EA011161B1 - 3- или 4-монозамещённые производные фенола и тиофенола, полезные в качестве h-лигандов - Google Patents
3- или 4-монозамещённые производные фенола и тиофенола, полезные в качестве h-лигандов Download PDFInfo
- Publication number
- EA011161B1 EA011161B1 EA200601868A EA200601868A EA011161B1 EA 011161 B1 EA011161 B1 EA 011161B1 EA 200601868 A EA200601868 A EA 200601868A EA 200601868 A EA200601868 A EA 200601868A EA 011161 B1 EA011161 B1 EA 011161B1
- Authority
- EA
- Eurasian Patent Office
- Prior art keywords
- alkyl
- formula
- phenyl
- mmol
- compound
- Prior art date
Links
- -1 4-monosubstituted phenol Chemical class 0.000 title claims abstract description 175
- 239000003446 ligand Substances 0.000 title claims description 15
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical class SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 title abstract description 13
- 239000000203 mixture Substances 0.000 claims abstract description 271
- 238000000034 method Methods 0.000 claims abstract description 112
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 30
- 201000010099 disease Diseases 0.000 claims abstract description 18
- 208000035475 disorder Diseases 0.000 claims abstract description 11
- 230000000172 allergic effect Effects 0.000 claims abstract description 5
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 426
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 157
- 229910052757 nitrogen Inorganic materials 0.000 claims description 52
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 40
- 150000003839 salts Chemical class 0.000 claims description 39
- 125000000623 heterocyclic group Chemical group 0.000 claims description 38
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 37
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 36
- 125000001424 substituent group Chemical group 0.000 claims description 35
- 229910052739 hydrogen Inorganic materials 0.000 claims description 32
- 239000003814 drug Substances 0.000 claims description 31
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 28
- 229910052736 halogen Inorganic materials 0.000 claims description 28
- 239000001257 hydrogen Substances 0.000 claims description 27
- 150000002367 halogens Chemical class 0.000 claims description 26
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 24
- 229910052799 carbon Inorganic materials 0.000 claims description 24
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 22
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 20
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims description 20
- 125000003282 alkyl amino group Chemical group 0.000 claims description 15
- 229910052760 oxygen Inorganic materials 0.000 claims description 15
- 239000012453 solvate Substances 0.000 claims description 14
- 229910052717 sulfur Chemical group 0.000 claims description 14
- 125000005843 halogen group Chemical group 0.000 claims description 13
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical group NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 claims description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 125000003277 amino group Chemical group 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- 206010020751 Hypersensitivity Diseases 0.000 claims description 8
- 230000007815 allergy Effects 0.000 claims description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 239000001301 oxygen Chemical group 0.000 claims description 7
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 7
- 239000011593 sulfur Chemical group 0.000 claims description 7
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 6
- 241000124008 Mammalia Species 0.000 claims description 6
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims description 6
- 125000005037 alkyl phenyl group Chemical group 0.000 claims description 6
- 206010006451 bronchitis Diseases 0.000 claims description 6
- 206010015037 epilepsy Diseases 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 229960001340 histamine Drugs 0.000 claims description 6
- 125000002950 monocyclic group Chemical group 0.000 claims description 6
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 6
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 6
- 125000004434 sulfur atom Chemical group 0.000 claims description 6
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 5
- 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 5
- 125000002393 azetidinyl group Chemical group 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 125000002757 morpholinyl group Chemical group 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 125000004193 piperazinyl group Chemical group 0.000 claims description 5
- 125000003386 piperidinyl group Chemical group 0.000 claims description 5
- 125000000335 thiazolyl group Chemical group 0.000 claims description 5
- 206010039085 Rhinitis allergic Diseases 0.000 claims description 4
- 208000036284 Rhinitis seasonal Diseases 0.000 claims description 4
- 206010064948 Viral rhinitis Diseases 0.000 claims description 4
- 201000010105 allergic rhinitis Diseases 0.000 claims description 4
- 208000010668 atopic eczema Diseases 0.000 claims description 4
- 230000004064 dysfunction Effects 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 230000002045 lasting effect Effects 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 208000037916 non-allergic rhinitis Diseases 0.000 claims description 4
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 4
- 208000024827 Alzheimer disease Diseases 0.000 claims description 3
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims description 3
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 claims description 3
- 206010006458 Bronchitis chronic Diseases 0.000 claims description 3
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 3
- 206010009137 Chronic sinusitis Diseases 0.000 claims description 3
- 201000003883 Cystic fibrosis Diseases 0.000 claims description 3
- 208000012661 Dyskinesia Diseases 0.000 claims description 3
- 208000027534 Emotional disease Diseases 0.000 claims description 3
- 206010014561 Emphysema Diseases 0.000 claims description 3
- 206010057672 Male sexual dysfunction Diseases 0.000 claims description 3
- 208000019695 Migraine disease Diseases 0.000 claims description 3
- 208000008589 Obesity Diseases 0.000 claims description 3
- 208000028017 Psychotic disease Diseases 0.000 claims description 3
- 208000012886 Vertigo Diseases 0.000 claims description 3
- 239000013543 active substance Substances 0.000 claims description 3
- 125000002947 alkylene group Chemical group 0.000 claims description 3
- 208000006673 asthma Diseases 0.000 claims description 3
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 claims description 3
- 208000007451 chronic bronchitis Diseases 0.000 claims description 3
- 208000027157 chronic rhinosinusitis Diseases 0.000 claims description 3
- 230000007278 cognition impairment Effects 0.000 claims description 3
- 208000010877 cognitive disease Diseases 0.000 claims description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 208000002173 dizziness Diseases 0.000 claims description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
- 208000027061 mild cognitive impairment Diseases 0.000 claims description 3
- 235000020824 obesity Nutrition 0.000 claims description 3
- 125000002971 oxazolyl group Chemical group 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 229940044551 receptor antagonist Drugs 0.000 claims description 3
- 239000002464 receptor antagonist Substances 0.000 claims description 3
- 206010039083 rhinitis Diseases 0.000 claims description 3
- 201000000980 schizophrenia Diseases 0.000 claims description 3
- 208000019116 sleep disease Diseases 0.000 claims description 3
- 230000035882 stress Effects 0.000 claims description 3
- 231100000889 vertigo Toxicity 0.000 claims description 3
- 125000006557 (C2-C5) alkylene group Chemical group 0.000 claims description 2
- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
- 208000035231 inattentive type attention deficit hyperactivity disease Diseases 0.000 claims description 2
- 238000005304 joining Methods 0.000 claims description 2
- 125000005961 oxazepanyl group Chemical group 0.000 claims description 2
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 claims description 2
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 2
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims 1
- 210000004392 genitalia Anatomy 0.000 claims 1
- 208000013403 hyperactivity Diseases 0.000 claims 1
- 210000002345 respiratory system Anatomy 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 50
- 238000002360 preparation method Methods 0.000 abstract description 16
- 208000023504 respiratory system disease Diseases 0.000 abstract description 4
- 208000026935 allergic disease Diseases 0.000 abstract description 3
- 230000002757 inflammatory effect Effects 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 552
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 286
- 239000000243 solution Substances 0.000 description 266
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 186
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 168
- 239000011541 reaction mixture Substances 0.000 description 162
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 156
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 156
- 238000005481 NMR spectroscopy Methods 0.000 description 138
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 133
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 108
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 93
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 87
- 239000007787 solid Substances 0.000 description 87
- 239000003921 oil Substances 0.000 description 81
- 235000019198 oils Nutrition 0.000 description 81
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 73
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 53
- 239000000377 silicon dioxide Substances 0.000 description 53
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 51
- 238000004440 column chromatography Methods 0.000 description 48
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 47
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 45
- 238000006243 chemical reaction Methods 0.000 description 45
- 239000002904 solvent Substances 0.000 description 44
- 239000012043 crude product Substances 0.000 description 43
- 239000000284 extract Substances 0.000 description 42
- 239000012044 organic layer Substances 0.000 description 42
- 238000010992 reflux Methods 0.000 description 38
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 36
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 35
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 35
- 239000010410 layer Substances 0.000 description 35
- 239000012299 nitrogen atmosphere Substances 0.000 description 35
- 239000000741 silica gel Substances 0.000 description 33
- 229910002027 silica gel Inorganic materials 0.000 description 33
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 32
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 32
- 239000000725 suspension Substances 0.000 description 31
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 30
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 29
- 239000002585 base Substances 0.000 description 29
- VWIQFPCPQASXPQ-UHFFFAOYSA-N 4-[4-[(dimethylamino)methyl]oxan-4-yl]phenol Chemical compound C=1C=C(O)C=CC=1C1(CN(C)C)CCOCC1 VWIQFPCPQASXPQ-UHFFFAOYSA-N 0.000 description 27
- 229920006395 saturated elastomer Polymers 0.000 description 27
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 26
- 238000000746 purification Methods 0.000 description 25
- 238000003756 stirring Methods 0.000 description 25
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 25
- 238000004587 chromatography analysis Methods 0.000 description 24
- 239000000047 product Substances 0.000 description 23
- 230000002829 reductive effect Effects 0.000 description 23
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 22
- 239000002552 dosage form Substances 0.000 description 22
- 238000010898 silica gel chromatography Methods 0.000 description 22
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 21
- 239000002253 acid Substances 0.000 description 21
- 239000012074 organic phase Substances 0.000 description 21
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 21
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 21
- 238000009472 formulation Methods 0.000 description 20
- 150000001412 amines Chemical class 0.000 description 19
- 239000008346 aqueous phase Substances 0.000 description 19
- 239000007864 aqueous solution Substances 0.000 description 19
- 239000012267 brine Substances 0.000 description 19
- OFLQDYJSAAJMIQ-UHFFFAOYSA-N 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]oxane-4-carbaldehyde Chemical compound C=1C=C(OCCCN2CCCC2)C=CC=1C1(C=O)CCOCC1 OFLQDYJSAAJMIQ-UHFFFAOYSA-N 0.000 description 18
- 229910021529 ammonia Inorganic materials 0.000 description 18
- GGQDDRZCQPULDP-UHFFFAOYSA-N 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]oxane-4-carbonitrile Chemical compound C=1C=C(OCCCN2CCCC2)C=CC=1C1(C#N)CCOCC1 GGQDDRZCQPULDP-UHFFFAOYSA-N 0.000 description 17
- 238000003818 flash chromatography Methods 0.000 description 17
- MFESCIUQSIBMSM-UHFFFAOYSA-N I-BCP Chemical compound ClCCCBr MFESCIUQSIBMSM-UHFFFAOYSA-N 0.000 description 16
- 102100037580 Sesquipedalian-1 Human genes 0.000 description 16
- 101710169844 Sesquipedalian-1 Proteins 0.000 description 16
- JIGYQYPDFHZOAO-UHFFFAOYSA-N [4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]oxan-4-yl]methanamine Chemical compound C=1C=C(OCCCN2CCCC2)C=CC=1C1(CN)CCOCC1 JIGYQYPDFHZOAO-UHFFFAOYSA-N 0.000 description 16
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 16
- 235000019341 magnesium sulphate Nutrition 0.000 description 16
- 229910000027 potassium carbonate Inorganic materials 0.000 description 16
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 16
- 239000003826 tablet Substances 0.000 description 16
- 239000002808 molecular sieve Substances 0.000 description 15
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 15
- 239000012230 colorless oil Substances 0.000 description 14
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
- 230000029936 alkylation Effects 0.000 description 13
- 238000005804 alkylation reaction Methods 0.000 description 13
- 238000009835 boiling Methods 0.000 description 13
- 235000011181 potassium carbonates Nutrition 0.000 description 13
- CXGROXURTMZSEK-UHFFFAOYSA-N 4-(4-hydroxyphenyl)oxane-4-carbonitrile Chemical compound C1=CC(O)=CC=C1C1(C#N)CCOCC1 CXGROXURTMZSEK-UHFFFAOYSA-N 0.000 description 12
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 12
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 12
- 229960000583 acetic acid Drugs 0.000 description 12
- 239000012298 atmosphere Substances 0.000 description 12
- 239000000843 powder Substances 0.000 description 12
- 230000002459 sustained effect Effects 0.000 description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
- 235000011054 acetic acid Nutrition 0.000 description 11
- 229940079593 drug Drugs 0.000 description 11
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 11
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 11
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 11
- 239000011734 sodium Substances 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
- 239000000538 analytical sample Substances 0.000 description 10
- 150000001721 carbon Chemical group 0.000 description 10
- 238000001816 cooling Methods 0.000 description 10
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 10
- YSYGZKGNABJODU-UHFFFAOYSA-N n-methyl-1-[4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]oxan-4-yl]methanamine Chemical compound C=1C=C(OCCCN2CCCC2)C=CC=1C1(CNC)CCOCC1 YSYGZKGNABJODU-UHFFFAOYSA-N 0.000 description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
- ZDEQFCJOJLVAAS-UHFFFAOYSA-N 1-[4-(3-bromopropoxy)phenyl]cyclohexane-1-carbonitrile Chemical compound C1=CC(OCCCBr)=CC=C1C1(C#N)CCCCC1 ZDEQFCJOJLVAAS-UHFFFAOYSA-N 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 8
- 239000003112 inhibitor Substances 0.000 description 8
- 238000004811 liquid chromatography Methods 0.000 description 8
- 229940002612 prodrug Drugs 0.000 description 8
- 239000000651 prodrug Substances 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- 102000005962 receptors Human genes 0.000 description 8
- 108020003175 receptors Proteins 0.000 description 8
- 102000004384 Histamine H3 receptors Human genes 0.000 description 7
- 108090000981 Histamine H3 receptors Proteins 0.000 description 7
- 150000001408 amides Chemical class 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- 239000005557 antagonist Substances 0.000 description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 7
- 239000003638 chemical reducing agent Substances 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 238000007429 general method Methods 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- 238000010561 standard procedure Methods 0.000 description 7
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 7
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Classifications
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| PCT/IB2005/001114 WO2005108384A1 (en) | 2004-05-07 | 2005-04-19 | 3- or 4-monosubstituted phenol and thiophenol derivatives useful as h3 ligands |
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| MY150088A (en) | 2003-05-19 | 2013-11-29 | Irm Llc | Immunosuppressant compounds and compositions |
| WO2005066135A2 (en) | 2003-12-29 | 2005-07-21 | Sepracor Inc. | Pyrrole and pyrazole daao inhibitors |
| JP2006213674A (ja) * | 2005-02-07 | 2006-08-17 | Ube Ind Ltd | 4−ホルミルテトラヒドロピラン化合物の製法 |
| AU2006264317B2 (en) | 2005-07-06 | 2012-02-23 | Sunovion Pharmaceuticals Inc. | Combinations of eszopiclone and trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine or trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine, and methods of treatment of menopause and mood, anxiety, and cognitive disorders |
| WO2007045989A1 (en) * | 2005-10-20 | 2007-04-26 | Pfizer Limited | Pyridyl derivatives useful as h3 ligands |
| NZ569630A (en) | 2006-01-06 | 2011-09-30 | Sepracor Inc | Cycloalkylamines as monoamine reuptake inhibitors |
| CN104276955A (zh) | 2006-01-06 | 2015-01-14 | 赛诺维信制药公司 | 基于四氢萘酮的单胺再摄取抑制剂 |
| AU2007233041B2 (en) | 2006-03-31 | 2013-05-02 | Sepracor Inc. | Preparation of chiral amides and amines |
| CL2007001006A1 (es) | 2006-04-11 | 2008-07-11 | Novartis Ag | Compuestos derivados de piperidina u 8-aza-biciclo[3.2.1]octano sustituidos; formulacion farmaceutica; producto; y uso para el tratamiento o prevencion de enfermedades tales como diabetes mellitus no insulino dependiente, artritis, obesidad, dislipid |
| RU2449989C2 (ru) | 2006-06-23 | 2012-05-10 | Эбботт Лэборетриз | Производные циклопропиламина в качестве модуляторов h3-гистаминового рецептора |
| US9108948B2 (en) | 2006-06-23 | 2015-08-18 | Abbvie Inc. | Cyclopropyl amine derivatives |
| US7884124B2 (en) | 2006-06-30 | 2011-02-08 | Sepracor Inc. | Fluoro-substituted inhibitors of D-amino acid oxidase |
| EP2124913A1 (en) * | 2006-12-22 | 2009-12-02 | Novartis AG | 1-aminomethyl- l- phenyl- cyclohexane derivatives as ddp-iv inhibitors |
| US7902252B2 (en) | 2007-01-18 | 2011-03-08 | Sepracor, Inc. | Inhibitors of D-amino acid oxidase |
| WO2008151156A1 (en) | 2007-05-31 | 2008-12-11 | Sepracor Inc. | Phenyl substituted cycloalkylamines as monoamine reuptake inhibitors |
| TW201039822A (en) | 2009-02-06 | 2010-11-16 | Taisho Pharmaceutical Co Ltd | Dihydroquinolinone derivatives |
| US9186353B2 (en) | 2009-04-27 | 2015-11-17 | Abbvie Inc. | Treatment of osteoarthritis pain |
| JP5813101B2 (ja) | 2010-06-04 | 2015-11-17 | アルバニー モレキュラー リサーチ, インコーポレイテッド | グリシントランスポーター−1阻害剤、その作製方法および使用方法 |
| WO2012037258A1 (en) | 2010-09-16 | 2012-03-22 | Abbott Laboratories | Processes for preparing 1,2-substituted cyclopropyl derivatives |
| SG11201401032YA (en) * | 2011-10-26 | 2014-07-30 | Pfizer Ltd | (4-phenylimidazol-2-yl) ethylamine derivatives useful as sodium channel modulators |
| WO2014095534A1 (en) * | 2012-12-19 | 2014-06-26 | Basf Se | New substituted triazoles and imidazoles and their use as fungicides |
| US9365511B2 (en) * | 2013-01-09 | 2016-06-14 | Arena Pharmaceuticals, Inc. | Biphenyl-ethyl-pyrrolidine derivatives as histamine H3 receptor modulators for the treatment of cognitive disorders |
| US9067914B1 (en) | 2013-12-10 | 2015-06-30 | Genzyme Corporation | Tropomyosin-related kinase (TRK) inhibitors |
| CN107231803B (zh) | 2014-12-18 | 2019-12-03 | 建新公司 | 原肌球蛋白相关激酶(trk)抑制剂的药物制剂 |
| CN113336715B (zh) * | 2021-08-04 | 2021-11-23 | 山东海利尔化工有限公司 | 一种含二氧戊环的三唑类化合物及其中间体的制备方法 |
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| DE3024836A1 (de) * | 1980-07-01 | 1982-01-28 | A. Nattermann & Cie GmbH, 5000 Köln | (3-alkylamino-2-hydroxy-propoxy)-benzylnitrile, verfahren zu deren herstellung und diese als wirkstof enthaltende arzneimittel |
| EP0269363A2 (en) * | 1986-11-21 | 1988-06-01 | A/S Cheminova | Amino-alkylated hydroxy compounds and their use as fungicides |
| WO2002006223A1 (en) * | 2000-07-13 | 2002-01-24 | Abbott Laboratories | 1,3-disubstituted and 1,3,3-trisubstituted pyrrolidines as histamine-3 receptor ligands and their therapeutic applications |
| WO2002012190A2 (en) * | 2000-08-08 | 2002-02-14 | Ortho Mcneil Pharmaceutical, Inc. | Non-imidazole aryloxypiperidines as h3 receptor ligands |
| WO2002076925A2 (en) * | 2001-03-23 | 2002-10-03 | Eli Lilly And Company | Non-imidazole aryl alkylamines compounds as histamine h3 receptor antagonists, preparation and therapeutic uses |
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2007
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3024836A1 (de) * | 1980-07-01 | 1982-01-28 | A. Nattermann & Cie GmbH, 5000 Köln | (3-alkylamino-2-hydroxy-propoxy)-benzylnitrile, verfahren zu deren herstellung und diese als wirkstof enthaltende arzneimittel |
| EP0269363A2 (en) * | 1986-11-21 | 1988-06-01 | A/S Cheminova | Amino-alkylated hydroxy compounds and their use as fungicides |
| WO2002006223A1 (en) * | 2000-07-13 | 2002-01-24 | Abbott Laboratories | 1,3-disubstituted and 1,3,3-trisubstituted pyrrolidines as histamine-3 receptor ligands and their therapeutic applications |
| WO2002012190A2 (en) * | 2000-08-08 | 2002-02-14 | Ortho Mcneil Pharmaceutical, Inc. | Non-imidazole aryloxypiperidines as h3 receptor ligands |
| WO2002076925A2 (en) * | 2001-03-23 | 2002-10-03 | Eli Lilly And Company | Non-imidazole aryl alkylamines compounds as histamine h3 receptor antagonists, preparation and therapeutic uses |
Non-Patent Citations (1)
| Title |
|---|
| DATABASE BEILSTEIN, BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; XP002300332, Database Accession No. 5690069 (Citation No.). & Z. CHEM., vol. 20, no. 8, 1980, pages 298-299 * |
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