EA038150B1 - Ингибиторы magl - Google Patents
Ингибиторы magl Download PDFInfo
- Publication number
- EA038150B1 EA038150B1 EA201991029A EA201991029A EA038150B1 EA 038150 B1 EA038150 B1 EA 038150B1 EA 201991029 A EA201991029 A EA 201991029A EA 201991029 A EA201991029 A EA 201991029A EA 038150 B1 EA038150 B1 EA 038150B1
- Authority
- EA
- Eurasian Patent Office
- Prior art keywords
- pharmaceutically acceptable
- acceptable salt
- formula
- compound
- solvate
- Prior art date
Links
- 239000003112 inhibitor Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 1108
- 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 17
- 150000003839 salts Chemical class 0.000 claims description 1053
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 233
- 125000000217 alkyl group Chemical group 0.000 claims description 198
- 229910052736 halogen Inorganic materials 0.000 claims description 130
- 150000002367 halogens Chemical class 0.000 claims description 128
- 229910052799 carbon Inorganic materials 0.000 claims description 116
- 229910052739 hydrogen Inorganic materials 0.000 claims description 113
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 111
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 20
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 19
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 14
- 206010015037 epilepsy Diseases 0.000 claims description 14
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 13
- 229910052731 fluorine Inorganic materials 0.000 claims description 12
- 201000006417 multiple sclerosis Diseases 0.000 claims description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
- 208000024827 Alzheimer disease Diseases 0.000 claims description 7
- 208000002551 irritable bowel syndrome Diseases 0.000 claims description 6
- 208000004998 Abdominal Pain Diseases 0.000 claims description 5
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims description 5
- 125000001188 haloalkyl group Chemical group 0.000 claims description 5
- -1 bicyclic carbamates Chemical class 0.000 abstract description 163
- 239000000203 mixture Substances 0.000 abstract description 76
- 102100029814 Monoglyceride lipase Human genes 0.000 abstract 1
- 101710116393 Monoglyceride lipase Proteins 0.000 abstract 1
- 235000002639 sodium chloride Nutrition 0.000 description 1036
- 239000012453 solvate Substances 0.000 description 974
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 112
- 238000000034 method Methods 0.000 description 87
- 239000000243 solution Substances 0.000 description 84
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 50
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 43
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 37
- 125000001072 heteroaryl group Chemical group 0.000 description 36
- 125000000753 cycloalkyl group Chemical group 0.000 description 35
- 239000007787 solid Substances 0.000 description 34
- 125000004093 cyano group Chemical group *C#N 0.000 description 33
- 239000003921 oil Substances 0.000 description 32
- 235000019198 oils Nutrition 0.000 description 32
- 238000003786 synthesis reaction Methods 0.000 description 31
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 30
- 125000003118 aryl group Chemical group 0.000 description 30
- 239000012267 brine Substances 0.000 description 30
- 125000004432 carbon atom Chemical group C* 0.000 description 30
- 239000012044 organic layer Substances 0.000 description 30
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 30
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 27
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 27
- 239000000741 silica gel Substances 0.000 description 27
- 229910002027 silica gel Inorganic materials 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
- 230000015572 biosynthetic process Effects 0.000 description 26
- 239000003814 drug Substances 0.000 description 26
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 25
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- 150000003254 radicals Chemical class 0.000 description 24
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 21
- 201000010099 disease Diseases 0.000 description 21
- 239000000126 substance Substances 0.000 description 21
- 230000002829 reductive effect Effects 0.000 description 20
- 229940124597 therapeutic agent Drugs 0.000 description 20
- 235000019439 ethyl acetate Nutrition 0.000 description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N Vilsmeier-Haack reagent Natural products CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- 239000002253 acid Substances 0.000 description 18
- 125000003545 alkoxy group Chemical group 0.000 description 18
- 125000002947 alkylene group Chemical group 0.000 description 18
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 17
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 17
- 125000003710 aryl alkyl group Chemical group 0.000 description 16
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 16
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 15
- 125000003709 fluoroalkyl group Chemical group 0.000 description 14
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 13
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 239000012043 crude product Substances 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 238000002953 preparative HPLC Methods 0.000 description 12
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 description 11
- 125000004450 alkenylene group Chemical group 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 11
- 239000000651 prodrug Substances 0.000 description 11
- 229940002612 prodrug Drugs 0.000 description 11
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- YRCGAHTZOXPQPR-UHFFFAOYSA-N 2-ethylnonanoic acid Chemical compound CCCCCCCC(CC)C(O)=O YRCGAHTZOXPQPR-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 102000005398 Monoacylglycerol Lipase Human genes 0.000 description 10
- 108020002334 Monoacylglycerol lipase Proteins 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 125000004122 cyclic group Chemical group 0.000 description 10
- 239000003937 drug carrier Substances 0.000 description 10
- 239000001257 hydrogen Substances 0.000 description 10
- 239000003208 petroleum Substances 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- 125000001424 substituent group Chemical group 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
- 125000003342 alkenyl group Chemical group 0.000 description 9
- 125000000304 alkynyl group Chemical group 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 8
- 239000000443 aerosol Substances 0.000 description 8
- 239000012299 nitrogen atmosphere Substances 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 7
- 125000004429 atom Chemical group 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 239000002775 capsule Substances 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 7
- 229920001223 polyethylene glycol Polymers 0.000 description 7
- 125000003107 substituted aryl group Chemical group 0.000 description 7
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 229960003767 alanine Drugs 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 229920002301 cellulose acetate Polymers 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 208000035475 disorder Diseases 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 150000002430 hydrocarbons Chemical group 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 125000004043 oxo group Chemical group O=* 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 description 5
- YHYNJGHMBMXAFB-UHFFFAOYSA-N 2-hydroxy-4-(trifluoromethyl)benzaldehyde Chemical compound OC1=CC(C(F)(F)F)=CC=C1C=O YHYNJGHMBMXAFB-UHFFFAOYSA-N 0.000 description 5
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 5
- 230000008901 benefit Effects 0.000 description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 125000005843 halogen group Chemical group 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- 125000000449 nitro group Chemical class [O-][N+](*)=O 0.000 description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 5
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- 230000001225 therapeutic effect Effects 0.000 description 5
- RCRCTBLIHCHWDZ-UHFFFAOYSA-N 2-Arachidonoyl Glycerol Chemical compound CCCCCC=CCC=CCC=CCC=CCCCC(=O)OC(CO)CO RCRCTBLIHCHWDZ-UHFFFAOYSA-N 0.000 description 4
- KFEHNXLFIGPWNB-UHFFFAOYSA-N 2-fluoro-4-(trifluoromethyl)benzaldehyde Chemical compound FC1=CC(C(F)(F)F)=CC=C1C=O KFEHNXLFIGPWNB-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 239000004471 Glycine Substances 0.000 description 4
- 206010065390 Inflammatory pain Diseases 0.000 description 4
- 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 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 125000004103 aminoalkyl group Chemical group 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000002648 combination therapy Methods 0.000 description 4
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- 229960002449 glycine Drugs 0.000 description 4
- 150000004677 hydrates Chemical class 0.000 description 4
- 125000001841 imino group Chemical group [H]N=* 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000000014 opioid analgesic Substances 0.000 description 4
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- UZPDXRXHTUSGLN-UHFFFAOYSA-N tert-butyl 1,8-diazaspiro[4.5]decane-8-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC11NCCC1 UZPDXRXHTUSGLN-UHFFFAOYSA-N 0.000 description 4
- DIIGJZHDCJAJCG-UHFFFAOYSA-N tert-butyl 4-[(4-methoxyphenyl)methylamino]butanoate Chemical compound COC1=CC=C(CNCCCC(=O)OC(C)(C)C)C=C1 DIIGJZHDCJAJCG-UHFFFAOYSA-N 0.000 description 4
- HSIRURABHBKFCM-UHFFFAOYSA-N 1-[2-(1,8-diazaspiro[4.5]decan-1-ylmethyl)-5-(trifluoromethyl)phenoxy]cyclopropane-1-carboxylic acid Chemical compound OC(=O)C1(CC1)OC1=C(CN2CCCC22CCNCC2)C=CC(=C1)C(F)(F)F HSIRURABHBKFCM-UHFFFAOYSA-N 0.000 description 3
- NWPRXAOLRJDQKS-UHFFFAOYSA-N 1-[2-[[8-[(2-methylpropan-2-yl)oxycarbonyl]-1,8-diazaspiro[4.5]decan-1-yl]methyl]-5-(trifluoromethyl)phenoxy]cyclopropane-1-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC2(CCCN2CC2=C(OC3(CC3)C(O)=O)C=C(C=C2)C(F)(F)F)CC1 NWPRXAOLRJDQKS-UHFFFAOYSA-N 0.000 description 3
- TYGNEUATMXTBOD-UHFFFAOYSA-N 1-[[5-chloro-2-(1,8-diazaspiro[4.5]decan-1-ylmethyl)phenoxy]methyl]cyclopropane-1-carboxylic acid Chemical compound OC(=O)C1(COC2=C(CN3CCCC33CCNCC3)C=CC(Cl)=C2)CC1 TYGNEUATMXTBOD-UHFFFAOYSA-N 0.000 description 3
- YMKVIHDYYRNJIO-UHFFFAOYSA-N 1-[[5-chloro-2-[[8-[(2-methylpropan-2-yl)oxycarbonyl]-1,8-diazaspiro[4.5]decan-1-yl]methyl]phenoxy]methyl]cyclopropane-1-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC2(CCCN2CC2=C(OCC3(CC3)C(O)=O)C=C(Cl)C=C2)CC1 YMKVIHDYYRNJIO-UHFFFAOYSA-N 0.000 description 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 3
- LMKCZFZHUCIRSZ-UHFFFAOYSA-N 2-[2-[[8-(1,1,1,3,3,3-hexafluoropropan-2-yloxycarbonyl)-1,8-diazaspiro[4.5]decan-1-yl]methyl]-5-(trifluoromethyl)phenoxy]acetic acid Chemical compound OC(=O)COC1=C(CN2CCCC22CCN(CC2)C(=O)OC(C(F)(F)F)C(F)(F)F)C=CC(=C1)C(F)(F)F LMKCZFZHUCIRSZ-UHFFFAOYSA-N 0.000 description 3
- KDTYZMOQCIVOQR-UHFFFAOYSA-N 2-[5-chloro-2-[[8-(1,1,1,3,3,3-hexafluoropropan-2-yloxycarbonyl)-1,8-diazaspiro[4.5]decan-1-yl]methyl]phenoxy]acetic acid Chemical compound OC(=O)COC1=C(CN2CCCC22CCN(CC2)C(=O)OC(C(F)(F)F)C(F)(F)F)C=CC(Cl)=C1 KDTYZMOQCIVOQR-UHFFFAOYSA-N 0.000 description 3
- IVLXQGJVBGMLRR-UHFFFAOYSA-N 2-aminoacetic acid;hydron;chloride Chemical compound Cl.NCC(O)=O IVLXQGJVBGMLRR-UHFFFAOYSA-N 0.000 description 3
- GFGOCSDIXPMYOL-UHFFFAOYSA-N 4-[3-[[8-(1,1,1,3,3,3-hexafluoropropan-2-yloxycarbonyl)-1,8-diazaspiro[4.5]decan-1-yl]methyl]-5-(trifluoromethyl)phenoxy]cyclohexane-1-carboxylic acid Chemical compound FC(C(C(F)(F)F)OC(=O)N1CCC2(CCCN2CC=2C=C(OC3CCC(CC3)C(=O)O)C=C(C=2)C(F)(F)F)CC1)(F)F GFGOCSDIXPMYOL-UHFFFAOYSA-N 0.000 description 3
- QVXSNELBIYNOOW-UHFFFAOYSA-N 4-[3-[[8-[(2-methylpropan-2-yl)oxycarbonyl]-1,8-diazaspiro[4.5]decan-1-yl]methyl]-5-(trifluoromethyl)phenoxy]cyclohexane-1-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC2(CCCN2CC2=CC(=CC(OC3CCC(CC3)C(O)=O)=C2)C(F)(F)F)CC1 QVXSNELBIYNOOW-UHFFFAOYSA-N 0.000 description 3
- RVIFSUKXMMTGPT-UHFFFAOYSA-N 4-[5-chloro-2-[[8-(1,1,1,3,3,3-hexafluoropropan-2-yloxycarbonyl)-1,8-diazaspiro[4.5]decan-1-yl]methyl]phenoxy]butanoic acid Chemical compound OC(=O)CCCOC1=C(CN2CCCC22CCN(CC2)C(=O)OC(C(F)(F)F)C(F)(F)F)C=CC(Cl)=C1 RVIFSUKXMMTGPT-UHFFFAOYSA-N 0.000 description 3
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- BMBYFGXPDKSVLM-UHFFFAOYSA-N tert-butyl 1-[[3-(4-ethoxycarbonylcyclohexyl)oxy-5-(trifluoromethyl)phenyl]methyl]-1,8-diazaspiro[4.5]decane-8-carboxylate Chemical compound CCOC(=O)C1CCC(CC1)Oc1cc(CN2CCCC22CCN(CC2)C(=O)OC(C)(C)C)cc(c1)C(F)(F)F BMBYFGXPDKSVLM-UHFFFAOYSA-N 0.000 description 1
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- KHPCPRHQVVSZAH-UHFFFAOYSA-N trans-cinnamyl beta-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OCC=CC1=CC=CC=C1 KHPCPRHQVVSZAH-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201662423102P | 2016-11-16 | 2016-11-16 | |
| PCT/US2017/061870 WO2018093949A1 (en) | 2016-11-16 | 2017-11-15 | Magl inhibitors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EA201991029A1 EA201991029A1 (ru) | 2019-12-30 |
| EA038150B1 true EA038150B1 (ru) | 2021-07-14 |
Family
ID=62145825
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EA201991029A EA038150B1 (ru) | 2016-11-16 | 2017-11-15 | Ингибиторы magl |
Country Status (27)
| Country | Link |
|---|---|
| US (2) | US11059822B2 (enExample) |
| EP (1) | EP3541820B1 (enExample) |
| JP (1) | JP7042468B2 (enExample) |
| KR (1) | KR20190080935A (enExample) |
| CN (1) | CN110267962B (enExample) |
| AU (1) | AU2017361253B2 (enExample) |
| BR (1) | BR112019009880A2 (enExample) |
| CA (1) | CA3043617A1 (enExample) |
| CL (1) | CL2019001336A1 (enExample) |
| CO (1) | CO2019004945A2 (enExample) |
| CR (1) | CR20190239A (enExample) |
| DO (1) | DOP2019000118A (enExample) |
| EA (1) | EA038150B1 (enExample) |
| EC (1) | ECSP19034535A (enExample) |
| ES (1) | ES2952582T3 (enExample) |
| IL (1) | IL266547B (enExample) |
| JO (1) | JOP20190107A1 (enExample) |
| MA (1) | MA46855A (enExample) |
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| US10781211B2 (en) | 2016-05-12 | 2020-09-22 | Lundbeck La Jolla Research Center, Inc. | Spirocycle compounds and methods of making and using same |
| CN110290791A (zh) | 2016-11-16 | 2019-09-27 | 灵北拉荷亚研究中心公司 | 药物制剂 |
| JOP20190105A1 (ar) * | 2016-11-16 | 2019-05-09 | Lundbeck La Jolla Research Center Inc | مثبطات أحادي أسيل جليسرول ليباز (magl) |
| JOP20190107A1 (ar) | 2016-11-16 | 2019-05-09 | Lundbeck La Jolla Research Center Inc | مثبطات أحادي أسيل جليسرول ليباز (magl) |
| EP3541807B1 (en) | 2016-11-16 | 2021-09-29 | H. Lundbeck A/S | A crystalline form of a magl inhibitor |
| RS64006B1 (sr) | 2017-05-23 | 2023-03-31 | H Lundbeck As | Pirazol magl inhibitori |
| US10927105B1 (en) | 2017-05-23 | 2021-02-23 | Lundbeck La Jolla Research Center, Inc. | Pyrazole MAGL inhibitors |
| ES2914363T3 (es) | 2017-08-29 | 2022-06-09 | H Lundbeck As | Compuestos espirocíclicos y métodos para su preparación y uso |
| MA50041A (fr) | 2017-08-29 | 2020-07-08 | Lundbeck La Jolla Research Center Inc | Composés spirocycliques et procédés de préparation et d'utilisation de ceux-ci |
| EP3823723A1 (en) * | 2018-07-19 | 2021-05-26 | Pfizer Inc. | Heterocyclic spiro compounds as magl inhibitors |
| HRP20241201T1 (hr) | 2018-08-13 | 2024-11-22 | F. Hoffmann - La Roche Ag | Novi heterociklički spojevi kao inhibitori monoacilglicerol lipaze |
| WO2021214550A1 (en) | 2020-04-21 | 2021-10-28 | H. Lundbeck A/S | Synthesis of a monoacylglycerol lipase inhibitor |
| UY39516A (es) | 2020-11-13 | 2022-05-31 | H Lundbeck As | Composición para el tratamiento de una enfermedad vascular, composición para la prevención de una enfermedad vascular, composición para el tratamiento de la hipertensión, y composición para la prevención de la hipertensión |
| WO2023130023A1 (en) | 2021-12-29 | 2023-07-06 | Psy Therapeutics, Inc. | Inhibiting monoacylglycerol lipase (magl) |
| US12378219B2 (en) | 2022-05-04 | 2025-08-05 | H. Lundbeck A/S | Crystalline forms of a MAGL inhibitor |
| WO2024168426A1 (en) | 2023-02-13 | 2024-08-22 | Apogee Pharmaceuticals, Inc. | Small molecules as monoacylglycerol lipase (magl) inhibitors, compositions and use thereof |
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2019
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