CN102015635A - 氮杂环丁烷衍生物 - Google Patents
氮杂环丁烷衍生物 Download PDFInfo
- Publication number
- CN102015635A CN102015635A CN2009801079287A CN200980107928A CN102015635A CN 102015635 A CN102015635 A CN 102015635A CN 2009801079287 A CN2009801079287 A CN 2009801079287A CN 200980107928 A CN200980107928 A CN 200980107928A CN 102015635 A CN102015635 A CN 102015635A
- Authority
- CN
- China
- Prior art keywords
- base
- milliliters
- compound
- phenyl
- azetidine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000001539 azetidines Chemical class 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 132
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 27
- 208000002193 Pain Diseases 0.000 claims abstract description 25
- 201000010099 disease Diseases 0.000 claims abstract description 25
- 230000036407 pain Effects 0.000 claims abstract description 23
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 20
- 206010061218 Inflammation Diseases 0.000 claims abstract description 10
- 230000004054 inflammatory process Effects 0.000 claims abstract description 10
- 208000019901 Anxiety disease Diseases 0.000 claims abstract description 7
- 230000036506 anxiety Effects 0.000 claims abstract description 7
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims abstract description 7
- 230000000626 neurodegenerative effect Effects 0.000 claims abstract 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 99
- 239000001301 oxygen Substances 0.000 claims description 99
- 229910052760 oxygen Inorganic materials 0.000 claims description 99
- 238000000034 method Methods 0.000 claims description 90
- -1 5-pyridylidene Chemical group 0.000 claims description 49
- 150000003839 salts Chemical class 0.000 claims description 28
- 208000024891 symptom Diseases 0.000 claims description 24
- 239000000460 chlorine Substances 0.000 claims description 14
- 125000004429 atom Chemical group 0.000 claims description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 208000010412 Glaucoma Diseases 0.000 claims description 7
- 239000011737 fluorine Substances 0.000 claims description 7
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 7
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 7
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 6
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 6
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 5
- 206010003591 Ataxia Diseases 0.000 claims description 5
- 206010013980 Dyssomnias Diseases 0.000 claims description 5
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 239000003981 vehicle Substances 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 4
- 206010047700 Vomiting Diseases 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 201000011510 cancer Diseases 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- ZRNSSRODJSSVEJ-UHFFFAOYSA-N 2-methylpentacosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCC(C)C ZRNSSRODJSSVEJ-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 208000026935 allergic disease Diseases 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 3
- 206010015037 epilepsy Diseases 0.000 claims description 3
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 230000008673 vomiting Effects 0.000 claims description 3
- 206010003497 Asphyxia Diseases 0.000 claims description 2
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 2
- 206010020772 Hypertension Diseases 0.000 claims description 2
- 241000700605 Viruses Species 0.000 claims description 2
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 2
- 102100027297 Fatty acid 2-hydroxylase Human genes 0.000 claims 2
- 101000937693 Homo sapiens Fatty acid 2-hydroxylase Proteins 0.000 claims 2
- 101000918494 Homo sapiens Fatty-acid amide hydrolase 1 Proteins 0.000 claims 2
- 208000000094 Chronic Pain Diseases 0.000 claims 1
- 208000001132 Osteoporosis Diseases 0.000 claims 1
- 208000030852 Parasitic disease Diseases 0.000 claims 1
- 206010046543 Urinary incontinence Diseases 0.000 claims 1
- 230000001154 acute effect Effects 0.000 claims 1
- 208000005298 acute pain Diseases 0.000 claims 1
- 230000001580 bacterial effect Effects 0.000 claims 1
- 230000001684 chronic effect Effects 0.000 claims 1
- 208000010643 digestive system disease Diseases 0.000 claims 1
- 208000002173 dizziness Diseases 0.000 claims 1
- 208000018685 gastrointestinal system disease Diseases 0.000 claims 1
- 208000026278 immune system disease Diseases 0.000 claims 1
- 230000001524 infective effect Effects 0.000 claims 1
- 210000003734 kidney Anatomy 0.000 claims 1
- 208000020016 psychiatric disease Diseases 0.000 claims 1
- 201000008827 tuberculosis Diseases 0.000 claims 1
- 108010046094 fatty-acid amide hydrolase Proteins 0.000 abstract description 45
- 102100029111 Fatty-acid amide hydrolase 1 Human genes 0.000 abstract description 44
- 230000000694 effects Effects 0.000 abstract description 19
- 239000003112 inhibitor Substances 0.000 abstract description 7
- 230000005764 inhibitory process Effects 0.000 abstract description 5
- 125000006413 ring segment Chemical group 0.000 abstract 4
- 208000030814 Eating disease Diseases 0.000 abstract 1
- 208000019454 Feeding and Eating disease Diseases 0.000 abstract 1
- 208000016285 Movement disease Diseases 0.000 abstract 1
- 208000015122 neurodegenerative disease Diseases 0.000 abstract 1
- 208000019116 sleep disease Diseases 0.000 abstract 1
- 239000002585 base Substances 0.000 description 277
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 121
- 239000000243 solution Substances 0.000 description 74
- 239000000203 mixture Substances 0.000 description 59
- VIKNJXKGJWUCNN-XGXHKTLJSA-N norethisterone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 VIKNJXKGJWUCNN-XGXHKTLJSA-N 0.000 description 56
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 55
- 150000001408 amides Chemical class 0.000 description 54
- 239000002904 solvent Substances 0.000 description 53
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 52
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 51
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 47
- 239000007787 solid Substances 0.000 description 47
- 235000019439 ethyl acetate Nutrition 0.000 description 45
- 238000005406 washing Methods 0.000 description 37
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 34
- 239000011541 reaction mixture Substances 0.000 description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 31
- 239000007864 aqueous solution Substances 0.000 description 30
- 235000002639 sodium chloride Nutrition 0.000 description 28
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 27
- 238000002360 preparation method Methods 0.000 description 27
- 239000000706 filtrate Substances 0.000 description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 23
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 21
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 21
- 238000003818 flash chromatography Methods 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 20
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 19
- 239000000047 product Substances 0.000 description 18
- 238000012360 testing method Methods 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- 238000002474 experimental method Methods 0.000 description 16
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 238000004128 high performance liquid chromatography Methods 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 15
- 241000700159 Rattus Species 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- 239000012043 crude product Substances 0.000 description 14
- 239000000843 powder Substances 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- 239000003153 chemical reaction reagent Substances 0.000 description 13
- 238000010790 dilution Methods 0.000 description 13
- 239000012895 dilution Substances 0.000 description 13
- 229910052938 sodium sulfate Inorganic materials 0.000 description 13
- 235000011152 sodium sulphate Nutrition 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 239000000872 buffer Substances 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 12
- 238000010438 heat treatment Methods 0.000 description 12
- 239000000126 substance Substances 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- BQFCCCIRTOLPEF-UHFFFAOYSA-N chembl1976978 Chemical compound CC1=CC=CC=C1N=NC1=C(O)C=CC2=CC=CC=C12 BQFCCCIRTOLPEF-UHFFFAOYSA-N 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
- 239000002253 acid Chemical class 0.000 description 10
- 150000001412 amines Chemical class 0.000 description 10
- GCUVBACNBHGZRS-UHFFFAOYSA-N cyclopenta-1,3-diene cyclopenta-2,4-dien-1-yl(diphenyl)phosphane iron(2+) Chemical compound [Fe++].c1cc[cH-]c1.c1cc[c-](c1)P(c1ccccc1)c1ccccc1 GCUVBACNBHGZRS-UHFFFAOYSA-N 0.000 description 10
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- 239000012299 nitrogen atmosphere Substances 0.000 description 10
- 238000005192 partition Methods 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- 238000004809 thin layer chromatography Methods 0.000 description 10
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- 230000014759 maintenance of location Effects 0.000 description 9
- 239000002480 mineral oil Substances 0.000 description 9
- 235000010446 mineral oil Nutrition 0.000 description 9
- 229910052763 palladium Inorganic materials 0.000 description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 9
- 235000015320 potassium carbonate Nutrition 0.000 description 9
- 239000012312 sodium hydride Substances 0.000 description 9
- 229910000104 sodium hydride Inorganic materials 0.000 description 9
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 8
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 8
- 239000003940 fatty acid amidase inhibitor Substances 0.000 description 8
- 235000019253 formic acid Nutrition 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- 241000375384 Cannaboides Species 0.000 description 7
- 230000003197 catalytic effect Effects 0.000 description 7
- 239000006185 dispersion Substances 0.000 description 7
- 235000015110 jellies Nutrition 0.000 description 7
- 239000008274 jelly Substances 0.000 description 7
- 239000000758 substrate Substances 0.000 description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 208000005392 Spasm Diseases 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 6
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 235000010418 carrageenan Nutrition 0.000 description 6
- 229920001525 carrageenan Polymers 0.000 description 6
- 239000012141 concentrate Substances 0.000 description 6
- 235000008504 concentrate Nutrition 0.000 description 6
- 150000002500 ions Chemical class 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 239000012266 salt solution Substances 0.000 description 6
- RVRPZVYPEZOEKF-UHFFFAOYSA-N (4-nitrophenyl) azetidine-1-carboxylate Chemical compound C1=CC([N+](=O)[O-])=CC=C1OC(=O)N1CCC1 RVRPZVYPEZOEKF-UHFFFAOYSA-N 0.000 description 5
- 206010065390 Inflammatory pain Diseases 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 5
- 230000036528 appetite Effects 0.000 description 5
- 235000019789 appetite Nutrition 0.000 description 5
- AIGRXSNSLVJMEA-FQEVSTJZSA-N ethoxy-(4-nitrophenoxy)-phenyl-sulfanylidene-$l^{5}-phosphane Chemical compound O([P@@](=S)(OCC)C=1C=CC=CC=1)C1=CC=C([N+]([O-])=O)C=C1 AIGRXSNSLVJMEA-FQEVSTJZSA-N 0.000 description 5
- 229960000905 indomethacin Drugs 0.000 description 5
- 230000004410 intraocular pressure Effects 0.000 description 5
- 125000001786 isothiazolyl group Chemical group 0.000 description 5
- 150000002632 lipids Chemical group 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 201000006417 multiple sclerosis Diseases 0.000 description 5
- 125000003226 pyrazolyl group Chemical group 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 238000005507 spraying Methods 0.000 description 5
- 238000010792 warming Methods 0.000 description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 4
- 239000005695 Ammonium acetate Substances 0.000 description 4
- 101100334123 Caenorhabditis elegans faah-1 gene Proteins 0.000 description 4
- CYQFCXCEBYINGO-UHFFFAOYSA-N THC Natural products C1=C(C)CCC2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3C21 CYQFCXCEBYINGO-UHFFFAOYSA-N 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 235000019257 ammonium acetate Nutrition 0.000 description 4
- 229940043376 ammonium acetate Drugs 0.000 description 4
- LGEQQWMQCRIYKG-DOFZRALJSA-N anandamide Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(=O)NCCO LGEQQWMQCRIYKG-DOFZRALJSA-N 0.000 description 4
- 238000013459 approach Methods 0.000 description 4
- 229940114079 arachidonic acid Drugs 0.000 description 4
- 235000021342 arachidonic acid Nutrition 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 description 4
- 235000014113 dietary fatty acids Nutrition 0.000 description 4
- 229960004242 dronabinol Drugs 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 239000000194 fatty acid Substances 0.000 description 4
- 229930195729 fatty acid Natural products 0.000 description 4
- 150000004665 fatty acids Chemical class 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- 239000012265 solid product Substances 0.000 description 4
- 239000012453 solvate Substances 0.000 description 4
- 208000011580 syndromic disease Diseases 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 239000006188 syrup Substances 0.000 description 4
- 235000020357 syrup Nutrition 0.000 description 4
- 125000001113 thiadiazolyl group Chemical group 0.000 description 4
- 125000000335 thiazolyl group Chemical group 0.000 description 4
- 125000001544 thienyl group Chemical group 0.000 description 4
- 125000004306 triazinyl group Chemical group 0.000 description 4
- 239000003643 water by type Substances 0.000 description 4
- YZUPZGFPHUVJKC-UHFFFAOYSA-N 1-bromo-2-methoxyethane Chemical compound COCCBr YZUPZGFPHUVJKC-UHFFFAOYSA-N 0.000 description 3
- XDELKSRGBLWMBA-UHFFFAOYSA-N 3-iodopyridine Chemical compound IC1=CC=CN=C1 XDELKSRGBLWMBA-UHFFFAOYSA-N 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- 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 3
- KGWDUNBJIMUFAP-KVVVOXFISA-N Ethanolamine Oleate Chemical compound NCCO.CCCCCCCC\C=C/CCCCCCCC(O)=O KGWDUNBJIMUFAP-KVVVOXFISA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- 235000010338 boric acid Nutrition 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 231100000673 dose–response relationship Toxicity 0.000 description 3
- 125000002541 furyl group Chemical group 0.000 description 3
- 125000002883 imidazolyl group Chemical group 0.000 description 3
- 230000010354 integration Effects 0.000 description 3
- 125000000842 isoxazolyl group Chemical group 0.000 description 3
- 235000010981 methylcellulose Nutrition 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical compound O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 201000007094 prostatitis Diseases 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 235000010356 sorbitol Nutrition 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 125000001425 triazolyl group Chemical group 0.000 description 3
- 238000000825 ultraviolet detection Methods 0.000 description 3
- 238000007738 vacuum evaporation Methods 0.000 description 3
- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 description 2
- CSNIZNHTOVFARY-UHFFFAOYSA-N 1,2-benzothiazole Chemical compound C1=CC=C2C=NSC2=C1 CSNIZNHTOVFARY-UHFFFAOYSA-N 0.000 description 2
- KTZQTRPPVKQPFO-UHFFFAOYSA-N 1,2-benzoxazole Chemical compound C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 description 2
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 2
- PSGQCCSGKGJLRL-UHFFFAOYSA-N 4-methyl-2h-chromen-2-one Chemical compound C1=CC=CC2=C1OC(=O)C=C2C PSGQCCSGKGJLRL-UHFFFAOYSA-N 0.000 description 2
- FWEOQOXTVHGIFQ-UHFFFAOYSA-N 8-anilinonaphthalene-1-sulfonic acid Chemical compound C=12C(S(=O)(=O)O)=CC=CC2=CC=CC=1NC1=CC=CC=C1 FWEOQOXTVHGIFQ-UHFFFAOYSA-N 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 2
- 229920000936 Agarose Polymers 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 description 2
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 description 2
- DJCBFKPREYVKGX-UHFFFAOYSA-N CC(C)(O)C(C)(C)O.OB(O)OC1=CC=CC(O)=C1 Chemical compound CC(C)(O)C(C)(C)O.OB(O)OC1=CC=CC(O)=C1 DJCBFKPREYVKGX-UHFFFAOYSA-N 0.000 description 2
- 244000025254 Cannabis sativa Species 0.000 description 2
- 235000012766 Cannabis sativa ssp. sativa var. sativa Nutrition 0.000 description 2
- 235000012765 Cannabis sativa ssp. sativa var. spontanea Nutrition 0.000 description 2
- 206010008190 Cerebrovascular accident Diseases 0.000 description 2
- 206010010904 Convulsion Diseases 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 208000011688 Generalised anxiety disease Diseases 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 208000031226 Hyperlipidaemia Diseases 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- 206010024264 Lethargy Diseases 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 208000001294 Nociceptive Pain Diseases 0.000 description 2
- 208000008589 Obesity Diseases 0.000 description 2
- 208000027089 Parkinsonian disease Diseases 0.000 description 2
- 206010034010 Parkinsonism Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 206010039361 Sacroiliitis Diseases 0.000 description 2
- 206010040070 Septic Shock Diseases 0.000 description 2
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 2
- 208000006011 Stroke Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- QHMBSVQNZZTUGM-UHFFFAOYSA-N Trans-Cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-UHFFFAOYSA-N 0.000 description 2
- ROFVXGGUISEHAM-UHFFFAOYSA-N URB597 Chemical compound NC(=O)C1=CC=CC(C=2C=C(OC(=O)NC3CCCCC3)C=CC=2)=C1 ROFVXGGUISEHAM-UHFFFAOYSA-N 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 2
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 2
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 2
- 239000012964 benzotriazole Substances 0.000 description 2
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 2
- YXVFYQXJAXKLAK-UHFFFAOYSA-N biphenyl-4-ol Chemical compound C1=CC(O)=CC=C1C1=CC=CC=C1 YXVFYQXJAXKLAK-UHFFFAOYSA-N 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- 239000004327 boric acid Substances 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 235000009120 camo Nutrition 0.000 description 2
- QHMBSVQNZZTUGM-ZWKOTPCHSA-N cannabidiol Chemical compound OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-ZWKOTPCHSA-N 0.000 description 2
- 229950011318 cannabidiol Drugs 0.000 description 2
- ZTGXAWYVTLUPDT-UHFFFAOYSA-N cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CC=C(C)C1 ZTGXAWYVTLUPDT-UHFFFAOYSA-N 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 235000005607 chanvre indien Nutrition 0.000 description 2
- QOPVNWQGBQYBBP-UHFFFAOYSA-N chloroethyl chloroformate Chemical compound CC(Cl)OC(Cl)=O QOPVNWQGBQYBBP-UHFFFAOYSA-N 0.000 description 2
- 210000000078 claw Anatomy 0.000 description 2
- 230000000994 depressogenic effect Effects 0.000 description 2
- 239000011903 deuterated solvents Substances 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000008157 edible vegetable oil Substances 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 208000029364 generalized anxiety disease Diseases 0.000 description 2
- 239000011487 hemp Substances 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 208000035231 inattentive type attention deficit hyperactivity disease Diseases 0.000 description 2
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 206010022437 insomnia Diseases 0.000 description 2
- 239000012948 isocyanate Substances 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 208000004296 neuralgia Diseases 0.000 description 2
- 230000004770 neurodegeneration Effects 0.000 description 2
- 208000021722 neuropathic pain Diseases 0.000 description 2
- 230000000324 neuroprotective effect Effects 0.000 description 2
- 235000020824 obesity Nutrition 0.000 description 2
- FATBGEAMYMYZAF-KTKRTIGZSA-N oleamide Chemical compound CCCCCCCC\C=C/CCCCCCCC(N)=O FATBGEAMYMYZAF-KTKRTIGZSA-N 0.000 description 2
- 229940113162 oleylamide Drugs 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- NWVVVBRKAWDGAB-UHFFFAOYSA-N p-methoxyphenol Chemical compound COC1=CC=C(O)C=C1 NWVVVBRKAWDGAB-UHFFFAOYSA-N 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000002831 pharmacologic agent Substances 0.000 description 2
- 238000000252 photodiode array detection Methods 0.000 description 2
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- LETVJWLLIMJADE-UHFFFAOYSA-N pyridazin-3-amine Chemical compound NC1=CC=CN=N1 LETVJWLLIMJADE-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 201000000980 schizophrenia Diseases 0.000 description 2
- 208000020431 spinal cord injury Diseases 0.000 description 2
- 230000035882 stress Effects 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- DWSBPCLAELVSFD-UHFFFAOYSA-N (2-fluorophenoxy)boronic acid Chemical compound OB(O)OC1=CC=CC=C1F DWSBPCLAELVSFD-UHFFFAOYSA-N 0.000 description 1
- CVISDVLTGPAQGC-UHFFFAOYSA-N (3-hydroxyphenoxy)boronic acid Chemical compound OB(O)OC1=CC=CC(O)=C1 CVISDVLTGPAQGC-UHFFFAOYSA-N 0.000 description 1
- PHBVXHIVWULVNF-UHFFFAOYSA-N (4-fluorophenoxy)boronic acid Chemical compound OB(O)OC1=CC=C(F)C=C1 PHBVXHIVWULVNF-UHFFFAOYSA-N 0.000 description 1
- ZSCHDSYZOUKNFL-DOFZRALJSA-N (8z,11z,14z,17z)-1,2,3-trihydroxytricosa-8,11,14,17-tetraen-4-one Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(=O)C(O)C(O)CO ZSCHDSYZOUKNFL-DOFZRALJSA-N 0.000 description 1
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 description 1
- 125000002733 (C1-C6) fluoroalkyl group Chemical group 0.000 description 1
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- 125000001989 1,3-phenylene group Chemical group [H]C1=C([H])C([*:1])=C([H])C([*:2])=C1[H] 0.000 description 1
- 125000001140 1,4-phenylene group Chemical group [H]C1=C([H])C([*:2])=C([H])C([H])=C1[*:1] 0.000 description 1
- VZNCSZQPNIEEMN-UHFFFAOYSA-N 1-fluoro-2-isocyanatobenzene Chemical compound FC1=CC=CC=C1N=C=O VZNCSZQPNIEEMN-UHFFFAOYSA-N 0.000 description 1
- RIKWVZGZRYDACA-UHFFFAOYSA-N 1-fluoro-3-isocyanatobenzene Chemical compound FC1=CC=CC(N=C=O)=C1 RIKWVZGZRYDACA-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- JUCXIWZFENGFJP-UHFFFAOYSA-N 3-chloro-4-methylpyridazine Chemical class CC1=CC=NN=C1Cl JUCXIWZFENGFJP-UHFFFAOYSA-N 0.000 description 1
- NPMDZXVUGYSEMH-UHFFFAOYSA-N 4-(2h-triazol-4-yl)oxadiazole Chemical compound C1=NNN=C1C1=CON=N1 NPMDZXVUGYSEMH-UHFFFAOYSA-N 0.000 description 1
- YRJLEOWRVNBAOI-WFZUHFMFSA-N 4-[(1r,2s)-2-amino-1-hydroxypropyl]benzene-1,2-diol;hydrochloride Chemical compound Cl.C[C@H](N)[C@H](O)C1=CC=C(O)C(O)=C1 YRJLEOWRVNBAOI-WFZUHFMFSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical compound [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 description 1
- PEAOEIWYQVXZMB-UHFFFAOYSA-N 5-bromo-2-chloropyridine Chemical compound ClC1=CC=C(Br)C=N1 PEAOEIWYQVXZMB-UHFFFAOYSA-N 0.000 description 1
- CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- 235000011437 Amygdalus communis Nutrition 0.000 description 1
- 244000144725 Amygdalus communis Species 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- 0 C*C1=CC(B2OC(C)(C)C(C)(C)O2)=CCC1 Chemical compound C*C1=CC(B2OC(C)(C)C(C)(C)O2)=CCC1 0.000 description 1
- PJLSNOYLAQEJLZ-UHFFFAOYSA-N COCCOc1cccc(-c(cn2)ccc2OC(C2)CN2C(Nc2nccnc2)=O)c1 Chemical compound COCCOc1cccc(-c(cn2)ccc2OC(C2)CN2C(Nc2nccnc2)=O)c1 PJLSNOYLAQEJLZ-UHFFFAOYSA-N 0.000 description 1
- JKZDNQWCCLHQNS-UHFFFAOYSA-N COCCOc1cccc(-c(cn2)ccc2OC(C2)CN2C(Nc2nnccc2)=O)c1 Chemical compound COCCOc1cccc(-c(cn2)ccc2OC(C2)CN2C(Nc2nnccc2)=O)c1 JKZDNQWCCLHQNS-UHFFFAOYSA-N 0.000 description 1
- 241000218236 Cannabis Species 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- QDODQNNHESSBFP-UHFFFAOYSA-N ClC1=C(C=C(C=C1)O)OB(O)O Chemical compound ClC1=C(C=C(C=C1)O)OB(O)O QDODQNNHESSBFP-UHFFFAOYSA-N 0.000 description 1
- 206010011793 Cystitis haemorrhagic Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 description 1
- 241000790917 Dioxys <bee> Species 0.000 description 1
- 206010052804 Drug tolerance Diseases 0.000 description 1
- 208000012661 Dyskinesia Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 239000004278 EU approved seasoning Substances 0.000 description 1
- 208000004232 Enteritis Diseases 0.000 description 1
- 208000004930 Fatty Liver Diseases 0.000 description 1
- 208000002091 Febrile Seizures Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 206010056328 Hepatic ischaemia Diseases 0.000 description 1
- 206010019708 Hepatic steatosis Diseases 0.000 description 1
- 208000004454 Hyperalgesia Diseases 0.000 description 1
- APFVZKRXHVQHRQ-UHFFFAOYSA-N Ic(cc1)cnc1OC(C1)CN1C(c1ccccc1)c1ccccc1 Chemical compound Ic(cc1)cnc1OC(C1)CN1C(c1ccccc1)c1ccccc1 APFVZKRXHVQHRQ-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 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 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- YOSUQMUUAGTQHP-UHFFFAOYSA-N N1(CC=CC=C1)C(=O)O.N1CCC1 Chemical compound N1(CC=CC=C1)C(=O)O.N1CCC1 YOSUQMUUAGTQHP-UHFFFAOYSA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- ODSUPKGRLUURIS-UHFFFAOYSA-N Nc1cc(-c(cn2)ccc2OC(C2)CN2C(Nc2cnccc2)=O)ccc1 Chemical compound Nc1cc(-c(cn2)ccc2OC(C2)CN2C(Nc2cnccc2)=O)ccc1 ODSUPKGRLUURIS-UHFFFAOYSA-N 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 101150003085 Pdcl gene Proteins 0.000 description 1
- 208000005374 Poisoning Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 208000007048 Polymyalgia Rheumatica Diseases 0.000 description 1
- 208000006399 Premature Obstetric Labor Diseases 0.000 description 1
- 206010036600 Premature labour Diseases 0.000 description 1
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 1
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 1
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 206010038910 Retinitis Diseases 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 229910004298 SiO 2 Inorganic materials 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 206010066218 Stress Urinary Incontinence Diseases 0.000 description 1
- 238000003639 Student–Newman–Keuls (SNK) method Methods 0.000 description 1
- 208000000491 Tendinopathy Diseases 0.000 description 1
- 206010043255 Tendonitis Diseases 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 208000030886 Traumatic Brain injury Diseases 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 208000010399 Wasting Syndrome Diseases 0.000 description 1
- AXJQTMCNUIVMSD-UHFFFAOYSA-N [O-][NH2+]c(cc1)ccc1OC(N(C1)CC1Oc(nc1)ccc1I)=O Chemical compound [O-][NH2+]c(cc1)ccc1OC(N(C1)CC1Oc(nc1)ccc1I)=O AXJQTMCNUIVMSD-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 201000007930 alcohol dependence Diseases 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000001741 anti-phlogistic effect Effects 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- LGEQQWMQCRIYKG-UHFFFAOYSA-N arachidonic acid ethanolamide Natural products CCCCCC=CCC=CCC=CCC=CCCCC(=O)NCCO LGEQQWMQCRIYKG-UHFFFAOYSA-N 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- CUBCNYWQJHBXIY-UHFFFAOYSA-N benzoic acid;2-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1O CUBCNYWQJHBXIY-UHFFFAOYSA-N 0.000 description 1
- AQOKCDNYWBIDND-FTOWTWDKSA-N bimatoprost Chemical compound CCNC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)CCC1=CC=CC=C1 AQOKCDNYWBIDND-FTOWTWDKSA-N 0.000 description 1
- 229960002470 bimatoprost Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000002639 bone cement Substances 0.000 description 1
- 125000005619 boric acid group Chemical class 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000001925 catabolic effect Effects 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229940112822 chewing gum Drugs 0.000 description 1
- 235000015218 chewing gum Nutrition 0.000 description 1
- 230000009693 chronic damage Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 206010009887 colitis Diseases 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000001995 cyclobutyl group Chemical class [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- UZBQIPPOMKBLAS-UHFFFAOYSA-N diethylazanide Chemical compound CC[N-]CC UZBQIPPOMKBLAS-UHFFFAOYSA-N 0.000 description 1
- PCXRACLQFPRCBB-ZWKOTPCHSA-N dihydrocannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)C)CCC(C)=C1 PCXRACLQFPRCBB-ZWKOTPCHSA-N 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 208000024732 dysthymic disease Diseases 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 230000006353 environmental stress Effects 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- MYIRARNXCGWFHI-UHFFFAOYSA-N ethoxyethane;2-methylpentane Chemical compound CCOCC.CCCC(C)C MYIRARNXCGWFHI-UHFFFAOYSA-N 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical group CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 208000010706 fatty liver disease Diseases 0.000 description 1
- 206010016284 febrile convulsion Diseases 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000004428 fluoroalkoxy group Chemical group 0.000 description 1
- 125000003709 fluoroalkyl group Chemical group 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 230000026781 habituation Effects 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 201000002802 hemorrhagic cystitis Diseases 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 208000009326 ileitis Diseases 0.000 description 1
- 230000007813 immunodeficiency Effects 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 208000002551 irritable bowel syndrome Diseases 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 235000011475 lollipops Nutrition 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000015654 memory Effects 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 210000000929 nociceptor Anatomy 0.000 description 1
- 229950009305 nordefrin Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 125000001312 palmitoyl group Chemical group O=C([*])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])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 208000026440 premature labor Diseases 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000001107 psychogenic effect Effects 0.000 description 1
- 235000019633 pungent taste Nutrition 0.000 description 1
- XFTQRUTUGRCSGO-UHFFFAOYSA-N pyrazin-2-amine Chemical compound NC1=CN=CC=N1 XFTQRUTUGRCSGO-UHFFFAOYSA-N 0.000 description 1
- OYRRZWATULMEPF-UHFFFAOYSA-N pyrimidin-4-amine Chemical compound NC1=CC=NC=N1 OYRRZWATULMEPF-UHFFFAOYSA-N 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 229910052814 silicon oxide Inorganic materials 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 231100000240 steatosis hepatitis Toxicity 0.000 description 1
- 208000022170 stress incontinence Diseases 0.000 description 1
- DHCDFWKWKRSZHF-UHFFFAOYSA-N sulfurothioic S-acid Chemical compound OS(O)(=O)=S DHCDFWKWKRSZHF-UHFFFAOYSA-N 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000009492 tablet coating Methods 0.000 description 1
- 239000002700 tablet coating Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 235000012976 tarts Nutrition 0.000 description 1
- 201000004415 tendinitis Diseases 0.000 description 1
- 206010043778 thyroiditis Diseases 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000009529 traumatic brain injury Effects 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Classifications
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- 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
- A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- 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
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
- A61P25/20—Hypnotics; Sedatives
-
- 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
- A61P25/22—Anxiolytics
-
- 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
- A61P25/24—Antidepressants
-
- 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
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- 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]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Immunology (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Cardiology (AREA)
- Psychiatry (AREA)
- Ophthalmology & Optometry (AREA)
- Urology & Nephrology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hospice & Palliative Care (AREA)
- Pulmonology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Vascular Medicine (AREA)
- Tropical Medicine & Parasitology (AREA)
- Virology (AREA)
- Diabetes (AREA)
- Child & Adolescent Psychology (AREA)
Abstract
Description
本发明涉及一类氮杂环丁烷衍生物,所述氮杂环丁烷衍生物是脂肪酸酰胺水解酶(FAAH)的抑制剂,能够用于治疗可以通过抑制FAAH活性而获益的疾病或医学状况,例如治疗焦虑,抑郁,疼痛,炎症,以及进食失调、睡眠失调、神经变性失调和运动失调。
发明背景
大麻素受体CB1和CB2的内源性显效剂包括脂肪酸酰胺花生四烯酸乙醇胺(anandamide)(AEA)。通过薄膜结合的蛋白质脂肪酸酰胺水解酶(FAAH)使得AEA水解形成花生四烯酸。Cravatt及其合作者于1996年对FAAH进行了表征(Cravatt,Nature 1996,384,83)。结果证明了FAAH另外还对很多种重要的脂质信号脂肪酸酰胺的分解代谢有影响,所述多种重要的脂质信号脂肪酸酰胺包括:另一种主要的内大麻素,2-花生四烯酰基甘油(arachidonoylglycerol)(2-AG)(Science 1992,258,1946-1949);诱发睡眠的物质,油酰胺(Science 1995,268,1506);食欲抑制剂,N-油酰基乙醇胺(OEA)(Rodriguez de Fonesca,Nature 2001,414,209);以及消炎剂,棕榈酰基乙醇酰胺(PEA)(Lambert,Curr.Med.Chem.2002,9(6),663)。
人们一直在寻求FAAH的抑制剂,因为这些抑制剂能够提高这些内源性信号脂质的浓度,由此产生相关的有益的药理学效果。已经有一些报道提到了各种FAAH抑制剂在预临床模型中的效果。这些效果包括止疼性质(见WO 02/087569,WO 04/033652);焦虑(Kathuria,Nat.Med.2003,9(1),76);痉挛(Baker,FASEB J.2001,15(2),300)。
对某些外源性大麻素的效果的研究结果也提出了FAAH抑制剂可以有效地治疗各种病征、疾病、紊乱或症状。包括疼痛,恶心/呕吐,厌食,痉挛,运动失调,癫痫和青光眼。迄今为止,已经得到证实的大麻素的治疗应用包括缓解癌症患者由于化疗造成的恶心和呕吐,提高由于消耗综合征造成的食欲减退的患有HIV/AIDS的患者的食欲。
除了已经获得证实的迹象以外,治疗领域对于大麻素在阵痛(即治疗疼痛)方面获得了很多的关注。五个小型随机对照试验显示,四氢大麻醇THC优于安慰剂,产生与剂量相关的镇痛效果(Robson,Br.J.Psychiatry2001,178,107-115)。
许多患有多发性硬化症的个人声称通过使用大麻可以减轻与疾病相关的疼痛和痉挛,小型对照试验支持了这一点(Svendsen,Br.Med.J.2004,329,253)。类似地,各种脊髓受伤的人员(例如截瘫病人)报告说通过吸食大麻可以缓解其痛苦的痉挛。一篇报道显示,大麻素似乎能够控制多发性硬化症的CREAE模型中的痉挛和震颤,表明这些效果是由CB1和CB2受体介导的(Baker,Nature 2000,404,84-87)。人们已经用四氢大麻醇/大麻二酚(THC/CBD)的窄比例混合物对多发性硬化症和脊髓受伤的病人进行了三期临床实验。
大麻素产生眼内压(IOP)的与剂量相关的减小,因此能够缓解青光眼症状。眼科医师(Ophthalmologist)已经为那些患有青光眼、而其它的药物又无法充分控制眼内压的病人开出了大麻处方(Robson,2001supra)。
除了FAAH抑制剂对AEA和其它内大麻素的效果以外,其它脂质媒介剂的FAAH分解代谢的抑制剂可以用来治疗其它的医疗病征。例如,已经证明PEA对动物模型的发炎、免疫抑制、痛感丧失和神经保护具有生物效果(Ueda,J.Biol.Chem.2001,276(38),35552)。油酰胺是另一种FAAH底物,它会诱发睡眠(Boger,Proc.Natl.Acad.Sci.USA 2000,97(10),5044;Mendelson,Neuropsychopharmacology 2001,25,S36)。
认为FAAH抑制剂可能能够用来治疗阿耳茨海默氏病,精神分裂症,抑郁症,酒精中毒,成瘾性,自杀,帕金森症,杭廷顿氏舞蹈病,中风,呕吐,早产,胚胎植入,内毒素性休克,肝硬化,动脉粥样硬化,癌症,外伤性头痛,青光眼,以及骨接合剂植入综合征。
其它可能能够通过抑制FAAH活性而获益的疾病或医学病征包括例如多发性硬化症,视网膜炎,肌萎缩性脊髓侧索硬化,免疫缺陷病毒引发的脑炎,注意力缺乏障碍[伴多动],疼痛,伤害性疼痛,神经性疼痛,炎性痛,非炎性痛,疼痛的出血性膀胱炎,肥胖症,高脂血症,代谢失调,摄食和禁食,起伏食欲,应激,记忆力,老化、高血压,脓毒性休克,心原性休克,肠炎和肠运动性,肠易激综合征,大肠炎,腹泻,回肠炎,局部缺血,脑缺血,肝缺血,心肌梗塞,大脑兴奋性中毒,癫痫发作,热性癫痫发作,神经中毒性,神经病,昏睡,引发昏睡,睡眠延长,失眠症和炎症。
可能通过抑制FAAH活性而获益的神经性和心理性的疾病或病征包括例如疼痛,抑郁,焦虑,青光眼,恶心,呕吐,丧失食欲,睡眠障碍,呼吸障碍,过敏,外伤性脑损伤,中风,泛化性焦虑症(GAD),强制性障碍,应激,压迫性尿失禁,注意缺陷障碍[伴多动],精神分裂症,精神病,帕金森症,肌肉痉挛,癫痫,运动障碍,癫痫发作,时差症和失眠症。
其它可能能够通过抑制FAAH活性而获益的疾病或医学病征包括例如各种代谢综合征,疾病,失调和/或病征,包括但不限于抗胰岛素综合征,糖尿病,高脂血症,脂肪肝,肥胖症,动脉粥样硬化和动脉硬化。
FAAH抑制剂可能可以用来治疗各种痛苦的综合征、疾病、失调和/或病征,包括但不限于具有以下特征的那些:非炎性痛,炎性痛,外围神经性疼痛,中枢性痛,非传入刺激性疼痛,慢性伤害性疼痛,疼痛受体刺激,幻觉和瞬时剧痛。
通过抑制FAAH活性还有可能能够用来治疗各种包括炎症的病征。这些病征包括但不限于关节炎(例如类风湿性关节炎,肩部腱炎或关节炎,痛风性关节炎以及风湿性多肌痛),器官特异性炎症(例如甲状腺炎,肝炎,炎性肠疾病),哮喘,其它自身免疫性疾病(例如多发性硬化症),慢性阻塞性肺病(COPD),过敏性鼻炎和心血管疾病。
FAAH抑制剂可能可以用来防止神经变性或者用于神经保护。
另外,已经证明当FAAH活性降低或者缺失的时候,其一种底物,花生四烯酸乙醇胺,作为COX-2的底物,将花生四烯酸乙醇胺转化为前列酰胺(prostamide)(Weber等人,J.Lipid.Res.2004;45:757)。在存在FAAH抑制剂的情况下,某些前列酰胺的浓度可能会增大。某些前列酰胺与眼内压减低和眼压低相关。因此,FAAH抑制剂可以用来治疗青光眼。
发明内容
本发明提供一类具有FAAH抑制活性的氮杂环丁烷衍生物,在下文中对其进行更充分的定义和描述。本发明的化合物可以用来治疗能够通过抑制FAAH活性而受益的疾病或医学病征。上文已经描述了这些疾病或病征。具体来说,本发明的化合物可以用来治疗焦虑,抑郁,疼痛,炎症,睡眠失调或运动失调。
发明详述
在一个方面,本发明提供了式(I)的化合物,或其药学上可接受的盐:
式中:
Ar1是任选取代的苯基或者包含5个或6个环原子的任选取代的单环杂芳基;
Ar2是任选取代的苯基,包含5个或6个环原子的任选取代的单环杂芳基,或者每个稠合的环中包含5个或6个环原子的任选取代的稠合的双环杂芳基;
Ar3是选自下组的二价基团:任选取代的亚苯基,以及包含5个或6个环原子的任选取代的单环亚杂芳基。
在其它的方面,本发明提供了:
(a)一种药学组合物,该组合物包含以上式(I)的化合物或其药学上可接受的盐,以及一种或多种药学上可接受的载体和/或赋形剂;
(b)以上式(I)的化合物或其药学上可接受的盐,在用于治疗可以通过抑制FAAH活性而受益的疾病或医学病征中的应用;
(c)一种对能够通过抑制FAAH活性而获益的疾病或医学病征进行治疗的方法,该方法包括给予患有所述疾病或病征的对象有效量的以上式(I)的化合物或其药学上可接受的盐。
能够通过抑制FAAH活性而受益的疾病或医学病征包括上文所述的那些,具体来说包括焦虑,抑郁,疼痛(特别是伤害性疼痛,神经性疼痛,内脏痛,外科手术后疼痛和癌症引起的疼痛),痒,炎症,睡眠失调和运动失调。
术语
在本发明中,术语“(Ca-Cb)烷基”是指有a至b个碳原子的直链或支链烷基,其中a和b是整数。因而,例如,当a是1而b是6时,该术语包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、和正己基。
在本文中,术语“(Ca-Cb)氟烷基”(其中a和b是整数)表示包含a至b个碳原子的直链或支链烷基,其中一个或多个氢原子被氟原子替代。此术语包括单氟甲基、二氟甲基和三氟甲基。
在本发明中,无条件限制的术语“杂芳基”是指包含一个或多个选自S、N和O的杂原子的单环或稠合双环的芳香基。单环杂芳基具体可以包含5个或6个环原子。在稠合的双环杂芳基中,每个稠合的环可以包含5个或6个环原子。杂芳基的例子为噻吩基,苯并噻吩基,呋喃基,苯并呋喃基,吡咯基,咪唑基,苯并咪唑基,噻唑基,苯并噻唑基,异噻唑基,苯并异噻唑基,吡唑基,噁唑基,苯并噁唑基,异噁唑基,苯并异噁唑基,异噻唑基,三唑基,苯并三唑基,噻二唑基,噁二唑基,吡啶基,哒嗪基,嘧啶基,吡嗪基,三嗪基,吲哚基和吲唑基。
“二价亚苯基”是具有两个不饱和价的苯环,包括1,3-亚苯基和1,4-亚苯基。
“二价亚杂芳基”是其中两个环碳原子具有不饱和价的杂芳环。例如,包含6个环原子的单环二价亚杂芳基包括:亚吡啶基,亚嘧啶基和亚吡嗪基:
包含5个环原子的单环二价亚杂芳基包括下式所示的这些:
式中X是-NH-,-N(CH3)-,N(CH2CH3)-,-O-或-S-,Y是=C-或=NH-。
除非上下文有另外的具体说明,否则当术语″取代的″用于任意苯基或杂芳基部分的时候,表示被至少一个取代基取代,例如所述至少一个取代基选自(C1-C6)烷基,(C1-C6)氟烷基,(C1-C6)烷氧基(包括在芳环相邻的碳原子上取代的亚甲基二氧基和亚乙基二氧基),(C1-C6)氟烷氧基,(C1-C6)烷氧基-(C1-C6)烷基,苄氧基-(C1-C6)烷基,(C1-C6)烷氧基-(C1-C6)烷氧基,苄氧基-(C1-C6)烷氧基,羟基,羟基(C1-C6)烷基,羟基(C1-C6)烷氧基,巯基,巯基(C1-C6)烷基,(C1-C6)烷硫基,环丙基,卤素(包括氟和氯),硝基,腈(氰基),-COOH,四唑基,-COORA,-CORA,-SO2RA,-CONH2,-SO2NH2,-CONHRA,-SO2NHRA,-CONRARB,-SO2NRARB,-NH2,-NHRA,-NRARB,-OCONH2,-OCONHRA,-OCONRARB,-NHCORA,-NHCOORA,-NRBCOORA,-NHSO2ORA,-NRBSO2ORA,-NHCONH2,-NRACONH2,-NHCONHRB-NRACONHRB,-NHCONRARB 或-NRACONRARB,其中RA和RB是独立的(C1-C4)烷基,或者当RA和RB与相同的氮相连的时候,它们可以与所述氮一起形成环状氨基,例如吗啉基,哌啶基或哌嗪基。“任选的取代基”可以是上文包括的取代基中的一种。
在本发明中,术语“盐”包括碱加成盐、酸加成盐及季盐。本发明的酸性的化合物可以与碱形成盐,包括药学或兽医学可接受的盐,所述碱是例如碱金属氢氧化物,例如氢氧化钠和氢氧化钾;碱土金属氢氧化物,例如氢氧化钙,氢氧化钡和氢氧化镁,以及有机碱,例如N-乙基哌啶,二苄基胺等。那些碱性的化合物(I)可以与无机酸、与有机酸形成盐,包括药学上或兽医学上可接受的盐,无机酸包括氢卤酸如盐酸或氢溴酸、硫酸、硝酸或磷酸等,有机酸包括乙酸、酒石酸、琥珀酸、富马酸、马来酸、苹果酸、水杨酸、柠檬酸、甲磺酸和对甲苯磺酸等。本文中任意非限制性地提到落入式(I)范围内的化合物时,都认为提到了该化合物,而不管其是否为盐的形式。
关于合适的盐的综述,参见药用盐手册:性质、选择及用途(Handbookof Pharmaceutical Salts:Properties,Selection,and Use),Stahl和Wermuth编著(Wiley-VCH,德国韦恩海姆,2002)。
通常可以用于药物的许多有机化合物中,预期至少一部分的本发明的化合物能够以晶体水合物和溶剂合物的形式回收。当然这些水合物和溶剂合物仅仅是本发明活性化合物的具体物理-化学形式,因此构成本发明的一部分。本发明任意非限制性地提到落入式(I)范围内的化合物的时候,则认为提到该化合物,而无论其是否为水合物或溶剂合物的形式。在本发明中,用术语“溶剂合物”描述一种包含本发明的化合物及化学计量的一种或多种药学上可接受的溶剂分子如乙醇的分子络合物。如果所述溶剂是水,则用术语“水合物”。
结构特征
在本发明的化合物中:
Ar1可以是任选取代的苯基,或者可以选自下组单环杂芳基:例如,吡啶基,噻吩基,呋喃基,吡咯基,咪唑基,噁唑基,异噁唑基,噻唑基,异噻唑基,吡唑基,三唑基,噁二唑基,噻二唑基,哒嗪基,嘧啶基,吡嗪基,四唑基和三嗪基,任意这些基团可以任选地被取代。在特殊的情况下,Ar1是苯基,2-,4-或5-噁唑基,2-,4-或5-噻唑基,[1,3,4]噻二唑-2-基,[1,3,4]噁二唑-2-基,[1,2,3]噁二唑-4-基,1-,4-吡唑基或[1,2,4]三唑-3-基,其中任意的基团可以任选地被取代。在具体的情况下,Ar1可以是例如苯基,2-氟苯基,3-(2-甲氧基-乙氧基)-苯基或2-甲氧基-5-(2-甲氧基-乙氧基)-苯基。
Ar2可以是任选取代的苯基;或者可以选自以下单环杂芳基,例如吡啶基,噻吩基,呋喃基,吡咯基,咪唑基,噁唑基,异噁唑基,噻唑基,异噻唑基,吡唑基,三唑基,噁二唑基,噻二唑基,哒嗪基,嘧啶基,吡嗪基和三嗪基,其中任意的基团可以被任选地取代;或者可以选自以下的稠合双环杂芳基,例如苯并噻吩基,苯并呋喃基,苯并咪唑基,苯并噻唑基,苯并异噻唑基,吡唑基,苯并噁唑基,苯并异噁唑基,苯并三唑基,吲哚基和吲唑基,任意这些基团可以任选地被取代。在具体的情况下,Ar2是苯基,2-,3-或4-吡啶基,2-,4-或5-嘧啶基,吡嗪-2-基,哒嗪-3-基,2-噻唑基,2-噁唑基,苯并[d]异噁唑-3-基,吲唑-3-基,5-噁二唑基或5-噻二唑基,任意这些基团可以被任选地取代。
目前优选的Ar2基团包括苯基,吡啶基,嘧啶基,吡嗪基或哒嗪基,任意这些基团被任选地取代。例如,Ar2可以是3-吡啶基,嘧啶-4-基,吡嗪-2-基或哒嗪-3-基。
Ar3可以是任选取代的亚苯基,例如1,4-亚苯基;或者可以选自例如二价亚吡啶基,亚噻吩基,亚呋喃基,亚吡咯基,亚咪唑基,亚噁唑基,亚异噁唑基,亚噻唑基,亚异噻唑基,亚吡唑基,亚三唑基,亚哒嗪基,亚嘧啶基,亚吡嗪基,亚三嗪基,亚噻二唑基,任意这些基团被任选地取代。
目前优选的Ar3包括亚苯基或亚吡啶基,例如任选取代的二价1,4-亚苯基或下式所示的2,5-亚吡啶基:
其中单个星号标记的键是与Ar1连接的,用两个星号标记的键与式(I)所示的氧连接。
亚杂芳基Ar3的其它具体例子包括以下二价基团,任意这些基团被任选地取代:
其中用单个星号标记的键与Ar1连接,用两个星号标记的键与氧连接。
通常在Ar1,Ar2和Ar3中,每个环上的任选取代基不大于2个。Ar1,Ar2和Ar3中任意任选的取代基可以独立地选自例如氯,氟,溴,环丙基,甲基,单甲基、二甲基或三甲基,三氟甲基,二氟甲基,单氟甲基,甲氧基,乙氧基,丙氧基,丁氧基,戊氧基,2-甲氧基乙氧基,2-苄氧基-乙氧基,2-羟基-乙氧基,单氟甲氧基、二氟甲氧基或三氟甲氧基,氰基,羟基,-CO2R1或-SO2R1,其中R1是氢,甲基或乙基,四唑基,-NR2R3,-CH2NR2R3和-C(=O)NR2R3,其中R2和R3独立地是氢,甲基或乙基。
在本发明的一些化合物中,基团Ar1-Ar3-是4-苯基苯基,例如是联苯-4-基。
在本发明的其它化合物中,Ar2是2-或3-氟苯基,或者是3-吡啶基。
在本发明化合物的一个目前优选的亚类中:
Ar2是3-吡啶基,嘧啶-4-基,吡嗪-2-基或哒嗪-3-基;
Ar3是任选取代的二价1,4-亚苯基或下式所示的2,5-亚吡啶基:
其中单个星号标记的键是与Ar1连接的,用两个星号标记的键与氧连接;并且
Ar1是任选取代的苯基。
在该优选的亚类中,Ar1可以是例如2-氟苯基,3-(2-甲氧基-乙氧基)-苯基或2-甲氧基-5-(2-甲氧基-乙氧基)-苯基,目前优选Ar2是哒嗪-3-基;
本发明化合物的具体例子包括本文实施例中的那些。
以下的本发明化合物优选具有以下性质的组合:在口服给药之后能够同时获得良好的内在的FAAH抑制趋势,具有高而持久的血浆浓度,通过实验室大鼠测试证明了这些性质:
3-(联苯-4-基氧基)-氮杂环丁烷-1-羧酸吡啶-3-基酰胺;
3-[5-(2-氟-苯基)-吡啶-2-基氧基]-氮杂环丁烷-1-羧酸哒嗪-3-基酰胺;
3-{5-[3-(2-甲氧基-乙氧基)-苯基]-吡啶-2-基氧基}-氮杂环丁烷-1-羧酸哒嗪-3-基酰胺;
3-(5-苯基-吡啶-2-基氧基)-氮杂环丁烷-1-羧酸哒嗪-3-基酰胺;
3-[5-(2-甲氧基-苯基)-吡啶-2-基氧基]-氮杂环丁烷-1-羧酸哒嗪-3-基酰胺;
以及这些化合物药学上可接受的盐。
合成
有多种合成路线用于合成本发明涉及的化合物(I),但是所有的路线都依赖于合成有机化学家已知的化学反应。因此,式(I)的化合物可以根据标准文献所述的步骤以及本领域普通技术人员众所周知的工艺合成。常规的文献来源是“高等有机化学(Advanced organic chemistry)”,第四版(Wiley),J March,“复杂有机转化(Comprehensive Organic Transformation)”,第二版(Wiley),R.C.Larock,“杂环化学手册(Handbook of HeterocyclicChemistry)”,第二版(Pergamon),A.R.Katritzky),综述文章,例如可在以下文献中找到的那些:“Synthesis”,“Acc.Chem.Res.”,“Chem.Rev”,或者标准文献在线检索给出的一级文献来源或者二级文献来源,例如“ChemicalAbstracts”或“Beilstein”。这类文献方法包括制备例的方法以及类似的方法。
例如,可以使得式(II)的氮杂环丁烷或其盐与式(III)的异氰酸酯反应,提供本发明的化合物。Ar1,Ar2或Ar3中的任意反应活性的任选取代基可以在反应过程中被保护,随后解保护:
本发明化合物的其它合成路径在以下实施例的历程1、2和3中进行了概括。
用途
如上所述,本发明的化合物可以用来治疗能够通过抑制FAAH活性而获益的疾病或医学病征,这些疾病和病征的例子如上文所述。
应当理解,针对特定患者的具体剂量水平取决于各种因素,包括所采用的具体化合物的活性、年龄、体重、总体健康情况、性别、饮食、给药时间、给药途径、排泄速度、药物组合、以及治疗中的特定疾病产生机理和严重性。一般来说,口服制剂的合适剂量通常为0.1-3000毫克,每天一次、两次或三次,或者通过注射、吸入、注入或其它途径每天给予相等的量。但是,本领域中通常最优剂量和给药频率由临床试验决定。
可以制备本发明涉及的化合物,采用与其药代动力学性质相一致的任何途径给药。口服给药组合物可以是以下的形式:片剂、胶囊、粉末、颗粒、锭剂、液体或凝胶制剂。口服给药的片剂和胶囊可以是单位剂量形式,并且可含有常用赋形剂,例如粘结剂,如糖浆、阿拉伯胶、明胶、山梨糖醇、黄芪胶或聚乙烯吡咯烷酮;填充剂,如乳糖、糖、玉米淀粉、磷酸钙、山梨糖醇或甘氨酸;压片润滑剂,如硬脂酸镁、滑石粉、聚乙二醇或氧化硅;崩解剂,如马铃薯淀粉;或者可接受的湿润剂如月桂基硫酸钠。可按照普通药学实践中熟知的方法对片剂包衣。口服液体制剂可以是(例如)水性或油性混悬剂、溶液剂、乳剂、糖浆或酏剂的形式,或者可以是临用前用水或其他合适载体重建的干燥产品。这类液体制剂可含有常用添加剂,例如助悬剂,如山梨糖醇、糖浆、甲基纤维素、葡萄糖糖浆、明胶、氢化食用油;乳化剂,如卵磷脂、去水山梨糖醇单油酸酯或阿拉伯胶;非水性载体(可包含食用油),如杏仁油、分级椰子油,油酯如甘油、丙二醇或乙醇;防腐剂,如对羟基苯甲酸甲酯或丙酯或者山梨酸,如果需要还含有常用调味剂或着色剂。其它用于口服给药的具体制剂包括包含本发明化合物的口香糖以及可吸入锭剂和棒棒糖。
外用于皮肤时,可将药物制成乳膏剂、洗剂或油膏剂。可用于该药物乳膏剂或油膏剂是本领域熟知的常规制剂,例如药剂学标准教科书如英国药典(British Pharmacopoeia)所述。通过持续释放的贴片对皮肤给药的输药方法也是本领域已知的。
活性成分也可以在无菌介质中经胃肠外途径给药。根据所用的运载体和浓度,药物可悬浮或溶解于该运载体中。有利的是,可将辅助试剂如局部麻醉剂、防腐剂和缓冲剂溶解于运载体中。
还可以将活性组分配制成用于吸入,例如作为鼻喷雾剂或者干粉或气溶胶吸入剂。为了通过吸入进行输送,所述活性化合物优选为微型颗粒的形式。它们可以通过各种技术制备,包括喷雾干燥、冷冻干燥和微粉化。气溶胶的形成可以使用例如压力驱动喷射雾化器或超声雾化器,优选使用推进剂驱动的计量的气溶胶或者源自例如吸入胶囊或者其它“干粉”输送系统的微粉化化合物形式的无推进剂给药进行。
本发明的化合物可以与其它种类的药学活性药物一起给药。
以下实施例显示了本发明具体化合物的制备和活性,但是本发明的范围不限于此。
部分A:实施例1-4
使用Bruker DPX-400MHz NMR波谱仪进行1H(400MHz)和13C(100MHz)核磁共振(NMR)分析。波谱参比样是已知的样品溶剂的化学位移。报道了1H nmr数据,其中显示化学位移(δ),多重性(s,单重峰;d,二重峰;t,三重峰;q,四重峰;m,多重峰;dd,双二重峰;br,宽峰;app,表观等),积分(例如1H),耦合常数(J),单位为Hz。报道了13C数据,列出了化学位移(δ)。氘代溶剂得自希格玛-艾尔德里奇化学公司(Sigma-Aldrich ChemicalCompany)或氟化学公司(Fluorochem)。
LCMS分析使用HP1100设备进行,该设备使用购自Phenomenex的Luna 3μM,C18(2),30毫米×4.6毫米内径的柱子,试验温度为22℃,流速为2毫升·分钟-1,使用以下溶剂体系:
溶剂A:HPLC级水+10mM的乙酸铵+0.08%v/v的甲酸。
溶剂B:95%v/v HPLC级丙烯腈+5%v/v溶剂A+0.08%v/v甲酸。
梯度:95∶5溶剂A∶溶剂B,0.00-0.25分钟;95∶5至5∶95的溶剂A∶溶剂B,0.25至2.50分钟;5∶95的溶剂A∶溶剂B,2.50至3.75分钟。
紫外检测在230nm,254nm和270nm波长下进行。质谱仪是HP1100MSD,Series A设备,在正离子或负离子电喷雾离子化模式下操作。分子量扫描范围是120至1000。样品以在DMSO中的1mM的溶液的形式提供,包括5微升的部分回路填充注入。
用Waters FractionLynx MS Autopurification系统进行制备性HPLC纯化,所述系统使用购自Phenomenex的5μM C18(2),100mm×20mm内径的柱子,流速为20毫升·分钟-1,使用紫外二极管阵列检测(210-400纳米)和质量指导的收集。每种化合物使用的梯度列于表1。溶剂A和B如以上分析条件所述。质谱仪是Waters Micromass ZQ2000质谱仪,在正离子或负离子电喷雾离子化模式下运作,分子量扫描范围为150-1000。
历程A
实施例1:3-(联苯-4-基氧基)-氮杂环丁烷-1-羧酸苯基酰胺
步骤1
1-二苯甲基-3-(联苯-4-基氧基)氮杂环丁烷
在室温下,4-苯基苯酚(8.51克,50毫摩),1-二苯甲基氮杂环丁烷-3-醇(11.97克,50毫摩)和三苯基膦(13.11克,50毫摩)在乙腈(250毫升)中搅拌20分钟,直至所有的反应物完全溶解。滴加入偶氮二羧酸二异丙酯(9.84毫升,10.11克,50毫摩)。形成白色沉淀,初始的反应温和放热。黄色的颜色立即退去。5分钟之后,将反应加热至回流温度,当沉淀溶解的时候,在此温度搅拌3.25小时。将该混合物冷却至室温,用刮刀刮擦以引发结晶。该混合物在冰上冷却,过滤收集固体。固体进一步用冷的乙腈洗涤,充分干燥,制得白色粉末状的醚(15.42克,79%);mp 141-142℃;Rf0.68(2∶1己烷∶EtOAc);LCMS保留时间2.57分,m/z 392.2[M+H]+;1H nmr(400MHz;DMSO-d6)δ7.60-7.52(m,4H),7.46-7.39(m,6H),7.31-7.26(m,5H),7.19(tt,2H,J=7.2和2.0Hz),6.90(d,2H,J=8.8Hz),4.88(app qn,1H,J=5.6Hz),4.53(s,1H),3.67-3.63(m,2H)和3.02-2.98(m,2H)。
步骤2
盐酸3-(联苯-4-基氧基)氮杂环丁烷
将1-二苯甲基-3-(联苯-4-基氧基)氮杂环丁烷(15.40克,39.34毫摩)溶解在二氯甲烷(400毫升)中,搅拌,用冰水浴冷却。在10分钟时间内,将氯甲酸-1-氯乙酯(8.49毫升,11.25克,78.69毫摩)分成1毫升的小份加入,该混合物在0℃再搅拌30分钟,然后在室温下搅拌25.5小时。另外加入氯甲酸-1-氯乙酯(4.25毫升,5.63克,39.35毫摩),对该混合物搅拌3天。溶剂在真空条件下蒸发,向制得的白色固体中加入甲醇(300毫升)。对混合物进行温和加热,使其溶解,然后在剧烈搅拌的同时使其冷却,此时形成白色沉淀。在室温下再搅拌2小时之后,过滤收集固体,得到白色固体胺(7.41克,72%);mp>195℃;LCMS保留时间1.64分,m/z 226.1[M+H]+;1H nmr(400MHz;DMSO-d6)δ9.26(br s,2H),7.64-7.60(m,4H),7.47-7.41(m,2H),7.33(tt,1H,J=7.3和1.2Hz),6.96(d,2H,J=8.8Hz),5.13(tt,1H,J=6.8和4.8Hz),4.46(dd,2H,J=12.4和6.8Hz)以及4.01(dd,2H,J=12.4和4.8Hz)。
步骤3:3-(联苯-4-基氧基)-氮杂环丁烷-1-羧酸苯基酰胺
向搅拌的盐酸3-(1,1’-联苯-4-基氧基)氮杂环丁烷(100毫克,382微摩)在二氯甲烷(2.5毫升)中的悬浮液加入二乙基胺(63微升,48毫克,478微摩),然后加入异氰酸苯酯(35微升,38毫克,320微摩),该反应在室温下搅拌2.5小时。将混合物直接加到2克预先填充的SCX-2料筒上,产物用1∶1的二氯甲烷∶甲醇(15毫升)洗脱。蒸发溶剂得到白色粉末脲(113毫克,100%);LCMS保留时间为2.57分,m/z 345.2[M+H]+;1H nmr(400MHz;DMSO-d6)δ8.54(s,1H),7.62(d,4H,J=7.6Hz),7.50(d,2H,J=8.0Hz),7.44(t,2H,J=7.6Hz),7.32(t,1H,J=7.2Hz),7.23(t,2H,J=7.8Hz),7.98-7.91(m,3H),5.09(m,1H),.4.46-4.42(m,2H)和3.95-3.91(m,2H)。
实施例2:3-(联苯-4-基氧基)-氮杂环丁烷-1-羧酸(3-氟-苯基)-酰胺
标题化合物按照实施例1的方式制备,但是使用异氰酸-3-氟苯基酯代替异氰酸苯基酯。制得的产物为白色粉末;LCMS保留时间2.61分钟,m/z363.1[M+H]+;1H nmr(400MHz;DMSO-d6)δ8.76(s,1H),7.64-7.61(m,4H),7.51-7.41(m,3H),7.34-7.23(m,3H),6.96(d,2H,J=8.4Hz),6.77-6.72(m,1H),5.12-5.07(m,1H),4.46(dd,2H,J=9.2和6.4Hz)以及3.94(dd,2H,J=9.2和4.0Hz)。
实施例3:3-(联苯-4-基氧基)-氮杂环丁烷-1-羧酸(2-氟-苯基)-酰胺
标题化合物按照实施例1的步骤制备,但是使用异氰酸-2-氟苯基酯代替异氰酸苯基酯。产物通过用二乙基醚研碎来进行纯化,制得灰白色固体标题化合物;LCMS保留时间2.60分钟,m/z 363.1[M+H]+;1H nmr(400MHz;DMSO-d6)8.33(s,1H),7.64-7.58(m,5H),7.44(t,2H,J=7.6Hz),7.32(t,1H,J=7.4Hz),7.23-7.17(m,1H),7.14-7.08(m,2H),6.96(d,2H,J=8.8Hz),5.13-5.07(m,1H),4.45(dd,2H,J=9.2和6.8Hz)以及3.94(dd,2H,J=9.2和3.6Hz)。
实施例4:3-(联苯-4-基氧基)-氮杂环丁烷-1-羧酸吡啶-3-基酰胺
在氮气气氛下将盐酸-3-(联苯-4-基氧基)氮杂环丁烷(3克,11.47毫摩)悬浮在二氯甲烷(45毫升)中,用三乙基胺(4.0毫升,28.68毫摩)进行处理,在室温下搅拌10分钟。将该混合物冷却至0℃,用分成几份的吡啶-3-异氰酸酯(1.15克,9.56毫摩)进行处理。在0℃搅拌10分钟,然后在室温下搅拌16小时。所述溶液进一步用二氯甲烷(200毫升)稀释,用H2O洗涤(2×100毫升),然后用盐水(50毫升)洗涤,(用MgSO4)干燥,真空蒸发溶剂得到灰白色固体。所述固体用二乙基醚研碎,然后在二氯甲烷/甲醇/乙腈混合物中与MP-异氰酸酯树脂一起搅拌3天。过滤该混合物,在真空条件下减少至干。制得的固体依次用二乙基醚、乙腈研碎,然后过滤,制得白色固体脲(1.2克,36%);Rf0.10(5%MeOH-DCM);LCMS保留时间2.08分钟,m/z 346.2[M+H]+;1H nmr(400MHz;DMSO-d6)δ8.97(s,1H),8.75(d,1H,J=2.3Hz),8.21(d,1H,J=4.7Hz),8.05-8.01(m,1H),7.65-7.60(m,4H),7.44(t,2H,J=7.9Hz),7.39(dd,1H,J=8.3和4.7Hz),7.32(t,1H,J=7.3Hz),6.96(d,2H,J=8.8Hz),5.14-5.08(m,1H),4.49(dd,2H,J=9.5和6.5Hz)和3.97(dd,2H,J=9.5和3.8Hz);13C nmr(100MHz;DMSO-d6)156.2(C),155.9(C),141.4(CH),139.6(C),138.9(CH),137.3(C),133.4(C),128.9(CH),128.1(CH),126.9(CH),126.8(CH),126.3(CH),123.9(CH),115.1(CH),65.6(CH)和56.4(CH2)。
B部分-实施例5-19
一般步骤
得自商业来源的所有反应物都不经进一步纯化直接使用。无水溶剂得自商业来源,不经进一步干燥直接使用。使用预先装填的硅胶料筒进行闪式色谱法(Strata SI-1;英国柴郡的费尼米尼克斯公司(Phenomenex,Cheshire UK)或IST Flash II,英国亨郭德市的阿尔戈公司(Argonaut,Hengoed,UK))。薄层色谱(TLC)在涂覆了Merck Type 60F254硅胶的5x10cm板上进行。一旦在紫外下可见,如果合适的话,可以通过用产物通过的距离除以溶剂(溶剂前锋)通过的总距离,得到各个点的保留因子(Rf)值。
本发明的一些化合物用LC/MS表征(方法A),该表征使用HewlettPackard 1100series LC/MSD,与四端电路检测器相连(离子化模式:电子喷雾正性或负性;柱子:Phenomenex Luna 3μM C18(2)30x4.6mm,柱温22℃)。通过将1.93g克乙酸铵溶解在2.5升HPLC级H2O中并加入2毫升甲酸,制备了缓冲剂A。通过将132毫升缓冲剂A加入2.5升HPLC级乙腈中并加入2毫升甲酸来制备缓冲剂B;在3.75分钟内洗脱梯度95∶5至5∶95的缓冲剂A∶缓冲剂B。(注射体积:2微升)。流速=2.0毫升/分钟。在230,254和270纳米处用二极管阵列检测器进行紫外检测。保留时间(RT)的单位为分钟。除非另外说明,否则离子化是正的。
本发明的一些化合物用另外的LC/MS法来表征(“方法B”),该方法使用Agilent 1200SL series设备,该设备与具有多模式源的Agilent MSD 6140单独四极相连;柱子:Phenomenex Luna 2.5μM C18,50x2mm,HST,柱温55℃。缓冲剂A:水/10mM甲酸铵/0.04%(v/v)甲酸,pH=3.5。缓冲剂B:乙腈/5.3%(v/v)A/0.04%(v/v)甲酸。方法B的梯度和流速见表1(注射体积:2微升)。使用二极管阵列检测器在230、254和270纳米处进行紫外检测。保留时间(RT)的单位为分钟。除非另外说明,否则离子化是正的。
表1:LC/MS方法B的溶剂梯度和流速。
时间(分钟) | 溶剂A(%) | 溶剂B(%) | 流速(毫升/分钟) |
0.00 | 95 | 5 | 1.1 |
0.12 | 95 | 5 | 1.1 |
1.30 | 5 | 95 | 1.1 |
1.35 | 5 | 95 | 1.7 |
1.85 | 5 | 95 | 1.7 |
1.90 | 5 | 95 | 1.1 |
1.95 | 95 | 5 | 1.1 |
核磁共振(NMR)分析使用Brucker DPX-400MHz NMR波谱仪进行。波谱参比物是溶剂的已知的化学位移。质子NMR数据报道如下:化学位移(δ)单位为ppm,多重性(s,单重峰;d,二重峰;t,三重峰;q,四重峰;p,五重峰;m,多重峰;dd,双二重峰;br,宽峰;),积分,耦合常数。
本发明的一些化合物通过制备用HPLC纯化。制备用HPLC纯化在Waters FractionLynx MS Autopurification系统上进行,使用购自费尼米尼克斯公司的5μM C18(2),100mm×20mm内径的柱子,流速为20毫升·分钟-1,使用紫外二极管阵列检测(210-400纳米)和质量指导的收集。对于各种具体的化合物决定化合物洗脱的合适溶剂梯度。
在pH=4的条件下:溶剂A:HPLC级水+10mM乙酸铵+0.08%v/v甲酸。
溶剂B:95%v/v HPLC级乙腈+5%v/v溶剂A+0.08%v/v甲酸。
在pH=9时:溶剂A:HPLC级水+10mM乙酸铵+0.08%v/v氨溶液。
溶剂B:95%v/v HPLC级乙腈+5%v/v溶剂A+0.08%v/v氨溶液
使用Bruker DPX-400MHz NMR波谱仪进行1H(400MHz)和13C(100MHz)核磁共振(NMR)分析。波谱参比物是样品溶剂的已知化学位移。报道了1H nmr数据,其中显示化学位移(δ),多重性(s,单重峰;d,二重峰;t,三重峰;q,四重峰;m,多重峰;dd,双二重峰;br,宽峰;app,表观等),积分(例如1H),耦合常数(J),单位为Hz。报道了13C数据,列出了化学位移(δ)。氘代溶剂得自希格玛-艾尔德里奇化学公司(Sigma-Aldrich ChemicalCompany)或氟化学公司(Fluorochem)。
质谱仪是Waters Micromass ZQ2000质谱仪,以正离子或负离子电喷雾离子化模式操作,分子量扫描范围是150-1000。
使用AutoNom标准获得IUPAC化学名称。
实施例中的一些化合物通过历程1所示的途径制备。
历程1
实施例的一些化合物通过以下历程2所示的途径制备。
历程2
实施例的一些化合物通过历程3所示的途径制备。实验方法、反应物和产物分离方法是有机合成领域的普通技术人员已知的。已知还可以采用其它的方法。
历程3
实施例5
3-{5-[3-(2-甲氧基-乙氧基)-苯基]-吡啶-2-基氧基}-氮杂环丁烷-1-羧酸嘧啶-4-基酰胺
步骤1
2-(1-二苯甲基-氮杂环丁烷-3-基氧基)-5-碘-吡啶
在氮气气氛下,将氢化钠(在矿物油中的60重量%的分散体,6.36克,0.156摩尔)分成数份加入1-二苯甲基-氮杂环丁烷-3-醇(25.38克,0.106摩尔)在无水二甲基甲酰胺(400毫升)的溶液中。使得形成沉淀,发生起泡现象。加完之后,反应混合物在环境温度下搅拌15分钟。使用滴液漏斗,在15分钟时间内向该反应混合物中加入2-氯-5-碘吡啶(25.40克,0.106摩尔)在二甲基甲酰胺(100毫升)中的溶液。加完之后,将反应混合物加热至70℃并在氮气气氛下搅拌4.5小时。然后使得反应混合物冷却至环境温度,然后加入饱和氯化铵水溶液(30毫升)。真空除去溶剂,残余的固体在乙酸乙酯(600毫升)和饱和碳酸氢钠水溶液(500毫升)之间配分。分离相,有机相用饱和氯化钠水溶液洗涤(3×300毫升),用硫酸钠干燥,过滤,真空除去滤液溶剂,制得黄棕色固体,该固体用二乙基醚研碎,过滤,真空干燥,制得米黄色固体标题化合物(33.41克,71%)
LCMS(方法A)RT=2.19分钟;m/z=443[M+H]+。
步骤2
盐酸2-(氮杂环丁烷-3-基氧基)-5-碘-吡啶
在环境温度下,通过注射器将氯代甲酸-1-氯乙酯(12.8毫升,0.104摩尔)逐滴加入2-(1-二苯甲基-氮杂环丁烷-3-基氧基)-5-碘-吡啶(23.03克,0.052摩尔)在二氯甲烷(250毫升)中的搅拌的溶液中。制得的溶液在环境温度下搅拌3.5小时,然后加入甲醇(250毫升),反应混合物在环境温度下搅拌16小时。真空除去溶剂,制得的固体残余物用二乙基醚研碎,过滤,然后真空干燥,制得奶油色固体标题产物(17.8克,大于定量产率)。粗产物不经纯化直接使用。
LCMS (方法A)RT=1.24分钟;m/z=277[M+H]+
步骤3
(中间体5)
3-(5-碘-吡啶-2-基氧基)-氮杂环丁烷-1-羧酸4-硝基-苯基酯
在环境温度下,将氯代甲酸-4-硝基苯基酯(692毫克,3.44毫摩)加入2-(1-二苯甲基-氮杂环丁烷-3-基氧基)-5-碘-吡啶(1.01克,2.29摩尔)在二氯甲烷(40毫升)中的搅拌的溶液中。制得的溶液在环境温度下搅拌18小时。真空除去溶剂,产物通过闪式色谱在硅胶(25g)上纯化,用二氯甲烷洗脱,制得无色固体标题化合物(474毫克,47%)。
LCMS(方法A)RT=2.54分钟;m/z=442[M+H]+.1H NMR:(400MHz,DMSO-d6)δ3.95-4.04(m,1H,4.16-4.24(m,1H),4.36-4.44(m,1H),4.56-4.74(m,1H),5.35-5.40*m,1H),6.84(d,1H,J=8.5Hz),7.43-7.47(m,2H),8.07(dd,1H,J=8.5,2.2Hz),8.26-8.29(m,2H),8.38(d,1H,J=2.1Hz)。
步骤4
3-(5-碘-吡啶-2-基氧基)-氮杂环丁烷-1-羧酸嘧啶-4-基酰胺
在氮气气氛下,使用注射器将4-氨基嘧啶(Aldrich,243毫克,2.54毫摩)在无水DMF(4毫升)中的溶液加入氢化钠(在矿物油中的60重量%的分散体,185毫克,4.62毫摩)在无水DMF(4毫升)中的悬浮液。该混合物搅拌5分钟,然后滴加入3-(5-碘-吡啶-2-基氧基)-氮杂环丁烷-1-羧酸4-硝基-苯基酯(1.02克,2.31毫摩)在无水DMF(6毫升)中的溶液,制得的黄色混浊的混合物在环境温度下搅拌1.5小时。将反应混合物倒入饱和氯化铵水溶液(30毫升)中,用乙酸乙酯萃取(3×100毫升)。合并的有机相用饱和氯化钠水溶液(100毫升)洗涤,用硫酸钠干燥。过滤该混合物,真空除去滤液的溶剂,制得黄色固体,该固体用二乙基醚研碎,过滤,干燥,制得无色固体标题化合物(594毫克,65%)。
LCMS(方法A)RT=1.89分钟;m/z=398[M+H]+。
步骤5
2-[3-(2-甲氧基-乙氧基)-苯基]-4,4,5,5-四甲基-[1,3,2]二噁环戊硼烷
在3-羟基苯基硼酸频那醇酯(Apollo,1.0克,4.55毫摩)的DMF(10毫升)溶液中加入碳酸钾(1.88克,13.65毫摩)。加入2-溴乙基甲基醚(0.41毫升,5.46毫摩),该反应混合物加热至100℃,加热1小时。使得反应混合物冷却,然后在乙酸乙酯(50毫升)和水(150毫升)之间配分。分离相,有机相用盐水(150毫升)洗涤,用无水硫酸钠干燥,过滤,真空除去滤液中的溶剂,制得浅棕色油状物标题化合物(1.1g),该化合物不经进一步纯化直接使用。
LCMS(方法A)RT=1.42分钟;m/z=无离子化。
步骤6
3-{5-[3-(2-甲氧基-乙氧基)-苯基]-吡啶-2-基氧基}-氮杂环丁烷-1-羧酸嘧啶-4-基酰胺
将2-[3-(2-甲氧基-乙氧基)-苯基]-4,4,5,5-四甲基-[1,3,2]二噁环戊硼烷(步骤5,109毫克,0.39毫摩)在THF/H2O(10∶1;3毫升)中的溶液加入包含3-(5-碘-吡啶-2-基氧基)-氮杂环丁烷-1-羧酸嘧啶-4-基酰胺(步骤4,104毫克,0.26毫摩)和碳酸钾(108毫克,0.786毫摩)的微波小瓶中。氮气鼓泡通过该混合物5分钟,然后加入含CH2Cl2的1,1’-双[(二苯基膦基)-二茂铁]二氯化钯(II)络合物(21毫克,10摩尔%),密封该小瓶,在微波合成器中,在100℃加热30分钟。冷却的反应混合物用乙酸乙酯(20毫升)稀释,通过C盐(2.5克IST料筒)进行洗涤。另外10毫升的乙酸乙酯通过所述C盐垫进行洗涤,合并的滤液依次用水(30毫升),1N的NaOH溶液(30毫升),水(30毫升),和饱和氯化钠溶液(30毫升)洗涤。混合物用硫酸钠干燥,然后过滤。真空除去滤液的溶剂,制得棕色胶状物,该棕色胶状物通过闪式色谱法纯化,用梯度为50-100%的乙酸乙酯-己烷洗脱剂洗脱,制得粘性固体。将产物溶解在二氯甲烷(25毫升)中,加入2N的NaOH(水溶液,25毫升),该混合物剧烈搅拌1小时。分离相,有机层用硫酸钠干燥,过滤,真空除去滤液中的溶剂,留下固体,该固体用二乙基醚研碎,过滤,然后干燥,制得无色固体标题化合物(50毫克,45%)
LCMS:(方法A)RT=1.97分钟;m/z=422[M+H]+。
TLC:Rf=0.39(100%EtOAc).1H NMR:(400MHz,DMSO-d6)δ3.32(s,3H),3.68(m,2H),4.03(brm,2H),4.17(m,2H),4.48(brm,2H),5.38(m,1H),6.95(dd,1H,J=8.1,2.5Hz),6.99(d,1H,J=8.6Hz),7.20-7.26(m,2H),7.37(dd,1H,J=8.3,8.3Hz),7.92(dd,1H,J=5.7,1.2Hz),8.08(dd,1H,J=8.6,2.5Hz),8.48-8.54(m,2H),8.57(m,1H),9.86(brs,1H).
实施例6
3-{5-[3-(2-甲氧基-乙氧基)-苯基]-吡啶-2-基氧基}-氮杂环丁烷-1-羧酸吡嗪-2-基酰胺
步骤1
2-(1-二苯甲基-氮杂环丁烷-3-基氧基)-5-溴-吡啶
该化合物通过实施例5的步骤1所示的方法制备。由此使得5-溴-2-氯吡啶(31.31克,0.163摩尔)与1-二苯甲基-氮杂环丁烷-3-醇(38.92克,0.163摩尔)反应,制得浅棕色固体标题化合物(44.14克,64%)。
LCMS:(方法A)RT=2.11分钟;m/z=397[M+H]+。
步骤2
盐酸2-(氮杂环丁烷-3-基氧基)-5-溴-吡啶
该化合物通过实施例5的步骤2所列的方法制备。由此使得盐酸2-(氮杂环丁烷-3-基氧基)-5-溴-吡啶(13.76克,0.035摩尔)与氯代甲酸-1-氯乙酯反应,制得棕色固体标题化合物(10.22克,大于计量产率)。
LCMS:(方法A)RT=1.15分钟;m/z=231[M+H]+。
步骤3
3-(5-溴-吡啶-2-基氧基)-氮杂环丁烷-1-羧酸4-硝基-苯基酯
该化合物通过实施例5的步骤3所示的方法制备。由此使得盐酸2-(氮杂环丁烷-3-基氧基)-5-溴-吡啶(2.0克,7.53毫摩)与氯代甲酸-4-硝基苯基酯反应,制得浅黄色固体标题化合物(1.11克,37%)。
LCMS:(方法A)RT=2.50分钟;m/z=396[M+H]+。
步骤4
3-(5-溴-吡啶-2-基氧基)-氮杂环丁烷-1-羧酸吡嗪-2-基酰胺
该化合物通过实施例5的步骤4所列的方法制备。由此使得3-(5-溴-吡啶-2-基氧基)-氮杂环丁烷-1-羧酸4-硝基-苯基酯(905毫克,2.30毫摩)与2-氨基吡嗪(243毫克,2.53毫摩)反应,制得灰白色固体标题化合物(454毫克,56%)。
LCMS:(方法A)RT=1.86分钟;m/z=352[M+H]+。
步骤5
3-{5-[3-(2-甲氧基-乙氧基)-苯基]-吡啶-2-基氧基}-氮杂环丁烷-1-羧酸吡嗪-2-基酰胺
该化合物通过实施例5的步骤6所示的方法制备。因此3-(5-溴-吡啶-2-基氧基)-氮杂环丁烷-1-羧酸吡嗪-2-基酰胺(100毫克,0.285毫摩)与2-[3-(2-甲氧基-乙氧基)-苯基]-4,4,5,5-四甲基-[1,3,2]二噁环戊硼烷(实施例5步骤5,118毫克,0.855毫摩)反应,制得无色粉末状标题化合物(70毫克,58%)。
LCMS:(方法A)RT=2.01分钟;m/z=422[M+H]+。
TLC:Rf=0.51(100%EtOAc)
1H NMR:(400MHz,DMSO-d6)δ3.32(s,3H),3.68(m,2H),4.03(m,2H),4.17(m,2H),4.48(m,2H),5.39(m,1H),6.95(m,1H),6.99(d,1H,J=8.6Hz),7.21-7.25(m,2H),7.37(dd,1H,J=8.3,8.3Hz),8.09(dd,1H,J=8.5,2.5Hz),8.22(d,1H,J=2.5Hz),8.29(m,1H)8.49(d,1H,J=2.0Hz),9.17(d,1H,J=1.5Hz),9.65(brs,1H)。
实施例7
3-{5-[3-(2-甲氧基-乙氧基)-苯基]-吡啶-2-基氧基}-氮杂环丁烷-1-羧酸哒嗪-3-基酰胺
步骤1
3-(5-碘-吡啶-2-基氧基)-氮杂环丁烷-1-羧酸哒嗪-3-基酰胺
在氮气气氛下,向冰浴冷却的氢化钠(矿物油中浓度60重量%,(2.1克,52.4毫摩))的DMF(50毫升)溶液(逐滴)加入3-氨基哒嗪(2.74克,28.79毫摩)的DMF(50毫升)溶液。几分钟之后,加入3-(5-碘-吡啶-2-基氧基)-氮杂环丁烷-1-羧酸4-硝基-苯基酯(实施例5,步骤3);11.54克,26.18毫摩)的DMF(40毫升)溶液。5分钟后撤去冷却浴,使得反应升温至环境温度,搅拌1.5小时。加入饱和碳酸氢钠溶液(500毫升),用EtOAc(4×400毫升)萃取该混合物。合并的有机相用饱和氯化钠溶液(500毫升)洗涤,用硫酸钠干燥,然后过滤。真空除去滤液中的溶剂,制得粗产物,该粗产物用二乙基醚研碎,制得无色固体标题化合物(7.52克,72%)。
LCMS:(方法A)RT=1.84分钟;m/z=398[M+H]+。
步骤2
3-{5-[3-(2-甲氧基-乙氧基)-苯基]-吡啶-2-基氧基}-氮杂环丁烷-1-羧酸哒嗪-3-基酰胺
该化合物通过与实施例5的步骤6所示的方法类似的方式制备。由此使得3-(5-碘-吡啶-2-基氧基)-氮杂环丁烷-1-羧酸哒嗪-3-基酰胺(456毫克,1.15毫摩)与2-[3-(2-甲氧基-乙氧基)-苯基]-4,4,5,5-四甲基-[1,3,2]二噁环戊硼烷(实施例5步骤5,392毫克,1.50毫摩)反应,制得无色粉末标题化合物(120毫克,25%)。
LCMS:(方法A)RT=1.18分钟;m/z=422[M+H]+。
1H NMR:(400MHz,DMSO-d6)δ3.32(s,3H),3.68(m,2H),4.04(brm,2H),4.17(m,2H),4.49(brm,2H),5.40(m,1H),6.95(m,1H),6.99(d,1H,J=8.9Hz),7.21-7.25(m,2H),7.37(dd,1H,J=8.3,8.3Hz),7.59(dd,1H,J=9.1,4.5Hz),8.09(dd,1H,J=8.6,2.6Hz),8.15(dd,1H,J=9.1,1.4Hz),8.50(d,1H,J=4.5,1.4Hz),8.85(dd,1H,J=4.5,1.4Hz),9.97(s,1H)。
实施例8
3-{5-[3-(2-甲氧基-乙氧基)-苯基]-吡啶-2-基氧基}-氮杂环丁烷-1-羧酸吡啶-3-基酰胺
步骤1
3-(5-碘-吡啶-2-基氧基)-氮杂环丁烷-1-羧酸吡啶-3-基酰胺
将盐酸2-(氮杂环丁烷-3-基氧基)-5-碘-吡啶(4.2克,13毫摩)悬浮在无水二氯甲烷(50毫升)中,加入三乙基胺(5.5毫升)。加入吡啶-3-异氰酸酯(1.45克,11.7毫摩),该反应混合物在环境温度下搅拌16小时。真空除去悬浮体的溶剂,残余物在乙酸乙酯(400毫升)和饱和碳酸氢钠水溶液(400毫升)之间配分。该混合物通过C盐垫过滤,对滤液进行相分离。有机相用饱和碳酸氢钠水溶液(250毫升)洗涤,然后用饱和氯化钠水溶液(250毫升)洗涤,用硫酸钠干燥,然后过滤。真空除去滤液的溶剂,制得黄色固体,该黄色固体在硅胶(100g)上通过闪式色谱纯化,用7N的氨的甲醇溶液∶二氯甲烷=1∶19的混合物洗脱。制得无色固体标题化合物(2.0克,42%)。
LCMS:(方法A)RT=1.04分钟;m/z=397[M+H]+。
步骤2
3-[5-(3-羟基-苯基)-吡啶-2-基氧基]-氮杂环丁烷-1-羧酸吡啶-3-基酰胺
该化合物通过实施例5的步骤6所示的方法制备。由此3-(5-碘-吡啶-2-基氧基)-氮杂环丁烷-1-羧酸吡啶-3-基酰胺(300毫克,0.76毫摩)与3-羟基苯基硼酸(156毫克,1.14毫摩)反应,制得粗产物,该粗产物在硅胶上通过闪式色谱法纯化,用溶剂梯度为1∶19至1∶9的7N的氨的甲醇溶液∶二氯甲烷洗脱。制得无色粉末标题化合物(130毫克,47%)。
LCMS:(方法A)RT=0.97分钟;m/z=363[M+H]+.
步骤3
3-{5-[3-(2-甲氧基-乙氧基)-苯基]-吡啶-2-基氧基}-氮杂环丁烷-1-羧酸吡啶-3-基酰胺
将碳酸钾(23毫克,165微摩)加入3-[5-(3-羟基-苯基)-吡啶-2-基氧基]-氮杂环丁烷-1-羧酸吡啶-3-基酰胺(20mg 55微摩)的DMF(0.5毫升)溶液。加入2-溴乙基甲基醚(6微升,66微摩),在微波合成器中,将反应混合物加热至100℃,加热1小时。使得反应混合物冷却,真空除去溶剂。通过制备性HPLC对粗产物进行纯化,制得无色固体标题产物(6.7毫克,29%)。
LCMS:(方法A)RT=1.11分钟;m/z=421[M+H]+。
1H NMR:(400MHz,DMSO-d6)δ3.32(s,3H),3.68(m,2H),3.99(m,2H),4.17(m,2H),4.44(m,2H),5.39(m,1H),6.92-6.97(m,1H),7.00(d,1H,J=8.6Hz),7.21-7.25(m,2H),7.27(dd,1H,J=8.3,4.8Hz),7.37(dd,1H,J=8.1,8.1Hz),7.93(dm,1H),8.09(dd,1H,J=8.6,2.6Hz),8.15(dd,1H,J=4.5,1.6Hz),8.49(d,1H,J=2.1Hz),8.66(d,1H,J=2.1Hz),8.75(s,1H)。
实施例9
3-{5-[3-(2-苄氧基-乙氧基)-苯基]-吡啶-2-基氧基}-氮杂环丁烷-1-羧酸哒嗪-3-基酰胺
步骤1
2-[3-(2-苄氧基-乙氧基)-苯基]-4,4,5,5-四甲基-[1,3,2]二噁环戊硼烷
通过实施例5的步骤5所示的方法制备了该化合物。由此使得3-羟基苯基硼酸频那醇酯(500毫克,2.27毫摩)与苄基-2-溴乙基醚(0.54毫升,3.41摩尔)反应,处理后的粗产物不经进一步纯化直接使用。
步骤2
3-{5-[3-(2-苄氧基-乙氧基)-苯基]-吡啶-2-基氧基}-氮杂环丁烷-1-羧酸哒嗪-3-基酰胺
该化合物通过实施例5步骤6列出的方法制备。由此使得3-(5-碘-吡啶-2-基氧基)-氮杂环丁烷-1-羧酸哒嗪-3-基酰胺(实施例7,步骤1)(600毫克,1.15毫摩)与2-[3-(2-苄氧基-乙氧基)-苯基]-4,4,5,5-四甲基-[1,3,2]二噁环戊硼烷(1.5当量)反应。粗产物在硅胶上通过闪式色谱法纯化,用4∶1的乙酸乙酯∶己烷洗脱,制得棕色泡沫标题化合物(214毫克,28%)。
LCMS:(方法B)RT=1.37分钟;m/z=498[M+H]+。
1H NMR:(400MHz,DMSO-d6)δ3.80(m,2H),4.04(m,2H),4.23(m,2H),4.49(m,2H),4.57(s,2H),5.40(m,1H),6.96(m,1H),6.99(d,1H,J=8.6Hz),7.21-7.25(m,2H),7.29(m,1H),7.33-7.39(m,5H),7.59(dd,1H,J=9.1,4.8Hz),8.08(dd,1H,J=8.6,2.5Hz),8.15(dd,1H,J=9.1,1.3Hz),8.49(d,1H,J=2.5Hz),8.84(dd,1H,J=4.5,1.3Hz),9.97(brs,1H)。
实施例10
3-{5-[3-(2-羟基-乙氧基)-苯基]-吡啶-2-基氧基}-氮杂环丁烷-1-羧酸哒嗪-3-基酰胺
步骤1
3-{5-[3-(2-羟基-乙氧基)-苯基]-吡啶-2-基氧基}-氮杂环丁烷-1-羧酸哒嗪-3-基酰胺
在氮气气氛下,将3-{5-[3-(2-苄氧基-乙氧基)-苯基]-吡啶-2-基氧基}-氮杂环丁烷-1-羧酸哒嗪-3-基酰胺(实施例9,325毫克,0.65毫摩)溶解在无水二氯甲烷(10毫升)中。该混合物用冰水浴冷却,逐滴加入三溴化硼的二氯甲烷溶液(1M,0.98毫升,0.98毫摩),制得沉淀。反应混合物在0℃搅拌2小时。过滤收集沉淀,在硅胶上闪式色谱纯化,使用乙酸乙酯、然后是5-10%的甲醇的DCM溶液洗脱。在pH=4的条件下用制备性HPLC进一步纯化,制得无色固体标题化合物(13毫克,5%)。
LCMS:(方法B)RT=1.05分钟;m/z=408[M+H]+。
1H NMR:(400MHz,DMSO-d6)δ3.73(m,2H),4.00-4.09(m,4H),4.49(m,2H),4.89(t,1H,J=5.5Hz),5.40(m,1H),6.94(dm,1H),7.00(d,1H,J=8.6Hz),7.20-7.25(m,2H),7.37(dd,1H,J=8.1,8.1Hz),7.58(dd,1H,J=9.1,4.8Hz),8.08(dd,1H,J=8.6,2.8Hz),8.15(dd,1H,J=8.8,1.2Hz),8.49(d,1H,J=1.7Hz),8.84(dd,1H,J=4.8,1.7Hz),9.97(brs,1H)。
实施例11
3-{5-[2-甲氧基-5-(2-甲氧基-乙氧基)-苯基]-吡啶-2-基氧基}-氮杂环丁烷-1-羧酸哒嗪-3-基酰胺
步骤1
乙酸4-甲氧基-苯基酯
在氮气气氛下,将三乙基胺(14.55毫升,104.43毫摩)加入冰浴冷却的4-甲氧基苯酚(5.185克,41.77毫摩)的无水醚(200毫升)溶液中。滴加乙酰氯(5.94毫升,83.53毫摩),然后使得反应混合物升温至室温,再搅拌10分钟。反应混合物在乙酸乙酯和饱和碳酸氢钠水溶液之间配分。分离相,有机相用硫酸钠干燥,过滤,真空除去滤液中的溶剂,制得棕色液体标题化合物(7.45克,定量)。
LCMS:(方法A)RT=1.88分钟;未离子化。
TLC:Rf=0.72(7∶3EtOAc∶己烷)
步骤2
乙酸3-溴-4-甲氧基-苯基酯
将乙酸(2.24毫升,7.4毫摩)加入乙酸4-甲氧基-苯基酯(1.0克,6.02毫摩)和乙酸钠(940毫克,11.46毫摩)的混合物中。滴加溴(0.37毫升,6.02毫摩)的乙酸(2.1毫升)溶液,然后该混合物在环境温度下搅拌18小时。再加入0.6毫升乙酸,然后再加入0.1毫升的溴。对混合物搅拌2小时,然后在乙酸乙酯(100毫升)和水(100毫升)之间配分。分离相,有机层依次用碳酸氢钠饱和水溶液(2x150毫升),硫代硫酸钠饱和水溶液(100毫升)和氯化钠饱和水溶液(100毫升)洗涤。有机相用硫酸钠干燥,过滤,真空除去滤液中的溶剂,制得油状物,该油状物在硅胶上通过闪式色谱纯化,用0-10%梯度的乙酸乙酯的己烷溶液洗脱,制得浅棕色油状物的标题化合物(1.2克,81%)。
LCMS:(方法A)RT=2.11分钟;未离子化。
TLC:Rf=0.20(1∶9EtOAc∶己烷)
步骤3
3-溴-4-甲氧基-苯酚
将氢氧化钾(290毫克,5.19毫摩)的水(2.5毫升)溶液加入乙酸3-溴-4-甲氧基-苯基酯(1.2克,4.9毫摩)的甲醇(18.5毫升)溶液中。混合物在环境温度下搅拌30分钟,然后真空除去溶剂,加入水(40毫升)。通过逐滴加入1.2M的HCl水溶液(4.3毫升)使得混合物呈酸性,用二氯甲烷萃取该混合物(2×40毫升)。合并的有机相用硫酸钠干燥,过滤,真空蒸发除去滤液溶剂,制得浅黄色固体标题化合物(976毫克,98%)。
LCMS:(方法A)RT=2.11分钟;未离子化
TLC:Rf=0.28(1∶4EtOAc∶己烷)
步骤4
2-溴-1-甲氧基-4-(2-甲氧基-乙氧基)-苯
将2-溴乙基甲基醚(0.07毫升,0.74毫摩)加入碳酸钾(136毫克,0,99毫摩)和3-溴-4-甲氧基-苯酚(100毫克,0.49毫摩)在DMF(2毫升)中的混合物中,在100℃混合加热1小时。使得反应混合物冷却,在乙酸乙酯(20毫升×2)和水(20毫升)之间配分。合并的有机相用饱和氯化钠水溶液(40毫升)洗涤,用硫酸钠干燥。真空除去溶剂,制得粗油状物,该粗油状物在硅胶上通过闪式色谱法纯化,用梯度为0-10%的乙酸乙酯的己烷溶液洗脱,制得无色液体标题化合物(113毫克,88%)。
LCMS:(方法A)RT=2.12分钟;未离子化。
TLC:Rf=0.34(1∶4EtOAc∶己烷)
步骤5
3-{5-[2-甲氧基-5-(2-甲氧基-乙氧基)-苯基]-吡啶-2-基氧基}-氮杂环丁烷-1-羧酸哒嗪-3-基酰胺
在氮气气氛下用CO2-丙酮浴将2-溴-1-甲氧基-4-(2-甲氧基-乙氧基)-苯(110毫克,0.42毫摩)在无水THF(2毫升)中的溶液冷却至-78℃。加入硼酸三异丙酯(0.19毫升,0.842毫摩),然后加入正丁基锂溶液(2.5M的己烷溶液,0.22毫升,0.55毫摩)。使得该混合物升温至环境温度,真空除去溶剂,制得无色固体。向粗硼酸中加入3-(5-碘-吡啶-2-基氧基)-氮杂环丁烷-1-羧酸哒嗪-3-基酰胺(实施例7,步骤1)(150毫克,0.38毫摩),1N的碳酸氢钠水溶液(1.26毫升),DMF(7毫升)和含CH2Cl2的1,1’-双[(二苯基膦基)-二茂铁]二氯化钯(II)络合物(15mg)。氮气鼓泡通过混合物5分钟,反应混合物在80℃加热2小时。使得混合物冷却,在乙酸乙酯(30毫升)和水(30毫升)之间配分。然后有机相用饱和氯化钠水溶液(60毫升)洗涤,用硫酸钠干燥。真空除去溶剂,制得粗油状物,该油状物在硅胶上通过闪式色谱纯化,用梯度为0-10%的乙酸乙酯的己烷溶液洗脱,制得浅黄色泡沫状标题化合物(77毫克,41%)。
LCMS:(方法A)RT=1.94分钟;m/z=450[M-H]-(负离子化)。
TLC:Rf=0.21(100%EtOAc)
1H NMR:(400MHz,CDCl3)δ3.45(s,3H),3.75(m,2H),3.77(s,3H),4.12(m,2H),4.21(m,2H),4.56(m,2H),5.48(m,1H),6.83(d,1H,J=8.6Hz),6.91(m,3H),7.42(dd,1H,J=9.1,4.8Hz),7.47(brs,1H),7.82(dd,1H,J=8.6,2.5Hz),8.25(d,1H,J=2.3Hz)8.38(dd,1H,J=9.1,1.3Hz),8.84(dd,1H,J=4.5,1.3Hz)。
实施例12
3-[5-(2,5-二甲氧基-苯基)-吡啶-2-基氧基]-氮杂环丁烷-1-羧酸哒嗪-3-基酰胺
该化合物通过实施例5步骤6所示的方法制备。由此3-(5-碘-吡啶-2-基氧基)-氮杂环丁烷-1-羧酸吡嗪-2-基酰胺(100毫克,0.25毫摩)与2,5-二甲氧基苯硼酸(Cas.No 107099-99-0,69毫克,0.38毫摩)反应,制得灰白色粉末标题化合物(84毫克,83%)。
LCMS:(方法B)RT=1.19分钟;m/z=408[M+H]+。
1H NMR:(400MHz,DMSO-d6)δ3.72(s,3H),3.75(s,3H),4.00-4.08(m,2H),4.46-4.51(m,2H),5.36-5.41(m,1H),6.91-6.97(m,3H),7.04-7.06(m,1H),7.58(dd,1H,J=4.5,9.1Hz)7.89(dd,1H,J=2.3,8.6Hz),8.15(dd,1H,J=1.5,9.1Hz),8.27(d,1H,J=1.7Hz),8.85(dd,1H,J=1.4,4.6Hz),9.96(s,1H)。
实施例13
3-(5-苯基-吡啶-2-基氧基)-氮杂环丁烷-1-羧酸哒嗪-3-基酰胺
该化合物通过实施例5步骤6所示的方法制备。由此将3-(5-碘-吡啶-2-基氧基)-氮杂环丁烷-1-羧酸吡嗪-2-基酰胺(750毫克,1.89毫摩),苯硼酸(345毫克,2.83毫摩),碳酸钾(783毫克,5.67毫摩),[1,1’-二(二苯基膦基)二茂铁]二氯化钯(II)(与二氯甲烷络合;155毫克,0.19毫摩)和THF-H2O(10∶1;15毫升)混合起来,密封在两个微波小瓶中,在100℃加热2小时。将小瓶合并,蒸发,加到DCM中的50克SiO2料筒中,然后充分干燥。产物用1∶1的异己烷∶EtOAc至EtOAc的洗脱剂洗脱,对含产物的馏分进行蒸发制得的产物在2∶1的二乙基醚-异己烷中研碎,通过过滤收集,制得白色粉末产物(702毫克,54%);mp 201-202℃;Rf0.17(EtOAc);LCMS rt 1.19分钟[方法B],m/z 348([M+H]+,100%);δH(399MHz;DMSO-d6)9.97(1H,br s),8.85(1H,dd,J=4.5和1.3Hz),8.48(1H,dd,J=2.5和0.5Hz),8.15(1H,dd,J=9.1和1.5Hz),8.08(1H,dd,J=8.6,2.5Hz),7.68-7.66(2H,m),7.59(1H,dd,J=9.1和4.5Hz),7.49-7.45(2H,m),7.39-7.36(1H,m),7.01(1H,dd,J=8.6和0.5Hz),5.40(1H,tt,J=6.6和4.0Hz),4.48(2H,dd,J=8.6和6.6Hz)和4.04(2H,dd,J=9.6和3.0Hz)。
实施例14
3-[5-(2,6-二氟-苯基)-吡啶-2-基氧基]-氮杂环丁烷-1-羧酸哒嗪-3-基酰胺
将3-(5-碘-吡啶-2-基氧基)-氮杂环丁烷-1-羧酸嘧啶-4-基酰胺(50毫克,0.126毫摩),2,6-二氟苯基三氟硼酸钾(29毫克,0.132毫摩),三乙基胺(0.05毫升,0.38毫摩),含CH2Cl2的1,1’-双[(二苯基膦基)-二茂铁]二氯化钯(II)络合物(5毫克,5摩尔%)和EtOH(108毫克,0.786毫摩)混合起来,在80℃加热16小时。该反应并未完成,因此另外加入2,6-二氟苯基三氟硼酸钾(29毫克,0.132毫摩),含CH2Cl2的1,1’-双[(二苯基膦基)-二茂铁]二氯化钯(II)络合物(5毫克,5摩尔%)和三乙基胺(0.05毫升,0.38毫摩),该混合物再加热5小时。使得反应混合物冷却,然后通过C盐垫,用EtOAc和MeOH洗涤。这些有机物在真空中蒸发,制得粗油状物,该粗油状物用闪式色谱法纯化,用梯度为0至4%的MeOH的CH2Cl2溶液洗脱,制得仍然含有杂质的棕色油状物产物。通过HPLC(pH=4,HCO2NH4/HCO2H/H2O/MeCN)对其进行纯化,制得所需的白色固体产物(8毫克,17%)。
LCMS:(方法B)RT=1.2分钟;m/z=384[M+H]+
1H NMR:(400MHz,CDCl3)δ4.06(m,2H),4.50(m,2H),5.41(m,1H),7.07(dd,1H,J=8.6,0.5Hz),7.26(m,2H),7.51(m,1H),7.59(dd,1H,J=4.5Hz),7.89(m,1H),8.15(dd,1H,J=9.0,1.5Hz)8.28(m,1H),8.85(dd,1H,J=4.5,1.3Hz),9.97(bs,1H)。
实施例15
1-(3-{5-[2-氯-5-(2-甲氧基-乙氧基)-苯基]-吡啶-2-基氧基}-氮杂环丁烷-1-基)-2-哒嗪-3-基-乙酮
步骤1
4-氯-3-(4,4,5,5-四甲基-[1,3,2]二噁环戊硼烷-2-基)-苯酚
将2-氯-5-羟基苯基硼酸(409毫克,2.37毫摩),频那醇(336毫克,2.85毫摩),甲苯(20毫升)和4埃的分子筛(400毫克)混合起来,在120℃加热2小时。使该反应混合物冷却,然后在EtOAc(2×30毫升)和水(30毫升)之间配分。合并的有机相用盐水(20毫升)洗涤,干燥(Na2SO4),在真空中蒸发,制得所需的白色固体状产物(500毫克,83%)。
LCMS:(方法A)RT=2.35分钟;m/z=253[M-H]-。
步骤2
1-(3-{5-[2-氯-5-(2-甲氧基-乙氧基)-苯基]-吡啶-2-基氧基}-氮杂环丁烷-1-基)-2-哒嗪-3-基-乙酮
在室温下、氮气中,将4-氯-3-(4,4,5,5-四甲基-[1,3,2]二噁环戊硼烷-2-基)-苯酚(495毫克,1.95毫摩),PPh3(765毫克,2.92毫摩)和THF(11毫升)混合。然后加入2-甲氧基乙醇(0.18毫升,2.34毫摩),对该反应混合物搅拌5分钟。然后将该混合物冷却至0℃,逐滴加入DIAD(0.57毫升,2.92毫摩)。使该混合物升温至室温,再搅拌2小时。反应混合物在EtOAc(2×30毫升)和水(30毫升)之间配分。合并的有机相用盐水(30毫升)洗涤,干燥(Na2SO4),真空蒸发,制得黄色油状物粗产物,该粗产物通过闪式色谱法纯化,用梯度为0至50%的EtOAc的己烷溶液洗脱,制得仍然含杂质的灰白色固体产物(316毫克,不纯)。将其与3-(5-碘-吡啶-2-基氧基)-氮杂环丁烷-1-羧酸嘧啶-4-基酰胺(64毫克,0.162毫摩),1M NaHCO3溶液(0.19毫升,0.194毫摩),PdCl2(PPh3)2(6毫克,2摩尔%)和DMF(4毫升)混合。通过将氮气鼓泡通过该混合物5分钟,使得该混合物脱气,然后在氮气气氛下,在80℃加热2小时。使得该反应冷却,然后通过C盐垫过滤,然后在EtOAc(2×20毫升)和水(25毫升)之间配分。合并的有机相进行干燥(Na2SO4),真空蒸发制得粗油状物,该粗油状物通过闪式色谱法纯化,用梯度为0至10%的MeOH的CH2Cl2溶液洗脱,制得仍然不纯的棕色油状物产物。该产物通过HPLC纯化(pH 4,HCO2NH4/HCO2H/H2O/MeCN),制得所需的白色固体状产物(48毫克,26%)
LCMS:(方法B)RT=1.28分钟;m/z=456[M+H]+
1H NMR:(400MHz,CDCl3)δ3.30(s,3H),3.65(m,2H),4.05(m,2H),4.15(m,2H),4.50(m,2H),5.41(m,1H),7.01(m,3H),7.47(d,1H,J=8.8Hz),7.59(dd,1H,J=4.5Hz),7.89(dd,1H,J=8.6,2.5Hz),8.15(dd,1H,J=9.1,1.5Hz)8.25(d,1H,J=2.5Hz),8.85(dd,1H,J=4.5,1.5Hz),9.97(bs,1H)。
实施例16
3-[5-(2-氟-苯基]-吡啶-2-基氧基]-氮杂环丁烷-1-羧酸吡嗪-2-基酰胺
向处于微波小瓶中的3-(5-溴-吡啶-2-基氧基)-氮杂环丁烷-1-羧酸吡嗪-2-基酰胺(实施例6步骤4;100毫克,0.285毫摩),2-氟苯基硼酸(Aldrich,60毫克,0.428毫摩),碳酸钾(118毫克,0.86毫摩)和含CH2Cl2的1,1’-双[(二苯基膦基)-二茂铁]二氯化钯(II)络合物(23毫克,10摩尔%)的混合物中加入THF/H2O(10∶1,3毫升)。氮气鼓泡通过该混合物5分钟,密封该小瓶,在微波合成器中,在100℃加热20分钟。冷却后的反应混合物用乙酸乙酯(20毫升)稀释,通过C盐过滤(2.5克IST料筒)。将另外10毫升乙酸乙酯洗涤通过所述C盐垫,合并的滤液用水(25毫升)洗涤,然后用饱和氯化钠溶液(25毫升)洗涤。混合物用硫酸钠干燥,然后过滤。真空除去滤液中的溶剂,制得粗产物,然后通过闪式色谱法对该粗产物进行纯化,用梯度为50-100%的乙酸乙酯的己烷溶液洗脱,制得粘性固体,然后用二乙基醚研碎,过滤,干燥,制得无色固体标题化合物(67毫克,64%)。
LCMS:(方法A)RT=2.09分钟;m/z=366.1[M+H]+。
TLC:Rf=0.16(EtOAc/己烷,1∶1)
1H NMR:(400MHz,DMSO-d6)δ4.00-4.07(m,2H),4.44-4.57(m,2H),5.37-5.43(m,1H),7.03(d,1H,J=8.6Hz),7.29-7.37(m,2H),7.40-7.48(m,1H),7.54-7.60(m,1H),7.95-7.99(m,1H),8.22(d,1H,J=2.5Hz),8.29-8.31(m,1H),8.34-8.36(brm,1H),9.17(d,1H,J=1.6Hz),9.65(s,1H)。
实施例17
3-[5-(2-甲氧基-苯基)-吡啶-2-基氧基]-氮杂环丁烷-1-羧酸哒嗪-3-基胺
将2-甲氧基苯基硼酸在THF/H2O(10∶1;40毫升)中的溶液加入包含3-(5-溴-吡啶-2-基氧基)-氮杂环丁烷-1-羧酸哒嗪-3-基酰胺(实施例19步骤1中制备)1.5克,4.28毫摩)和碳酸钾(1.78克,12.86毫摩)的微波小瓶中。氮气鼓泡通过该混合物5分钟,然后加入含CH2Cl2的1,1’-双[(二苯基膦基)-二茂铁]二氯化钯(II)络合物(0.350克,10摩尔%),密封该小瓶,在微波合成器中,在100℃加热30分钟。冷却的反应混合物用乙酸乙酯(100毫升)稀释,然后用饱和碳酸钠水溶液(100毫升)洗涤,然后用饱和氯化钠溶液(100毫升)洗涤。混合物用硫酸镁干燥,然后过滤。真空除去滤液中的溶剂,制得棕色胶状物,该棕色胶状物通过闪式色谱法纯化,用梯度为80-100%的乙酸乙酯的己烷溶液洗脱,制得浅黄色固体。产物用二乙基醚研碎,过滤,然后干燥,制得白色固体标题化合物(1.098克,68%)
LCMS:(方法A)RT=2.04分钟;m/z=378[M+H]+。
1H NMR:(400MHz,DMSO-d6)δ3.78(s,3H),4.04(brm,2H),4.49(brm,2H),5.39(m,1H),6.96(d,1H,J=8.6Hz),7.04(m,1H),7.13(d,1H,J=8.2Hz),7.33(dd,1H,J=7.5,1.6Hz),7.37(m,1H),7.59(dd,1H,J=9.1,4.7Hz),7.88(dd,1H,J=8.6,2.5Hz),8.16(dd,1H,J=9.1,1.4Hz),8.25(d,1H,J=2.5Hz),8.85(dd,1H,J=4.7,1.4Hz),9.96(s,1H)。
实施例18
3-[5-(2-氟-苯基)-吡啶-2-基氧基]-氮杂环丁烷-1-羧酸哒嗪-3-基酰胺
将4-氟苯基硼酸(0.254毫克,1.81毫摩)在THF/H2O(10∶1;10毫升)中的溶液加入包含3-(5-碘-吡啶-2-基氧基)-氮杂环丁烷-1-羧酸哒嗪-3-基酰胺(实施例7,步骤1)(0.480克,1.21毫摩)和碳酸钾(0.50克,3.63毫摩)的微波小瓶中。氮气鼓泡通过混合物5分钟,然后加入含CH2Cl2的1,1’-双[(二苯基膦基)-二茂铁]二氯化钯(II)络合物(0.099克,10摩尔%),密封该小瓶,在微波合成器中,在100℃加热30分钟。冷却的反应混合物用乙酸乙酯(20毫升)稀释,然后用饱和碳酸钠水溶液(20毫升)洗涤,然后用饱和氯化钠水溶液(20毫升)洗涤。该混合物用硫酸镁干燥,然后过滤。真空除去滤液的溶剂,制得棕色胶状物,该胶状物通过闪式色谱法纯化,用梯度为50%至100%的乙酸乙酯的己烷溶液洗脱,制得白色固体(0.235克,53%)
LCMS:(方法B)RT=1.20分钟;m/z=366[M+H]+。
1H NMR:(400MHz,DMSO-d6)δ4.05(brm,2H),4.50(brm,2H),5.41(m,1H),7.04(d,1H,J=8.6Hz),7.29-7.38(m,2H),7.45(m,1H),7.54-7.62(m,2H),7.97(m,1H),8.15(dd,1H,J=9.1,1.4Hz),8.36(app s,1H),8.85(dd,1H,J=4.6,1.4Hz),9.97(s,1H)。
实施例19
3-[5-(2-氟-3-甲氧基-苯基)-吡啶-2-基氧基]-氮杂环丁烷-1-羧酸哒嗪-3-基酰胺
步骤1
3-(5-溴-吡啶-2-基氧基)-氮杂环丁烷-1-羧酸哒嗪-3-基酰胺的合成
在氮气气氛下,向冰浴冷却的氢化钠(60重量%的矿物油溶液,(0.946克,23.6毫摩))的DMF(21毫升)溶液(逐滴)加入3-氨基哒嗪(1.24克,13.01毫摩)的DMF(21毫升)溶液。几分钟之后,加入3-(5-溴-吡啶-2-基氧基)-氮杂环丁烷-1-羧酸4-硝基-苯基酯(实施例10,步骤3;4.66克,11.83毫摩)的DMF(17毫升)溶液。5分钟后,移去冷却浴,使得反应升温至环境温度,搅拌1.5小时。加入饱和碳酸氢钠溶液(500毫升),该混合物用EtOAc萃取(4×400毫升)。合并的有机相用饱和氯化钠溶液(500毫升)洗涤,用硫酸钠干燥,然后过滤。真空除去滤液中的溶剂,制得粗产物,该粗产物用二乙基醚研碎,制得无色固体标题化合物(3.32克,80%)。
LCMS:(方法A)RT=1.81分钟;m/z=352[M+H]+。
步骤2
3-[5-(2-氟-3-甲氧基-苯基)-吡啶-2-基氧基]-氮杂环丁烷-1-羧酸哒嗪-3-基酰胺
将2-氟-3-甲氧基苯基硼酸(0.065克,0.38毫摩)的THF/H2O(10∶1;2毫升)溶液加入包含3-(5-溴-吡啶-2-基氧基)-氮杂环丁烷-1-羧酸哒嗪-3-基酰胺(步骤1制备)(0.100克,0.25毫摩)和碳酸钾(0.105克,0.76毫摩)的微波小瓶中。氮气鼓泡通过该混合物5分钟,然后加入含CH2Cl2的1,1’-双[(二苯基膦基)-二茂铁]二氯化钯(II)络合物(0.020克,10摩尔%),密封该小瓶,在微波合成器中,在100℃加热30分钟。冷却的反应混合物用乙酸乙酯(20毫升)稀释,然后用饱和碳酸钠水溶液(20毫升)洗涤,然后用饱和氯化钠水溶液(20毫升)洗涤。混合物用硫酸镁干燥,然后过滤。真空除去滤液中的溶剂,制得棕色胶状物,通过闪式色谱法纯化,用梯度为80至100%的乙酸乙酯的己烷溶液洗脱,制得灰白色固体(0.079克,78%)。
LCMS:(方法B)RT=1.18分钟;m/z=408[M+H]+。
1H NMR:(400MHz,DMSO-d6)δ3.88(s,3H),4.05(brm,2H),4.49(brm,2H),5.41(m,1H),7.03(d,1H,J=8.6Hz),7.08(m,1H),7.17-7.26(m,2H),7.59(dd,1H,J=9.1,4.6Hz),7.94(m,1H),8.15(dd,1H,J=9.1,1.4Hz),8.33(app s,1H),8.85(dd,1H,J=4.6,1.4Hz),9.96(s,1H)。
实施例20
3-[5-(2-氟-苯基)-吡啶-2-基氧基]-氮杂环丁烷-1-羧酸(6-甲基-哒嗪-3-基)-酰胺
步骤1
2-(1-二苯甲基-氮杂环丁烷-3-基氧基)-5-(2-氟-苯基)-吡啶
向2-氟-硼酸(1.45克,10.36毫摩)和2-(1-二苯甲基-氮杂环丁烷-3-基氧基)-5-碘-吡啶(3.53克,7.97毫摩)在DMF(180毫升)中的溶液加入悬浮在水(20毫升)中碳酸氢钠(2.01g)。该反应混合物在氮气流中搅拌1小时,然后加入包含CH2Cl2的1,1’-双[(二苯基膦基)-二茂铁]二氯化钯(II)络合物(326毫克,5摩尔%),然后在室温下搅拌18小时。
对该反应混合物进行真空浓缩,用乙酸乙酯(400毫升)稀释,然后用C盐过滤,然后用饱和碳酸氢钠水溶液洗涤(3×150毫升),然后用饱和氯化钠溶液(150毫升)洗涤。混合物用硫酸镁干燥,然后过滤。真空除去滤液溶剂,然后残余物用闪式色谱法纯化(4%的甲醇的DCM溶液)制得标题化合物(2.18克,67%)
LCMS:(方法A)RT=2.54分钟;m/z=411[M+H]+。
1H NMR:(400MHz,CDCl3)δ3.12-3.20(m,2H),3.74-3.80(m,2H),4.45(s,1H),5.27-5.33(m,1H),6.81(d,1H,J 8.6),7.11-7.22(m,4H),7.28-7.40(m,6H),7.43-7.46(m,4H),7.75-7.78(m,1H),8.21-8.28(m,1H)。
步骤2
3-[5-(2-氟-苯基)-吡啶-2-基氧基]-氮杂环丁烷-1-羧酸4-硝基-苯基酯
在环境温度下,将氯代甲酸-4-硝基苯基酯(734毫克,3.64毫摩)加入2-(1-二苯甲基-氮杂环丁烷-3-基氧基)-5-(2-氟-苯基)-吡啶(996毫克,2.43摩尔)在二氯甲烷(25毫升)中的搅拌的溶液中。制得的溶液在环境温度下搅拌18小时,用二氯甲烷(150毫升)稀释,然后用饱和碳酸氢钠水溶液洗涤(3×150毫升),然后用饱和氯化钠溶液(150毫升)洗涤。有机相用硫酸镁干燥,然后过滤。真空除去滤液中的溶剂,用甲基叔丁基醚(25毫升)研碎来纯化,过滤后制得黄色固体(786毫克,79%)。
LCMS:(方法A)RT=2.46分钟;m/z=410[M+H]+。
1H NMR:(400MHz,CDCl3)δ4.20-4.26(m,1H),4,26-4.34(m,1H),4.52-4.60(m,1H),4.60-4.72(m,1H),5.46-5.52(m,1H),6.90(d,1H,J 8.6),7.15-7.25(m,2H),7.33(d,2H,J 9.4),7.31-7.43(m,3H),7.82-7.86(m,1H),8.25(d,2H,J 9.1),8.28-8.32(m,1H)。
步骤3
3-[5-(2-氟-苯基)-吡啶-2-基氧基]-氮杂环丁烷-1-羧酸(6-甲基-哒嗪-3-基)-酰胺
在0℃下,向6-甲基-哒嗪-3-基胺(60毫克,0.55毫摩,[Cas.No18591-82-7])的DMF(3毫升)溶液中加入氢化钠(20毫克,0.5毫摩,60%的在矿物油中的分散体)。在0℃搅拌15分钟之后,滴加3-[5-(2-氟-苯基)-吡啶-2-基氧基]-氮杂环丁烷-1-羧酸4-硝基-苯基酯(102毫克,0.25毫摩)在DMF(4毫升)中的溶液。在环境温度下搅拌16小时之后,该反应混合物在真空下浓缩,用乙酸乙酯(50毫升)稀释,然后用饱和碳酸氢钠水溶液洗涤(2×50毫升),然后用饱和氯化钠溶液洗涤(50毫升)。用硫酸镁干燥该混合物,然后过滤。真空除去滤液中的溶剂,残余物通过闪式色谱法纯化(40%的乙酸乙酯的DCM溶液)制得标题化合物(48毫克,49%)。
LCMS:(方法A)RT=1.86分钟;m/z=380[M+H]+。
1H NMR:(400MHz,CDCl3)δ2.60(s,3H),4.19-4.23(m,2H),4.54-4.58(m,2H),5.45-5.50(m,1H),6.88(d,1H,J 8.6),7.14-7.24(m,2H),7.27-7.41(m,3H),7.80-7.84(m,1H),8.25-8.30(m,2H)。
实施例21
3-[5-(2-氟-苯基)-吡啶-2-基氧基]-氮杂环丁烷-1-羧酸(6-甲氧基-哒嗪-3-基)-酰胺
在0℃下,向6-甲氧基-哒嗪-3-基胺(39毫克,0.31毫摩,[Cas.No.7252-84-8])的DMF(3毫升)溶液中加入氢化钠(20毫克,0.5毫摩,60%的在矿物油中的分散体)。在0℃搅拌15分钟之后,滴加3-[5-(2-氟-苯基)-吡啶-2-基氧基]-氮杂环丁烷-1-羧酸4-硝基-苯基酯(102毫克,0.25毫摩)的DMF(4毫升)溶液。在环境温度下搅拌16小时之后,所述反应混合物在真空中浓缩,用乙酸乙酯(50毫升)稀释,然后用饱和碳酸氢钠水溶液洗涤(2×50毫升),然后用饱和氯化钠溶液(50毫升)洗涤。混合物用硫酸镁干燥,然后过滤。真空除去滤液中的溶剂,残余物用闪式色谱法(乙酸乙酯)纯化,制得标题化合物(35毫克,37%)。
LCMS:(方法A)RT=1.97分钟;m/z=396[M+H]+。
1H NMR:(400MHz,CDCl3)δ4.03(s,3H),4.21-4.25(m,2H),4.55-4.59(m,2H),5.45-5.50(m,1H),6.88(d,1H,J 8.6),7.02(d,1H,J 9.6),7.15-7.25(m,2H),7.31-7.42(m,2H),7.81-7.84(m,1H),8.28(bs,1H),8.35(d,1H,J9.3)。
实施例22
3-[5-(2-氟-苯基)-吡啶-2-基氧基]-氮杂环丁烷-1-羧酸(5-甲基-[1,3,4]噁二唑-2-基)-酰胺
在0℃下,向5-甲基-[1,3,4]噁二唑-2-基胺(31毫克,0.31毫摩,[Cas.No.52838-39-8])的DMF(3毫升)溶液加入氢化钠(20毫克,0.5毫摩,60%的在矿物油中的分散体)。在0℃搅拌15分钟之后,滴加3-[5-(2-氟-苯基)-吡啶-2-基氧基]-氮杂环丁烷-1-羧酸4-硝基-苯基酯(102毫克,0.25毫摩)的DMF(4毫升)溶液。在环境温度下搅拌16小时之后,反应混合物在真空中浓缩,用乙酸乙酯(50毫升)稀释,然后用饱和碳酸氢钠水溶液(2×50毫升)洗涤,然后用饱和氯化钠溶液(50毫升)洗涤。混合物用硫酸镁干燥,然后进行过滤。真空除去滤液的溶剂,残余物用制备性HPLC纯化,制得标题化合物(10毫克,11%)。
LCMS:(方法A)RT=1.77分钟;m/z=370[M+H]+。
1H NMR:(400MHz,CD3OD)δ2.34(s,3H),3.96-4.00(m,2H),4.36-4.40(m,2H),5.33-5.39(m,1H),6.94(d,1H,J 8.8),7.18-7.29(m,2H),7.36-7.41(m,1H),7.46-7.50(m,1H),7.88-7.91(m,1H),8.29(bs,1H)。
实施例23
3-[5-(2-氟-苯基)-吡啶-2-基氧基]-氮杂环丁烷-1-羧酸哒嗪-4-基酰胺
在0℃下,向哒嗪-4-基胺(30毫克,0.31毫摩,[Cas.No.20744-39-2])的DMF(3毫升)溶液加入氢化钠(20毫克,0.5毫摩,60%的在矿物油中的分散体)。在0℃搅拌15分钟之后,滴加3-[5-(2-氟-苯基)-吡啶-2-基氧基]-氮杂环丁烷-1-羧酸4-硝基-苯基酯(102毫克,0.25毫摩)的DMF(4毫升)溶液。在环境温度下搅拌16小时之后,该反应混合物在真空下浓缩,用乙酸乙酯(50毫升)稀释,然后用饱和碳酸氢钠水溶液(2×50毫升)洗涤,然后用饱和氯化钠溶液(50毫升)洗涤。混合物用硫酸镁干燥,然后过滤。真空除去滤液中的溶剂,残余物用制备性HPLC纯化,制得标题化合物(15毫克,16%)。
LCMS:(方法A)RT=1.74分钟;m/z=366[M+H]+。
1H NMR:(400MHz,CD3OD)δ4.15-4.18(m,2H),4.56-4.61(m,2H),5.46-5.51(m,1H),6.98(d,1H,J 8.6),7.19-7.29(m,2H),7.37-7.42(m,1H),7.46-7.50(m,1H),7.91-7.94(m,1H),7.95-7.98(m,1H),8.31(bs,1H),8.87(d,1H,J6.1),9.26-9.28(m,1H)。
实施例24
6-氯-4-甲基-哒嗪-3-基胺和6-氯-5-甲基-哒嗪-3-基胺
在加压反应容器中,在130℃下,对3,6-二氯-4-甲基-哒嗪(3.0克,18.40毫摩)在氨水(28-30%;150毫升)中的溶液加热16小时。将该反应混合物冷却至环境温度,用二氯甲烷(10×100毫升)萃取。合并有机层,干燥(MgSO4),过滤,浓缩,制得标题化合物的混合物(853mg;32%)。
LCMS:(方法)ART=0.45分钟;m/z=144[M+H]+。
1H NMR:(400MHz,DMSO-d6)δ2.07(s,3H),2.18(s,3H),6.47(bs,2H),6.49(bs,2H),6.74(s,1H),7.31(s,1H)。
实施例25
3-[5-(2-氟-苯基)-吡啶-2-基氧基]-氮杂环丁烷-1-羧酸(5-甲基-哒嗪-3-基)-酰胺和3-[5-(2-氟-苯基)-吡啶-2-基氧基]-氮杂环丁烷-1-羧酸(4-甲基-哒嗪-3-基)-酰胺
在0℃下,向6-氯-4-甲基-哒嗪-3-基胺和6-氯-5-甲基-哒嗪-3-基胺的混合物(143毫克,1.0毫摩)在DMF(6毫升)中的溶液中加入氢化钠(80毫克,2.0毫摩,60%的在矿物油中的分散体)。在0℃搅拌15分钟之后,滴加3-[5-(2-氟-苯基)-吡啶-2-基氧基]-氮杂环丁烷-1-羧酸4-硝基-苯基酯(204毫克,0.5毫摩)的DMF(6毫升)溶液。在环境温度下搅拌16小时之后,该反应混合物在真空条件下浓缩,用乙酸乙酯(50毫升)稀释,然后用饱和碳酸氢钠水溶液(2×50毫升)洗涤,然后用饱和氯化钠溶液(50毫升)洗涤。混合物用硫酸镁干燥,然后过滤。真空除去滤液中的溶剂,区域异构体(regioisomer)通过闪式色谱法(4%的甲醇的DCM溶液)部分分离,通过在环境压力下独立地氢化(10%Pd/C,乙醇),在制备性HPLC纯化之后制得区域异构体。
3-[5-(2-氟-苯基)-吡啶-2-基氧基]-氮杂环丁烷-1-羧酸(5-甲基-哒嗪-3-基)-酰胺(24毫克,6%)。
LCMS:(方法A)RT=1.91分钟;m/z=380[M+H]+。
1H NMR:(400MHz,CD3OD)δ2.38(s,3H),4.15-4.18(m,2H),4.56-4.61(m,2H),5.45-5.51(m,1H),6.98(d,1H,J 8.6),7.19-7.29(m,2H),7.37-7.41(m,1H),7.46-7.50(m,1H),7.90-7.93(m,1H),8.12(bs,1H),8.31(bs,1H),8.69(bs,1H)。
3-[5-(2-氟-苯基)-吡啶-2-基氧基]-氮杂环丁烷-1-羧酸(4甲基-哒嗪-3-基)-酰胺(11毫克,3%)。
LCMS:(方法A)RT=1.82分钟;m/z=380[M+H]+。
生物学结果
部分A
大鼠FAAH抑制实验
根据文献所述将活性大鼠FAAH蛋白(30-579)分离。将大鼠的FAAH氨基酸30-579编码序列克隆到表达载体pET28a中,提供N-末端His-标记。在表达之后,使用基于Patricelli等人的方法(1998年;Biochemistry,第37卷,第15177页),通过螯合琼脂糖,肝素琼脂糖和体积排阻色谱法的组合分离His-标记的FAAH(30-579)。
通过测量在FAAH使得底物花生四烯酰基-7-氨基,4-甲基香豆素酰胺(AAMCA)水解过程中释放的高荧光性的7-氨基,4-甲基香豆素(AMC)来确定FAAH活性。通过测定在不存在某种化合物的时候,荧光减少的百分比来确定FAAH活性的抑制。
该实验在黑色壁、透明底的384孔板上进行。以120nM的浓度预先培养27.5微升FAAH蛋白质(在FAAH实验中缓冲剂:50mM Hepes,0.01%Triton X-100,1mM EDTA,0.5mg/ml BSA(无脂肪酸),pH 8.2),在室温下,化合物的浓度增大(2.5微升,在100%DMSO中),0小时、1小时和3小时。加入2.5微升DMSO作为‘全部’参比(100%FAAH活性)和2.5微升URB-597,已知的FAAH活性抑制剂,(最终饱和浓度10μM)用于‘非特定’参比(0%FAAH活性)。然后在所有的孔中加入20微升7.5μM的AAMCA底物(在FAAH实验缓冲剂中),在室温下再培养1.5小时。使用Flexstation板读取器(Molecular Devices,UK)在激发波长355纳米、发射波长460纳米的条件下测定荧光。测得化合物造成的FAAH活性抑制是相对于“全部”参比(不存在化合物的情况)减去“非特定”参比的减小百分比,单位是相对荧光单位(RFU)。使用4参数逻辑拟合模型(信号模拟剂量响应模型(Sigmoidal Dose-Response Model)),在XL-Fit中由10点剂量响应曲线确定IC50值。
以下表1提供了在以上大鼠FAAH抑制实验中,实施例1-4的化合物的3小时培养测试结果。
表1
部分B
人FAAH 1实验
通过测量FAAH造成底物花生四烯酰基-7-氨基,4-甲基香豆素酰胺(AAMCA)水解过程中释放的高荧光性的7-氨基,4-甲基香豆素(AMC)来确定人FAAH 1活性。测得人FAAH 1的活性抑制表示为不存在化合物的情况下测得的荧光的减小百分数。
该实验在黑色壁、透明底的384孔板上进行。以10nM的浓度预先培养27.5微升的人FAAH 1蛋白质(在FAAH实验中缓冲剂:50mM Hepes,0.01%Triton X-100,1mM EDTD,0.5mg/ml BSA(无脂肪酸),pH 8.2),在室温下,化合物的浓度增大(2.5微升,在100%DMSO中),1小时。加入2.5微升DMSO作为‘全部’参比(100%FAAH活性),2.5微升URB-597,已知的FAAH活性抑制剂,(最终饱和浓度10μM)用于‘非特定’参比(0%FAAH活性)。然后在所有的孔中加入20微升7.5μM的AAMCA底物(在FAAH实验缓冲剂中),在室温下再培养4小时。使用Flexstation板读取器(MolecularDevices,UK)在激发波长355纳米、发射波长460纳米的条件下测定荧光。测得化合物造成的人FAAH 1活性抑制是相对于“全部”参比(不存在化合物的情况)减去“非特定”参比的减小百分比,单位是相对荧光单位(RFU)。使用4参数逻辑拟合模型(信号模拟剂量响应模型(Sigmoidal Dose-ResponseModel)),在XL-Fit中由10点剂量响应曲线确定IC50值。
以下表2提供了在以上人FAAH抑制实验中,实施例5-19的化合物的1小时培养测试结果。
表2
部分C
炎性痛的大鼠角叉菜胶引发的热痛觉过敏模型
在局部脚掌内给予角叉菜胶之前和之后,通过将会聚的光束施加在雄性Wistar大鼠的后爪上,记录下后爪缩回的时间,从而评价大鼠对热痛觉的灵敏性。3小时后,再次评价处理过和未处理过的后爪在给予测试化合物或媒介剂之前的热痛觉灵敏性。给予吲哚美辛(indomethacin)作为正参比。
方案
对雄性Sprague Dawley大鼠进行尾部标记,进行三次独立的实验(测试日之前6,5和1天),在每次实验之前,在足底箱上适应至少5分钟。在测试日之前的一天,大鼠在测试之前,在测试室内呆至少30分钟以使其习惯。将大鼠放入Hargreaves足底箱中,使其平静约3-5分钟,用便携式辐射热源进行测试。两次测定从热源缩回左后爪和右后爪的反应时间(间隔3分钟)。两次测试中的平均值作为每个动物的基线。大鼠18和30具有非常高的基线读数,因此不用于该研究,用61和63号大鼠代替。然后将大鼠指定进行药物治疗,以确保各组中的基线反应时间平衡。
在测试日,在测试之前3小时的时间,对大鼠的右后足脚掌内给予角叉菜胶λ(100uL,1%的盐水溶液)或盐水。测试之前4小时,大鼠接受VER-158416(1,3,或10mg/kg)或者媒介剂(5%EtOH∶95%(1%甲基纤维素水溶液)。然后在测试之前30分钟时,对大鼠第二次注射吲哚美辛10mg/kg或媒介剂(50%0.1M Na2CO3∶47.5%磷酸盐缓冲的盐水(PBS)∶2.5%1MHCl)。在药物治疗之后规定的测试时间,用单次读数重新评价脚爪从辐射热源缩回的反应时间。
例如测得以上实施例13化合物的实验如下:
在t=0的时刻对大鼠脚掌内给予角叉菜胶;在t=2小时的时刻给予实施例13的化合物(1,3&10mg/kg po)或媒介剂(5%EtOH∶95%(1%甲基纤维素水溶液);在t=2.5小时的时刻给予吲哚美辛(10mg/kg,脚掌内)或媒介剂,在t=3小时的时刻测试热痛灵敏性。因此所有的大鼠都接受口服给药和脚掌内给药。
实施例13的化合物(1,3,10mg/kg p.o.)引起了与剂量相关的角叉菜胶引发的热超敏性的抑制,在3毫克/千克和10毫克/千克剂量下达到了统计显著性(参见媒介剂/角叉菜胶组;一次ANOVA,接着Newman-Keuls后hoc测试)。该化合物没有将疼痛灵敏性减小到低于常规水平,对于对侧的爪子对热疼痛的灵敏性没有效果。该化合物的最大效果与正参比吲哚美辛类似。
参考文献
Hargreaves,K.,Dubner,R.,Brown,F.,Flores,C.,Joris,J.,(1988).皮肤痛觉过敏中测量热疼痛感受的新的灵敏的方法(A new and sensitive methodfor measuring thermal nociception in cutaneous hyperalgesia),疼痛学(Pain),32,77-88。
Hedo,G.,Laird,J.M.A.,Lopez-Garcia,J.A.,(1999).年轻大鼠中角叉菜胶引发的炎症之后脊椎灵敏性的时间历程:体内和体外电生理学和行为研究的比较(Time course of spinal sensitization following carrageenan-inducedinflammation in the young rat:a comparative electrophysiological andbehavioural study in vitro and in vivo),神经科学(Neuroscience),92,309-318。
Morris,C.J.,(2003).角叉菜胶引发的大鼠和小鼠的脚爪水肿(Carrageenan-induced paw edema in the rat and mouse),Methods in MolBiol.,225,115-121。
Claims (17)
2.如权利要求1所述的化合物,其特征在于,Ar1是任选取代的苯基。
3.如权利要求1或2所述的化合物,其特征在于,Ar2是苯基,吡啶基,嘧啶基,吡嗪基或哒嗪基,任意这些基团被任选地取代。
4.如权利要求1或2所述的化合物,其特征在于,Ar2是3-吡啶基,嘧啶-4-基,吡嗪-2-基或哒嗪-3-基,任意这些基团被任选地被取代。
5.如以上权利要求中任一项所述的化合物,其特征在于,Ar3是任选取代的二价亚苯基或亚吡啶基。
6.如权利要求5所述的化合物,其特征在于,Ar3是任选取代的二价1,4-亚苯基或下式所示的2,5-亚吡啶基:
其中单个星号标记的键是与Ar1连接的,用两个星号标记的键与氧连接。
7.如以上权利要求中任一项所述的化合物,其特征在于,Ar1,Ar2和Ar3中的任意任选的取代基独立地选自氯,氟,溴,环丙基,甲基,单甲基、二甲基或三甲基,三氟甲基,二氟甲基,单氟甲基,甲氧基,乙氧基,丙氧基,丁氧基,戊氧基,2-甲氧基乙氧基,2-苄氧基-乙氧基,2-羟基-乙氧基,单氟甲氧基、二氟甲氧基或三氟甲氧基,氰基,羟基;
-CO2R1和-SO2R1,其中R1是氢,甲基或乙基;四唑基;-NR2R3,
-CH2NR2R3和-C(=O)NR2R3,其中R2和R3独立地是氢,甲基或乙基。
8.如权利要求1所述的化合物,其特征在于,:
Ar2是3-吡啶基,嘧啶-4-基,吡嗪-2-基或哒嗪-3-基;
Ar3是任选取代的二价1,4-亚苯基或下式所示的2,5-亚吡啶基:
其中单个星号标记的键是与Ar1连接的,用两个星号标记的键与氧连接;
Ar1是任选取代的苯基。
9.如权利要求8所述的化合物,其特征在于,Ar1是苯基,2-氟苯基,3-(2-甲氧基-乙氧基)-苯基,或2-甲氧基-5-(2-甲氧基-乙氧基)-苯基。
10.如权利要求8或9所述的化合物,其特征在于,Ar2是哒嗪-3-基。
11.如以上权利要求中任一项所述的化合物,其特征在于,所述化合物为本发明任意实施例的主题。
12.一种药学组合物,其包含以上权利要求中任一项所述的化合物,以及一种或多种药学上可接受的载体和/或赋形剂。
13.如权利要求1-11中任一项所述的化合物在药物中的应用。
14.如以上权利要求1-11中任一项所述的化合物在治疗能够通过抑制FAAH活性而获益的疾病或医学病征中的应用。
15.一种对能够从抑制FAAH活性而获益的疾病或医学病征的治疗方法,所述方法包括给予患有所述疾病或病征的对象有效量的如权利要求1-11中任一项所述的化合物。
16.如权利要求14所述的应用或者如权利要求15所述的方法,其特征在于,所述疾病或病征选自:急性痛或慢性痛,眩晕,呕吐,恶心,进食失调,神经错乱和精神错乱,急性或慢性神经退化病,癫痫,睡眠失调,心血管病,肾脏局部缺血,癌症,免疫系统失调,变应性病,寄生虫病,病毒或细菌感染疾病,炎症,骨质疏松症,眼病,肺病,肠胃病,青光眼相关的高血压和尿失禁。
17.如权利要求14所述的应用或者如权利要求15所述的方法,其特征在于,所述疾病或病征是焦虑,抑郁,疼痛,炎症,痒,睡眠失调或运动失调。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0804006.5 | 2008-03-04 | ||
GBGB0804006.5A GB0804006D0 (en) | 2008-03-04 | 2008-03-04 | Azetidine derivatives |
GBGB0821694.7A GB0821694D0 (en) | 2008-11-27 | 2008-11-27 | Azetidine derivatives |
GB0821694.7 | 2008-11-27 | ||
PCT/GB2009/000568 WO2009109743A1 (en) | 2008-03-04 | 2009-02-27 | Azetidine derivatives |
Publications (2)
Publication Number | Publication Date |
---|---|
CN102015635A true CN102015635A (zh) | 2011-04-13 |
CN102015635B CN102015635B (zh) | 2013-05-08 |
Family
ID=40613126
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2009801079287A Active CN102015635B (zh) | 2008-03-04 | 2009-02-27 | 氮杂环丁烷衍生物 |
Country Status (18)
Country | Link |
---|---|
US (6) | US8450346B2 (zh) |
EP (1) | EP2265578B1 (zh) |
JP (2) | JP5624894B2 (zh) |
CN (1) | CN102015635B (zh) |
AU (1) | AU2009220974B2 (zh) |
BR (1) | BRPI0909782B8 (zh) |
CA (1) | CA2717750C (zh) |
DK (1) | DK2265578T3 (zh) |
EA (1) | EA017842B1 (zh) |
ES (1) | ES2550367T3 (zh) |
HU (1) | HUE025411T2 (zh) |
IL (1) | IL207768A (zh) |
MX (1) | MX2010009658A (zh) |
NZ (1) | NZ587532A (zh) |
PL (1) | PL2265578T3 (zh) |
PT (1) | PT2265578E (zh) |
WO (1) | WO2009109743A1 (zh) |
ZA (1) | ZA201006270B (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107011229A (zh) * | 2012-01-06 | 2017-08-04 | 诺华股份有限公司 | 杂环化合物和它们的使用方法 |
CN112374984A (zh) * | 2020-11-06 | 2021-02-19 | 苏州求索生物科技有限公司 | 一种2-溴-4-羟基苯甲醚的制备工艺 |
Families Citing this family (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2265578B1 (en) | 2008-03-04 | 2015-09-16 | Vernalis (R&D) Ltd. | Azetidine derivatives |
WO2011085216A2 (en) | 2010-01-08 | 2011-07-14 | Ironwood Pharmaceuticals, Inc. | Use of faah inhibitors for treating parkinson's disease and restless legs syndrome |
WO2011123719A2 (en) | 2010-03-31 | 2011-10-06 | Ironwood Pharmaceuticals, Inc. | Use of faah inhibitors for treating abdominal, visceral and pelvic pain |
KR101273566B1 (ko) * | 2011-09-05 | 2013-06-11 | 한국과학기술연구원 | 신규한 아제티딘 유도체 및 이를 함유하는 항우울제 조성물 |
WO2016014975A2 (en) * | 2014-07-25 | 2016-01-28 | Northeastern University | Urea/carbamates faah magl or dual faah/magl inhibitors and uses thereof |
JOP20190072A1 (ar) * | 2016-10-13 | 2019-04-07 | Glaxosmithkline Ip Dev Ltd | مشتقات 1، 3 سيكلوبوتان ثنائي الاستبدال أو آزيتيدين كمثبطات للإنزيم المخلق للبروستاجلاندين d المكون للدم |
AU2018277983B2 (en) * | 2017-06-02 | 2021-04-08 | Fujifilm Toyama Chemical Co., Ltd. | Amyloid-β protein level decreasing agent |
JP7370859B2 (ja) * | 2017-06-02 | 2023-10-30 | 富士フイルム富山化学株式会社 | タウオパチー予防または治療剤 |
WO2018221730A1 (ja) | 2017-06-02 | 2018-12-06 | 富山化学工業株式会社 | 脊髄小脳変性症予防または治療剤 |
KR20190137936A (ko) * | 2017-06-02 | 2019-12-11 | 후지필름 도야마 케미컬 가부시키가이샤 | 뇌 위축 예방 또는 치료제 |
WO2018221728A1 (ja) | 2017-06-02 | 2018-12-06 | 富山化学工業株式会社 | アルツハイマー型認知症予防または治療剤 |
US11548878B2 (en) | 2017-10-30 | 2023-01-10 | Fujifilm Toyama Chemical Co., Ltd. | Emopamil binding protein binding agent and use thereof |
WO2022020222A1 (en) * | 2020-07-21 | 2022-01-27 | Neuritek Ltd. | Uses of fatty acid amide hydrolase inhibitors in treatment of trauma related psychiatric disorders |
US11141404B1 (en) | 2020-11-18 | 2021-10-12 | Anebulo Pharmaceuticals, Inc. | Formulations and methods for treating acute cannabinoid overdose |
US11795146B2 (en) | 2021-10-11 | 2023-10-24 | Anebulo Pharmaceuticals, Inc. | Crystalline forms of a cannabinoid receptor type 1 (CB1) modulator and methods of use and preparation thereof |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5183902A (en) * | 1985-02-28 | 1993-02-02 | A. H. Robins Company, Incorporated | Method of treating muscular tension, muscle spasticity and anxiety with 3-aryloxy and 3-arylthioazetidinecarboxamides |
WO1999037614A1 (en) * | 1998-01-23 | 1999-07-29 | Vernalis Research Limited | Azetidinecarboxamide derivatives for the treatment of cns disorders |
US6335445B1 (en) * | 1997-03-24 | 2002-01-01 | Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) | Derivatives of 2-(iminomethyl)amino-phenyl, their preparation, their use as medicaments and the pharmaceutical compositions containing them |
WO2005090347A1 (fr) * | 2004-02-26 | 2005-09-29 | Sanofi-Aventis | Derives d’aryl- et d’heteroaryl-piperidinecarboxylates, leur preparation et leur application comme inhibiteurs de l'enzyme faah |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IN162808B (zh) * | 1985-02-28 | 1988-07-09 | Robins Co Inc A H | |
EP2265578B1 (en) * | 2008-03-04 | 2015-09-16 | Vernalis (R&D) Ltd. | Azetidine derivatives |
-
2009
- 2009-02-27 EP EP09716712.6A patent/EP2265578B1/en active Active
- 2009-02-27 AU AU2009220974A patent/AU2009220974B2/en active Active
- 2009-02-27 PT PT97167126T patent/PT2265578E/pt unknown
- 2009-02-27 US US12/920,181 patent/US8450346B2/en active Active
- 2009-02-27 JP JP2010549188A patent/JP5624894B2/ja active Active
- 2009-02-27 HU HUE09716712A patent/HUE025411T2/en unknown
- 2009-02-27 DK DK09716712.6T patent/DK2265578T3/en active
- 2009-02-27 CN CN2009801079287A patent/CN102015635B/zh active Active
- 2009-02-27 CA CA2717750A patent/CA2717750C/en active Active
- 2009-02-27 WO PCT/GB2009/000568 patent/WO2009109743A1/en active Application Filing
- 2009-02-27 BR BRPI0909782A patent/BRPI0909782B8/pt active IP Right Grant
- 2009-02-27 ES ES09716712.6T patent/ES2550367T3/es active Active
- 2009-02-27 EA EA201001414A patent/EA017842B1/ru not_active IP Right Cessation
- 2009-02-27 NZ NZ587532A patent/NZ587532A/en unknown
- 2009-02-27 PL PL09716712T patent/PL2265578T3/pl unknown
- 2009-02-27 MX MX2010009658A patent/MX2010009658A/es active IP Right Grant
-
2010
- 2010-08-24 IL IL207768A patent/IL207768A/en active IP Right Grant
- 2010-09-01 ZA ZA2010/06270A patent/ZA201006270B/en unknown
-
2013
- 2013-04-19 US US13/866,059 patent/US9006269B2/en active Active
-
2014
- 2014-09-29 JP JP2014198461A patent/JP5986163B2/ja active Active
-
2015
- 2015-03-09 US US14/641,783 patent/US9475800B2/en active Active
-
2016
- 2016-09-28 US US15/278,386 patent/US10383871B2/en active Active
-
2019
- 2019-07-09 US US16/506,225 patent/US10918640B2/en active Active
-
2021
- 2021-01-14 US US17/148,785 patent/US20210267974A1/en active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5183902A (en) * | 1985-02-28 | 1993-02-02 | A. H. Robins Company, Incorporated | Method of treating muscular tension, muscle spasticity and anxiety with 3-aryloxy and 3-arylthioazetidinecarboxamides |
US6335445B1 (en) * | 1997-03-24 | 2002-01-01 | Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) | Derivatives of 2-(iminomethyl)amino-phenyl, their preparation, their use as medicaments and the pharmaceutical compositions containing them |
WO1999037614A1 (en) * | 1998-01-23 | 1999-07-29 | Vernalis Research Limited | Azetidinecarboxamide derivatives for the treatment of cns disorders |
WO2005090347A1 (fr) * | 2004-02-26 | 2005-09-29 | Sanofi-Aventis | Derives d’aryl- et d’heteroaryl-piperidinecarboxylates, leur preparation et leur application comme inhibiteurs de l'enzyme faah |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107011229A (zh) * | 2012-01-06 | 2017-08-04 | 诺华股份有限公司 | 杂环化合物和它们的使用方法 |
CN107011229B (zh) * | 2012-01-06 | 2019-11-05 | 诺华股份有限公司 | 杂环化合物和它们的使用方法 |
CN112374984A (zh) * | 2020-11-06 | 2021-02-19 | 苏州求索生物科技有限公司 | 一种2-溴-4-羟基苯甲醚的制备工艺 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN102015635B (zh) | 氮杂环丁烷衍生物 | |
JP5124471B2 (ja) | 置換二環式ピリミドン誘導体 | |
US20110166161A1 (en) | Heterocyclic carboxamide compounds | |
KR20170082577A (ko) | 치환된 피라졸로(1,5-a)피리미딘 및 의학적 장애의 치료에서의 그의 용도 | |
CA2895448A1 (en) | Autotaxin inhibitors | |
CN101903372A (zh) | 作为食欲肽受体拮抗剂的杂芳基衍生物 | |
JP2010524908A (ja) | トリアゾロピリジンカルボキサミド誘導体およびトリアゾロピリミジンカルボキサミド誘導体、これらの調製、ならびにこれらの治療的使用 | |
JP2007519628A (ja) | 1−ピペラジン−および1−ホモピペラジン−カルボキシレートの誘導体、その調製方法、およびfaah酵素の阻害剤としてのその使用 | |
CN101616894A (zh) | 作为丝氨酸蛋白酶抑制剂的式(ⅰ)化合物 | |
EP1858872A1 (fr) | Dérivés de n-[(4,5-diphenyl-3-alkyl-2-thienyl)methyl]amine (amide, thiourée et urée) comme antagonistes des récepteurs cb1 des cannabinoïdes | |
US20190389865A1 (en) | SUBSTITUTED PYRROLO[1,2-a]TRIAZINES AND RELATED COMPOUNDS AND THEIR USE IN THE TREATMENT OF MEDICAL DISORDERS | |
JP2005255675A (ja) | 医薬組成物 | |
EP3348550A1 (en) | Substituted benzothiazoles and therapeutic uses thereof for the treatment of human diseases | |
JP2007522146A (ja) | 炎症性疾患の治療または予防のためのα4インテグリン介在細胞接着阻害物質 | |
EP2234966B1 (fr) | Derives d'azetidines, leur preparation et leur application en therapeutique | |
JP2007063268A (ja) | 医薬組成物 | |
JP2007513863A (ja) | 新規化合物 | |
CN101500986B (zh) | 作为glyt1抑制剂的二-芳基取代的酰胺 | |
JP2018513153A (ja) | Pde10インヒビターならびに関連する組成物および方法 | |
JP2011529871A (ja) | チオフェン−2−カルボキサミド誘導体、これらの調製およびこれらの治療的使用 | |
FR2911136A1 (fr) | Derives de n-(4-cyano-1h-pyrazol-3-yl)methylamine substitues leur preparation et leur application en therapeutique. | |
JP2007023029A (ja) | 医薬組成物 | |
FR2930940A1 (fr) | Derives de pyrrole, leur preparation et leur application en therapeutique | |
FR2925051A1 (fr) | Derives d'azetidines,leur preparation et leur application en therapeutique | |
FR2930941A1 (fr) | Derives d'azetidines, leur preparation et leur application en therapeutique |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant |