CN112341514B - 脱氧胆酸类化合物、药物组合物及其用途 - Google Patents
脱氧胆酸类化合物、药物组合物及其用途 Download PDFInfo
- Publication number
- CN112341514B CN112341514B CN202010765952.8A CN202010765952A CN112341514B CN 112341514 B CN112341514 B CN 112341514B CN 202010765952 A CN202010765952 A CN 202010765952A CN 112341514 B CN112341514 B CN 112341514B
- Authority
- CN
- China
- Prior art keywords
- acid
- compound
- formula
- pharmaceutically acceptable
- substituted
- 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.)
- Active
Links
- -1 Deoxycholic acid compound Chemical class 0.000 title claims abstract description 26
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 21
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 title abstract description 6
- 229960003964 deoxycholic acid Drugs 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 62
- 150000003839 salts Chemical class 0.000 claims abstract description 23
- 239000003814 drug Substances 0.000 claims abstract description 19
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 31
- 125000000217 alkyl group Chemical group 0.000 claims description 28
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 24
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 16
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 16
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 16
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 13
- 229910052740 iodine Inorganic materials 0.000 claims description 13
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 13
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 9
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 238000009472 formulation Methods 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 7
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 6
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 claims description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- 150000007522 mineralic acids Chemical class 0.000 claims description 6
- 150000007524 organic acids Chemical class 0.000 claims description 6
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 claims description 5
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 5
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 5
- 210000000941 bile Anatomy 0.000 claims description 5
- 239000003613 bile acid Substances 0.000 claims description 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 5
- 239000011975 tartaric acid Substances 0.000 claims description 5
- 235000002906 tartaric acid Nutrition 0.000 claims description 5
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 claims description 4
- 208000033222 Biliary cirrhosis primary Diseases 0.000 claims description 4
- 206010012735 Diarrhoea Diseases 0.000 claims description 4
- 208000012654 Primary biliary cholangitis Diseases 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 208000007232 portal hypertension Diseases 0.000 claims description 4
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
- PXACTUVBBMDKRW-UHFFFAOYSA-N 4-bromobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(Br)C=C1 PXACTUVBBMDKRW-UHFFFAOYSA-N 0.000 claims description 3
- 239000005711 Benzoic acid Substances 0.000 claims description 3
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 claims description 3
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 3
- 206010019728 Hepatitis alcoholic Diseases 0.000 claims description 3
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 3
- 235000011054 acetic acid Nutrition 0.000 claims description 3
- 208000002353 alcoholic hepatitis Diseases 0.000 claims description 3
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 235000010323 ascorbic acid Nutrition 0.000 claims description 3
- 239000011668 ascorbic acid Substances 0.000 claims description 3
- 229960005070 ascorbic acid Drugs 0.000 claims description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 3
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 3
- 235000010233 benzoic acid Nutrition 0.000 claims description 3
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 3
- 235000015165 citric acid Nutrition 0.000 claims description 3
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 3
- 239000001530 fumaric acid Substances 0.000 claims description 3
- 239000000174 gluconic acid Substances 0.000 claims description 3
- 235000012208 gluconic acid Nutrition 0.000 claims description 3
- 235000013922 glutamic acid Nutrition 0.000 claims description 3
- 239000004220 glutamic acid Substances 0.000 claims description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 3
- 229940071870 hydroiodic acid Drugs 0.000 claims description 3
- 239000004310 lactic acid Substances 0.000 claims description 3
- 235000014655 lactic acid Nutrition 0.000 claims description 3
- 239000012669 liquid formulation Substances 0.000 claims description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 3
- 239000011976 maleic acid Substances 0.000 claims description 3
- 239000001630 malic acid Substances 0.000 claims description 3
- 235000011090 malic acid Nutrition 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- 229910017604 nitric acid Inorganic materials 0.000 claims description 3
- 235000006408 oxalic acid Nutrition 0.000 claims description 3
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 claims description 3
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 3
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 claims description 3
- 235000019260 propionic acid Nutrition 0.000 claims description 3
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 3
- 229960004889 salicylic acid Drugs 0.000 claims description 3
- 208000010157 sclerosing cholangitis Diseases 0.000 claims description 3
- 230000028327 secretion Effects 0.000 claims description 3
- 206010008609 Cholangitis sclerosing Diseases 0.000 claims description 2
- 230000010234 biliary secretion Effects 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 201000000742 primary sclerosing cholangitis Diseases 0.000 claims description 2
- 239000006188 syrup Substances 0.000 claims description 2
- 235000020357 syrup Nutrition 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 8
- 208000035475 disorder Diseases 0.000 claims 2
- 239000007972 injectable composition Substances 0.000 claims 1
- 239000007788 liquid Substances 0.000 claims 1
- 239000000375 suspending agent Substances 0.000 claims 1
- 239000003826 tablet Substances 0.000 claims 1
- 210000004185 liver Anatomy 0.000 abstract description 34
- 229940079593 drug Drugs 0.000 abstract description 12
- 230000000694 effects Effects 0.000 abstract description 9
- 208000019423 liver disease Diseases 0.000 abstract description 7
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 abstract description 3
- 239000004380 Cholic acid Substances 0.000 abstract description 3
- 229960002471 cholic acid Drugs 0.000 abstract description 3
- 235000019416 cholic acid Nutrition 0.000 abstract description 3
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical class C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 abstract description 3
- 230000000857 drug effect Effects 0.000 abstract description 3
- 230000008685 targeting Effects 0.000 abstract description 3
- 231100000331 toxic Toxicity 0.000 abstract description 2
- 230000002588 toxic effect Effects 0.000 abstract description 2
- 210000002381 plasma Anatomy 0.000 description 24
- ZXERDUOLZKYMJM-ZWECCWDJSA-N obeticholic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)CCC(O)=O)CC[C@H]21 ZXERDUOLZKYMJM-ZWECCWDJSA-N 0.000 description 21
- 125000000623 heterocyclic group Chemical group 0.000 description 20
- 229960001601 obeticholic acid Drugs 0.000 description 19
- 125000001072 heteroaryl group Chemical group 0.000 description 18
- 229910052739 hydrogen Inorganic materials 0.000 description 16
- 239000001257 hydrogen Substances 0.000 description 16
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 14
- 241000700159 Rattus Species 0.000 description 14
- 150000002431 hydrogen Chemical class 0.000 description 14
- 125000002947 alkylene group Chemical group 0.000 description 12
- 125000003118 aryl group Chemical group 0.000 description 12
- 125000004419 alkynylene group Chemical group 0.000 description 10
- 125000000732 arylene group Chemical group 0.000 description 10
- 125000000753 cycloalkyl group Chemical group 0.000 description 10
- 125000005842 heteroatom Chemical group 0.000 description 10
- 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 10
- 229910052760 oxygen Inorganic materials 0.000 description 10
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 10
- 125000000547 substituted alkyl group Chemical group 0.000 description 10
- 229910052717 sulfur Inorganic materials 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 125000003342 alkenyl group Chemical group 0.000 description 8
- 125000004450 alkenylene group Chemical group 0.000 description 8
- 125000000304 alkynyl group Chemical group 0.000 description 8
- 125000005017 substituted alkenyl group Chemical group 0.000 description 8
- 125000004426 substituted alkynyl group Chemical group 0.000 description 8
- 125000003107 substituted aryl group Chemical group 0.000 description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 7
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 230000002496 gastric effect Effects 0.000 description 6
- 229910052736 halogen Inorganic materials 0.000 description 6
- 150000002367 halogens Chemical class 0.000 description 6
- 125000005549 heteroarylene group Chemical group 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 5
- 239000004471 Glycine Substances 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 238000002390 rotary evaporation Methods 0.000 description 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 4
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 4
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 229910001424 calcium ion Inorganic materials 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 208000019425 cirrhosis of liver Diseases 0.000 description 4
- 125000002993 cycloalkylene group Chemical group 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 208000010706 fatty liver disease Diseases 0.000 description 4
- 125000005647 linker group Chemical group 0.000 description 4
- 125000002950 monocyclic group Chemical group 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 229910001414 potassium ion Inorganic materials 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910001415 sodium ion Inorganic materials 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 125000005717 substituted cycloalkylene group Chemical group 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 4
- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical compound CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 4
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 4
- OSBSFAARYOCBHB-UHFFFAOYSA-N tetrapropylammonium Chemical compound CCC[N+](CCC)(CCC)CCC OSBSFAARYOCBHB-UHFFFAOYSA-N 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 208000004930 Fatty Liver Diseases 0.000 description 3
- 206010019708 Hepatic steatosis Diseases 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 210000005228 liver tissue Anatomy 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 231100000240 steatosis hepatitis Toxicity 0.000 description 3
- CRDAMVZIKSXKFV-FBXUGWQNSA-N (2-cis,6-cis)-farnesol Chemical compound CC(C)=CCC\C(C)=C/CC\C(C)=C/CO CRDAMVZIKSXKFV-FBXUGWQNSA-N 0.000 description 2
- 239000000260 (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-ol Substances 0.000 description 2
- 125000006587 (C5-C10) heteroarylene group Chemical group 0.000 description 2
- VXNZUUAINFGPBY-UHFFFAOYSA-N 1-Butene Chemical group CCC=C VXNZUUAINFGPBY-UHFFFAOYSA-N 0.000 description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 2
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 description 2
- 125000000041 C6-C10 aryl group Chemical group 0.000 description 2
- ISZKKWKBYKPCSI-UHFFFAOYSA-N CC(C)C[Na] Chemical compound CC(C)C[Na] ISZKKWKBYKPCSI-UHFFFAOYSA-N 0.000 description 2
- 208000010201 Exanthema Diseases 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical group CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 description 2
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 description 2
- 208000001145 Metabolic Syndrome Diseases 0.000 description 2
- 239000004743 Polypropylene Substances 0.000 description 2
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 150000001342 alkaline earth metals Chemical class 0.000 description 2
- 125000005275 alkylenearyl group Chemical group 0.000 description 2
- IYABWNGZIDDRAK-UHFFFAOYSA-N allene Chemical group C=C=C IYABWNGZIDDRAK-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 150000001767 cationic compounds Chemical class 0.000 description 2
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 2
- 125000004980 cyclopropylene group Chemical group 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 201000005884 exanthem Diseases 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 229940043259 farnesol Drugs 0.000 description 2
- 229930002886 farnesol Natural products 0.000 description 2
- 229910001411 inorganic cation Inorganic materials 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 2
- 229910001425 magnesium ion Inorganic materials 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 125000004957 naphthylene group Chemical group 0.000 description 2
- 150000002892 organic cations Chemical class 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 2
- 206010037844 rash Diseases 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 2
- CRDAMVZIKSXKFV-UHFFFAOYSA-N trans-Farnesol Natural products CC(C)=CCCC(C)=CCCC(C)=CCO CRDAMVZIKSXKFV-UHFFFAOYSA-N 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- RUDATBOHQWOJDD-UHFFFAOYSA-N (3beta,5beta,7alpha)-3,7-Dihydroxycholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 RUDATBOHQWOJDD-UHFFFAOYSA-N 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 206010008635 Cholestasis Diseases 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 208000034826 Genetic Predisposition to Disease Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 206010067125 Liver injury Diseases 0.000 description 1
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000002300 anti-fibrosis Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 208000015337 arteriosclerotic cardiovascular disease Diseases 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000023852 carbohydrate metabolic process Effects 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 229960001091 chenodeoxycholic acid Drugs 0.000 description 1
- RUDATBOHQWOJDD-BSWAIDMHSA-N chenodeoxycholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-BSWAIDMHSA-N 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 229940121360 farnesoid X receptor (fxr) agonists Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 231100000753 hepatic injury Toxicity 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- COQRGFWWJBEXRC-UHFFFAOYSA-N hydron;methyl 2-aminoacetate;chloride Chemical compound Cl.COC(=O)CN COQRGFWWJBEXRC-UHFFFAOYSA-N 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 230000006609 metabolic stress Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 102000006255 nuclear receptors Human genes 0.000 description 1
- 108020004017 nuclear receptors Proteins 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 239000012053 oil suspension Substances 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 238000009832 plasma treatment Methods 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 229910052712 strontium Inorganic materials 0.000 description 1
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/12—Antidiarrhoeals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
- C07J41/0061—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives one of the carbon atoms being part of an amide group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0088—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing unsubstituted amino radicals
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Gastroenterology & Hepatology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
一种脱氧胆酸类化合物及其药物组合物和它们在制备治疗肝脏疾病药物中的用途。所述脱氧胆酸类化合物的结构如式I所示，或其药学上可接受的盐。该类化合物具有显著的肝脏靶向特性，其在提高药效的同时，降低循环系统中的药物浓度，从而降低毒副作用。
Description
技术领域
本发明涉及一种脱氧胆酸类化合物、药物组合物及其用途。
背景技术
非酒精性脂肪性肝病(Non-Alcohol Fatty Liver Diseases,NAFLD)是指除酒精和其他明确的损肝因素所致的肝细胞内脂肪过度沉积为主要特征的临床病理综合征，与胰岛素抵抗和遗传易感性密切相关的获得性代谢应激性肝损伤。包括单纯性脂肪肝(SFL)、非酒精性脂肪性肝炎(NASH)及其相关肝硬化。随着肥胖及其相关代谢综合征全球化的流行趋势，非酒精性脂肪性肝病现已成为欧美等发达国家和我国富裕地区慢性肝病的重要病因，普通成人NAFLD患病率10％～30％，其中10％～20％为NASH，后者10年内肝硬化发生率高达25％。
非酒精性脂肪性肝病除可直接导致失代偿期肝硬化、肝细胞癌和移植肝复发外，还可影响其他慢性肝病的进展，并参与2型糖尿病和动脉粥样硬化的发病。代谢综合征相关恶性肿瘤、动脉硬化性心脑血管疾病以及肝硬化。为此，非酒精性脂肪性肝病是当代医学领域的新挑战。但在目前没有有效的治疗方法。
脱氧胆酸类化合物，如鹅脱氧胆酸和鹅脱氧胆酸的6位取代衍生物，可激活法尼醇X受体(FXR)，具有抗淤胆、抗纤维化的效果。FXR是一种核受体，为一种胆酸传感器，可调控胆酸的合成和胆汁在肝内的流动，同时对于胆汁内环境稳定、脂质代谢、糖代谢以及炎症/免疫应答都有作用。研究数据表明，6-α-乙基鹅脱氧胆酸(奥贝胆酸，OCA)可以用于治疗原发性胆汁性肝硬化(PBC)、门静脉高压(Portal hypertension)、非酒精性脂肪肝炎(NASH)、胆汁酸性腹泻(Bile acid diarrhea)、酒精性肝炎、原发性硬化性胆管炎(PSC)等与胆汁分泌有关的疾病(Drug Discovery Today.Volume 17,Numbers 17/18,2012)。
然而奥贝胆酸在临床上治疗肝脏疾病、如脂肪肝时皮肤瘙痒的发生率达到63％，皮疹的发生率也达到32％，有时必须用其它药物同时使用，以控制奥贝胆酸对皮肤的毒副作用。使奥贝胆酸的临床应用受到了限制。
脱氧胆酸类化合物
奥贝胆酸(OCA)在体内主要与甘氨酸(Glycine,Gly)和牛磺酸(Taurine,Tau)分别代谢成代谢共轭物OCA-Gly和OCA-Tau，已有研究表明，奥贝胆酸的上述代谢共轭物具有与奥贝胆酸同样的生理作用，例如，激活法尼醇X受体(FXR)的活性与奥贝胆酸几乎相同(参考文献：Obeticholic acid,a selective farnesoid X receptor agonist,regulates bileacid homeostasis in sandwich-cultured human hepatocytes.PharmacologyResearch&Perspectives.2017,vol.5,iss.4)。
奥贝胆酸在体内代谢及其产物
发明内容
发明人意外发现，奥贝胆酸甘氨酸共轭物(OCA-Gly)的一类衍生物具有显著的肝脏靶向特性，肝脏中活性药物浓度约为血浆中的20倍。因此，采用该类化合物治疗脂肪肝等肝脏疾病时，由于活性药物在肝脏内的浓度大大提高而提高药效，且因血浆中的有效药物浓度显著降低而减少皮疹等副作用。
鉴于此，本发明提供一种式I所示的化合物或其药学上可接受的盐：
其中：
R1和R2独立地选自：氢、-COR'、-CONHR'、-CONR'R”、或-COOR'；
R3选自：氢、甲基、或乙基；
R4选自：氢、烷基或取代烷基，烯基或取代烯基，炔基或取代炔基，环烷基或取代环烷基，芳基或取代芳基，杂芳基或取代杂芳基，杂环基或取代杂环基；
Linker不存在或选自：亚烷基或取代亚烷基，亚烯基或取代亚烯基，亚炔基或取代亚炔基，亚环烷基或取代亚环烷基，亚芳基或取代亚芳基，亚杂芳基或取代亚杂芳基，亚杂环基或取代亚杂环基；
R5和R6独立地选自：氢、烷基或取代烷基；或者，R5和R6相互连接，与它们相连的C原子一起形成含有0个、1个或2个选自O、S或N的杂原子的3-7元环；
R选自烷基或取代烷基，烯基或取代烯基，炔基或取代炔基，环烷基或取代环烷基，芳基或取代芳基，亚烷基-芳基、亚烷基-取代芳基，杂芳基或取代杂芳基，杂环基或取代杂环基；
或者R选自无机阳离子或有机阳离子，所述无机阳离子选自钠离子、钾离子、镁离子或钙离子；所述有机阳离子选自铵、四甲基铵，四乙基铵，四丙基铵或四丁基铵；
各个R'和R”各自独立地选自：氢、烷基或取代烷基，烯基或取代烯基，炔基或取代炔基，环烷基或取代环烷基，芳基或取代芳基，杂芳基或取代杂芳基，杂环基或取代杂环基；
所述取代烷基、取代亚烷基、取代烯基、取代亚烯基、取代炔基、取代亚炔基、取代环烷基、取代亚环烷基、取代芳基、取代亚芳基、亚烷基-取代芳基、取代杂芳基、取代亚杂芳基、取代杂环基或取代亚杂环基中各自的取代基各自独立地选自：卤素，氰基，氨基，硝基，羟基，烷基，烷氧基，改性烷基，
可选地，所述式I化合物不为化合物：
可选地，所述式I化合物中的R不为甲基。
可选地，所述“卤素”选自：F、Cl、Br或I；
可选地，所述“烷基”、“烷氧基”中的“烷基”为C1-C20直链或支链烷基，可选地，选自：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基；
可选地，所述“亚烷基”、“亚烷基-芳基”、“亚烷基-取代芳基”中的“亚烷基”为C1-C10直链或支链亚烷基，可选地，选自：亚甲基、亚乙基、亚正丙基、亚异丙基、亚正丁基、亚异丁基、亚叔丁基、亚仲丁基、亚正戊基；
可选地，所述“改性烷基”为烷基的任意碳原子被选自-O-、-CO-、-NH2、-OH、卤素、-CN、-NO2中的一种或几种基团置换所得的基团；
可选地，所述“烯基”为C2-C6的烯基；
可选地，所述“亚烯基”为C2-C6的亚烯基；
可选地，所述“炔基”为C2-C6的炔基；
可选地，所述“亚炔基”为C2-C6的亚炔基；
可选地，所述“环烷基”为C3-C10单环或双环环烷基；
可选地，所述“亚环烷基”为C3-C10单环或双环亚环烷基；
可选地，所述“芳基”、“亚烷基-芳基”、“亚烷基-取代芳基”中的“芳基”为6-10元芳基；可选为苯基或萘基；
可选地，所述“亚芳基”为6-10元亚芳基；可选为亚苯基或亚萘基；
可选地，所述“杂芳基”为含有1个、2个或3个选自N、O和S中的杂原子的5-10元杂芳环；
可选地，所述“亚杂芳基”为含有1个、2个或3个选自N、O和S中的杂原子的5-10元亚杂芳环；
可选地，所述“杂环基”为环上含有1个、2个或3个选自N、O、S的杂原子的3-10元非芳香杂环；
可选地，所述“亚杂环基”为环上含有1个、2个或3个选自N、O、S的杂原子的3-10元非芳香亚杂环。
可选地，各个R'和R”各自独立地选自：氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、苄基、仲丁基、正戊基、
可选地，R1和R2独立地选自：氢、乙酰基，丙酰基，异丙酰基，丁酰基，异丁酰基；
可选地，R3选自：氢、甲基、或乙基；
可选地，R4选自：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基；
可选地，Linker不存在或选自：-CH2-、-CH2CH2-、-CH2CH2CH2-、亚环丙基、
可选地，R5和R6独立地选自：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基，或者R5和R6相互连接，与它们相连的C原子一起形成选自下式的任一基团：
可选地，R选自：乙基、丙基、丁基、异丙基、异丁基、叔丁基、仲丁基、正戊基、 杂环基或取代杂环基、钠离子、钾离子、镁离子、钙离子、铵、四甲基铵，四乙基铵，四丙基铵或四丁基铵；各个X各自独立地选自：0个、1个、2个或3个选自：F、Cl、Br、I、-NH2、-OH、-甲氧基、乙氧基、丙氧基、异丙氧基、-CN、甲基、乙基、正丙基、异丙基、正丁基或异丁基的基团，或者各个X各自独立地为C5-C10的直链或支链烷基的任意碳原子被选自-O-、-CO-、-NH2、中的一种或几种基团置换所得的基团。
可选地，式I化合物选自下列式II化合物：
其中：
R3、R如上所定义。
可选地，式II中，R3选自：H、甲基、或乙基；R选自：乙基、正丙基、异丙基、正丁基、异丁基、钠离子、钾离子、钙离子，各个X各自独立地选自：0个、1个、2个或3个选自：F、Cl、Br、I、-NH2、-OH、-甲氧基，乙氧基，丙氧基，异丙氧基、-CN、甲基、乙基、正丙基、异丙基、正丁基或异丁基的基团，或者各个X各自独立地为C5-C10的直链或支链烷基的任意碳原子被选自-O-、-CO-、-NH2、中的一种或几种基团置换所得的基团。
可选地，所述式I化合物或其药学上可接受的盐选自下列化合物：
式I-7中：X是1个、2个或3个取代基，独立地选自F，Cl，Br，I，-CN，-NH2，-NO2或-OH，甲基，乙基，丙基，异丙基，甲氧基，乙氧基，丙氧基，异丙氧基。
式I-8中：X是1个、2个或3个取代基，独立地选自F，Cl，Br，I，-CN，-NH2，-NO2或-OH，甲基，乙基，丙基，异丙基，甲氧基，乙氧基，丙氧基，异丙氧基。
可选地，所述式I化合物选自下表所列化合物：
/>
/>
/>
可选地，所述药学上可接受的盐包括式I化合物的盐，这些阳离子盐包括碱金属的盐、碱土金属的盐、铵盐；可选地，所述碱金属包括钠、钾、锂、铯，所述碱土金属包括镁、钙、锶；
可选地，所述药学上可接受的盐包括式I化合物与酸形成的盐；可选地，所述酸包括无机酸、有机酸；可选地，所述无机酸包括盐酸、氢溴酸、氢碘酸、硫酸、硝酸、磷酸、碳酸；可选地，所述有机酸包括甲酸、抗坏血酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、柠檬酸、枸橼酸、酒石酸、葡萄糖酸、酒石氢酸、葡萄糖醒酸、碳酸、苦味酸、甲磺酸、乙磺酸、对甲苯磺酸、苯甲酸、苯磺酸、对溴苯磺酸、谷氨酸、水杨酸、双羟萘酸。
本发明另一方面，提供一种药物组合物，其包含治疗有效剂量的下述式I化合物或其药学上可接受的盐中的一种或多种，以及任选存在的药学上可接受的载体，
式I中：
R1和R2独立地选自：氢、-COR'、-CONHR'、-CONR'R”、或-COOR'；
R3选自：氢、甲基、或乙基；
R4选自：氢、烷基或取代烷基，烯基或取代烯基，炔基或取代炔基，环烷基或取代环烷基，芳基或取代芳基，杂芳基或取代杂芳基，杂环基或取代杂环基；
Linker不存在或选自：亚烷基或取代亚烷基，亚烯基或取代亚烯基，亚炔基或取代亚炔基，亚环烷基或取代亚环烷基，亚芳基或取代亚芳基，亚杂芳基或取代亚杂芳基，亚杂环基或取代亚杂环基；
R5和R6独立地选自：氢、烷基或取代烷基；或者，R5和R6相互连接，与它们相连的C原子一起形成含有0个、1个或2个选自O、S或N的杂原子的3-7元环；
R选自烷基或取代烷基，烯基或取代烯基，炔基或取代炔基，环烷基或取代环烷基，芳基或取代芳基，亚烷基-芳基、亚烷基-取代芳基，杂芳基或取代杂芳基，杂环基或取代杂环基；
或者R选自无机阳离子或有机阳离子，所述无机阳离子选自钠离子、钾离子、镁离子或钙离子；所述有机阳离子选自铵、四甲基铵，四乙基铵，四丙基铵或四丁基铵；
各个R'和R”各自独立地选自：氢、烷基或取代烷基，烯基或取代烯基，炔基或取代炔基，环烷基或取代环烷基，芳基或取代芳基，杂芳基或取代杂芳基，杂环基或取代杂环基；
所述取代烷基、取代亚烷基、取代烯基、取代亚烯基、取代炔基、取代亚炔基、取代环烷基、取代亚环烷基、取代芳基、取代亚芳基、亚烷基-取代芳基、取代杂芳基、取代亚杂芳基、取代杂环基或取代亚杂环基中各自的取代基各自独立地选自：卤素，氰基，氨基，硝基，羟基，烷基，烷氧基，改性烷基。
可选地，所述的药物组合物中，可选所述“卤素”选自：F、Cl、Br或I；
可选地，所述“烷基”、“烷氧基”中的“烷基”为C1-C20直链或支链烷基，可选地，选自：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基；
可选地，所述“亚烷基”、“亚烷基-芳基”、“亚烷基-取代芳基”中的“亚烷基”为C1-C10直链或支链亚烷基，可选地，选自：亚甲基、亚乙基、亚正丙基、亚异丙基、亚正丁基、亚异丁基、亚叔丁基、亚仲丁基、亚正戊基；
可选地，所述“改性烷基”为烷基的任意碳原子被选自-O-、-CO-、-NH2、-OH、卤素、-CN、-NO2中的一种或几种基团置换所得的基团；
可选地，所述“烯基”为C2-C6的烯基；
可选地，所述“亚烯基”为C2-C6的亚烯基；
可选地，所述“炔基”为C2-C6的炔基；
可选地，所述“亚炔基”为C2-C6的亚炔基；
可选地，所述“环烷基”为C3-C10单环或双环环烷基；
可选地，所述“亚环烷基”为C3-C10单环或双环亚环烷基；
可选地，所述“芳基”、“亚烷基-芳基”、“亚烷基-取代芳基”中的“芳基”为6-10元芳基；可选为苯基或萘基；
可选地，所述“亚芳基”为6-10元亚芳基；可选为亚苯基或亚萘基；
可选地，所述“杂芳基”为含有1个、2个或3个选自N、O和S中的杂原子的5-10元杂芳环；
可选地，所述“亚杂芳基”为含有1个、2个或3个选自N、O和S中的杂原子的5-10元亚杂芳环；
可选地，所述“杂环基”为环上含有1个、2个或3个选自N、O、S的杂原子的3-10元非芳香杂环；
可选地，所述“亚杂环基”为环上含有1个、2个或3个选自N、O、S的杂原子的3-10元非芳香亚杂环。
可选地，各个R'和R”各自独立地选自：氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、苄基、仲丁基、正戊基、
可选地，R1和R2独立地选自：氢、乙酰基，丙酰基，异丙酰基，丁酰基，异丁酰基；
可选地，R3选自：氢、甲基、或乙基；
可选地，R4选自：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基；
可选地，Linker不存在或选自：-CH2-、-CH2CH2-、-CH2CH2CH2-、亚环丙基、
可选地，R5和R6独立地选自：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基，或者R5和R6相互连接，与它们相连的C原子一起形成选自下式的任一基团：
可选地，R选自：乙基、丙基、丁基、异丙基、异丁基、叔丁基、仲丁基、正戊基、 杂环基或取代杂环基、钠离子、钾离子、镁离子、钙离子、铵、四甲基铵，四乙基铵，四丙基铵或四丁基铵；各个X各自独立地选自：0个、1个、2个或3个选自：F、Cl、Br、I、-NH2、-OH、-甲氧基，乙氧基，丙氧基，异丙氧基、-CN、甲基、乙基、正丙基、异丙基、正丁基或异丁基的基团，或者各个X各自独立地为C5-C10的直链或支链烷基的任意碳原子被选自-O-、-CO-、-NH2、中的一种或几种基团置换所得的基团。
可选地，所述的药物组合物中，所述式I化合物选自下列式II化合物：
其中：
R3、R如上述定义。
可选地，所述的药物组合物中，R3选自：H、甲基、或乙基；R选自：乙基、正丙基、异丙基、正丁基、异丁基、钠离子、钾离子、钙离子，各个X各自独立地选自：0个、1个、2个或3个选自：F、Cl、Br、I、-NH2、-OH、-甲氧基，乙氧基，丙氧基，异丙氧基、-CN、甲基、乙基、正丙基、异丙基、正丁基或异丁基的基团，或者各个X各自独立地为C5-C10的直链或支链烷基的任意碳原子被选自-O-、-CO-、-NH2、中的一种或几种基团置换所得的基团。
可选地，所述药物组合物中，所述式I化合物选自下列化合物：
/>
/>
式I-7中：X是1个、2个或3个取代基，独立地选自F，Cl，Br，I，-CN，-NH2，-NO2或-OH，甲基，乙基，丙基，异丙基，甲氧基，乙氧基，丙氧基，异丙氧基。
式I-8中：X是1个、2个或3个取代基，独立地选自F，Cl，Br，I，-CN，-NH2，-NO2或-OH，甲基，乙基，丙基，异丙基，甲氧基，乙氧基，丙氧基，异丙氧基。
可选地，所述的药物组合物中，所述式I化合物药学上可接受的盐包括式I化合物与酸形成的盐；可选地，所述酸包括无机酸、有机酸；可选地，所述无机酸包括盐酸、氢溴酸、氢碘酸、硫酸、硝酸、磷酸、碳酸；可选地，所述有机酸包括甲酸、抗坏血酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、柠檬酸、枸橼酸、酒石酸、葡萄糖酸、酒石氢酸、葡萄糖醒酸、碳酸、苦味酸、甲磺酸、乙磺酸、对甲苯磺酸、苯甲酸、苯磺酸、对溴苯磺酸、谷氨酸、水杨酸、双羟萘酸。
可选地，所述药物组合物的剂型包括口服制剂，注射剂型；
可选地，所述口服制剂包括固体制剂、液体制剂；
可选地，所述固体制剂包括片剂、粉剂、粒剂、胶囊；
可选地，所述液体制剂包括水或油悬浮剂、糖浆。
另一方面提供上述的药物组合物，或者上述的式I化合物或其药学上可接受的盐在制备治疗非酒精性脂肪肝炎药物中的用途。
另一方面提供上述的药物组合物，或者上述的式I化合物或其药学上可接受的盐在制备治疗原发性胆汁性肝硬化药物中的用途。
另一方面提供上述的药物组合物，或者上述的式I化合物或其药学上可接受的盐药物组合物在制备治疗胆汁分泌相关的疾病药物中的用途；
可选地，所述胆汁分泌相关的疾病包括：门静脉高压、胆汁酸性腹泻、酒精性肝炎和原发性硬化性胆管炎。
具体实施方式
以下对本发明的具体实施方式进行详细的说明。应当理解的是，此处所描述的具体实施方式仅用于示例性地对本发明进行说明，并不用于限制本发明。
实施例1化合物的制备
1、制备化合物4：
A、将原料1(0.8g,1.90mmol,1.0eq)，甘氨酸甲酯盐酸盐(2，356mg,2.85mmol)，EDCI(546mg,2.85mmol)，DMAP(696mg,5.70mmol)溶于DCM(10mL)中，氮气保护，室温反应过夜，TLC检测反应完毕，旋蒸除去DCM，加EtOAC溶解，用1N HCl 5mL×2洗，除去过量的DMAP，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩得到化合物3(900mg，96％)。1H NMR(400MHz,CDCl3)δ5.94(s,1H),4.0(d,J＝5.1Hz,2H),3.76(s,3H),3.70(s,1H),3.44-3.36(m,1H),2.34-2.27(m,1H),2.18-2.10(m,1H),1.97-0.89(m,36H),0.65(s,3H)。
B、将化合物3(900mg,1.83mmol)，NaOH(111mg,2.78mmol)加入到CH3OH-H2O(4mL，V:V＝1:1)中，回流反应3h，TLC检测反应完毕，旋蒸除去甲醇，加EtOAC萃取，除去有机杂质，水相用1N HCl调pH至5左右，有白色固体析出，加EtOAC溶解萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩得到化合物4(795mg，91％)。1H NMR(400MHz,DMSO)δ12.4(s,1H),8.1(t,J＝5.9Hz,1H),4.3(s,1H),4.05(d,J＝4.9Hz,1H),3.7(d,J＝5.9Hz,2H),3.5(s,1H),3.16-3.10(m,1H),2.18-2.11(m,1H),2.07-2.01(m,1H),1.97-0.89(m,34H),0.61(s,3H)；m/z(ESI)[M-H]-＝476.4。
2、制备化合物I-4：
将原料4(1.3g,2.72mmol)，异丙醇(245mg,4.08mmol)，EDCI(782mg,4.08mmol)，DMAP(498mg,4.08mmol)溶于DCM(10mL)中，氮气保护，室温反应过夜,TLC检测反应完毕，旋蒸除去DCM，加EtOAc溶解，用1N HCl 10mL×2洗，除去过量的DMAP，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩，过柱(DCM:MeOH＝20:1)得到化合物I-4(653mg，46％)。1H NMR(400MHz,CDCl3)δ5.94(s,1H),5.10-5.04(m,1H),4.0(d,J＝5.0Hz,2H),3.7(s,1H),3.44-3.36(m,1H),2.34-2.27(m,1H),2.17-2.07(m,1H),1.97-0.89(m,42H),0.65(s,3H)。
3、制备化合物I-5：
将原料4(2.27g,4.75mmol)，苯甲醇(770mg,7.12mmol)，EDCI(1.36g,7.12mmol)，DMAP(870mg,7.12mmol)溶于DCM(30mL)中，氮气保护，室温反应过夜，TLC检测反应完毕，旋蒸除去DCM，加EtOAc溶解，用1N HCl 10mL×2洗，除去过量的DMAP，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩，过柱(DCM:MeOH＝20:1)得到化合物I-5(1.72g，64％)。1H NMR(400MHz,CDCl3)δ7.39-7.32(m,5H),5.94(t,J＝4.8Hz,1H),5.18(s,2H),4.08(d,J＝5.2Hz,2H),3.7(s,1H),3.44-3.36(m,1H),2.34-2.27(m,1H),2.17-2.07(m,1H),1.97-0.89(m,36H),0.65(s,3H)；m/z(ESI)[M+Na]+＝590.5。
4、制备化合物I-6：
/>
A、将原料4(2.27g,4.75mmol)，化合物5(2.20g,7.12mmol)，EDCI(1.36g,7.12mmol)，DMAP(870mg,7.12mmol)溶于DCM(30mL)中，氮气保护，室温反应过夜，LC-MS检测反应完毕，加水淬灭，萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，过柱(DCM:MeOH＝20:1)得化合物6(750mg，21％)。1H NMR(400MHz,CDCl3)δ7.15(d,J＝8.5Hz,2H),7.03(d,J＝8.5Hz,2H),5.98(t,J＝5.2Hz,1H),5.0(d,J＝8.0Hz,1H),4.54(dd,J＝6.3Hz,J＝13.8Hz,1H),4.28(d,J＝5.2Hz,2H),4.15(t,J＝7.2Hz,2H),3.70(s,1H),3.40(s,1H),3.13-3.02(m,2H),2.37-2.29(m,1H),2.21-2.13(m,1H),1.97-0.89(m,48H),0.65(s,3H)。
B、将化合物6(750mg，0.98mmol)溶于DCM(10mL)中，室温下通入HCl气体，溶液由澄清变为浑浊，TLC检测反应完毕，旋蒸除去溶剂，乙醚带2次变为泡沫状固体，得到化合物I-6(550mg，84％)。1H NMR(400MHz,DMSO)δ8.67(d,J＝4.2Hz,3H),8.45(t,J＝5.7Hz,1H),7.30(d,J＝8.5Hz,2H),7.07(d,J＝8.5Hz,2H),4.24(dd,J＝6.8Hz,J＝12.4Hz,1H),4.14-4.08(m,4H),3.49(s,1H),3.24-3.03(m,3H),2.22-2.16(m,1H),2.12-2.05(m,1H),1.97-0.89(m,39H),0.59(s,3H)；m/z(ESI)[M-HCl+H]+＝669.5。
5、制备化合物I-1：
化合物3用NaOH水解或者化合物4用NaOH水溶液处理得到化合物I-1。
试验例1药代动力学试验
1、制剂配制和剂量给药：将适量的供试品精确称重，并与适当体积的溶媒混合，以获得清晰的溶液或均匀的悬浮液。在制备制剂后4小时内给动物给药。剂量制剂将按照设施标准操作规程通过口服管饲进行给药。剂量体积将由给药当天早上收集的动物体重决定。
2、采血：每次采血(每一时间点约0.2毫升)将在每一时间点从每只动物的颈静脉点穴进入聚丙烯管。所有血液样本将被转移到预冷的商业EDTA-K2试管中，并置于湿冰上，直到离心分离。
3、血浆处理：血液样本将在约4℃下离心(3200转/分，10分钟)处理。分别收集血浆，并在每个时间点将其转移到湿冰中的预先标记的PP管中，然后立即使用ACN(6IS)沉淀(血浆：ACN的比例为1:4)。再次离心(10分钟，12000转/分)并获得上清液。在干冰上快速冷冻，并保持在-70±10℃，直到进行LC/MS/MS分析。
4、肝脏处理：每个时间点采集肝组织，用预冷去离子水洗两次，滤纸吸干水分。肝组织立即采用10倍体积的甲醇-水溶液(1:2，v/v)甲醇-水溶液(1:2，v/v)匀浆，匀浆完立即取一分部肝组织匀浆液(比如200uL匀浆液)给到分析同事，在湿冰上沉淀样品之后，离心取上清，于-70±10℃冰箱贮存，直至LC-MS/MS分析。剩余肝匀浆液取800uL作为备用。
大鼠分别灌胃服用化合物(I-4、I-5、I-6和OCA，给药剂量均为0.0576mmol/kg)，分别在0.25、0.5、1、2、4、8、12、24h时间点取得大鼠血浆和肝脏样品，按照上述方法，用LC-MS/MS测试，分别测定上述化合物的体内活性代谢产物在血浆和肝脏中的浓度(见表1-4)。
大鼠灌胃化合物I-4后，测得大鼠体内活性化合物为化合物4，其在血浆和肝脏中的浓度见表1。
表1
血浆和肝脏总AUC＝110506，AUC Ratio＝肝脏/血浆＝105664/4845＝21.8。
大鼠灌胃化合物I-5后，测得大鼠体内活性化合物为化合物4，其在血浆和肝脏中的浓度见表2。
表2
血浆和肝脏总AUC＝150442，AUC Ratio＝肝脏/血浆＝142808/7634＝18.7。
大鼠灌胃化合物I-6后，测得大鼠体内活性化合物为化合物4，其在血浆和肝脏中的浓度见表3。
表3
血浆和肝脏总AUC＝87730，AUC Ratio＝肝脏/血浆＝83872/3858＝21.7。
大鼠灌胃奥贝胆酸后，测得大鼠体内活性化合物为奥贝胆酸(OCA)和化合物4，其在血浆和肝脏中的浓度见表4。
表4
血浆和肝脏总AUC＝91386；AUC Ratio＝肝脏/血浆＝43030/48356＝0.89。
大鼠灌胃化合物4后，测得大鼠体内活性化合物为化合物4，其在血浆和肝脏中的浓度见表5。
表5
血浆和肝脏总AUC＝117503，AUC Ratio＝肝脏/血浆＝14.7。
从表1、2、3和4的数据可以看出，灌胃大鼠化合物OCA后，大量的药物OCA(血浆中OCA的AUC+OCA-Gly的AUC总量为48360)在血液中循环，这可能导致其引起的皮肤副作用，而肝脏的总有效药物(肝脏OCA的AUC+OCA-Gly的AUC总量为43030)相应减少。而本发明所述化合物I-4、I-5和I-6分别同摩尔剂量灌胃大鼠后，肝脏的总有效药物量显著增加。尤其是，化合物I-5，肝脏有效药物AUC达到142808，是直接用OCA得到的肝脏有效药物的3.3倍。而血液中的有效药物AUC从直接用OCA的48360减少到7634，减少了84％。比较相同摩尔剂量奥贝胆酸-甘氨酸共轭物4与其苄酯I-5灌胃大鼠后，苄酯I-5产生的奥贝胆酸-甘氨酸共轭物4在肝脏/血浆的暴露量比达到18.7，而直接用奥贝胆酸-甘氨酸共轭物4产生的相应暴露量比只有14.7，酯酶富集于肝脏可能是苄酯I-5的肝靶向性更高的原因之一。苄酯I-5产生的化合物4的肝脏和血浆的总暴露量150442也较直接灌胃大鼠化合物4的117503显著提高28％。
因此，使用本发明所述的化合物治疗相应的肝脏疾病时，可望在提高治疗肝脏疾病药效的同时，显著减少对皮肤的副作用，而且达到同样疗效所需的用药剂量显著减少。
Claims (12)
1.一种式II化合物或其药学上可接受的盐，
其中：
R3为乙基；
R选自：乙基、正丙基、异丙基、正丁基、异丁基、各个X各自独立地选自：0个、1个、2个或3个选自：F、Cl、Br、I、-NH2、-OH、-甲氧基，乙氧基，丙氧基，异丙氧基、-CN、甲基、乙基、正丙基、异丙基、正丁基或异丁基的基团，或者各个X各自独立地为C5-C10的直链或支链烷基的任意碳原子被选自-O-、-CO-、-NH2、中的一种或几种基团置换所得的基团。
2.根据权利要求1所述的式II化合物或其药学上可接受的盐，其特征在于，选自下列化合物：
式I-7中：X是1个、2个或3个取代基，独立地选自F，Cl，Br，I，-CN，-NH2，-NO2或-OH，甲基，乙基，丙基，异丙基，甲氧基，乙氧基，丙氧基，异丙氧基；
式I-8中：X是1个、2个或3个取代基，独立地选自F，Cl，Br，I，-CN，-NH2，-NO2或-OH，甲基，乙基，丙基，异丙基，甲氧基，乙氧基，丙氧基，异丙氧基。
3.根据权利要求1或2所述的式II化合物或其药学上可接受的盐，其特征在于，所述药学上可接受的盐为式II化合物与酸形成的盐。
4.根据权利要求3所述的式II化合物或其药学上可接受的盐，其特征在于，所述酸为无机酸、有机酸；所述无机酸为盐酸、氢溴酸、氢碘酸、硫酸、硝酸、磷酸、碳酸；所述有机酸为甲酸、抗坏血酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、柠檬酸、枸橼酸、酒石酸、葡萄糖酸、酒石氢酸、葡萄糖醒酸、苦味酸、甲磺酸、乙磺酸、对甲苯磺酸、苯甲酸、苯磺酸、对溴苯磺酸、谷氨酸、水杨酸、双羟萘酸。
5.一种药物组合物，其特征在于，包含治疗有效剂量的权利要求1-4任一项所述的式II化合物或其药学上可接受的盐中的一种或多种，以及任选存在的药学上可接受的载体：
式II中：
R3和R的定义如权利要求1-4任一项所述。
6.根据权利要求5所述的药物组合物，其特征在于，所述药物组合物的剂型为口服制剂，注射剂型。
7.根据权利要求6所述的药物组合物，其特征在于，所述口服制剂为固体制剂、液体制剂。
8.根据权利要求7所述的药物组合物，其特征在于，所述固体制剂为片剂、粉剂、粒剂、胶囊；
所述液体制剂为水或油悬浮剂、糖浆。
9.权利要求1-4任一项所述的式II化合物或其药学上可接受的盐，或者权利要求5所述的药物组合物所述的在制备治疗非酒精性脂肪肝炎药物中的用途。
10.权利要求1-4任一项所述的式II化合物或其药学上可接受的盐，或者权利要求5所述的药物组合物在制备治疗原发性胆汁性肝硬化药物中的用途。
11.权利要求1-4任一项所述的式II化合物或其药学上可接受的盐，或者权利要求5任一项所述的药物组合物在制备治疗胆汁分泌相关的疾病药物中的用途。
12.根据权利要求11所述的用途，其特征在于，所述胆汁分泌相关的疾病为：门静脉高压、胆汁酸性腹泻、酒精性肝炎和原发性硬化性胆管炎。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2019107213980 | 2019-08-06 | ||
| CN201910721398 | 2019-08-06 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112341514A CN112341514A (zh) | 2021-02-09 |
| CN112341514B true CN112341514B (zh) | 2023-11-21 |
Family
ID=74358253
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010765952.8A Active CN112341514B (zh) | 2019-08-06 | 2020-08-03 | 脱氧胆酸类化合物、药物组合物及其用途 |
Country Status (4)
| Country | Link |
|---|---|
| US (1) | US20230146782A1 (zh) |
| EP (1) | EP4011899A4 (zh) |
| CN (1) | CN112341514B (zh) |
| WO (1) | WO2021023100A1 (zh) |
Citations (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001020331A1 (en) * | 1999-09-14 | 2001-03-22 | Xenoport, Inc. | Substrates and screening methods for transport proteins |
| WO2002044324A2 (en) * | 2000-10-06 | 2002-06-06 | Xenoport, Inc. | Bile-acid derived compounds for enhancing oral absorption and systemic bioavailability of drugs |
| WO2005082925A2 (en) * | 2004-02-26 | 2005-09-09 | Intercept Pharmaceuticals Inc. | Novel steroid agonist for fxr |
| CN101307088A (zh) * | 2008-07-08 | 2008-11-19 | 四川大学 | 一种胆酸偶联物的制备方法 |
| KR20090090432A (ko) * | 2008-02-21 | 2009-08-26 | 부산대학교 산학협력단 | 케노데옥시콜린산 유도체를 유효성분으로 함유하는 간암치료용 약학조성물 |
| WO2010062369A2 (en) * | 2008-11-03 | 2010-06-03 | Tufts University | Methods and compositions for inhibiting clostridium difficile spore germination and outgrowth |
| CN102225962A (zh) * | 2011-04-21 | 2011-10-26 | 东北林业大学 | 小檗碱9位酰胺键合胆酸的新衍生物及制备方法 |
| WO2013037482A1 (en) * | 2011-09-15 | 2013-03-21 | Phenex Pharmaceuticals Ag | Farnesoid x receptor agonists for cancer treatment and prevention |
| CN104789611A (zh) * | 2015-03-31 | 2015-07-22 | 国家海洋局第三海洋研究所 | 一种岩藻黄醇的制备方法 |
| WO2016073767A1 (en) * | 2014-11-06 | 2016-05-12 | Enanta Pharmaceuticals, Inc. | Bile acid analogs an fxr/tgr5 agonists and methods of use thereof |
| WO2017180577A1 (en) * | 2016-04-13 | 2017-10-19 | Intercept Pharmaceuticals, Inc. | Methods of treating cancer |
| WO2019023103A1 (en) * | 2017-07-24 | 2019-01-31 | Intercept Pharmaceuticals, Inc. | BILIARY ACID DERIVATIVES WITH ISOTOPIC MARKING |
-
2020
- 2020-07-31 US US17/632,532 patent/US20230146782A1/en active Pending
- 2020-07-31 WO PCT/CN2020/106117 patent/WO2021023100A1/zh unknown
- 2020-07-31 EP EP20850984.4A patent/EP4011899A4/en active Pending
- 2020-08-03 CN CN202010765952.8A patent/CN112341514B/zh active Active
Patent Citations (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001020331A1 (en) * | 1999-09-14 | 2001-03-22 | Xenoport, Inc. | Substrates and screening methods for transport proteins |
| WO2002044324A2 (en) * | 2000-10-06 | 2002-06-06 | Xenoport, Inc. | Bile-acid derived compounds for enhancing oral absorption and systemic bioavailability of drugs |
| WO2005082925A2 (en) * | 2004-02-26 | 2005-09-09 | Intercept Pharmaceuticals Inc. | Novel steroid agonist for fxr |
| KR20090090432A (ko) * | 2008-02-21 | 2009-08-26 | 부산대학교 산학협력단 | 케노데옥시콜린산 유도체를 유효성분으로 함유하는 간암치료용 약학조성물 |
| CN101307088A (zh) * | 2008-07-08 | 2008-11-19 | 四川大学 | 一种胆酸偶联物的制备方法 |
| WO2010062369A2 (en) * | 2008-11-03 | 2010-06-03 | Tufts University | Methods and compositions for inhibiting clostridium difficile spore germination and outgrowth |
| CN102225962A (zh) * | 2011-04-21 | 2011-10-26 | 东北林业大学 | 小檗碱9位酰胺键合胆酸的新衍生物及制备方法 |
| WO2013037482A1 (en) * | 2011-09-15 | 2013-03-21 | Phenex Pharmaceuticals Ag | Farnesoid x receptor agonists for cancer treatment and prevention |
| WO2016073767A1 (en) * | 2014-11-06 | 2016-05-12 | Enanta Pharmaceuticals, Inc. | Bile acid analogs an fxr/tgr5 agonists and methods of use thereof |
| CN104789611A (zh) * | 2015-03-31 | 2015-07-22 | 国家海洋局第三海洋研究所 | 一种岩藻黄醇的制备方法 |
| WO2017180577A1 (en) * | 2016-04-13 | 2017-10-19 | Intercept Pharmaceuticals, Inc. | Methods of treating cancer |
| WO2019023103A1 (en) * | 2017-07-24 | 2019-01-31 | Intercept Pharmaceuticals, Inc. | BILIARY ACID DERIVATIVES WITH ISOTOPIC MARKING |
Non-Patent Citations (8)
| Title |
|---|
| 9-(Chloromethyl)anthracene:ausefulderivatizingreagentforenhanced ultraviolet and fluorescence detection of carboxylic acids with liquid chromatography;W.D.KORTE;《Journal of Chromatography》;19821231(第243期);第153-157页 * |
| Chenodeoxycholic Acid Derivative HS-1200 Inhibits Hepatocarcinogenesis and Improves Liver Function in Diethylnitrosamine-Exposed Rats by Downregulating MTH1;Miao Xu 等;《BioMed Research International》;20170101;第2017卷;第1-9页 * |
| Design, Synthesis and Photochemical Properties of Caged Bile Acids;Yuuki Hirayama 等;《Bioorganic & Medicinal Chemistry Letters》;20030301;第13卷(第5期);第905-908页 * |
| N-Cholyl Amino Acid Alkyl Esters 2 A Novel Class of Organogelators;Hendra M. Willemen等;《EUR.J.Org.Chem.》;20011231(第12期);第2329-2335页 * |
| Structural requirements of bile acid transporters: C-3 and C-7 modifications;Vidula Kolhatkar 等;《European Journal of Pharmaceutical Science》;20130303(第46期);第86-99页 * |
| Synthesis and Evaluation of Bile Acid–Ribavirin Conjugates as Prodrugs to Target the Liver;ZHONGQI DONG 等;《JOURNAL OF PHARMACEUTICAL SCIENCES》;20150901;第104卷(第9期);第2864-2876页 * |
| Synthesis of 3-Glucuronides of Unconjugated and Conjugated Bile Acids;Goto Junichi等;《Chem Pharm Bull》;19801231;第28卷(第4期);第1258-1264页 * |
| 鹅脱氧胆酸衍生物HS-1200诱导人肝癌细胞株凋亡的作用及机制;秦成勇 等;《世界华人消化杂志》;20100308;第18卷(第7期);第641-645页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| EP4011899A1 (en) | 2022-06-15 |
| CN112341514A (zh) | 2021-02-09 |
| US20230146782A1 (en) | 2023-05-11 |
| EP4011899A4 (en) | 2022-09-28 |
| WO2021023100A1 (zh) | 2021-02-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP3260463B1 (en) | Deuterated chenodeoxycholic acid derivative and pharmaceutical composition comprising compound thereof | |
| EP3336097B1 (en) | Preparation of the non-crystalline form of obeticholic acid | |
| TW202003480A (zh) | 用於製備1,5-苯并噻氮呯化合物之方法 | |
| WO2011083304A1 (en) | Prodrugs of opioids and uses thereof | |
| RU2659784C2 (ru) | Сложноэфирное хиральное соединение (n-замещенный имидазол)-карбоновой кислоты, содержащее простую эфирную боковую цепь, его получение и применение | |
| CN112543755A (zh) | 一类细胞坏死抑制剂及其制备方法和用途 | |
| US10273263B2 (en) | Pro-drug forming compounds | |
| WO2013000286A1 (zh) | 蟾毒配基衍生物及其制备方法、包含该衍生物的组合物、及其用途 | |
| CN103622954A (zh) | 倍半萜内酯类化合物及其衍生物在糖尿病中的应用 | |
| EP4153589A1 (en) | Ampk activators | |
| CN102304103A (zh) | 一种非诺贝特酸盐、制备方法、药物组合物及应用 | |
| CN114948953A (zh) | 一种杂原子取代芳香类化合物及其盐的用途 | |
| EP3747881B1 (en) | Nitrogen-containing benzoheterocycle compound comprising carboxylic acid group, preparation method and use thereof | |
| EP3177599A1 (en) | Fumarate analogs and uses thereof in the treatment of an autoimmune disease or an inflammatory disease | |
| TWI665211B (zh) | 去氧膽酸之組成物及用途及其相關方法 | |
| CN112341514B (zh) | 脱氧胆酸类化合物、药物组合物及其用途 | |
| CN112334467A (zh) | Fxr受体激动剂 | |
| CN112321452B (zh) | 厚朴酚衍生物、和厚朴酚衍生物及其盐酸盐、制备方法及应用 | |
| WO2023193563A1 (zh) | 一种噻吩并吡啶化合物的晶型a、制备方法及其药物组合物 | |
| JP2019531353A (ja) | 重水素化化合物及びその医薬的用途 | |
| CN116375634A (zh) | 卡瑞斯汀对甲苯磺酸盐的晶型和无定型 | |
| WO2021088762A1 (zh) | 肝靶向药、其药物组合物及其用途 | |
| CN114671839A (zh) | 达格列净的固体形式复合物及其制备方法与应用 | |
| CN110256461B (zh) | 稠杂嘧啶衍生物及其制备方法和应用 | |
| CN108210933B (zh) | 一种地佐辛与聚乙二醇的结合物 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |