EA010583B1 - Производные азетидинкарбоксамида и их применение при лечении нарушений, опосредованных св1 рецепторами - Google Patents

Info

Publication number

EA010583B1

EA010583B1 EA200501585A EA200501585A EA010583B1 EA 010583 B1 EA010583 B1 EA 010583B1 EA 200501585 A EA200501585 A EA 200501585A EA 200501585 A EA200501585 A EA 200501585A EA 010583 B1 EA010583 B1 EA 010583B1

Authority

EA

Eurasian Patent Office

Prior art keywords

azetidine

carboxamide

trifluoromethyl

compound

butyl

Prior art date

2003-05-01

Links

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• Global Dossier
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• 238000011282 treatment Methods 0.000 title claims abstract description 37
• PVXOUGHWLCBJOW-UHFFFAOYSA-N azetidine-1-carboxamide Chemical class NC(=O)N1CCC1 PVXOUGHWLCBJOW-UHFFFAOYSA-N 0.000 title claims description 129
• 230000001404 mediated effect Effects 0.000 title abstract description 8
• 102000005962 receptors Human genes 0.000 title description 15
• 108020003175 receptors Proteins 0.000 title description 15
• 150000001875 compounds Chemical class 0.000 claims abstract description 386
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 62
• 125000003118 aryl group Chemical group 0.000 claims abstract description 23
• 208000008589 Obesity Diseases 0.000 claims abstract description 21
• 235000020824 obesity Nutrition 0.000 claims abstract description 21
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 19
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 14
• 239000001257 hydrogen Substances 0.000 claims abstract description 13
• 150000003839 salts Chemical class 0.000 claims abstract description 13
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 9
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 5
• -1 2,4,4'-trichlorobenzhydryloxy Chemical group 0.000 claims description 316
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 221
• DBJVTHJNBWQMKQ-UHFFFAOYSA-N N-tert-butylazetidine-1-carboxamide Chemical compound CC(C)(C)NC(=O)N1CCC1 DBJVTHJNBWQMKQ-UHFFFAOYSA-N 0.000 claims description 115
• 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 22
• 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 21
• 229920006395 saturated elastomer Polymers 0.000 claims description 20
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 18
• 125000001072 heteroaryl group Chemical group 0.000 claims description 17
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 17
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
• 125000005842 heteroatom Chemical group 0.000 claims description 15
• 125000003545 alkoxy group Chemical group 0.000 claims description 14
• 229910052736 halogen Inorganic materials 0.000 claims description 12
• 150000002367 halogens Chemical class 0.000 claims description 12
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 12
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 11
• 125000004122 cyclic group Chemical group 0.000 claims description 11
• 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 10
• 125000002015 acyclic group Chemical group 0.000 claims description 10
• 208000035475 disorder Diseases 0.000 claims description 10
• NRHVKVXTTAYEAD-UHFFFAOYSA-N n-butan-2-ylazetidine-1-carboxamide Chemical compound CCC(C)NC(=O)N1CCC1 NRHVKVXTTAYEAD-UHFFFAOYSA-N 0.000 claims description 9
• 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 8
• 208000030814 Eating disease Diseases 0.000 claims description 8
• 208000019454 Feeding and Eating disease Diseases 0.000 claims description 8
• 239000000460 chlorine Substances 0.000 claims description 8
• 235000014632 disordered eating Nutrition 0.000 claims description 8
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
• 229910052757 nitrogen Chemical group 0.000 claims description 8
• 230000005586 smoking cessation Effects 0.000 claims description 8
• 125000004001 thioalkyl group Chemical group 0.000 claims description 8
• SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 claims description 7
• 125000004663 dialkyl amino group Chemical group 0.000 claims description 7
• 229960002715 nicotine Drugs 0.000 claims description 7
• SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 claims description 7
• 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 7
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
• 229910052794 bromium Inorganic materials 0.000 claims description 6
• 125000004985 dialkyl amino alkyl group Chemical group 0.000 claims description 6
• 229910052740 iodine Inorganic materials 0.000 claims description 6
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 6
• LXHLNKHMBZUMPH-UHFFFAOYSA-N n-cyclopentylazetidine-1-carboxamide Chemical compound C1CCN1C(=O)NC1CCCC1 LXHLNKHMBZUMPH-UHFFFAOYSA-N 0.000 claims description 6
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 5
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 5
• 125000004103 aminoalkyl group Chemical group 0.000 claims description 5
• 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 5
• 229910052801 chlorine Inorganic materials 0.000 claims description 5
• 125000004340 exo-2-norbornyl group Chemical group [H]C1([H])C([H])([H])[C@@]2([H])C([H])([H])[C@]1([H])C([H])([H])[C@]2([H])* 0.000 claims description 5
• 235000013305 food Nutrition 0.000 claims description 5
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
• 239000011630 iodine Substances 0.000 claims description 5
• 238000004519 manufacturing process Methods 0.000 claims description 5
• 125000002950 monocyclic group Chemical group 0.000 claims description 5
• 125000001624 naphthyl group Chemical group 0.000 claims description 5
• 229910052760 oxygen Inorganic materials 0.000 claims description 5
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
• 206010057852 Nicotine dependence Diseases 0.000 claims description 4
• 208000007271 Substance Withdrawal Syndrome Diseases 0.000 claims description 4
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
• 208000025569 Tobacco Use disease Diseases 0.000 claims description 4
• 125000000278 alkyl amino alkyl group Chemical group 0.000 claims description 4
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
• 239000011737 fluorine Substances 0.000 claims description 4
• 229910052731 fluorine Inorganic materials 0.000 claims description 4
• 150000002431 hydrogen Chemical class 0.000 claims description 4
• 239000001301 oxygen Substances 0.000 claims description 4
• 239000011593 sulfur Chemical group 0.000 claims description 4
• 229910052717 sulfur Inorganic materials 0.000 claims description 4
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
• ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
• 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 2
• 125000004947 alkyl aryl amino group Chemical group 0.000 claims description 2
• 125000004986 diarylamino group Chemical group 0.000 claims description 2
• PSHBWZXKCZVAAI-UHFFFAOYSA-N n-(1-phenylpropyl)azetidine-1-carboxamide Chemical compound C=1C=CC=CC=1C(CC)NC(=O)N1CCC1 PSHBWZXKCZVAAI-UHFFFAOYSA-N 0.000 claims description 2
• IYXCXVJHLUYQDO-UHFFFAOYSA-N n-ethylazetidine-1-carboxamide Chemical compound CCNC(=O)N1CCC1 IYXCXVJHLUYQDO-UHFFFAOYSA-N 0.000 claims description 2
• 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 claims description 2
• 125000004043 oxo group Chemical group O=* 0.000 claims description 2
• 208000024891 symptom Diseases 0.000 claims description 2
• 229930195734 saturated hydrocarbon Natural products 0.000 claims 6
• 229930195735 unsaturated hydrocarbon Natural products 0.000 claims 6
• KNXVOGGZOFOROK-UHFFFAOYSA-N trimagnesium;dioxido(oxo)silane;hydroxy-oxido-oxosilane Chemical compound [Mg+2].[Mg+2].[Mg+2].O[Si]([O-])=O.O[Si]([O-])=O.[O-][Si]([O-])=O.[O-][Si]([O-])=O KNXVOGGZOFOROK-UHFFFAOYSA-N 0.000 claims 3
• 206010048010 Withdrawal syndrome Diseases 0.000 claims 1
• 229940002612 prodrug Drugs 0.000 abstract description 6
• 239000000651 prodrug Substances 0.000 abstract description 6
• 238000002560 therapeutic procedure Methods 0.000 abstract description 2
• 238000000034 method Methods 0.000 description 170
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 141
• 238000002360 preparation method Methods 0.000 description 129
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 97
• 239000000243 solution Substances 0.000 description 77
• BJWVNHFRLAOBOZ-UHFFFAOYSA-N 3-[bis(4-chlorophenyl)methoxy]azetidine Chemical compound C1=CC(Cl)=CC=C1C(C=1C=CC(Cl)=CC=1)OC1CNC1 BJWVNHFRLAOBOZ-UHFFFAOYSA-N 0.000 description 60
• 239000000203 mixture Substances 0.000 description 59
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• 239000012948 isocyanate Substances 0.000 description 52
• 150000002513 isocyanates Chemical class 0.000 description 51
• 150000001412 amines Chemical class 0.000 description 46
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 44
• 239000000047 product Substances 0.000 description 43
• MMAJXKGUZYDTHV-UHFFFAOYSA-N 1-benzhydrylazetidin-3-ol Chemical compound C1C(O)CN1C(C=1C=CC=CC=1)C1=CC=CC=C1 MMAJXKGUZYDTHV-UHFFFAOYSA-N 0.000 description 32
• MBBKCJZYSUKZID-UHFFFAOYSA-N 3-[bis(2-chlorophenyl)methoxy]azetidine;hydrochloride Chemical compound Cl.ClC1=CC=CC=C1C(C=1C(=CC=CC=1)Cl)OC1CNC1 MBBKCJZYSUKZID-UHFFFAOYSA-N 0.000 description 32
• VIQAFLOBAKDKJT-UHFFFAOYSA-N 3-[(4-chlorophenyl)-[2-(trifluoromethyl)phenyl]methoxy]azetidine;hydrochloride Chemical compound Cl.FC(F)(F)C1=CC=CC=C1C(C=1C=CC(Cl)=CC=1)OC1CNC1 VIQAFLOBAKDKJT-UHFFFAOYSA-N 0.000 description 31
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• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 27
• 239000010410 layer Substances 0.000 description 27
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• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 22
• 102000018208 Cannabinoid Receptor Human genes 0.000 description 21
• 108050007331 Cannabinoid receptor Proteins 0.000 description 21
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• AIATVWCFSQVGGM-UHFFFAOYSA-N 3-[(2-chlorophenyl)-(4-chlorophenyl)methoxy]azetidine;hydrochloride Chemical compound Cl.C1=CC(Cl)=CC=C1C(C=1C(=CC=CC=1)Cl)OC1CNC1 AIATVWCFSQVGGM-UHFFFAOYSA-N 0.000 description 19
• HKWASYGQXGCPNH-UHFFFAOYSA-N 3-[bis(4-bromophenyl)methoxy]azetidine;hydrochloride Chemical compound Cl.C1=CC(Br)=CC=C1C(C=1C=CC(Br)=CC=1)OC1CNC1 HKWASYGQXGCPNH-UHFFFAOYSA-N 0.000 description 19
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• GECDOTBPWMDILY-UHFFFAOYSA-N 1-benzhydryl-3-[(4-chlorophenyl)-(2,4-dichlorophenyl)methoxy]azetidine Chemical compound C1=CC(Cl)=CC=C1C(C=1C(=CC(Cl)=CC=1)Cl)OC1CN(C(C=2C=CC=CC=2)C=2C=CC=CC=2)C1 GECDOTBPWMDILY-UHFFFAOYSA-N 0.000 description 16
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• 238000012360 testing method Methods 0.000 description 15
• NDYPSMOJVSYYOA-UHFFFAOYSA-N 3-[(4-fluorophenyl)-[2-(trifluoromethyl)phenyl]methoxy]azetidine;hydrochloride Chemical compound Cl.C1=CC(F)=CC=C1C(C=1C(=CC=CC=1)C(F)(F)F)OC1CNC1 NDYPSMOJVSYYOA-UHFFFAOYSA-N 0.000 description 14
• 239000007864 aqueous solution Substances 0.000 description 14
• HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 14
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• LGHCSIDWBZYWOY-UHFFFAOYSA-N 3-[phenyl-[2-(trifluoromethyl)phenyl]methoxy]azetidine;hydrochloride Chemical compound Cl.FC(F)(F)C1=CC=CC=C1C(C=1C=CC=CC=1)OC1CNC1 LGHCSIDWBZYWOY-UHFFFAOYSA-N 0.000 description 12
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