoic acid Chemical compound CC(=O)C(O)=O.OC(=O)[C@@H](N)CCC(O)=O YHDUQRGEHNIMJY-DFWYDOINSA-N 0.000 description 1
- CAYQIZIAYYNFCS-UHFFFAOYSA-N (4-chlorophenyl)boronic acid Chemical compound OB(O)C1=CC=C(Cl)C=C1 CAYQIZIAYYNFCS-UHFFFAOYSA-N 0.000 description 1
- ABFQGXBZQWZNKI-UHFFFAOYSA-N 1,1-dimethoxyethanol Chemical compound COC(C)(O)OC ABFQGXBZQWZNKI-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- NEWKHUASLBMWRE-UHFFFAOYSA-N 2-methyl-6-(phenylethynyl)pyridine Chemical compound CC1=CC=CC(C#CC=2C=CC=CC=2)=N1 NEWKHUASLBMWRE-UHFFFAOYSA-N 0.000 description 1
- HRULVFZMZKQTBK-UHFFFAOYSA-N 3-(4-chlorophenyl)-2-(4-chlorophenyl)sulfonylthieno[2,3-b]pyridine Chemical compound C1=CC(Cl)=CC=C1C1=C(S(=O)(=O)C=2C=CC(Cl)=CC=2)SC2=NC=CC=C12 HRULVFZMZKQTBK-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- UZOFELREXGAFOI-UHFFFAOYSA-N 4-methylpiperidine Chemical class CC1CCNCC1 UZOFELREXGAFOI-UHFFFAOYSA-N 0.000 description 1
- CFBNXTGJJPBTBK-UHFFFAOYSA-N 6,7-dihydrothieno[3,2-b]pyridine Chemical class N1=CCCC2=C1C=CS2 CFBNXTGJJPBTBK-UHFFFAOYSA-N 0.000 description 1
- MQJNETSYXIIIKE-UHFFFAOYSA-N 7h-thieno[2,3-b]pyridin-6-one Chemical compound N1C(=O)C=CC2=C1SC=C2 MQJNETSYXIIIKE-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 102000014156 AMP-Activated Protein Kinases Human genes 0.000 description 1
- 108010011376 AMP-Activated Protein Kinases Proteins 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 229920000945 Amylopectin Polymers 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 206010003805 Autism Diseases 0.000 description 1
- 208000020706 Autistic disease Diseases 0.000 description 1
- 206010004663 Biliary colic Diseases 0.000 description 1
- 208000020925 Bipolar disease Diseases 0.000 description 1
- 229940078581 Bone resorption inhibitor Drugs 0.000 description 1
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- 206010012689 Diabetic retinopathy Diseases 0.000 description 1
- 201000010374 Down Syndrome Diseases 0.000 description 1
- 206010013654 Drug abuse Diseases 0.000 description 1
- 208000008967 Enuresis Diseases 0.000 description 1
- OUVXYXNWSVIOSJ-UHFFFAOYSA-N Fluo-4 Chemical compound CC1=CC=C(N(CC(O)=O)CC(O)=O)C(OCCOC=2C(=CC=C(C=2)C2=C3C=C(F)C(=O)C=C3OC3=CC(O)=C(F)C=C32)N(CC(O)=O)CC(O)=O)=C1 OUVXYXNWSVIOSJ-UHFFFAOYSA-N 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 102000018899 Glutamate Receptors Human genes 0.000 description 1
- 108010027915 Glutamate Receptors Proteins 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 108010078321 Guanylate Cyclase Proteins 0.000 description 1
- 102000014469 Guanylate cyclase Human genes 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010021639 Incontinence Diseases 0.000 description 1
- 206010065390 Inflammatory pain Diseases 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- 102100037611 Lysophospholipase Human genes 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 208000036626 Mental retardation Diseases 0.000 description 1
- 102100037636 Metabotropic glutamate receptor 8 Human genes 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 208000019022 Mood disease Diseases 0.000 description 1
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 description 1
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 102000011420 Phospholipase D Human genes 0.000 description 1
- 108090000553 Phospholipase D Proteins 0.000 description 1
- 108010058864 Phospholipases A2 Proteins 0.000 description 1
- 206010036376 Postherpetic Neuralgia Diseases 0.000 description 1
- 208000004550 Postoperative Pain Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- 235000011034 Rubus glaucus Nutrition 0.000 description 1
- 244000235659 Rubus idaeus Species 0.000 description 1
- 235000009122 Rubus idaeus Nutrition 0.000 description 1
- 206010039361 Sacroiliitis Diseases 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N 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
- 239000004098 Tetracycline Substances 0.000 description 1
- 240000006474 Theobroma bicolor Species 0.000 description 1
- 208000009205 Tinnitus Diseases 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 102000003929 Transaminases Human genes 0.000 description 1
- 108090000340 Transaminases Proteins 0.000 description 1
- 206010044688 Trisomy 21 Diseases 0.000 description 1
- 102000014384 Type C Phospholipases Human genes 0.000 description 1
- 108010079194 Type C Phospholipases Proteins 0.000 description 1
- 108010084455 Zeocin Proteins 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 102000030621 adenylate cyclase Human genes 0.000 description 1
- 108060000200 adenylate cyclase Proteins 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical group 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000001857 anti-mycotic effect Effects 0.000 description 1
- 239000003173 antianemic agent Substances 0.000 description 1
- 239000002543 antimycotic Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000000305 astragalus gummifer gum Substances 0.000 description 1
- 238000000889 atomisation Methods 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- CUBCNYWQJHBXIY-UHFFFAOYSA-N benzoic acid;2-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1O CUBCNYWQJHBXIY-UHFFFAOYSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical class B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 1
- 239000007963 capsule composition Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 210000003710 cerebral cortex Anatomy 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 210000000860 cochlear nerve Anatomy 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 229940095074 cyclic amp Drugs 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
- 238000000151 deposition Methods 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000007598 dipping method Methods 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- HALQELOKLVRWRI-VDBOFHIQSA-N doxycycline hyclate Chemical compound O.[Cl-].[Cl-].CCO.O=C1C2=C(O)C=CC=C2[C@H](C)[C@@H]2C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H]([NH+](C)C)[C@@H]1[C@H]2O.O=C1C2=C(O)C=CC=C2[C@H](C)[C@@H]2C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H]([NH+](C)C)[C@@H]1[C@H]2O HALQELOKLVRWRI-VDBOFHIQSA-N 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- NJSUFZNXBBXAAC-UHFFFAOYSA-N ethanol;toluene Chemical compound CCO.CC1=CC=CC=C1 NJSUFZNXBBXAAC-UHFFFAOYSA-N 0.000 description 1
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 description 1
- 230000002964 excitative effect Effects 0.000 description 1
- 208000030533 eye disease Diseases 0.000 description 1
- 238000000249 far-infrared magnetic resonance spectroscopy Methods 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- YRTCKZIKGWZNCU-UHFFFAOYSA-N furo[3,2-b]pyridine Chemical compound C1=CC=C2OC=CC2=N1 YRTCKZIKGWZNCU-UHFFFAOYSA-N 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000002650 habitual effect Effects 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000001320 hippocampus Anatomy 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229960001438 immunostimulant agent Drugs 0.000 description 1
- 239000003022 immunostimulating agent Substances 0.000 description 1
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000001057 ionotropic effect Effects 0.000 description 1
- 208000002551 irritable bowel syndrome Diseases 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000008176 lyophilized powder Substances 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
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000005906 menstruation Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 108010038448 metabotropic glutamate receptor 8 Proteins 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 210000003061 neural cell Anatomy 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 230000003961 neuronal insult Effects 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 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
- 239000002674 ointment Substances 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 230000035778 pathophysiological process Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- UEXCJVNBTNXOEH-UHFFFAOYSA-N phenyl acethylene Natural products C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 description 1
- CWCMIVBLVUHDHK-ZSNHEYEWSA-N phleomycin D1 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC[C@@H](N=1)C=1SC=C(N=1)C(=O)NCCCCNC(N)=N)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C CWCMIVBLVUHDHK-ZSNHEYEWSA-N 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000020341 sensory perception of pain Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229960003329 sulfinpyrazone Drugs 0.000 description 1
- MBGGBVCUIVRRBF-UHFFFAOYSA-N sulfinpyrazone Chemical compound O=C1N(C=2C=CC=CC=2)N(C=2C=CC=CC=2)C(=O)C1CCS(=O)C1=CC=CC=C1 MBGGBVCUIVRRBF-UHFFFAOYSA-N 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000009492 tablet coating Methods 0.000 description 1
- 239000002700 tablet coating Substances 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000003760 tallow Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 229940040944 tetracyclines Drugs 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- RBNBDIMXFJYDLQ-UHFFFAOYSA-N thieno[3,2-d]pyrimidine Chemical class C1=NC=C2SC=CC2=N1 RBNBDIMXFJYDLQ-UHFFFAOYSA-N 0.000 description 1
- 231100000886 tinnitus Toxicity 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 125000006168 tricyclic group Chemical group 0.000 description 1
- 206010044652 trigeminal neuralgia Diseases 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
Abstract
The present invention relates to new mGluRl and mGluR5 receptor subtype preferring ligands of formula (I) wherein X represents a group selected from CO, SO, SO2; Y represents a group selected from 0, OCH2, (CH2)n, NH, NHCH2; n is an integer of 0 to 2; R1 is an optionally substituted alkyl, cycloalkyl, phenyl, biphenyl, heterocyclyl; ; R2 is an optionally substituted phenyl, heterocyclyl or NR3R4 group wherein R3 and R4 are independently selected from the group of hydrogen, alkyl, or R3 and R4 together with the N atom to which they are attached can form an optionally substituted C5-7 heterocyclyl group, containing one or more heteroatom(s) selected from the group of N, O, S, and/or tautomers and/or salts and/or hydrates and/or solvates thereof, to the processes for producing the same, to pharmaceutical compositions containing the same and to their use in therapy and/or prevention of pathological conditions which require the modulation of mGluRl and mGluR5 receptors such as neurological disorders, psychiatric disorders, acute and chronic pain, neuromuscular dysfunctions of the lower urinary tract and gastrointestinal disorders.
Description
Invention field
The present invention relates to new mGluR1 and mGluR5 receptor subtype preference part and/or its tautomer and/or salt and/or the hydrate and/or the solvate of formula (I), the preparation method who relates to them, relate to the pharmaceutical composition that contains these compounds, and relate to their application in the illness that treats and/or prevents needs regulation and control mGluR1 and mGluR5 acceptor.
Background of invention
Main excitatory neurotransmitter in the mammalian central nervous system (CNS) is the L-glutamic acid molecule, and its meeting is in conjunction with neurone, thus the activating cells surface receptor.Based on the constitutional features of receptor protein, acceptor signal transduction is advanced mode and pharmacological characteristics in the cell, these acceptors can be divided into 2 big classes, i.e. ionic (ionotropic) and metabolic pattern (metabotropic) glutamate receptor.
Metabotropic glutamate receptor (mGluR) is G albumen-coupled receptor, and it activates second messenger system in many cells after in conjunction with L-glutamic acid.The activation of mGluR can cause one or more following reactions: the activation of Phospholipase C in the complete mammalian nervous unit; The increase of phosphoinositide (PI) hydrolysis; Intracellular Ca2+ discharges; The activation of Phospholipase D; The activation of adenylate cyclase or inhibition; Increase or minimizing that cyclic amp (cAMP) forms; The activation of guanylate cyclase; The increase that cyclic guanosine monophosphate (cGMP) forms; The activation of Phospholipase A2; The increase that arachidonic acid discharges; And voltage-and active increase or reduction (TrendsPharmacol.Sci., 1993,14,13 of part-gated ion channel; Neurochem.Int., 1994,24,439; Neuropharmacology, 1995,34,1; Prog.Neurobiol., 1999,59,55; Berl.Psychopharmacology 2005,179, and 4).
By molecular cloning, identified 8 kinds of different mGluR hypotypes, be called mGluR1 to mGluR8 (Neuron, 1994,13,1031; Neuropharmacology, 1995,34,1; J.Med.Chem., 1995,38,1417).The expression of the alternative splicing form by some mGluR hypotype produces further acceptor diversity (PNAS.1992,89,10331; BBRC, 1994,199,1136; J.Neurosci., 1995,15,3970).
Based on amino acid sequence homology, the second messenger system of acceptor use and their pharmacological characteristic, the metabotropic glutamate receptor hypotype can be subdivided into 3 groups, promptly I organizes, II group and III group mGluR.I group mGluR comprises mGluR1, the variant of mGluR5 and their alternative splicing.
The trial prompting of the physiological role of explaination I group mGluR, the activation of these acceptors can cause neuronal excitation.Evidence suggests that this excitement is that the neurotransmitter that causes increasing discharges (Trends Pharmacol.Sci., 1992,15,92 because the direct activation of postsynaptic mGluR has still also hinted the activation that presynaptic mGluR takes place; Neurochem.Int., 1994,24,439; Neuropharmacology, 1995,34,1; Trends Pharmacol.Sci., 1994,15,33).
Metabotropic glutamate receptor has involved in the many normal processes among the Mammals CNS.Verified, the activation of mGluR is to induce the long time-histories of hippocampus to strengthen and the long time-histories inhibition of cerebellum required (Nature, 1993,363,347; Nature, 1994,368,740; Cell, 1994,79,365; Cell, 1994,79,377).Also verified mGluR activates effect (Neuroreport, 1993,4,879 in nociception and analgesia; Brain Res., 1999,871,223).
Propose, I group metabotropic glutamate receptor and more specifically mGluR5 in the pathophysiological processes of many CNS of influence and illness, work.They comprise apoplexy, head trauma, anoxic and ischemia injury, hypoglycemia, epilepsy, neurodegenerative disorders is Alzheimer for example, acute and chronic pain, drug abuse and drug withdrawal, fat and gastroesophageal reflux disease (GERD) (people such as Schoepp, Trends Pharmacol.Sci.1993,14:13; People such as Cunningham, Life Sci.1994,54:135; People such as Hollman, Ann.Rev.Neurosci.1994,17:31; People such as Pin, Neuropharmacology 1995,34:1; People such as Knopfel, J.Med.Chem.1995,38:1417; People such as Spooren, TrendsPharmacol.Sci.2001,22:331; People Curr.Opin.Pharmacol.2002 such as Gasparini, 2:43; Neugebauer Pain 2002,98:1, people such as Slassi, Curr Top Med Chem.2005; 5 (9): 897-911).MGluR5-optionally compound for example 2-methyl-6-(phenylacetylene base)-pyridine (" MPEP ") be effectively (people such as Spooren, J.Pharmacol.Exp.Ther.2000,295:1267 in the mood disorder animal model of (comprising anxiety and depression); People such as Tatarczynska, Br.J.Pharmacol.2001,132:1423; People such as Klodzynska, Pol.J.Pharmacol, 2001,132:1423).Think that the many pathologic conditions in these illnesss are because the CNS neuronal excitation of over-drastic glutamate induction.As if because I group mGluR can discharge the neuronal excitation that increases the L-glutamic acid mediation by postsynaptic mechanism and enhanced presynaptic L-glutamic acid, their activation may be facilitated pathologic condition.Therefore, the selective antagonist of I group mGluR acceptor may be that treatment is upward useful, especially as neuroprotective, anodyne or anticonvulsive drug.
Think that the many pathologic conditions in these illnesss are because the CNS neuronal excitation of over-drastic glutamate induction.As if because I group mGluR (mGluR1 and mGluR5) can discharge the neuronal excitation that increases the L-glutamic acid mediation by postsynaptic mechanism and enhanced presynaptic L-glutamic acid, their activation may be facilitated pathologic condition.Therefore, the selective antagonist of I group mGluR acceptor may be that treatment is upward useful, especially as neuroprotective, anodyne or anticonvulsive drug.
Germany (East Germany) patent DD 00285356 has described 6,7-dihydro-thienopyridine derivative and their preparation method.
Patent application US 20050038068 has described new Thienopyridinone derivatives, and it can be used for the treatment of diabetes as adenosine monophosphate activated protein kinase activator, metabolism syndrome and obesity.
Japanese Patent JP 07076586 has described furo pyridine and thienopyridine, is used for the treatment of osteoporosis as bone resorption inhibitor.
Thienopyridine derivative can be used as hematopoietic, and antineoplastic agent and immunostimulant are as described in JP 07053562 patent application.
According to people such as E.Zeinab (Arch.Pharm, 1992,325 (5), 301), synthesized thienopyridine and Thienopyridinone and Thienopyrimidine derivative, and estimated their mycotoxins inhibitor activity.Some compound can suppress the generation and the fungal growth of mycotoxins.
International Patent Application WO 03/033502 has been described Thienopyridinone derivatives, and they are the kinase whose effective inhibitor of p38, can be used to prevent or treats the kinase mediated disease of p38, for example rheumatoid arthritis.
The compound of mentioning in the above-mentioned publication is not declared or even is not hinted that the mGluR acceptor is had activity.
Summary of the invention
The present invention relates to the new mGluR1 and the mGluR5 receptor subtype preference part of formula (I):
Wherein
The X representative is selected from following group: CO, SO, SO
2
The Y representative is selected from following group: O, OCH
2, (CH
2)
n, NH, NHCH
2
N is the integer of 0-2;
R
1Be optional substituted alkyl, cycloalkyl, phenyl, xenyl, heterocyclic radical;
R
2Be optional substituted phenyl, heterocyclic radical, or NR
3R
4Group, wherein R
3And R
4Be independently selected from hydrogen, alkyl, or R
3And R
4Can form optional substituted C with their bonded N atoms
5-7Heterocyclic radical, it contains the heteroatoms of one or more N of being selected from, O, S,
And/or its tautomer and/or salt and/or hydrate and/or solvate, the preparation method who relates to them, relate to the pharmaceutical composition that contains them, and relate to their application in the pathological condition that treats and/or prevents needs regulation and control mGluR1 and mGluR5 acceptor, described pathological condition is neurological disorder for example, psychiatric disorders, the neuromuscular dysfunction and the disorder of gastrointestinal tract of acute and chronic pain and lower urinary tract.
Detailed Description Of The Invention
The present invention relates to the new mGluR1 and the mGluR5 receptor subtype preference part of formula (I):
Wherein
The X representative is selected from following group: CO, SO, SO
2
The Y representative is selected from following group: O, OCH
2, (CH
2)
n, NH, NHCH
2
N is the integer of 0-2;
R
1Be optional substituted alkyl, cycloalkyl, phenyl, xenyl, heterocyclic radical;
R
2Be optional substituted phenyl, heterocyclic radical, or NR
3R
4Group, wherein R
3And R
4Be independently selected from hydrogen, alkyl, or R
3And R
4Can form optional substituted C with their bonded N atoms
5-7Heterocyclic radical, it contains the heteroatoms of one or more N of being selected from, O, S,
And/or its tautomer and/or salt and/or hydrate and/or solvate.
Work as R
1When representing alkyl, described alkyl contains 1-4 carbon atom, is straight or branched; and described alkyl can be alternatively be selected from following substituting group and replaces by one or more: methoxyl group, trifluoromethyl, amino; alkylamino, dialkyl amido, amino methyl; the alkylamino methyl, dialkyl amino ylmethyl, acyl amino; cyano group; fluorine, chlorine, bromine.
Work as R
1During representation ring alkyl, described cycloalkyl moiety contains 3-10 carbon atom, and can be monocyclic, bicyclic or tricyclic group; for example cyclohexyl or adamantyl, and described cycloalkyl can be alternatively be selected from following substituting group and replaces by one or more: methyl, methoxyl group; trifluoromethyl, amino, alkylamino; dialkyl amido, amino methyl, alkylamino methyl; the dialkyl amino ylmethyl, acyl amino, cyano group; fluorine, chlorine, bromine.
Work as R
1And/or R
2Represent phenyl or R
1When representing xenyl, described phenyl or xenyl can be alternatively be selected from following substituting group and replace by one or more: methyl, methoxyl group; trifluoromethyl, amino, alkylamino; dialkyl amido, amino methyl, alkylamino methyl; the dialkyl amino ylmethyl; acyl amino, cyano group, fluorine; chlorine, bromine.
Work as R
1And/or R
2When representing heterocyclic radical, described heterocycle can be saturated or unsaturated monocycle or dicyclo, and it contains the heteroatoms that 1-4 is selected from O, N or S, pyridyl for example, quinolyl, thiazolyl, piperidyl, morpholinyl, tetrahydric quinoline group.Work as R
2Contain heteroatomic ring and do not have the aromatic series characteristic time, it must contain at least one basic nitrogen atom, heterocyclic group partly is connected with thienopyridine by this basic nitrogen atom.Heterocyclic radical can be replaced by following substituting group alternatively: methyl, methoxyl group, trifluoromethyl, amino, alkylamino, dialkyl amido, amino methyl, alkylamino methyl, dialkyl amino ylmethyl, acyl amino, cyano group, fluorine, chlorine, bromine.
About R
1, R
2, R
3And R
4Substituting group, the term alkyl is meant the alkyl of the straight or branched that contains 1-4 carbon atom.
According to circumstances, formula (I) compound also can exist with their tautomeric forms (6-hydroxyl-thieno-[2,3-b] pyridine derivate).These forms and their mixture are equally within the scope of the present invention.
Formula (I) compound can form salt with acid.The present invention also relates to formula (I) compound and the sour salt that forms, particularly with the acceptable sour salt that forms of pharmacy.The implication of formula (I) compound is free alkali or salt, even without indicating respectively.
Organic and mineral acid may be used to the formation of acid salt.The mineral acid that is fit to can be for example hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid.Monovalence organic acid representative can be for example formic acid, acetate, propionic acid and different butyric acid, valeric acid and capric acid.Divalence organic acid representative can be for example oxalic acid, propanedioic acid, toxilic acid, fumaric acid and succsinic acid.Also can use other organic acids, alcohol acid for example, for example citric acid, tartrate, perhaps aromatic carboxylic acid, for example phenylformic acid or Whitfield's ointment, and aliphatic series and aromatic sulfonic acid, for example methylsulfonic acid, naphthene sulfonic acid and tosic acid.Especially valuable acid salt group is that wherein acid constituents itself is acceptable on the physiology, and does not have result of treatment in applied dosage, and perhaps it does not have adverse influence to the effect of activeconstituents.These acid salt are pharmaceutically-acceptable acid addition.The acid salt that does not belong to pharmaceutically-acceptable acid addition also belongs to the present invention, and its reason is they can help required compound under set situation a purifying and separate.
The solvate and/or the hydrate that also comprise formula (I) compound within the scope of the invention.
Formula of the present invention (I) compound of particularly important is as follows:
2-(4-chloro-benzenesulfonyl)-3-(4-chloro-phenyl)-7H-thieno-[2,3-b] pyridine-6-ketone,
3-[3-(4-chloro-phenyl)-6-oxygen-6,7-dihydro-thieno-[2,3-b] pyridine-2-sulfuryl base]-benzonitrile,
3-(4-chloro-phenyl)-6-oxygen-6,7-dihydro-thieno-[2,3-b] pyridine-2-formic acid 4-fluoro-benzyl ester,
3-(4-chloro-phenyl)-2-(Toluene-3,4-dithiol-alkylsulfonyl)-7H-thieno-[2,3-b] pyridine-6-ketone,
3-(4-chloro-phenyl)-2-(3-fluoro-4-methyl-benzenesulfonyl)-7H-thieno-[2,3-b] pyridine-6-ketone,
3-[3-(4-chloro-phenyl)-6-oxygen-6,7-dihydro-thieno-[2,3-b] pyridine-2-sulfuryl base]-5-fluoro-benzonitrile,
3-(4-chloro-phenyl)-2-(3-fluoro-benzenesulfonyl)-7H-thieno-[2,3-b] pyridine-6-ketone,
2-(4-chloro-benzenesulfonyl)-3-(4-methyl-piperidines-1-yl)-7H-thieno-[2,3-b] pyridine-6-ketone.
Pharmaceutical preparation
The present invention also relates to pharmaceutical composition, it contains formula (I) compound and/or its tautomer and/or physiologically acceptable salt and/or hydrate and/or solvate as activeconstituents and one or more physiologically acceptable carriers.
Formula (I) compound and/or its tautomer and/or physiologically acceptable salt and/or hydrate and/or solvate can pass through ordinary method administration arbitrarily, for example (comprise subcutaneous by per os, parenteral, intramuscular, with intravenous), contain clothes, hypogloeeis, intranasal, rectum or transdermal administration, described pharmaceutical composition correspondingly adapts with it.
Activated formula (I) compound and/or its tautomer and/or physiologically acceptable salt and/or hydrate and/or solvate can be mixed with liquid or solid when oral administration, syrup for example, suspensoid or emulsion, tablet, capsule and lozenge.
The liquid preparation of formula (I) compound and/or its tautomer and/or physiologically acceptable salt and/or hydrate and/or solvate is usually by formula (I) compound and/or its tautomer and/or physiologically acceptable salt and/or hydrate and/or suspension or the solution composition of solvate in the suitable liquid carrier, described liquid vehicle is water-containing solvent for example, for example water and ethanol or glycerine, or non-aqueous solvent, for example polyoxyethylene glycol or oil.Preparation also can contain suspension agent, sanitas, correctives or tinting material.
What the solid form tablet composition was used to prepare solid preparation on can use habit is fit to the pharmaceutical carrier preparation arbitrarily.The example of this class carrier comprises lactose, terra alba, sucrose, talcum powder, gelatin, agar, pectin, gum arabic, Magnesium Stearate, stearic acid etc.Alternatively, by the water-based or the non-aqueous technology of standard, can be with tablet coating.
The solid form capsule composition can utilize habitual encapsulate prepared.For example, can use the standard vector preparation to contain the particle of activeconstituents, then they are filled in the hard gelatin capsule; Perhaps, can use the pharmaceutical carrier that is fit to arbitrarily to prepare dispersion or suspension, for example water-based natural gum, Mierocrystalline cellulose, silicate or oil are filled into dispersion or suspension in the soft gelatin capsule then.
Typical parenteral composition is made up of formula (I) compound and/or its tautomer and/or physiologically acceptable salt and/or hydrate and/or the solution or the suspension of solvate in sterile aqueous carrier or the acceptable oil of parenteral (for example polyoxyethylene glycol, polyvinylpyrrolidone, Yelkin TTS, peanut oil or sesame oil).Perhaps, the solution freeze-drying can be used the solvent reprovision that is fit to then before facing administration.
The present composition that contains formula (I) compound and/or its tautomer and/or physiologically acceptable salt and/or hydrate and/or solvate that is used for nasal administration can be mixed with aerosol, drops, gel and pulvis expediently.Aerosol formulations of the present invention comprises formula (I) compound and/or its tautomer and/or physiologically acceptable salt and/or hydrate and/or solvate solution or the fine suspension in acceptable water-based or the non-aqueous solvent on physiology usually, usually present list or multiple doses with sterile form in sealed vessel, container can be taked the form of cartridge case or recharge for using (using atomisation unit).Perhaps, sealed vessel can be the unit distribution device, for example nasal inhaler of single dose or aerosol dispenser, and it is equipped with metering valve, in case container contents is depleted promptly discardable.If formulation comprises aerosol dispenser, it will contain propelling agent, and this can be a pressurized gas, pressurized air for example, perhaps organic propelling agent, for example fluorochlorohydrocarbon.Aerosol dosage forms also can be taked the form of pump formula spraying gun.
The present composition that contains formula (I) compound and/or its tautomer and/or physiologically acceptable salt and/or hydrate and/or solvate that is suitable for containing clothes or sublingual administration comprises tablet, lozenge and pastille, wherein prepare activeconstituents, for example sugar and gum arabic, tragacanth gum or gelatin, glycerine etc. with carrier.
The present composition that contains formula (I) compound and/or its tautomer and/or physiologically acceptable salt and/or hydrate and/or solvate that is used for rectal administration is the form of suppository expediently, contain conventional suppository base, for example theobroma oil and this area other material commonly used.Can followingly form suppository expediently: the carrier of blend composition and remollescent or thawing at first, cooling then, and in mould, be shaped.
The present composition that contains formula (I) compound and/or its tautomer and/or physiologically acceptable salt and/or hydrate and/or solvate that is used for transdermal administration comprises ointment, gel and patch.
The present composition that contains formula (I) compound and/or its tautomer and/or physiologically acceptable salt and/or hydrate and/or solvate is unit dosage form, for example tablet, capsule or ampoule preferably.
Each dose unit of the present invention that is used for oral administration preferably contains 0.1 to 500mg formula (I) compound and/or its tautomer and/or physiologically acceptable salt and/or hydrate and/or solvate, calculates with free alkali.
Each dose unit of the present invention that is used for administered parenterally preferably contains 0.1 to 500mg formula (I) compound and/or its tautomer and/or physiologically acceptable salt and/or hydrate and/or solvate, calculates with free alkali.
Formula (I) compound and/or its tautomer and/or physiologically acceptable salt and/or hydrate and/or solvate usually can be in administrations in the every day dosage.In the illness of mGluR1 and mGluR5 mediation (schizophrenia for example, anxiety, depressed, panic, bipolar disorder and diel rhythm obstacle or chronic and acute pain illness) treatment in, every day about 0,01mg/kg is suitable for to the dosage level of about 140mg/kg body weight, perhaps every about 0.5mg patient's every day about 7g extremely.
Can with solid support material combination amount with the activeconstituents that produces single formulation, change with the host and the specific administration pattern of treatment.For example, be used for human peroral administration preparation and can contain the 0.5mg that has an appointment expediently to about 5g promoting agent, its solid support material with suitable and convenient amount combines, and the latter can account for about 5 to about 95% of total composition.Unit dosage contains have an appointment the extremely activeconstituents of about 1000mg of 1mg, 25mg, 50mg, 100mg, 200mg, 250-300mg, 400mg, 500mg, 600mg, 800mg or 1000mg usually usually.
But, be to be understood that, any specific patient's concrete dosage level will depend on many factors, comprise age, body weight, general health, sex, diet, administration time, route of administration, discharge rate, drug regimen and the seriousness of the specified disease of receiving treatment.
Medical use
Have been found that, formula of the present invention (I) compound and/or its tautomer and/or physiologically acceptable salt and/or hydrate and/or solvate can show the biological activity at mGluR1 and mGluR5 acceptor, and expection can be used for the treatment of the illness of mGluR1 and mGluR5 mediation.
Have been found that according to compound or its salt of the present invention and can show the effectiveness of height and the selectivity of each metabotropic glutamate receptor (mGluR) hypotype.More specifically, exist effectively and to mGluR1 and mGluR5 receptor-selective according to compound of the present invention.Therefore, expecting that compound of the present invention can be used to prevent and/or treat activate relevant illness and be used to suppress with the excitability of mGluR1 and mGluR5 acceptor activates the neuronal damage that causes by the excitability of mGluR1 and mGluR5 acceptor.Described compound can be used for producing Mammals (comprising the mankind) restraining effect of mGluR1 and mGluR5.
Thereby, expect that compound of the present invention is highly suitable for preventing and/or treating mGluR1 and the receptor-mediated illness of mGluR5, for example acute and chronic nerve and mental disorder, the neuromuscular dysfunction and the disorder of gastrointestinal tract of chronic and acute pain illness and lower urinary tract.
Therapeutic or the required dosage of prophylactic treatment particular disorder, inevitable host and route of administration with treatment changes.
The present invention relates to formula (I) compound of preamble definition, be used for the treatment of.
The present invention relates to formula (I) compound of preamble definition, be used to prevent and/or treat the receptor-mediated illness of mGluR1 and mGluR5.
The present invention relates to formula (I) compound of preamble definition, be used to prevent and/or treat neurological disorder.
The present invention relates to formula (I) compound of preamble definition, be used to prevent and/or treat psychiatric disorders.
The present invention relates to formula (I) compound of preamble definition, be used to prevent and/or treat chronic and the acute pain illness.
The present invention relates to formula (I) compound of preamble definition, be used to prevent and/or treat the neuromuscular dysfunction and the disorder of gastrointestinal tract of lower urinary tract.
The present invention relates to formula (I) compound of preamble definition, be used to prevent and/or treat the pain relevant with migraine, inflammatory pain, the neuropathic pain illness is diabetic neuropathy, sacroiliitis and atrophic diseases for example, pain in the back, postoperative pain and (comprise stenocardia, in kidney or biliary colic with multiple different syndromes, in the menstruation, migraine and gout) relevant pain.
The present invention relates to formula (I) compound of preamble definition, be used to prevent and/or treat Alzheimer, senile dementia, AIDS-inductive dementia, Parkinson's disease, amyotrophic lateral sclerosis, Huntington chorea, migraine, epilepsy, schizophrenia, depression, anxiety, acute anxiety, obesity, obsessive compulsive disorder, eye disease is retinopathy for example, diabetic retinopathy, glaucoma, the auditory nerve illness is tinnitus for example, the neuropathy of chemotherapy induction, postherpetic neuralgia and trigeminal neuralgia, tolerance, dependency, fragile X, autism, mental retardation, schizophrenia and mongolism.
The present invention relates to formula (I) compound of preamble definition, be used to prevent and/or treat apoplexy, head trauma, anoxic and ischemia injury, hypoglycemia, cardiovascular disorder and epilepsy.
Described compound also is highly suitable for treating the neuromuscular dysfunction of lower urinary tract, urgent urination for example, bladder hyperaction, frequent micturition, uropoiesis conformability, urocystitis, incontinence, the enuresis and the misnicturition of reduction.
In addition, described compound also is highly suitable for treating disorder of gastrointestinal tract, for example temporary transient LESR (TLESR), stomach and intestine backflow disease and irritable bowel syndrome.
The present invention also relates to the application of compound in producing medicine of the formula (I) of preamble definition, described medicine is used to prevent and/or treat mGluR1 and the receptor-mediated illness of mGluR5 and any illness of listing above.
The present invention also provides to treat and/or prevent suffers from mGluR1 and the receptor-mediated illness of mGluR5 and any illness listed above or the method that is in the described illness of the patient in its danger, and it comprises the compound of formula (I) of using the preamble definition of significant quantity to described patient.
In the context of the present specification, term " treatment " comprises treatment and prevention, unless there is opposite concrete indication.Should correspondingly understand term " treatment " and " remedially ".
In this manual, except as otherwise noted, term " antagonist " is meant by any-mode partially or even wholly blocks the compound that causes part to produce the transduction pathway of response.
Except as otherwise noted, term " illness " is meant and metabotropic glutamate receptor active relevant any illness and disease.
The preparation method
Abbreviation
Abbreviation used herein has the implication of listing below.The abbreviation of not listing below has their normally used implications, unless specify in addition.
DMF N, dinethylformamide
Can prepare compound of the present invention according to following method.Except as otherwise noted, substituent implication such as toply defined by formula I, or those skilled in the art are conspicuous.
According to the present invention, provide the method for preparation formula (I) compound and/or its tautomer and/or salt and/or hydrate and/or solvate
Wherein
The X representative is selected from following group: CO, SO, SO
2
The Y representative is selected from following group: O, OCH
2, (CH
2)
n, NH, NHCH
2
N is the integer of 0-2;
R
1Be optional substituted alkyl, cycloalkyl, phenyl, xenyl, heterocyclic radical;
R
2Be optional substituted phenyl, heterocyclic radical,
Wherein make the thienopyridine derivative of formula (II)
Wherein X, Y, R
1And R
2Implication such as toply defined by formula (I) compound,
React in solvent with metachloroperbenzoic acid or Peracetic Acid, to obtain formula (III) compound
Wherein X, Y, R
1And R
2Implication such as toply defined by formula (I) compound,
Formula (III) compound and trifluoroacetic anhydride or diacetyl oxide are reacted in dimethyl formamide, and after this production (I) compound forms tautomer and/or salt and/or the hydrate and/or the solvate of formula (I) compound alternatively, or
Make the thienopyridine derivative of formula (IV)
Wherein X, Y and R
1Implication such as toply defined by formula (I)
React in solvent with metachloroperbenzoic acid or Peracetic Acid, to obtain the formula V compound
Wherein X, Y and R
1Implication such as toply defined coupling formula V compound and formula (VI) compound after this by formula (I)
R
2-B(OH)
2
(VI)
R wherein
2Be optional substituted phenyl or heterocyclic radical, to obtain formula (III) compound
Wherein X, Y, R
1And R
2Implication such as toply defined by formula (I)
With coupling formula (III) compound and trifluoroacetic anhydride or diacetyl oxide in dimethyl formamide,, after this form tautomer and/or salt and/or the hydrate and/or the solvate of formula (I) compound alternatively to obtain formula (I) compound.
The method of another kind of preparation formula (I) compound and/or its tautomer and/or salt and/or hydrate and/or solvate
Wherein
The X representative is selected from following group: CO, SO, SO
2
The Y representative is selected from following group: O, OCH
2, (CH
2)
n, NH, NHCH
2
N is the integer of 0-2;
R
1Be optional substituted alkyl, cycloalkyl, phenyl, xenyl, heterocyclic radical;
R
2Be optional substituted NR
3R
4Group, wherein R
3And R
4Be independently selected from hydrogen, alkyl, or R
3And R
4Can form optional substituted C with their bonded N atoms
5-7Heterocyclic radical, it contains the heteroatoms of one or more N of being selected from, O, S,
Coupling formula V compound and formula (VII) compound in dimethyl formamide wherein
Wherein X, Y and R
1Implication such as toply defined by formula (I)
HNR
3R
4
(VII)
R wherein
3And R
4Be independently selected from hydrogen, alkyl, or R
3And R
4Can form optional substituted C with their bonded N atoms
5-7Heterocyclic radical, it contains the heteroatoms of one or more N of being selected from, O, S,
To obtain formula (III) compound
Wherein X, Y, R
1And R
2Implication such as toply defined by formula (I)
With formula (II) compound and trifluoroacetic anhydride or diacetyl oxide are reacted in dimethyl formamide, to obtain formula (I) compound, after this form tautomer and/or salt and/or the hydrate and/or the solvate of formula (I) compound alternatively.
Scheme 1
A. metachloroperbenzoic acid, CHCl
3, 0-30 ℃, 24-72 hour;
B.Polonovsky type reaction (CF
3CO)
2O, DMF, 0-30 ℃, 3-20 hour;
According to Hungarian patent application P0501168 or the described method of P0501171, the compound of preparation formula (II).
Method (J.Heterocyclic Chem. by W.Boisvert, 1987,24,1467), in envrionment temperature, at The suitable solvent (chloroform, methylene dichloride, acetate etc.) in, by with for example metachloroperbenzoic acid or Peracetic Acid oxidation, from the N-oxide derivative of the compound formula (III) of formula (II).
Use the method (J.Heterocyclic Chem., 1976,13,1197) of R.Hartling,, in dimethyl formamide, handle formula (III) compound with trifluoroacetic anhydride or diacetyl oxide by the reaction of Polonovsky type.The described envrionment temperature that is reflected at is carried out, production (I) compound.
The formula that obtains (I) compound can carry out purifying by crystallization or by column chromatography.
Method according to scheme 1 can be used for preparation formula (I) compound, wherein R
2Be optional substituted phenyl or heterocyclic radical.
Scheme 2
A. metachloroperbenzoic acid, CHCl
3, 0-30 ℃, 24-72 hour;
B. formula (VI) compound, Na
2CO
3, ethanol-toluene, or dimethoxy-ethanol, Pd (PPh
3)
4, 1-5 hour, 20-110 ℃;
C. (CF
3CO)
2O, DMF, 0-30 ℃, 3-20 hour;
According to the described method of Hungarian patent application P0501171, the compound of preparation formula (IV).
Method (J.Heterocyclic Chem. by W.Boisvert, 1987,24,1467), in envrionment temperature, at The suitable solvent (chloroform, methylene dichloride, acetate etc.) in, by with for example metachloroperbenzoic acid or Peracetic Acid oxidation, from the N-oxide derivative of the compound formula V of formula (IV).
By well-known Suzuki linked reaction method (A.Suzuki ﹠amp; H.C.Brown:Organic Syntheses via Boranes Vol.1-3), from formula V and a compounds accepted way of doing sth (III) compound (VI).
Use the method (J.Heterocyclic Chem., 1976,13,1197) of R.Hartling,, in dimethyl formamide, handle formula (III) compound with trifluoroacetic anhydride or diacetyl oxide by the reaction of Polonovsky type.The described envrionment temperature that is reflected at is carried out, production (I) compound.
The formula that obtains (I) compound can carry out purifying by crystallization or by column chromatography.
Method according to scheme 2 can be used for preparation formula (I) compound, wherein R
2Be optional substituted phenyl or heterocyclic radical.
Scheme 3
A. the compound of formula (VII), DMF, 100-140 ℃, 1-4 hour;
B. (CF
3CO)
2O, DMF, 0-30 ℃, 3-20 hour;
By D.Prim and G.Kirsch (Tetrahedron, 1999,55, improved method 6511-6526) is from formula V compound formula (III) compound.
Use the method (J.Heterocyclic Chem., 1976,13,1197) of R.Hartling,, in dimethyl formamide, handle formula (III) compound with trifluoroacetic anhydride or diacetyl oxide by the reaction of Polonovsky type.The described envrionment temperature that is reflected at is carried out, production (I) compound.
The formula that obtains (I) compound can carry out purifying by crystallization or by column chromatography.
Method according to scheme 3 can be used for preparation formula (I) compound, wherein R
2Be optional substituted NR
3R
4Group, wherein R
3And R
4Be independently selected from hydrogen, alkyl, or R
3And R
4Can form optional substituted C with their bonded N atoms
5-7Heterocyclic radical, it contains the heteroatoms of one or more N of being selected from, O, S.
The biology testing method
The experiment of MGluR1 receptors bind
According to the improved method of people such as Lavreysen (Mol.Pha rm., 2003,63,1082), carry out the experiment of MGluR1 receptors bind.Based on the high homology between people and the rat mGluR1 acceptor, use the rat cerebellum membrane product to measure the feature that combines of reference compound and new compound and rat mGluR1.[3H] R214127 (3nM) is as radioligand, measures non-specific binding having in the presence of the 1 μ MR214127.
By nonlinear regression analysis, measure the IC-50 value from displacement curve, and change into K by the equation method of Cheng and Prusoff (Biochem.Pharmacol., 1973,22,3099)
iValue.
The experiment of MGluR5 receptors bind
(Bioorg.Med.Chem.Lett.2000 12:407-409), through revising, measures the MGluR5 receptors bind according to people such as Gasparini.Use the rat cerebral cortex membrane product to measure the feature that combines of reference compound and new compound and rat mGluR5.A18 clone (available from Euroscreen) that use to express hmGluR5a is measured the feature that combines of chemical compound and people mGluR5a acceptor.[3H]-M-MPEP (2nM) is as radioligand.Measure non-specific binding having in the presence of the 10 μ M M-MPEP.
The evaluation of functionally active
The cell culture of natural rat mGluR5 and mGluR1 acceptor
Use respectively be derived from Charles River rat embryo in 17 day age former generation the neocortex cell culture and be derived from Wistar rat in 4 day age former generation cerebellum cell culture (about the details of neuronal cell cultures thing preparation, referring to Johnson, M.I.; Bunge, R.P. (1992): Primary cell cultures of peripheral and central neurons and glia.In:Protocols for Neural Cell Culture, eds:Fedoroff, S.; Richardson A., The Humana Press Inc., 51-77), the function that is evaluated at natural rat mGluR5 and mGluR1 acceptor is renderd a service.After the separation, the cell plating to the 96-hole microtest plate of standard, is maintained 95% air-5%CO with culture
2Atmosphere, 37 ℃.Neocortex and cerebellum culture are respectively applied at 5-7 and the external calcium after 3-4 days and measure.
The cell culture of recombinant human mGluR5a acceptor
In the F12 substratum that contains 10%FCS, the antimycotic solution of 1% microbiotic, 400 μ g/ml G418,250 μ g/ml zeocin, 5 μ g/ml tetracyclines, cultivate Chinese hamster ovary (CHO) cell (CHO-mGluR5a is available from Euroscreen) of stably express recombinant human mGluR5a acceptor.Cell is remained in 37 ℃, humidification incubator, at 5%CO
2Under/95% air atmosphere, go down to posterity weekly 3 times.With 2.5-3.5 * 10
4Cells/well on the microtest plate of the 96-hole of standard, by add the 600ng/ml Vibravenos in next day, is induced expression of receptor with cell inoculation.Added behind the inductor 16-24 hour, and carried out calcium and measure.
The fluorescence measurement of cytoplasmic calcium concentration
Former generation neocortex and the cerebellum culture on and on the CHO-mGluR5a cell of stably express people mGluR5a acceptor, measure cytoplasmic calcium concentration ([Ca
2+]
i).Culturing cell in the microtest plate of the 96-hole of standard, before measurement, pair cell loads Ca
2+-fluorescent dye sensitive fluo-4/AM (2 μ M): neural culture loads in their growth medium, (under the situation of CHO-mGluR5a cell, these additives also are present in [Ca to the CHO-mGluR5a cell in having added 2mM Sodium.alpha.-ketopropionate and 30 μ g/ml L-glutamic acid-pyruvic acid transaminases
2+]
iIn the measuring process) test damping fluid (145mM NaCl, 5mM KCl, 2mM MgCl
2, 2mMCaCl
2, 10mM HEPES, 20mM D-glucose, 2mM probenecid, pH=7.4) the middle loading.By with 100 μ l/ hole dye solutions 37 ℃, in the humidification incubator, at 5%CO
2Incubation cell 40-120min finishes loading under the atmosphere of/95% air.Load in order to stop dyestuff, with testing the damping fluid washed cell 2 times.After the washing, depend on experiment setting, in each hole, add the experimental compound (in the test damping fluid, diluting whole DMSO/DMF concentration＜0.1%) or the damping fluid of different concns by DMSO or dimethyl formamide (DMF) stock solution.Under the situation of neocortex culture, the test damping fluid also contains TTX, and (0.5 μ M to suppress the spontaneous oscillation of [Ca2+] i, under the situation of cerebellum culture, substitutes probenecid with sulfinpyrazone (0.25mM).
Behind 37 ℃ of incubation 10-20min, measure [Ca2+] i that baseline and agonist bring out with dull and stereotyped reading photofluorometer (FlexStation II, Molecular Devices) by row and change.From the bottom of flat board, the detection that excites and launch.Carry out whole measuring process at 37 ℃, with the software control of customization.By measuring [the Ca that agonist brings out in the presence of the compound of different concns is being arranged
2+]
iThe reduction that raises, the inhibition of evaluation experimental compound is renderd a service.DHPG is as the agonist of all 3 kinds of cultures, is respectively 20 and 100 μ M to the concentration of neocortex and cerebellum culture.Under the situation of CHO-mGluR5a cell, use the DHPG of EC80 concentration, described EC80-value is derived from the dose-response curve of measuring every day.Fluorescence data is expressed as Δ F/F (with change in fluorescence with respect to baseline criteriaization).
In a plurality of holes, measure all processing to single flat board.With institute's foraminous data equalization of same processing, mean value is used for analyzing.To render a service the inhibition per-cent that is expressed as the response of contrast agonist in the inhibition of the compound of single concentration point.With S shape concentration-inhibition fitting of a curve data (being derived from least 3 independent experiments), the IC50-value is defined as producing maximum that compound causes suppresses the concentration of half.Use Soft Max Pro (Molecular Devices) to analyze original fluorescence data, carry out curve fitting with GraphPad Prism.
The result
Formula of the present invention (I) compound shows the avidity to rat and people mGluR1 and mGluR5 acceptor, and confirms it is functional antagonist, and they suppress the function response that the mGluR5 receptor for stimulating causes.
Table
*K
i＜500nM
**K
i＞500nM
Following non-limiting example has further been explained the present invention.
Embodiment
Embodiment 1
2-(4-chloro-benzenesulfonyl)-3-(4-chloro-phenyl)-thieno-[2,3-b] pyridine-N-oxide
(2.35g is 5.6mmol) in the solution in chloroform (50ml) to 2-(4-chloro-benzenesulfonyl)-3-(4-chloro-phenyl)-thieno-[2,3-b] pyridine; add metachloroperbenzoic acid (2.52g; 11.2mmol, 77%), with reaction mixture stirring at room 2 days.Add NaHCO then
3(10%, 30ml) solution, after being separated, water (10ml) washing organic phase is through Na
2SO
4Drying is filtered vacuum concentration.By handling with E-C (1: 1), the purifying crude product produces 1.9g (78%) title compound.MS：m/e＝437.2(M+H)
+。
Embodiment 2
2-(4-chloro-benzenesulfonyl)-3-(4-chloro-phenyl)-7H-thieno-[2,3-b] pyridine-6-ketone
(compound 1)
(5.5ml, (0.57g, 1.3mmol) suspension in DMF (6ml) is 7 hours 39.5mmol) to handle 2-(4-chloro-benzenesulfonyl)-3-(4-chloro-phenyl)-thieno-[2,3-b] pyridine-N-oxide with trifluoroacetic anhydride in room temperature.When reaction finished, it became solution, with half of the whole volume of its vacuum concentration.Add entry (0.3ml), leach crystalline product, water-DMF mixture (1: 1) washing.Reaction produces 0.35g (61%) title compound.MS：m/e＝437.2(M+H)
+。
Compound 2 and 3 preparation are as mentioned above.
Embodiment 3
3-(3-bromo-thieno-[2,3-b] pyridine-2-sulfuryl base)-5-fluoro-benzonitrile-N-oxide compound
(3.51g 8.8mmol) in the solution in chloroform (130ml), adds metachloroperbenzoic acid (6.08g, 35mmol, 77%), spends the night at the stirring at room reaction mixture to 3-(3-bromo-thieno-[2,3-b] pyridine-2-sulfuryl base)-5-fluoro-benzonitrile.Use NaHCO
3(10%, 50ml) washing soln is 3 times, and water (25ml) washed twice then is through Na
2SO
4Drying is filtered, and vacuum concentration.By handle the purifying crude product with ether, produce 3.06g (84%) title compound.MS：m/e＝414.1(M+H)
+。
Embodiment 4
3-[3-(4-chloro-phenyl)-thieno-[2,3-b] pyridine-2-sulfuryl base]-5-fluoro-benzonitrile-N-oxide compound
Under argon gas, with 3-(3-bromo-thieno-[2,3-b] pyridine-2-sulfuryl base)-(2.1g 5mmol) is dissolved in toluene (40ml) and the ethanol (45ml) 5-fluoro-benzonitrile-N-oxide compound (embodiment 3).In this solution, add Pd (PPh
3)
4(0.28g, 0.25mmol), the 4-chlorophenylboronic acid (0.94g, 6mmol) and 2M Na
2CO
3Solution (23ml) is then with reaction mixture refluxed 1 hour.Add entry (50ml), extract resulting suspension 3 times with ethyl acetate (50ml).Water (50ml) washing organic phase is through Na
2SO
4Drying is filtered vacuum concentration.(Kieselgel 60, eluent: ethyl acetate: purifying crude product normal hexane=5: 1) produces 1.26g (56%) title compound by column chromatography.MS：m/e＝445.2(M+H)
+。
Embodiment 5
3-[3-(4-chloro-phenyl)-6-oxygen-6,7-dihydro-thieno-[2,3-b] pyridine-2-sulfuryl base]-5-fluoro-benzonitrile
(compound 6)
Room temperature with trifluoroacetic anhydride (6ml 43mmol) handles 3-[3-(4-chloro-phenyl)-thieno-[2,3-b] pyridine-2-sulfuryl base]-(0.94g, 2mmol) suspension in DMF (8ml) is 2 hours for 5-fluoro-benzonitrile-N-oxide compound (embodiment 4).When reaction finished, it became solution, with half of the whole volume of its vacuum concentration.Add entry (6ml), leach crystalline product, water-DMF mixture (1: 1) washing.Reaction produces 0.7g (74%) title compound.MS：m/e＝445.2(M+H)
+。
According to aforesaid method, preparation compound 4,5 and 7.
Embodiment 6
2-(4-chloro-benzenesulfonyl)-3-(4-methyl-piperidines-1-yl)-thieno-[2,3-b] pyridine-N-oxide
80 ℃ stir 3-(3-bromo-thieno-[2,3-b] pyridine-2-sulfuryl base)-5-fluoro-benzonitrile-N-oxide compound (embodiment 3) in DMF (30ml) (4.1g, 10mmol) and 4-methyl-piperidines (6ml, 50mmol) 2 hours.Vacuum concentrated solution is suspended in resistates in the water (100ml).Filtering-depositing, (3 * 20ml) washings produce 3,76g (92%) title compound to water.MS：m/e＝423.1(M+H)
+。
Embodiment 7
3-[3-(4-chloro-phenyl)-6-oxygen-6,7-dihydro-thieno-[2,3-b] pyridine-2-sulfuryl base]-5-fluoro-benzonitrile
(compound 8)
According to embodiment 5 described methods, from 2-(4-chloro-benzenesulfonyl)-3-(4-methyl-piperidines-1-yl)-thieno-[2,3-b] pyridine-N-oxide (embodiment 6) preparation title compound.MS：m/e＝423.2(M+H)
+。
Embodiment 8
Preparation of drug combination:
A) tablet:
Activeconstituents with the formula (I) of 0.01-50%, the lactose of 15-50%, the yam starch of 15-50%, the polyvinylpyrrolidone of 5-15%, the talcum powder of 1-5%, the Magnesium Stearate of 0.01-3%, the amylopectin of crossing of the colloid silica of 1-3% and 2-7% mixes, then by wet granulation and be pressed into tablet.
B) coated tablet, thin membrane coated tablet:
The tablet of preparation according to the method described above used by intestines or the molten film of stomach forms, or layer dressing of forming by sugar or talcum powder.Coated tablet polishes with beeswax and the cured mixture of carnuba.
C) capsule:
Formula (I) activeconstituents with 0.01-50%, the sodium lauryl sulphate of 1-5%, the starch of 15-50%, the lactose of 15-50%, the Magnesium Stearate thorough mixing of the colloid silica of 1-3% and 0.01-3% sieves mixture and is filled in the hard gelatin capsule.
D) suspension:
The formula of composition: 0.01-15% (I) activeconstituents, the sodium hydroxide of 0.1-2%, the citric acid of 0.1-3%, the Tegosept E of 0.05-0.2% (4-methyl hydroxybenzoate sodium), the propylparaben of 0.005-0.02%, the carboxyvinyl polymer of 0.01-0.5% (polyacrylic acid), 96% ethanol of 0.1-5%, the correctives of 0.1-1%, the distilled water of the sorbyl alcohol of 20-70% (70% aqueous solution) and 30-50%.
Under vigorous stirring, by aliquot carboxyvinyl polymer is added in the Tegosept E and citric acid solution in 20ml distilled water, and solution is placed 10-12h.Under agitation be added in the sodium hydroxide in the 1ml distilled water then, sorbitol aqueous solution, and finally add the ethanol raspberry flavour.In carrier, press aliquot adding activeconstituents and use the dipping refiner to suspend.With distilled water this suspension agent is added to required final volume at last, and should cross colloidal grinding equipment by the suspension syrup.
E) suppository:
To each suppository, with formula (I) activeconstituents of 0.01-15% and the lactose thorough mixing of 1-20%, then animal tallow before the suppository of 50-95% (adeps pro suppository) (for example Witepsol 4) is melted and be cooled to 35 ℃, mix therein with the mixture of homogenizer with activeconstituents and lactose.With gained mixture cooling mold.
F) lyophilized powder ampoule composition:
Make 5% N.F,USP MANNITOL or lactose solution with the injection distilled water, this solution is filtered to obtain sterile solution.The solution of 0.01-5% formula (I) activeconstituents is also made with the injection distilled water, and this solution is filtered to obtain sterile solution.Under aseptic condition, these two kinds of solution are mixed, partly pack in the ampoule with 1ml, with the freeze-drying of ampoule content, and with ampoule at the nitrogen lower seal.Before using, with the ampoule contents melting in the aseptic sodium chloride aqueous solution of sterilized water or 0.9% (physiological).
Claims (17)
1. formula (I) compound:
Wherein
The X representative is selected from following group: CO, SO, SO
2
The Y representative is selected from following group: O, OCH
2, (CH
2)
n, NH, NHCH
2
N is the integer of 0-2;
R
1Be optional substituted alkyl, cycloalkyl, phenyl, xenyl, heterocyclic radical;
R
2Be optional substituted phenyl, heterocyclic radical or NR
3R
4Group, wherein R
3And R
4Be independently selected from hydrogen, alkyl, or R
3And R
4Can form optional substituted C with their bonded N atoms
5-7Heterocyclic radical, it contains the heteroatoms of one or more N of being selected from, O, S,
And/or its tautomer and/or salt and/or hydrate and/or solvate.
2. be selected from following compound
2-(4-chloro-benzenesulfonyl)-3-(4-chloro-phenyl)-7H-thieno-[2,3-b] pyridine-6-ketone,
3-[3-(4-chloro-phenyl)-6-oxygen-6,7-dihydro-thieno-[2,3-b] pyridine-2-sulfuryl base]-benzonitrile,
3-(4-chloro-phenyl)-6-oxygen-6,7-dihydro-thieno-[2,3-b] pyridine-2-formic acid 4-fluoro-benzyl ester,
3-(4-chloro-phenyl)-2-(Toluene-3,4-dithiol-alkylsulfonyl)-7H-thieno-[2,3-b] pyridine-6-ketone,
3-(4-chloro-phenyl)-2-(3-fluoro-4-methyl-benzenesulfonyl)-7H-thieno-[2,3-b] pyridine-6-ketone,
3-[3-(4-chloro-phenyl)-6-oxygen-6,7-dihydro-thieno-[2,3-b] pyridine-2-sulfuryl base]-5-fluoro-benzonitrile,
3-(4-chloro-phenyl)-2-(3-fluoro-benzenesulfonyl)-7H-thieno-[2,3-b] pyridine-6-ketone,
2-(4-chloro-benzenesulfonyl)-3-(4-methyl-piperidines-1-yl)-7H-thieno-[2,3-b] pyridine-6-ketone.
3. the method for preparation formula (I) compound and/or its tautomer and/or salt and/or hydrate and/or solvate
Wherein
The X representative is selected from following group: CO, SO, SO
2
The Y representative is selected from following group: O, OCH
2, (CH
2)
n, NH, NHCH
2
N is the integer of 0-2;
R
1Be optional substituted alkyl, cycloalkyl, phenyl, xenyl, heterocyclic radical;
R
2Be optional substituted phenyl, heterocyclic radical,
A. make the thienopyridine derivative of formula (II)
Wherein X, Y, R
1And R
2Implication such as toply defined by formula (I) compound,
React in solvent with metachloroperbenzoic acid or Peracetic Acid, to obtain formula (III) compound
Wherein X, Y, R
1And R
2Implication such as toply defined by formula (I) compound,
Formula (III) compound and trifluoroacetic anhydride or diacetyl oxide are reacted in dimethyl formamide, and after this production (I) compound forms tautomer and/or salt and/or the hydrate and/or the solvate of formula (I) compound alternatively, or
B. make the thienopyridine derivative of formula (IV)
Wherein X, Y and R
1Implication such as toply defined by formula (I)
React in solvent with metachloroperbenzoic acid or Peracetic Acid, to obtain the formula V compound
Wherein X, Y and R
1Implication such as toply defined coupling formula V compound and formula (VI) compound after this by formula (I)
R
2-B(OH)
2
(VI)
R wherein
2Be optional substituted phenyl or heterocyclic radical, to obtain formula (III) compound
Wherein X, Y, R
1And R
2Implication such as toply defined by formula (I)
With coupling formula (III) compound and trifluoroacetic anhydride or diacetyl oxide in dimethyl formamide,, after this form tautomer and/or salt and/or the hydrate and/or the solvate of formula (I) compound alternatively to obtain formula (I) compound.
4. the method for preparation formula (I) compound and/or its tautomer and/or salt and/or hydrate and/or solvate
Wherein
The X representative is selected from following group: CO, SO, SO
2
The Y representative is selected from following group: O, OCH
2, (CH
2)
n, NH, NHCH
2
N is the integer of 0-2;
R
1Be optional substituted alkyl, cycloalkyl, phenyl, xenyl, heterocyclic radical;
R
2Be optional substituted NR
3R
4Group, wherein R
3And R
4Be independently selected from hydrogen, alkyl, or R
3And R
4Can form optional substituted C with their bonded N atoms
5-7Heterocyclic radical, it contains the heteroatoms of one or more N of being selected from, O, S
Coupling formula V compound and formula (VII) compound in dimethyl formamide wherein
Wherein X, Y and R
1Implication such as toply defined by formula (I)
HNR
3R
4
(VII)
R wherein
3And R
4Be independently selected from hydrogen, alkyl, or R
3And R
4Can form optional substituted C with their bonded N atoms
5-7Heterocyclic radical, it contains the heteroatoms of one or more N of being selected from, O, S,
To obtain formula (III) compound
Wherein X, Y, R
1And R
2Implication such as toply defined by formula (I)
With in dimethyl formamide, make formula (II) compound and trifluoroacetic anhydride or acetic anhydride, to obtain formula (I) compound, after this form tautomer and/or salt and/or the hydrate and/or the solvate of formula (I) compound alternatively.
5. pharmaceutical preparation, it comprises formula (I) compound for the treatment of significant quantity:
Wherein
The X representative is selected from following group: CO, SO, SO
2
The Y representative is selected from following group: O, OCH
2, (CH
2)
n, NH, NHCH
2
N is the integer of 0-2;
R
1Be optional substituted alkyl, cycloalkyl, phenyl, xenyl, heterocyclic radical;
R
2Be optional substituted phenyl, heterocyclic radical, or NR
3R
4Group, wherein R
3And R
4Be independently selected from hydrogen, alkyl, or R
3And R
4Can form optional substituted C with their bonded N atoms
5-7Heterocyclic radical, it contains the heteroatoms of one or more N of being selected from, O, S,
And/or its tautomer and/or physiologically acceptable salt and/or hydrate and/or solvate, and one or more physiologically acceptable thinners, vehicle and/or inert support.
6. according to the pharmaceutical composition of claim 5, it is used to prevent and/or treat mG1uR1 and the receptor-mediated illness of mG1uR5.
7. formula (I) compound and/or its tautomer and/or physiologically acceptable salt and/or hydrate and/or the solvate purposes that is used to produce medicine:
Wherein
The X representative is selected from following group: CO, SO, SO
2
The Y representative is selected from following group: O, OCH
2, (CH
2)
n, NH, NHCH
2
N is the integer of 0-2;
R
1Be optional substituted alkyl, cycloalkyl, phenyl, xenyl, heterocyclic radical;
R
2Be optional substituted phenyl, heterocyclic radical, or NR
3R
4Group, wherein R
3And R
4Be independently selected from hydrogen, alkyl, or R
3And R
4Can form optional substituted C with their bonded N atoms
5-7Heterocyclic radical, it contains the heteroatoms of one or more N of being selected from, O, S,
Described medicine is used for the treatment of and/or prevents mG1uR1 and the receptor-mediated illness of mG1uR5.
8. according to the purposes of the compound of claim 7, the receptor-mediated illness of wherein said mG1uR1 and mG1uR5 is a psychiatric disorders.
9. according to the purposes of the compound of claim 7, the receptor-mediated illness of wherein said mG1uR1 and mG1uR5 is a neurological disorder.
10. according to the purposes of the compound of claim 7, the receptor-mediated illness of wherein said mG1uR1 and mG1uR5 is chronic and acute pain.
11. according to the purposes of the compound of claim 7, the receptor-mediated illness of wherein said mG1uR1 and mG1uR5 is the neuromuscular dysfunction and the disorder of gastrointestinal tract of lower urinary tract.
12. prevent and/or treat the method for mG1uR1 and the receptor-mediated illness of mG1uR5, it comprises formula (I) compound to the such administration that the prevents and/or treats treatment significant quantity of needs:
Wherein
The X representative is selected from following group: CO, SO, SO
2
The Y representative is selected from following group: O, OCH
2, (CH
2)
n, NH, NHCH
2
N is the integer of 0-2;
R
1Be optional substituted alkyl, cycloalkyl, phenyl, xenyl, heterocyclic radical;
R
2Be optional substituted phenyl, heterocyclic radical, or NR
3R
4Group, wherein R
3And R
4Be independently selected from hydrogen, alkyl, or R
3And R
4Can form optional substituted C with their bonded N atoms
5-7Heterocyclic radical, it contains the heteroatoms of one or more N of being selected from, O, S,
And/or its tautomer and/or physiologically acceptable salt and/or hydrate and/or solvate.
13. according to the method for claim 12, wherein said Mammals is the people.
14. according to the method for claim 12, the receptor-mediated illness of wherein said mG1uR1 and mG1uR5 is a psychiatric disorders.
15. according to the method for claim 12, the receptor-mediated illness of wherein said mG1uR1 and mG1uR5 is a neurological disorder.
16. according to the method for claim 12, the receptor-mediated illness of wherein said mG1uR1 and mG1uR5 is chronic and the acute pain illness.
17. according to the method for claim 12, the receptor-mediated illness of wherein said mG1uR1 and mG1uR5 is the neuromuscular dysfunction and the disorder of gastrointestinal tract of lower urinary tract.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HUP0501166 | 2005-12-20 | ||
| HU0501166A HU0501166D0 (en) | 2005-12-20 | 2005-12-20 | New compounds |
| HUP0600919 | 2006-12-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101341153A true CN101341153A (en) | 2009-01-07 |
Family
ID=89986465
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006800481946A Pending CN101341153A (en) | 2005-12-20 | 2006-12-19 | New compounds |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN101341153A (en) |
| HU (1) | HU0501166D0 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111909181A (en) * | 2019-05-09 | 2020-11-10 | 北京普济远成生物科技有限公司 | Ubiquitination specific protease inhibitor and preparation method and application thereof |
-
2005
- 2005-12-20 HU HU0501166A patent/HU0501166D0/en unknown
-
2006
- 2006-12-19 CN CNA2006800481946A patent/CN101341153A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111909181A (en) * | 2019-05-09 | 2020-11-10 | 北京普济远成生物科技有限公司 | Ubiquitination specific protease inhibitor and preparation method and application thereof |
| WO2020224652A1 (en) * | 2019-05-09 | 2020-11-12 | 北京普济远成生物科技有限公司 | Ubiquitin-specific protease inhibitors, and preparation method therefor and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| HU0501166D0 (en) | 2006-02-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102977086B (en) | Oxadiazole derivatives and their use as metabotropic glutamate receptor potentiators - 842 | |
| JP6232418B2 (en) | Substituted pyrazoloquinazolinones and pyrroloquinazolinones as allosteric modulators of group II metabotropic glutamate receptors | |
| JP5201817B2 (en) | Pharmaceutical composition | |
| CN102574842B (en) | Pyridinyl-imidazolone derivatives for inhibiting pi3 kinases | |
| EP2350049A2 (en) | P38 map kinase inhibitors | |
| BRPI0619407A2 (en) | pyridiazinone derivatives for the treatment of tumors | |
| CN104470902A (en) | N-(3-heteroarylaryl)-4-arylarylcarboxamtdes and analogs as hedgehog pathway inhibitors and use thereof | |
| CN102066342A (en) | Quinoxalinedione derivatives | |
| BRPI0616999A2 (en) | 1-acyl dihydroazole derivatives | |
| WO2005035526A1 (en) | Bicyclic compounds and their therapeutic use | |
| CN101730684B (en) | Sulfonyl-quinoline derivatives | |
| CA2792918A1 (en) | Benzazepine compound | |
| CN101346385A (en) | New compounds | |
| CN101341154A (en) | Thienopyridine derivatives as modulators of metabotropic glutamate receptors | |
| CN101341153A (en) | New compounds | |
| KR20200083448A (en) | Aromatic derivatives, methods for their preparation and medical applications thereof | |
| US20090149495A1 (en) | Compounds | |
| CN101341152A (en) | New compounds | |
| CN117285484A (en) | Benzothiadiazine 1, 1-dioxide compounds inhibiting HDAC6 enzyme, preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20090107 |