CN116867775A - 作为trpm8激活剂的有机化合物 - Google Patents
作为trpm8激活剂的有机化合物 Download PDFInfo
- Publication number
- CN116867775A CN116867775A CN202280013860.1A CN202280013860A CN116867775A CN 116867775 A CN116867775 A CN 116867775A CN 202280013860 A CN202280013860 A CN 202280013860A CN 116867775 A CN116867775 A CN 116867775A
- Authority
- CN
- China
- Prior art keywords
- alkyl group
- alkyl
- hydrogen
- imidazol
- tolyl
- 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
- 102000003610 TRPM8 Human genes 0.000 title abstract 2
- 101150111302 Trpm8 gene Proteins 0.000 title abstract 2
- 239000012190 activator Substances 0.000 title description 2
- 150000002894 organic compounds Chemical class 0.000 title description 2
- 238000001816 cooling Methods 0.000 claims abstract description 43
- 210000004400 mucous membrane Anatomy 0.000 claims abstract description 17
- 230000002500 effect on skin Effects 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 141
- 229910052739 hydrogen Inorganic materials 0.000 claims description 93
- 125000000217 alkyl group Chemical group 0.000 claims description 92
- -1 2- (1- (2-methylbutanoyl) piperidin-2-yl) -4- (p-tolyl) -1H-imidazol-1-yl Chemical group 0.000 claims description 87
- 239000001257 hydrogen Substances 0.000 claims description 78
- 239000000203 mixture Substances 0.000 claims description 49
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 47
- 229910052799 carbon Inorganic materials 0.000 claims description 39
- 229910052717 sulfur Inorganic materials 0.000 claims description 34
- 125000005843 halogen group Chemical group 0.000 claims description 31
- 150000002431 hydrogen Chemical class 0.000 claims description 31
- 150000003839 salts Chemical class 0.000 claims description 29
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 28
- 125000001424 substituent group Chemical group 0.000 claims description 28
- 238000000034 method Methods 0.000 claims description 26
- 229910052757 nitrogen Inorganic materials 0.000 claims description 24
- 239000012453 solvate Substances 0.000 claims description 24
- 125000005842 heteroatom Chemical group 0.000 claims description 22
- 229910052760 oxygen Inorganic materials 0.000 claims description 22
- 125000004432 carbon atom Chemical group C* 0.000 claims description 19
- 229910052731 fluorine Inorganic materials 0.000 claims description 19
- 229910052736 halogen Inorganic materials 0.000 claims description 19
- 150000002367 halogens Chemical class 0.000 claims description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
- 125000004429 atom Chemical group 0.000 claims description 15
- NDOVLWQBFFJETK-UHFFFAOYSA-N 1,4-thiazinane 1,1-dioxide Chemical compound O=S1(=O)CCNCC1 NDOVLWQBFFJETK-UHFFFAOYSA-N 0.000 claims description 14
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 14
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 14
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 14
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 claims description 14
- 230000035597 cooling sensation Effects 0.000 claims description 13
- 102000005962 receptors Human genes 0.000 claims description 13
- 108020003175 receptors Proteins 0.000 claims description 13
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 11
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 11
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 10
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical group C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 claims description 8
- 239000001301 oxygen Chemical group 0.000 claims description 8
- 239000011593 sulfur Substances 0.000 claims description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 7
- 125000001072 heteroaryl group Chemical group 0.000 claims description 7
- 125000002950 monocyclic group Chemical group 0.000 claims description 7
- 241001465754 Metazoa Species 0.000 claims description 6
- 235000013305 food Nutrition 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- NFLGAXVYCFJBMK-RKDXNWHRSA-N (+)-isomenthone Natural products CC(C)[C@H]1CC[C@@H](C)CC1=O NFLGAXVYCFJBMK-RKDXNWHRSA-N 0.000 claims description 5
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 claims description 5
- 235000002637 Nicotiana tabacum Nutrition 0.000 claims description 5
- 235000015218 chewing gum Nutrition 0.000 claims description 5
- ZYTMANIQRDEHIO-KXUCPTDWSA-N isopulegol Chemical compound C[C@@H]1CC[C@@H](C(C)=C)[C@H](O)C1 ZYTMANIQRDEHIO-KXUCPTDWSA-N 0.000 claims description 5
- 229940041616 menthol Drugs 0.000 claims description 5
- 229930007503 menthone Natural products 0.000 claims description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 4
- 102000027545 TRPM Human genes 0.000 claims description 4
- 108091008847 TRPM Proteins 0.000 claims description 4
- 229940112822 chewing gum Drugs 0.000 claims description 4
- 230000001939 inductive effect Effects 0.000 claims description 4
- 125000004289 pyrazol-3-yl group Chemical group [H]N1N=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- FINKDHKJINNQQW-UHFFFAOYSA-N 5-methyl-2-propan-2-ylcyclohexane-1-carboxamide Chemical compound CC(C)C1CCC(C)CC1C(N)=O FINKDHKJINNQQW-UHFFFAOYSA-N 0.000 claims description 3
- JFMRFPMNLJJLFX-UHFFFAOYSA-N CC(C(N(CCCC1)C1C1=NC(C2=CC=C(C)C=C2)=CN1C(C1=CC=CC=C1)=O)=O)SC Chemical compound CC(C(N(CCCC1)C1C1=NC(C2=CC=C(C)C=C2)=CN1C(C1=CC=CC=C1)=O)=O)SC JFMRFPMNLJJLFX-UHFFFAOYSA-N 0.000 claims description 3
- ZZZXADMFUHVKIY-UHFFFAOYSA-N CC(C)C(N1C(C(CCCC2)N2C(C(C)SC)=O)=NC(C2=CC=C(C)C=C2)=C1)=O Chemical compound CC(C)C(N1C(C(CCCC2)N2C(C(C)SC)=O)=NC(C2=CC=C(C)C=C2)=C1)=O ZZZXADMFUHVKIY-UHFFFAOYSA-N 0.000 claims description 3
- GGUAOVAWBOAVMX-UHFFFAOYSA-N CCC(C)C(N(CCCC1)C1C1=NC(C2=CC=C(C)C=C2)=CN1C(C(C)C)=O)=O Chemical compound CCC(C)C(N(CCCC1)C1C1=NC(C2=CC=C(C)C=C2)=CN1C(C(C)C)=O)=O GGUAOVAWBOAVMX-UHFFFAOYSA-N 0.000 claims description 3
- YPWRLOGRJMKCDP-UHFFFAOYSA-N CCC(C)C(N(CCCC1)C1C1=NC(C2=CC=C(C)C=C2)=CN1C(C)=O)=O Chemical compound CCC(C)C(N(CCCC1)C1C1=NC(C2=CC=C(C)C=C2)=CN1C(C)=O)=O YPWRLOGRJMKCDP-UHFFFAOYSA-N 0.000 claims description 3
- FDWFPOKVYOEEDY-UHFFFAOYSA-N CCC(C)C(N(CCCC1)C1C1=NC(C2=CC=C(C)C=C2)=CN1C(COC)=O)=O Chemical compound CCC(C)C(N(CCCC1)C1C1=NC(C2=CC=C(C)C=C2)=CN1C(COC)=O)=O FDWFPOKVYOEEDY-UHFFFAOYSA-N 0.000 claims description 3
- ANAJGWSBHQDXMU-UHFFFAOYSA-N CCC(C)C(N(CCCC1)C1C1=NC(C2=CC=C(C)C=C2)=CN1C(COCC1=CC=CC=C1)=O)=O Chemical compound CCC(C)C(N(CCCC1)C1C1=NC(C2=CC=C(C)C=C2)=CN1C(COCC1=CC=CC=C1)=O)=O ANAJGWSBHQDXMU-UHFFFAOYSA-N 0.000 claims description 3
- QZQMVQNZMHSFAQ-UHFFFAOYSA-N CCC(N1C(C(CCCC2)N2C(CC)=O)=NC(C2=CC=C(C)C=C2)=C1)=O Chemical compound CCC(N1C(C(CCCC2)N2C(CC)=O)=NC(C2=CC=C(C)C=C2)=C1)=O QZQMVQNZMHSFAQ-UHFFFAOYSA-N 0.000 claims description 3
- VGJBDDNGXCXTJK-UHFFFAOYSA-N CCCCCC(N1C(C(CCCC2)N2C(C(C)SC)=O)=NC(C2=CC=C(C)C=C2)=C1)=O Chemical compound CCCCCC(N1C(C(CCCC2)N2C(C(C)SC)=O)=NC(C2=CC=C(C)C=C2)=C1)=O VGJBDDNGXCXTJK-UHFFFAOYSA-N 0.000 claims description 3
- XJUUEVFNZVABBK-UHFFFAOYSA-N CCCCCCCCCCCC(N1C(C(CCCC2)N2C(C(C)CC)=O)=NC(C2=CC=C(C)C=C2)=C1)=O Chemical compound CCCCCCCCCCCC(N1C(C(CCCC2)N2C(C(C)CC)=O)=NC(C2=CC=C(C)C=C2)=C1)=O XJUUEVFNZVABBK-UHFFFAOYSA-N 0.000 claims description 3
- IIKNJDNTJQCGCH-UHFFFAOYSA-N CCCCCCCCCCCC(N1C(C(CCCC2)N2C(C(C)SC)=O)=NC(C2=CC=C(C)C=C2)=C1)=O Chemical compound CCCCCCCCCCCC(N1C(C(CCCC2)N2C(C(C)SC)=O)=NC(C2=CC=C(C)C=C2)=C1)=O IIKNJDNTJQCGCH-UHFFFAOYSA-N 0.000 claims description 3
- NFLGAXVYCFJBMK-UHFFFAOYSA-N Menthone Chemical compound CC(C)C1CCC(C)CC1=O NFLGAXVYCFJBMK-UHFFFAOYSA-N 0.000 claims description 3
- 235000013361 beverage Nutrition 0.000 claims description 3
- 239000001871 (1R,2R,5S)-5-methyl-2-prop-1-en-2-ylcyclohexan-1-ol Substances 0.000 claims description 2
- GDFRCQHXPPCFLE-UHFFFAOYSA-N 1-(1-methyl-2-propan-2-ylcyclohexyl)propane-1,2,3-triol Chemical compound C1(C(CCCC1)C(C)C)(C)C(O)C(O)CO GDFRCQHXPPCFLE-UHFFFAOYSA-N 0.000 claims description 2
- MDVYIGJINBYKOM-IBSWDFHHSA-N 3-[(1r,2s,5r)-5-methyl-2-propan-2-ylcyclohexyl]oxypropane-1,2-diol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OCC(O)CO MDVYIGJINBYKOM-IBSWDFHHSA-N 0.000 claims description 2
- CTMTYSVTTGVYAW-FRRDWIJNSA-N 5-[(1r,2s,5r)-5-methyl-2-propan-2-ylcyclohexyl]oxy-5-oxopentanoic acid Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)CCCC(O)=O CTMTYSVTTGVYAW-FRRDWIJNSA-N 0.000 claims description 2
- LISKOBIDGJGQDN-UHFFFAOYSA-N CC(C(N(CCCC1)C1C1=NC(C2=CC=C(C)C=C2)=CN1C(C)=O)=O)SC Chemical compound CC(C(N(CCCC1)C1C1=NC(C2=CC=C(C)C=C2)=CN1C(C)=O)=O)SC LISKOBIDGJGQDN-UHFFFAOYSA-N 0.000 claims description 2
- FOWDUPMGYONKNA-UHFFFAOYSA-N CC(C(N1C(C(CCCC2)N2C(C(C)SC)=O)=NC(C2=CC=C(C)C=C2)=C1)=O)SC Chemical compound CC(C(N1C(C(CCCC2)N2C(C(C)SC)=O)=NC(C2=CC=C(C)C=C2)=C1)=O)SC FOWDUPMGYONKNA-UHFFFAOYSA-N 0.000 claims description 2
- OZMILORGJVWWBU-UHFFFAOYSA-N CC(C)C(N1C(C(CCCC2)N2C(C(C)C)=O)=NC(C2=CC=C(C)C=C2)=C1)=O Chemical compound CC(C)C(N1C(C(CCCC2)N2C(C(C)C)=O)=NC(C2=CC=C(C)C=C2)=C1)=O OZMILORGJVWWBU-UHFFFAOYSA-N 0.000 claims description 2
- LMXFTMYMHGYJEI-UHFFFAOYSA-N Menthoglycol Natural products CC1CCC(C(C)(C)O)C(O)C1 LMXFTMYMHGYJEI-UHFFFAOYSA-N 0.000 claims description 2
- BLILOGGUTRWFNI-UHFFFAOYSA-N Monomenthyl succinate Chemical compound CC(C)C1CCC(C)CC1OC(=O)CCC(O)=O BLILOGGUTRWFNI-UHFFFAOYSA-N 0.000 claims description 2
- FSTIPIUBKPAVGS-UHFFFAOYSA-N N-(3-hydroxy-4-methoxyphenyl)-5,5-dimethyl-2-propan-2-ylcyclohexane-1-carboxamide Chemical compound OC=1C=C(C=CC=1OC)NC(=O)C1C(CCC(C1)(C)C)C(C)C FSTIPIUBKPAVGS-UHFFFAOYSA-N 0.000 claims description 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000005605 benzo group Chemical group 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 229940095045 isopulegol Drugs 0.000 claims description 2
- 238000000968 medical method and process Methods 0.000 claims description 2
- ZYTMANIQRDEHIO-UHFFFAOYSA-N neo-Isopulegol Natural products CC1CCC(C(C)=C)C(O)C1 ZYTMANIQRDEHIO-UHFFFAOYSA-N 0.000 claims description 2
- 241000208125 Nicotiana Species 0.000 claims 2
- 108010037150 Transient Receptor Potential Channels Proteins 0.000 claims 2
- 102000011753 Transient Receptor Potential Channels Human genes 0.000 claims 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 claims 1
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims 1
- YEMXMTNNIQKZHP-UHFFFAOYSA-N N-[4-(cyanomethyl)phenyl]-5,5-dimethyl-2-propan-2-ylcyclohexane-1-carboxamide Chemical compound C(#N)CC1=CC=C(C=C1)NC(=O)C1C(CCC(C1)(C)C)C(C)C YEMXMTNNIQKZHP-UHFFFAOYSA-N 0.000 claims 1
- UJNOLBSYLSYIBM-WISYIIOYSA-N [(1r,2s,5r)-5-methyl-2-propan-2-ylcyclohexyl] (2r)-2-hydroxypropanoate Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)[C@@H](C)O UJNOLBSYLSYIBM-WISYIIOYSA-N 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 153
- 239000000686 essence Substances 0.000 description 50
- 239000000047 product Substances 0.000 description 50
- 239000000243 solution Substances 0.000 description 37
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 36
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 32
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 32
- 239000000796 flavoring agent Substances 0.000 description 31
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- 235000019634 flavors Nutrition 0.000 description 28
- 239000007787 solid Substances 0.000 description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 20
- 239000012267 brine Substances 0.000 description 20
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 20
- 238000005160 1H NMR spectroscopy Methods 0.000 description 18
- 239000013058 crude material Substances 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
- 238000003818 flash chromatography Methods 0.000 description 17
- 239000000741 silica gel Substances 0.000 description 17
- 229910002027 silica gel Inorganic materials 0.000 description 17
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 16
- 235000019341 magnesium sulphate Nutrition 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 12
- 235000019439 ethyl acetate Nutrition 0.000 description 12
- 235000011121 sodium hydroxide Nutrition 0.000 description 12
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 11
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 11
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 239000003921 oil Substances 0.000 description 10
- 235000019198 oils Nutrition 0.000 description 10
- HZOUQFSRYFMEKS-UHFFFAOYSA-N CC(C(=O)N1C(CCCC1)C=1NC(=CN=1)C1=CC=C(C=C1)C)CC Chemical compound CC(C(=O)N1C(CCCC1)C=1NC(=CN=1)C1=CC=C(C=C1)C)CC HZOUQFSRYFMEKS-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 description 8
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 8
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 8
- 239000012876 carrier material Substances 0.000 description 8
- 229940093499 ethyl acetate Drugs 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- ZIQSNLRVUZTLJR-UHFFFAOYSA-N 1-[2-[5-(4-methylphenyl)-1H-imidazol-2-yl]piperidin-1-yl]-2-methylsulfanylpropan-1-one Chemical compound CSC(C(=O)N1C(CCCC1)C=1NC(=CN=1)C1=CC=C(C=C1)C)C ZIQSNLRVUZTLJR-UHFFFAOYSA-N 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- 244000246386 Mentha pulegium Species 0.000 description 7
- 235000016257 Mentha pulegium Nutrition 0.000 description 7
- 235000004357 Mentha x piperita Nutrition 0.000 description 7
- 239000011575 calcium Substances 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- 235000003599 food sweetener Nutrition 0.000 description 7
- 235000001050 hortel pimenta Nutrition 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 239000003765 sweetening agent Substances 0.000 description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 6
- 239000000499 gel Substances 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- 239000002304 perfume Substances 0.000 description 6
- MOOGCAQAJNQXGL-UHFFFAOYSA-N 2-[5-(4-methylphenyl)-1H-imidazol-2-yl]piperidine Chemical compound C1=CC(C)=CC=C1C1=CN=C(C2NCCCC2)N1 MOOGCAQAJNQXGL-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000002537 cosmetic Substances 0.000 description 5
- 239000000551 dentifrice Substances 0.000 description 5
- 239000003623 enhancer Substances 0.000 description 5
- 239000004744 fabric Substances 0.000 description 5
- 150000002430 hydrocarbons Chemical group 0.000 description 5
- 239000001525 mentha piperita l. herb oil Substances 0.000 description 5
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 5
- 239000002324 mouth wash Substances 0.000 description 5
- 235000019477 peppermint oil Nutrition 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 4
- DGMOBVGABMBZSB-UHFFFAOYSA-N 2-methylpropanoyl chloride Chemical compound CC(C)C(Cl)=O DGMOBVGABMBZSB-UHFFFAOYSA-N 0.000 description 4
- 239000004215 Carbon black (E152) Substances 0.000 description 4
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
-
- 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
- C07D401/06—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 carbon chain containing only aliphatic carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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Abstract
公开了由式(I)定义的TRPM8调节剂,用于实现对皮肤和黏膜的清凉效果。
Description
技术领域
本发明涉及能够激活TRPM8离子通道的特定类别的化合物。本发明还涉及所述化合物用于引起冷感的用途以及包含这些化合物的消费品。
背景
TRPM8(瞬时受体电位melastatin成员8,也称为Trp-p8或MCR1)被无害的冷激活并因此作为温度传感器起着重要作用。通道广泛分布于不同组织(例如人体皮肤和黏膜(例如口腔黏膜,咽喉黏膜和鼻黏膜),男性泌尿生殖道,肺上皮细胞和动脉肌细胞)。它们是Ca2+可渗透的非选择性阳离子通道,具有多模式门控机制,被无害的冷至低温,膜去极化和称为清凉剂的分子(包括天然和合成化合物)激活。2002年,该受体在许多出版物中首次被描述为冷感受器。
本发明基于以下发现:当在体外和体内与TRPM8受体接触时,可以使用特定类别的化合物来驱动清凉响应。
长期以来,提供清凉感的化合物在香精香料工业中发挥着重要作用,以产生与新鲜度和清洁度的关联。清凉化合物广泛用于各种产品,例如食品,烟草制品,饮料,洁牙剂,漱口剂,牙膏和洗浴用品。所提供的清凉感有助于消费品的吸引力和可接受性。特别是,口腔护理产品,例如洁牙剂和漱口剂,是用清凉剂配制的,因为它们提供口气清新效果和口腔清洁,清凉,清新的感觉。
已经描述了大量提供清凉感的化合物。最著名的天然化合物是薄荷醇,尤其是L-薄荷醇。在提供清凉感的合成化合物中,许多是薄荷醇的衍生物或在结构上与薄荷醇相关,即含有环己烷部分,并衍生有官能团,包括甲酰胺,缩酮,酯,醚和醇。
申请人令人惊奇地发现了一类新的化合物,其在结构方面与迄今已知的TRPM8调节剂显著不同。令人惊奇地发现,本文进一步描述的这类化合物可以在非常低的浓度下对人体皮肤和/或黏膜提供持久的清凉。
概述
在第一方面提供了式(I)的化合物,其盐或溶剂合物(特别用于提供清凉感)
其中X1,X2和X3之一为>N-C(O)R,且其它两个独立地选自C,N和O,条件是它们二者不均为C,并且其中R选自任选地包含一个选自O和S的杂原子的C1-C15烃残基;和
a)R1为H;且B表示一价残基(a)
或
b)R1选自
卤素(包括Br,Cl和F),C6-C10芳基(例如苯基或萘基),其任选地被至多四个(例如1,2或3个)独立地选自下组的取代基取代:
卤素(包括F,Cl,Br);
OH(羟基);
C≡N(氰基);
NO2(硝基);
C1-C6烷基,其任选地包含至多5个卤素原子(例如F),例如CH3,CF3或CHF2;
C1-C3烷基,其包含至多3个OH基团,例如CH2OH;
C2-C6烯基,例如-CH=CH2;
C1-C6烷氧基,其任选地包含至多3个卤素原子(例如F),例如OCH3,OCH3,OCF3;
C1-C3烷氧基C1-C3烷基,例如2-甲氧基-乙基;
C3-C7环烷基,例如环丙基,环丁基;
-C(O)R10,其中R10选自C1-C3烷基;
-OC(O)R11,其中R11选自H和C1-C3烷基;
-C(O)O-R12,其中R12选自氢和C1-C3烷基;
-(CH2)mN(R13)R14,其中m为0或1,R13选自氢,C1-C3烷基和-SO2R15,其中R15为C1-C3烷基,且R14选自氢,C1-C3烷基和-SO2R16,其中R16为C1-C3烷基,或其中R13和R14与它们所连接的N原子一起形成吗啉,硫代吗啉或1,1-二氧代硫代吗啉;
-SR17,其中R17选自氢和C1-C3烷基;和
-S(O)2R18,其中R18选自氢和C1-C3烷基;
条件是,当芳基环被两个或更多个取代基取代时,两个取代基可以与它们所连接的碳原子一起形成环,和
C5-C10单-或双环杂芳基,其中至多2个C原子被独立地选自硫,氮和氧的杂原子替代,所述杂芳基任选地被至多四个(例如1,2或3个)选自下组的取代基取代:
卤素(包括F,Cl,Br);OH(羟基);
C≡N(氰基);
NO2(硝基);
C1-C6烷基,其任选地包含至多5个卤素原子(例如F),例如CH3,CF3或CHF2;
C2-C6烯基,例如-CH=CH2;
C1-C6烷氧基,其任选地包含至多3个卤素原子(例如F),例如OCH3,OCH3,OCF3;
C1-C3烷氧基C1-C3烷基,例如2-甲氧基-乙基;
C3-C7环烷基,例如环丙基,环丁基;
-C(O)R20,其中R20选自C1-C3烷基;
-OC(O)R21,其中R21选自H和C1-C3烷基;
-C(O)O-R22,其中R22选自氢和C1-C3烷基);
-(CH2)mN(R23)R24,其中m为0或1,R23选自氢,C1-C3烷基和-SO2R25,其中R25为C1-C3烷基,且R24选自氢,C1-C3烷基和-SO2R26,其中R26为C1-C3烷基,或其中R23和R24与它们所连接的N原子一起形成吗啉,硫代吗啉或1,1-二氧代硫代吗啉;
-SR27,其中R27选自氢和C1-C3烷基;和
-S(O)2R28,其中R28选自氢和C1-C3烷基;
和
B表示一价残基(b)
其中
R4,R5和R6与它们所连接的碳原子一起形成任选地包含至多五个(例如1,2,3,4个)选自O,N,S和F的杂原子的烃基(优选该烃基包含2至15个C原子(例如3,4,5,6,7,8,9,10,11,12,13或14个C原子);和
Z是C,S或S(O)。
在根据第二个方面,提供了一种调节(体外和体内调节)瞬时受体电位melastatin成员8(TRPM8)的方法,所述方法包括使所述受体与式(I)的化合物或其盐或溶剂合物接触。
在第三个方面,提供了一种在人或动物中引起清凉感的方法,所述方法包括使所述人或动物与式(I)的化合物或其盐或溶剂合物接触。
在在第四个方面,提供了消费品,特别是与人体皮肤和/或黏膜接触的消费品,其包含由式(I)定义的化合物或其盐或溶剂合物。
在第五个方面,提供了一种包含清凉感的组合物,其中所述组合物包含至少一种式(I)的化合物,其盐或溶剂合物和另外的清凉化合物。
在在第六个方面,提供了药物组合物,其包含一种或多种由式(I)定义的化合物或其盐或溶剂合物。
提供的与本发明的任何特定一个或多个所述方面相关的细节,实施例和优选项将在本文中进一步描述并且同样适用于本发明的所有方面。除非本文另有说明或与上下文明显矛盾,否则本文所述的实施方案,实施例和优选项的所有可能变化形式的任何组合都包含在本发明中。
详述
在本发明至少部分基于在结构方面与迄今已知的TRPM8调节剂显著不同的一类新化合物的惊人发现,其能够激活TRPM8离子通道,从而导致Ca2+流入冷敏感神经元。结果产生的电信号最终被感知为冷感。申请人惊奇地发现,本文进一步描述的这类化合物可以在非常低的浓度下对人体皮肤和/或黏膜提供持久的清凉。
因此,在第一方面提供了式(I)的化合物,其盐或溶剂合物(特别用于提供清凉感)
其中X1,X2和X3之一为>N-C(O)R,且其它两个独立地选自C,N和O,条件是它们二者不均为C,并且其中R选自任选地包含一个选自O和S的杂原子的C1-C15烃残基;
和
a)R1为H;且B表示一价残基(a)
或
b)R1选自
卤素(包括Br,Cl和F),C6-C10芳基(例如苯基或萘基),其任选地被至多四个(例如1,2或3个)独立地选自下组的取代基取代:
卤素(包括F,Cl,Br);
OH(羟基);
C≡N(氰基);
NO2(硝基);
C1-C6烷基,其任选地包含至多5个卤素原子(例如F),例如CH3,CF3或CHF2;
C1-C3烷基,其包含至多3个OH基团,例如CH2OH;
C2-C6烯基,例如-CH=CH2;
C1-C6烷氧基,其任选地包含至多3个卤素原子(例如F),例如OCH3,OCH3,OCF3;
C1-C3烷氧基C1-C3烷基,例如2-甲氧基-乙基;
C3-C7环烷基,例如环丙基,环丁基;
-C(O)R10,其中R10选自C1-C3烷基;
-OC(O)R11,其中R11选自H和C1-C3烷基;
-C(O)O-R12,其中R12选自氢和C1-C3烷基;
-(CH2)mN(R13)R14,其中m为0或1,R13选自氢,C1-C3烷基和-SO2R15,其中R15为C1-C3烷基,且R14选自氢,C1-C3烷基和-SO2R16,其中R16为C1-C3烷基,或其中R13和R14与它们所连接的N原子一起形成吗啉,硫代吗啉或1,1-二氧代硫代吗啉;
-SR17,其中R17选自氢和C1-C3烷基;和
-S(O)2R18,其中R18选自氢和C1-C3烷基;
条件是,当芳基环被两个或更多个取代基取代时,两个取代基可以与它们所连接的碳原子一起形成环,和
C5-C10单-或双环杂芳基,其中至多2个C原子被独立地选自硫,氮和氧的杂原子替代,所述杂芳基任选地被至多四个(例如1,2或3个)选自下组的取代基取代:
卤素(包括F,Cl,Br);OH(羟基);
C≡N(氰基);
NO2(硝基);
C1-C6烷基,其任选地包含至多5个卤素原子(例如F),例如CH3,CF3或CHF2;
C2-C6烯基,例如-CH=CH2;
C1-C6烷氧基,其任选地包含至多3个卤素原子(例如F),例如OCH3,OCH3,OCF3;
C1-C3烷氧基C1-C3烷基,例如2-甲氧基-乙基;
C3-C7环烷基,例如环丙基,环丁基;
-C(O)R20,其中R20选自C1-C3烷基;
-OC(O)R21,其中R21选自H和C1-C3烷基;
-C(O)O-R22,其中R22选自氢和C1-C3烷基);
-(CH2)mN(R23)R24,其中m为0或1,R23选自氢,C1-C3烷基和-SO2R25,其中R25为C1-C3烷基,且R24选自氢,C1-C3烷基和-SO2R26,其中R26为C1-C3烷基,或其中R23和R24与它们所连接的N原子一起形成吗啉,硫代吗啉或1,1-二氧代硫代吗啉;
-SR27,其中R27选自氢和C1-C3烷基;和
-S(O)2R28,其中R28选自氢和C1-C3烷基;
和
B表示一价残基(b)
其中
R4,R5和R6与它们所连接的碳原子一起形成任选地包含至多五个(例如1,2,3,4个)选自O,N,S和F的杂原子的烃基(优选该烃基包含2至15个C原子(例如3,4,5,6,7,8,9,10,11,12,13或14个C原子);和
Z是C,S或S(O)。
进一步的非限制性实例是式(Ib)的化合物,其盐或溶剂合物
其中
R选自C1-C15烃残基,其任选地包含一个选自O和S的杂原子;
R1选自
卤素(包括Br,Cl和F),
C6-C10芳基(例如苯基或萘基),其任选地被至多四个(例如1,2或3个)独立地选自下组的取代基取代:
卤素(包括F,Cl,Br);OH(羟基);C≡N(氰基);NO2(硝基);
C1-C6烷基,其任选地包含至多5个卤素原子(例如F),例如CH3,CF3或CHF2;
C1-C3烷基,其包含至多3个OH基团,例如CH2OH;
C2-C6烯基,例如-CH=CH2;
C1-C6烷氧基,其任选地包含至多3个卤素原子(例如F),例如OCH3,OCH3,OCF3;
C1-C3烷氧基C1-C3烷基,例如2-甲氧基-乙基;
C3-C7环烷基,例如环丙基,环丁基;
-C(O)R10,其中R10选自C1-C3烷基;
-OC(O)R11,其中R11选自H和C1-C3烷基;
-C(O)O-R12,其中R12选自氢和C1-C3烷基;
-(CH2)mN(R13)R14,其中m为0或1,R13选自氢,C1-C3烷基和-SO2R15,其中R15为C1-C3烷基,且R14选自氢,C1-C3烷基和-SO2R16,其中R16为C1-C3烷基,或其中R13和R14与它们所连接的N原子一起形成吗啉,硫代吗啉或1,1-二氧代硫代吗啉;
-SR17,其中R17选自氢和C1-C3烷基;和
-S(O)2R18,其中R18选自氢和C1-C3烷基;
条件是,当芳基环被两个或更多个取代基取代时,两个取代基可以与它们所连接的碳原子一起形成环,和
C5-C10单-或双环杂芳基,其中至多2个C原子被独立地选自硫,氮和氧的杂原子替代,所述杂芳基任选地被至多四个(例如1,2或3个)选自下组的取代基取代:
卤素(包括F,Cl,Br);OH(羟基);C≡N(氰基);NO2(硝基);
C1-C6烷基,其任选地包含至多5个卤素原子(例如F),例如CH3,CF3或CHF2;
C2-C6烯基,例如-CH=CH2;
C1-C6烷氧基,其任选地包含至多3个卤素原子(例如F),例如OCH3,OCH3,OCF3;
C1-C3烷氧基C1-C3烷基,例如2-甲氧基-乙基;
C3-C7环烷基,例如环丙基,环丁基;
-C(O)R20,其中R20选自C1-C3烷基;
-OC(O)R21,其中R21选自H和C1-C3烷基;
-C(O)O-R22,其中R22选自氢和C1-C3烷基);
-(CH2)mN(R23)R24,其中m为0或1,R23选自氢,C1-C3烷基和-SO2R25,其中R25为C1-C3烷基,且R24选自氢,C1-C3烷基和-SO2R26,其中R26为C1-C3烷基,或其中R23和R24与它们所连接的N原子一起形成吗啉,硫代吗啉或1,1-二氧代硫代吗啉;
-SR27,其中R27选自氢和C1-C3烷基;和
-S(O)2R28,其中R28选自氢和C1-C3烷基;
R4,R5和R6与它们所连接的碳原子一起形成任选地包含至多五个(例如1,2,3,4个)选自O,N,S和F的杂原子的烃基(优选该烃基包含2至15个C原子(例如3,4,5,6,7,8,9,10,11,12,13或14个C原子);
和
X2和X3独立地选自C,N和O,条件是X2或X3不为C。
进一步的非限制性实例是式(Ic)的化合物,其盐或溶剂合物
其中R,R1和R4至R6具有与式(Ib)相同的含义。
进一步的非限制性实例是式(Id)的化合物,其盐或溶剂合物
其中R和R4至R6具有与式(Ic)相同的含义。
进一步的非限制性实例是式(Ie)的化合物,其盐或溶剂合物
其中R选自C1-C15烃残基,其任选地包含一个选自O和S的杂原子。
进一步的非限制性实例是式(I),(Ia),(Ib),(Ic),(Id)和(Ie)的化合物,其中R选自C1-C15直链或支链烷基(包括乙基,异丙基,直链C4-C15烷基,例如C5-,C6-,C7-,C8-,C9-,C10-,C11-,C12-,C13-和C14-烷基),苯基,2-异丙基-5-甲基环己烷-1-基(包括(1R,2S,5R)-2-异丙基-5-甲基环己烷-1-基),2-硫杂-丁-3-基,2-氧杂-丙-1-基和3-苯基-2-氧杂-丙-1-基。
进一步的非限制性实例是式(I),(Ia),(Ib),(Ic)和(Id)的化合物,其中R4选自氢和甲基;
R5选自氢,C1-C2烷基和C2-C3烯基;和
R6选自C1-C4烷基,含有一个或两个双键的C2-C5烯基,C1-C3烷氧基,C1-C4烷基-C(O)-,C1-C4烷基-S-,C1-C4烷基-SCH2-,C1-C4烯基-S-,C1-C4烷基-S(O)-,C1-C4烷基-S(O)2-,C1-C4烯基-S(O)-,C1-C4烯基-S(O)2-,-SH,CF3S-,环丙基,环丁基,任选地被甲基取代的呋喃基(例如2-呋喃基或3-呋喃基),C1-C6氟-烷基(例如五氟乙基,二氟甲基,三氟甲基,2,2,2-三氟乙基或二氟乙基)和-NR30R31,其中R30和R31独立地选自氢和C1-C3烷基;
或
R6和R5与它们所连接的碳原子一起形成
a)羰基(C=O)或乙烯基(C=CR32R33,其中R32和R33独立地选自H或C1-C3烷基);或
b)3至7-元饱和或不饱和环,其包含至多3个选自氧,氮和硫的杂原子,其中所述环任选地被一个或两个独立地选自C1-C3烷基(例如甲基,乙基,异丙基),C1-C3烷氧基的基团取代;(例如R5和R6与它们所连接的碳原子一起形成噻二唑或呋喃基)。
进一步的非限制性实例是式(I),(Ia),(Ib),(Ic)和(Id)的化合物,其中R4选自氢和甲基;R5选自氢,C1-C2烷基,C2-C3烯基;且R6选自C1-C4烷基,含有一个或两个双键的C2-C5烯基,C1-C3烷氧基,C1-C4烷基-C(O)-,C1-C4烷基-S-,C1-C4烷基-SCH2-,C1-C4烯基-S-,C1-C4烷基-S(O)-,C1-C4烷基-S(O)2-,C1-C4烯基-S(O)-,C1-C4烯基-S(O)2-,-SH,CF3S-,环丙基,环丁基,任选地被甲基取代的呋喃基(例如2-呋喃基或3-呋喃基),C1-C6氟-烷基(例如五氟乙基,二氟甲基,三氟甲基,2,2,2-三氟乙基或二氟乙基)和-NR30R31,其中R30和R31独立地选自氢和C1-C3烷基。
进一步的非限制性实例是式(I),(Ia),(Ib),(Ic)和(Id)的化合物,其中R4,R5和R6与它们所连接的碳原子一起形成选自以下的烃基:3-硫杂丁-2-基,2-甲基-3-硫杂丁-2-基,3-硫杂戊-2-基,4-硫杂戊-2-基,2-硫杂丙-1-基,2-甲基-3-硫杂戊-2-基,3-氧代-3-硫杂丁-2-基,3-氧代-2-甲基-3-硫杂丁-2-基,3-氧代-3-硫杂戊-2-基,4-氧代-4-硫杂戊-2-基,2-氧代-2-硫杂丙-1-基,3-氧代-2-甲基-3-硫杂戊-2-基,丁-2-基,戊-2-基,丁-3-烯-2-基,戊-3-烯-2-基,丁-2-烯-2-基,戊-2-烯-2-基,丁-1-烯-2-基,戊-1-烯-2-基,2-甲基丁-2-基,2-甲基戊-2-基,2-甲基丁-3-烯-2-基,3-甲基丁-2-基,3-甲基丁-3-烯-2-基,3-甲基丁-2-烯-2-基,2,3-二甲基丁-2-基,2,3-二甲基戊-2-基,2,3-二甲基丁-3-烯-2-基,2,3-二甲基戊-3-烯-2-基,2-甲基戊-3-烯-2-基,丙-2-基,丙-1-基,乙基,环丙基,1,1-二甲基环丙-2-基,1-甲基环丙-2-基,1-甲基环丙-1-基,3-硫杂己-5-烯-2-基,2-甲基-3-硫杂己-5-烯-2-基,1-巯基乙-1-基,2-巯基丙-2-基,3,3,3-三氟丙-2-基,2-甲基-3,3,3-三氟丙-2-基,1-(2-呋喃基)乙-1-基,1-(5-甲基呋喃-2-基)乙-1-基,2-(2-呋喃基)丙-2-基,1-(3-呋喃基)乙-1-基,1-(5-甲基呋喃-3-基)乙-1-基,2-(3-呋喃基)丙-2-基,1-(2-四氢呋喃基)乙-1-基,2-(2-四氢呋喃基)丙-2-基,1-(3-四氢呋喃基)乙-1-基,2-(3-四氢呋喃基)丙-2-基,1-环丙基乙-1-基,2-环丙基丙-2-基,1-环丁基乙-1-基,2-环丁基丙-2-基,环丁基,环戊基,戊-2-烯-3-基,1-甲氧基丙-1-基,1-甲氧基乙-1-基,1,1,1-三氟丁-3-基和3-硫杂环丁-1-基。
进一步的非限制性实例是式(I),(Ia),(Ib),(Ic)和(Id)的化合物,其中R4选自氢和甲基,R5选自氢,C1-C2烷基,C2-C3烯基,且R6选自C1-C4烷基,含有一个或两个双键的C2-C5烯基,C1-C3烷氧基,C1-C4烷基-C(O)-,C1-C4烷基-S-,C1-C4烷基-SCH2-,C1-C4烯基-S-,C1-C4烷基-S(O)-,C1-C4烷基-S(O)2-,C1-C4烯基-S(O)-,C1-C4烯基-S(O)2-和-SH。
进一步的非限制性实例是式(Ic)的化合物,其中R1为对甲苯基,且R4,R5和R6与它们所连接的碳原子一起形成2-甲基-3-硫杂丁-2-基或丁-2-基。
进一步的非限制性实例是式(I)的化合物,其选自1-(2-(1-丙酰基-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)丙-1-酮;1-(2-(1-异丁酰基-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)-2-甲基丙-1-酮;2-(甲基硫基)-1-(2-(1-(2-(甲基硫基)丙酰基)-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)丙-1-酮;1-(2-(1-乙酰基-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)-2-(甲基硫基)丙-1-酮;1-(2-(1-异丁酰基-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)-2-(甲基硫基)丙-1-酮;1-(2-(1-苯甲酰基-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)-2-(甲基硫基)丙-1-酮;1-(2-(1-((1R,2S,5R)-2-异丙基-5-甲基环己烷-1-羰基)-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)-2-(甲基硫基)丙-1-酮;1-(2-(1-乙酰基-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)-2-甲基丁-1-酮;1-(2-(1-异丁酰基-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)-2-甲基丁-1-酮;1-(2-(1-((1R,2S,5R)-2-异丙基-5-甲基环己烷-1-羰基)-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)-2-甲基丁-1-酮;1-(2-(1-(2-甲氧基乙酰基)-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)-2-甲基丁-1-酮;1-(2-(1-(2-(苄基氧基)乙酰基)-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)-2-甲基丁-1-酮;1-(2-(1-(2-(甲基硫基)丙酰基)哌啶-2-基)-4-(对甲苯基)-1H-咪唑-1-基)十二烷-1-酮;1-(2-(1-(2-甲基丁酰基)哌啶-2-基)-4-(对甲苯基)-1H-咪唑-1-基)十二烷-1-酮;1-(2-(1-(2-(甲基硫基)丙酰基)哌啶-2-基)-4-(对甲苯基)-1H-咪唑-1-基)己-1-酮;1-(2-(1-(2-甲基丁酰基)哌啶-2-基)-4-(对甲苯基)-1H-咪唑-1-基)己-1-酮;N-(1-苯甲酰基-1H-吡唑-3-基)-N-(噻吩-2-基甲基)-2-(对甲苯基氧基)乙酰胺;N-(1-异丁酰基-1H-吡唑-3-基)-N-(噻吩-2-基甲基)-2-(对甲苯基氧基)乙酰胺;和N-(1-乙酰基-1H-吡唑-3-基)-N-(噻吩-2-基甲基)-2-(对甲苯基氧基)乙酰胺。
由式(I)定义的化合物(其包括式(Ia),(Ib),(Ic),(Id)和(Ie)的化合物)包含几个手性中心(其中两个在各自的式中用*表示)并且因此可以以立体异构体的混合物形式存在,或者它们可以被拆分为异构体纯形式。拆分立体异构体增加了这些化合物的制造和纯化的复杂性,仅仅是因为经济原因,优选以它们的立体异构体的混合物形式使用这些化合物。然而,如果需要制备单独的立体异构体,这可以根据本领域已知的方法来实现,例如制备型HPLC和GC,结晶或立体选择性合成。由式(I)定义的化合物(其包括式(Ia),(Ib),(Ic),(Id)和(Ie)的化合物)也可以以各种互变异构形式存在,包括1H-咪唑-3H-咪唑形式。因此,本文描述的化学结构包括所示化合物的所有可能的立体异构体和互变异构体形式。
还应注意,由式(I)定义的化合物(其包括式(Ia),(Ib),(Ic),(Id)和(Ie)的化合物)可以以非溶剂化形式以及溶剂化形式(包括水合形式)存在,和作为N-氧化物。通常,化合物可以是水合的,溶剂化的或N-氧化物。某些化合物可以以多种结晶或无定形形式存在。一般而言,所有物理形式旨在落入本发明的范围内。
“溶剂合物”是指通过溶剂化(溶剂分子与溶质的分子或离子的组合)形成的化合物,或由溶质离子或分子,即由式(I)定义的化合物(其包括式(Ia),(Ib)和(Ic)的化合物)与一种或多种溶剂分子组成的聚集体。当水为溶剂时,相应的溶剂合物为“水合物”。其它合适的溶剂可以是但不限于:丙酮,乙腈,苯,环己烷,二氢左旋葡糖烯酮(dihydrolevoglucosenone),甲基-四氢呋喃,戊二醇,乙二醇,石油醚,乳酸乙酯,乳酸甲酯,乳酸丙酯,二乙醚,叔丁基甲基醚,二甲亚砜,N,N-二甲基甲酰胺,N,N-二甲基乙酰胺,二噁烷,乙醇,乙酸乙酯,乙二醇,二甘醇,丙二醇,庚烷,己烷,甲醇,甲苯和二甲苯。
“盐”是指由式(I)定义的化合物(其包括式(Ia),(Ib),(Ic),(Id)和(Ie)的化合物)的盐,其具有母体化合物的所需药理学活性。此类盐包括:(1)酸加成盐,与无机酸如盐酸,氢溴酸,硫酸,硝酸,磷酸等形成;或与有机酸如氨基酸,乙酸,三氟乙酸,丙酸,己酸,环戊烷丙酸,乙醇酸,丙酮酸,乳酸,丙二酸,琥珀酸,苹果酸,马来酸,富马酸,酒石酸,柠檬酸,苯甲酸,3-(4-羟基苯甲酰基)苯甲酸,肉桂酸,扁桃酸,甲磺酸,乙磺酸,1,2-乙二磺酸,2-羟基乙磺酸,苯磺酸,4-氯苯磺酸,2-萘磺酸,4-甲苯磺酸,樟脑磺酸,4-甲基二环[2.2.2]-辛-2-烯-1-甲酸,葡庚糖酸,3-苯基丙酸,三甲基乙酸,叔丁基乙酸,十二烷基硫酸,葡萄糖酸,谷氨酸,羟基萘酸,水杨酸,硬脂酸,粘康酸等形成;或(2)当母体化合物中存在的酸质子被金属离子例如碱金属离子,碱土离子或铝离子取代;或与有机碱如乙醇胺,二乙醇胺,三乙醇胺,N-甲基葡糖胺等配位时形成的盐。
由式(I)定义的化合物(其包括式(Ia),(Ib),(Ic),(Id)和(Ie)的化合物)是“TRPM8激动剂”,这意味着它们对TRPM8通道的细胞Ca2+离子渗透性具有激动作用。因此,“TRPM8激动剂”是指任何化合物,当与TRPM8受体接触时,使用如Klein等人(Chem.Senses36:649-658,2011)所述的FLIPR方法,所述化合物相对于背景产生荧光增加,这在实验部分也有更详细的描述。
因此,在第二方面提供了一种调节(体外和体内调节)瞬时受体电位melastatin成员8(TRPM8)的方法,所述方法包括使所述受体与式(I)的化合物或其盐或溶剂合物接触。
在本发明第二方面的某些实施方案中,所述调节方法是体外方法。
在第三方面,提供了一种在人或动物中引起清凉感的非医疗方法,所述方法包括使人或动物与式(I)的化合物(其包括式(Ia),(Ib),(Ic),(Id)和(Ie)的化合物)或其盐或溶剂合物接触。
在某些实施方案中,所述方法是实现对皮肤或黏膜的清凉效果的方法,包括使皮肤或黏膜与包含一种或多种式(I)的化合物或其盐或溶剂合物的产品接触。
不希望受理论束缚,据信本文定义的式(I)的化合物的酰基(>N-C(O)R)可以在某些条件下裂解,从而缓慢释放式(I’)的化合物
其中X1,X2和X3之一为>NH,且其它两个独立地选自C,N和O,条件是它们二者不均为C;并且R1和B具有与式(I)相同的含义。
酰基的性质可以调节式(I’)的化合物的释放动力学。例如,式(I’)的化合物(即水解的式(I)的化合物)公开在专利申请PCT/EP2020/079009(WO2021/074281)中。
因此,在进一步的实施方案中提供了一种在皮肤或黏膜上实现清凉效果的方法,所述方法包括在与皮肤或黏膜接触之前水解式(I)的化合物的乙酰基(>N-C(O)R)。
式(I)的化合物(其包括式(Ia),(Ib),(Ic),(Id)和(Ie)的化合物)可直接施用或作为溶液或悬浮液施用,其包含有效量的式(I)的化合物。有效的量尤其取决于人体的目标TRPM8区域,还取决于化合物或化合物混合物的清凉效力。
在第四方面,提供了包含由式(I)定义的化合物(其包括式(Ia),(Ib),(Ic),(Id)和(Ie)的化合物)的消费品,特别是与人体皮肤和/或黏膜接触的消费品。
与黏膜接触的消费品包括但不限于食品,饮料,口香糖,烟草和烟草替代产品,牙科护理产品,个人护理产品,包括唇部护理产品,性健康和私密护理产品。
在某些实施方案中,牙科护理产品为口腔护理产品,牙齿护理产品,假牙清洁剂,假牙粘合剂等。
在某些实施方案中,食品是冰镇消费品,例如冰淇淋,冰糕;糖食,例如糖果和巧克力;含有薄荷或薄荷香料的食品,酱汁,乳制品,例如牛奶饮料和酸奶;和小吃。
在某些实施方案中,烟草替代产品是适合通过电子方式消费的液体或固体,例如用于电子烟的液体。
在某些实施方案中,与黏膜接触的个人护理产品是唇膏,鼻喷雾剂和滴眼剂。
与人体皮肤接触的消费品包括但不限于化妆品。在某些实施方案中,化妆品是护肤产品,尤其是沐浴产品,皮肤洗涤和清洁产品,护肤产品,眼妆,指甲护理产品,足部护理产品等。在某些实施方案中,化妆品是具有特定效果的产品,尤其是防晒剂,驱虫产品,美黑产品,去色素产品,除臭剂,止汗剂,脱毛剂和剃须产品。在某些实施方案中,化妆品是护发产品,尤其是洗发香波,护发产品,头发定型产品,美发产品和染发产品以及头皮护理产品,例如头皮清凉洗发香波和乳剂。
在某些实施例中,消费品选自空气护理产品,例如可用于家庭空间(房间,冰箱,橱柜,鞋子或汽车)和/或公共场所(大厅,酒店,商场等......)的空气清新剂或“即用型”粉末状空气清新剂。
消费品可以是任何物理形式,例如固体,半固体,膏药,溶液,悬浮液,洗剂,乳剂,泡沫,凝胶,糊剂或其组合。适合的消费品的物理形式很大程度上取决于这种消费品应该满足的具体作用,例如清洁,软化,护理,清凉等。
在某些实施方案中,与人体皮肤接触的消费品是织物护理产品(例如织物清洁剂,织物调理剂(包括滚筒干衣片)和增香剂(液体或固体),它们在第一步中被应用于织物,例如,当洗涤织物时,所述经处理的织物随后与人体皮肤接触。
本发明的化合物(由式(I)定义的化合物,包括式(Ia),(Ib),(Ic),(Id)和(Ie)的化合物)的使用水平尤其取决于身体的目标TRPM8区域,还取决于化合物或化合物混合物的清凉效力。例如在本发明化合物的空腔应用例如洁牙剂,牙线,口香糖或美白牙贴(whitestrip)中,使用水平可以是组合物重量的约0.00001%(0.01ppm)至约0.1%(1000ppm);约0.00005%(0.5ppm)至约0.1%(1000ppm);约0.0001%(1ppm)至约0.05%(500ppm);或约0.001%(10ppm)至约0.01%(100ppm)。当本发明的化合物用于漱口剂中时,使用水平可以是组合物重量的约0.000001%(10ppb)至约0.01%(100ppm)或约0.0001%(1ppm)至约0.001%(10ppm)。当本发明的化合物被局部递送例如在洗发香波和洗剂中时,其水平可以为组合物重量的约0.001%(10ppm)至约0.5%(5000ppm)或组合物重量的约0.01%(100ppm)至约0.4%(4000ppm)。
化合物的清凉效力(强度)由其EC50值定义。EC50(半最大有效浓度)是指在指定的暴露时间后,在基线和最大值中间引起响应的化合物的浓度。它通常用作效力的量度。EC50是浓度的量度,以μM(μmolar)单位表示,其中1μM相当于1μmol/L。
EC50为10μM或更低的化合物被人类感知为清凉。EC50值越低,清凉效力越高。例如,EC50值为约0.1μM的化合物被认为是强清凉化合物。
然而,化合物的清凉特性不仅取决于其强度(效力;EC50),还取决于其持续时间,即感知清凉效果的时间段(以分钟为单位)。持续时间可以从冲洗后的几秒钟到几小时甚至几天不等。在口腔护理产品的情况下,优选的“持久”效果通常在冲洗后20分钟到3小时之间。
由式(I)定义的化合物(其包括式(Ia),(Ib),(Ic),(Id)和(Ie)的化合物)通常在所需浓度下很好地溶于水。然而,为了增加溶解度,可以使用特定的异构体来代替异构体混合物。如本领域技术人员所熟知的,顺式/反式异构体和/或非对映异构体可能具有不同的溶解性,因此可以选择异构体的混合物或单独的异构体用于消费品,这取决于要达到何种清凉效果。
式(I)的化合物(其包括式(Ia),(Ib),(Ic),(Id)和(Ie)的化合物)在相对低浓度下非常有效。因此,优选制备储备溶液,所述储备溶液在与消费品混合之前被进一步稀释。除了水,特别合适的溶剂是甘油三乙酸酯和丙二醇。还可提及丙酮,苯甲醇,二氢左旋葡糖烯酮,甲基-四氢呋喃,戊二醇,乙二醇,乳酸乙酯,乳酸甲酯,乳酸丙酯,二甲亚砜,乙醇,乙酸乙酯,乙二醇,二甘醇,丙二醇和甘油三乙酸酯,它们是式(I)的化合物(其包括式(Ia),(Ib),(Ic),(Id)和(Ie)的化合物)的合适溶剂。但也可以使用包含表面活性剂的其它溶剂体系。
为了改进如本文由式(I)定义的化合物(其包括式(Ia),(Ib),(Ic),(Id)和(Ie)的化合物)的清凉效果,可以将所述化合物,其盐或溶剂合物与选自钙离子和盐,镁离子和盐,精氨酸或任何能够结合钙或镁的螯合剂的化合物组合。
已知这些化合物能够调节细胞外空间中此类离子的浓度,因此影响TRPM8离子通道的响应,从而导致感知的清凉效果发生变化。
根据Kizilbash等人(WO2019/121193A1),当与具有增强所述效果的特性的试剂组合时,清凉强度和风味强度二者可以得到增强。因此,本文由式(I)定义的化合物可以在一个特定实施方案中与WO2019/121193中公开的增强剂组合,WO2019/121193以引用的方式并入,特别是关于增效剂的内容。
作为进一步的增强剂,可以举出N-乳酰基乙醇胺(2-羟基-N-(2-羟基乙基)丙酰胺;CAS 5422-34-4),其作为清凉剂的增强剂已知,例如来自PCT国际公开WO2008/107137,其通过引用并入,特别是关于由式(I)定义的清凉增强物质的内容。
式(I)的化合物(其包括式(Ia),(Ib),(Ic),(Id)和(Ie)的化合物)可以与本领域已知的其它清凉化合物组合使用。
因此,在第五方面提供了一种包含清凉感的组合物,其中该组合物包含至少一种式(I)的化合物,其盐或溶剂合物和另外的清凉化合物。
在一个具体实施方案中,式(I)的化合物(其包括式(Ia),(Ib),(Ic),(Id)和(Ie)的化合物)可以与薄荷醇(例如胡椒薄荷油和/或留兰香油的形式),薄荷酮,对薄荷烷甲酰胺,N-2,3-三甲基-2-异丙基-丁酰胺(WS-23),乳酸薄荷酯(ML),薄荷酮甘油缩醛(/>MGA),3-(1-薄荷氧基)-丙-1,2-二醇(TK-10),对薄荷烷-3,8-二醇(称为Coolact38D),异胡薄荷醇(称为Coolact P),琥珀酸单薄荷酯/>戊二酸单薄荷酯,邻薄荷基甘油,N,N-二甲基琥珀酰胺酸薄荷酯,2-(仲丁基)环己-1-酮(鲜薄荷酮),N-(吡唑-3-基)-N-(噻吩-2-基甲基)-2-(对甲苯基氧基)乙酰胺,2-(4-乙基苯氧基)-N-(吡唑-3-基)-N-(噻吩-2-基甲基)乙酰胺,3-(苯并[d][1,3]二氧杂环戊二烯-5-基)-N,N-二苯基丙烯酰胺,4-(2-(4-烯丙基-2,6-二甲氧基苯氧基)-1-乙氧基丙基)-2-甲氧基苯酚,4-(2-(4-烯丙基-2,6-二甲氧基苯氧基)-1-((2-异丙基-5-甲基环己基)氧基)丙基)-2-甲氧基苯酚(包括4-(2-(4-烯丙基-2,6-二甲基苯氧基)-1-(((1S,2R,5S)-2-异丙基-5-甲基环己基)氧基)丙基)-2-甲氧基苯酚)和4-(2-(4-烯丙基-2,6-二甲基苯氧基)-1-(((1R,2S,5R)-2-异丙基-5-甲基环己基)氧基)丙基)-2-甲氧基苯酚),N-(2-羟基-2-苯基乙基)-2-异丙基-5,5-二甲基环己烷-1-甲酰胺,N-(4-(氰基甲基)苯基)-2-异丙基-5,5-二甲基环己烷甲酰胺和N-(3-羟基-4-甲氧基苯基)-2-异丙基-5,5-二甲基环己烷甲酰胺。
对薄荷烷甲酰胺的实例包括化合物例如N-乙基-对薄荷烷-3-甲酰胺(商业上称为WS-3),N-乙氧基羰基甲基-对薄荷烷-3-甲酰胺(WS-5),N-(4-甲氧基苯基)-对薄荷烷-3-甲酰胺(WS-12)和N-叔丁基-对薄荷烷-3-甲酰胺(WS-14),N-(4-(氰基甲基)苯基)-2-异丙基-5-甲基环己烷-1-甲酰胺(商业上称为Evercool 180),2-异丙基-5-甲基-N-(2-(吡啶-2-基)乙基)环己烷-1-甲酰胺(商业上称为Evercool 190)和(1R,2S,5R)-N-((S)-2-((R)-2-氨基丙酰氨基)-2-苯基乙基)-2-异丙基-5-甲基环己烷-1-甲酰胺。
为了实现不仅仅是清凉效果,式(I)的化合物(其包括式(Ia),(Ib),(Ic),(Id)和(Ie)的化合物),其盐或溶剂合物可以与其它活性物质组合,例如香精,香料和甜味剂。
香料成分的实例包括天然香料,人造香料,辛香料,调味品等。示例性香料成分包括合成香料油和调味芳香剂和/或油,油树脂,精油和馏出物以及包含上述至少一种的组合。
香料油包括留兰香油,肉桂油(cinnamon oil),冬青油(水杨酸甲酯),胡椒薄荷油,日本薄荷油,丁香油,月桂油,茴香油,桉叶油,百里香油,柏叶油,肉豆蔻油,多香果,鼠尾草油,肉豆蔻衣,苦杏仁油和肉桂皮油(cassia oil);有用的增香剂包括人造,天然和合成水果香精,例如香荚兰,和柑橘油,包括柠檬,橙子,酸橙,葡萄柚,日本柚子(yuzu),酢橘(sudachi),以及水果精油,包括苹果,梨,桃子,葡萄,覆盆子,黑莓,醋栗,蓝莓,草莓,樱桃,李子,李子干(prune),葡萄干(raisin),可乐(cola),瓜拉那(guarana),橙花,菠萝,杏子,香蕉,甜瓜,杏子,樱桃,热带水果,芒果,山竹果,石榴,番木瓜等。
香料组合物赋予的另外的示例性香精包括牛奶香精,黄油香精,干酪香精,奶油香精和酸奶香精;香荚兰香精;茶或咖啡香精,例如绿茶香精,乌龙茶香精,茶香精,可可香精,巧克力香精和咖啡香精;薄荷香精,例如胡椒薄荷香精,留兰香香精和日本薄荷香精;辛香精,例如阿魏香精,香旱芹(ajowan)香精,茴香(anise)香精,当归属香精,小茴香(fennel)香精,多香果香精,肉桂香精,黄春菊香精,芥茉香精,小豆蔻香精,葛缕子(caraway)香精,枯茗(cumin)香精,丁香香精,胡椒香精,芫荽子香精,黄樟香精,香薄荷(savory)香精,川花椒香精,紫苏香精,杜松子香精,姜香精,八角茴香香精,辣根香精,百里香香精,龙蒿(tarragon)香精,莳萝(dill)香精,辣椒香精,肉豆蔻香精,罗勒香精,马郁兰(marjoram)香精,迷迭香香精,月桂叶香精和山葵(wasabi)(日本辣根)香精;坚果香精,例如杏仁香精,榛子香精,澳洲坚果香精,花生香精,美洲山核桃香精,开心果(pistachio)香精和胡桃香精;酒香精,例如葡萄酒香精,威士忌香精,白兰地香精,朗姆酒香精,杜松子酒香精和利口酒香精;花香精;和蔬菜香精,例如洋葱香精,大蒜香精,甘蓝香精,胡萝卜香精,芹菜香精,蘑菇香精和蕃茄香精。
通常可以使用任何香精或食品添加剂(包括食用色素),例如由Leatherhead FoodInternational Ltd.提供的“Essential guide to food additives”,2008年第三版,第101-321页(ISBN:978-1-905224-50-0)中所述的那些,该出版物通过引用并入本文。
在一个具体的实施方案中,式(I)的化合物(其包括式(Ia),(Ib),(Ic),(Id)和(Ie)的化合物)可以与茴香脑,左旋薄荷醇,左旋香芹酮,乙基麦芽酚,香草醛,桉叶油素,丁香酚,外消旋薄荷醇,顺式-3-己烯醇,芳樟醇,薄荷油(例如胡椒薄荷油(peppermintarvensis oil),薄荷胡椒油(peppermint piperita oil),留兰香天然油,留兰香苏格兰油),甲基环戊烯醇酮(corylone),丁酸乙酯,乙酸顺式-3-己烯酯,柠檬醛,桉树油,乙基香草醛,水杨酸甲酯,2’-羟基苯丙酮,乙酸乙酯,二氢茉莉酮酸甲酯,香叶醇,柠檬油,乙酸异戊酯,百里酚,乙位紫罗兰酮,乙酸芳樟酯,癸醛,(±)-二氢薄荷内酯(3,6-二甲基-3a,4,5,6,7,7a-六氢-3H-苯并呋喃-2-酮),顺式茉莉酮,己酸乙酯,甜瓜醛(2,6-二甲基庚-5-烯醛),香茅醇,乙酰乙酸乙酯,肉豆蔻油和丁香油或它们的混合物组合。
在一个具体实施方案中,式(I)的化合物是式(Ic)的化合物,其中R1为对甲苯基,并且R4,R5和R6与它们所连接的碳原子一起形成2-甲基-3-硫杂丁-2-基或丁-2-基。
甜味剂的实例包括但不限于蔗糖,果糖,葡萄糖,高果糖玉米糖浆,玉米糖浆,木糖,阿拉伯糖,鼠李糖,赤藓醇,木糖醇,甘露糖醇,山梨醇,肌醇,丁磺氨钾,阿司帕坦,纽甜,三氯蔗糖(sucralose)和糖精及其混合物;三叶苷,橙皮素二氢查耳酮糖苷,柚苷二氢查耳酮,罗汉果苷V,罗汉果提取物,甜叶悬钩子苷,悬钩子提取物,菝葜苷(glycyphyllin),异罗汉果苷V(isomogroside V),罗汉果苷IV,赛门苷I(siamenoside I),新罗汉果苷,木库罗苷IIb(mukurozioside IIb),(+)-hernandulcin,4β-hydroxyhernandulcin,白元参苷(baiyunoside),糙苏苷I(phlomisoside I),异株泻根甜味苷(bryodulcoside),bryosidebryonoside,相思子三萜苷A-E(abrusosides A-E),青钱柳苷A(cyclocarioside A),青钱柳苷I(cyclocaryoside I),albiziasaponins A-E,甘草皂苷(glycyrrhizin),araboglycyrrhizin,巴西甘草甜素I-V(periandrins I-V),蝶卡苷(pterocaryosides)A和B,奥斯拉津(osladin),polypodosides A和B,telosmoside A8-18,甜茶内酯(phyllodulcin),huangqioside E neoastilbin,莽那亭(monatin),3-乙酰氧基-5,7-二羟基-4’-甲氧基黄烷酮,2R,3R-(+)-3-乙酰氧基-5,7,4’-三羟基黄烷酮,(2R,3R)-二氢槲皮素3-O-乙酸酯,二氢槲皮素3-O-乙酸酯4’-甲醚,甜味蛋白(brazzein),仙茅甜蛋白(curculin),马槟榔甜蛋白(mabinlin),莫尼糖蛋白(monellin),neoculin,潘塔亭(pentadin),非洲竹芋甜素(thaumatin)及其组合。上述举出的一些化合物是已知的甜味增强剂和甜味剂。当用作甜味增强剂时,它们通常以低于其甜味检测阈的量使用。
在某些实施方案中,式(I)的化合物可以与共同涉及口腔可接受的载体材料的另外的成分组合。
在一些方面,口服可接受的载体可以包含一种或多种适合于局部口服给药的相容的固体或液体赋形剂或稀释剂。如本文所用,“相容”是指组合物的组分能够混合,而不会以显著降低稳定性和/或功效的方式相互作用。载体可以包括洁牙剂,非磨蚀性凝胶,龈下凝胶,漱口剂或冲洗剂,口腔喷雾剂,口香糖,锭剂和薄荷糖的常用和常规组分。所用载体的选择基本上取决于将组合物引入口腔的方式。用于牙膏,牙胶等的载体材料包括研磨材料,起泡剂,粘合剂,保湿剂,调味剂和甜味剂等,如在例如授予Benedict的美国专利No.3,988,433中所公开的。用于双相洁牙剂制剂的载体材料公开于均授予Lukacovic等人的美国专利No.5,213,790;5,145,666和5,281,410,以及授予Schaeffer的美国专利4,849,213和4,528,180中。漱口剂,漱口液或口腔喷雾剂载体材料通常包括水,香料和甜味剂等,如在例如授予Benedict的美国专利No.3,988,433中所公开的。锭剂载体材料通常包括糖果基料;口香糖载体材料包括胶基,香料和甜味剂,如在例如授予Grabenstetter等人的美国专利No.4,083,955。小袋载体材料通常包括小袋,调味剂和甜味剂。对于用于将活性物质递送到牙周袋中或牙周袋周围的龈下凝胶,选择“龈下凝胶载体”,如在例如均授予Damani的美国专利No.5,198,220和5,242,910。适用于制备本公开的组合物的载体是本领域众所周知的。它们的选择将取决于次要考虑,例如味道,成本和货架稳定性等。
其它合适类型的口服可接受的载体材料或赋形剂列于WO2010/059289,特别是第17-31页,其通过引用并入。
科学文献指出,TRPM8通道的激活可能有助于治疗大多数TRPM8介导的病理症状(J.Med.Chem.2016,59(22),10006-10029)。因此,可以设想式(I)的化合物也可能适用于治疗前列腺癌,膀胱无力,炎症或疼痛,包括使患者与本文定义的一种或多种式(I)的化合物接触。人们还可以设想本文定义的式(I)的化合物适用于缓解咳嗽和感冒,刺激,喉咙痛或声音嘶哑的症状,以及治疗咽喉吞咽困难(Int.J.Mol.Sci.2018,19,4113)。
因此,在第六方面提供了药物组合物,其包含一种或多种由式(I)定义的化合物(其包括式(Ia),(Ib),(Ic),(Id)和(Ie)的化合物)或其盐或溶剂合物。
取决于所考虑的具体治疗方案,包含一种或多种式(I)的化合物的药物组合物可以肠胃外,局部,口服或局部给药。药物组合物可以是液体,悬浮液或固体制剂。
在某些实施方案中,药物组合物是鼻喷雾剂,局部乳剂,皮肤喷雾剂,咽喉喷雾剂,滴眼剂或止咳糖浆。
如上文所定义的式(I)的化合物未在文献中描述,因此它们本身是新颖的。
因此,在本发明的另一方面提供了式(I)的化合物
其中X1,X2和X3之一为>N-C(O)R,且其它两个独立地选自C,N和O,条件是它们二者不均为C,并且其中R选自任选地包含一个选自O和S的杂原子的C1-C15烃残基;
和
c)R1为H;且B表示一价残基(a)
或
d)R1选自
卤素(包括Br,Cl和F),C6-C10芳基(例如苯基或萘基),其任选地被至多四个(例如1,2或3个)独立地选自下组的取代基取代:
卤素(包括F,Cl,Br);
OH(羟基);
C≡N(氰基);
NO2(硝基);
C1-C6烷基,其任选地包含至多5个卤素原子(例如F),例如CH3,CF3或CHF2;
C1-C3烷基,其包含至多3个OH基团,例如CH2OH;
C2-C6烯基,例如-CH=CH2;
C1-C6烷氧基,其任选地包含至多3个卤素原子(例如F),例如OCH3,OCH3,OCF3;
C1-C3烷氧基C1-C3烷基,例如2-甲氧基-乙基;
C3-C7环烷基,例如环丙基,环丁基;
-C(O)R10,其中R10选自C1-C3烷基;
-OC(O)R11,其中R11选自H和C1-C3烷基;
-C(O)O-R12,其中R12选自氢和C1-C3烷基;
-(CH2)mN(R13)R14,其中m为0或1,R13选自氢,C1-C3烷基和-SO2R15,其中R15为C1-C3烷基,且R14选自氢,C1-C3烷基和-SO2R16,其中R16为C1-C3烷基,或其中R13和R14与它们所连接的N原子一起形成吗啉,硫代吗啉或1,1-二氧代硫代吗啉;
-SR17,其中R17选自氢和C1-C3烷基;和
-S(O)2R18,其中R18选自氢和C1-C3烷基;
条件是,当芳基环被两个或更多个取代基取代时,两个取代基可以与它们所连接的碳原子一起形成环,和
C5-C10单-或双环杂芳基,其中至多2个C原子被独立地选自硫,氮和氧的杂原子替代,所述杂芳基任选地被至多四个(例如1,2或3个)选自下组的取代基取代:
卤素(包括F,Cl,Br);OH(羟基);
C≡N(氰基);
NO2(硝基);
C1-C6烷基,其任选地包含至多5个卤素原子(例如F),例如CH3,CF3或CHF2;
C2-C6烯基,例如-CH=CH2;
C1-C6烷氧基,其任选地包含至多3个卤素原子(例如F),例如OCH3,OCH3,OCF3;
C1-C3烷氧基C1-C3烷基,例如2-甲氧基-乙基;
C3-C7环烷基,例如环丙基,环丁基;
-C(O)R20,其中R20选自C1-C3烷基;
-OC(O)R21,其中R21选自H和C1-C3烷基;
-C(O)O-R22,其中R22选自氢和C1-C3烷基);
-(CH2)mN(R23)R24,其中m为0或1,R23选自氢,C1-C3烷基和-SO2R25,其中R25为C1-C3烷基,且R24选自氢,C1-C3烷基和-SO2R26,其中R26为C1-C3烷基,或其中R23和R24与它们所连接的N原子一起形成吗啉,硫代吗啉或1,1-二氧代硫代吗啉;
-SR27,其中R27选自氢和C1-C3烷基;和
-S(O)2R28,其中R28选自氢和C1-C3烷基;
和
B表示一价残基(b)
其中
R4,R5和R6与它们所连接的碳原子一起形成任选地包含至多五个(例如1,2,3,4个)选自O,N,S和F的杂原子的烃基(优选该烃基包含2至15个C原子(例如3,4,5,6,7,8,9,10,11,12,13或14个C原子);和
Z是C,S或S(O)。
式(I)的化合物一般可从本文上面所定义的式(I’)的化合物来制备(式(I’)的化合物可以如例如国际专利申请PCT/EP2020/079009(WO2021/074281)中所述来制备),所述制备通过使它们与R-C(O)-X类型的相应活化羧酸衍生物(其中R具有与本文式(I)所提供的相同的含义,而X为卤素,例如氯化物,溴化物或氟化物)反应来进行。该反应可在碱例如有机碱(例如三乙胺,二异丙基乙胺)或无机碱(例如碳酸钾,磷酸钾,碳酸氢钠,氢氧化钠)存在下在合适的溶剂(例如二氯甲烷,水,二噁烷,N,N-二甲基甲酰胺,四氢呋喃)中或在无溶剂条件下进行。该反应可以受益于添加亲核催化剂例如N,N-二甲基-4-氨基吡啶(DMAP)。或者,所述活化羧酸可以是R-C(O)-O-C(O)-R类型的酸酐(其中R具有与本文式(I)所提供的相同的含义)或类似的酸酐(例如混合酸酐)。也可以使用有机合成领域技术人员熟知的用于合成式(I)的化合物的其它试剂和条件。
现在参考以下非限制性实施例进一步描述本发明。这些示例仅出于说明的目的,并且应当理解,本领域技术人员可以做出变化和修改。
实施例
实施例A:2-(甲基硫基)-1-(2-(5-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)丙-1-酮
实施例Aa:2-(1H-咪唑-2-基)哌啶-1-甲酸叔丁酯:在0℃向2-甲酰基哌啶-1-甲酸叔丁酯(9.5g,35.6mmol)和乙二醛(40%在水中,25.9g,178mmol)的甲醇(100mL)溶液中滴加氨溶液(25%在水中,17.0g,249mmol)。使溶液升温至rt.(室温)并在rt.下搅拌16h。然后将溶液减压浓缩,所得残余物用乙酸乙酯(100mL*3)萃取。过滤除去任何沉淀,有机相用饱和NaHCO3水溶液(100mL)和盐水(100mL)洗涤。然后将溶液在减压下浓缩,得到2-(1H-咪唑-2-基)哌啶-1-甲酸叔丁酯(5.2g,收率:58%),为白色固体。GC/MS(EI):m/z(%):251(3)[M+],195(4),178(10),150(20),134(13),122(5),95(100),82(10),57(21)。
实施例Ab:2-(4,5-二溴-1H-咪唑-2-基)哌啶-1-甲酸叔丁酯:在0℃经10分钟将N-溴代琥珀酰亚胺(7.4g,41.8mmol)分批加入到2-(1H-咪唑-2-基)哌啶-1-甲酸叔丁酯(5.0g,19.9mmol)在二氯甲烷(100mL)中的溶液中。将混合物在0℃再搅拌2h,然后通过旋转蒸发浓缩。将残余物溶解在乙酸乙酯(250mL)中,用水(100mL*2)和盐水(100mL)洗涤,用MgSO4干燥,浓缩得到深棕色的残余物。残余物用二氯甲烷/己烷(1:1)重结晶,得到2-(4,5-二溴-1H-咪唑-2-基)哌啶-1-甲酸叔丁酯(6.0g,收率:74%),为白色固体。GC/MS(EI):m/z(%):411(2)[M+],409(4)[M+],407(2)[M+],355(6),353(12),351(6),311(11),309(22),307(11),294(11),292(22),290(11),255(50),253(100),251(50),242(12),240(24),238(12),148(9),57(50)。
实施例Ac:2-(5-溴-1H-咪唑-2-基)哌啶-1-甲酸叔丁酯:将2-(4,5-二溴-1H-咪唑-2-基)哌啶-1-甲酸叔丁酯(34.0g,90%,74.8mmol)和Na2SO3(94g,748mmol)在乙醇(300mL)和水(300mL)中的悬浮液回流过夜。然后冷却并浓缩。残余物在CH2Cl2(200mL)和H2O(200mL)之间分配。水层用乙酸乙酯(200mL*3)萃取。合并的有机层用盐水(200mL)洗涤,用Na2SO4干燥,过滤并蒸发。残余物通过硅胶柱色谱法纯化,得到2-(5-溴-1H-咪唑-2-基)哌啶-1-甲酸叔丁酯(23.0g,收率:93%),为白色固体。GC/MS(EI):m/z(%):329(3)[M+],331(3)[M+],275(10),273(10),258(9),256(9),230(20),228(20),214(26),212(26)。175(100),173(100),162(9),160(9),93(8),57(44)。
实施例Ad:2-(5-(对甲苯基)-1H-咪唑-2-基)哌啶-1-甲酸叔丁酯:向压力容器中装入2-(5-溴咪唑-2-基)哌啶-1-甲酸叔丁酯(400mg,1.211mmol),对甲苯基硼酸(181mg,1.332mmol,1.1当量),碳酸钠(257mg,2.42mmol,2当量),1,1’-双(二苯基膦基)-二茂铁-二氯化钯(II)二氯甲烷络合物(49mg,0.061mmol,0.05当量),四氢呋喃(5mL)和水(1mL)。通过用氮气吹扫使混合物脱气并将容器密封。将混合物搅拌并加热至100℃过夜。将所得混合物冷却至0℃,打开容器并将内容物倒入NaHCO3水溶液(50mL)中,用EtOAc(2×50mL)萃取,用水(50mL)和盐水(50mL)洗涤,经MgSO4干燥并减压浓缩。将粗物质通过硅胶快速柱色谱法纯化,用庚烷中的EtOAc梯度洗脱,得到2-(5-(对甲苯基)咪唑-2-基)哌啶-1-甲酸叔丁酯(314mg,0.920mmol,76%收率),为白色固体。MS(EI,70eV):341(4,[M]+·),285(11),268(3),240(30),185(100),172(16),91(6),57(99)。1H NMR(DMSO-d6,400MHz,旋转异构体和互变异构体的混合物):δ11.66-12.09(m,1H),7.49-7.70(m,2H),7.20-7.48(m,1H),7.08-7.23(m,2H),5.34-5.23(m,1H),3.89(br d,J=12.1Hz,1H),3.05(br t,J=10.9Hz,1H),2.28(s,3H),2.18-2.25(m,1H),1.65-1.78(m,1H),1.22-1.63(m,13H)ppm。13C NMR(75MHz,DMSO,互变异构体的混合物)δ155.1(q),147.5(q),140.2(q),135.3(q),132.7(q),129.4(t),124.6(t),112.5(t),79.3(q),63.3(d),49.7(t),41.2(d),28.5(s),28.4(d),26.8(d),25.3(d),21.2(s),19.9(d)ppm。
实施例Ae:2-(5-(对甲苯基)-1H-咪唑-2-基)哌啶:在5℃用三氟乙酸(0.549mL,7.12mmol,8当量)逐滴处理2-(5-(对甲苯基)咪唑-2-基)哌啶-1-甲酸叔丁酯(304mg,0.890mmol)在二氯甲烷(3mL)中的溶液,并将所得混合物在室温下搅拌2小时或直至起始材料完全消耗。将混合物倒入冰水(30mL)中并通过加入1M NaOH水溶液使pH呈碱性。然后将混合物用二氯甲烷(3×20mL)萃取,用MgSO4干燥并减压浓缩,得到2-(5-(对甲苯基)咪唑-2-基)哌啶(160mg,0.664mmol,收率74%),为淡黄色油状物,其未经进一步纯化用于下一步。MS(EI,70eV):241(6,[M]+·),185(100),172(13),158(8),91(3),84(4)。1H NMR(氯仿-d,400MHz):δ8.67-8.89(br s,1H),7.50(d,J=8.1Hz,2H),7.19(d,J=7.8Hz,2H),7.13(s,1H),4.14(dd,J=12.3,3.1Hz,1H),3.30(br d,J=12.7Hz,1H),2.71-2.84(m,1H),2.37(s,3H),2.15-2.27(m,1H),2.01(br dd,J=14.4,3.2Hz,1H),1.90(br d,J=13.4Hz,1H),1.67-1.77(m,2H),1.32-1.46ppm(m,1H)。
实施例Af:2-(甲基硫基)-1-(2-(5-(对甲苯基)咪唑-2-基)哌啶-1-基)丙-1-酮:在0~5℃下,向2-(5-(对甲苯基)咪唑-2-基)哌啶(0.88mmol)在二氯甲烷(2mL)中的溶液中添加HOBt(1.056mmol,1.2当量)和3-(((乙基亚氨基)亚甲基)氨基)-N,N-二甲基丙-1-胺盐酸盐(1.056mmol,1.2当量),并将混合物在室温下搅拌0.5h。然后将该混合物用2-(甲基硫基)丙酸(0.968mmol,1.1当量)和N,N-二异丙基乙胺(0.88mmol,1当量)处理,并将所得混合物在室温下搅拌16h。过滤混合物并除去溶剂,并将粗物质通过硅胶色谱法(庚烷中的EtOAc梯度)纯化,得到2-(甲基硫基)-1-(2-(5-(对甲苯基)咪唑-2-基)哌啶-1-基)丙-1-酮,为白色固体。MS(EI,70eV):343(2,[M]+·),241(17),240(100),213(13),185(18),184(9),75(55),56(11),55(9),47(10),41(11)。1H NMR(400MHz,DMSO-d6,立体异构体和互变异构体的混合物)δ12.07,11.99,11.95,11.76(brs,1H),7.72-7.60(m,2H),7.59-7.42(m,1H),7.26-7.08(m,2H),5.75-5.39(m,1H),4.49-3.00(m,3H),2.71-2.15(m,1H),2.30(s,3H),2.07-1.96(m,3H),1.94-1.48(m,5H),1.43-1.34(m,3H)ppm。13C NMR(101MHz,DMSO-d6,立体异构体和互变异构体的混合物)δ170.2(q),170.2(q),170.0(q),147.0(q),146.8(q),146.7(q),140.4(q),140.3(q),139.9(q),135.3(q),135.2(q),135.1(q),132.7(q),132.6(q),132.6(q),129.7(t),129.3(t),124.6(t),113.0(t),112.6(t),112.5(t),51.5(t),47.3(t),47.0(t),43.1(d),43.0(d),38.8(d),38.0(t),37.6(t),37.3(t),28.8(d),28.6(d),28.1(d),27.9(d),26.1(d),25.7(d),25.4(d),21.2(s),20.3(d),20.1(d),18.3(s),18.0(s),17.8(s),11.9(s),11.7(s),11.6(s)ppm。
实施例B:2-甲基-1-(2-(5-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)丁-1-酮
使用与实施例Af相同的方案,使用2-甲基丁酸代替2-(甲基硫基)丙酸制备,得到2-甲基-1-(2-(5-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)丁-1-酮,为白色固体。GC/MS(EI):m/z(%):325(10)[M+],268(2),240(100),224(3),185(10),159(2),142(1),84(2),57(4)。1H NMR(300MHz,DMSO-d6,立体异构体和互变异构体的混合物)δ12.05-11.72(m,1H),7.73-7.53(m,2H),7.51-7.40(m,1H),7.27-7.03(m,2H),5.81-5.28(m,1H),4.61-3.16(m,2H),2.87-2.58(m,1H),2.38-2.19(m,4H),1.86-1.49(m,5H),1.46-1.23(m,2H),1.09-0.95(m,3H),0.94-0.80(m,3H)。13C NMR(75MHz,DMSO-d6,立体异构体和互变异构体的混合物)δ175.4(q),175.2(q),147.3(q),147.2(q),140.5(q),140.1(q),135.2(q),132.7(q),129.7(t),129.3(t),124.6(t),112.9(t),112.6(t),51.5(t),46.9(t),46.8(t),42.6(d),38.6(d),36.8(t),36.5(t),36.1(t),29.2(d),28.9(d),28.4(d),27.2(d),26.9(d),26.2(d),25.4(d),25.2(d),21.2(s),20.3(d),18.4(s),17.7(s),17.3(s),12.2(s),12.0(s),11.9(s)ppm。
实施例1:1-(2-(1-异丁酰基-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)-2-(甲基硫基)丙-1-酮:将2-(甲基硫基)-1-(2-(5-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)丙-1-酮(0.2g,0.58mmol,1.0当量)在二氯甲烷(2mL)中的溶液用异丁酰氯(0.074g,0.70mmol,1.2当量)处理。将反应混合物在环境温度下搅拌30min,然后倒入冰水(50mL)中,用DCM(3×50mL)萃取,用水和盐水(各50mL)洗涤,用硫酸镁干燥并浓缩。将得到的将粗物质通过硅胶快速色谱法(7-50%EtOAc的庚烷溶液)纯化,得到1-(2-(1-异丁酰基-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)-2-(甲基硫基)丙-1-酮(0.21g,0.51mmol,87%收率),为灰白色固体。
GC/MS(EI):m/z(%):413(3)[M+],398(4),367(6),343(4),338(5),268(37),240(100)。13C NMR(101MHz,DMSO-d6):δ=176.7,176.2,171.5,170.8,170.6,151.5,151.4,150.5,139.5,137.2,137.1,137.0,130.6,130.5,130.4,129.6,129.6,129.4,125.3,125.2,124.6,114.5,114.0,113.8,60.2,51.1,48.1,47.9,44.2,43.7,42.2,38.5,38.3,37.4,34.7,34.5,28.9,28.4,28.1,25.6,25.3,21.3,21.2,19.5,19.5,19.5,19.4,19.4,19.1,18.1,17.9,17.7,17.3,15.5,14.5,12.2,12.1,11.3。
实施例2:1-(2-(1-乙酰基-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)-2-(甲基硫基)丙-1-酮:类似于实施例1,由2-(甲基硫基)-1-(2-(5-(对甲苯基)咪唑-2-基)哌啶-1-基)丙-1-酮和乙酰氯制备,得到标题化合物,为灰白色固体。
GC/MS(EI):m/z(%):385(7)[M+],370(2),339(19),268(36),240(100)。13C NMR(101MHz,DMSO-d6):δ=171.5,170.8,170.6,170.0,169.5,151.3,139.2,137.1,137.0,130.5,130.5,129.7,129.6,125.2,125.1,115.4,114.9,114.7,60.2,51.0,48.1,47.9,44.3,43.8,38.5,38.2,37.4,31.7,28.8,28.3,28.0,25.6,25.3,25.2,25.1,22.6,21.3,21.2,19.4,18.1,17.9,17.7,14.6,14.4,12.2,12.1,11.3。
实施例3:1-(2-(1-丙酰基-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)丙-1-酮:a)在5℃下向2-(5-(对甲苯基)-1H-咪唑-2-基)哌啶-1-甲酸叔丁酯(7.6g,20.03mmol)在二氯甲烷(200mL)中的溶液中添加2,2,2-三氟乙酸(18.3g,160mmol),并将混合物在室温下搅拌2h。通过TLC监测反应的完成。将反应溶液冷却至室温,并添加饱和NaHCO3溶液(200mL),用EA(100mL*3)萃取并浓缩有机相,得到2-(5-(2,4-二氟苯基)-1H-咪唑-2-基)哌啶,为黄色固体(4.9g,收率:91%)。
b)在0~5℃下向2-(5-(对甲苯基)-1H-咪唑-2-基)哌啶(300mg,1.243mmol)和三乙胺(189mg,1.865mmol)在二氯甲烷(30ml)中的溶液中添加丙酰氯(138mg,1.492mmol),并将混合物在室温下搅拌6h。过滤混合物并除去溶剂,并通过硅胶色谱法(己烷:EA=2:1)纯化,得到1-(2-(3-丙酰基-5-(对甲苯基)咪唑-2-基)哌啶-1-基)丙-1-酮(165mg,收率38%),为白色固体。
GC/MS(EI):m/z(%):353(2)[M+],296(3),280(20),240(100),224(16),185(26),130(4),117(6),84(4)。1H NMR(300MHz,DMSO-d6)δ8.29-8.06(m,1H),7.84-7.62(m,2H),7.32-7.13(m,2H),6.22-5.86(m,1H),4.55-3.59(m,2H),3.18-2.94(m,2H),2.46-2.21(m,5H),2.31(s,3H),2.10-1.25(m,6H),1.19-1.09(m,3H),1.01-0.89(m,3H)。13C NMR(75MHz,DMSO-d6)δ173.6(q),173.3(q),172.7(q),151.5(q),150.7(q),139.5(q),139.3(q),137.0(q),130.4(q),130.3(q),129.6(t),125.2(t),114.3(t),113.8(t),51.0(t),47.5(t),43.4(d),29.7(d),28.9(d),28.1(d),26.7(d),26.2(d),25.5(d),25.0(d),21.2(s),19.4(d),19.3(d),9.8(s),9.6(s),8.6(s),8.5(s)ppm。
实施例4:1-(2-(1-异丁酰基-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)-2-甲基丙-1-酮:按照与实施例3类似的步骤,使2-(5-(对甲苯基)-1H-咪唑-2-基)哌啶(300mg,1.243mmol),异丁酰氯(159mg,1.492mmol)和三乙胺(189mg,1.865mmol)在二氯甲烷(30ml)中反应,得到标题产物(140mg,收率:29%),为白色固体。
GC/MS(EI):m/z(%):381(2)[M+],310(13),294(19),240(100),224(18),185(26),159(4),130(3),117(5),71(9)。1H NMR(300MHz,DMSO-d6)δ8.38-8.17(m,1H),7.73(d,J=7.5Hz,2H),7.21(d,J=7.5Hz,2H),6.16-5.95(m,1H),4.56-3.83(m,2H),3.08-2.58(m,1H),2.30(s,3H),2.12-1.28(m,7H),1.28-1.12(m,6H),1.08-0.67(m,6H)。13C NMR(75MHz,DMSO-d6)δ176.5(q),176.1(q),151.7(q),139.5(q),137.1(q),130.5(q),129.6(t),125.2(t),113.7(t),47.7(t),43.4(d),34.5(t),29.9(t),28.1(d),25.7(d),21.2(s),19.8(s),19.5(d),19.4(s),19.4(s),18.9(s)ppm。
实施例5:2-(甲基硫基)-1-(2-(1-(2-(甲基硫基)丙酰基)-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)丙-1-酮:在0℃下将2-(5-(对甲苯基)-1H-咪唑-2-基)哌啶(2.1g,8.7mmol,1.0当量)在二氯甲烷(DCM)(15mL)中的溶液用三乙胺(1.82mL,13.1mmol,1.5当量)处理,然后滴加2-(甲基硫基)丙酰氯(1.33g,9.59mmol,1.1当量)。将混合物搅拌13h,然后倒在冰冷的1M HCl水溶液(50mL)上,用EtOAc(3×50mL)萃取,用饱和NaHCO3水溶液(50mL),水(50mL),盐水(50mL)洗涤,用硫酸镁干燥并浓缩。将粗物质通过硅胶快速色谱法(7-80%EtOAc的庚烷溶液)纯化,得到2-(甲基硫基)-1-(2-(1-(2-(甲基硫基)丙酰基)-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)丙-1-酮(1.96g,4.4mmol,50%收率),为黄色蜡状物。
DIP/MS(EI):m/z(%):370(1)[M+-C3H7S],268(5),240(26),185(14),75(100)[C3H7S+]。1H NMR(400MHz,氯仿-d,25℃):δ=7.63-7.76(m,2H),7.52-7.62(m,1H),7.15-7.25(m,2H),5.87-6.56(m,1H),4.22-4.76(m,1H),3.88-4.15(m,2H),3.65-3.81(m,1H),2.38(s,3H),2.07-2.18(m,4H),1.22-1.76(m,10H),0.84-0.98ppm(m,4H)。
实施例6:1-(2-(1-苯甲酰基-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)-2-(甲基硫基)丙-1-酮:在环境温度下将2-(甲基硫基)-1-(2-(5-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)丙-1-酮(0.2g,0.582mmol)在二氯甲烷(2mL)中的溶液用苯甲酰氯(0.098g,0.699mmol)处理。将反应混合物在环境温度下搅拌2h,然后倒入冰水中,用DCM(3×25mL)萃取,用水(25mL)和盐水(25mL)洗涤,用硫酸镁干燥并浓缩。将粗物质通过硅胶快速色谱法(7-60%EtOAc的庚烷溶液)纯化,得到1-(2-(1-苯甲酰基-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)-2-(甲基硫基)丙-1-酮(0.13g,0.290mmol,50%收率),为黄色油状蜡状物。
DIP/MS(EI):m/z(%):447(1)[M+],432(1),401(1),372(2),344(4),240(35),105(100),75(32)。1H NMR(400MHz,DMSO-d6,25℃):δ=7.69-8.11(m,6H),7.48-7.68(m,2H),7.11-7.27(m,2H),5.73-6.36(m,1H),3.73-4.09(m,3H),2.31(s,3H),1.94-2.13(m,4H),1.75-1.88(m,2H),1.62(br s,2H),1.13-1.41ppm(m,4H)。
实施例7:N-(1-苯甲酰基-1H-吡唑-3-基)-N-(噻吩-2-基甲基)-2-(对甲苯基氧基)乙酰胺:在5℃下将N-(1H-吡唑-3-基)-N-(噻吩-2-基甲基)-2-(对甲苯基氧基)乙酰胺(0.150g,0.458mmol)和三乙胺(0.056g,0.550mmol)在二氯甲烷(3mL)中的溶液用苯甲酰氯(0.077g,0.550mmol)处理。移去冷却浴,并将反应混合物在环境温度下搅拌2h,然后倒入冰水中,用DCM(3×25mL)萃取,用水(25mL)和盐水(25mL)洗涤,用硫酸镁干燥并浓缩。将粗物质通过硅胶快速色谱法(7-30%EtOAc的庚烷溶液)纯化,得到N-(1-苯甲酰基-1H-吡唑-3-基)-N-(噻吩-2-基甲基)-2-(对甲苯基氧基)乙酰胺(0.17g,0.394mmol,86%收率),为白色固体。
DIP/MS(EI):m/z(%):431(1)[M+],324(2),282(2),121(5),105(100),97(57),91(18),77(37)。1H NMR(400MHz,DMSO-d6,25℃):δ=8.61(d,J=2.9Hz,1H),7.77-8.03(m,2H),7.65-7.73(m,1H),7.50-7.58(m,2H),7.39-7.47(m,1H),7.04(d,J=8.3Hz,3H),6.83-6.99(m,2H),6.61-6.77(m,2H),5.06-5.35(m,2H),4.49-5.05(m,2H),2.19-2.25ppm(m,3H)。
实施例8:N-(1-异丁酰基-1H-吡唑-3-基)-N-(噻吩-2-基甲基)-2-(对甲苯基氧基)乙酰胺:在5℃下将N-(1H-吡唑-3-基)-N-(噻吩-2-基甲基)-2-(对甲苯基氧基)乙酰胺(0.15g,0.458mmol)和三乙胺(0.056g,0.550mmol)在二氯甲烷(3mL)中的溶液用异丁酰氯(0.059g,0.550mmol)处理。除去冷却浴,并将反应混合物在环境温度下搅拌2h,然后倒入冰水中,用DCM(3×25mL)萃取,用水(25mL)和盐水(25mL)洗涤,用硫酸镁干燥并浓缩。将粗物质通过硅胶快速色谱法(7-30%EtOAc的庚烷溶液)纯化,得到N-(1-异丁酰基-1H-吡唑-3-基)-N-(噻吩-2-基甲基)-2-(对甲苯基氧基)乙酰胺(0.175g,0.440mmol,96%收率),为无色液体。
GC/MS(EI):m/z(%):397(7)[M+],327(1),290(2),220(29),178(21),121(8),97(100),71(15),43(33)。1H NMR(400MHz,DMSO-d6,25℃):δ=8.41(d,J=2.9Hz,1H),7.44(dd,J=5.0,1.1Hz,1H),7.01-7.11(m,3H),6.95(br dd,J=4.9,3.7Hz,1H),6.77-6.90(m,1H),6.68-6.76(m,2H),5.10-5.32(m,2H),4.98(br s,2H),3.67(dt,J=13.3,6.5Hz,1H),2.22(s,3H),1.18ppm(d,J=6.8Hz,6H)。
实施例9:N-(1-乙酰基-1H-吡唑-3-基)-N-(噻吩-2-基甲基)-2-(对甲苯基氧基)乙酰胺:在5℃下将N-(1H-吡唑-3-基)-N-(噻吩-2-基甲基)-2-(对甲苯基氧基)乙酰胺(0.15g,0.458mmol)和三乙胺(0.056g,0.550mmol)在二氯甲烷(3mL)中的溶液用乙酰氯(0.043g,0.550mmol)处理。除去冷却浴,并将反应混合物在环境温度下搅拌2h,然后倒入冰水中,用DCM(3×25mL)萃取,用水(25mL)和盐水(25mL)洗涤,用硫酸镁干燥并浓缩。将粗物质通过硅胶快速色谱法(7-30%EtOAc的庚烷溶液)纯化,得到N-(1-乙酰基-1H-吡唑-3-基)-N-(噻吩-2-基甲基)-2-(对甲苯基氧基)乙酰胺(0.140g,0.379mmol,83%收率),为白色固体。GC/MS(EI):m/z(%):369(8)[M+],262(6),220(35),178(23),97(100),43(15)。1HNMR(400MHz,氯仿-d,25℃):δ=8.21(d,J=2.7Hz,1H),7.25(dd,J=5.1,1.2Hz,1H),7.07(d,J=8.3Hz,2H),7.01(br s,1H),6.95(dd,J=5.0,3.5Hz,1H),6.75(br d,J=8.1Hz,2H),6.14-6.56(m,1H),5.06-5.43(m,2H),4.87(s,2H),2.58-2.68(m,3H),2.29ppm(s,3H)。
实施例10:1-(2-(1-((1R,2S,5R)-2-异丙基-5-甲基环己烷-1-羰基)-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)-2-(甲基硫基)丙-1-酮:在5℃下将2-(甲基硫基)-1-(2-(5-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)丙-1-酮(1g,2.91mmol)和乙基二(异丙基)胺(DIPEA)(0.508mL,2.91mmol)在二氯甲烷(5mL)中的溶液用在二氯甲烷(5mL)中的(1R,2S,5R)-2-异丙基-5-甲基环己烷-1-甲酰氯(0.590g,2.91mmol)处理。移去冷却浴,并将反应混合物在环境温度下搅拌过夜,然后倒入冰冷的1M HCl水溶液(5mL)中,用DCM(3×25mL)萃取,用1M NaOH水溶液(10mL),水(25mL)和盐水(25mL)洗涤,用硫酸镁干燥并浓缩。将粗物质通过硅胶快速色谱法(7-30%EtOAc的庚烷溶液)纯化,得到1-(2-(1-((1R,2S,5R)-2-异丙基-5-甲基环己烷-1-羰基)-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)-2-(甲基硫基)丙-1-酮(1.1g,2.158mmol,74%收率),为黄色粘性液体。DIP/MS(EI):m/z(%):509(2)[M+],463(2),434(1),342(9),296(6),268(23),240(100),75(27)。1H NMR(400MHz,DMSO-d6,25℃):δ=8.39-8.56(m,1H),7.64-7.89(m,2H),7.09-7.40(m,2H),5.90-6.37(m,1H),3.76-4.28(m,3H),3.21-3.49(m,3H),2.32(s,3H),2.13(td,J=11.6,3.4Hz,1H),1.83-2.07(m,4H),1.53-1.82(m,13H),1.22-1.42(m,7H),1.03-1.21(m,4H),0.84-0.93(m,13H),0.69-0.81ppm(m,5H)。
实施例11:1-(2-(1-乙酰基-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)-2-甲基丁-1-酮:在5℃下将2-甲基-1-(2-(5-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)丁-1-酮(0.5g,1.536mmol)和DIPEA(0.295mL,1.690mmol)在二氯甲烷(5mL)中的溶液用乙酰氯(0.120mL,1.690mmol)在二氯甲烷(5mL)中的溶液处理。添加之后,移去冷却浴,并将反应混合物在环境温度下搅拌过夜,然后倒入冰冷的1M HCl水溶液(5mL)中,用DCM(3×25mL)萃取,用1M NaOH水溶液(10mL),水(25mL)和盐水(25mL)洗涤,用硫酸镁干燥并浓缩。将粗物质通过硅胶快速色谱法(7-30%EtOAc的庚烷溶液)纯化,得到1-(2-(1-乙酰基-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)-2-甲基丁-1-酮(0.30g,0.816mmol,53%收率),为白色固体。GC/MS(EI):m/z(%):367(5)[M+],324(1),282(2),240(100),43(42)。1H NMR(400MHz,DMSO-d6,25℃):δ=8.09-8.22(m,1H),7.72(d,J=8.1Hz,2H),7.22(br d,J=7.8Hz,2H),5.86-6.24(m,1H),3.60-4.54(m,2H),2.73-2.92(m,1H),2.62-2.71(m,3H),2.26-2.43(m,3H),1.91-1.99(m,1H),1.66-1.89(m,2H),1.22-1.64(m,5H),0.92-1.05(m,3H),0.69-0.90(m,3H),0.43ppm(t,J=7.3Hz,1H)。13C NMR(101MHz,DMSO-d6,25℃):δ=176.3,175.9,169.4,151.6,151.5,139.2,139.2,137.0,137.0,130.6,129.6,129.6,125.2,125.1,125.1,120.0,114.7,60.2,47.8,47.7,43.6,43.5,36.7,36.4,28.1,28.0,27.0,26.9,25.8,25.1,21.3,21.2,19.6,17.8,16.8,14.5,12.2,11.8ppm。
实施例12:1-(2-(1-异丁酰基-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)-2-甲基丁-1-酮:在5℃下将2-甲基-1-(2-(5-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)丁-1-酮(0.5g,1.536mmol)和DIPEA(0.295mL,1.690mmol)在二氯甲烷(5mL)中的溶液用异丁酰氯(0.180g,1.690mmol)在二氯甲烷(5mL)中的溶液处理。添加之后,移去冷却浴,并将反应混合物在环境温度下搅拌2h,然后倒入冰冷的1M HCl水溶液(5mL)中,用DCM(3×25mL)萃取,用1M NaOH水溶液(10mL),水(25mL)和盐水(25mL)洗涤,用硫酸镁干燥并浓缩。将粗物质通过硅胶快速色谱法(1-30%EtOAc的庚烷溶液)纯化,得到1-(2-(1-异丁酰基-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)-2-甲基丁-1-酮(0.13g,0.329mmol,21%收率),为白色固体。DIP/MS(EI):m/z(%):395.3(10)[M+],352.3(1),324.2(4),240.2(100),185.2(38),71.2(16),57.1(44),43.1(96)。1H NMR(400MHz,DMSO-d6,25℃):δ=8.23-8.38(m,1H),7.74(br d,J=7.8Hz,2H),7.17-7.25(m,2H),5.87-6.21(m,1H),3.92-4.51(m,2H),3.44-3.70(m,1H),2.73-2.90(m,1H),2.25-2.42(m,3H),1.66-1.98(m,3H),1.27-1.64(m,5H),1.23(t,J=6.7Hz,6H),0.91-1.08(m,3H),0.67-0.87(m,3H),0.43ppm(br t,J=7.2Hz,1H)。
实施例13:1-(2-(1-((1R,2S,5R)-2-异丙基-5-甲基环己烷-1-羰基)-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)-2-甲基丁-1-酮:在5℃下将2-甲基-1-(2-(5-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)丁-1-酮(2g,6.15mmol)和DIPEA(1.073mL,6.15mmol)在二氯甲烷(15mL)中的溶液用(1R,2S,5R)-2-异丙基-5-甲基环己烷-1-甲酰氯(1.246g,6.15mmol)在二氯甲烷(5mL)中的溶液处理。移去冷却浴,并将反应混合物在环境温度下搅拌过夜。薄层色谱法(TLC)分析显示残留的起始材料。添加N,N-二甲基-4-氨基吡啶(DMAP)(0.1g,0.81mmol),并将反应混合物在环境温度下搅拌3h,然后倒入冰冷的1M HCl水溶液(15mL)中,用DCM(3×75mL)萃取,用1M NaOH水溶液(30mL),水(75mL)和盐水(75mL)洗涤,用硫酸镁干燥并浓缩。将粗物质通过硅胶快速色谱法(7-30%EtOAc的庚烷溶液)纯化,得到1-(2-(1-((1R,2S,5R)-2-异丙基-5-甲基环己烷-1-羰基)-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)-2-甲基丁-1-酮(2.8g,5.69mmol,93%收率),为白色固体。DIP/MS(EI):m/z(%):491(2)[M+],448(1),406(1),324(10),240(100),185(93),43(12)。1H NMR(400MHz,DMSO-d6,25℃):δ=8.41-8.55(m,1H),7.75(br d,J=7.8Hz,2H),7.18-7.27(m,2H),5.78-6.26(m,1H),3.94-4.50(m,2H),3.25-3.73(m,4H),2.73-2.90(m,1H),2.36(br dd,J=11.6,3.3Hz,1H),1.51-1.98(m,13H),1.22-1.50(m,6H),0.63-1.16ppm(m,25H)。
实施例14:1-(2-(1-(2-甲氧基乙酰基)-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)-2-甲基丁-1-酮:在5℃下将2-甲基-1-(2-(5-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)丁-1-酮(2g,6.15mmol),DMAP(0.075g,0.615mmol)和三乙胺(TEA)(0.942mL,6.76mmol)在二氯甲烷(10mL)中的溶液用2-甲氧基乙酰氯(0.734g,6.76mmol)在二氯甲烷(10mL)中的溶液处理。添加之后,移去冷却浴,并将反应混合物在环境温度下搅拌过夜。TLC分析显示约50%的转化率。将反应混合物用2-甲氧基乙酰氯(0.4g,3.69mmol)处理,并在环境温度下搅拌另外3h,然后倒入冰冷的1M HCl水溶液(15mL)中,用DCM(3×75mL)萃取,用1M NaOH水溶液(30mL),水(75mL)和盐水(75mL)洗涤,用硫酸镁干燥并浓缩。将粗物质通过硅胶快速色谱法(1-30%EtOAc的庚烷溶液)纯化,得到1-(2-(1-(2-甲氧基乙酰基)-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)-2-甲基丁-1-酮(1.70g,4.28mmol,70%收率),为白色固体。DIP/MS(EI):m/z(%):397(5)[M+],352(5),324(2),312(13),240(49),84(50),45(100)。1H NMR(400MHz,DMSO-d6,25℃):δ=8.00-8.13(m,1H),7.67-7.76(m,2H),7.18-7.27(m,2H),5.90-6.25(m,1H),4.68-4.83(m,2H),3.63-4.53(m,2H),3.44(s,3H),2.75-2.92(m,1H),2.32(s,3H),1.93-2.05(m,1H),1.69-1.91(m,2H),1.23-1.64(m,5H),0.40-1.07ppm(m,6H)。
实施例15:1-(2-(1-(2-(苄基氧基)乙酰基)-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)-2-甲基丁-1-酮:在5℃下将2-甲基-1-(2-(5-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)丁-1-酮(2g,6.15mmol),DMAP(0.075g,0.615mmol)和TEA(0.942mL,6.76mmol)在二氯甲烷(10mL)中的溶液用2-(苄基氧基)乙酰氯(1.248g,6.76mmol)在二氯甲烷(10mL)中的溶液处理。添加之后,移去冷却浴,并将反应混合物在环境温度下搅拌过夜。TLC显示有剩余的起始材料,因此添加额外的2-(苄基氧基)乙酰氯(0.5g,2.71mmol),并将反应混合物在环境温度下搅拌另外3h,然后倒入冰冷的1M HCl水溶液(15mL)中,用DCM(3×75mL)萃取,用1MNaOH水溶液(30mL),水(75mL)和盐水(75mL)洗涤,用硫酸镁干燥并浓缩。将粗物质通过硅胶快速色谱法(1-30%EtOAc的庚烷溶液)纯化,得到1-(2-(1-(2-(苄基氧基)乙酰基)-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)-2-甲基丁-1-酮(2.70g,5.70mmol,93%收率),为白色固体。
DIP/MS(EI):m/z(%):473(6)[M+],388(7),382(5),352(9),324(6),240(62),91(100),57(32)。1H NMR(400MHz,氯仿-d,25℃):δ=7.60-7.71(m,2H),7.32-7.47(m,6H),7.19(d,J=7.8Hz,2H),5.96-6.47(m,1H),4.49-4.81(m,4H),4.13-4.37(m,1H),3.87-4.13(m,1H),2.68-2.87(m,1H),2.38(s,3H),2.03-2.15(m,1H),1.81-2.02(m,2H),1.63-1.80(m,2H),1.35-1.59(m,2H),0.53-1.21ppm(m,6H)。
实施例16:1-(2-(1-(2-(甲基硫基)丙酰基)哌啶-2-基)-4-(对甲苯基)-1H-咪唑-1-基)十二烷-1-酮:在5℃下将2-(甲基硫基)-1-(2-(5-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)丙-1-酮(1.5g,4.37mmol),DMAP(0.053g,0.437mmol)和DIPEA(1.068mL,6.11mmol)在二氯甲烷(10mL)溶液用十二烷酰氯(1.146g,5.24mmol)在二氯甲烷(10mL)中的溶液处理。移去冷却浴,并将反应混合物在环境温度下搅拌过夜,然后倒入冰冷的1M HCl水溶液(25mL)中,用DCM(3×75mL)萃取,用1M NaOH水溶液(50mL),水(75mL)和盐水(75mL)洗涤,用硫酸镁干燥并浓缩。将粗物质通过硅胶快速色谱法(7-30%EtOAc的庚烷溶液)纯化,得到1-(2-(1-(2-(甲基硫基)丙酰基)哌啶-2-基)-4-(对甲苯基)-1H-咪唑-1-基)十二烷-1-酮(1.1g,2.09mmol,48%收率),为灰白色固体。
DIP/MS(EI):m/z(%):525(3)[M+],510(1),479(3),450(2),422(1),240(93),185(100),75(28)。1H NMR(400MHz,DMSO-d6,25℃):δ=8.14-8.28(m,1H),7.69-7.78(m,2H),7.16-7.25(m,2H),5.89-6.28(m,1H),4.11-4.52(m,1H),3.47-4.11(m,3H),2.93-3.12(m,2H),2.31(d,J=2.7Hz,3H),2.02-2.28(m,2H),1.89-1.98(m,1H),1.44-1.76(m,6H),1.21-1.40(m,25H),0.81-0.90ppm(m,4H)。
实施例17:1-(2-(1-(2-甲基丁酰基)哌啶-2-基)-4-(对甲苯基)-1H-咪唑-1-基)十二烷-1-酮:在5℃下将2-甲基-1-(2-(5-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)丁-1-酮(1.5g,4.61mmol),DMAP(0.056g,0.461mmol)和DIPEA(1.127mL,6.45mmol)在二氯甲烷(10mL)中的溶液用十二烷酰氯(1.210g,5.53mmol)在二氯甲烷(10mL)中的溶液处理。移去冷却浴,并将反应混合物在环境温度下搅拌过夜,然后倒入冰冷的1M HCl水溶液(25mL)中,用DCM(3×75mL)萃取,用1M NaOH水溶液(50mL),水(75mL)和盐水(75mL)洗涤,用硫酸镁干燥并浓缩。将粗物质通过硅胶快速色谱法(7-30%EtOAc的庚烷溶液)纯化,得到1-(2-(1-(2-甲基丁酰基)哌啶-2-基)-4-(对甲苯基)-1H-咪唑-1-基)十二烷-1-酮(1.75g,3.45mmol,75%收率),为白色固体。
DIP/MS(EI):m/z(%):507(5)[M+],422(1),240(100),185(26),57(20)。1H NMR(400MHz,DMSO-d6,25℃):δ=8.13-8.29(m,1H),7.69-7.77(m,2H),7.14-7.26(m,2H),5.88-6.25(m,1H),3.58-4.54(m,2H),2.93-3.13(m,2H),2.72-2.89(m,1H),2.31(s,3H),1.95(br d,J=13.0Hz,1H),1.60-1.84(m,4H),1.41-1.59(m,3H),1.21-1.40(m,19H),0.37-1.06ppm(m,10H)。
实施例18:1-(2-(1-(2-(甲基硫基)丙酰基)哌啶-2-基)-4-(对甲苯基)-1H-咪唑-1-基)己-1-酮:在5℃下将2-(甲基硫基)-1-(2-(5-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)丙-1-酮(2g,5.82mmol),DMAP(0.071g,0.582mmol)和DIPEA(1.525mL,8.73mmol)在二氯甲烷(10mL)中的溶液用己酰氯(1.176g,8.73mmol)在二氯甲烷(10mL)中的溶液处理。移去冷却浴,并将反应混合物在环境温度下搅拌过夜,然后倒入冰冷的1M HCl水溶液(25mL)中,用DCM(3×75mL)萃取,用1M NaOH水溶液(50mL),水(75mL)和盐水(75mL)洗涤,用硫酸镁干燥并浓缩。将粗物质通过硅胶快速色谱法(7-30%EtOAc的庚烷溶液)纯化,得到1-(2-(1-(2-(甲基硫基)丙酰基)哌啶-2-基)-4-(对甲苯基)-1H-咪唑-1-基)己烷-1-酮(2.2g,4.98mmol,86%收率),为白色固体。
DIP/MS(EI):m/z(%):441(5)[M+],426(2),395(5),366(4),240(80),185(100),99(16),75(44),43(66)。1H NMR(400MHz,DMSO-d6,25℃):δ=8.15-8.29(m,1H),7.69-7.79(m,2H),7.14-7.25(m,2H),5.90-6.32(m,1H),3.49-4.52(m,3H),2.93-3.14(m,2H),2.15-2.50(m,4H),1.86-2.06(m,3H),1.45-1.82(m,8H),1.20-1.42(m,11H),0.83-0.96ppm(m,5H)。
实施例19:1-(2-(1-(2-甲基丁酰基)哌啶-2-基)-4-(对甲苯基)-1H-咪唑-1-基)己-1-酮:在5℃下将2-甲基-1-(2-(5-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)丁-1-酮(1.5g,4.61mmol),DMAP(0.056g,0.461mmol)和DIPEA(1.127mL,6.45mmol)在二氯甲烷(10mL)中的溶液用己酰氯(0.869g,6.45mmol)在二氯甲烷(10mL)中的溶液处理。移去冷却浴,并将反应混合物在环境温度下搅拌过夜,然后倒入冰冷的1M HCl水溶液(25mL)中,用DCM(3×75mL)萃取,用1M NaOH水溶液(50mL),水(75mL)和盐水(75mL)洗涤,用硫酸镁干燥并浓缩。将粗物质通过硅胶快速色谱法(7-30%EtOAc的庚烷溶液)纯化,得到1-(2-(1-(2-甲基丁酰基)哌啶-2-基)-4-(对甲苯基)-1H-咪唑-1-基)己烷-1-酮(1.85g,4.37mmol,95%收率),为白色固体。
DIP/MS(EI):m/z(%):423(5)[M+],338(2),240(100),185(52),99(6),57(10)。1HNMR(400MHz,DMSO-d6,25℃):δ=8.12-8.31(m,1H),7.67-7.78(m,2H),7.13-7.30(m,2H),5.87-6.26(m,1H),3.56-4.55(m,2H),2.73-3.14(m,3H),2.14-2.49(m,4H),1.62-2.01(m,5H),1.21-1.61(m,14H),0.38-1.06ppm(m,12H)。
实施例20:TRPM8调节剂测定
根据Klein等人(Chem.Senses 36:649-658,2011)生成了稳定表达hTRPM8的HEK293细胞系,并通过Flexstation中的钙成像监测受体激活。对于TRPM8通道激活的Ca成像测定,细胞在第0天以每孔12000个细胞的密度接种在涂有0.001%聚乙烯亚胺(分子量=60000,Acros Organics)的黑色透明底部96孔板中的Dulbecco改良Eagle培养基(DMEM)中,该培养基含有9%胎牛血清。在第2天,使用Fluo-4通过钙成像评估激动剂。简要地,弃去生长培养基,并将细胞在50μL加样缓冲液中于37℃在黑暗中孵育1h,该缓冲液由DMEM(不含血清)中的2.7μM Fluo-4 AM(Invitrogen)和2.5μM丙磺舒(Sigma-Aldrich)组成。孵育后,用100μL的检测缓冲液(单位:mM:130 NaCl,5 KCl,10 HEPES,2 CaCl2和10葡萄糖,pH 7.4)洗涤板5次,然后在室温下黑暗中进一步孵育30分钟。然后用100μL测定缓冲液洗涤细胞五次,然后在Flexstation 3(Molecular Devices)中测量本发明化合物的系列稀释液的钙流入量。在加入20μl的10倍浓缩配体储备溶液后引发受体激活,该配体储备溶液也在测定缓冲液中制备。在添加配体之前持续监测荧光15秒,并在添加配体之后持续监测荧光105秒,总共120秒。确定了与溶剂对照相关和相对于31.6μM薄荷醇的最大受体激活。使用KNIME工作流程处理来自系列稀释液的数据,以拟合S型剂量-响应曲线并推断EC50值。
表现出低于35μM的EC50值的TRPM8激动剂列于下表1中。
表1
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++++ EC50值在0.05μM及更低范围内
+++ EC50值在0.05-0.3μM范围内
++ EC50值在0.3-1.00μM范围内
+ EC50值在1.00-35μM范围内
Claims (14)
1.调节瞬时受体电位通道melastatin成员8(TRPM8)的方法,包括使所述受体与式(I)的化合物,其盐或溶剂合物接触,
其中X1,X2和X3之一为>N-C(O)R,且其它两个独立地选自C,N和O,条件是它们二者不均为C,并且其中R选自任选地包含一个选自O和S的杂原子的C1-C15烃残基;
和
a)R1为H;且B表示一价残基(a)
或
b)R1选自
i)卤素,
ii)C6-C10芳基,其任选地被至多四个独立地选自下组的取代基取代:
卤素;OH(羟基);C≡N(氰基);NO2(硝基);
C1-C6烷基,其任选地包含至多5个卤素原子;
C1-C3烷基,其包含至多3个OH基团;
C2-C6烯基;
C1-C6烷氧基,其任选地包含至多3个卤素原子;
C1-C3烷氧基C1-C3烷基;
C3-C7环烷基;
-C(O)R10,其中R10选自C1-C3烷基;
-OC(O)R11,其中R11选自H和C1-C3烷基;
-C(O)O-R12,其中R12选自氢和C1-C3烷基;
-(CH2)mN(R13)R14,其中m为0或1,R13选自氢,C1-C3烷基和-SO2R15,其中R15为C1-C3烷基,且R14选自氢,C1-C3烷基和-SO2R16,其中R16为C1-C3烷基,或其中R13和R14与它们所连接的N原子一起形成吗啉,硫代吗啉或1,1-二氧代硫代吗啉;
-SR17,其中R17选自氢和C1-C3烷基;和
-S(O)2R18,其中R18选自氢和C1-C3烷基;
条件是,当芳基环被两个或更多个取代基取代时,两个取代基可以与它们所连接的碳原子一起形成环,和
iii)C5-C10单-或双环杂芳基,其中至多2个C原子被独立地选自硫,氮和氧的杂原子替代,所述杂芳基任选地被至多四个选自下组的取代基取代:
卤素;OH;C≡N;NO2;
C1-C6烷基,其任选地包含至多5个卤素原子;
C2-C6烯基;
C1-C6烷氧基,其任选地包含至多3个卤素原子;
C1-C3烷氧基C1-C3烷基;
C3-C7环烷基;
-C(O)R20,其中R20选自C1-C3烷基;
-OC(O)R21,其中R21选自H和C1-C3烷基;
-C(O)O-R22,其中R22选自氢和C1-C3烷基;
-(CH2)mN(R23)R24,其中m为0或1,R23选自氢,C1-C3烷基和-SO2R25,其中R25为C1-C3烷基,且R24选自氢,C1-C3烷基和-SO2R26,其中R26为C1-C3烷基,或其中R23和R24与它们所连接的N原子一起形成吗啉,硫代吗啉或1,1-二氧代硫代吗啉;
-SR27,其中R27选自氢和C1-C3烷基;和
-S(O)2R28,其中R28选自氢和C1-C3烷基;
和
B表示一价残基(b)
其中
R4,R5和R6与它们所连接的碳原子一起形成任选地包含至多五个选自O,N,S和F的杂原子的烃基;和
Z是C,S或S(O)。
2.根据权利要求2的方法,其中所述式(I)的化合物选自:
1-(2-(1-丙酰基-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)丙-1-酮;
1-(2-(1-异丁酰基-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)-2-甲基丙-1-酮;
2-(甲基硫基)-1-(2-(1-(2-(甲基硫基)丙酰基)-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)丙-1-酮;
1-(2-(1-乙酰基-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)-2-(甲基硫基)丙-1-酮;
1-(2-(1-异丁酰基-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)-2-(甲基硫基)丙-1-酮;
1-(2-(1-苯甲酰基-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)-2-(甲基硫基)丙-1-酮;
1-(2-(1-((1R,2S,5R)-2-异丙基-5-甲基环己烷-1-羰基)-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)-2-(甲基硫基)丙-1-酮;
1-(2-(1-乙酰基-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)-2-甲基丁-1-酮;
1-(2-(1-异丁酰基-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)-2-甲基丁-1-酮;
1-(2-(1-((1R,2S,5R)-2-异丙基-5-甲基环己烷-1-羰基)-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)-2-甲基丁-1-酮;
1-(2-(1-(2-甲氧基乙酰基)-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)-2-甲基丁-1-酮;
1-(2-(1-(2-(苄基氧基)乙酰基)-4-(对甲苯基)-1H-咪唑-2-基)哌啶-1-基)-2-甲基丁-1-酮;
1-(2-(1-(2-(甲基硫基)丙酰基)哌啶-2-基)-4-(对甲苯基)-1H-咪唑-1-基)十二烷-1-酮;
1-(2-(1-(2-甲基丁酰基)哌啶-2-基)-4-(对甲苯基)-1H-咪唑-1-基)十二烷-1-酮;
1-(2-(1-(2-(甲基硫基)丙酰基)哌啶-2-基)-4-(对甲苯基)-1H-咪唑-1-基)己-1-酮;
1-(2-(1-(2-甲基丁酰基)哌啶-2-基)-4-(对甲苯基)-1H-咪唑-1-基)己-1-酮;
N-(1-苯甲酰基-1H-吡唑-3-基)-N-(噻吩-2-基甲基)-2-(对甲苯基氧基)乙酰胺;
N-(1-异丁酰基-1H-吡唑-3-基)-N-(噻吩-2-基甲基)-2-(对甲苯基氧基)乙酰胺;和
N-(1-乙酰基-1H-吡唑-3-基)-N-(噻吩-2-基甲基)-2-(对甲苯基氧基)乙酰胺。
3.在人或动物中引起清凉感的非医学方法,包括使人或动物与如在权利要求1中所定义的式(I)的化合物或其盐或溶剂合物接触。
4.在皮肤或黏膜上实现清凉效果的方法,包括使皮肤或黏膜与包含一种或多种如在权利要求1中所定义的式(I)的化合物的产品接触。
5.式(I)的化合物,其盐或溶剂合物
其中X1,X2和X3之一为>N-C(O)R,且其它两个独立地选自C,N和O,条件是它们二者不均为C,并且其中R选自任选地包含一个选自O和S的杂原子的C1-C15烃残基;
和
a)R1为H;且B表示一价残基(a)
或
b)R1选自
i)卤素,
ii)C6-C10芳基,其任选地被至多四个独立地选自下组的取代基取代:
卤素;OH(羟基);C≡N(氰基);NO2(硝基);
C1-C6烷基,其任选地包含至多5个卤素原子;
C1-C3烷基,其包含至多3个OH基团;
C2-C6烯基;
C1-C6烷氧基,其任选地包含至多3个卤素原子;
C1-C3烷氧基C1-C3烷基;
C3-C7环烷基;
-C(O)R10,其中R10选自C1-C3烷基;
-OC(O)R11,其中R11选自H和C1-C3烷基;
-C(O)O-R12,其中R12选自氢和C1-C3烷基;
-(CH2)mN(R13)R14,其中m为0或1,R13选自氢,C1-C3烷基和-SO2R15,其中R15为C1-C3烷基,且R14选自氢,C1-C3烷基和-SO2R16,其中R16为C1-C3烷基,或其中R13和R14与它们所连接的N原子一起形成吗啉,硫代吗啉或1,1-二氧代硫代吗啉;
-SR17,其中R17选自氢和C1-C3烷基;和
-S(O)2R18,其中R18选自氢和C1-C3烷基;
条件是,当芳基环被两个或更多个取代基取代时,两个取代基可以与它们所连接的碳原子一起形成环,和
iii)C5-C10单-或双环杂芳基,其中至多2个C原子被独立地选自硫,氮和氧的杂原子替代,所述杂芳基任选地被至多四个选自下组的取代基取代:
卤素;OH;C≡N;NO2;
C1-C6烷基,其任选地包含至多5个卤素原子;
C2-C6烯基;
C1-C6烷氧基,其任选地包含至多3个卤素原子;
C1-C3烷氧基C1-C3烷基;
C3-C7环烷基;
-C(O)R20,其中R20选自C1-C3烷基;
-OC(O)R21,其中R21选自H和C1-C3烷基;
-C(O)O-R22,其中R22选自氢和C1-C3烷基;
-(CH2)mN(R23)R24,其中m为0或1,R23选自氢,C1-C3烷基和-SO2R25,其中R25为C1-C3烷基,且R24选自氢,C1-C3烷基和-SO2R26,其中R26为C1-C3烷基,或其中R23和R24与它们所连接的N原子一起形成吗啉,硫代吗啉或1,1-二氧代硫代吗啉;
-SR27,其中R27选自氢和C1-C3烷基;和
-S(O)2R28,其中R28选自氢和C1-C3烷基;
和
B表示一价残基(b)
其中
R4,R5和R6与它们所连接的碳原子一起形成任选地包含至多五个选自O,N,S和F的杂原子的烃基;和
Z是C,S或S(O)。
6.消费品,包含一种或多种如在权利要求5中所定义的式(I)的化合物。
7.药物组合物,包含一种或多种如在权利要求5中所定义的式(I)的化合物。
8.如在权利要求5中所定义的式(I)的化合物,用于提供清凉感。
9.如在权利要求5中所定义的式(I)的化合物,用作药物。
10.包含清凉感的组合物,其中所述组合物包含如在权利要求5中所定义的式(I)的化合物。
11.根据权利要求10的组合物,包含至少一种式(I)的化合物,其盐或溶剂合物和另外的清凉化合物。
12.根据权利要求11的组合物,其中所述另外的清凉化合物选自薄荷醇,薄荷酮,对薄荷烷甲酰胺,N-2,3-三甲基-2-异丙基丁酰胺,乳酸薄荷酯,薄荷酮甘油缩醛,3-(1-薄荷氧基)-丙-1,2-二醇,对薄荷烷-3,8-二醇,异胡薄荷醇,琥珀酸单薄荷酯,戊二酸单薄荷酯,邻薄荷基甘油,N,N-二甲基琥珀酰胺酸薄荷酯,2-(仲丁基)环己-1-酮,N-(吡唑-3-基)-N-(噻吩-2-基甲基)-2-(对甲苯基氧基)乙酰胺,2-(4-乙基苯氧基)-N-(吡唑-3-基)-N-(噻吩-2-基甲基)乙酰胺,3-(苯并[d][1,3]二氧杂环戊二烯-5-基)-N,N-二苯基丙烯酰胺,4-(2-(4-烯丙基-2,6-二甲氧基苯氧基)-1-乙氧基丙基)-2-甲氧基苯酚,4-(2-(4-烯丙基-2,6-二甲氧基苯氧基)-1-((2-异丙基-5-甲基环己基)氧基)丙基)-2-甲氧基苯酚,N-(2-羟基-2-苯基乙基)-2-异丙基-5,5-二甲基环己烷-1-甲酰胺,N-(4-(氰基甲基)苯基)-2-异丙基-5,5-二甲基环己烷甲酰胺和N-(3-羟基-4-甲氧基苯基)-2-异丙基-5,5-二甲基环己烷甲酰胺。
13.在皮肤或黏膜上实现清凉效果的方法,包括水解权利要求1中所定义的式(I)的化合物的乙酰基(>N-C(O)R),得到式(I’)的化合物
其中X1,X2和X3之一为>NH,且其它两个独立地选自C,N和O,条件是它们二者不均为C;
和
a)R1为H;且B表示一价残基(a)
或
b)R1选自
i)卤素,
ii)C6-C10芳基,其任选地被至多四个独立地选自下组的取代基取代:
卤素;OH(羟基);C≡N(氰基);NO2(硝基);
C1-C6烷基,其任选地包含至多5个卤素原子;
C1-C3烷基,其包含至多3个OH基团;
C2-C6烯基;
C1-C6烷氧基,其任选地包含至多3个卤素原子;
C1-C3烷氧基C1-C3烷基;
C3-C7环烷基;
-C(O)R10,其中R10选自C1-C3烷基;
-OC(O)R11,其中R11选自H和C1-C3烷基;
-C(O)O-R12,其中R12选自氢和C1-C3烷基;
-(CH2)mN(R13)R14,其中m为0或1,R13选自氢,C1-C3烷基和-SO2R15,其中R15为C1-C3烷基,且R14选自氢,C1-C3烷基和-SO2R16,其中R16为C1-C3烷基,或其中R13和R14与它们所连接的N原子一起形成吗啉,硫代吗啉或1,1-二氧代硫代吗啉;
-SR17,其中R17选自氢和C1-C3烷基;和
-S(O)2R18,其中R18选自氢和C1-C3烷基;
条件是,当芳基环被两个或更多个取代基取代时,两个取代基可以与它们所连接的碳原子一起形成环,和
iii)C5-C10单-或双环杂芳基,其中至多2个C原子被独立地选自硫,氮和氧的杂原子替代,所述杂芳基任选地被至多四个选自下组的取代基取代:
卤素;OH;C≡N;NO2;
C1-C6烷基,其任选地包含至多5个卤素原子;
C2-C6烯基;
C1-C6烷氧基,其任选地包含至多3个卤素原子;
C1-C3烷氧基C1-C3烷基;
C3-C7环烷基;
-C(O)R20,其中R20选自C1-C3烷基;
-OC(O)R21,其中R21选自H和C1-C3烷基;
-C(O)O-R22,其中R22选自氢和C1-C3烷基;
-(CH2)mN(R23)R24,其中m为0或1,R23选自氢,C1-C3烷基和-SO2R25,其中R25为C1-C3烷基,且R24选自氢,C1-C3烷基和-SO2R26,其中R26为C1-C3烷基,或其中R23和R24与它们所连接的N原子一起形成吗啉,硫代吗啉或1,1-二氧代硫代吗啉;
-SR27,其中R27选自氢和C1-C3烷基;和
-S(O)2R28,其中R28选自氢和C1-C3烷基;
和
B表示一价残基(b)
其中
R4,R5和R6与它们所连接的碳原子一起形成任选地包含至多五个选自O,N,S和F的杂原子的烃基;和
Z是C,S或S(O)。
14.根据权利要求10-12之一的组合物,其用作瞬时受体电位通道melastatin成员8(TRPM8)的介体,所述组合物选自食品,饮料,口香糖,烟草和烟草替代产品,牙科护理产品,个人护理产品和私密护理产品。
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US5198220A (en) | 1989-11-17 | 1993-03-30 | The Procter & Gamble Company | Sustained release compositions for treating periodontal disease |
US5145666A (en) | 1991-10-23 | 1992-09-08 | The Proctor & Gamble Co. | Methods of reducing plaque and gingivitis with reduced staining |
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