EA038090B1 - Ингибиторы magl - Google Patents

Info

Publication number

EA038090B1

EA038090B1 EA201991073A EA201991073A EA038090B1 EA 038090 B1 EA038090 B1 EA 038090B1 EA 201991073 A EA201991073 A EA 201991073A EA 201991073 A EA201991073 A EA 201991073A EA 038090 B1 EA038090 B1 EA 038090B1

Authority

EA

Eurasian Patent Office

Prior art keywords

pharmaceutically acceptable

compound

formula

acceptable salt

solvate

Prior art date

2016-11-16

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• 239000003112 inhibitor Substances 0.000 title description 5
• 150000001875 compounds Chemical class 0.000 claims abstract description 669
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 26
• 208000002193 Pain Diseases 0.000 claims abstract description 25
• 238000011282 treatment Methods 0.000 claims abstract description 15
• 150000003839 salts Chemical class 0.000 claims description 618
• 125000000217 alkyl group Chemical group 0.000 claims description 111
• 229910052736 halogen Inorganic materials 0.000 claims description 106
• 150000002367 halogens Chemical class 0.000 claims description 104
• 229910052739 hydrogen Inorganic materials 0.000 claims description 32
• 229910052799 carbon Inorganic materials 0.000 claims description 30
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 18
• 206010015037 epilepsy Diseases 0.000 claims description 14
• 201000006417 multiple sclerosis Diseases 0.000 claims description 10
• 125000001188 haloalkyl group Chemical group 0.000 claims description 9
• 208000024827 Alzheimer disease Diseases 0.000 claims description 7
• 208000004998 Abdominal Pain Diseases 0.000 claims description 6
• 208000002551 irritable bowel syndrome Diseases 0.000 claims description 6
• 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims description 5
• 239000000203 mixture Substances 0.000 abstract description 89
• 102100029814 Monoglyceride lipase Human genes 0.000 abstract description 3
• CWPIBZMCMRNFHK-UHFFFAOYSA-N piperazin-1-ium;carbamate Chemical class NC(O)=O.C1CNCCN1 CWPIBZMCMRNFHK-UHFFFAOYSA-N 0.000 abstract description 2
• 101710116393 Monoglyceride lipase Proteins 0.000 abstract 1
• 235000002639 sodium chloride Nutrition 0.000 description 614
• 239000012453 solvate Substances 0.000 description 568
• -1 -CN radical Chemical class 0.000 description 226
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 168
• 239000000243 solution Substances 0.000 description 146
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 103
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 97
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 86
• 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 85
• 238000000034 method Methods 0.000 description 85
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 82
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 80
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 74
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• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 61
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• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 36
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• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 22
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• 125000000592 heterocycloalkyl group Chemical group 0.000 description 22
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• 239000012043 crude product Substances 0.000 description 21
• 229910052757 nitrogen Inorganic materials 0.000 description 21
• 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 21
• 239000000126 substance Substances 0.000 description 21
• 201000010099 disease Diseases 0.000 description 20
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 20
• ZMXDDKWLCZADIW-UHFFFAOYSA-N Vilsmeier-Haack reagent Natural products CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 19
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 19
• 229940124597 therapeutic agent Drugs 0.000 description 19
• 125000002947 alkylene group Chemical group 0.000 description 18
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
• 125000003710 aryl alkyl group Chemical group 0.000 description 17
• 239000012299 nitrogen atmosphere Substances 0.000 description 17
• 239000001257 hydrogen Substances 0.000 description 15
• RFIOZSIHFNEKFF-UHFFFAOYSA-M piperazine-1-carboxylate Chemical compound [O-]C(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-M 0.000 description 15
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 14
• 125000003709 fluoroalkyl group Chemical group 0.000 description 14
• 239000012321 sodium triacetoxyborohydride Substances 0.000 description 14
• 238000005160 1H NMR spectroscopy Methods 0.000 description 13
• 125000004446 heteroarylalkyl group Chemical group 0.000 description 13
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 13
• 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 13
• 239000003208 petroleum Substances 0.000 description 13
• UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 13
• DHMQDGOQFOQNFH-UHFFFAOYSA-M Aminoacetate Chemical compound NCC([O-])=O DHMQDGOQFOQNFH-UHFFFAOYSA-M 0.000 description 12
• OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 12
• 102000005398 Monoacylglycerol Lipase Human genes 0.000 description 12
• 108020002334 Monoacylglycerol lipase Proteins 0.000 description 12
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
• FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 11
• 229910000024 caesium carbonate Inorganic materials 0.000 description 11
• 229920002301 cellulose acetate Polymers 0.000 description 11
• YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 description 11
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• 125000004122 cyclic group Chemical group 0.000 description 10
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• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 8
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• 235000011181 potassium carbonates Nutrition 0.000 description 8
• SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 description 8
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