CN1890208A - 类鸦片受体拮抗剂 - Google Patents
类鸦片受体拮抗剂 Download PDFInfo
- Publication number
- CN1890208A CN1890208A CNA2004800364712A CN200480036471A CN1890208A CN 1890208 A CN1890208 A CN 1890208A CN A2004800364712 A CNA2004800364712 A CN A2004800364712A CN 200480036471 A CN200480036471 A CN 200480036471A CN 1890208 A CN1890208 A CN 1890208A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- group
- compound
- alkaryl
- thiazolinyl
- 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.)
- Pending
Links
- 229940123257 Opioid receptor antagonist Drugs 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 152
- 239000000203 mixture Substances 0.000 claims abstract description 56
- 208000008589 Obesity Diseases 0.000 claims abstract description 39
- 235000020824 obesity Nutrition 0.000 claims abstract description 38
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 29
- 150000003839 salts Chemical class 0.000 claims abstract description 27
- 238000011282 treatment Methods 0.000 claims abstract description 24
- 201000010099 disease Diseases 0.000 claims abstract description 21
- 239000012453 solvate Substances 0.000 claims abstract description 14
- -1 methoxyl group Chemical group 0.000 claims description 59
- 238000000034 method Methods 0.000 claims description 37
- 229910052760 oxygen Inorganic materials 0.000 claims description 36
- 239000001301 oxygen Substances 0.000 claims description 34
- 125000003118 aryl group Chemical group 0.000 claims description 30
- 239000000460 chlorine Substances 0.000 claims description 27
- 239000001257 hydrogen Substances 0.000 claims description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims description 25
- 229910052736 halogen Inorganic materials 0.000 claims description 24
- 150000002367 halogens Chemical class 0.000 claims description 24
- 239000000470 constituent Substances 0.000 claims description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 22
- 229960003966 nicotinamide Drugs 0.000 claims description 22
- 235000005152 nicotinamide Nutrition 0.000 claims description 22
- 239000011570 nicotinamide Substances 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 21
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 20
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 19
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 239000003814 drug Substances 0.000 claims description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 17
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- 125000002933 cyclohexyloxy group Chemical group C1(CCCCC1)O* 0.000 claims description 14
- 125000000623 heterocyclic group Chemical group 0.000 claims description 14
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- 229910052801 chlorine Inorganic materials 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 150000001721 carbon Chemical group 0.000 claims description 11
- 208000024891 symptom Diseases 0.000 claims description 11
- 239000011737 fluorine Substances 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 10
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 claims description 9
- 241001465754 Metazoa Species 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 9
- 239000000833 heterodimer Substances 0.000 claims description 9
- 229910000037 hydrogen sulfide Inorganic materials 0.000 claims description 9
- 208000024732 dysthymic disease Diseases 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 7
- 229940079593 drug Drugs 0.000 claims description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 6
- 208000019901 Anxiety disease Diseases 0.000 claims description 6
- 125000002521 alkyl halide group Chemical group 0.000 claims description 6
- 230000036506 anxiety Effects 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 230000035622 drinking Effects 0.000 claims description 6
- 125000005936 piperidyl group Chemical group 0.000 claims description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000002769 thiazolinyl group Chemical group 0.000 claims description 6
- 206010008190 Cerebrovascular accident Diseases 0.000 claims description 5
- 208000006011 Stroke Diseases 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 4
- 230000036528 appetite Effects 0.000 claims description 4
- 235000019789 appetite Nutrition 0.000 claims description 4
- 230000000903 blocking effect Effects 0.000 claims description 4
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims description 4
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 241000208125 Nicotiana Species 0.000 claims description 3
- 235000002637 Nicotiana tabacum Nutrition 0.000 claims description 3
- 201000001880 Sexual dysfunction Diseases 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 235000019788 craving Nutrition 0.000 claims description 3
- 230000002503 metabolic effect Effects 0.000 claims description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
- 231100000872 sexual dysfunction Toxicity 0.000 claims description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- 206010047700 Vomiting Diseases 0.000 claims description 2
- 231100000867 compulsive behavior Toxicity 0.000 claims description 2
- 235000019633 pungent taste Nutrition 0.000 claims description 2
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 201000009032 substance abuse Diseases 0.000 claims description 2
- 231100000736 substance abuse Toxicity 0.000 claims description 2
- 208000011117 substance-related disease Diseases 0.000 claims description 2
- 208000011580 syndromic disease Diseases 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- 230000008673 vomiting Effects 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 10
- 206010012335 Dependence Diseases 0.000 claims 1
- 230000005764 inhibitory process Effects 0.000 claims 1
- 230000009329 sexual behaviour Effects 0.000 claims 1
- 230000002265 prevention Effects 0.000 abstract description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 51
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 48
- 239000002585 base Substances 0.000 description 48
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- 239000000243 solution Substances 0.000 description 34
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 33
- 239000011541 reaction mixture Substances 0.000 description 31
- 238000003756 stirring Methods 0.000 description 29
- 238000006243 chemical reaction Methods 0.000 description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 22
- 235000019439 ethyl acetate Nutrition 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- 239000002904 solvent Substances 0.000 description 18
- 150000002825 nitriles Chemical class 0.000 description 17
- 238000012360 testing method Methods 0.000 description 17
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 16
- 235000019504 cigarettes Nutrition 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- 239000000370 acceptor Substances 0.000 description 15
- 230000000694 effects Effects 0.000 description 15
- 239000012044 organic layer Substances 0.000 description 15
- 150000002431 hydrogen Chemical class 0.000 description 14
- 238000002360 preparation method Methods 0.000 description 14
- 238000007670 refining Methods 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 108090000137 Opioid Receptors Proteins 0.000 description 13
- 102000003840 Opioid Receptors Human genes 0.000 description 13
- 238000001914 filtration Methods 0.000 description 13
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000005557 antagonist Substances 0.000 description 12
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 12
- 230000008569 process Effects 0.000 description 12
- 229910052938 sodium sulfate Inorganic materials 0.000 description 12
- 235000011152 sodium sulphate Nutrition 0.000 description 12
- 238000004587 chromatography analysis Methods 0.000 description 11
- 125000003003 spiro group Chemical group 0.000 description 11
- 239000003795 chemical substances by application Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 239000008896 Opium Substances 0.000 description 9
- 239000003513 alkali Substances 0.000 description 9
- 238000001819 mass spectrum Methods 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- 229960001027 opium Drugs 0.000 description 9
- 230000009467 reduction Effects 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- 239000002775 capsule Substances 0.000 description 8
- 239000002994 raw material Substances 0.000 description 8
- 229910000104 sodium hydride Inorganic materials 0.000 description 8
- 229920002472 Starch Polymers 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 238000005576 amination reaction Methods 0.000 description 7
- 238000010511 deprotection reaction Methods 0.000 description 7
- 238000011161 development Methods 0.000 description 7
- 208000035475 disorder Diseases 0.000 description 7
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 7
- 235000015320 potassium carbonate Nutrition 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- 150000003254 radicals Chemical class 0.000 description 7
- 239000008107 starch Substances 0.000 description 7
- 229940032147 starch Drugs 0.000 description 7
- 235000019698 starch Nutrition 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 6
- 239000012141 concentrate Substances 0.000 description 6
- 235000008504 concentrate Nutrition 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- 235000019359 magnesium stearate Nutrition 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- 239000012312 sodium hydride Substances 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 239000004215 Carbon black (E152) Substances 0.000 description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 5
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N acetaldehyde dimethyl acetal Natural products COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 5
- 150000001299 aldehydes Chemical class 0.000 description 5
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 125000004122 cyclic group Chemical group 0.000 description 5
- 206010012601 diabetes mellitus Diseases 0.000 description 5
- 229930195733 hydrocarbon Natural products 0.000 description 5
- 229910052500 inorganic mineral Inorganic materials 0.000 description 5
- 235000010755 mineral Nutrition 0.000 description 5
- 239000011707 mineral Substances 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 239000000556 agonist Substances 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- 229950002494 diprenorphine Drugs 0.000 description 4
- 230000000857 drug effect Effects 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 150000002430 hydrocarbons Chemical class 0.000 description 4
- 230000006872 improvement Effects 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 229940016286 microcrystalline cellulose Drugs 0.000 description 4
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 4
- 239000008108 microcrystalline cellulose Substances 0.000 description 4
- 239000012279 sodium borohydride Substances 0.000 description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 description 4
- 235000011121 sodium hydroxide Nutrition 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000006188 syrup Substances 0.000 description 4
- 235000020357 syrup Nutrition 0.000 description 4
- XOFLBQFBSOEHOG-UUOKFMHZSA-N γS-GTP Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=S)[C@@H](O)[C@H]1O XOFLBQFBSOEHOG-UUOKFMHZSA-N 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 101100244562 Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1) oprD gene Proteins 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 235000010980 cellulose Nutrition 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 108700023159 delta Opioid Receptors Proteins 0.000 description 3
- 102000048124 delta Opioid Receptors Human genes 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- BMFVGAAISNGQNM-UHFFFAOYSA-N isopentylamine Chemical compound CC(C)CCN BMFVGAAISNGQNM-UHFFFAOYSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 210000003205 muscle Anatomy 0.000 description 3
- LKPFBGKZCCBZDK-UHFFFAOYSA-N n-hydroxypiperidine Chemical compound ON1CCCCC1 LKPFBGKZCCBZDK-UHFFFAOYSA-N 0.000 description 3
- 238000010641 nitrile hydrolysis reaction Methods 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 150000003141 primary amines Chemical class 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 150000003335 secondary amines Chemical class 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- 108020001588 κ-opioid receptors Proteins 0.000 description 3
- 108020001612 μ-opioid receptors Proteins 0.000 description 3
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical group NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- LLSKXGRDUPMXLC-UHFFFAOYSA-N 1-phenylpiperidine Chemical compound C1CCCCN1C1=CC=CC=C1 LLSKXGRDUPMXLC-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-M 3-carboxy-2,3-dihydroxypropanoate Chemical compound OC(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-M 0.000 description 2
- YGCZTXZTJXYWCO-UHFFFAOYSA-N 3-phenylpropanal Chemical compound O=CCCC1=CC=CC=C1 YGCZTXZTJXYWCO-UHFFFAOYSA-N 0.000 description 2
- JDCKFZKIONSZHJ-UHFFFAOYSA-N 4-(4-oxocyclohexyl)oxybenzamide Chemical compound C1=CC(C(=O)N)=CC=C1OC1CCC(=O)CC1 JDCKFZKIONSZHJ-UHFFFAOYSA-N 0.000 description 2
- WDYVUKGVKRZQNM-UHFFFAOYSA-N 6-phosphonohexylphosphonic acid Chemical compound OP(O)(=O)CCCCCCP(O)(O)=O WDYVUKGVKRZQNM-UHFFFAOYSA-N 0.000 description 2
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 208000000103 Anorexia Nervosa Diseases 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- 206010007559 Cardiac failure congestive Diseases 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- 206010010904 Convulsion Diseases 0.000 description 2
- 208000002249 Diabetes Complications Diseases 0.000 description 2
- 206010012655 Diabetic complications Diseases 0.000 description 2
- 206010012689 Diabetic retinopathy Diseases 0.000 description 2
- 206010013980 Dyssomnias Diseases 0.000 description 2
- 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 2
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 description 2
- 206010019280 Heart failures Diseases 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 208000003251 Pruritus Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 239000005864 Sulphur Substances 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 230000003042 antagnostic effect Effects 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- XDFORSMZCYHNBG-UHFFFAOYSA-N benzonitrile;hydrochloride Chemical compound Cl.N#CC1=CC=CC=C1 XDFORSMZCYHNBG-UHFFFAOYSA-N 0.000 description 2
- SNIABFMMCKVXSY-UHFFFAOYSA-N benzoylazanium;chloride Chemical compound Cl.NC(=O)C1=CC=CC=C1 SNIABFMMCKVXSY-UHFFFAOYSA-N 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 2
- SIPUZPBQZHNSDW-UHFFFAOYSA-N diisobutylaluminium hydride Substances CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 201000005577 familial hyperlipidemia Diseases 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 239000007902 hard capsule Substances 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 2
- 150000004678 hydrides Chemical class 0.000 description 2
- 201000001421 hyperglycemia Diseases 0.000 description 2
- 208000006575 hypertriglyceridemia Diseases 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- 102000048260 kappa Opioid Receptors Human genes 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- XJRBAMWJDBPFIM-UHFFFAOYSA-N methyl vinyl ether Chemical compound COC=C XJRBAMWJDBPFIM-UHFFFAOYSA-N 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- 102000051367 mu Opioid Receptors Human genes 0.000 description 2
- 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 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 210000001577 neostriatum Anatomy 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 150000003053 piperidines Chemical class 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 150000003140 primary amides Chemical class 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- OBLVPWTUALCMGD-UHFFFAOYSA-N pyridin-1-ium-3-carboxamide;chloride Chemical compound Cl.NC(=O)C1=CC=CN=C1 OBLVPWTUALCMGD-UHFFFAOYSA-N 0.000 description 2
- 239000002287 radioligand Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000001525 receptor binding assay Methods 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 238000004062 sedimentation Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 230000035939 shock Effects 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000011182 sodium carbonates Nutrition 0.000 description 2
- 239000008109 sodium starch glycolate Substances 0.000 description 2
- 229940079832 sodium starch glycolate Drugs 0.000 description 2
- 229920003109 sodium starch glycolate Polymers 0.000 description 2
- PWQLFIKTGRINFF-UHFFFAOYSA-N tert-butyl 4-hydroxypiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(O)CC1 PWQLFIKTGRINFF-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 1
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 1
- HPZJMUBDEAMBFI-WTNAPCKOSA-N (D-Ala(2)-mephe(4)-gly-ol(5))enkephalin Chemical compound C([C@H](N)C(=O)N[C@H](C)C(=O)NCC(=O)N(C)[C@@H](CC=1C=CC=CC=1)C(=O)NCCO)C1=CC=C(O)C=C1 HPZJMUBDEAMBFI-WTNAPCKOSA-N 0.000 description 1
- IGVKWAAPMVVTFX-BUHFOSPRSA-N (e)-octadec-5-en-7,9-diynoic acid Chemical compound CCCCCCCCC#CC#C\C=C\CCCC(O)=O IGVKWAAPMVVTFX-BUHFOSPRSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- PYYPLTLIHKSZON-UHFFFAOYSA-N 1-methoxy-2-[methyl(phenyl)phosphoryl]benzene Chemical compound COC1=CC=CC=C1P(C)(=O)C1=CC=CC=C1 PYYPLTLIHKSZON-UHFFFAOYSA-N 0.000 description 1
- 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 1
- KKZUMAMOMRDVKA-UHFFFAOYSA-N 2-chloropropane Chemical group [CH2]C(C)Cl KKZUMAMOMRDVKA-UHFFFAOYSA-N 0.000 description 1
- FFNVQNRYTPFDDP-UHFFFAOYSA-N 2-cyanopyridine Chemical compound N#CC1=CC=CC=N1 FFNVQNRYTPFDDP-UHFFFAOYSA-N 0.000 description 1
- CSDSSGBPEUDDEE-UHFFFAOYSA-N 2-formylpyridine Chemical compound O=CC1=CC=CC=N1 CSDSSGBPEUDDEE-UHFFFAOYSA-N 0.000 description 1
- ALKYHXVLJMQRLQ-UHFFFAOYSA-M 3-carboxynaphthalen-2-olate Chemical compound C1=CC=C2C=C(C([O-])=O)C(O)=CC2=C1 ALKYHXVLJMQRLQ-UHFFFAOYSA-M 0.000 description 1
- LYUQWQRTDLVQGA-UHFFFAOYSA-N 3-phenylpropylamine Chemical compound NCCCC1=CC=CC=C1 LYUQWQRTDLVQGA-UHFFFAOYSA-N 0.000 description 1
- OLMSRAHTXPWNQQ-UHFFFAOYSA-N 4-(4-oxocyclohexyl)oxybenzonitrile Chemical compound C1CC(=O)CCC1OC1=CC=C(C#N)C=C1 OLMSRAHTXPWNQQ-UHFFFAOYSA-N 0.000 description 1
- WFJIVOKAWHGMBH-UHFFFAOYSA-N 4-hexylbenzene-1,3-diol Chemical class CCCCCCC1=CC=C(O)C=C1O WFJIVOKAWHGMBH-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- MITGKKFYIJJQGL-UHFFFAOYSA-N 9-(4-chlorobenzoyl)-6-methylsulfonyl-2,3-dihydro-1H-carbazol-4-one Chemical compound ClC1=CC=C(C(=O)N2C3=CC=C(C=C3C=3C(CCCC2=3)=O)S(=O)(=O)C)C=C1 MITGKKFYIJJQGL-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- 108700022183 Ala(2)-MePhe(4)-Gly(5)- Enkephalin Proteins 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- VOPWNXZWBYDODV-UHFFFAOYSA-N Chlorodifluoromethane Chemical compound FC(F)Cl VOPWNXZWBYDODV-UHFFFAOYSA-N 0.000 description 1
- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 description 1
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 1
- 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 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 108700022182 D-Penicillamine (2,5)- Enkephalin Proteins 0.000 description 1
- 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 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- MCMMCRYPQBNCPH-WMIMKTLMSA-N DPDPE Chemical compound C([C@H](N)C(=O)N[C@@H]1C(C)(C)SSC([C@@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)CNC1=O)C(O)=O)(C)C)C1=CC=C(O)C=C1 MCMMCRYPQBNCPH-WMIMKTLMSA-N 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 108010010803 Gelatin Proteins 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
- 229920000084 Gum arabic Polymers 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 206010019196 Head injury Diseases 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
- 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
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 101000860173 Myxococcus xanthus C-factor Proteins 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- OTEXLUNEZBUONK-UHFFFAOYSA-N O=C1CCC(CC1)Oc1ccccc1C#N Chemical compound O=C1CCC(CC1)Oc1ccccc1C#N OTEXLUNEZBUONK-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 1
- 206010033307 Overweight Diseases 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 229920002253 Tannate Polymers 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- ZALFMVYYPCKSHA-UHFFFAOYSA-N [K].C[Si](C)(C)[Si](C)(C)C Chemical compound [K].C[Si](C)(C)[Si](C)(C)C ZALFMVYYPCKSHA-UHFFFAOYSA-N 0.000 description 1
- JJLXCWBAIHUBIW-UHFFFAOYSA-N [N-]=[N+]=[N-].[K+].[Si+4].[N-]=[N+]=[N-].[N-]=[N+]=[N-].[N-]=[N+]=[N-].[N-]=[N+]=[N-] Chemical compound [N-]=[N+]=[N-].[K+].[Si+4].[N-]=[N+]=[N-].[N-]=[N+]=[N-].[N-]=[N+]=[N-].[N-]=[N+]=[N-] JJLXCWBAIHUBIW-UHFFFAOYSA-N 0.000 description 1
- IVAOQJNBYYIDSI-UHFFFAOYSA-N [O].[Na] Chemical compound [O].[Na] IVAOQJNBYYIDSI-UHFFFAOYSA-N 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 238000009825 accumulation Methods 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
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 201000007930 alcohol dependence Diseases 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 125000004450 alkenylene group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 125000005219 aminonitrile group Chemical group 0.000 description 1
- 230000000578 anorexic effect Effects 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 239000000883 anti-obesity agent Substances 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 229940125710 antiobesity agent Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 239000012148 binding buffer Substances 0.000 description 1
- AZWXAPCAJCYGIA-UHFFFAOYSA-N bis(2-methylpropyl)alumane Chemical compound CC(C)C[AlH]CC(C)C AZWXAPCAJCYGIA-UHFFFAOYSA-N 0.000 description 1
- 229910052797 bismuth Inorganic materials 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 229910010277 boron hydride Inorganic materials 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
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium 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
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 description 1
- 229940090805 clavulanate Drugs 0.000 description 1
- HZZVJAQRINQKSD-PBFISZAISA-N clavulanic acid Chemical compound OC(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 HZZVJAQRINQKSD-PBFISZAISA-N 0.000 description 1
- 210000000078 claw Anatomy 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- WJTCGQSWYFHTAC-UHFFFAOYSA-N cyclooctane Chemical compound C1CCCCCCC1 WJTCGQSWYFHTAC-UHFFFAOYSA-N 0.000 description 1
- 239000004914 cyclooctane Substances 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- KWZWNVAHEQHCTQ-UHFFFAOYSA-N diacetyloxyboranyl acetate Chemical compound CC(=O)OB(OC(C)=O)OC(C)=O KWZWNVAHEQHCTQ-UHFFFAOYSA-N 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 229940009662 edetate Drugs 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000002996 emotional effect Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 229950000206 estolate Drugs 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- BZKQJSLASWRDNE-UHFFFAOYSA-N ethyl 4-hydroxycyclohexane-1-carboxylate Chemical compound CCOC(=O)C1CCC(O)CC1 BZKQJSLASWRDNE-UHFFFAOYSA-N 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- 229910021485 fumed silica Inorganic materials 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229960001731 gluceptate Drugs 0.000 description 1
- KWMLJOLKUYYJFJ-VFUOTHLCSA-N glucoheptonic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)C(O)=O KWMLJOLKUYYJFJ-VFUOTHLCSA-N 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-M glutaminate Chemical compound [O-]C(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-M 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000009931 harmful effect Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-N lactobionic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 235000020997 lean meat Nutrition 0.000 description 1
- 235000012204 lemonade/lime carbonate Nutrition 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 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
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- LRMHVVPPGGOAJQ-UHFFFAOYSA-N methyl nitrate Chemical compound CO[N+]([O-])=O LRMHVVPPGGOAJQ-UHFFFAOYSA-N 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-N methyl sulfate Chemical class COS(O)(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-N 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 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
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 230000002969 morbid Effects 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 229940014662 pantothenate Drugs 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical class NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical class NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 description 1
- PJESVVYWPFAJCS-UHFFFAOYSA-N pyridazine-3-carbonitrile Chemical compound N#CC1=CC=CN=N1 PJESVVYWPFAJCS-UHFFFAOYSA-N 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000009256 replacement therapy Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 208000020431 spinal cord injury Diseases 0.000 description 1
- GOLXNESZZPUPJE-UHFFFAOYSA-N spiromesifen Chemical compound CC1=CC(C)=CC(C)=C1C(C(O1)=O)=C(OC(=O)CC(C)(C)C)C11CCCC1 GOLXNESZZPUPJE-UHFFFAOYSA-N 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- DHCDFWKWKRSZHF-UHFFFAOYSA-L thiosulfate(2-) Chemical compound [O-]S([S-])(=O)=O DHCDFWKWKRSZHF-UHFFFAOYSA-L 0.000 description 1
- 210000001519 tissue Anatomy 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
- 229950004288 tosilate Drugs 0.000 description 1
- 238000012546 transfer Methods 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
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 210000000635 valve cell Anatomy 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/46—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
-
- 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
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- 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
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
-
- 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
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/34—Tobacco-abuse
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
-
- 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
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Psychiatry (AREA)
- Addiction (AREA)
- Reproductive Health (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Pain & Pain Management (AREA)
- Gynecology & Obstetrics (AREA)
- Pregnancy & Childbirth (AREA)
- Child & Adolescent Psychology (AREA)
- Endocrinology (AREA)
- Hospice & Palliative Care (AREA)
- Otolaryngology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Hydrogenated Pyridines (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
公开了一种可用于肥胖症和相关疾病的治疗、预防或改善的式(I)化合物,其中变量X1~X5、R1~R7包括R3’、E、q、v、y、z、A和B如所描述,或其医药上可接受盐、溶剂合物、对映体、外消旋物、非对映体或混合物。
Description
技术领域
本发明属于医药化学领域。本发明具体地涉及可用来作为类鸦片拮挤剂的化合物、其治疗方法、使用方法和医药组合物。
背景技术
一般来说,已报告了三种类型的类鸦片受体,即μ、κ、和δ类鸦片受体。最近的证据指向μ、κ和/或δ受体的受体二聚体组合(称为杂二聚体)之间的相互作用,因为这也对类鸦片活性有贡献。已经有人暗示,类鸦片受体及其正常调节或缺乏与动物中的一些疾病状态有关,其中包括刺激性肠综合征、恶心、呕吐、瘙痒性皮肤病、抑郁症、烟瘾和酒瘾,性功能障碍、中风和创伤。因此,并不令人惊讶的是,已经有人显示拮抗性地结合类鸦片受体的能力在受到这些疾病状态中一种或多种影响的动物包括人中产生改善的、预防的和/或治疗的效果。
最近,已经有人发现类鸦片受体的某些拮抗剂能增加代谢能耗、肥胖症大鼠的体重降低同时维持肌肉质量。这些发现表明,有效的类鸦片拮抗剂可能可用于预防、治疗和/或改善肥胖效果。考虑到西方社会中肥胖人口的百分率和与治疗肥胖症及相关疾病的效应和症状有关的间接成本,这些发现的重要性无论怎么说都不过分。
尽管已经公开了很多类鸦片拮抗剂,但对替代的和/或改善的或更有效的、总体上有益于患者且很少或没有重大副作用的拮抗剂的探索还在继续。美国专利No.4,891,379公开了可用于糖尿病和肥胖症治疗的苯基哌啶类鸦片拮抗剂。具体地说,美国专利4,891,379公开了以下结构代表的化合物LY255582:
美国专利No.4,191,771也公开了可用来作为类鸦片拮抗剂的化合物。Wentland等,Bioorganic and Mdeicinal Chemistry Letters 11(2001)623-626也制备了苯基哌啶的双环类似物并作为类鸦片拮抗剂报告;也请参阅Wentland等,Bioorganic and Medicinal Chemistry Letters 11(2001)1717-1721。最后,2000年5月18日提交的欧洲专利申请No.EP 1072592 A2公开了式1的苯基哌啶化合物
式中A、D、R1、R2、R3、X、和n有该说明书中给出的定义,该化合物可用于预防和治疗类鸦片受体介导的疾病例如瘙痒。
美国专利No.6,140,352和相关专利公开了式(1)化合物
式中变量X1、X2、X3、R1、R3、R4、R5和R6如该文中所述,作为可用于糖尿病和肥胖症治疗的β-肾上腺素能受体的激动剂。
不管可用来作为类鸦片受体拮抗剂或可用于经由其它机理治疗肥胖症和/或糖尿病的化合物的这些及其它公开,目前对于与类鸦片受体有关的疾病、尤其肥胖症和相关疾病的安全、有效和/或替代治疗或预防仍然存在未得到满足的医学需要。
发明内容
本发明提供式I化合物
式中
X1、X2、X3、X4、和X5中每一个都是C、CH、或N;前提是环B有不多于2个氮原子;
X是NH或CH2,使得环A为环己基、环己烯基、或哌啶基;
E是NH或O;
V是0、1、2、或3;
q是0或1,前提是当A环为环己基或环己烯基时q是1,且前提是v和q不同时为0;
R1和R2独立地选自氢、C1-C8烷基、C2-C8烯基、C2-C8炔基、芳基、C3-C8环烷基、C1-C10烷芳基、杂环基、C1-C10-烷基杂环、-C1-C8烷基C(O)C1-C8烷基、-(CH2)n(CO)C3-C8环烷基、-C2-C8烷基CH(OH)芳基、-CO(O)C1-C8烷基、-SO2C1-C8烷基、-SO2C1-C10烷芳基、-SO2C1-C8烷基杂环、C1-C8烷基环烷基、-(CH2)nC(O)OR8、-(CH2)nC(O)R8、-(CH2)mC(O)NR8R8、和-(CH2)mNSO2R8;其中烷基、烯基、环烷基、杂环、和芳基基团各自任选地有1~5个独立地选自下列的基团取代:卤素、C1-C8卤烷基、C1-C8硫烷基、C1-C8烷基、C2-C8烯基、芳基、-C1-C8烷芳基、-C(O)C1-C8烷基、-SO2C1-C8烷基、-SO2C1-C8烷芳基、-C1-C8烷基环烷基;且其中R1和R2可以任选地彼此组合形成一个4员、5员、6员、或7员含氮杂环,该含氮杂环可以进一步有选自下列组成的一组的取代基:氨基、C1-C8烷基、C2-C8烯基、C2-C8炔基、芳基、C1-C8烷芳基、-C(O)C1-C8烷基、-CO(O)C1-C8烷基、卤素、氧代、C1-C8卤烷基;
R3和R3’各自独立地选自氢、C1-C8烷基、C2-C8烯基、C2-C8炔基、芳基、-C1-C8烷基环烷基、或-C1-C8烷芳基、C1-C8烷基杂环;或R3和R3’组合形成一个C3-C8环烷基、C4-C8环烯基、或C5-C10杂环;
R4和R5各自独立地选自氢、C1-C8烷基、C2-C8烯基、C2-C8炔基、-C1-C8烷氧烷基、C1-C8硫烷基、卤素、C1-C8卤烷基、-C1-C8烷氧卤烷基、芳基、-C1-C8烷芳基、-C(O)C1-C8烷基、或-C(O)OC1-C8烷基、-C1-C8烷胺基、-C1-C8烷基环烷基、-(CH2)mC(O)C1-C8烷基、和(CH2)nNR8R8,其中每个R4或R5都只连接到其各自环的碳原子上,且其中y是0、1、2、或3,且其中z是0、1、2、或3;
R6和R7各自独立地选自氢、C1-C8烷基、C2-C8烯基、C2-C8炔基、-C(O)C1-C8烷基、羟基、C1-C8烷氧基、-SO2C1-C8烷基、SO2C1-C8烷芳基、-SO2C1-C8烷基杂环、芳基、-C1-C8烷芳基、C3-C7环烷基、-C1-C6烷基环烷基、-(CH2)nC(O)R8、(CH2)mC(O)NR8R8、和-(CH2)mNSO2R8;其中烷基、烯基、和芳基中每一个都任选地有1~5个独立地选自C1-C8烷基、C2-C8烯基、芳基、和C1-C8烷芳基的基团取代;且其中R6和R7可以独立地彼此组合形成一个4员、5员、6员、或7员含氮杂环,该含氮杂环可以任选地有选自下列组成的一组的取代基:氧代、C1-C8烷基、C2-C8烯基、C2-C8炔基、芳基、C1-C8烷芳基、-C(O)C1-C8烷基、-CO(O)C1-C8烷基、羟基、C1-C8烷氧基、-C1-C8烷胺、氨基、卤素、和卤烷基;
R8是氢、C1-C8烷基、C2-C8烯基、C1-C8烷芳基、-C(O)C1-C8烷基、或-C(O)OC1-C8烷基;且其中n是0、1、2、3或4,且m是1、2、或3;
或其医药上可接受盐、溶剂合物、对映体、外消旋物、非对映体或非对映体混合物。
本发明也提供一种医药配方,包含与载体、稀释剂和/或赋形剂配合的式I化合物。
本发明也涉及肥胖症和相关疾病的治疗和/或预防方法,相关疾病包括饮食失调(贪食、神经性食欲缺乏等)、糖尿病、糖尿病并发症、糖尿病性视网膜病、性/生殖失调、与肥胖有关的抑郁症、与肥胖有关的焦虑、癫痫发作、高血压、脑出血、充血性心力衰竭、睡眠失调、动脉粥样硬化、中风、代谢疾病及其症状、高脂血、高甘油三酯血、高血糖、高脂蛋白血、物质滥用、用药过量、强迫行为失调(例如狗用舌头舔爪子)、和成瘾行为例如赌博和醇中毒,所述方法包含给药治疗有效量的式I化合物或其医药上可接受盐、溶剂合物、对映体、外消旋物、非对映体或非对映体混合物。
本发明提供可用于与肥胖症和相关疾病有关的症状的治疗、预防和/或改善用药剂制造的式I化合物。
在另一种实施方案中,本发明提供可用来作为食欲抑制剂的式I化合物或其医药上可接受盐、溶剂合物、对映体、外消旋物、非对映体或非对映体混合物。
在另一种实施方案中,本发明提供一种达到减肥(weight loss)同时维持或最大限度减少瘦肉质量损失的方法,包含对有此需要的患者给药式I化合物或其医药上可接受盐、溶剂合物、对映体、外消旋物、非对映体或混合物。
在又另一种实施方案中,本发明对有其需要的患者提供与肥胖症和相关疾病治疗的其它有效疗法组合的式I化合物或其医药上可接受盐、溶剂合物、对映体、外消旋物、非对映体或混合物。
本文中使用的“肥胖症”这一术语有其共同理解的含义例如“过度肥胖”,并包括医学文献和支撑机构或公共卫生机构的小册子上所定义的过度肥胖的临床指定。例如,Dorland’s Illustrated MedicalDictionary(29 th edition,W.B.Saunders Company,Philadelphia USA)将肥胖症定义为“由于体内脂肪过度积累的结果,体重增加超过骨骼和身体要求的限制”。由于本发明化合物对患者适当给药的决定要由有资格的医师或有资格的护理人员做出,因而,患者固有地由给药护理人员认定为适度还是过度肥胖。
本文中使用的“患者”这一术语包括人类和非人类动物例如同伴动物(狗和猫)和家畜动物。
肥胖症和相关疾病的治疗、改善和/或预防的较好患者是人类。
本文中使用的“治疗”和“医治”这些术语包括其公认的含义,即本文中所述的病理学病症或其后遗症的进展或严重性的预防、禁止、限制、缓解、改善、减慢、阻止或逆转。
“改善”、“预防”、“防止”等术语在本文中是互换地使用的,而且系指减轻患有肥胖症和相关疾病的患者中与肥胖症和相关疾病有关的症状的严重性,或减少式I化合物的接受者发生或发展本文中所述病理学病症中任何一种或其后遗症的可能性。
本文中使用的“有效量”这一术语是与“有效剂量”同义的,而且系指式I化合物在一次或多次给药中足以预防、改善或治疗本文中所述病症或其有害效果的数量,式I化合物足以拮抗类鸦片受体而达到本发明范围内所希望的结果的数量。
“医药上可接受”这一术语在本文中是作为形容词使用的,而且意味着对受药患者实质上无害。
本文中使用的“有效成分”这一术语系指式I化合物或式I化合物的组合或式I化合物与类鸦片受体共拮抗剂的组合或式I化合物加上其它有效抗肥胖剂、减肥剂或抗糖尿病剂的组合。
“配方”这一术语,如同在医药配方或“医药组合物”中一样,意图涵盖一种包含有效成分(如以上定义)和给药时构成载体的惰性成分或药物的其它成分的产品,以及从任何两种或更多种有效成分的组合、复合或聚集或者从一种或多种有效成分的离解而直接或间接得到的任何产品。因此,本发明的医药配方涵盖通过掺和本发明化合物和医药载体制成的任何有效组合物。本发明的医药配方也涵盖式I化合物和医药上可接受类鸦片受体共拮抗剂或可用于肥胖症或相关疾病治疗和/或预防的其它有效疗法。
本文中使用的“相关疾病”系指由过度肥胖病症引起、加剧、诱发或附属的此类症状、疾病或病症。这样的疾病、病症和/或症状包括但不限于饮食失调(贪食、神经性食欲缺乏等)、糖尿病、糖尿病并发症、糖尿病性视网膜病、性/生殖失调、与肥胖有关的抑郁症、与肥胖有关的焦虑、癫痫发作、高血压、脑出血、充血性心力衰竭、睡眠失调、动脉粥样硬化、中风、代谢疾病及其症状、高脂血、高甘油三酯血、高血糖、高脂蛋白血。本文中使用的“与肥胖有关的抑郁症”和“与肥胖有关的焦虑”这些术语是分别为抑郁症和焦虑的病症,它们有某些过度肥胖患者的症状,而且可能由对过度肥胖病症的认识或自我意识引起,还可能偶合某个或某些个人或广大公众对认可或排斥的真实或领悟的感受。与肥胖有关的抑郁症或焦虑一般可以通过给药式I化合物而与过度肥胖或超重的基础病症一起缓解或治疗和/或预防。
“适用溶剂”这一术语系指对正在进行的反应惰性的、能使反应物充分增溶从而提供用来进行所希望反应的介质的任何溶剂或溶剂混合物。
“互溶剂”这一术语系指一种用来使反应或混合物的2种或更多种成分在反应或混合之前分别充分溶解的溶剂,即一种对混合物的不止一种试剂或成分共同的溶剂。
“含氮杂环”这一术语系指一种芳香族的或非芳香族的、单环的或双环的、4员、5员、6员、或7员环的环系,该环系除完成该环大小的碳原子外还含有1个、2个或3个氮原子,或除完成该环大小的适当碳原子数外还含有1个氮原子和1个或2个选自氧和硫的原子的组合。这里使用的含氮杂环可以有0、1、2或3个双键。
“C1-C8烷基”或“C1-8烷基”这一术语系指并包括有1~8个碳原子的烷基的所有基团、结构异构体和/或同系物。当C1-C8烷基这一术语在另一个基团前面或后面时,C1-C8烷基这一术语只限定烷基成分中碳原子的数目。例如,C1-C8烷芳基系指一种有一个C1-C8烷基取代基的芳基,使得C1-C8烷芳基基团中碳原子的数目有效地是该芳基中碳原子的数目加上该C1-C8烷基中碳原子的数目。类似地,“C1-C8烷基环烷基”这一术语系指一种有一个C1-C8烷基取代基的环烷烃,且其中C1-C8烷基环烷烃整个基团本身可以是一种要么在烷基基团上要么在环烷基上连接到基材上的取代基。这一定义和使用同样适用于C1-C8的其它同系物例如C1-C7、C1-C6等。一般地说,且必要时,在仅次于某基团的位置放一个短杠(-)以清晰地指出连接点。不过,短杠不存在并不否定对业内技术人员已知的明显连接位置的位置。
“环烷烃”或“环烷基”这一术语系指有3~8个碳原子的环烷烃,即从环丙烷到环辛烷。
本文中使用的“卤”或“卤素”这一术语系指包括氟、氯、溴或碘在内的卤素。
“卤烷烃”或“卤烷基”这一术语系指有价键考虑所允许的1~8个碳原子和1~3个卤原子的卤烷烃。实例包括氯乙基、三氟甲基、2-氯丙基等。
本文中使用的“烯基”这一术语系指有1或2个碳-碳双键的直链或支化链烃基。
本文中使用的“炔基”这一术语系指有1或2个碳-碳三键的直链或支化链烃基。
本文中使用的“烷氧基”这一术语系指“O-烷基”这一基团,其中烷基同以上定义。
本文中使用的“芳基”这一术语系指有休克尔4n+2π电子排布的化合物或基团并包括诸如苯基、苄基、萘基、四氢萘基、苯并噻吩等,但不包括咔唑及其它稠合三环式环结构。
本文中使用的“芳氧基”或“芳基氧”这一术语系指“O-芳基”这一基团,其中芳基同以上定义。
本文中使用的“稠合双环”这一术语系指稠合的环烷烃环系,其中每个环有4~8个碳原子(即C8~C16稠合双环),且该稠合环系有0~3个桥头碳原子。该稠合环中一个或两个环可以含有0~1个双键。稠合双环的实例包括但不限于双环[2,2,1]庚基、双环[2,2,1]庚烯基。
本文中使用的“杂环的”或“杂环基”或“杂环”这一术语是可互换使用的,而且有其通常含义并包括单环、双环或三环或螺环的杂环基,除非另有说明。本文中使用的杂环可以含有1、2或3个独立地选自氮、氧或硫的杂原子、除非另有指出。适用于本发明的杂环基的实例包括但不限于吡喃基、哌嗪基、吡咯基、氮杂环庚基、氮杂芴基、异喹啉基、二氢吲哚基、噻吩基、苯并噻吩基、唑基、吗啉基、噻吗啉基和哌啶基。这些杂环基中每一个都可以有一取代或二取代,或如所规定的有所定义的烷基、环烷基、芳基等取代基取代。进而,取代可以在诸如哌嗪、吡咯烷的1位或杂原子上或在碳原子上或二者兼而有之。
本文中使用的“保护基”这一术语系指可用于掩蔽分子中的反应性部位以提高另一个基团的反应性或允许反应在另一个或多个所希望的部位进行的基团,反应后该保护基可以脱除。保护基通常用来保护或掩蔽包括但不限于-OH、-NH、和-COOH的基团。适用的保护基是业内技术人员已知的,并描述于Protecting Groups in OrganicSynthesis,3rd edition,Greene,T.Wi.;Wuts,P.G.M.Eds.,John Wileyand Sons,New York,1999。
本文中使用的“溶剂合物”这一术语是本发明化合物的一种形式,其中本发明化合物的一种或多种结晶是从化学论量或非化学论量的式I化合物和溶剂生成的。典型的、能生成溶剂合物的溶剂包括例如水、甲醇、乙醇、丙酮和二甲基甲酰胺。
在本发明化合物有酸性或碱性官能团的情况下,可以生成比母体化合物更具水溶性和/或生理学上更适用的各种盐。代表性的医药上可接受盐包括但不限于碱金属盐和碱土金属盐,例如锂、钠、钾、钙、镁、铝等的盐。通过用碱处理溶液中的酸或使酸暴露于离子交换树脂,就能方便地从游离酸制备盐。
医药上可接受盐的定义内包括的是本发明化合物的相对无毒、无机碱和有机碱加成盐,例如从有足够碱性的含氮碱衍生的铵、季铵、和胺阳离子与本发明化合物生成盐(见例如S.M.Berge,et al.,“Pharmaceutical Salts”,
J.Phar.Sic.,66:1-19(1977))。进而,本发明化合物的碱性基团可以与适当无机酸或有机酸反应生成盐,例如乙酸盐、苯磺酸盐、苯甲酸盐、碳酸氢盐、硫酸氢盐、酒石酸氢盐、硼酸盐、氢溴酸盐、camsylate、碳酸盐、clavulanate、柠檬酸盐、氯化物、乙二胺四乙酸盐、edisylate、estolate、esylate、氟化物、富马酸盐、gluceptate、葡糖酸盐、谷氨酸盐、乙醇酰阿散酸盐、己基间苯二酚盐、盐酸盐、羟基萘甲酸盐、氢碘酸盐、异硫代硫酸盐、乳酸盐、乳糖酸盐、月桂酸盐、马来酸盐、扁桃酸盐、甲磺酸盐、甲基溴化物、甲基硝酸盐、硫酸甲酯盐、粘酸盐、napsylate、硝酸盐、油酸盐、单酸盐、棕榈酸盐、泛酸盐、磷酸盐、聚半乳糖醛酸盐、水杨酸盐、硬脂酸盐、碱式乙酸盐、琥珀酸盐、单宁酸盐、酒石酸盐、甲苯磺酸盐、三氟乙酸盐、三氟甲磺酸盐、和戊酸盐。为了本发明之目的,较好的盐包括盐酸盐、氢溴酸盐、硫酸氢盐、甲磺酸盐、对甲苯磺酸盐、酒石酸氢盐、乙酸盐、和柠檬酸盐。
式I所说明的本发明化合物可以作为其位置异构体、立体化学异构体、或区域异构体中任何一种存在,这些全部是本发明的目标。本发明的某些化合物可以有一个或多个手性中心,因而可以光学活性形式存在。同样,当该化合物含有烯基或亚烯基时,就存在该化合物的顺式和反式异构体形式的可能性。R-和S-异构体及其混合物,包括外消旋混合物以及对映体或顺式和反式异构体的混合物,都是本发明所期待的。另外的非对称碳原子可能存在于取代基例如烷基中。所有这样的异构体以及其混合物都意图纳入本发明。当一种特定立体异构体是所希望的时,它可以由业内众所周知的方法使用立体特异反应以含有不对称中心而且已经拆解的起始原料,或者由能导致立体异构体混合物的方法且随后用已知方法拆解来制备。例如,外消旋混合物可以与某种其它化合物的单一对映体即手性拆解试剂反应。这使该外消旋形式变成立体异构体和非对映体的混合物,因为它们有不同的熔点、不同的沸点、和不同的溶解度,而且可以用惯常手段例如结晶分离。
2002年10月10日公布的PCT国际申请WO 02/078693 A2公开了下式化合物
式中R1、R2、R3、R4和X如该文中所述,作为5-HT6受体的拮抗剂用于治疗包括认知失调、与年龄有关的失调、情绪失调、精神病等在内的失调。然而,本发明化合物可用于治疗和/或预防肥胖症和相关疾病。本发明化合物也已经显示出开胃效应抑制,因而可用来作为食欲抑制剂,要么作为单一疗法,要么作为与锻炼及其它有效食欲抑制或减肥药疗法配合的组合疗法。
本发明的某些化合物的功效已经由其在若干生物学模型中的活性或药效所证实,该模型包括结合闪烁近似试验(SPA)和功能GTP-γ-S试验。
具体实施方式
式I化合物较好作为游离碱或医药上可接受盐存在。更好的是式I化合物的盐酸盐、硫酸氢盐、甲磺酸盐或草酸盐。
式I化合物的较好实施方案包括如下所示亚结构Ia、Ib、Ic和Id:
对于基团R1和R2
较好的R1和R2基团独立地选自氢、甲基、乙基、丙基、戊基、苯基、萘基、苯并噻吩、和异丙基组成的一组。
也较好的是独立地选自下列组成的一组的R1和R2基团:甲基、乙基、丙基、异丙基、苯基、
其中每一个都任选地有选自下列组成的一组的基团取代:卤素、C1-C8烷基、C1-C8卤烷基、C1-C8硫烷基、C1-C8烷胺基、苯基、有C1-C8烷基取代的苯基、C4-C8杂环或-C1-C4烷基杂环;或与选自下列的基团组合形成一种有取代或无取代双环或三环:C1-C8烷基、卤素、C1-C8卤烷基、C1-C8硫烷基、C1-C8烷胺基、苯基、有C1-C8烷基取代的苯基、C4-C8杂环或C1-C4烷基杂环,且其中n较好是1、2、或3。
也较好的是彼此组合或与氮原子的1个或2个相邻原子组合形成一种选自下列组成的一组的基团的R1和R2基团:
其中每一个都任选地有选自下列组成的一组的基团取代:卤素、氨基、C1-C8烷基、C1-C8卤烷基、C1-C8硫烷基、-C1-C8烷胺基、苯基、有C1-C8烷基取代的苯基、C4-C8杂环、或C1-C4烷基杂环。
较好的R3和R3’基团
较好的R3是氢。较好的R3’基团选自氢、甲基、乙基、丙基、异丙基、丁基、异丁基、苯基和苄基。
较好的R4基团
较好的R4基团选自下列组成的一组:氢、卤素、C1-C5烷基、C1-C5卤烷基、C1-C5烷氧基、-C1-C5烷胺基、-N(C1-C5烷基)2、-NHC1-C5烷基、-C1-C5烷基N(C1-C5烷基)2、-C1-C5烷基NHC1-C5烷基、苯基、-C1-C5烷基苯基、-C1-C5烷基环烷基、和C1-C5硫烷基。更好的是选自下列组成的一组的R4基团:氢、甲基、乙基、异丙基、氯、氟、三氟甲基、甲氧基、乙氧基、硫甲基、苯基、和苄基。最好的是选自下列组成的一组的R4基团:氢、甲基、乙基、异丙基、氟、氯、三氟甲基、甲氧基、乙氧基、丙氧基、异丙氧基、和苄基。
尽管基团R4和R5可以作为其各自环基材上的多取代基存在,但本发明的较好实施方案涉及这样的化合物,其中R4和R5中每一个都独立地单取代或双取代于其各自的环基材上。
较好的R5基团
较好的R5基团选自下列组成的一组:氢、卤素、C1-C5烷基、C1-C5卤烷基、C1-C5烷氧基、-C1-C5O烷胺基、-N(C1-C5烷基)2、-NHC1-C5-烷基、-C1-C5烷基N(C1-C5烷基)2、-C1-C5烷基NHC1-C5烷基、苯基、-C1-C5烷基苯基、-C1-C5烷基环烷基、和C1-C5硫烷基。更好的是选自下列组成的一组的R5基团:氢、甲基、乙基、异丙基、氯、氟、三氟甲基、甲氧基、乙氧基、硫甲基、苯基、和苄基。最好的R5基团选自下列组成的一组:氢、甲基、乙基、异丙基、氟、氯、三氟甲基、甲氧基、乙氧基、三氟甲氧基、和苄基。
较好的R6和R7基团
较好的R6和R7基团独立地选自下列组成的一组:氢、甲基、乙基、丙基、戊基、异丙基、苯基和苄基。
也较好的是式I化合物,其中R6和R7独立地彼此组合、和与它们所连接的氮原子组合或与该氮原子的1个或2个相邻原子组合,形成一种4员、5员、6员、7员含氮杂环,该含氮杂环可任选地有选自下列组成的一组的取代基:氧代、氨基、C1-C8烷基、C2-C8烯基、C2-C8炔基、苯基、-C1-C8烷芳基、-C(O)C1-C8烷基、-CO(O)C1-C8烷基、羟基、C1-C8烷氧基、卤素、和卤烷基。
较好的q值
当A环为哌啶基时q较好是0。当A环是环己基时q较好是1。
较好的E基团
最好的E基团是氧原子(O)。
较好的A环
较好的A环是环己基或哌啶基。最好的A环是环己基。
较好的B环
较好的B环是苯环、吡嗪环、嘧啶环、或吡啶环。最好的B环是苯环、吡嗪环或吡啶环。
较好的v、n和m值
较好的v值是0、1、或2。
较好的n值是1、2、或3。
较好的m值是1或2。
按照本发明的较好化合物是选自下列组成的一组的化合物:
±6-{4-[2-(四氢吡喃-4-基)乙胺基]环己氧基}烟酰胺,
±6-[4-(3-甲基丁胺基)环己氧基]烟酰胺,
±6-[4-(2-噻吩-2-基乙胺基)环己氧基]烟酰胺,
±4-[4-(3-苯基丙胺基)环己氧基]苯甲酰胺,
反式-6-(4-苄胺基环己氧基)烟酰胺,
6-(1-吡啶-2-基甲基哌啶-4-氧基)烟酰胺,
6-(1-环丙基甲基哌啶-4-氧基)烟酰胺,
6-[1-(1H-吲哚-2-基甲基)哌啶-4-氧基]烟酰胺,
4-(1-苄基哌啶-4-氧基)苯甲酰胺,
4-[1-(3-苯基丙基)哌啶-4-氧基]苯甲酰胺,
和其医药上可接受盐、溶剂合物、对映体、非对映体、或非对映体混合物。
本发明化合物制备
以下流程1说明本发明化合物及其中间体的典型制备方案,其中A环是一种有任选取代的环己基。
流程1
按照流程1,起始原料3,3-二甲基-1,5-二氧杂螺[5.5]十一烷酮(1)及其类似物通过在一种甲醇溶剂中与有聚合物载体的硼氢化物反应还原成相应的醇3,3-二甲基-1,5-二氧杂螺[5.5]十一烷-9-醇(2)。业内技术人员知道,可以利用其它还原剂和还原方式(例如无聚合物载体)来得到化合物2及其类似物。酮1及其类似物可以购自化学品分销商,例如Aldrich Chemical Co.(Milawaukee,USA)。然后,使化合物3,3-二甲基-1,5-二氧杂螺[5.5]十一烷-9-醇(2)与卤烟腈或卤苄腈或其它B环源偶合,得到有氧键的化合物3或其类似物。例如,在碱性条件下,让有任选取代的4-氯烟腈与化合物2反应,得到有氧键的化合物3。碱性条件包括选自无机碱和有机碱的碱的使用。有用的无机碱的实例包括但不限于碳酸钾、氢化钠、碳酸钠、氢氧化钠、氢氧化钾、碳酸钙和碳酸铯。有机碱的实例包括但不限于六甲基二硅叠氮化钾、正丁基锂、六甲基磷三酰胺(HMPT)等。该碱性条件是由一种溶剂、较好一种有机溶剂的存在予以补充的。较好的有机溶剂包括质子溶剂或极性非质子溶剂。最好的溶剂包括二甲基甲酰胺、甲醇、二甲基乙酰胺(DMA)、二甲基亚砜。最好的碱性反应条件涉及在约60~100℃的温度在二甲基乙酰胺中碳酸钾的使用。化合物3的保护基(二甲基缩醛基)是通过与一种酸性基例如盐酸反应脱除的,得到化合物4。化合物4用一种所希望的胺进行还原胺化,得到氨基化合物5,即本发明化合物。该还原胺化可以分2步进行,也可以用一步进行,因亚胺中间体这一中间体的稳定性而异。典型地说,化合物4是在作为溶剂的甲醇中与一种伯胺或仲胺(显示伯胺)反应的。可以添加分子筛,以提高亚胺生成效率。第2步,向该反应混合物中添加还原剂,典型地硼氢化钠或其它氢化物还原剂。该反应的进展可以用TLC、HPLC、LC-MS或业内技术人员已知的其它分析技术监测,以确定每一步的实质性完成和下一种试剂添加的时间。所得到的氨基腈化合物5在氰基上水解,得到伯酰胺6。腈水解较好通过与过氧化氢和一种无机碱例如碳酸钠、较好在压力下反应来进行。适合于进行上述腈水解的溶剂是DMSO或DMF。
有一个或多个取代基R基团的化合物3和5的类似物可以通过使用有适当取代的起始原料或通过取代基官能度相互转化来制备。例如,A环或B环上的初始任选取代基基团可以进行适当保护和脱保护来达到所希望的最终取代基R。替而代之,初始取代基可以用已知的1步、2步或3步反应转化成其它所希望的最终取代基。
流程2中说明的一种替代方案显示苯甲酰胺作为环B来源的使用。
流程2
对于其B环是吡啶基、哒嗪基、吡嗪基、或嘧啶基的本发明化合物来说,酰胺起始原料的使用是特别好的。羧酰胺或杂环酰胺可以作为该起始原料的组成部分导入,其中B环的适当代用品是可市购的或可使用已知方法制备的。例如,吡嗪羧酰胺、烟酰胺或其有取代类似物的使用导致式3a或6a化合物的有取代衍生物或类似物,这些也是本发明化合物。如流程2中所示,伯胺和仲胺可用于使化合物4a转化成化合物6a的还原胺化。可用于该还原胺化的胺的实例包括但不限于苯乙胺、3-甲基丁胺、丙胺、异丙胺、苄胺和异戊胺。
用这种流程或者本文中公开的或业内技术人员已知的其它流程制备的化合物,都可以像诸如流程3中所示那样进一步转化成酸加成盐。
流程3
流程3显示盐酸盐12a即其R1R2NH是3-甲基丁胺或其它仲胺基且R4和R5都是氢的本发明化合物的制备。如所示,起始原料7是氮原子用叔丁氧羰基酐(Boc-酐)保护的4-羟基哌啶。Boc-保护的哌啶醇(7)与所希望的B-环来源例如卤苄腈、或卤烟腈(所显示的6-氯烟腈(8))或卤哒嗪腈或其羧酰胺反应。生成醚键(9)的偶合反应是在一种适当溶剂例如DMA、DMF、或DMSO中在一种碱例如氢化钠或碳酸钠的存在下进行的。然后,使所得到的醚(9)的腈基水解生成伯酰胺。该腈的水解是在过氧化氢和一种碱例如碳酸钠的存在下完成的。所得到的酰胺10在酸性条件下水解,得到脱保护的化合物11。Boc基团的脱保护最好使用HCl、TFA或HF进行。Boc保护和脱保护的程序是业内技术人员已知的,而且描述于一般有机化学文献,包括ProtectingGroupsin Organic Synthesis,3rd edition,Greene,T.W.;Wuts,P.G.M.Eds.,John Wiley and Sons,New York,1999。具体程序也可以参阅本文中实验节。化合物11的游离哌啶NH基可以与一种有所希望烷基、烷芳基、环烷基、烷基环烷基、烷基杂环基或本发明范围内的其它取代基的醛反应,得有所希望N取代的哌啶基化合物12。
将化合物12溶解于乙醇中,并在约0℃~室温范围内的温度添加稍微过量(例如,以碱性部位数目为基准,1.0~1.5摩尔当量)1N盐酸。可以让该混合物冷却或不冷却地随时间推移结晶,还可以使之蒸发,得到该盐酸盐,后者可以用适当有机溶剂例如甲苯、己烷、二乙醚或其混合物研制而进一步精制。替而代之,可以将无水HCl通入化合物12的冷溶液中直至该反应完成或该溶液饱和,适当时该混合物进行后处理,得到化合物12a。业内技术人员了解酸加成盐制备、分离和精制的细微差别和各种技术,而且应当使用适合于特定基材又无过多实验的方法而达到可比的结果。
流程4中提供了本发明化合物的改进制备方案,其中生成醚键的亲核置换反应是朝着该合成的终点而不是初期进行的。
流程4
按照流程4,起始原料是一种氮上用Boc酐保护的有适当取代的羟基哌啶(7)。也许可以买到有Boc保护的羟基哌啶。让有Boc保护的羟基哌啶7与一种B环来源例如4-氟苄腈反应,得到有醚键的化合物9。其它B环来源包括,例如,苯基或吡啶羧酰胺、苄腈或吡啶腈及其类似物。进行偶合反应的方法已在前面公开。化合物9可以经由腈基水解成酰胺、像以上公开的那样通过脱除Boc基团脱保护、最后进行还原胺化、得到本发明化合物。替而代之,醚化合物9可以通过脱除Boc基团脱保护,得到化合物13。该保护基可以通过使用盐酸或三氟乙酸、利用业内技术人员已知的程序脱除。业内技术人员知道,式13化合物的有适当取代类似物可以通过从有适当取代的起始原料或其可转化成所希望取代基的代用品出发来制备。
化合物9脱保护生成化合物13,随后进行还原胺化生成有N-取代哌啶基化合物14。有N-取代哌啶基化合物14最后在腈基上水解,得到化合物15,即本发明化合物。
其v为1的式I化合物可以遵照以下所述合成流程制造:
流程5
如流程5中所示,可以让4-羟基环己烷羧酸乙酯(可购自AldrichChemical Company,Milwankee,USA,或其它精细化学品供应商)与一种B环来源例如卤苄腈或卤烟腈反应,生成有醚键的产物13。生成该醚键的偶合反应是在一种适当溶剂例如DMA、DMF或DMSO中在一种碱例如氢化钠或碳酸钾的存在下进行的。然后使该羧酸酯选择性地还原,给出相应的醛14。这种还原是用氢化物例如氢化二异丁基铝(DIBAL-H)进行的。然后,用所希望的氨基片断使醛14还原胺化,生成胺15。然后,使所得到的氨基前体物的腈水解,得到本发明化合物16。
流程6中显示式I化合物的又另一种制备方案。
流程6
流程5的醛14在一种强碱例如正丁基锂、仲丁基锂、或六甲基二硅烷钾等的存在下与甲氧甲基二苯基膦氧化物或氯化甲氧甲基三苯反应,得到乙烯基甲基醚17。然后使乙烯基甲基醚17在酸性条件下水解,得到更高级的醛18。然后,如前面所显示和讨论的,使醛18转化成所希望的式I化合物20。
本发明的使用方法
如以上所说明的,本发明的化合物可用于阻断μ、κ、和/或δ类鸦片受体上的激动剂效应。因此,本发明也提供哺乳动物中μ、κ、δ受体或其受体组合(杂二聚物)的阻断方法,包含对所述哺乳动物给药受体阻断剂量的式I化合物。
本文中使用的“受体阻断剂量”这一术语系指在对需要阻断μ、κ、或δ受体或其受体组合(杂二聚物)的哺乳动物给药之后,阻断μ、κ、或δ受体或其受体组合(杂二聚物)所需要的式I化合物的数量。
式I化合物或其组合是在广阔剂量范围内有效的。例如,每日剂量通常会落入约0.05~约250mg/kg体重的范围内。在成年人的治疗中,呈单一剂量或多个分剂量的约0.5~约100mg/kg的范围是较好的。然而,要理解的是,实际给药的该化合物的数量将由医师根据相关情况确定,其中包括要治疗的病症、要给药的化合物的选择、个体患者的年龄、体重、和反应、患者症状的严重性、和所选择的给药途径。因此,上述剂量无意以任何方式限制本发明范围。该化合物可以经由各种各样的途径例如经口、经皮、经皮下、经舌下、经鼻内、经肌内和经静脉内途径给药。
已经有人显示各种各样的生理功能遭遇到或受到大脑中μ、κ、或δ受体或受体组合(杂二聚体)影响。因此,相信本发明化合物有能力治疗与这些受体或其组合有关的失调,例如饮食失调、类鸦片剂量过大、抑郁症、烟瘾、酒瘾、性功能障碍、休克、中风、脊椎损伤和头部创伤。因此,本发明也提供了通过阻断其μ、κ、δ受体或受体组合(杂二聚体)上的激动剂效应来治疗上述失调的方法。已经发现本发明化合物在类鸦片受体结合试验中显示优异活性,该试验测定该化合物阻断μ、κ、δ受体或其受体组合(杂二聚物)的能力。
GTP-γ-s结合试验
基于SPA的GTP-γ-S试验格式是在以前的类鸦片试验格式(Emmerson等,J.Pharm Exp Ther 278,1121,1996;Horng等,Societyfor Neuroscience Abstracts,434.6,2000)和蕈毒试验格式(DeLapp等,JPET 289,946,1999)的基础上发展的。将膜再悬浮于20mM HEPES、100mM NaCl、5mM MgCl2、1mM DTT、和1mM EDTA中。向透明底96孔试验平皿中添加50mL GTP-γ-[35S]、化合物、膜悬浮液(20μg/孔)、和涂布了小麦胚芽凝集索的SPA珠(1mg/孔)。在添加到该试验平皿中之前向该膜溶液中添加GDP(200mM)。将平皿密封并在室温培养4小时。然后置于冰箱中过夜,使该珠粒沉降。实测4℃的信号稳定性>60小时。让平皿回升到室温、用一台Wallac Microbeta闪烁计数器计数。对于拮抗试验,以下列浓度添加特定激动剂:(MOR)DAMGO 1μM,(DOR)DPDPE 30nM,(KOR)U69593 300nM。Kb值是用Cheng-Prusoff方程确定的(见Cheng and Prusoff,Biochem.Pharmacol.22,3099,1973)。本发明化合物的代表性样品在GTP-γ-S结合试验中所得到的结果列于以下表1中。
表1
离体拮抗作用GTP-γ-S结合试验
化合物实施例号 | Kb(uM)μ | Kb(uM)κ | Kb(uM)δ |
12678910 | 0.5660.594>1.8001.785>1.8501.1200.453 | 0.6010.6200.4301.0510.9370.9300.999 | 0.8190.996>7.300>7.300>7.300>7.3001.965 |
活体外(ex vivo)受体结合
为了将离体结合亲合力和拮抗剂药效与活体内药效和功效联系起来,申请者们已经发展了一种大鼠大脑的活体外受体结合试验。这种试验量度了从接受载体/化合物处理的动物分离出来的脑组织中高亲合力非选择性类鸦片受体放射性配体(3H-二丙诺啡)的缔合(结合)差异(3H-二丙诺啡的结合越少=化合物与类鸦片受体的缔合越大)。使用该活体外受体结合试验的研究已经证实在食谱诱发的肥胖症大鼠中也与24小时功效相关的活性(药效与活性持续时间)与……之间的正相关。
方法。类鸦片受体活体外结合试验测量了经口给药之后大鼠纹状体/核横卧体—大脑中含有高密度μ、δ和κ受体的一个区域—中的3H-二丙诺啡结合(0.1~0.4nMμ、δ和κ受体的亲合力放射性配体)。在实验上,对大鼠经口给药7mg/kg化合物或载体的筛查剂量。化合物给药后6小时,将动物宰杀、分离出纹状体/核横卧体、并在10体积(重量/体积)结合缓冲剂中均化。然后,该均化物用于使用饱和浓度的3H-二丙诺啡的均化物结合试验30分钟。均化和试验是在4℃进行的,以使化合物在该试验的离体结合部分的再分配降到最低限度。结果是作为比结合常数Ki(μM)报告的(表2)。
表2
SPA结合亲合力试验Ki(μM)
化合物实施例号 | μ | κ | δ |
34 | 0.1370.620 | 2.561>5.000 | 0.3532.345 |
配方
本发明化合物较好以医药配方形式提供,该配方包含医药上可接受载体、稀释剂或赋形剂和本发明化合物。这样的组合物将含有约0.1wt%~约90.0wt%本发明化合物(有效成分)。因此,本发明也提供包含本发明化合物及其医药上可接受载体、稀释剂或赋形剂的医药配方。
在制造本发明组合物时,有效成分通常会与载体混合、或用载体稀释、或封闭于载体内,该载体可以呈胶囊、舌囊、纸或其它容器的形式。当该载体充当稀释剂时,它可以是一种固体、半固体或液体材料,该材料起到有效成分的载体、赋形剂、或介质的作用。因此,该组合物可以呈片剂、丸剂、散剂、糖锭剂、舌囊剂、扁囊剂、酏剂、乳状液剂、溶液剂、糖浆剂、悬浮液剂、气雾剂(作为固体或在液体介质中)、软胶囊剂和硬胶囊剂的形式。
适用的载体、赋形剂、和稀释剂的实例包括乳糖、右旋糖、蔗糖、山梨糖醇、甘露糖醇、淀粉、阿拉伯胶、磷酸钙、藻酸盐、硅酸钙、微晶纤维素、聚乙烯基吡咯烷酮、纤维素、西黄蓍胶、明胶、糖浆、甲基纤维素、羟基苯甲酸甲酯和丙酯、滑石、硬脂酸镁、水、和矿物油。该配方也可以包括润湿剂、乳化剂、悬浮剂、防腐剂、增甜剂、或矫味矫臭剂。本发明的配方可以采用业内众所周知的程序,配制得能在对患者给药之后提供有效成分的迅速、持久、或延时释放。
对于经口给药,有效成分即本发明化合物可以与载体和稀释剂掺和并成形为片剂或封闭于胶囊中。
该组合物较好配制成单元剂量形式,每个剂量含有约1~约500mg、更通常约5~约300mg有效成分。“单元剂量形式”这一术语系指适合作为人类患者及其它动物的单元剂量的物理上分立单元,每个单元含有与适当医药载体配合的、计算得能产生所希望疗效的预定量有效材料。
为了更充分地说明本发明的运作,提供了下列配方实施例。这些实施例只是说明性的,且无意限制本发明的范围。这些配方可以采用本发明化合物中任何一种作为有效成分。
配方1
使用下列成分制备硬胶囊剂:
化合物 | 每胶囊数量(mg) | 浓度(wt%) |
有效成分 | 250 | 55 |
干燥淀粉 | 200 | 43 |
硬脂酸镁 | 10 | 2 |
上述成分混合并以460mg数量灌装到硬明胶胶囊中。
配方2
每个含有20mg药剂的胶囊剂制作如下:
化合物 | 每胶囊数量(mg) | 浓度(wt%) |
有效成分 | 20 | 10 |
淀粉 | 89 | 44.5 |
微晶纤维素 | 89 | 44.5 |
硬脂酸镁 | 2 | 1 |
将有效成分、纤维素、淀粉、和硬脂酸镁掺合、通过45号目数美国筛并灌装到硬明胶胶囊中。
配方3
每个含有100mg有效成分的胶囊剂制作如下:
化合物 | 每胶囊数量(mg) | 浓度(wt%) |
有效成分 | 100 | 30 |
聚氧乙烯脱水山梨糖醇-油酸酯 | 50μg | 0.02 |
淀粉粉末 | 250 | 69.98 |
上述成分充分混合并置于空明胶胶囊中。
配方4
每个含有10mg有效成分的片剂制备如下:
化合物 | 每片数量(mg) | 浓度(wt%) |
有效成分 | 10 | 10 |
淀粉 | 45 | 45 |
微晶纤维素 | 35 | 35 |
聚乙烯基吡咯烷酮(10%水溶液) | 4 | 4 |
羧甲基淀粉钠 | 4.5 | 4.5 |
硬脂酸镁 | 0.5 | 0.5 |
滑石 | 1 | 1 |
让有效成分、淀粉、和纤维素通过45号目数美国筛并充分混合。使聚乙烯基吡咯烷酮溶液与所得到的粉末混合,然后通过14号目数美国筛。这样产生的颗粒在50~60℃干燥并通过18号目数美国筛。然后,将事先通过60号目数美国筛的羧甲基淀粉钠、硬脂酸镁和滑石添加到该颗粒中,混合之后用压片机压缩,得到一种重100mg的片剂。
配方5
可以使用下列成分制备一种片剂配方:
化合物 | 每片数量(mg) | 百分率(wt%) |
有效成分 | 250 | 38 |
微晶纤维素 | 400 | 60 |
热解法二氧化硅 | 10 | 1.5 |
硬脂酸 | 5 | 0.5 |
将各成分掺合并压缩形成每片重665mg的片剂。
配方6
每5mL剂量各含5mg药剂的悬浮液剂制作如下:
化合物 | 每5mL悬浮液剂的数量(ml) |
有效成分 | 5 |
羧甲基纤维素钠 | 50 |
糖浆 | 1.25 |
苯甲酸溶液 | 0.10 |
香味剂 | 适量 |
着色剂 | 适量 |
水 | 足以达到5mL的量 |
让药剂通过45号目数美国筛,并与羧甲基纤维素钠和糖浆混合,形成一种光滑糊状物。苯甲酸溶液、香味剂和着色剂用部分水稀释,并在搅拌下添加到该糊状物中。然后添加足以产生所需要体积的水。
配方7
制备一种含有下列成分的气备剂溶液:
化合物 | 浓度(wt%) |
有效成分 | 0.25 |
乙醇 | 29.75 |
推进剂22(氯二氟甲烷) | 70.0 |
让活性化合物与乙醇混合,将混合物添加到一份冷却到-30℃的推进剂22中,并转移到灌装器具中。然后,将所需要的量加进一个不锈钢容器中,并以剩余数量的推进剂进一步稀释。然后,把阀单元装配到该容器上。
实施例
实施例1
±6-{4-[2-(四氢吡喃-4-基)乙胺基]环己氧基}烟酰胺
步骤1
3,3-二甲基-1,5-二氧杂螺[5.5]十一烷-9-醇的制备
使3,3-二甲基-1,5-二氧杂螺[5.5]十一烷-9-酮(Aldrich,750mg,3.78mmol)与有聚合物载体的硼氢化物(Aldrich,3026mg,7.56mmol)在甲醇(30mL)中合并。旋转摇荡所得到的混合物过夜。过滤该反应混合物、浓缩滤液。残渣用0.1M盐酸洗涤、用EtOAc萃取。有机层用硫酸钠干燥、过滤、浓缩。
步骤2
6-(3,3-二甲基-1,5-二氧杂螺[5.5]十一烷-9-氧基)烟腈的制备
将3,3-二甲基-1,5-二氧杂螺[5.5]十一烷-9-醇的制备(1445mg,7.22mmol)在DMF(2.1mL)中的溶液滴加到氢化钠(433mg,10.82mmol)在DMF(8.6mL)中的悬浮液中。让反应混合物在室温搅拌1h,然后在50℃边搅拌边加热20min。滴加6-氯烟腈(1200mg,8.66mmol)在DMF(4.5mL)中的溶液。继续在60℃加热和搅拌过夜。浓缩反应混合物使DMF脱除。残渣用水(15mL)洗涤、用EtOAc/己烷(20mL)萃取。有机层用硫酸钠干燥、过滤、浓缩。残渣用闪急色谱法(洗脱剂CH2Cl2/己烷2/1)精制,给出2000mg(92%产率)标题化合物。
步骤3
6-(4-氧代环己氧基)烟腈的制备
让盐酸(1.0M水溶液,20mL)与6-(3,3-二甲基-1,5-二氧杂螺[5.5]十一烷-9-氧基)烟腈(2000mg,6.61mmol)在丙酮(25mL)中的溶液合并。在室温搅拌2h、然后在40~50℃搅拌1h。浓缩反应混合物。让残渣在EtOAc/己烷(25mL)与K2CO3(饱和水溶液,20mL)之间分配。有机层用水、食盐水洗涤、用硫酸钠使其干燥、过滤、浓缩。残渣用EtOAc/己烷(1/4)研制,提供一种白色固体,后者用闪急色谱法(EtOAc/己烷1/4)进一步精制,给出1010mg(71%产率)白色固体。
步骤4
6-{4-[2-(四氢呋喃-4-基)乙胺基]环己氧基}烟腈(NE4-A05445-035)的制备
将前面得到的6-(4-氧代环己氧基)烟腈(200mg,0.925mmol)、2-(四氢吡喃-4-基)乙胺(Aldrich,125mg,0.971mmol)和一勺分子筛3在甲醇(4mL)中合并。让反应混合物搅拌过夜,然后添加硼氢化钠(70mg,1.85mmol)。继续搅拌过夜。反应混合物通过装到SCX柱上精制,用甲醇洗涤、用氨/甲醇(2.0M)洗脱。残渣用2次闪急色谱法(40/1 CH2Cl2/氨甲醇溶液)精制,提供199mg(65%)浅黄色油状标题化合物。
步骤5
将前面得到的6-{4-[2-(四氢呋喃-4-基)乙胺基]环己氧基}烟腈(199mg,0.604mmol)和碳酸钾在DMSO(4mL)中合并。使反应混合物冷却到0℃,然后滴加过氧化氢(0.181mL)。让反应混合物在室温搅拌3h。将混合物倾入水中。过滤沉淀物并重新溶于甲醇中。浓缩并通过SCX柱精制,提供标题化合物。质谱(离子喷雾):m/z=348.3(M+1);1H NMR(CDCl3):8.62(s,1H),8.04(m,1H),6.75(m,1H),6.01(bs,2H),5.32(bs,1H),5.07(m,1H),3.97(dd,J=11.0 and 4.0Hz,2H),3.40(t,J=11.4Hz,2H),2.73-2.54(m,3H),2.21-2.03(m,3H),1.79-1.28(m,12H).
实施例2
±6-[4-(3-甲基丁胺基)环己氧基]烟酰胺
使用类似于实施例1的方法给出标题化合物(199mg,96%)。质谱(离子喷雾):
m/z=306.3(M+1);1H NMR(CDCl3):8.66(s,1H),8.13-8.10(m,1H),7.96(bs,1H),7.39(bs,1H),6.81(m,1H),5.17(s,1H),5.00(m,1H),2.49(m,3H),2.06-1.14(m,14H),0.88(t,J=6.6Hz,6H).
实施例3
±6-[4-(2-噻吩-2-基乙胺基)环己氧基]烟酰胺
使用类似于实施例1的方法给出标题化合物(203mg,87%)。质谱(离子喷雾):
m/z=346.1(M+1);1H NMR(CDCl3):8.61(s,1H),8.05-8.00(m,1H),7.17(m,1H),6.96(m,1H),6.87(s,1H),6.98-6.95(m,1H),6.03(bs,2H),5.31-5.04(m,1H),3.07-2.96(m,4H),2.67-2.55(m,1H),2.20-2.00(m,3H),1.78-1.26(m,6H).
实施例4
4-[4-(3-苯基丙胺基)环己氧基]苯甲酰胺
步骤1
4-(3,3-二甲基-1,5-二氧杂螺[5.5]十一烷-9-氧基)苄腈
将3,3-二甲基-1,5-二氧杂螺[5.5]十一烷-9-醇的制备(NE4-A05445-029,1377mg,6.88mmol)在DMF(2.0mL)中的溶液滴加到氢化钠(412mg,10.32mmol)在DMF(8.0mL)中的悬浮液中。让反应混合物在室温搅拌1h,然后在50℃边搅拌边加热20min。滴加4-氟苄腈(1000mg,8.26mmol)在DMF(4.2mL)中的溶液。继续在60℃加热和搅拌2h。浓缩反应混合物以去除DMF。残渣用水(15mL)洗涤、用EtOAc/己烷(20mL)萃取。有机层用硫酸钠干燥、过滤、浓缩。残渣用闪急色谱法(洗脱剂CH2Cl2/己烷2/1)精制,给出xxx mg(xx%产率)标题化合物。
步骤2
4-(4-氧代环己氧基)苄腈
合并盐酸(1.0M水溶液,20mL)与4-(3,3-二甲基-1,5-二氧杂螺[5.5]十一烷-9-氧基)苄腈在丙酮(25mL)中的溶液。在室温搅拌2h、然后在40~50℃搅拌1h。浓缩反应混合物。使残渣在EtOAc/己烷(25mL)与K2CO3(饱和水溶液,20mL)之间分配。有机层用水、食盐水洗涤。有机层用硫酸钠干燥、过滤和浓缩。残渣用EtOAc/己烷(1/4)研制,提供一种白色固体,后者用闪急色谱法(EtOAc/己烷1/4)进一步精制,给出mg(%产率)白色固体。
步骤3
4-(4-氧代-环己氧基)苯甲酰胺
合并以上得到的4-(4-氧代环己氧基)苄腈(100mg,0.464mmol)、K2CO3(32mg,0.232mmol)和DMSO(23mL)。将反应混合物冷却到0℃,添加过氧化氢(0.139mL)。让反应混合物在室温搅拌4h。用水(15mL)使反应混合物终止反应。用EtOAc/己烷2/1(3×20mL)萃取。用硫酸钠干燥、过滤、浓缩。残渣用闪急色谱法(20/1 CH2Cl2/氨甲醇溶液2.0M)精制,提供标题化合物(40mg,37%)。
步骤4
合并4-(4-氧代-环己氧基)苯甲酰胺(20mg,0.085mmol)、3-苯基丙胺(11mg,0.085mmol)、三乙酰氧硼氢化物(23mg,0.111mmol)和乙酸(5μL,0.085mmol)和CH2Cl2(1mL)。混合物搅拌过液。用SCX柱(氨/甲醇溶液,2.0M)精制。残渣用EtOAc/己烷1/1研制,提供一种白色粉末(25mg,86%)。
实施例5
反式-6-(4-苄胺基环己氧基)烟酰胺
步骤1
4-苄胺基环己醇
合并反式-4-氨基环己醇(2.0g,17.4mmol)和甲醇(75mL)于封管中,添加苯甲醛(1.85mL,18.23mmol)。反应混合物在70℃边搅拌边加热2h。然后,让反应混合物冷却、分批添加硼氢化钠(2.46g,65.1mmol)。搅拌过液。蒸发溶剂直至原体积的1/3。让反应混合物在EtOAc(50mL)与水(40mL)之间分配。水层用EtOAc(20mL)再萃取。合并有机层、用硫酸钠干燥。过滤、浓缩,提供标题化合物(3.5g),后者直接用于下一步。
步骤2
6-(4-苄胺基环己氧基)烟腈
滴加4-苄胺基环己醇(675mg,3.28mmol)在DMF(2mL)中的溶液至NaH(196mg,4.92mmol)在DMF(3mL)中的悬浮液中。在室温搅拌45min、然后在50℃再搅拌40min。滴加6-氯烟腈(500mg,3.61mmol)在DMF(1.8mL)中的溶液,在60℃搅拌过夜。使反应混合物冷却、蒸发溶剂。残渣用水(10mL)洗涤、用EtOAc/己烷(2/1,15mL)萃取。合并有机层,用硫酸钠干燥。过滤、浓缩。所得到的残渣通过SCX柱精制。用色谱法[CH2Cl2/NH3(2.0M,甲醇溶液)20/1]进一步精制,提供标题化合物(890mg,88%)。
步骤3
将K2CO3(200mg,1.44mmol)添加到6-(4-苄胺基环己氧基)烟腈(890mg,2.89mmol)在DMSO(25mL)中的溶液中。使反应物冷却到0℃,添加过氧化氢(0.87mL)。所得到的反应混合物在室温搅拌2h。然后该反应混合物用水(25mL)骤冷,用EtOAc(30mL)萃取。用硫酸钠干燥、过滤、浓缩。残渣用SCX色谱法进一步精制,提供标题化合物(700mg,74%)。质谱(离子喷雾):
m/z=326.0(M+1);1H NMR(CDCl3):8.61(s,1H),8.04(m,1H),7.36(m,5H),6.74(d,J=8.8Hz,1H),5.10(m,1H),3.87(s,2H),2.64(m,1H),2.22-2.07(m,4H),1.58-1.33(m,4H).
实施例6
6-(1-吡啶-2-基甲基哌啶-4-氧基)烟酰胺
步骤1
4-(5-氰基吡啶-2-氧基)哌啶-1-羧酸叔丁酯
将4-羟基哌啶-1-羧酸叔丁酯(1210mg,6.01mmol)在DMF(1.8mL)中的溶液滴加到NaH(360mg,9.02mmol)在DMF(7.2mL)中的悬浮液中。在室温搅拌45min、然后在50℃再搅拌40min。滴加6-氯烟腈(1000mg,7.22mmol)在DMF(3.6mL)中的溶液,在60℃搅拌过夜。使反应混合物冷却,蒸发溶剂。残渣用水(10mL)洗涤、用EtOAc/己烷(2/1,15mL)萃取。合并有机层、用硫酸钠干燥。过滤、浓缩。所得到的残渣通过SCX柱精制。用色谱法[CH2Cl2/NH3(2.0M甲醇溶液)20/1]进一步精制,提供标题化合物(1.73g,94%)。
步骤2
4-(5-氨基甲酰吡啶-2-氧基)哌啶-1-羧酸叔丁酯
将4-(5-氰基吡啶-2-氧基)哌啶-1-羧酸叔丁酯(1630mg,5.38mmol)在DMSO(50mL)中的溶液与碳酸钾(371mg,2.69mmol)合并。使该溶液冷却到0℃,徐徐添加过氧化氢(1.61mL)。10分钟后,反应混合物在室温搅拌2h。加水(25mL),用CH2Cl2(30mL)萃取2次。有机层用硫酸钠干燥、过滤、浓缩,提供白色固体状标题化合物(1669mg,97%)。
步骤3
6-(哌啶-4-氧基)烟酰胺盐酸盐
将4-(5-氨基甲酰吡啶-2-氧基)哌啶-1-羧酸叔丁酯(1559mg,4.85mmol)在四氢呋喃(25mL)中的溶液与盐酸(4.0M二烷溶液,15mL)合并。所得到的反应混合物搅拌48h。过滤白色沉淀、用EtOAc(10mL)洗涤。使白色固体再溶解于甲醇中,浓缩,提供标题化合物(1195mg,89%)。
步骤4
将6-(哌啶-4-氧基)烟酰胺盐酸盐(100mg,0.45mmol)与三乙酰氧硼氢化钠(124mg,0.59mmol)、吡啶-2-醛(43μL,0.45mmol)和CH2Cl2(1.5mL)合并。反应混合物搅拌3h。然后,该反应混合物用CH2Cl2(5mL)稀释、用NaOH(1M水溶液,5mL)洗涤。有机层用硫酸钠干燥、过滤、浓缩。残渣通过SCX色谱法精制,提供标题化合物(83mg,59%)。质谱(离子喷雾):
m/z=313.1(M+1);1H NMR(DMSO-d6):8.67(ad,J=2.2Hz,1H),8.50(m,1H),8.12(dd,J=2.6和8.8Hz,1H),7.98(bs,1H),7.80-7.76(m,1H),7.47(d,J=7.9Hz,1H),7.41(bs,1H),7.29-7.26(m,1H),6.84(d,J=8.8Hz,1H),5.10(m,1H),3.63(m,2H),2.77-2.74(m,2H),2.35-2.30(m,2H),1.99(bs,2H),1.75-1.69(m,2H).
实施例7
6-(1-环丙基甲基哌啶-4-氧基)烟酰胺
使用类似于实施例6的方法,给出标题化合物(89mg,72%)。质谱(离子喷雾):
m/z=276.1(M+1);1H NMR(DMSO-d6):8.66(m,1H),8.12(app.dd,J=2.2和8.3Hz,1H),7.97(bs,1H),7.40(bs,1H),6.84(app.d,J=8.3Hz,1H),5.08-5.03(m,1H),2.82(bs,2H),2.52(s,1H),2.27-2.20(m,3H),1.99(m,2H),1.72(m,2H),0.86-0.83(m,1H),0.50-0.45(m,2H),0.10-0.07(m,2H)。
实施例8
6-[1-(1H-吲哚-2-甲基)哌啶-4-氧基]烟酰胺
使用类似于实施例6的方法,给出标题化合物(110mg,70%)。质谱(离子喷雾):m/z=351.1(M+1)。
实施例9
4-(1-苄基哌啶-4-氧基)苯甲酰胺
步骤1
4-(4-氰基苯氧基)哌啶-1-羧酸叔丁酯
将N-Boc-4-羟基哌啶(3.0g,14.9mmol)在DMF(5mL)中的溶液添加到氢化钠(894mg,22.4mmol)在DMF(17mL)中的悬浮液中。反应混合物边在50℃加热边搅拌45min。然后添加4-氟苄腈(2.16g,17.9mmol)在DMF(5mL)中的溶液。在50℃搅拌和加热2h。使其冷却到室温,用水(0.5mL)终止反应。蒸发DMF。所得到的残渣再溶解于EtOAc/己烷(2/1,20mL)中、用水(3×15mL)洗涤。有机层用硫酸镁干燥、过滤、浓缩。用色谱法(EtOAc/己烷20%和EtOAc/己烷10%)精制,得到标题化合物(2.32g,52%)。
步骤2
4-(哌啶-4-氧基)苄腈盐酸盐
在0℃将乙酰氯(2.5mL)滴加到甲醇(5.0mL)中。所得到的溶液在0℃搅拌90min。然后添加4-(4-氰基苯氧基)哌啶-1-羧酸叔丁酯(284mg,0.94mmol)在甲醇中的溶液。所得到的混合物搅拌3h。蒸发溶剂、用二乙醚研制,提供标题化合物(216mg,96%)。
步骤3
4-(1-苄基哌啶-4-氧基)苄腈
将4-(哌啶-4-氧基)苄腈盐酸盐(64mg,0.268mmol)、苯甲醛(55μL,0.536mmol)和三乙酰氧基硼氢化钠(85mg,0.402mmol)、CH2Cl2(3mL)合并。在室温搅拌过夜。反应混合物用CH2Cl2(3mL)稀释、用NaOH(1M水溶液,5mL)洗涤。分离有机层,并将其置于SCX柱中,用氨(2.0M甲醇溶液)洗脱,提供标题化合物(74mg,95%)。
步骤4
将4-(1-苄基哌啶-4-氧基)苄腈(74mg,0.25mmol)、DMSO(2.5mL)和粉末碳酸钾(18mg,0.13mmol)合并。将所得到的混合物冷却到0℃,添加过氧化氢(76μL)。添加后,该混合物在室温搅拌1h。该反应混合物用水(2mL)终止反应。所生成的沉淀过滤、用二乙醚漂洗、给出标题化合物(57mg,73%)。质谱(离子喷雾):
m/z=311.1(M+1);1H NMR(CDCl3):7.79(ad,J=8.6Hz,3H),7.32-7.21(m,5H),7.14(bs,1H),6.95(d,J=8.6Hz,2H),4.49-4.42(m,1H),3.31(s,2H),2.69-2.62(m,2H),2.27-2.19(m,2H),1.96-1.89(m,2H),1.66-1.56(m,2H).
实施例10
4-[1-(3-苯基丙基)哌啶-4-氧基]苯甲酰胺
步骤1
4-(4-氨基甲酰苯氧基)哌啶-1-羧酸叔丁酯
在0℃将4-(4-氰基苯氧基)哌啶-1-羧酸叔丁酯(实施例9步骤1,215mg,0.71mmol)、碳酸钾(49mg,0.36mmol)和DMSO(35mL)合并。然后滴加过氧化氢(213μL)。然后在室温搅拌1h。用水(10mL)终止反应,用EtOAc/己烷(2/1,3×20mL)萃取。合并有机层,用硫酸镁干燥、过滤、浓缩,给出标题化合物。
步骤2
4-(哌啶-4-氧基)苯甲酰胺盐酸盐
将盐酸(4M二烷溶液,3mL)滴加到4-(4-氨基甲酰苯氧基)哌啶-1-羧酸叔丁酯(228mg,0.71mmol)在THF(2mL)中的溶液中。在室温搅拌7h。将固体滤出、减压干燥,给出盐酸盐形式的标题化合物(180mg,99%)。
步骤3
将4-(哌啶-4-氧基)苯甲酰胺盐酸盐(102mg,0.397mmol)、3-苯基丙醛(106μL,0.796mmol)、三乙酰氧基硼氢化物(127mg,0.597mmol)和CH2Cl2(3mL)合并。反应混合物在室温搅拌过夜。反应混合物用CH2Cl2(3mL)稀释、用氢氧化钠(1N,水溶液,5mL)洗涤。分离有机层,并置于SCX柱上,用氨(2.0M甲醇溶液)直接洗脱。所得到的残渣用CH2Cl2和二乙醚研制,提供白色固体状标题化合物(63mg,47%)。质谱(离子喷雾):
m/z=339.1(M+1);1H NMR(CDCl3):7.79(ad,J=9.0Hz,3H),7.28-7.12(m,6H),6.95(d,J=9.0Hz,2H),4.74-4.40(m,1H),2.70-2.63(bm,2H),2.56(t,J=7.6Hz,2H),2.31-2.25(bm,2H),2.22-2.15(bm,2H),1.96-1.89(bm,2H),1.71(pentet,J=7.3Hz,2H),1.63-1.56(m,2H).
Claims (21)
1.式I化合物
式中
X1、X2、X3、X4、和X5中每一个都是C、CH、或N;前提是环B有不多于2个氮原子;
X是NH或CH2,使得环A为环己基、环己烯基、或哌啶基;
E是NH或O;
V是0、1、2、或3;
q是0或1,前提是当A环为环己基或环己烯基时q是1,且前提是v和q不同时为0;
R1和R2独立地选自氢、C1-C8烷基、C2-C8烯基、C2-C8炔基、芳基、C3-C8环烷基、C1-C10烷芳基、杂环基、C1-C10-烷基杂环、-C1-C8烷基C(O)C1-C8烷基、-(CH2)n(CO)C3-C8环烷基、-C2-C8烷基CH(OH)芳基、-CO(O)C1-C8烷基、-SO2C1-C8烷基、-SO2C1-C10烷芳基、-SO2C1-C8烷基杂环、C1-C8烷基环烷基、-(CH2)nC(O)OR8、-(CH2)nC(O)R8、-(CH2)mC(O)NR8R8、和-(CH2)mNSO2R8;其中烷基、烯基、环烷基、杂环、和芳基基团各自任选地有1~5个独立地选自下列的基团取代:卤素、C1-C8卤烷基、C1-C8硫烷基、C1-C8烷基、C2-C8烯基、芳基、-C1-C8烷芳基、-C(O)C1-C8烷基、-SO2C1-C8烷基、-SO2C1-C8烷芳基、-C1-C8烷基环烷基;且其中R1和R2可以任选地彼此组合形成一个4员、5员、6员、或7员含氮杂环,该含氮杂环可以进一步有选自下列组成的一组的取代基:氨基、C1-C8烷基、C2-C8烯基、C2-C8炔基、芳基、C1-C8烷芳基、-C(O)C1-C8烷基、-CO(O)C1-C8烷基、卤素、氧代、C1-C8卤烷基;
R3和R3’各自独立地选自氢、C1-C8烷基、C2-C8烯基、C2-C8炔基、芳基、-C1-C8烷基环烷基、或-C1-C8烷芳基、C1-C8烷基杂环;或R3和R3’组合形成一个C3-C8环烷基、C4-C8环烯基、或C5-C10杂环;
R4和R5各自独立地选自氢、C1-C8烷基、C2-C8烯基、C2-C8炔基、-C1-C8烷氧烷基、C1-C8硫烷基、卤素、C1-C8卤烷基、-C1-C8烷氧卤烷基、芳基、-C1-C8烷芳基、-C(O)C1-C8烷基、或-C(O)OC1-C8烷基、-C1-C8烷胺基、-C1-C8烷基环烷基、-(CH2)mC(O)C1-C8烷基、和(CH2)nNR8R8,其中每个R4或R5都只连接到其各自环的碳原子上,且其中y是0、1、2、或3,且其中z是0、1、2、或3;
R6和R7各自独立地选自氢、C1-C8烷基、C2-C8烯基、C2-C8炔基、-C(O)C1-C8烷基、羟基、C1-C8烷氧基、-SO2C1-C8烷基、SO2C1-C8烷芳基、-SO2C1-C8烷基杂环、芳基、-C1-C8烷芳基、C3-C7环烷基、-C1-C6烷基环烷基、-(CH2)nC(O)R8、(CH2)mC(O)NR8R8、和-(CH2)mNSO2R8;其中烷基、烯基、和芳基中每一个都任选地有1~5个独立地选自C1-C8烷基、C2-C8烯基、芳基、和C1-C8烷芳基的基团取代;且其中R6和R7可以独立地彼此组合形成一个4员、5员、6员、或7员含氮杂环,该含氮杂环可以任选地有选自下列一组的取代基:氧代、C1-C8烷基、C2-C8烯基、C2-C8炔基、芳基、C1-C8烷芳基、-C(O)C1-C8烷基、-CO(O)C1-C8烷基、羟基、C1-C8烷氧基、-C1-C8烷胺、氨基、卤素、和卤烷基;
R8是氢、C1-C8烷基、C2-C8烯基、C1-C8烷芳基、-C(O)C1-C8烷基、或-C(O)OC1-C8烷基;且其中n是0、1、2、3或4,且m是1、2、或3;
或其医药上可接受盐、溶剂合物、对映体、外消旋物、非对映体或非对映体混合物。
2.按照权利要求1的化合物,其中A环是环己基。
3.按照权利要求1的化合物,其中B环选自苯基、吡啶基、嘧啶基、吡嗪基、和哒嗪基组成的一组。
4.按照权利要求1的化合物,其中A环是哌啶基。
5.按照权利要求1的化合物,其中E是一个氧原子。
6.按照权利要求1的化合物,其中y是0、1、或2,且R4独立地选自氢、氟、氯、溴、甲氧基、乙氧基、甲基、乙基、异丙基、三氟甲基、三氟甲氧基、苯基、和苄基。
7.按照权利要求1的化合物,其中z是0、1或2,且R5独立地选自氢、氟、氯、溴、甲氧基、乙氧基、甲基、乙基、异丙基、三氟甲基、三氟甲氧基、苯基、和苄基。
8.按照权利要求1的化合物,其中R1和R2各自独立地选自由氢、甲基、乙基、丙基、异丙基、苯基、
组成的一组,且其中n是1、2或3。
9.按照权利要求1的化合物,其中R6和R7各自独立地选自由氢、甲基、乙基、丙基、异丙基、苯基组成的一组。
10.按照权利要求1的化合物,其中E是一个氧原子,且R6和R7都是氢原子。
11.按照权利要求1的化合物,其中v是1或2。
12.按照权利要求1的化合物,其中v是1,m是1,n是1,y是0或1,且z是0或1。
13.选自下列一组的化合物:
6-{4-[2-(四氢吡喃-4-基)乙胺基]环己氧基}烟酰胺,
6-[4-(3-甲基丁胺基)环己氧基]烟酰胺,
6-[4-(2-噻吩-2-基乙胺基)环己氧基]烟酰胺,
4-[4-(3-苯基丙胺基)环己氧基]苯甲酰胺,
反式-6-(4-苄胺基环己氧基)烟酰胺,
6-(1-吡啶-2-基甲基哌啶-4-氧基)烟酰胺,
6-(1-环丙基甲基哌啶-4-氧基)烟酰胺,
6-[1-(1H-吲哚-2-基甲基)哌啶-4-氧基]烟酰胺,
4-(1-苄基哌啶-4-氧基)苯甲酰胺,
4-[1-(3-苯基丙基)哌啶-4-氧基]苯甲酰胺,
和其医药上可接受盐、溶剂合物、对映体、非对映体、或非对映体混合物。
14.按照权利要求1的化合物、其中医药上可接受盐是盐酸盐、甲磺酸盐、氢溴酸盐、硫酸氢盐或酒石酸盐。
15.一种医药组合物,包含与载体、稀释剂和/或赋形剂配合的、治疗有效量的按照权利要求1的化合物。
16.动物中μ、κ、δ受体或其受体组合(杂二聚物)的阻断方法,包含对需要阻断μ、κ、δ受体或其受体组合(杂二聚物)的动物给药受体阻断剂量的按照权利要求1的化合物、或其医药上可接受盐、对映体、外消旋物、非对映体混合物或溶剂合物。
17.与肥胖症有关的疾病的治疗和/或预防方法,该疾病包括刺激性肠综合征、恶心、呕吐、与肥胖症有关的抑郁症、与肥胖症有关的焦虑、烟瘾、酒瘾、性功能障碍、物质滥用、药物剂量过大、瘾性行为失调、强迫行为代谢疾病及其症状和中风,该方法包含给药治疗有效量的式I化合物。
18.肥胖症和相关疾病的治疗和/或预防方法,包含对有其需要的患者给药治疗有效量的式I化合物。
19.有其需要的患者中食欲的抑制方法,包含给药治疗有效量的式I化合物。
20.肥胖症患者中进行减肥的方法,包含给药有效量的式I化合物或其医药上可接受盐、溶剂合物、外消旋物或对映体。
21.与肥胖症和相关疾病有关的症状的治疗和/或改善用医药组合物,含有按照权利要求1的式I化合物作为有效成分。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US52906103P | 2003-12-12 | 2003-12-12 | |
US60/529,061 | 2003-12-12 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1890208A true CN1890208A (zh) | 2007-01-03 |
Family
ID=34710109
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNA2004800364712A Pending CN1890208A (zh) | 2003-12-12 | 2004-12-06 | 类鸦片受体拮抗剂 |
Country Status (9)
Country | Link |
---|---|
US (1) | US7196100B2 (zh) |
EP (1) | EP1697307B1 (zh) |
JP (1) | JP2007516256A (zh) |
CN (1) | CN1890208A (zh) |
AU (1) | AU2004303790A1 (zh) |
BR (1) | BRPI0417156A (zh) |
CA (1) | CA2549009A1 (zh) |
ES (1) | ES2456705T3 (zh) |
WO (1) | WO2005061442A1 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104016980A (zh) * | 2008-04-23 | 2014-09-03 | 里格尔药品股份有限公司 | 用于治疗代谢障碍的甲酰胺化合物 |
CN113402402A (zh) * | 2021-06-29 | 2021-09-17 | 江西荣兴药业有限公司 | 低浓度废液回收反式-对氨基环己醇的方法 |
Families Citing this family (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2499690C (en) * | 2002-09-19 | 2011-05-24 | Eli Lilly And Company | Diaryl ethers as opioid receptor antagonist |
ATE399164T1 (de) | 2004-03-12 | 2008-07-15 | Lilly Co Eli | Antagonisten des opioidrezeptors |
CA2558568A1 (en) | 2004-03-12 | 2005-09-29 | Eli Lilly And Company | Opioid receptor antagonists |
ES2379362T3 (es) | 2004-03-15 | 2012-04-25 | Eli Lilly And Company | Antagonistas del receptor opioide |
WO2005090303A1 (en) | 2004-03-15 | 2005-09-29 | Eli Lilly And Company | 4- (5- (aminomethyl) -indole-1-ylmethyl) -benzamide derivatives and related compounds as opioid receptor antagonists for the treatment of obesity |
US20090036429A1 (en) * | 2006-02-17 | 2009-02-05 | Ohler Norman E | Hydroxypiperidine Derivatives and Uses Thereof |
WO2008032156A1 (en) | 2006-09-08 | 2008-03-20 | Pfizer Products Inc. | Diaryl ether derivatives and uses thereof |
EP2079694B1 (en) * | 2006-12-28 | 2017-03-01 | Rigel Pharmaceuticals, Inc. | N-substituted-heterocycloalkyloxybenzamide compounds and methods of use |
EP2141994A4 (en) * | 2007-04-26 | 2011-05-18 | Avalon Pharmaceuticals | POLYCYCLIC COMPOUNDS AND USES THEREOF |
WO2008142454A1 (en) | 2007-05-22 | 2008-11-27 | Prosidion Limited | Bicyclic aryl and heteroaryl compounds for the treatment of metabolic disorders |
US8063247B2 (en) | 2007-09-07 | 2011-11-22 | Prosidion Limited | Bicyclic aryl and heteroaryl receptor modulators |
EP2214672B1 (en) * | 2007-10-18 | 2012-10-17 | Aiko Biotechnology | Combination analgesic employing opioid and neutral antagonist |
US8748448B2 (en) | 2007-10-18 | 2014-06-10 | Aiko Biotechnology | Combination analgesic employing opioid agonist and neutral antagonist |
BRPI0820171B8 (pt) * | 2007-11-16 | 2021-05-25 | Rigel Pharmaceuticals Inc | compostos de carboxamida, sulfonamida e amina para distúrbios metabólicos, composição farmacêutica, e, uso dos mesmos |
WO2009076631A1 (en) * | 2007-12-12 | 2009-06-18 | Rigel Pharmaceuticals, Inc. | Carboxamide, sulfonamide and amine compounds for metabolic disorders |
WO2009079489A1 (en) * | 2007-12-17 | 2009-06-25 | The Ohio State University Research Foundation | Methods for screening of opioid receptor neutral antagonists and inverse agonists and uses thereof |
US7709522B2 (en) * | 2008-01-22 | 2010-05-04 | Eli Lilly And Company | Kappa selective opioid receptor antagonist |
EP2331507A2 (en) * | 2008-09-18 | 2011-06-15 | Astellas Pharma Inc. | Heterocyclic carboxamide compounds |
CA2739491A1 (en) * | 2008-10-16 | 2010-04-22 | Schering Corporation | Azine derivatives and methods of use thereof |
NZ598783A (en) * | 2009-09-18 | 2013-07-26 | Adolor Corp | Use of opioid receptor antagonist for gastrointestinal tract disorders |
MX338707B (es) | 2010-07-29 | 2016-04-28 | Rigel Pharmaceuticals Inc | Compuestos heterociclicos activadores de proteina cinasa activada por 5'-amp (ampk) y metodos para emplearlos. |
AR082640A1 (es) * | 2011-08-25 | 2012-12-19 | Amarin Technologies S A | Un dispositivo para la administracion transdermal de compuestos alcalinos susceptibles a la degradacion en su forma no salificada |
EP3053911B1 (en) * | 2013-09-30 | 2020-01-22 | The University of Tokyo | Adiponectin receptor-activating compound |
US20220370409A1 (en) | 2021-05-04 | 2022-11-24 | Janssen Pharmaceuticals, Inc. | Compositions And Methods For The Treatment Of Depression |
US11998524B2 (en) | 2022-03-07 | 2024-06-04 | Janssen Pharmaceuticals, Inc. | Forms of aticaprant |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4191771A (en) | 1974-09-06 | 1980-03-04 | Eli Lilly And Company | Analgesic method using 1,3,4-trisubstituted-4-arylpiperidines |
EP0827746B1 (en) | 1996-09-05 | 2002-04-03 | Eli Lilly And Company | Carbazole analogues as selective beta3 adrenergic agonists |
EP1049676B1 (en) | 1997-12-24 | 2005-10-12 | Ortho-Mcneil Pharmaceutical, Inc. | 4- aryl(piperidin-4-yl)] aminobenzamides which bind to the delta-opioid receptor |
GB9912411D0 (en) | 1999-05-28 | 1999-07-28 | Pfizer Ltd | Compounds useful in therapy |
SE9904674D0 (sv) | 1999-12-20 | 1999-12-20 | Astra Pharma Inc | Novel compounds |
SE0001208D0 (sv) | 2000-04-04 | 2000-04-04 | Astrazeneca Canada Inc | Novel compounds |
AU2002234010A1 (en) * | 2000-12-14 | 2002-06-24 | Ortho-Mcneil Pharmaceutical, Inc. | Benzamidine derivatives |
HU227543B1 (en) | 2001-09-28 | 2011-08-29 | Richter Gedeon Nyrt | N-[4-(2-piperazin- and 2-piperidin-1-yl-ethyl)-cyclohexyl]-sulfon- and sulfamides, process for their preparation, their use and pharmaceutical compositions containing them |
EP1500643A4 (en) | 2002-04-03 | 2007-03-28 | Dainippon Sumitomo Pharma Co | BENZAMIDE DERIVATIVES |
JP4329381B2 (ja) * | 2002-04-04 | 2009-09-09 | 田辺三菱製薬株式会社 | 医薬組成物 |
CA2499690C (en) | 2002-09-19 | 2011-05-24 | Eli Lilly And Company | Diaryl ethers as opioid receptor antagonist |
AU2003274053A1 (en) | 2002-10-22 | 2004-05-13 | Glaxo Group Limited | Aryloxyalkylamine derivates as h3 receptor ligands |
DE602004016127D1 (de) | 2003-03-07 | 2008-10-09 | Lilly Co Eli | Antagonisten der opioidrezeptoren |
EP1613597B1 (en) | 2003-03-07 | 2007-11-07 | Eli Lilly and Company | 6-substituted nicotinamide derivatives as opioid receptor antagonists |
-
2004
- 2004-12-06 CA CA002549009A patent/CA2549009A1/en not_active Abandoned
- 2004-12-06 ES ES04811079.5T patent/ES2456705T3/es active Active
- 2004-12-06 US US10/581,164 patent/US7196100B2/en not_active Expired - Fee Related
- 2004-12-06 BR BRPI0417156-0A patent/BRPI0417156A/pt not_active Application Discontinuation
- 2004-12-06 JP JP2006543831A patent/JP2007516256A/ja not_active Withdrawn
- 2004-12-06 CN CNA2004800364712A patent/CN1890208A/zh active Pending
- 2004-12-06 EP EP04811079.5A patent/EP1697307B1/en not_active Not-in-force
- 2004-12-06 WO PCT/US2004/038227 patent/WO2005061442A1/en active Application Filing
- 2004-12-06 AU AU2004303790A patent/AU2004303790A1/en not_active Abandoned
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104016980A (zh) * | 2008-04-23 | 2014-09-03 | 里格尔药品股份有限公司 | 用于治疗代谢障碍的甲酰胺化合物 |
CN104016980B (zh) * | 2008-04-23 | 2016-12-07 | 里格尔药品股份有限公司 | 用于治疗代谢障碍的甲酰胺化合物 |
CN106928211A (zh) * | 2008-04-23 | 2017-07-07 | 里格尔药品股份有限公司 | 用于治疗代谢障碍的甲酰胺化合物 |
CN106928211B (zh) * | 2008-04-23 | 2020-09-08 | 里格尔药品股份有限公司 | 用于治疗代谢障碍的甲酰胺化合物 |
CN112079769A (zh) * | 2008-04-23 | 2020-12-15 | 里格尔药品股份有限公司 | 用于治疗代谢障碍的甲酰胺化合物 |
CN113402402A (zh) * | 2021-06-29 | 2021-09-17 | 江西荣兴药业有限公司 | 低浓度废液回收反式-对氨基环己醇的方法 |
CN113402402B (zh) * | 2021-06-29 | 2023-08-18 | 江西荣兴药业有限公司 | 低浓度废液回收反式-对氨基环己醇的方法 |
Also Published As
Publication number | Publication date |
---|---|
ES2456705T3 (es) | 2014-04-23 |
US7196100B2 (en) | 2007-03-27 |
WO2005061442A1 (en) | 2005-07-07 |
EP1697307B1 (en) | 2014-03-12 |
JP2007516256A (ja) | 2007-06-21 |
CA2549009A1 (en) | 2005-07-07 |
AU2004303790A1 (en) | 2005-07-07 |
EP1697307A1 (en) | 2006-09-06 |
BRPI0417156A (pt) | 2007-03-06 |
US20070010558A1 (en) | 2007-01-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1890208A (zh) | 类鸦片受体拮抗剂 | |
CN1165537C (zh) | 作为5-ht2c兴奋剂的吡咯并吲哚、吡啶并吲哚和氮杂�并吲哚 | |
CN1142144C (zh) | 4-苯基-吡啶衍生物 | |
CN1036652C (zh) | 碱式季酰胺,其制备方法及其药物组合物 | |
CN1894240A (zh) | 阿片受体拮抗剂 | |
CN1298391A (zh) | 1-[(1-取代-4-哌啶基)甲基]-4-哌啶衍生物、其生产方法、含有该化合物的药物组合物和这些化合物的中间体 | |
CN1756746A (zh) | 作为阿片样物质受体拮抗剂的6-取代的烟酰胺衍生物 | |
CN1192028C (zh) | 用作中枢神经系统药物的杂环取代的氨基氮杂环 | |
CN1316993A (zh) | 具有阿片样物质受体活性的4,4-二芳基哌啶衍生物 | |
CN1845915A (zh) | 作为亲代谢谷氨酸受体-5的调节剂的联吡啶胺和醚类化合物 | |
CN1871244A (zh) | 作为腺苷受体配体的噻唑并吡啶衍生物 | |
CN1288464A (zh) | 作为orl-1受体激动剂的4-(2-酮-1-苯并咪唑啉基)哌啶化合物 | |
CN101076517A (zh) | 作为多巴胺神经传递调节剂的新的取代的哌啶类 | |
CN101068551A (zh) | 喹啉速激肽受体拮抗剂 | |
CN1946685A (zh) | 氮杂环丁烷甘氨酸转运蛋白抑制剂 | |
CN1930158A (zh) | 新季铵化的奎宁环酯 | |
CN1675206A (zh) | 奎宁环衍生物及含有相同化合物的药用组合物 | |
CN1784408A (zh) | 8-取代的-6,7,8,9-四氢嘧啶并[1,2-a]嘧啶-4-酮衍生物 | |
CN1148340A (zh) | 治疗与5htzb受体有关病症的方法 | |
CN1147248A (zh) | N-(3-吡咯烷基)苯甲酰胺衍生物 | |
CN1483030A (zh) | 用于治疗神经系统疾病的酰胺烷基哌啶和酰胺烷基哌嗪衍生物 | |
CN1516580A (zh) | 磺酰胺类 | |
CN1798744A (zh) | 作为nmda/nr2b拮抗剂的3-氟-哌啶化合物 | |
CN1884262A (zh) | 4-氨基哌啶类化合物及其医药用途 | |
CN1268949A (zh) | 稠合噻吩化合物及其医药用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |