EA020848B1 - Спиропиперидиновые соединения в качестве антагонистов рецептора orl-1 - Google Patents

Info

Publication number

EA020848B1

EA020848B1 EA201290352A EA201290352A EA020848B1 EA 020848 B1 EA020848 B1 EA 020848B1 EA 201290352 A EA201290352 A EA 201290352A EA 201290352 A EA201290352 A EA 201290352A EA 020848 B1 EA020848 B1 EA 020848B1

Authority

EA

Eurasian Patent Office

Prior art keywords

methyl

mmol

pyran

piperidine

pyridyl

Prior art date

2009-11-16

Links

• Espacenet
• Global Dossier
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• 239000002464 receptor antagonist Substances 0.000 title abstract description 5
• 229940044551 receptor antagonist Drugs 0.000 title abstract description 5
• 108010020615 nociceptin receptor Proteins 0.000 title abstract description 4
• JUXAVSAMVBLDKO-UHFFFAOYSA-N 1-(1-azabicyclo[2.2.2]octan-3-yl)-3-[3-(1h-indol-3-yl)-1-oxo-1-spiro[1,2-dihydroindene-3,4'-piperidine]-1'-ylpropan-2-yl]urea Chemical class C1N(CC2)CCC2C1NC(=O)NC(C(=O)N1CCC2(C3=CC=CC=C3CC2)CC1)CC1=CNC2=CC=CC=C12 JUXAVSAMVBLDKO-UHFFFAOYSA-N 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 238
• 208000008589 Obesity Diseases 0.000 claims abstract description 15
• 235000020824 obesity Nutrition 0.000 claims abstract description 15
• 206010033307 Overweight Diseases 0.000 claims abstract description 14
• 208000019695 Migraine disease Diseases 0.000 claims abstract description 8
• 206010027599 migraine Diseases 0.000 claims abstract description 8
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 96
• -1 cyano, cyanomethyl Chemical group 0.000 claims description 92
• 150000003839 salts Chemical class 0.000 claims description 42
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 25
• 239000011737 fluorine Substances 0.000 claims description 21
• 229910052731 fluorine Inorganic materials 0.000 claims description 21
• 229910052739 hydrogen Inorganic materials 0.000 claims description 15
• 239000000935 antidepressant agent Substances 0.000 claims description 14
• 229940005513 antidepressants Drugs 0.000 claims description 14
• 239000000460 chlorine Substances 0.000 claims description 13
• 239000001257 hydrogen Substances 0.000 claims description 13
• 230000001430 anti-depressive effect Effects 0.000 claims description 12
• 229910052801 chlorine Inorganic materials 0.000 claims description 12
• 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 12
• NKQHBJNRBKHUQR-UHFFFAOYSA-N [2-[4-[(2-chloro-4,4-difluorospiro[5h-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methylpyrazol-1-yl]pyridin-3-yl]methanol Chemical compound C1=C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)C(C)=NN1C1=NC=CC=C1CO NKQHBJNRBKHUQR-UHFFFAOYSA-N 0.000 claims description 11
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 11
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 10
• 239000008194 pharmaceutical composition Substances 0.000 claims description 10
• 239000003085 diluting agent Substances 0.000 claims description 7
• 239000003937 drug carrier Substances 0.000 claims description 7
• 125000001153 fluoro group Chemical group F* 0.000 claims description 7
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
• ZAOZBWZTMUTPSX-UHFFFAOYSA-N [4-[(2-chloro-4,4-difluorospiro[5h-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-1-(3-fluoropyridin-2-yl)pyrazol-3-yl]methanol Chemical compound C1=C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)C(CO)=NN1C1=NC=CC=C1F ZAOZBWZTMUTPSX-UHFFFAOYSA-N 0.000 claims description 5
• 208000020401 Depressive disease Diseases 0.000 claims description 4
• 125000004849 alkoxymethyl group Chemical group 0.000 claims description 4
• 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 claims description 4
• 239000012896 selective serotonin reuptake inhibitor Substances 0.000 claims description 4
• 230000001225 therapeutic effect Effects 0.000 claims description 4
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
• 239000012634 fragment Substances 0.000 claims description 3
• 239000004615 ingredient Substances 0.000 claims description 3
• 125000004353 pyrazol-1-yl group Chemical group [H]C1=NN(*)C([H])=C1[H] 0.000 claims description 3
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
• 125000001607 1,2,3-triazol-1-yl group Chemical group [*]N1N=NC([H])=C1[H] 0.000 claims description 2
• 125000003626 1,2,4-triazol-1-yl group Chemical group [*]N1N=C([H])N=C1[H] 0.000 claims description 2
• TVSCFMXJYNZEER-UHFFFAOYSA-N 7-methoxy-11a-methyl-1,9b,10,11-tetrahydronaphtho[1,2-g]indole Chemical compound C1CC2(C)CC=NC2=C2C=CC3=CC(OC)=CC=C3C21 TVSCFMXJYNZEER-UHFFFAOYSA-N 0.000 claims description 2
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
• 125000004859 cyclopropyloxymethyl group Chemical group C1(CC1)OC* 0.000 claims description 2
• 125000004284 isoxazol-3-yl group Chemical group [H]C1=C([H])C(*)=NO1 0.000 claims description 2
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
• 125000004304 oxazol-5-yl group Chemical group O1C=NC=C1* 0.000 claims description 2
• 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 5
• 150000002431 hydrogen Chemical class 0.000 claims 3
• XTVMMUUMUBGOPK-UHFFFAOYSA-N 2-chloro-4,4-difluoro-1'-[[3-methyl-1-[3-(pyrazol-1-ylmethyl)pyridin-2-yl]pyrazol-4-yl]methyl]spiro[5h-thieno[2,3-c]pyran-7,4'-piperidine] Chemical compound C1=C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)C(C)=NN1C1=NC=CC=C1CN1C=CC=N1 XTVMMUUMUBGOPK-UHFFFAOYSA-N 0.000 claims 1
• 238000000034 method Methods 0.000 abstract description 21
• 239000005557 antagonist Substances 0.000 abstract description 14
• 238000002360 preparation method Methods 0.000 abstract description 9
• 238000010171 animal model Methods 0.000 abstract description 5
• 238000012423 maintenance Methods 0.000 abstract description 3
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 231
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 210
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 155
• 239000000203 mixture Substances 0.000 description 154
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 154
• 239000000243 solution Substances 0.000 description 131
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 112
• 239000002904 solvent Substances 0.000 description 84
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 76
• 229940095064 tartrate Drugs 0.000 description 67
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 66
• 239000011541 reaction mixture Substances 0.000 description 62
• 238000004519 manufacturing process Methods 0.000 description 60
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 57
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 53
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 52
• 239000012044 organic layer Substances 0.000 description 51
• 239000012071 phase Substances 0.000 description 47
• 102000005962 receptors Human genes 0.000 description 45
• 108020003175 receptors Proteins 0.000 description 44
• 230000002829 reductive effect Effects 0.000 description 43
• 239000007787 solid Substances 0.000 description 43
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 40
• 239000002244 precipitate Substances 0.000 description 40
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 38
• 235000019341 magnesium sulphate Nutrition 0.000 description 38
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 36
• 238000004587 chromatography analysis Methods 0.000 description 35
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 33
• 125000003003 spiro group Chemical group 0.000 description 32
• 239000000725 suspension Substances 0.000 description 32
• 238000006243 chemical reaction Methods 0.000 description 31
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 30
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 29
• 230000000694 effects Effects 0.000 description 29
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 28
• 229910052938 sodium sulfate Inorganic materials 0.000 description 28
• 235000011152 sodium sulphate Nutrition 0.000 description 28
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
• 241000699670 Mus sp. Species 0.000 description 25
• 239000003480 eluent Substances 0.000 description 25
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 22
• 102000048266 Nociceptin Human genes 0.000 description 21
• 108090000622 Nociceptin Proteins 0.000 description 21
• 239000007864 aqueous solution Substances 0.000 description 21
• PULGYDLMFSFVBL-SMFNREODSA-N nociceptin Chemical compound C([C@@H](C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)[C@@H](C)O)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 PULGYDLMFSFVBL-SMFNREODSA-N 0.000 description 21
• 239000012043 crude product Substances 0.000 description 20
• 229910000027 potassium carbonate Inorganic materials 0.000 description 20
• 239000012267 brine Substances 0.000 description 19
• 229920006395 saturated elastomer Polymers 0.000 description 19
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 19
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
• 238000003756 stirring Methods 0.000 description 18
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 17
• 235000017557 sodium bicarbonate Nutrition 0.000 description 17
• 238000012360 testing method Methods 0.000 description 17
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 16
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 16
• RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
• 239000012074 organic phase Substances 0.000 description 16
• 239000000902 placebo Substances 0.000 description 16
• 229940068196 placebo Drugs 0.000 description 16
• 238000000746 purification Methods 0.000 description 16
• 108091006146 Channels Proteins 0.000 description 15
• 230000015572 biosynthetic process Effects 0.000 description 14
• MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 14
• QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 14
• 239000000741 silica gel Substances 0.000 description 14
• 229910002027 silica gel Inorganic materials 0.000 description 14
• NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 14
• 230000027455 binding Effects 0.000 description 13
• 239000010410 layer Substances 0.000 description 13
• DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 12
• FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 12
• GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 12
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• 239000012299 nitrogen atmosphere Substances 0.000 description 12
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• 150000001768 cations Chemical class 0.000 description 11
• 229910052757 nitrogen Inorganic materials 0.000 description 11
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• RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 0.000 description 10
• YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 10
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
• 239000000284 extract Substances 0.000 description 10
• 229960002464 fluoxetine Drugs 0.000 description 10
• AMWRITDGCCNYAT-UHFFFAOYSA-L hydroxy(oxo)manganese;manganese Chemical compound [Mn].O[Mn]=O.O[Mn]=O AMWRITDGCCNYAT-UHFFFAOYSA-L 0.000 description 10
• 239000000126 substance Substances 0.000 description 10
• YYNOJCBVROUTEB-UHFFFAOYSA-N 2-chloro-4,4-difluorospiro[5h-thieno[2,3-c]pyran-7,4'-piperidine] Chemical compound C1=2SC(Cl)=CC=2C(F)(F)COC21CCNCC2 YYNOJCBVROUTEB-UHFFFAOYSA-N 0.000 description 9
• XKMLYUALXHKNFT-UUOKFMHZSA-N Guanosine-5'-triphosphate Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XKMLYUALXHKNFT-UUOKFMHZSA-N 0.000 description 9
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• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
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• QUFOXOBRXVPNNQ-UHFFFAOYSA-N 2-[4-[(2-chloro-4,4-difluorospiro[5h-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methylpyrazol-1-yl]pyridine-3-carbaldehyde Chemical compound C1=C(CN2CCC3(CC2)C=2SC(Cl)=CC=2C(F)(F)CO3)C(C)=NN1C1=NC=CC=C1C=O QUFOXOBRXVPNNQ-UHFFFAOYSA-N 0.000 description 7
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• 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 6
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• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
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• NEWLOSCWMVKPGI-UHFFFAOYSA-N 2-bromo-3-(bromomethyl)pyridine Chemical compound BrCC1=CC=CN=C1Br NEWLOSCWMVKPGI-UHFFFAOYSA-N 0.000 description 5
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• UEQLAZGHIUZUEO-UHFFFAOYSA-N ethyl 4-formyl-1h-pyrazole-5-carboxylate Chemical compound CCOC(=O)C=1NN=CC=1C=O UEQLAZGHIUZUEO-UHFFFAOYSA-N 0.000 description 5
• 125000004494 ethyl ester group Chemical group 0.000 description 5
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• 125000006239 protecting group Chemical group 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
• 239000010802 sludge Substances 0.000 description 5
• URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical class [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 5
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