CN117586241A - P2x3受体拮抗剂及其制备方法和应用 - Google Patents
P2x3受体拮抗剂及其制备方法和应用 Download PDFInfo
- Publication number
- CN117586241A CN117586241A CN202310991769.3A CN202310991769A CN117586241A CN 117586241 A CN117586241 A CN 117586241A CN 202310991769 A CN202310991769 A CN 202310991769A CN 117586241 A CN117586241 A CN 117586241A
- Authority
- CN
- China
- Prior art keywords
- compound
- pharmaceutically acceptable
- mmol
- group
- aryl
- 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
- 238000002360 preparation method Methods 0.000 title claims description 12
- 229940126202 P2X3 receptor antagonist Drugs 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 140
- 206010011224 Cough Diseases 0.000 claims abstract description 25
- 239000003814 drug Substances 0.000 claims abstract description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- 208000013116 chronic cough Diseases 0.000 claims abstract description 9
- 125000003118 aryl group Chemical group 0.000 claims description 27
- 150000003839 salts Chemical class 0.000 claims description 23
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 15
- 230000000155 isotopic effect Effects 0.000 claims description 14
- 239000002207 metabolite Substances 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 13
- 102100040460 P2X purinoceptor 3 Human genes 0.000 claims description 12
- 101710189970 P2X purinoceptor 3 Proteins 0.000 claims description 12
- 125000000623 heterocyclic group Chemical group 0.000 claims description 12
- 238000011282 treatment Methods 0.000 claims description 11
- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 8
- 238000006467 substitution reaction Methods 0.000 claims description 8
- 201000010099 disease Diseases 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 230000001404 mediated effect Effects 0.000 claims description 6
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 208000023504 respiratory system disease Diseases 0.000 claims description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
- 201000009273 Endometriosis Diseases 0.000 claims description 3
- 206010020853 Hypertonic bladder Diseases 0.000 claims description 3
- 208000009722 Overactive Urinary Bladder Diseases 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000001188 haloalkyl group Chemical group 0.000 claims description 3
- 208000020629 overactive bladder Diseases 0.000 claims description 3
- 208000009079 Bronchial Spasm Diseases 0.000 claims description 2
- 208000014181 Bronchial disease Diseases 0.000 claims description 2
- 206010006482 Bronchospasm Diseases 0.000 claims description 2
- 208000005171 Dysmenorrhea Diseases 0.000 claims description 2
- 206010013935 Dysmenorrhoea Diseases 0.000 claims description 2
- 208000002193 Pain Diseases 0.000 claims description 2
- 208000029082 Pelvic Inflammatory Disease Diseases 0.000 claims description 2
- 208000025609 Urogenital disease Diseases 0.000 claims description 2
- 206010046798 Uterine leiomyoma Diseases 0.000 claims description 2
- 208000006673 asthma Diseases 0.000 claims description 2
- 229940125890 compound Ia Drugs 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 201000010260 leiomyoma Diseases 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 208000005069 pulmonary fibrosis Diseases 0.000 claims description 2
- 210000002229 urogenital system Anatomy 0.000 claims description 2
- 208000035475 disorder Diseases 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000011321 prophylaxis Methods 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 10
- 230000000954 anitussive effect Effects 0.000 abstract description 4
- -1 glidants Substances 0.000 description 57
- 238000006243 chemical reaction Methods 0.000 description 46
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 46
- 238000012360 testing method Methods 0.000 description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 28
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 25
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- 235000002639 sodium chloride Nutrition 0.000 description 19
- 241000700159 Rattus Species 0.000 description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 238000001035 drying Methods 0.000 description 15
- 238000001914 filtration Methods 0.000 description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 14
- 239000011734 sodium Substances 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 11
- 238000004440 column chromatography Methods 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 238000002474 experimental method Methods 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 9
- 125000001424 substituent group Chemical group 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- GTQPEQGDLVSFJO-CXAGYDPISA-N 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-oxolan-3-yl]oxy-N-[(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]benzamide Chemical compound CC1=CN=C(S1)C=1C=C(C(=O)N[C@H](C)C=2C=NC(=NC=2)C(F)(F)F)C=C(C=1)O[C@H]1COCC1 GTQPEQGDLVSFJO-CXAGYDPISA-N 0.000 description 7
- 238000011534 incubation Methods 0.000 description 7
- 210000004185 liver Anatomy 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 6
- 230000002440 hepatic effect Effects 0.000 description 6
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 6
- 229910052760 oxygen Inorganic materials 0.000 description 6
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 5
- 239000005557 antagonist Substances 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- 125000002619 bicyclic group Chemical group 0.000 description 5
- 230000001684 chronic effect Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 230000002503 metabolic effect Effects 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 239000011591 potassium Substances 0.000 description 5
- 229910052700 potassium Inorganic materials 0.000 description 5
- 239000000523 sample Substances 0.000 description 5
- 241000894007 species Species 0.000 description 5
- 239000007821 HATU Substances 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- XJLXINKUBYWONI-NNYOXOHSSA-N NADP zwitterion Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-NNYOXOHSSA-N 0.000 description 4
- 102000004257 Potassium Channel Human genes 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 239000000556 agonist Substances 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000000796 flavoring agent Substances 0.000 description 4
- YNBADRVTZLEFNH-UHFFFAOYSA-N methyl nicotinate Chemical compound COC(=O)C1=CC=CN=C1 YNBADRVTZLEFNH-UHFFFAOYSA-N 0.000 description 4
- 230000003228 microsomal effect Effects 0.000 description 4
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 4
- 108020001213 potassium channel Proteins 0.000 description 4
- 230000002441 reversible effect Effects 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- HIHOEGPXVVKJPP-JTQLQIEISA-N 5-fluoro-2-[[(1s)-1-(5-fluoropyridin-2-yl)ethyl]amino]-6-[(5-methyl-1h-pyrazol-3-yl)amino]pyridine-3-carbonitrile Chemical compound N([C@@H](C)C=1N=CC(F)=CC=1)C(C(=CC=1F)C#N)=NC=1NC=1C=C(C)NN=1 HIHOEGPXVVKJPP-JTQLQIEISA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 235000001258 Cinchona calisaya Nutrition 0.000 description 3
- 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 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 229930195725 Mannitol Natural products 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 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 3
- 229930006000 Sucrose Natural products 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 125000002723 alicyclic group Chemical group 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 230000017531 blood circulation Effects 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 238000007405 data analysis Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 210000003722 extracellular fluid Anatomy 0.000 description 3
- 235000013355 food flavoring agent Nutrition 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 3
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 238000004949 mass spectrometry Methods 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- 125000002757 morpholinyl group Chemical group 0.000 description 3
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 3
- 235000001968 nicotinic acid Nutrition 0.000 description 3
- 239000011664 nicotinic acid Substances 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 3
- 125000003386 piperidinyl group Chemical group 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 229960000948 quinine Drugs 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 229940032147 starch Drugs 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 239000008399 tap water Substances 0.000 description 3
- 235000020679 tap water Nutrition 0.000 description 3
- 238000010998 test method Methods 0.000 description 3
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- COXVPYKZDDKVRF-ULQDDVLXSA-N (4,4-difluorocyclohexyl)methyl N-[(2S)-4-methyl-1-oxo-1-[[(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]pentan-2-yl]carbamate Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](C[C@@H]1CCNC1=O)C=O)NC(=O)OCC2CCC(CC2)(F)F COXVPYKZDDKVRF-ULQDDVLXSA-N 0.000 description 2
- UXKLQDCALAWFIU-VKNDCNMPSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-tetradecoxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@H](O)[C@H](C(O2)(C(O)=O)C(O)(C(O1)C(O)=O)C(O)=O)OCCCCCCCCCCCCCC)C1=CC=CC=C1 UXKLQDCALAWFIU-VKNDCNMPSA-N 0.000 description 2
- VGNCBRNRHXEODV-XXVHXNRLSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-6-dodecoxy-4,7-dihydroxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@H](O)[C@H](C(O2)(C(O)=O)C(O)(C(O1)C(O)=O)C(O)=O)OCCCCCCCCCCCC)C1=CC=CC=C1 VGNCBRNRHXEODV-XXVHXNRLSA-N 0.000 description 2
- VAVHMEQFYYBAPR-ITWZMISCSA-N (e,3r,5s)-7-[4-(4-fluorophenyl)-1-phenyl-2-propan-2-ylpyrrol-3-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound CC(C)C1=C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)C(C=2C=CC(F)=CC=2)=CN1C1=CC=CC=C1 VAVHMEQFYYBAPR-ITWZMISCSA-N 0.000 description 2
- MPQKYZPYCSTMEI-FLZPLBAKSA-N (r)-[(2s,4s,5r)-5-ethenyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methanol;dihydrate;hydrochloride Chemical compound O.O.Cl.C([C@H]([C@H](C1)C=C)C2)CN1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 MPQKYZPYCSTMEI-FLZPLBAKSA-N 0.000 description 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 2
- 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- JGMXNNSYEFOBHQ-OWOJBTEDSA-N 2-[(e)-4-morpholin-4-ylbut-2-enyl]-1,1-dioxothieno[3,2-e]thiazine-6-sulfonamide Chemical compound O=S1(=O)C=2SC(S(=O)(=O)N)=CC=2C=CN1C\C=C\CN1CCOCC1 JGMXNNSYEFOBHQ-OWOJBTEDSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- XDCOYBQVEVSNNB-UHFFFAOYSA-N 4-[(7-naphthalen-2-yl-1-benzothiophen-2-yl)methylamino]butanoic acid Chemical compound OC(=O)CCCNCc1cc2cccc(-c3ccc4ccccc4c3)c2s1 XDCOYBQVEVSNNB-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- QBXVXKRWOVBUDB-GRKNLSHJSA-N ClC=1C(=CC(=C(CN2[C@H](C[C@H](C2)O)C(=O)O)C1)OCC1=CC(=CC=C1)C#N)OCC1=C(C(=CC=C1)C1=CC2=C(OCCO2)C=C1)C Chemical compound ClC=1C(=CC(=C(CN2[C@H](C[C@H](C2)O)C(=O)O)C1)OCC1=CC(=CC=C1)C#N)OCC1=C(C(=CC=C1)C1=CC2=C(OCCO2)C=C1)C QBXVXKRWOVBUDB-GRKNLSHJSA-N 0.000 description 2
- 241000699802 Cricetulus griseus Species 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 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 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- TZYWCYJVHRLUCT-VABKMULXSA-N N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal Chemical compound CC(C)C[C@@H](C=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCC1=CC=CC=C1 TZYWCYJVHRLUCT-VABKMULXSA-N 0.000 description 2
- TZCCKCLHNUSAMQ-DUGSHLAESA-N NC(=O)C[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](Cc2ccc(F)cc2)NC(=O)[C@H](Cc3c[nH]c4ccccc34)NC(=O)Cc5cccs5)C(=O)N Chemical compound NC(=O)C[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](Cc2ccc(F)cc2)NC(=O)[C@H](Cc3c[nH]c4ccccc34)NC(=O)Cc5cccs5)C(=O)N TZCCKCLHNUSAMQ-DUGSHLAESA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 230000003185 calcium uptake Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 235000019438 castor oil Nutrition 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 150000002391 heterocyclic compounds Chemical class 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 210000001853 liver microsome Anatomy 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 2
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 210000001672 ovary Anatomy 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 235000021317 phosphate Nutrition 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 2
- 210000003370 receptor cell Anatomy 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 125000003107 substituted aryl group Chemical group 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 238000004885 tandem mass spectrometry Methods 0.000 description 2
- 125000003831 tetrazolyl group Chemical group 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 1
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 1
- KAFZOLYKKCWUBI-HPMAGDRPSA-N (2s)-2-[[(2s)-2-[[(2s)-1-[(2s)-3-amino-2-[[(2s)-2-[[(2s)-2-(3-cyclohexylpropanoylamino)-4-methylpentanoyl]amino]-5-methylhexanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]butanediamide Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CCC(C)C)C(=O)N[C@@H](CN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(N)=O)C(N)=O)C(=O)CCC1CCCCC1 KAFZOLYKKCWUBI-HPMAGDRPSA-N 0.000 description 1
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 1
- 239000001096 (4-ethenyl-1-azabicyclo[2.2.2]octan-7-yl)-(6-methoxyquinolin-4-yl)methanol hydrochloride Substances 0.000 description 1
- BIWQNIMLAISTBV-UHFFFAOYSA-N (4-methylphenyl)boronic acid Chemical compound CC1=CC=C(B(O)O)C=C1 BIWQNIMLAISTBV-UHFFFAOYSA-N 0.000 description 1
- QBTROWHSMGZXCV-RQURQNPSSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecoxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OCCCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 QBTROWHSMGZXCV-RQURQNPSSA-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
- JNPGUXGVLNJQSQ-BGGMYYEUSA-M (e,3r,5s)-7-[4-(4-fluorophenyl)-1,2-di(propan-2-yl)pyrrol-3-yl]-3,5-dihydroxyhept-6-enoate Chemical compound CC(C)N1C(C(C)C)=C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C1 JNPGUXGVLNJQSQ-BGGMYYEUSA-M 0.000 description 1
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- 125000004502 1,2,3-oxadiazolyl group Chemical group 0.000 description 1
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 description 1
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 1
- 125000004506 1,2,5-oxadiazolyl group Chemical group 0.000 description 1
- 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- FLBAYUMRQUHISI-UHFFFAOYSA-N 1,8-naphthyridine Chemical compound N1=CC=CC2=CC=CN=C21 FLBAYUMRQUHISI-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- WGIMXKDCVCTHGW-UHFFFAOYSA-N 2-(2-hydroxyethoxy)ethyl dodecanoate Chemical compound CCCCCCCCCCCC(=O)OCCOCCO WGIMXKDCVCTHGW-UHFFFAOYSA-N 0.000 description 1
- FKOKUHFZNIUSLW-UHFFFAOYSA-N 2-Hydroxypropyl stearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(C)O FKOKUHFZNIUSLW-UHFFFAOYSA-N 0.000 description 1
- KLFWJAAGXUDNIS-UHFFFAOYSA-N 2-bromo-4-methyl-1,3-thiazole Chemical group CC1=CSC(Br)=N1 KLFWJAAGXUDNIS-UHFFFAOYSA-N 0.000 description 1
- IMRWILPUOVGIMU-CDYZYAPPSA-N 2-bromopyridine Chemical group BrC1=CC=CC=[15N]1 IMRWILPUOVGIMU-CDYZYAPPSA-N 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- MIDXCONKKJTLDX-UHFFFAOYSA-N 3,5-dimethylcyclopentane-1,2-dione Chemical compound CC1CC(C)C(=O)C1=O MIDXCONKKJTLDX-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- 125000005986 4-piperidonyl group Chemical group 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical compound [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 description 1
- CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 229940125761 Compound 6g Drugs 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- UDIPTWFVPPPURJ-UHFFFAOYSA-M Cyclamate Chemical compound [Na+].[O-]S(=O)(=O)NC1CCCCC1 UDIPTWFVPPPURJ-UHFFFAOYSA-M 0.000 description 1
- 229920000858 Cyclodextrin Polymers 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-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
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- HSWVJQBEXRKOBZ-QGZVFWFLSA-N FC1=C(OC2CCN(CC2)C=2N=C3C(=NC=2N[C@H]2COCC2)CN(CC3)C(C)=O)C=CC(=C1)F Chemical compound FC1=C(OC2CCN(CC2)C=2N=C3C(=NC=2N[C@H]2COCC2)CN(CC3)C(C)=O)C=CC(=C1)F HSWVJQBEXRKOBZ-QGZVFWFLSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 241000282414 Homo sapiens Species 0.000 description 1
- 101001047090 Homo sapiens Potassium voltage-gated channel subfamily H member 2 Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010021639 Incontinence Diseases 0.000 description 1
- 208000029523 Interstitial Lung disease Diseases 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- 229930194542 Keto Natural products 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 241000195947 Lycopodium Species 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 244000246386 Mentha pulegium Species 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 235000004357 Mentha x piperita Nutrition 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- 102100022807 Potassium voltage-gated channel subfamily H member 2 Human genes 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical group [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 229920006243 acrylic copolymer Polymers 0.000 description 1
- 229920006397 acrylic thermoplastic Polymers 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000004442 acylamino group Chemical group 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229940023476 agar Drugs 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000005089 alkenylaminocarbonyl group Chemical group 0.000 description 1
- 125000005090 alkenylcarbonyl group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 description 1
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000004947 alkyl aryl amino group Chemical group 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 description 1
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 description 1
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 1
- 125000004691 alkyl thio carbonyl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000008122 artificial sweetener Substances 0.000 description 1
- 235000021311 artificial sweeteners Nutrition 0.000 description 1
- 125000005125 aryl alkyl amino carbonyl group Chemical group 0.000 description 1
- 125000005099 aryl alkyl carbonyl group Chemical group 0.000 description 1
- 125000001769 aryl amino group Chemical group 0.000 description 1
- 125000004658 aryl carbonyl amino group Chemical group 0.000 description 1
- 125000005129 aryl carbonyl group Chemical group 0.000 description 1
- 125000005199 aryl carbonyloxy group Chemical group 0.000 description 1
- 125000005110 aryl thio group Chemical group 0.000 description 1
- 125000005200 aryloxy carbonyloxy group Chemical group 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- 229940092782 bentonite Drugs 0.000 description 1
- 235000012216 bentonite Nutrition 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 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
- 230000004071 biological effect Effects 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 201000009267 bronchiectasis Diseases 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- NKWPZUCBCARRDP-UHFFFAOYSA-L calcium bicarbonate Chemical compound [Ca+2].OC([O-])=O.OC([O-])=O NKWPZUCBCARRDP-UHFFFAOYSA-L 0.000 description 1
- 229910000020 calcium bicarbonate Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 235000013736 caramel Nutrition 0.000 description 1
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- DCSUBABJRXZOMT-IRLDBZIGSA-N cisapride Chemical compound C([C@@H]([C@@H](CC1)NC(=O)C=2C(=CC(N)=C(Cl)C=2)OC)OC)N1CCCOC1=CC=C(F)C=C1 DCSUBABJRXZOMT-IRLDBZIGSA-N 0.000 description 1
- 229960005132 cisapride Drugs 0.000 description 1
- DCSUBABJRXZOMT-UHFFFAOYSA-N cisapride Natural products C1CC(NC(=O)C=2C(=CC(N)=C(Cl)C=2)OC)C(OC)CN1CCCOC1=CC=C(F)C=C1 DCSUBABJRXZOMT-UHFFFAOYSA-N 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 239000000625 cyclamic acid and its Na and Ca salt Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 230000006240 deamidation Effects 0.000 description 1
- 238000005238 degreasing Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- 125000004986 diarylamino group Chemical group 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 230000035622 drinking Effects 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 230000007831 electrophysiology Effects 0.000 description 1
- 238000002001 electrophysiology Methods 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 229940070277 eliapixant Drugs 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000007071 enzymatic hydrolysis Effects 0.000 description 1
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 206010016256 fatigue Diseases 0.000 description 1
- 238000013100 final test Methods 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 238000001917 fluorescence detection Methods 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 239000004088 foaming agent Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 235000012907 honey Nutrition 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical group O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- HOBCFUWDNJPFHB-UHFFFAOYSA-N indolizine Chemical compound C1=CC=CN2C=CC=C21 HOBCFUWDNJPFHB-UHFFFAOYSA-N 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- JFOZKMSJYSPYLN-QHCPKHFHSA-N lifitegrast Chemical compound CS(=O)(=O)C1=CC=CC(C[C@H](NC(=O)C=2C(=C3CCN(CC3=CC=2Cl)C(=O)C=2C=C3OC=CC3=CC=2)Cl)C(O)=O)=C1 JFOZKMSJYSPYLN-QHCPKHFHSA-N 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000028161 membrane depolarization Effects 0.000 description 1
- 238000010197 meta-analysis Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910001092 metal group alloy Inorganic materials 0.000 description 1
- VUQUOGPMUUJORT-UHFFFAOYSA-N methyl 4-methylbenzenesulfonate Chemical compound COS(=O)(=O)C1=CC=C(C)C=C1 VUQUOGPMUUJORT-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 229960001047 methyl salicylate Drugs 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 229960002900 methylcellulose Drugs 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 210000001589 microsome Anatomy 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- KVKFRMCSXWQSNT-UHFFFAOYSA-N n,n'-dimethylethane-1,2-diamine Chemical compound CNCCNC KVKFRMCSXWQSNT-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 239000000820 nonprescription drug Substances 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 210000004279 orbit Anatomy 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 238000012402 patch clamp technique Methods 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 125000005498 phthalate group Chemical class 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000004928 piperidonyl group Chemical group 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000259 polyoxyethylene lauryl ether Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940116317 potato starch Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940093625 propylene glycol monostearate Drugs 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 description 1
- 125000004940 pyridazin-4-yl group Chemical group N1=NC=C(C=C1)* 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 150000004040 pyrrolidinones Chemical class 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 238000005173 quadrupole mass spectroscopy Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 229960001811 quinine hydrochloride Drugs 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 235000019613 sensory perceptions of taste Nutrition 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229960001462 sodium cyclamate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical group [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000035923 taste sensation Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ISXSCDLOGDJUNJ-UHFFFAOYSA-N tert-butyl prop-2-enoate Chemical compound CC(C)(C)OC(=O)C=C ISXSCDLOGDJUNJ-UHFFFAOYSA-N 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000009210 therapy by ultrasound Methods 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 238000012384 transportation and delivery Methods 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000005591 trimellitate group Chemical group 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
Classifications
-
- 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
- C07D405/14—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 three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/14—Antitussive agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了具有镇咳活性的化合物，本发明还公开了本发明化合物或其药物组合在制备药物中的用途，该药物可在治疗慢性咳嗽方面发挥作用。
Description
技术领域
本发明属于医药化学领域，具体涉及一类新的具有镇咳活性的小分子化合物及其制备方法，以及这类化合物在治疗慢性咳嗽方面的用途。
背景技术
难治性咳嗽是以咳嗽为主诉，症状持续8周以上，常规治疗无效的慢性咳嗽。难治性咳嗽可以分为病因不明和病因清楚两类病因不明的难治性咳嗽是病因无法查明，或因病因少见；病因清楚者多见部分慢性间质性肺病、慢性阻塞性肺疾病、感染后咳嗽或支气管扩张症等患者。
全球社区成人慢性咳嗽患病率为7.6％～11.7％，亚洲为1.8％～7.4％，在咳嗽专家门诊，慢性难治性咳嗽患者占比20％～46％。
患有不明原因的慢性咳嗽患者的生活质量明显下降，身体上(例如疲劳、呼吸困难、睡眠障碍、失禁等)和心理上(易怒，沮丧和焦虑)的负面因素会促使慢性咳嗽患者向医生寻求帮助，目前虽然有许多治疗咳嗽的OTC药物，但meta分析基本无证据证明此类药物对难治性咳嗽的有效性，迄今为止，慢性难治性咳嗽患者的治疗选择极为有限，许多患者已经咳嗽多年没有得到缓解，因此，有必要确定慢性难治性咳嗽的有效治疗方法。
目前国内尚无获批用于治疗慢性难治性咳嗽的药物，但很多临床研究已证明P2X3拮抗剂对慢性咳嗽治疗有效，目前大多数咳嗽新药研发管线的新药都采用P2X3靶点进行开发。BAY1817080(eliapixant)是拜耳公司正在开发的一款P2X3拮抗剂，目前在全球处于II期临床开发阶段，该药物耐受性良好；拜耳公司目前在全球开展多项BAY1817080的临床试验，涉及的适应症包括子宫内膜异位、咳嗽、膀胱过动症等。国内专利CN202010852140.7，CN202011203843.3，CN202010777545.9，CN201880060205.5等专利也公开了一系列P2X3拮抗剂。
本发明提供了具有镇咳活性的P2X3拮抗剂，与其它已知化合物相比，本发明化合物具有较优的药代动力学特征和更高的安全性。
发明内容
本发明涉及一类具有镇咳活性的P2X3拮抗剂，具体涉及式(I)所示的化合物、其可药用盐、其代谢物、及其同位素衍生物，
其中R1为芳基或杂芳基，优选地为6-8元芳基或5-6元杂芳基，其中所述的芳基或杂芳基任选地被Ra取代；
Ra为卤素、-C1-3烷基或-C1-3卤代烷基；
R2为-O(CH2)nR3或-CH2R4；
R3和R4分别独立地为-C3-6环烷基或4-6元杂环基，其中所述的C3-6环烷基或4-6元杂环基任选地被Rb取代；
Rb为-H、-C1-3烷基或-C(O)-Rc；
Rc为-C1-3烷基或-C1-3烷氧基；
n为0或1。
在本发明的一些实施方式中，R1为
Ra为-C1-3烷基；
R3和R4分别独立地为在本发明的一些实施方式中，R1为/>在本发明的一些实施方式中，
R2为
在本发明的一些实施方式中，本发明的化合物、其可药用盐、其代谢物、及其同位素衍生物，选自如下化合物、其可药用盐、其代谢物、及其同位素衍生物：
本发明还提供了通式I所示的化合物的制备方法，可以是方案一或方案二，
方案一：
当R1为芳基时，化合物Ia与酸反应得到化合物Ib；化合物Ib和化合物Ic反应得到化合物Id；化合物Id在碱性条件下水解为化合物Ie；化合物Ie和化合物If反应得到化合物I；
方案二：
当R1为杂芳基时，化合物IIa与R1-X反应得到化合物IIb，其中X为卤素；化合物IIb在碱性条件下水解为化合物IIc；化合物IIc和化合物IId反应得到化合物I；
R1、R2具有如前所述的含义。
本发明还提供一种药物组合物，包括治疗有效量的式I所示化合物、其可药用盐、其代谢物、其同位素衍生物或它们的混合物，以及药学上可接受的载剂和/或稀释剂。
所含药学上可接受的载剂和/或稀释剂可以是一种或多种。
本发明还提供所述的式I所示化合物、其可药用盐、其代谢物、及其同位素衍生物或它们的混合物，或者所述的药物组合物在制备用于预防和/或治疗P2X3介导的疾病的药物中的用途。
在本发明的一些实施方式中，所述P2X3介导的疾病包括呼吸系统疾病、泌尿生殖系统疾病和疼痛。
在本发明的一些实施方式中，所述呼吸系统疾病为哮喘、支气管痉挛、肺纤维化、急性咳嗽或慢性咳嗽；所述泌尿生殖系统疾病为子宫内膜异位症、子宫肌瘤、痛经、盆腔炎性疾病及膀胱过动症。
本发明还提供治疗P2X3介导的疾病的方法，包括给需要这种治疗的患者施用治疗有效量的式I所示化合物、其可药用盐、其代谢物、其同位素衍生物或它们的混合物。
本发明所提供的药物组合物可以制备为任何形式，例如颗粒、粉末、片剂、包衣片剂、胶囊、药丸、糖浆、滴剂、溶液、混悬剂和乳剂，或者活性成分的缓释制剂，其中胶囊剂的实例包括硬或软明胶胶囊剂，颗粒剂和粉剂可以是非泡腾或泡腾形式。
本发明的药物组合物可进一步包括一种或多种医药或生理上可接受的载体,这些载体将适当配制以便于给药。例如，医药或生理上可接受的载体可以是盐水、热压水、林格氏液、缓冲盐水、葡萄糖、醇、蜂蜜、甘露醇、山梨醇、糊精、乳糖、焦糖、明胶、硫酸钙、硬脂酸镁、滑石粉、高岭土、甘油、吐温、琼脂、碳酸钙、碳酸氢钙、表面活性剂、环糊精及其衍生物、磷脂类、磷酸盐类、淀粉类及其衍生物、硅衍生物、纤维素类及其衍生物、吡咯烷酮类、聚乙二醇类、丙烯酸树脂类、酞酸酯类、丙烯酸共聚物、苯三酸酯类中的一种或几种。
本发明的药物组合物还可以包括医药或生理上可接受的添加剂，例如稀释剂、润滑剂、粘合剂、助流剂、崩解剂、甜味剂、矫味剂、湿润剂、分散剂、表面活性剂、溶剂、涂层剂、发泡剂、或芳香剂。
可以使用的稀释剂的实例包括但不限于乳糖、蔗糖、淀粉、盐、甘露糖醇和磷酸二钙；润滑剂的实例包括但不限于滑石、淀粉、镁或钙的硬脂酸盐、石松子和硬脂酸；粘合剂的实例包括但不限于微晶纤维素、黄蓍胶、葡萄糖溶液、阿拉伯胶浆、明胶溶液、蔗糖和淀粉糊；助流剂的实例包括但不限于胶体二氧化硅；崩解剂的实例包括但不限于交联羧甲基纤维素钠、淀粉羟乙酸钠、藻酸、玉米淀粉、马铃薯淀粉、膨润土、甲基纤维素、琼脂和羧甲基纤维素；甜味剂的实例包括但不限于蔗糖、乳糖、甘露糖醇和人工甜味剂，例如环磺酸钠和糖精，和任意数量的喷雾干燥矫味剂；矫味剂的实例包括但不限于从植物提取的天然矫味剂,例如果实，和味道较好的化合物，例如但不限于薄荷和水杨酸甲酯；湿润剂的实例包括但不限于丙二醇一硬脂酸酯、脱水山梨醇一油酸酯、二甘醇一月桂酸酯和聚氧乙烯月桂基醚。
本发明的药物组合物可以根据传统方法来通过各种途径给药，包括灌胃、静脉内、动脉内、腹腔内、胸腔内、透皮、鼻腔、吸入、直肠、眼部和皮下导入。
本发明所提供的化合物一般的剂量范围为约每天0.05mg/Kg至1000mg/kg，优选为约1mg/kg至100mg/kg，更优选为约1至50mg/kg，药物组合物的剂量范围为以其含有的上述化合物的量来计算。
具体实施方式
定义和说明
除非另外定义，否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。
除非另有说明，否则采用本领域技术范围内的常规方法，如质谱、NMR、和药理学方法。除非提出具体定义，否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送，以及对患者的治疗中使用标准技术。例如，可利用厂商对试剂盒的使用说明，或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述，按照本领域熟知的常规方法实施上述技术和方法。
术语“被取代的”是指所指定原子或基团上的任一或多个氢被指定基团的选择替代，条件为不超过所指定原子的正常价态。当取代基是氧代或酮基(即＝O)时，则所述原子上的2个氢被替代。
取代基和/或变量的组合仅在这些组合产生稳定化合物或可用的合成的中间体时才允许。稳定化合物或稳定结构是指足够稳定以经受自反应混合物以有用的纯度分离出并随后配制成有效治疗药物的化合物。
在本发明中，“任选”或“任选地”表示随后描述的事件或状况可能发生也可能不发生，且该描述同时包括该事件或状况发生和不发生的情况。“任选被取代”是指具有0个、1个、2个或更多个取代基的基团。本领域技术人员应理解，对于含有一或多个取代基的任何基团而言，这些基团可以相同或不相同，并且这些基团不会引入任何立体上不合实际、合成上不可行和/或固有地不稳定的取代或取代模式。例如，“任选地被取代的芳基”表示芳基被取代或未被取代，且该描述同时包括被取代的芳基与未被取代的芳基。
术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之，所述术语也包括“基本上由…构成”、或“由…构成”。
除非具体指明，否则本文中化合物在其范围内涵盖化合物、其可药用盐、其代谢物及其同位素衍生物，本发明化合物在其范围内还涵盖其立体异构体、及多晶型物、溶剂合物、前药。
除非具体指明，否则本文中立体异构体在其范围内涵盖互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、及其混合物形式。
术语“代谢物”指即在给药本发明的化合物时体内形成的物质。例如被给药的化合物的氧化、还原、水解、酰胺化、脱酰胺化、酯化、脱脂化、酶解等产生的化合物。
术语“同位素衍生物”指化合物中一个或多个原子被其同位素(具有相同原子序数但原子质量或质量数不同于在自然界中占优势的原子质量或质量数的原子)替代的衍生物。同位素的实例包括但不限于，氢的同位素(例如2H、3H)、碳的同位素(例如11C、13C及14C)、氟的同位素(例如18F)、氮的同位素(例如13N及15N)、氧的同位素(例如15O、17O及18O)。
术语“芳基”为具有至少一个含指定环体系碳原子数的一价芳香性或部分芳香性的单环、双环或三环取代基；例如“6-8元芳基”应理解为具有6-8个碳原子的一价芳香性或部分芳香性的单环、双环或三环取代基；特别是具有6个碳原子的环(“C6芳基”)，例如苯基；当所述6-8元芳基被取代时，其可以为单取代或者多取代。并且，对其取代位点没有限制，例如可以为邻位、对位或间位取代。
在本发明的一些实施例中，6-8元芳基为苯基，其可以为甲基取代，例如对甲苯基、邻位甲苯基或间甲苯基。
术语“烷基”或”亚烷基”是指包括具有指定碳原子数的支链和直链饱和脂肪族烃基。例如，“C1-C10烷基”(或亚烷基)是指包括C1、C2、C3、C4、C5、C6、C7、C8、C9和C10烷基。另外，例如，“C1-C6烷基”表示具有1至6个碳原子的烷基。烷基可以是未被取代的或被取代的，从而使它的一或多个氢被另一化学基团替代。烷基的实例包括但不限于，甲基(Me)、乙基(Et)、丙基(例如，正丙基和异丙基)、丁基(例如，正丁基、异丁基、叔丁基)、戊基(例如，正戊基、异戊基、新戊基)、己基(例如，正己基、异己基)等。术语“C1-3烷基”是指包含1至3个碳原子的烷基，具体指甲基、乙基、正丙基及异丙基。
术语“卤素(halo或halogen)”是指氯、溴、氟和碘。
术语“卤代烷基”是指具有一或多个卤素取代基的被取代的烷基。例如，“氟代甲基”包括CF3、CHF2、CH2F。
术语“烷氧基”(alkyloxy)是指本文所定义的烷基和氧原子连接形成的取代基。C1-3烷氧基指包含1至3个碳原子的烷氧基，例如，甲氧基、乙氧基、丙氧基和异丙氧基。
术语“环烷基”是指环化的烷基，包括单环、二环或多环体系，其中单环、二环或多环体系的环不包含芳香环。所述环烷基基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。
C3-6环烷基是指包含3至6个碳原子的环烷基。例如，环丙基、环丁基、环戊基、环己基等。术语“杂环”或“杂环基”具有相同的含义，是指包含至少一个环杂原子(例如，氮原子、氧原子或硫原子)的任何环结构(饱和的、不饱和的或芳族的)。杂环包括“脂杂环”和“芳杂环”。
在本发明的一些实施例中，杂环基为4-6元杂环基，其实例包括但不限于，呋喃基、咪唑烷基、咪唑啉基、咪唑基、异喹啉基、噻唑基、异噻唑基、异恶唑基、亚甲二氧基苯基、吗啉基、恶唑烷基、恶唑基、恶二唑基、1,2,3-恶二唑基、1,2,4-恶二唑基、1,2,5-恶二唑基、1,3,4-恶二唑基、1,2,4-恶二唑5(4H)-酮基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶基、嘧啶基、吡咯烷基、吡咯啉基、2H-吡咯基、吡咯基、四氢呋喃基、四唑基、噻吩基、四氢噻吩、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基、氧杂环丁烷、氮杂环丁烷。术语“脂杂环”或“脂杂环基”具有相同的含义，是指没有芳香特征的杂环化合物，例如，氧杂环丁烷、氮杂环丁烷、吡咯烷基、2H-吡咯基、四氢呋喃基、吗啉基、哌啶基。
在本发明的一些实施例中，4-6元杂环基为四氢呋喃基、吗啉基或哌啶基。
术语“芳杂环”、“芳杂环基”、“杂芳基”或“杂芳环基”具有相同的含义，是指有芳香特征的杂环化合物，包括单杂环芳基和稠杂环芳基。所述杂原子独立地选自氮、氧和硫，氮原子可以被取代或不被取代，氮和硫杂原子可任选被氧化(即，N→O和S(O)p，其中p＝1或2)，芳杂环中硫和氧原子的总数不超过1。
在本发明的一些实施方式中，单杂环芳基可以是5-6元杂芳基，其可以包含1-4个杂原子，例如吡咯、呋喃、噻吩、噻唑、异噻唑、咪唑、三唑、四唑、吡唑、噁唑、异噁唑、吡啶、吡嗪、哒嗪和嘧啶等。
典型的5-6元杂芳基包括但不限于，2-或3-噻吩基；2-或3-呋喃基；2-或3-吡咯基；2-、4-或5-咪唑基；3-、4-或5-吡唑基；2-、4-或5-噻唑基；3-、4-或5-异噻唑基；2-、4-或5-唑基；3-、4-或5-异唑基；3-或5-1，2，4-三唑基；4-或5-1，2，3-三唑基；四唑基；2-、3-或4-吡啶基；3-或4-哒嗪基；3-、4-或5-吡嗪基；2-吡嗪基；2-、4-或5-嘧啶基。
在本发明的一些实施方式中，5-6元杂芳基为任选地被甲基取代的噻唑基或吡啶基，例如4-甲基噻唑基、5-甲基噻唑基、邻甲基吡啶基、间甲基吡啶基或对甲基吡啶基。
在本发明的一些实施方式中，稠杂环芳基可以是三环、二环，例如苯并唑、苯并二唑、苯并噻唑、苯并咪唑、苯并噻吩、亚甲二氧基苯基、喹啉、异喹啉、萘啶、吲哚、苯并呋喃、嘌呤、苯并呋喃、脱氮嘌呤或中氮茚。
“杂芳基”的芳环可以在一个或多个环位置上被上文所述的取代基取代，例如卤素、羟基、烷氧基、烷基羰基氧基、芳基羰基氧基、烷氧基羰基氧基、芳基氧基羰基氧基、羟基羰基、烷基羰基、烷基氨基羰基、芳基烷基氨基羰基、烯基氨基羰基、烷基羰基、芳基羰基、芳基烷基羰基、烯基羰基、烷氧基羰基、氨基羰基、烷硫基羰基、磷酸酯、膦酸酯、氰基、氨基(包括烷基氨基、二烷基氨基、芳基氨基、二芳基氨基和烷基芳基氨基)、酰基氨基(包括烷基羰基氨基、芳基羰基氨基、氨基甲酰基和脲基)、脒基、亚氨基、巯基、烷硫基、芳硫基、羟基硫代羰基、硫酸酯、烷基亚磺酰基、磺酸酯基、氨磺酰基、磺酰氨基、硝基、三氟甲基、氰基、叠氮基、杂环基、烷基芳基，或芳族基团或杂芳族基团，其中芳基基团也可以与非芳族的脂环或杂环稠合或桥连，以形成多环(例如四氢萘)。
术语“可药用盐”、“药用盐”和“药用可接受的盐”、“药学上可接受的盐”可互换，其包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的，与无机酸或有机酸所形成的盐。无机酸盐例如盐酸盐、氢溴酸盐等；有机酸盐例如甲酸盐、乙酸盐等。
在本发明的化合物分子中包含至少一个可成盐的氮原子时，可以通过在有机溶剂如乙腈、四氢呋喃中与相应的有机酸或无机酸反应，从而转化为相应的盐。典型的有机酸有甲酸、乙酸，典型的无机酸有盐酸、氢溴酸。
通过以下实施例进一步举例描述本发明，这些方案是说明性的，并不以任何方式限制本发明。对本发明所作的本领域普通技术人员容易实现的任何改动或改变都将落入本发明的范围内。
本发明中使用的缩写具有本领域常规含义，例如以下缩写的含义如下：
本发明中“烟酸“、”尼古丁酸”“吡啶-3-羧酸”具有相同的含义。
化合物的制备方法
实施例1
6-羰基-5-(((R)-四氢呋喃-3-基)氧代)-1-(p-甲苯基)-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-1,6-二氢吡啶-3-甲酰胺1
第一步甲基(R)-6-甲氧基-5-((四氢呋喃-3-基)氧代)尼古丁酸甲酯1c
将化合物1a(2.00g，10.9mmol)溶于DMF(20mL)中，加入化合物1b(3.17g,13.1mmol)和Cs2CO3(7.10g,21.8mmol)。90℃反应3小时。LCMS显示反应完全。加水(100mL)，EA(100mL×3)萃取。合并有机相，饱和食盐水(100mL)洗涤，无水Na2SO4干燥，过滤，浓缩。残余物柱层析(PE/EA＝100/1至1/100)得1c(2.10g)。
LCMS(ESI-MS)m/z:254.1(M+H+).
第二步甲基(R)-6-羟基-5-((四氢呋喃-3-基)氧代)尼古丁酸甲酯1d
将化合物1c(2.10g,8.30mmol)溶于THF(15.0mL)中，加入浓HCl(30.0mL)。50℃反应24小时。LCMS显示反应完全。加水(100mL)，用NaHCO3水溶液调节pH至7-8，DCM(100mL×3)萃取。合并有机相，饱和食盐水(100mL)洗涤，无水Na2SO4干燥，过滤，浓缩得化合物1d(1.60g)。
LCMS(ESI-MS)m/z:240.1(M+H+).
第三步甲基(R)-6-羰基-5-((四氢呋喃-3-基)氧代)-1-(p-苯甲基)-1,6-二氢吡啶-3-羧酸酯1f
将化合物1d(0.24g，1.00mmol)溶于DCM(5mL)中，加入化合物1e(0.16g，1.2mmol)，吡啶(0.16g,2.00mmol)和Cu(AcO)2(0.40g,2.00mmol)。室温反应2小时。LCMS显示反应完全。加水(20mL)，DCM(20mL×3)萃取。合并有机相，饱和食盐水(20mL)洗涤，无水Na2SO4干燥，过滤，浓缩。残余物柱层析(DCM/MeOH＝100/1至10/1)得化合物1f(0.18g)。
LCMS(ESI-MS)m/z:330.2(M+H+).
第四步(R)-6-羰基-5-((四氢呋喃-3-基)氧代)-1-(p-苯甲基)-1,6-二氢吡啶-3-羧酸1g
将化合物1f(0.18g，0.55mmol)溶于THF(2mL)中，加入溶有LiOH(65mg，2.74mmol)的水溶液(2.00mL)。常温反应过夜。LCMS显示反应完全。加水(10mL)，用2N HCl的水溶液调节pH至5-6，DCM(10mL×3)萃取。合并有机相，饱和食盐水(10mL)洗涤，无水Na2SO4干燥，过滤，浓缩至干燥后得化合物1g(0.15g)。
LCMS(ESI-MS)m/z:316.2(M+CH3 +).
第五步6-羰基-5-(((R)-四氢呋喃-3-基)氧代)-1-(p-甲苯基)-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-1,6-二氢吡啶-3-甲酰胺1
将化合物1g(0.15g，0.47mmol)溶于DMF(5.0mL)中，加入化合物1h(90mg，0.47mmol)，HATU(0.22g，0.57mmol)和DIEA(0.12g，0.95mmol)。室温反应2小时。LCMS显示反应完全。反应液无需后处理，直接浓缩后，残余物反相柱层析制备得白色固体化合物1(69mg)。
LCMS(ESI-MS)m/z:489.3(M+H+).
1H NMR(400MHz,CDCl3)δ8.95(s,2H),8.59(brs,1H),7.77(s,1H),7.00–6.77(m,5H),5.32(s,1H),4.71(s,1H),3.66–3.02(m,4H),2.03-1.88(m,5H),1.62(d,J＝6.8Hz,3H).
实施例2
1-(5-甲基噻唑-2-基)-6-羰基-5-(((R)-四氢呋喃-3-基)氧代)-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-1,6-二氢吡啶-3-甲酰胺2
第一步甲基(R)-1-(5-甲基噻唑-2-基)-6-羰基-5-((四氢呋喃-3-基)氧代)-1,6-二氢吡啶-3-羧酸甲酯2c
将化合物1d(0.20g，0.83mmol)溶于dioxane(5mL)中，加入化合物2a(0.15g，0.83mmol)，CuI(32mg,0.17mmol)，N,N’-二甲基乙二胺(15mg,0.17mmol)和Cs2CO3(0.54g,1.67mmol)。N2保护下回流反应3小时。LCMS显示反应完全。加水(20mL)，DCM(20mL×3)萃取。合并有机相，饱和食盐水(20mL)洗涤，无水Na2SO4干燥，过滤，浓缩。残余物柱层析(DCM/MeOH＝100/1至10/1)得化合物2b(0.12g)。
LCMS(ESI-MS)m/z:337.2(M+H+).
第二步(R)-1-(5-甲基噻唑-2-基)-6-羰基-5-((四氢呋喃-3-基)氧代)-1,6-二氢吡啶-3-羧酸2c
将化合物2b(0.12g，0.35mmol)溶于THF(1mL)中，加入溶有LiOH(42mg，1.78mmol)的水溶液(1.00mL)。常温反应过夜。LCMS显示反应完全。加水(5mL)，用2N HCl的水溶液调节pH至5-6，DCM(5mL×3)萃取。合并有机相，饱和食盐水(10mL)洗涤，无水Na2SO4干燥，过滤，浓缩至干燥后得化合物2c(0.10g)。
LCMS(ESI-MS)m/z:323.1(M+H+).
第三步1-(5-甲基噻唑-2-基)-6-羰基-5-(((R)-四氢呋喃-3-基)氧代)-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-1,6-二氢吡啶-3-甲酰胺2
将化合物2c(0.10g，0.31mmol)溶于DMF(2.0mL)中，加入化合物1h(59mg，0.31mmol)，HATU(0.14g，0.37mmol)和DIEA(80mg，0.62mmol)。室温反应2小时。LCMS显示反应完全。反应液无需后处理，直接浓缩后，残余物反相柱层析制备得化合物2(31mg)。
LCMS(ESI-MS)m/z:496.3(M+H+).
1H NMR(400MHz,CDCl3)δ8.96(s,2H),8.92(d,J＝1.2Hz,1H),7.31(d,J＝1.2Hz,1H),7.10(d,J＝1.6Hz,1H),6.90(d,J＝5.2Hz,1H),5.33(t,J＝5.2Hz,1H),4.98(s,1H),4.03–3.89(m,4H),2.49(d,J＝0.8Hz,3H),2.26–2.19(m,2H),1.74(d,J＝6.0Hz,3H).
实施例3
1-(4-甲基噻唑-2-基)-6-氧代-5-((R)-四氢呋喃-3-氧基)-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-1,6-二氢吡啶-3-甲酰胺3
按照实施例2的方法，以2-溴-4-甲基噻唑替代2a可得化合物3。
LCMS(ESI-MS)m/z:496.2(M+H+).
1H NMR(400MHz,CDCl3)δ8.98(s,2H),7.09(s,1H),7.03(brs,1H),6.89(s,1H),5.34–5.32(m,1H),4.98(s,1H),4.00–3.88(m,4H),2.43(s,3H),2.25–2.18(m,2H),1.76(d,J＝6.8Hz,3H).
实施例4
5'-甲基-2-羰基-3-(((R)-四氢呋喃-3-基)氧代)-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-2H-[1,2'-联吡啶]-5-甲酰胺4
按照实施例2的方法，以2-溴吡啶替代2a可得化合物4。
LCMS(ESI-MS)m/z:490.3(M+H+).
1H NMR(400MHz,CDCl3)δ8.93(s,2H),8.30(s,1H),8.01(s,1H),7.80–7.73(m,2H),7.54(brs,1H),7.01(s,1H),5.29(s,1H),4.94(s,1H),3.96–3.88(m,4H),2.40(s,3H),2.22–2.09(m,2H),1.66(d,J＝6.8Hz,3H).
实施例5
5-(((R)-4-甲基吗啉-2-基)甲氧基)-6-氧代-1-(对甲苯基)-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-1,6-二氢吡啶-3-甲酰胺5
第一步((R)-4-甲基吗啉-2-基)甲基-4-甲基苯磺酸酯5b
将化合物5a(2.0g，15mmol)溶于DCM(30mL)中，依次加入化合物TsCl(4.4g，23mmol)，DMAP(366mg,3mmol)和DIEA(3.9g,30mmol)。N2保护下室温反应过夜。LCMS显示反应完全。加aq.NaHCO3(20mL)淬灭，EA(20mL×3)萃取。合并有机相，饱和食盐水(20mL)洗涤，无水Na2SO4干燥，过滤，浓缩。残余物柱层析(PE/EA＝1/0至0/1)得化合物5b(3.6g)。
LCMS(ESI-MS)m/z:286.1(M+H+).
第二步6-甲氧基-5-(((R)-4-甲基吗啉-2-基)甲氧基)烟酸甲酯5c
将化合物5b(3.4g，12mmol)和化合物1a(1.8g，10mmol)溶于DMF(20mL)中，加入Cs2CO3(6.5g，20mmol)。N2保护下90℃反应3h。LCMS显示反应完全。加水(20mL)，EA(20mL×3)萃取。合并有机相，饱和食盐水(20mL)洗涤，无水Na2SO4干燥，过滤，浓缩。残余物柱层析(PE/EA/EtOH＝1/0/0至0/1/0.2)得化合物5c(4.7g)。
LCMS(ESI-MS)m/z:297.2(M+H+).
第三步6-羟基-5-(((R)-4-甲基吗啉-2-基)甲氧基)烟酸甲酯5d
将化合物5c(4.7g，16mmol)溶于THF(30mL)中，加入conc.HCl(60mL)。50℃反应3小时。LCMS显示反应完全。反应用aq.NaHCO3调节pH至7，EA(20mL×2)萃取洗去杂质。水相直接冻干，粗品再用DCM/MeOH(10:1)打浆，过滤，滤液旋干，得化合物5d(5.0g)。
LCMS(ESI-MS)m/z:283.1(M+H+).
第四步5-(((R)-4-甲基吗啉-2-基)甲氧基)-6-氧代-1-(对甲苯基)-1,6-二氢吡啶-3-羧酸甲酯5e
将化合物5d(2.0g，7.1mmol)溶于DCM(30mL)中，依次加入化合物TolB(OH)2(1.2g，8.5mmol)，Py.(1.1mL,14.2mmol)和Cu(OAc)2(2.8g,14.2mmol)。敞口室温反应7小时。LCMS显示反应完全。反应经Celite过滤，EA洗涤。浓缩，残余物柱层析(EA/EtOH＝4:1)得化合物5e(1g)。
LCMS(ESI-MS)m/z:373.2(M+H+).
第五步5-(((R)-4-甲基吗啉-2-基)甲氧基)-6-氧代-1-(对甲苯基)-1,6-二氢吡啶-3-羧酸5f
将化合物5e(1g，2.7mmol)溶于THF(10mL)中，加入溶有LiOH(324mg，13.5mmol)的水溶液(10mL)。常温反应过夜。LCMS显示反应完全。加水(10mL)，用2N HCl的水溶液调节pH至5-6，DCM(10mL×3)萃取。合并有机相，饱和食盐水(10mL)洗涤，无水Na2SO4干燥，过滤，浓缩至干燥后得化合物5f(0.9g)。
LCMS(ESI-MS)m/z:359.2(M+H+).
第六步5-(((R)-4-甲基吗啉-2-基)甲氧基)-6-氧代-1-(对甲苯基)-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-1,6-二氢吡啶-3-甲酰胺5
将化合物5f(359mg，1mmol)溶于DMF(5mL)中，再依次加入化合物1h(248mg，1.3mmol)，HATU(456mg，1.2mmol)和DIEA(258mg，2.0mmol)。室温反应2小时。LCMS显示反应完全。反应液无需后处理，直接浓缩后，残余物反相柱层析制备得化合物5(140mg)。
LCMS(ESI-MS)m/z:532.3(M+H+).
1H NMR(400MHz,d6-DMSO)δ9.84(brs,1H),9.06(s,2H),8.76–8.74(m,1H),8.09–8.08(m,1H),7.37–7.29(m,4H),5.22–5.16(m,1H),4.11–4.02(m,4H),3.74–3.68(m,1H),3.55–3.52(m,1H),3.07–3.00(m,3H),2.86(s,3H),2.39(s,3H),1.54(d,J＝8Hz,3H).
实施例6
甲基3-((2-羰基-1-(p-苯甲基)-5-(((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)氨基甲酰)-1,2-二氢吡啶-3-基)甲基)哌啶-1-羧酸酯6
/>
第一步叔丁基-(E)-3-(溴亚甲基)哌啶-1-羧酸酯6c
将化合物6b(23.01g，52.76mmol)溶于THF(100mL)中，在零下20度左右缓慢滴价LiHMDS(52.76ml,52.76mmol),滴完后在零下20度下搅拌三十分钟，再滴加加入化合物6a(10g，50.2mmol)的THF溶液，缓慢升到室温搅拌2小时，加水和EA萃取，有机相水洗，饱和食盐水洗，无水Na2SO4干燥，过滤，浓缩。残余物柱层析(PE：EA＝10/1至10/1)得化合物6c(10.5g)。
LCMS(ESI-MS)m/z:220.1(M-55).
第二步叔丁基-(E)-3-((4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)亚甲基)哌啶-1-羧酸酯6d
将化合物6c(10.0g，36.3mmol)溶于DMSO(60mL)中，加入双联硼酯(18.4g，72.7,mmol)，Pd(Dppf)Cl2(2.65g,3.63mmol),P(Cy)3(2.035g,7.26mmol),KOAc(10.68g,108.9mmol),氮气保护，90℃加热反应2小时，送LC-MS检测，反应完毕。加水，用EA萃取，饱和食盐水洗涤，无水Na2SO4干燥，过滤，浓缩过Flash柱(PE：EA＝10/1至10/1)得化合物6d(17g)。
LCMS(ESI-MS)m/z:324.23(M+H+).
第三步甲基-(Z)-5-((1-(叔-丁氧基羰基)哌啶-3-亚基)甲基)-6-甲氧基尼古丁酸酯6f
将化合物6d(13.18g，40.8mmol)、6e(10.0g，40.8mmol)溶于Dioxane(6.0mL)和水(20ml)中，加入化合物Pd(Dppf)Cl2(2.98g,4.08mmol)，Cs2CO3(26.5g，81.6mmol)氮气保护，100℃反应2小时。LCMS显示反应完全。加水，用EA萃取，饱和食盐水洗涤，无水Na2SO4干燥，过滤，滤液浓缩，过Flash柱(PE：EA＝6/1)得化合物6f(5.5g)。
LCMS(ESI-MS)m/z:363.2(M+H+).
第四步甲基-5-((1-(叔-丁氧基羰基)哌啶-3-基)甲基)-6-甲氧基尼古丁酸酯6g
将化合物6f(5.5g，15.19mmol)溶于乙醇(35mL)中，加入化合物钯碳(1.0g)，氢气保护，室温反应过夜。LCMS显示反应完全后，过滤，滤液旋干得到目标化合物6g(5.0g)。
LCMS(ESI-MS)m/z:365.2(M+H+).
第五步甲基-6-羟基-5-(哌啶-3-基甲基)尼古丁酸酯6h
将化合物6g(2.5g，6.87mmol)溶于乙腈(10.0mL)中，加入化合物TMSCl(3.57g,34.34mmol)，NaI(5.12g，34.34mmol)室温反应过夜，LCMS显示反应完全。加水，用EA萃取，水相旋干，加入甲醇，过滤，滤液浓缩得化合物6h(3g，粗品)。
LCMS(ESI-MS)m/z:251.1.(M+H+).
第六步甲基6-羟基-5-(1-(甲酸甲酯)哌啶-3-基)甲基)尼古丁酸酯6j
将化合物6h(3g，粗品)溶于THF(20.0mL)中，加入化合物6i(1.21g,7.96mmol),DIPEA(3.3g,25.58mmol)，70℃反应4小时。LCMS显示反应完全。加水，用EA萃取，饱和食盐水洗涤，无水Na2SO4干燥，过滤，浓缩过Flash柱(PE：(EA/EtOH＝3:1)＝1/1)得化合物6j(1.0g)。
LCMS(ESI-MS)m/z:309.2(M+H+).
第七步甲基5-((1-(甲酸甲酯)哌啶-3-基)甲基)-6-羰基-1-(p-苯甲基)-1,6-二氢吡啶-3-羧酸酯6k
将化合物6j(308g，1mmol)溶于DCM(4.0mL)中，加入化合物对甲苯硼酸(272mg,2mmol),Cu(OAC)2(400mg,2mmol)，吡啶(0.4ml),室温搅拌过夜，剩余30％左右的原料，加硅胶，旋干，过Flash柱(PE：(EA/EtOH＝3:1)＝3/1)得化合物6k(250mg)。
LCMS(ESI-MS)m/z:399.2(M+H+).
第八步5-(1-(甲酸甲酯)哌啶-3-基)甲基)-6-羰基-1-(p-苯甲基)-1,6-二氢吡啶-3-羧酸6l
将化合物6k(250mg，0.63mmol)溶于THF(2.0mL)中，加入化合物2N NaOH(2ml)室温搅拌过夜,用2N HCl调pH至6，用EA萃取，有机相旋干，过Flash柱(PE：(EA/EtOH＝3:1)＝1/1)得化合物6l(220mg)。
LCMS(ESI-MS)m/z:385.2(M+H+).
第九步甲基3-((2-羰基-1-(p-苯甲基)-5-(((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)氨基甲酰)-1,2-二氢吡啶-3-基)甲基)哌啶-1-羧酸酯6
将化合物6l(220mg，0.55mmol)溶于DMF(2.0mL)中，加入化合物1h(150mg,0.66mmol),HATU(313mg,0.825mmol)DIPEA(142mg,1.2mmol)，室温搅2小时，送LC-MS检测反应完毕，反应液无需后处理，直接浓缩后残余物反相柱层析制备得化合物6(112mg)。
LCMS(ESI-MS)m/z:558.3(M+H+).
1H NMR(400MHz,DMSO-d6)δ9.06(s,2H),8.71(d,J＝6.8Hz,1H),8.30–8.23(m,1H),7.75(d,J＝2.6Hz,1H),7.33(s,4H),5.20(p,J＝7.1Hz,1H),3.76(d,J＝13.5Hz,2H),3.55-3.30(m,5H),2.81(t,J＝12.0Hz,1H),2.40-2.20(m,4H),1.79-1.50(m,6H),1.34–1.10(m,2H).
生物活性试验实验一、实时荧光检测(Fluorescence imaging plate reader，FLIPR)测定法筛选比较化合物对hP2X3和hP2X2/3受体的拮抗活性
1.细胞准备
将稳定转染hP2X3受体或稳定转染hP2X2/3受体的1321N1受体细胞消化，离心后用铺板培养基重悬并计数，在384孔测试板中每孔铺50微升(μL)细胞，置于5％ CO2，37℃培养箱中培养16-24小时。
2.化合物准备
2.1供试品：用二甲基亚砜(DMSO)配制180倍所需浓度供试化合物，每孔取500纳升(nL)加到化合物板中，补充30微升(μL)测试缓冲液，振摇20-40分钟以混匀。
2.2激动剂：用测试缓冲液配制3倍所需浓度激动剂α,β-me-ATP，每孔加45微升(μL)激动剂到细胞板中。
3.染料孵育
取出细胞板，吸去细胞上清，每孔加入30微升(μL)染料(钙4测定试剂盒(Calcium 4Assay Kit)，测试缓冲液稀释)，孵育1小时。
4.FLIPR检测
向细胞板中每孔加15微升(μL)化合物(FLIPR仪器加样)，15分钟后，每孔加22.5微升(μL)激动剂，检测荧光信号(激发光波长470纳米(nm)-495纳米(nm)，发射波长515纳米(nm)-575纳米(nm))。
5.数据处理
取信号峰值和谷值的差值作为基础数据，在软件Graphpad Prism6上拟合化合物的抑制效应曲线并计算半数抑制浓度(IC50)值。
6.实验结果
表1实施例化合物在1321N1-hP2X3受体细胞功能钙流试验中的结果
7.实验结论
以上方案测得结果表明，本发明所示的化合物在1321N1-hP2X3受体细胞功能钙流试验中显示出较好的抑制作用及较好的选择性。
实验二、本发明化合物在大鼠中药物代谢动力学实验
1.实验目的
以SD大鼠为例，以液相色谱-串联质谱(LS/MS/MS)法测定了大鼠分别灌胃(IG)和静脉(IV)给予实施例化合物后，不同时刻血浆中药物浓度，并计算相关药代参数，评价本发明实施例化合物在大鼠体内的药代动力学特性。
2.试验方案
2.1试验药物
实施例化合物1-2、BAY1817080；
2.2试验动物
健康成年的SD大鼠，SPF级，雄性，购自上海西普尔-必凯实验动物有限公司，许可证号SCXK(沪)2018-0006。
2.3药物配置
称取一定量的化合物，溶于5％二甲基亚砜(DMSO)，然后加入5％蓖麻油，最后加入90％生理盐水，超声，配置成均一的溶液。
2.4给药
具体给药按照试验方案进行，详情见表2。
表2.大鼠药代动力学试验方案
2.5采血时间及样品处理
灌胃给药后15分钟、0.5小时、1小时、2小时、4小时、6小时、8小时及24小时，静脉给药后5分钟、15分钟、0.5小时、1小时、2小时、4小时、8小时及24小时分别通过眼眶采血，每次采血0.2毫升(mL)，置于抗凝管中，混匀，保存于-20℃冰箱中备用。
3.样品测试及数据分析
采用液相色谱-串联质谱(LS/MS/MS)方法测定大鼠全血中化合物的含量。
利用WinNonLin5.3软件的非房室模型计算给药后化合物的药代动力学参数。
4.试验结果
本发明化合物给药后药代动力学参数见以下表3。由表3所示，本发明的化合物具有较好的代谢特征及生物利用度。
表3.本发明的化合物的药代动力学参数
5.试验结论
药代结果表明，本发明实施例化合物1-2在大鼠体内表现为吸收速度适中，暴露量AUC和最大血药浓度Cmax较高且生物利用度较高的药代动力学特征。
实验三、本发明化合物的肝微粒体代谢稳定性试验
1.试验目的
使用不同种属(小鼠、大鼠、犬、人)肝微粒体代谢酶系统研究实施例化合物的体外肝微粒体代谢稳定性。
2.试验步骤
2.1微粒体孵育
精密称量一定质量的化合物，以100％二甲基亚砜(DMSO)溶解获得浓度为10毫摩尔(mM)的储备液。以乙腈和水按一定比例稀释储备液获得浓度为100微摩尔(μM)的工作溶液。
代谢稳定性实验在96深孔板中进行，两个复孔。每个孔内加入肝微粒体，对照化合物或受试物，氯化镁(MgCl2)，及磷酸盐缓冲液，在37℃预孵5分钟后加入烟酰胺腺嘌呤二核苷酸磷酸(NADPH)起始反应。阴性对照组用等体积磷酸盐缓冲液取代NADPH。反应体系总体积为250μL，其中各组分的终浓度为肝微粒体蛋白0.5mg/mL，化合物1μM，NADPH 1.0mM。孵育0、5、10、20、40分钟后加入3-5倍体积含有内标的冰乙腈终止反应。阴性对照组仅在孵育0、40分钟终止反应。
2.2液质联用分析
2.2.1仪器
色谱系统为ACQUITY UPLC高效液相色谱系统(Waters，美国)。质谱系统为ABSciex API4000三级四级杆质谱配备电喷雾电离源(ESI)(Applied Biosystems，加拿大)。用于控制液质联用仪和定量分析的软件为Analyst 1.6(Applied Biosystems，加拿大)。
2.2.2色谱条件
液相条件见表4：
表4.液相条件
2.3样品准备
不同时间点所取样品加入3倍体积含内标的乙腈，以4000转离心20分钟，取上清混合相等体积的水后进行LC-MS/MS分析。
2.4数据分析
以孵育体系中药物的剩余率的对数值对孵育时间作图，进行线性回归得到斜率k，按公式计算体外消除半衰期T1/2(分钟)；根据公式可计算内在清除率(CLint，毫升/分钟/毫克)；根据公式按不同种属动物生理系数(即a、b、d值)换算可推导出肝脏的内在(表观)清除率(CLapp，mL/min/kg)；在考虑到肝血流量的情况下根据公式可推导出肝脏总清除率(CLh，mL/min/kg)；根据公式可计算出肝提取率(Eh，Hepatic extraction ratio)。不同种属的生理系数和肝血流量见表5。
表5.不同种属动物的相关生理系数和肝血流量
3.试验结果
表6实施例化合物的消除半衰期、清除率和肝提取率
4.试验结论
实施例化合物3-4在小鼠、大鼠、人和犬上均显示出低肝摄取率，说明实施例化合物在以上种属肝微粒体代谢稳定性较高。
实验四、本发明化合物的SD大鼠味觉敏感性试验
1.试验目的
观察实施例化合物对SD大鼠味觉的影响
2.试验方案
2.1试验动物
健康成年的SD大鼠，SPF级，雄性，购自上海西普尔-必凯实验动物有限公司，许可证号SCXK(沪)2018-0006。
2.2奎宁水溶液及实施例化合物的配制
称取适量的奎宁单盐酸二水合物，用超纯水配置成浓度3mM的溶液备用。另称取适量的实施例化合物，用5％二甲基亚砜(DMSO)+5％蓖麻油+90％生理盐水配置为目标浓度备用。
2.3试验步骤
2.3.1分组：试验开始前1天，根据大鼠体重将其随机分为4组，每组10只，分别为溶剂对照组，实施例1化合物10mg/kg组、实施例2化合物10mg/kg组，实施例3化合物10mg/kg组、实施例4化合物10mg/kg组，BAY1817080 10mg/kg组，并于给药前16小时禁水，不禁食。
2.3.2给药：试验当天按试验设计进行大鼠给药。
2.3.3饮水量测量：给药后的大鼠放回原来的笼子，给药一定时间后在每个笼子轻柔地放入一瓶灭菌的自来水，一瓶含3mM盐酸奎宁的灭菌自来水，所有笼子的水瓶放置的左右位置一致。让动物自由饮水30分钟后，分别测量两瓶水的饮用量。
2.3.4数据统计：计算奎宁水饮用量占总饮水量的百分比，用方差分析比较各组间的差异有无显著性差异。
3.试验结果
表7各组SD大鼠正常自来水和含奎宁的苦味水的饮水量结果
4.试验结论
在本试验条件下实施例化合物对大鼠味觉相比BAY1817080具有明显改善作用。
实验五、本发明化合物的hERG检测
1.试验目的
使用电生理手动膜片钳方法测试化合物对hERG钾通道(human Ether-a-go-goRelated Gene potassium channel)电流的影响。
2.试验方法
2.1细胞培养和处理
稳定表达hERG的CHO(Chinese Hamster Ovary)细胞培养于直径35毫米(mm)的细胞培养皿中，置于37℃，5％ CO2的培养箱培养，每48小时按1:5比例进行传代。试验当天，吸走细胞培养液，用细胞外液淋洗一遍后加入0.25％胰蛋白酶，在室温下消化3-5分钟。吸走消化液，用细胞外液重悬后将细胞转移到用于电生理记录的实验皿中备用。
2.2化合物准备
测试当天，将化合物二甲基亚砜(DMSO)母液用100％二甲基亚砜进行3倍连续稀释成中间浓度。
然后再取10微升(μL)的化合物中间浓度加入到4990微升(μL)细胞外液中，500倍稀释得到需要测试的最终浓度。
阳性对照化合物西沙必利准备：稀释得到需要测试的最终浓度300纳摩尔每升(nM)。
最终测试浓度中的二甲基亚砜(DMSO)含量不超过0.2％，此浓度对hERG钾通道没有影响。
2.3电生理记录过程
稳定表达hERG钾通道的CHO(Chinese Hamster Ovary)细胞，在室温下用全细胞膜片钳技术记录hERG钾通道电流。玻璃微电极由玻璃电极毛胚(BF150-86-10，Sutter)经拉制仪拉制而成，灌注电极内液后的尖端电阻为2-5毫欧(MΩ)左右，将玻璃微电极插入放大器探头即可连接至膜片钳放大器。钳制电压和数据记录由pClamp 10软件通过电脑控制和记录，采样频率为10千赫兹(kHz)，滤波频率为2千赫兹(kHz)。在得到全细胞记录后，细胞钳制在-80毫伏(mV)，诱发hERG钾电流(I hERG)的步阶电压从-80毫伏(mV)给予一个2秒的去极化电压到+20毫伏(mV)，再复极化到-50毫伏(mV)，持续1秒后回到-80毫伏(mV)。每10秒给予此电压刺激，确定hERG钾电流稳定后(1分钟)开始给药过程。化合物每个测试浓度给予1分钟。化合物每个浓度至少测试2个细胞(n≥2)。
2.4数据处理
数据分析处理采用pClamp 10，GraphPad Prism 5和Excel软件。不同化合物浓度对hERG钾电流(-50毫伏(mV)时诱发的hERG尾电流峰值)的抑制程度用以下公式计算：Inhibition％＝[1–(I/Io)]×100％
其中，Inhibition％代表化合物对hERG钾电流的抑制百分率，I和Io分别表示在加药后和加药前hERG钾电流的幅度。
化合物IC50使用GraphPad Prism 5软件通过以下方程拟合计算得出：
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
其中，X为供试品检测浓度的Log值，Y为对应浓度下抑制百分率，Bottom和Top分别为最小和最大抑制百分率。
3.试验结果
试验结果如表8所示：
表8实施例化合物hERG检测结果
/>
4.试验结论
实施例化合物2及化合物4的hERG IC50均大于40μM，心脏安全性较好，而BAY1817080的hERG IC50为小于40μM，存在一定心脏安全性风险。
Claims (11)
1.一种通式(I)所示的化合物、其可药用盐、其代谢物、及其同位素衍生物，
其中R1为芳基或杂芳基，优选地为6-8元芳基或5-6元杂芳基，其中所述的芳基或杂芳基任选地被Ra取代；
Ra为卤素、-C1-3烷基或-C1-3卤代烷基；
R2为-O(CH2)nR3或-CH2R4；
R3和R4分别独立地为-C3-6环烷基或4-6元杂环基，其中所述的C3-6环烷基或4-6元杂环基任选地被Rb取代；
Rb为-H、-C1-3烷基或-C(O)-Rc；
Rc为-C1-3烷基或-C1-3烷氧基；
n为0或1。
2.根据权利要求1所述的化合物、其可药用盐、其代谢物、及其同位素衍生物，其特征在于，R1为
Ra为-C1-3烷基；
R3和R4分别独立地为
3.根据权利要求1-2任一项所述的化合物、其可药用盐、其代谢物、及其同位素衍生物，其特征在于，R1为
4.根据权利要求1-3任一项所述的化合物、其可药用盐、其代谢物、及其同位素衍生物，其特征在于，
R2为
5.根据权利要求1-4任一项所述的化合物其可药用盐、其代谢物、及其同位素衍生物，其特征在于，所述化合物选自如下化合物、其可药用盐、其代谢物、及其同位素衍生物：
6.权利要求1-5中任一项所述式I所示化合物的制备方法，其特征在于，包含方案一或方案二的步骤，
方案一：
当R1为芳基时，化合物Ia与酸反应得到化合物Ib；化合物Ib和化合物Ic反应得到化合物Id；化合物Id在碱性条件下水解为化合物Ie；化合物Ie和化合物If反应得到化合物I；
方案二：
当R1为杂芳基时，化合物IIa与R1-X反应得到化合物IIb，其中X为卤素；化合物IIb在碱性条件下水解为化合物IIc；化合物IIc和化合物IId反应得到化合物I；
R1、R2具有如权利要求1-5任一项所述的含义。
7.一种药物组合物，其特征在于，包括治疗有效量的权利要求1-5中任一项所述的式I所示化合物、其可药用盐、其代谢物、其同位素衍生物或它们的混合物，以及药学上可接受的载剂和/或稀释剂。
8.根据权利要求1-5任一项所述的式I所示化合物、其可药用盐、其代谢物、及其同位素衍生物或它们的混合物，或者根据权利要求7所述的药物组合物在制备用于预防和/或治疗P2X3介导的疾病的药物中的用途。
9.根据权利要求8所述的用途，其特征在于，所述P2X3介导的疾病包括呼吸系统疾病、泌尿生殖系统疾病和疼痛。
10.根据权利要求9所述的用途，其特征在于，所述呼吸系统疾病为哮喘、支气管痉挛、肺纤维化、急性咳嗽或慢性咳嗽；所述泌尿生殖系统疾病为子宫内膜异位症、子宫肌瘤、痛经、盆腔炎性疾病及膀胱过动症。
11.治疗P2X3介导的疾病的方法，包括给需要这种治疗的患者施用治疗有效量的权利要求1-5中任一项所述的式I所示化合物、其可药用盐、其代谢物、其同位素衍生物或它们的混合物。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210966072 | 2022-08-12 | ||
| CN2022109660726 | 2022-08-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117586241A true CN117586241A (zh) | 2024-02-23 |
Family
ID=89915552
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310991769.3A Pending CN117586241A (zh) | 2022-08-12 | 2023-08-08 | P2x3受体拮抗剂及其制备方法和应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117586241A (zh) |
-
2023
- 2023-08-08 CN CN202310991769.3A patent/CN117586241A/zh active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109810041B (zh) | 卤代烯丙基胺类ssao/vap-1抑制剂及其应用 | |
| AU2007273333B2 (en) | Novel biaryl benzoimidazole derivatives and pharmaceutical composition comprising the same | |
| EP4227299A1 (en) | Benzimidazolone glp-1 receptor agonist and use thereof | |
| JP7162132B2 (ja) | ピリダジノン化合物およびその使用 | |
| CN107428690B (zh) | 可用于治疗癌症的突变idh1抑制剂 | |
| US7053094B2 (en) | Compositions and methods for treating heart failure | |
| WO2011007819A1 (ja) | ラクタムまたはベンゼンスルホンアミド化合物を含有する医薬 | |
| KR20220047318A (ko) | 비펩타이드 소마토스타틴 5형 수용체 작용제 및 이의 용도 | |
| EP3814343B1 (en) | Cardiac sarcomere inhibitors | |
| TW200538130A (en) | Heteroarylaminopyrazole derivatives useful for the treatment of diabetes | |
| TW202233181A (zh) | 五並五員環衍生物及其在醫藥上的應用 | |
| EP4317142A1 (en) | Thiophene glp-1 receptor agonist and use thereof | |
| KR20160006207A (ko) | 사이클로알킬산 유도체, 그의 제조 방법, 및 그의 약학적 용도 | |
| BR112017009012B1 (pt) | Derivados de anel benzo de seis membros como inibidor de dpp-4 e uso dos mesmos | |
| TW202214584A (zh) | Shp2抑制劑及其組合物和應用 | |
| CA2933682A1 (en) | Maleimide derivatives as modulators of wnt pathway | |
| EP3950676A1 (en) | Preparation method for amide compound and application thereof in field of medicine | |
| JP2019509272A (ja) | 脊髄性筋萎縮症の治療のための併用療法 | |
| JP2020535208A (ja) | 新規な複素環式化合物 | |
| US20110318266A1 (en) | Phthalimide derivative metabotropic glutamate r4 ligands | |
| CN105367565B (zh) | 哌嗪(啶)环己基衍生物及其治疗精神神经疾病的应用 | |
| JP2012528870A (ja) | メラニン凝集ホルモン受容体１アンタゴニストとしてのビス−ピリジルピリドン | |
| JP2022517723A (ja) | Ｃｄｋ阻害剤としての大環状化合物、その製造方法及びその医薬品における応用 | |
| KR20100031610A (ko) | 아데노신 Ａ3 수용체 리간드로서의 트리아졸로[1,5-ａ]퀴놀린 | |
| US20130231354A1 (en) | Substituted azaindazole compounds |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication |