SA07280518B1 - معدلات المستقبل 5 للجلوتامات ذات الانتحاء الأيضي - Google Patents

Info

Publication number

SA07280518B1

SA07280518B1 SA07280518A SA07280518A SA07280518B1 SA 07280518 B1 SA07280518 B1 SA 07280518B1 SA 07280518 A SA07280518 A SA 07280518A SA 07280518 A SA07280518 A SA 07280518A SA 07280518 B1 SA07280518 B1 SA 07280518B1

Authority

SA

Saudi Arabia

Prior art keywords

compound

methyl

mmol

triazol

mhz

Prior art date

2006-10-05

Links

• Espacenet
• Global Dossier
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• 150000001875 compounds Chemical class 0.000 claims abstract description 203
• 150000003839 salts Chemical class 0.000 claims description 34
• -1 triazol -3-yl Chemical group 0.000 claims description 33
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 22
• 229910052739 hydrogen Inorganic materials 0.000 claims description 17
• 239000001257 hydrogen Substances 0.000 claims description 16
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
• 210000000111 lower esophageal sphincter Anatomy 0.000 claims description 14
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
• 239000003814 drug Substances 0.000 claims description 12
• 229940079593 drug Drugs 0.000 claims description 10
• AAILEWXSEQLMNI-UHFFFAOYSA-N 1h-pyridazin-6-one Chemical compound OC1=CC=CN=N1 AAILEWXSEQLMNI-UHFFFAOYSA-N 0.000 claims description 9
• 239000008194 pharmaceutical composition Substances 0.000 claims description 9
• 208000002193 Pain Diseases 0.000 claims description 8
• 239000004480 active ingredient Substances 0.000 claims description 8
• 208000021302 gastroesophageal reflux disease Diseases 0.000 claims description 8
• 238000004519 manufacturing process Methods 0.000 claims description 8
• 230000036407 pain Effects 0.000 claims description 7
• 125000004284 isoxazol-3-yl group Chemical group [H]C1=C([H])C(*)=NO1 0.000 claims description 5
• 230000001225 therapeutic effect Effects 0.000 claims description 4
• 208000019901 Anxiety disease Diseases 0.000 claims description 3
• 230000036506 anxiety Effects 0.000 claims description 3
• 208000002551 irritable bowel syndrome Diseases 0.000 claims description 3
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
• 230000003287 optical effect Effects 0.000 claims description 2
• 125000001305 1,2,4-triazol-3-yl group Chemical group [H]N1N=C([*])N=C1[H] 0.000 claims 4
• YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 claims 1
• WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 abstract description 13
• 229930195712 glutamate Natural products 0.000 abstract description 13
• 230000002503 metabolic effect Effects 0.000 abstract description 3
• OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 106
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 102
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 87
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 80
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 74
• 238000005481 NMR spectroscopy Methods 0.000 description 72
• 239000000203 mixture Substances 0.000 description 61
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 58
• 238000006243 chemical reaction Methods 0.000 description 57
• 239000000243 solution Substances 0.000 description 56
• 239000007787 solid Substances 0.000 description 49
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 41
• 239000011541 reaction mixture Substances 0.000 description 39
• 238000000034 method Methods 0.000 description 37
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
• 239000002904 solvent Substances 0.000 description 36
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
• 239000002253 acid Substances 0.000 description 33
• 235000019439 ethyl acetate Nutrition 0.000 description 33
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 30
• 239000000047 product Substances 0.000 description 28
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 27
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 25
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
• 238000003756 stirring Methods 0.000 description 24
• 239000000543 intermediate Substances 0.000 description 22
• 102000005962 receptors Human genes 0.000 description 22
• 108020003175 receptors Proteins 0.000 description 22
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 21
• 208000035475 disorder Diseases 0.000 description 21
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 20
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 20
• 125000000217 alkyl group Chemical group 0.000 description 19
• 229910052938 sodium sulfate Inorganic materials 0.000 description 19
• 235000011152 sodium sulphate Nutrition 0.000 description 19
• 210000004027 cell Anatomy 0.000 description 17
• 230000000694 effects Effects 0.000 description 17
• 239000000126 substance Substances 0.000 description 16
• 239000002585 base Substances 0.000 description 15
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
• 230000004913 activation Effects 0.000 description 14
• 238000007792 addition Methods 0.000 description 14
• 230000015572 biosynthetic process Effects 0.000 description 14
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 13
• 238000004440 column chromatography Methods 0.000 description 13
• 239000012043 crude product Substances 0.000 description 13
• 239000012044 organic layer Substances 0.000 description 13
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
• 238000003786 synthesis reaction Methods 0.000 description 12
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
• 239000003921 oil Substances 0.000 description 11
• 235000019198 oils Nutrition 0.000 description 11
• 208000020016 psychiatric disease Diseases 0.000 description 11
• 238000012360 testing method Methods 0.000 description 11
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
• 210000004556 brain Anatomy 0.000 description 10
• 239000000741 silica gel Substances 0.000 description 10
• 229910002027 silica gel Inorganic materials 0.000 description 10
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
• QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 9
• 239000012267 brine Substances 0.000 description 9
• 210000002569 neuron Anatomy 0.000 description 9
• 210000003169 central nervous system Anatomy 0.000 description 8
• 238000000605 extraction Methods 0.000 description 8
• 229910052736 halogen Inorganic materials 0.000 description 8
• 239000000463 material Substances 0.000 description 8
• 239000002244 precipitate Substances 0.000 description 8
• 230000008569 process Effects 0.000 description 8
• 230000009467 reduction Effects 0.000 description 8
• 238000010992 reflux Methods 0.000 description 8
• 239000011734 sodium Substances 0.000 description 8
• UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
• 239000012279 sodium borohydride Substances 0.000 description 8
• 229910000033 sodium borohydride Inorganic materials 0.000 description 8
• 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 7
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 7
• 208000012902 Nervous system disease Diseases 0.000 description 7
• 208000025966 Neurological disease Diseases 0.000 description 7
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
• 150000007513 acids Chemical class 0.000 description 7
• 230000003213 activating effect Effects 0.000 description 7
• 230000005284 excitation Effects 0.000 description 7
• 230000000926 neurological effect Effects 0.000 description 7
• 239000012074 organic phase Substances 0.000 description 7
• 229910000027 potassium carbonate Inorganic materials 0.000 description 7
• 238000002360 preparation method Methods 0.000 description 7
• 239000011780 sodium chloride Substances 0.000 description 7
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
• 108010027915 Glutamate Receptors Proteins 0.000 description 6
• 102000018899 Glutamate Receptors Human genes 0.000 description 6
• 239000007995 HEPES buffer Substances 0.000 description 6
• LGDSHSYDSCRFAB-UHFFFAOYSA-N Methyl isothiocyanate Chemical compound CN=C=S LGDSHSYDSCRFAB-UHFFFAOYSA-N 0.000 description 6
• CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 6
• QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 6
• 125000003545 alkoxy group Chemical group 0.000 description 6
• 125000003118 aryl group Chemical group 0.000 description 6
• 239000011575 calcium Substances 0.000 description 6
• 230000001684 chronic effect Effects 0.000 description 6
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
• 201000010099 disease Diseases 0.000 description 6
• 150000002148 esters Chemical class 0.000 description 6
• 238000002474 experimental method Methods 0.000 description 6
• 238000001914 filtration Methods 0.000 description 6
• 150000002367 halogens Chemical class 0.000 description 6
• 239000010410 layer Substances 0.000 description 6
• 150000002825 nitriles Chemical class 0.000 description 6
• 238000000746 purification Methods 0.000 description 6
• UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 6
• 230000004044 response Effects 0.000 description 6
• 229920006395 saturated elastomer Polymers 0.000 description 6
• 239000000377 silicon dioxide Substances 0.000 description 6
• 229910052708 sodium Inorganic materials 0.000 description 6
• FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 6
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
• OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 5
• CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 5
• 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 5
• 230000002378 acidificating effect Effects 0.000 description 5
• 230000029936 alkylation Effects 0.000 description 5
• 238000005804 alkylation reaction Methods 0.000 description 5
• 238000004458 analytical method Methods 0.000 description 5
• 239000007864 aqueous solution Substances 0.000 description 5
• 229910052791 calcium Inorganic materials 0.000 description 5
• 239000003638 chemical reducing agent Substances 0.000 description 5
• 125000000068 chlorophenyl group Chemical group 0.000 description 5
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
• 239000000706 filtrate Substances 0.000 description 5
• 238000009472 formulation Methods 0.000 description 5
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• 229960000367 inositol Drugs 0.000 description 5
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• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
• CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 5
• LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Substances [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 5
• 239000007858 starting material Substances 0.000 description 5
• 210000002784 stomach Anatomy 0.000 description 5
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• MTVWFVDWRVYDOR-UHFFFAOYSA-N 3,4-Dihydroxyphenylglycol Chemical compound OCC(O)C1=CC=C(O)C(O)=C1 MTVWFVDWRVYDOR-UHFFFAOYSA-N 0.000 description 4
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
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• 208000018522 Gastrointestinal disease Diseases 0.000 description 4
• SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 description 4
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• 241000124008 Mammalia Species 0.000 description 4
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• 229910019142 PO4 Inorganic materials 0.000 description 4
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• MMWCIQZXVOZEGG-HOZKJCLWSA-N [(1S,2R,3S,4S,5R,6S)-2,3,5-trihydroxy-4,6-diphosphonooxycyclohexyl] dihydrogen phosphate Chemical compound O[C@H]1[C@@H](O)[C@H](OP(O)(O)=O)[C@@H](OP(O)(O)=O)[C@H](O)[C@H]1OP(O)(O)=O MMWCIQZXVOZEGG-HOZKJCLWSA-N 0.000 description 4
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• 230000014509 gene expression Effects 0.000 description 4
• HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 description 4
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• 125000001188 haloalkyl group Chemical group 0.000 description 4
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• CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
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• 238000000844 transformation Methods 0.000 description 4
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• NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 3
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• NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 3
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• 208000019695 Migraine disease Diseases 0.000 description 3
• PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 3
• NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 3
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• 206010067171 Regurgitation Diseases 0.000 description 3
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
• OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 3
• WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 3
• 239000012346 acetyl chloride Substances 0.000 description 3
• 150000001408 amides Chemical class 0.000 description 3
• 150000001412 amines Chemical class 0.000 description 3
• 229910021529 ammonia Inorganic materials 0.000 description 3
• 150000008064 anhydrides Chemical class 0.000 description 3
• 125000001246 bromo group Chemical group Br* 0.000 description 3
• 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
• 230000000747 cardiac effect Effects 0.000 description 3
• 239000003795 chemical substances by application Substances 0.000 description 3
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