CN104672290B - A kind of medicine of disease for preventing or treating FXR mediations and its production and use - Google Patents
A kind of medicine of disease for preventing or treating FXR mediations and its production and use Download PDFInfo
- Publication number
- CN104672290B CN104672290B CN201510002830.2A CN201510002830A CN104672290B CN 104672290 B CN104672290 B CN 104672290B CN 201510002830 A CN201510002830 A CN 201510002830A CN 104672290 B CN104672290 B CN 104672290B
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- disease
- pharmaceutically acceptable
- acceptable salt
- 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.)
- Expired - Fee Related
Links
- 239000003814 drug Substances 0.000 title claims abstract description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 12
- 201000010099 disease Diseases 0.000 title claims abstract description 11
- 238000004519 manufacturing process Methods 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 88
- 238000002360 preparation method Methods 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 239000003826 tablet Substances 0.000 claims description 6
- 210000001367 artery Anatomy 0.000 claims description 5
- 208000034189 Sclerosis Diseases 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 239000003999 initiator Substances 0.000 claims description 3
- 238000002347 injection Methods 0.000 claims description 3
- 239000007924 injection Substances 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 2
- 208000035150 Hypercholesterolemia Diseases 0.000 claims description 2
- 239000000853 adhesive Substances 0.000 claims description 2
- 230000001070 adhesive effect Effects 0.000 claims description 2
- 239000003963 antioxidant agent Substances 0.000 claims description 2
- 230000003078 antioxidant effect Effects 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 239000007910 chewable tablet Substances 0.000 claims description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 2
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 208000016097 disease of metabolism Diseases 0.000 claims description 2
- 239000000945 filler Substances 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 238000005984 hydrogenation reaction Methods 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 208000006575 hypertriglyceridemia Diseases 0.000 claims description 2
- 208000019423 liver disease Diseases 0.000 claims description 2
- 239000000314 lubricant Substances 0.000 claims description 2
- 208000030159 metabolic disease Diseases 0.000 claims description 2
- 229940100688 oral solution Drugs 0.000 claims description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 2
- 239000000049 pigment Substances 0.000 claims description 2
- 239000003755 preservative agent Substances 0.000 claims description 2
- 230000002335 preservative effect Effects 0.000 claims description 2
- 239000003223 protective agent Substances 0.000 claims description 2
- 239000000829 suppository Substances 0.000 claims description 2
- 239000004094 surface-active agent Substances 0.000 claims description 2
- 239000000375 suspending agent Substances 0.000 claims description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical group FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims 1
- 208000024172 Cardiovascular disease Diseases 0.000 claims 1
- 208000032928 Dyslipidaemia Diseases 0.000 claims 1
- 208000017170 Lipid metabolism disease Diseases 0.000 claims 1
- 239000011248 coating agent Substances 0.000 claims 1
- 239000007884 disintegrant Substances 0.000 claims 1
- 208000028774 intestinal disease Diseases 0.000 claims 1
- 210000002784 stomach Anatomy 0.000 claims 1
- 208000018556 stomach disease Diseases 0.000 claims 1
- 235000019605 sweet taste sensations Nutrition 0.000 claims 1
- 230000001404 mediated effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene chloride Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 35
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 26
- 239000000203 mixture Substances 0.000 description 24
- 239000000243 solution Substances 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- 235000019439 ethyl acetate Nutrition 0.000 description 18
- 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 description 17
- 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 description 15
- 239000004380 Cholic acid Substances 0.000 description 15
- 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 15
- 229960002471 cholic acid Drugs 0.000 description 15
- 235000019416 cholic acid Nutrition 0.000 description 15
- 238000005160 1H NMR spectroscopy Methods 0.000 description 14
- 241000700159 Rattus Species 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 10
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 9
- 239000012266 salt solution Substances 0.000 description 9
- 229910052938 sodium sulfate Inorganic materials 0.000 description 9
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 9
- 239000007832 Na2SO4 Substances 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 5
- 229940126062 Compound A Drugs 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 239000000370 acceptor Substances 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 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 4
- 229960001091 chenodeoxycholic acid Drugs 0.000 description 4
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 235000012000 cholesterol Nutrition 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 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 2
- 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 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- SMEROWZSTRWXGI-UHFFFAOYSA-N Lithocholsaeure Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 SMEROWZSTRWXGI-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound 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 description 2
- 229960003964 deoxycholic acid Drugs 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- -1 ethyl chenodeoxycholic acids Chemical class 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 2
- 210000003405 ileum Anatomy 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- SMEROWZSTRWXGI-HVATVPOCSA-N lithocholic acid Chemical compound 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)CC1 SMEROWZSTRWXGI-HVATVPOCSA-N 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- UYVVLXVBEQAATF-UHFFFAOYSA-N 4-(1,3,7,12-tetrahydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl)pentanoic acid Chemical compound OC1CC2CC(O)CC(O)C2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 UYVVLXVBEQAATF-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- 241000272814 Anser sp. Species 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- OAADDYAILOPMMY-UWSJZGMXSA-N CCC([C@H]1C[C@@H](CC2)O)(C1[C@@]2(C)C(CC1)C2C(CC3)[C@@]1(C)[C@]31C(CCC(O)=O)[C@H]1C)[C@H]2O Chemical compound CCC([C@H]1C[C@@H](CC2)O)(C1[C@@]2(C)C(CC1)C2C(CC3)[C@@]1(C)[C@]31C(CCC(O)=O)[C@H]1C)[C@H]2O OAADDYAILOPMMY-UWSJZGMXSA-N 0.000 description 1
- 0 CC[C@](C(C[C@@](CC1)O)[C@@]1(C)C(CC1)C2C(CC3)[C@@]1(C)*3[C@](C)CCC(OCC(C)C)=O)[C@]2O Chemical compound CC[C@](C(C[C@@](CC1)O)[C@@]1(C)C(CC1)C2C(CC3)[C@@]1(C)*3[C@](C)CCC(OCC(C)C)=O)[C@]2O 0.000 description 1
- 102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 description 1
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 108091027981 Response element Proteins 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 210000004100 adrenal gland Anatomy 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000002300 anti-fibrosis Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000012490 blank solution Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000004700 cellular uptake Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 208000010643 digestive system disease Diseases 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 230000002183 duodenal effect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000009123 feedback regulation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 208000018685 gastrointestinal system disease Diseases 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 231100000753 hepatic injury Toxicity 0.000 description 1
- 239000000833 heterodimer Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000010813 internal standard method Methods 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 238000013252 liver disease animal model Methods 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 1
- 102000027507 nuclear receptors type II Human genes 0.000 description 1
- 108091008686 nuclear receptors type II Proteins 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 108090000629 orphan nuclear receptors Proteins 0.000 description 1
- 102000004164 orphan nuclear receptors Human genes 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000009790 rate-determining step (RDS) Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- GRONZTPUWOOUFQ-UHFFFAOYSA-M sodium;methanol;hydroxide Chemical compound [OH-].[Na+].OC GRONZTPUWOOUFQ-UHFFFAOYSA-M 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Substances C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 1
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 239000010937 tungsten Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
- C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of medicine of disease for preventing or treating FXR mediations and its production and use.Wherein, for preventing or treating the medicine of the disease that FXR is mediated with the structure shown in (I),Wherein, R is CO (O) R ' or P (O) (OH)2, wherein R ' is C1‑C6Alkyl.Compound half-life of the invention significantly extends, and Oral availability is significantly improved.
Description
Technical field
The present invention relates to a kind of medicine of disease for preventing or treating FXR- mediations and its production and use.
Background technology
Method Buddhist nun ester X acceptors (FXR) is orphan nuclear receptor family member, is equal to nineteen ninety-five in rat liver by Forman earliest
Cloned in cDNA library and found, because its transcriptional activity can be named by the enhancing of the method Buddhist nun ester of supraphysiologic levels.Northern and original
Position analysis display FXR is in lung, intestines, great expression in kidney, and adrenal gland.FXR is formed with 9- cis-retinoic acids acceptor (RXR)
Heterodimer is combined with DNA.FXR/RXR heterodimers preferentially with by have AG (G/T) TCA double-core acceptor half site group
Into composition combine, it forms inverted repeat and the single nucleosides of an ancient exorcistic ceremony separates (IR-1 die bodys).However, these compounds cannot be activated
Mouse and mankind FXR so that the naturality of endogenous FXR aglucons does not know also.Some abiogenous cholic acid are in physiological concentration
Lower combination simultaneously activates FXR.Cholic acid as FXR aglucons includes chenodesoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid
(LCA), and these cholic acid taurine and amion acetic acid conjugate.
Cholic acid is to form and be secreted into duodenal cholesterol metabolic product in liver, and it is in food fat and Wei Sheng
Play an important roll in the dissolving and absorption of element.Most of cholic acid are then absorbed and are returned to by enterohepatic circulatory system in ileum
Liver.Cholesterol is changed into feedback regulation to cholic acid in liver：Cholic acid lowers the transcription of Cytochrome P450 7a (CYP7a),
The enzyme of its coding catalysis cholic acid biosynthesis rate-limiting step.Data display FXR is relevant to the suppression that CYP7a is expressed with cholic acid, though
So accurate mechanism is still not known.In ileum, the expression of cholic acid induction enteral cholic acid associated proteins (IBABP), its be it is a kind of with
High-affinity is combined with cholic acid, and the intracellular protein related to its cellular uptake and transhipment.Two groups to have been found that cholic acid is escaped too drastic
FXR living adjusts it for the effect that IBABP is expressed, and the FXR combination mankind guard in rat, and mouse IBABP gene promoters
IR-1 type response elements.The activation (IBABP) and suppression of the target gene in these FXR and cholic acid and cholesterol
(CYP7a) it is related.
EP 1392714 discloses 3 а, 7 а-bis- а of hydroxyl-6-β of ethyl-5-cholane-24- carboxylic acids (i.e. 6- ethyls-goose deoxidation
Cholic acid, 6-EDCA).Clinical research proves, its can activation method Buddhist nun ester X acceptors (FXR), with anti-silt courage, the effect of anti-fibrosis,
There is certain curative effect to PBC (PBC).It is the medicine of a treatment NASH, it is a large amount of in early stage
Animal experiment in, can effectively prevent even reverse liver disease animal model progressivity liver fibrosis caused by hepatic injury.But
The medicine still has half-life short, Oral availability defect not high.
The content of the invention
In order to overcome the defect of prior art, the present invention to provide a kind of for preventing or treating the new of the disease of FXR- mediations
Medicine, i.e. the precursor compound of 6-a ethyls chenodeoxycholic acid, compared with 6-a ethyl chenodeoxycholic acids, half-life period shows the medicine
Extension is write, Oral availability is significantly improved.The present invention also provides the Preparation method and use of the medicine.
The present invention is achieved by the following technical solution.
On the one hand, the present invention provides the compound or its pharmaceutically acceptable salt shown in a kind of formula (I),
Wherein, R is CO (O) R ' or P (O) (OH)2, wherein R ' is C1-C6Alkyl.
Preferably, in formula (I), R is CO (O) R ', and wherein R ' is C1-C6Alkyl, preferably C1-C4Alkyl.When R is
During CO (O) R ', the compound of formula (I) can be expressed as lower formula (II)：
Preferably, in formula (I), R is CO (O) R ', and R ' is C1-C6Alkyl, preferably C1-C4Alkyl, and R ' be second
Base.
Preferably, in formula (I), R is CO (O) R ', and R ' is methyl, propyl group, isopropyl, butyl or isobutyl group；Preferably, R '
It is propyl group, isopropyl, butyl or isobutyl group；It is highly preferred that R ' is propyl group or isopropyl.
Preferably, the compound of formula (I) is：
On the other hand, the present invention provides a kind of preparation method of the compound shown in formula (II),
The preparation method includes：Make the step of compound and R ' OH are reacted shown in formula (III)；
Wherein, R ' is defined as described above.
Preferably, the compound shown in formula (III) is prepared by the following method：
(1) compound and R shown in formula 1 are made1OH reacts the compound shown in the formula of being formed 2；
(2) compound and organosilyl protective agents shown in formula 2, such as TMSCl is made to react the compound shown in the formula of being formed 3；
(3) compound of formula 3 is made in initiator, such as BF3-OEt2In the presence of with acetaldehyde reaction, then slough organosilicon guarantor
Shield base, forms the compound shown in formula 4；
(4) compound shown in formula (III) is formed after compound hydrogenation, the hydrolysis shown in formula 4；
Wherein, R1It is C1-C4Alkyl, preferably methyl.
Another aspect, the compound or its pharmaceutically acceptable salt that the present invention provides described in a kind of formula (I) is preparing use
Purposes in the disease or the medicine of situation for preventing and/or treating FXR- mediations.
Preferably, the disease or situation of FXR- mediation are selected from chronic liver disease, gastrointestinal disease, ephrosis, angiocardiopathy,
Silt courage is lacked of proper care, metabolic disease；Preferably, the ephrosis is diabetic nephropathy；The angiocardiopathy is selected from artery sclerosis, blood fat
Obstacle, hypercholesterolemia, wherein hypertriglyceridemia, artery sclerosis are atherosclerosis.
Another further aspect, the present invention also provides a kind of pharmaceutical composition, and the pharmaceutical composition includes the compound described in formula (I)
Or its pharmaceutically acceptable salt, and pharmaceutically acceptable auxiliary material.
Preferably, described pharmaceutical composition is tablet, suppository, dispersible tablet, enteric coatel tablets, chewable tablets, oral disintegrating tablet, capsule, sugar
Clothing agent, granule, dry powder doses, oral solution, the small pin of injection, injection freeze-dried powder or big transfusion；
Preferably, the pharmaceutically acceptable auxiliary material includes following one or more：Diluent, solubilizer, disintegration
Agent, suspending agent, lubricant, adhesive, filler, flavouring, sweetener, antioxidant, surfactant, preservative, parcel
Agent and pigment.
Medicine of the invention is the precursor compound of existing 6-a ethyls chenodeoxycholic acid, is gone with existing 6-a ethyls goose
Oxycholic acid is compared, and half-life period significantly extends, and Oral availability is significantly improved.
Brief description of the drawings
Hereinafter, embodiments of the invention are described in detail with reference to accompanying drawing：
Fig. 1-Fig. 6 is respectively the active compound (chemical combination shown in formula (III) after the oral compound A-F of the invention of male SD rat
Thing) PC, wherein Fig. 1 is compound A, and Fig. 2 is compound B, and Fig. 3 is compound C, and Fig. 4 is compound D, Fig. 5 to change
Compound E；Fig. 6 is compound F.
Specific embodiment
Illustrate technical scheme by way of example below, but following examples are not intended to limit the present invention
Scope.
In following examples,1H H NMR spectroscopies Bruker Avance III 400MHz and Bruker Fourier300MHz
Nuclear magnetic resonance spectrometer detects that tetramethylsilane (TMS) is used as internal standard.
LCMS uses the serial level Four bar mass spectrograph (posts of Agilent LC/MSD 1200：ODS 2000(50×4.6mm,5μ
M), with ES (+) or (-) for ionization mode is run, T=30 DEG C；Flow velocity=1.5mL/min；Detection wavelength：214nm.
The preparation of the compound shown in the formula of embodiment 1 (III)
To adding p-TsOH.H in methyl alcohol (60mL) solution of compound 1 (2.5g, 6.4mmol)2O (p-methyl benzenesulfonic acid one
Hydrate) (0.12g, 0.64mmol).The mixture of formation is stirred at room temperature 3 hours.Evaporation solvent under reduced pressure, residue is molten
Solution is in EtOAc (ethyl acetate) (150mL).With NaHCO3(saturation, 100mL), water (50mL) and salt solution (50mL) washing two
Secondary, organic layer is with Na2SO4Dry, and evaporation under reduced pressure is obtaining the white solid (2.5g, 96%) of product 2.
1H NMR(400MHz,CDCl3):δ 3.66 (s, 3H), 3.60 (m, 1H), 2.85 (dd, J=12.4,6.0Hz, 1H),
2.47-2.30(m,2H),2.28-2.20(m,2H),2.05-1.60(m,10H),1.50-1.09(m,14H),0.92(d,3H),
0.65 (m, J=6.4Hz, 3H)
To the dry tetrahydrofuran (30mL) of diisopropylamine (5.2mL, 39.5mmol) under -78 DEG C, nitrogen atmosphere
The solution of n-BuLi (15.8mL, 2.5M hexane solution, 39.5mmol) is added dropwise in solution.After stirring 30 minutes, plus
Enter trim,ethylchlorosilane (9.0mL, 48.5mmol), the mixture of formation is stirred for 10 minutes at -78 DEG C, by compound 2
Dry tetrahydrofuran (10mL) solution of (2.5g, 6.2mmol) was added dropwise in the mixture in 30 minutes.By the system
Kept again at -78 DEG C 30 minutes, then add triethylamine (12.1mL, 90mmol).After 1 hour, reactant mixture is heated
To -20 DEG C, with NaHCO3Saturated aqueous solution (25mL) treatment, was warmed up at room temperature in 3 hours.Separate organic phase, water with
EtOAc (3x 25mL) is extracted.With NaHCO3The organic phase that saturated aqueous solution, water and salt water washing merge.With anhydrous Na2SO4It is dry
After dry, vaporising under vacuum solvent is obtaining the crude product of 3 g of compound 3：Rf=0.86 (PE/EtOAc, 9:1) (petroleum ether/second
Acetoacetic ester, 9:1)；1H NMR(400MHz,CDCl3):δ 4.57 (dd, J=6.0,1.6Hz, 1H), 3.69 (s, 3H), 3.53 (m,
1H), 0.94 (d, J=6.4Hz, 3H), 0.84 (s, 3H), 0.70 (s, 3H), 0.13-0.18 (m, 18H)
To (- 78 DEG C) acetaldehyde (0.65mL, 11.0mmol) and -5 β of the trimethyl silicane alkoxy-courage -6- of 3 α, 7- bis- of cooling
Alkene -24-'s acid methyl esters 3 (3.0g) dries CH2Cl2BF is added dropwise in the mixed solution of (20mL)3-OEt2(22.0mmol's)
CH2Cl2Solution 15mL.Reactant mixture stirs 2h at -78 DEG C, is heated to room temperature.Mixture is with NaHCO3Saturated solution end
Only react, with CH2Cl2Extraction.With the organic extract that salt water washing merges, (Na is dried2SO4), and be concentrated under vacuum.Slightly
Residue is dissolved in CH2Cl2In (45mL), processed with HCl (3N, 10mL), and stirred 1 hour at 0 DEG C.Reactant mixture with
NaHCO3The saturated aqueous solution terminating reaction of (25mL), and with CH2Cl2Extraction.With anhydrous Na2SO4Dry the organic phase for merging, mistake
Filter, evaporates under reduced pressure.Thick residue uses PE/EtOAc (petrol ether/ethyl acetate) 7 on a silica gel column:3 is logical as eluent
Cross flash chromatography to be purified, to obtain 1.2 grams of compound 4 (two steps 45%).1H NMR(400MHz,CDCl3):δ6.17
(q, J=7.2Hz, 1H), 3.56-3.69 (m, 4H), 2.55-2.58 (m, 1H), 1.68 (d, J=7.17Hz, 3H), 1.00 (s,
3H), 0.92 (d, J=6.4Hz, 3H), 0.63 (s, 3H)
Glacial acetic acid/HCl (50/2.5mL, v/v) solution of compound 4 (1.0g, 2.3mmol) is deposited in platinum oxide (0.2g)
Hydrogenated 24 hours under 50psi under.Filtering catalyst, filtrate is concentrated.Residue adds water (50mL) and EtOAc (50mL)
Mixture in, with NaHCO3Saturated aqueous solution neutralize.With the water layer of EtOAc (3x 50mL) extract and separate.With salt water washing
The organic phase of merging, dries (Na2SO4), evaporate under reduced pressure.Crude product using NaOH methanol solution (10%,
100mL) hydrolyse over night.Then mixture is concentrated under vacuum, is diluted with water, be acidified with 11N HCl, with ethyl acetate (3x
50mL) extract.With the organic phase that salt water washing is collected, with anhydrous Na2SO4Dry, evaporate under reduced pressure.Residue is dissolved in THF/
H2O solution (100mL, 4:1, v/v) in, with NaBH4Process at room temperature overnight.After solvent evaporation, residue is diluted with water, with
HCl 3N are acidified, with DCM/MeOH 9：1 (3x 50mL) is extracted.With the organic phase that salt water washing merges, with anhydrous Na2SO4It is dry
It is dry, evaporate under reduced pressure.Thick residue uses methylene chloride/methanol (7:3, v/v) pass through fast on silica column as eluent
Fast chromatogram is purified, to obtain 0.5 gram of compound (III) (50% yield).1H NMR(300MHz,CDCl3):δ3.72
(s, 1H), 3.47-3.38 (m, 1H), 0.94 (d, J=6.6Hz, 3H), 0.91-0.89 (m, 6H), 0.67 (s, 3H) .LC-MS:
m/z 385.3[M-H]-.
The preparation of the compound A of embodiment 2
To addition TsOH (p-methyl benzenesulfonic acid) in MeOH (10mL) solution of compound (III) (83mg, 0.2mmol)
(5.1mg,0.03mmol).Mixture is stirred at room temperature 16 hours.Solvent evaporates under reduced pressure, and residue is dissolved in EtOAc
In (20ml), washed with the aqueous solution (2x10ml) of saturated sodium bicarbonate, water (10ml) and salt solution (10ml).Organic layer is with anhydrous
Sodium sulphate is dried, and is evaporated.Residue is purified (with DCM/MeOH (methylene chloride/methanol)=100 on silica gel by column chromatography:1 to
80:1 wash-out), to obtain the white solid (42mg, 50%) of compound A.
1H NMR(400MHz,CDCl3):3.70(s,1H),3.66(s,3H),3.43-3.37(m,1H),2.39-2.31
(m, 1H), 2.26-2.18 (m, 1H), 1.00 (td, J=14.0,3.2Hz, 1H), 0.93-0.388 (m, 9H), 0.66 (s, 3H)
.LC-MS:m/z 869.7[2M+H]+,452.3[M+H2O]+.
The preparation of the compound B of embodiment 3
To in EtOH (10mL) solution of compound (III) (83mg, 0.2mmol) add TsOH (5.1mg,
0.03mmol).Mixture is stirred at room temperature 16 hours.Solvent is evaporated under reduced pressure, and residue is dissolved in EtOAc (20ml),
Washed with the aqueous solution (2x 10ml) of saturated sodium bicarbonate, water (10ml) and salt solution (10ml).Organic layer is dry with anhydrous sodium sulfate
It is dry, it is evaporated.Residue is purified (with DCM/MeOH=100 on silica gel by column chromatography:1 to 80:1 wash-out), to obtain compound B
White solid (30mg, 36%).
1H NMR(400MHz,CDCl3):4.12 (q, J=7.2Hz, 2H), 3.70 (s, 1H), 3.43-3.35 (m, 1H),
2.38-2.30(m,1H),2.26-2.18(m,1H),0.95-0.86(m,12H),0.66(s,3H).LC-MS:m/z 897.7
[2M+H]+,466.4[M+H2O]+.
The preparation of the compound C of embodiment 4
To in normal propyl alcohol (10mL) solution of compound (III) (83mg, 0.2mmol) add TsOH (5.1mg,
0.03mmol).Mixture is stirred at room temperature 16 hours.Solvent is evaporated under reduced pressure, and residue is dissolved in EtOAc (20ml),
Washed with the aqueous solution (2x 10ml) of saturated sodium bicarbonate, water (10ml) and salt solution (10ml).Organic layer is dry with anhydrous sodium sulfate
It is dry, it is evaporated.Residue is purified (with DCM/MeOH=100 on silica gel by column chromatography:1 to 80:1 wash-out), to obtain compound C
White solid (42mg, 50%).
1H NMR(400MHz,CDCl3):4.02 (t, J=6.8Hz, 2H), 3.70 (s, 1H), 3.45-3.37 (m, 1H),
2.38-2.30(m,1H),2.26-2.18(m,1H),0.95-0.86(m,12H),0.66(s,3H).LC-MS:m/z 925.8
[2M+H]+,480.4[M+H2O]+.
The preparation of the compound D of embodiment 5
To in isopropanol (10mL) solution of compound (III) (83mg, 0.2mmol) add TsOH (5.1mg,
0.03mmol).Mixture flows back 16 hours at 95 DEG C.Solvent is evaporated under reduced pressure, and residue is dissolved in EtOAc (20ml),
Washed with the aqueous solution (2x 10ml) of saturated sodium bicarbonate, water (10ml) and salt solution (10ml).Organic layer is dry with anhydrous sodium sulfate
It is dry, it is evaporated.Residue is purified (with DCM/MeOH=100 on silica gel by column chromatography:1 to 80:1 wash-out), to obtain compound D
White solid (35mg, 42%).
1H NMR(400MHz,CDCl3):5.00 (heptet, J=6.4Hz, 1H), 3.70 (s, 1H), 3.45-3.37 (m,
1H), 2.38-2.30 (m, 1H), 2.26-2.18 (m, 1H), 1.29 (d, J=6.4Hz, 6H), 0.95-0.86 (m, 9H), 0.66
(s,3H).LC-MS:m/z 925.7[2M+H]+,480.4[M+H2O]+.
The preparation of the compound E of embodiment 6
To in isobutanol (10mL) solution of compound (III) (83mg, 0.2mmol) add TsOH (5.1mg,
0.03mmol).Mixture is stirred 16 hours at 40 DEG C.Solvent is evaporated under reduced pressure, and residue is dissolved in EtOAc (20ml),
Washed with the aqueous solution (2x 10ml) of saturated sodium bicarbonate, water (10ml) and salt solution (10ml).Organic layer is dry with anhydrous sodium sulfate
It is dry, it is evaporated.Residue is purified (with DCM/MeOH=100 on silica gel by column chromatography:1 to 80:1 wash-out), to obtain compound E
White solid (40mg, 47%).
1H NMR(400MHz,CDCl3):3.84 (d, J=6.4Hz, 2H), 3.70 (s, 1H), 3.45-3.37 (m, 1H),
2.38-2.30(m,1H),2.26-2.18(m,1H),0.95-0.86(m,15H),0.66(s,3H).LC-MS:m/z 953.8
[2M+H]+,441.3[M-2H2O+H]+,944.4[M+H2O]+.
The preparation of the compound F of embodiment 7
To in n-butanol (10mL) solution of compound (III) (83mg, 0.2mmol) add TsOH (5.1mg,
0.03mmol).Mixture is stirred at room temperature 16 hours.Solvent is evaporated under reduced pressure, and residue is dissolved in EtOAc (20ml),
Washed with the aqueous solution (2x 10ml) of saturated sodium bicarbonate, water (10ml) and salt solution (10ml).Organic layer is dry with anhydrous sodium sulfate
It is dry, it is evaporated.Residue is purified (with DCM/MeOH=100 on silica gel by column chromatography:1 to 80:1 wash-out), to obtain compound E
White solid (45mg, 52%).
1H NMR(400MHz,CDCl3):4.06 (t, J=6.4Hz, 1H), 3.70 (s, 1H), 3.45-3.37 (m, 1H),
2.37-2.28(m,1H),2.25-2.15(m,1H),0.95-0.86(m,12H),0.66(s,3H).LC-MS:m/z 953.8
[2M+H]+,944.4[M+H2O]+.
The preparation of the compound G of embodiment 8
Et is added in DCM (10mL) solution at 0 DEG C to compound (III) (552mg, 3.09mmol)3N(1.25g,
12.4mmol) and Ac2O(949mg,9.30mmol).Mixture is stirred 1 hour at 0 DEG C, is stirred 3 hours at room temperature.Dropwise plus
Enter DCM (10mL) solution of DMAP (753mg, 6.18mmol).Mixture is stirred 10 hours at 45 DEG C.Then DCM is passed through
(100mL) dilutes, and is washed by water (100mL) and salt solution (100mL), with Na2SO4Dry, filtering, concentration.Crude product is in silica gel
It is upper to be purified (with PE/EtOAc=50 by column chromatography:1 to 10:1 wash-out), with obtain compound 6 white solid (650mg,
80%).
1H NMR(400MHz,CDCl3):δ0.67(s,3H),0.90-0.93(m,9H),2.02(s,3H),2.10(s,
3H),2.42-2.21(m,4H),4.57(m,1H),5.10(s,1H)
To addition NIS (346mg, 2.0mmol) in DCE (10mL) solution of compound 6 (500mg, 0.99mmol).Mixing
Thing flows back 4 hours under 500W tungsten lamps.The mixture of formation is added dropwise to NaHSO3In solution.Then DCM is passed through
(100mL) dilutes, and is washed by water (40mL) and salt solution (30mL), with Na2SO4It is dried, filters, concentration.Crude product is in silicon
Purified (with PE/EtOAc=50 by column chromatography on glue:1 to 30:1 wash-out), to obtain the pale yellow oil of compound 7
(250mg, 43%).
1H NMR(400MHz,CDCl3):δ0.67(s,3H),0.90-0.95(m,12H),2.02(s,3H),2.08(d,
3H), (s, the 1H) of 3.09 (m, 1H), 3.31 (m, 1H), 4.57 (m, 1H), 5.10
By the P (OEt) of compound 7 (552mg, 0.94mmol)3(5mL) solution flows back 5 hours.Cooling mixture, concentration
To obtain residue.By preparing thin-layer chromatography (PE/EtOAc=2:1) purify, to obtain the nothing of compound 8 (400mg, 71%)
Color grease.(I2As TLC coloring agents)
1H NMR(400MHz,CDCl3):δ 0.58 (s, 3H), 0.85-0.96 (m, 12H), 1.97 (s, 3H), 2.01 (s,
3H), 4.02 (d, J=7.2Hz, 4H), 4.50 (m, 1H), 5.03 (s, 1H)
In DCM (5mL) solution at 0 DEG C to compound 8 (400mg, 0.67mmol) add TMSI (536mg,
2.68mmol).Mixture is stirred at room temperature 12 hours, concentrates the mixture.To in residue add NaOMe (400mg,
MeOH (8mL) solution 7.4mmol).The mixture of formation is stirred 10 hours at 60 DEG C.Then diluted by DCM (20mL),
Washed by water (10mL).Inorganic layer is adjusted to PH=3, concentrates to obtain solid.Solid is diluted in MeOH, is filtered.
Concentrated screening, to obtain residue, is purified, to obtain target compound G (94mg, 30%) by preparative high performance liquid chromatography
White solid.
1H NMR(400MHz,DMSO-d6+D2O):δ0.61(s,3H),0.80-0.94(m,9H),1.00-1.60(m,
23H),1.62-1.92(m,6H),3.12(m,1H),3.14(m,1H).LC-MS:m/z455.3[M-H]-.
Pharmacokinetic trial in the body of embodiment 9
The present embodiment have detected the internal medicine of compound A-F of the invention and the compound shown in formula (III) for power
Learn.
Specifically, to Oral Administration in Rats or i.v. injection of compounds A-F (being prepared by embodiment 2-7) and formula (III) institute
The compound for showing, evaluates Pharmacokinetic Characteristics of the compound of the invention with the compound shown in formula (III) in rat body,
The conversion situation of compound of the compound conversion in the body of the invention shown in formula (III) is investigated, and is surveyed by certain hour
Determine the blood concentration of the compound shown in the formula (III) in rat body, compound relatively more of the invention and the change shown in formula (III)
The bioavilability of compound.
Experimental animal is male SD rat, 6 to 8 week old, 190-215 grams of body weight, purchased from Beijing Wei Litonghua experimental animals
Technology Co., Ltd..8 groups, every group of 3 animals are randomly divided into based on SD rat body weights.The administration compound formulation of each group rat,
Dosage, method of administration etc. are shown in Table 1.
The pharmacokinetic trial situation of table 1.
Before pharmacokinetic trial, by SD Rat Fasts 16 hours.Then according to through vein or orally single shown in table 1
The compound or blank solution of individual dosage.Take the mode of the jugular puncture μ L of timed collection blood 200 upon administration.It is wherein right
In the animal groups through intravenously administrable, blood is collected within 0.08,0.25,0.5,1,2,4,8 and 24 hours upon administration；For orally giving
The animal groups of medicine, collect blood in 0.25,0.5,1,2,4,8 and 24 hours upon administration.By blood sample collection in the sample with EDTA
In QC, then blood plasma is transferred in another sample cell with 4000rpm centrifugation of blood samples 5 minutes at 4 DEG C immediately, stored
In -20 degrees Celsius.
Pharmacokinetics inspection is carried out to sample, the method and instrument of use are as follows：
HPLC：Shimadzu(DGV-20A3,Serial NO:SSI-3-0536；LC-20AD Serial NO:
L20104551674USB and L20104551673USB；),CTC Analytics HTC PAL System(Serial NO:
4353)；
MS：AB API4000Q Trap LC/MS/MS instrument(Serial NO.AR19020706)
Pillar：Phenomenex Luna 5μC18(2.0×50mm)
Mobile phase：95% acetonitrile (0.1% formic acid) and 5% acetonitrile (0.1% formic acid)
Quantitative approach：Internal standard method
The pharmacokinetics collection of illustrative plates of compound A-F is shown in Fig. 1-Fig. 6 respectively.Chemical combination shown in compound A-F and formula (III)
The comparative result of the pharmacokinetic parameter of thing is shown in Table 2.
The pharmacokinetic data of table 2. compares
NA：Data are not obtained.
Pharmacokinetic studies prove that compound A-F changes the compound shown in an accepted way of doing sth (III) in rat body, and change
The Oral availability of compound C, D, E, F is more superior than the compound shown in formula (III), also more superior than compound A and B.Compound C and
The Half-life in vivo of D significantly extends than the compound shown in formula (III).
Claims (15)
1. the compound or its pharmaceutically acceptable salt shown in a kind of formula (I),
Wherein, R is CO (O) R ', and wherein R ' is C1-C6Alkyl, and R ' be methyl and ethyl.
2. compound according to claim 1 or its pharmaceutically acceptable salt, it is characterised in that R ' is C1-C4Alkane
Base.
3. compound according to claim 1 and 2 or its pharmaceutically acceptable salt, it is characterised in that R ' is propyl group, different
Propyl group, butyl or isobutyl group.
4. compound according to claim 3 or its pharmaceutically acceptable salt, it is characterised in that R ' is propyl group or isopropyl
Base.
5. compound according to claim 1 and 2 or its pharmaceutically acceptable salt, it is characterised in that the compound
For：
6. the preparation method of compound shown in a kind of formula (II),
The preparation method includes：Make the step of compound and R ' OH are reacted shown in formula (III)；
Wherein, R ' such as any one of Claims 1-4 is defined.
7. preparation method according to claim 6, it is characterised in that the compound shown in formula (III) is by the following method
To prepare：
(1) compound and R shown in formula 1 are made1OH reacts the compound shown in the formula of being formed 2；
(2) make the compound shown in formula 2 that the compound shown in the formula of being formed 3 is reacted with organosilyl protective agents TMSCl；
(3) compound of formula 3 is reacted with acetaldehyde in the presence of initiator, then slough organosilicon protection group, formed shown in formula 4
Compound；
(4) compound shown in formula (III) is formed after compound hydrogenation, the hydrolysis shown in formula 4；
Wherein, R1It is C1-C4Alkyl.
8. preparation method according to claim 7, it is characterised in that in step (3), the initiator is BF3-OEt2。
9. the preparation method according to claim 7 or 8, it is characterised in that R1It is methyl.
10. compound according to any one of claim 1 to 5 or its pharmaceutically acceptable salt are being prepared for preventing
And/or the purposes in the disease for the treatment of FXR- mediations or the medicine of situation.
11. compounds according to claim 10 or its pharmaceutically acceptable salt are being prepared for preventing or treating FXR-
Purposes in the disease of mediation or the medicine of situation, wherein, the disease or situation of the FXR- mediations are selected from chronic liver disease, stomach and intestine
Disease, ephrosis, angiocardiopathy, silt courage imbalance, metabolic disease.
12. purposes according to claim 11, it is characterised in that the ephrosis is diabetic nephropathy；The cardiovascular disease
Disease is selected from artery sclerosis, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, wherein the artery sclerosis is artery congee
Sample is hardened.
A kind of 13. pharmaceutical compositions, the pharmaceutical composition comprising compound according to any one of claim 1 to 5 or
Its pharmaceutically acceptable salt, and pharmaceutically acceptable auxiliary material.
14. pharmaceutical compositions according to claim 13, it is characterised in that described pharmaceutical composition is tablet, suppository, divides
Discrete piece, enteric coatel tablets, chewable tablets, oral disintegrating tablet, capsule, sugar-coat agent, granule, dry powder doses, oral solution, the small pin of injection, note
Penetrate with freeze-dried powder or big transfusion.
15. pharmaceutical compositions according to claim 13, it is characterised in that under the pharmaceutically acceptable auxiliary material includes
One or more for stating：Diluent, solubilizer, disintegrant, suspending agent, lubricant, adhesive, filler, flavouring, sweet taste
Agent, antioxidant, surfactant, preservative, coating agent and pigment.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510002830.2A CN104672290B (en) | 2015-01-05 | 2015-01-05 | A kind of medicine of disease for preventing or treating FXR mediations and its production and use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510002830.2A CN104672290B (en) | 2015-01-05 | 2015-01-05 | A kind of medicine of disease for preventing or treating FXR mediations and its production and use |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104672290A CN104672290A (en) | 2015-06-03 |
| CN104672290B true CN104672290B (en) | 2017-06-06 |
Family
ID=53307922
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510002830.2A Expired - Fee Related CN104672290B (en) | 2015-01-05 | 2015-01-05 | A kind of medicine of disease for preventing or treating FXR mediations and its production and use |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104672290B (en) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9982008B2 (en) | 2012-06-19 | 2018-05-29 | Intercept Pharmaceuticals, Inc. | Preparation and uses of obeticholic acid |
| CN107250150B (en) * | 2015-04-28 | 2019-11-22 | 江苏豪森药业集团有限公司 | Chlolic acid derivatives and preparation method thereof and medical usage |
| TW201704251A (en) * | 2015-04-29 | 2017-02-01 | 正大天晴藥業集團股份有限公司 | Derivatives of chenodeoxycholic acid |
| CN105175473B (en) * | 2015-08-19 | 2018-12-21 | 丽珠医药集团股份有限公司 | A kind of Austria shellfish cholic acid crystal form I and preparation method thereof, pharmaceutical composition and purposes |
| CN105085597B (en) * | 2015-08-28 | 2017-03-29 | 成都百裕制药股份有限公司 | A kind of preparation method of unformed shellfish cholic acid difficult to understand |
| CN106749466B (en) * | 2015-11-23 | 2019-05-21 | 南京济群医药科技股份有限公司 | A kind of preparation method of high-purity Austria shellfish cholic acid |
| TW201738254A (en) * | 2016-04-19 | 2017-11-01 | 英特賽普醫藥品公司 | Methods for the preparation of obeticholic acid and derivatives thereof |
| CN105859817A (en) * | 2016-05-09 | 2016-08-17 | 成都宇西医药技术有限公司 | Method for preparing 3 alpha-hydroxy-6-vinyl-7-ketone-5 beta-ursodeoxycholic acid |
| TW201802103A (en) * | 2016-07-13 | 2018-01-16 | 江蘇恆瑞醫藥股份有限公司 | Preparation method of obeticholic acid and intermediates thereof |
| CN108218946B (en) * | 2016-12-15 | 2021-04-16 | 宁波百纳西药业有限公司 | Deoxycholic acid compound, preparation method and application thereof |
| CN108218945B (en) * | 2016-12-15 | 2021-05-28 | 宁波百纳西药业有限公司 | Deoxycholic acid derivative, preparation method, pharmaceutical composition and application thereof |
| CN107383139A (en) * | 2017-08-09 | 2017-11-24 | 杭州和泽医药科技有限公司 | The method that a kind of β cholanic acid new derivatives of 7 oxo of 3 α hydroxyls 5 prepare shellfish cholic acid difficult to understand |
| JP6948680B2 (en) * | 2017-12-19 | 2021-10-13 | 西安奥立泰医薬科技有限公司Ｘｉ’Ａｎ Ｂｉｏｃａｒｅ Ｐｈａｒｍａ Ｌｔｄ． | Compounds for the treatment of metabolic diseases, methods for producing them, and applications |
| CN113493485A (en) * | 2020-04-08 | 2021-10-12 | 西安奥立泰医药科技有限公司 | Bile acid derivative salt, crystal form structure thereof, and preparation method and application thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4021327B2 (en) * | 2001-03-12 | 2007-12-12 | インターセプト ファーマスーティカル インコーポレイテッド | Steroids as agonists for FXR |
| ITMI20021532A1 (en) * | 2002-07-12 | 2004-01-12 | Roberto Pellicciari | CHEMICAL COMPOUNDS |
| ES2592452T3 (en) * | 2008-11-19 | 2016-11-30 | Intercept Pharmaceuticals, Inc. | TGR5 modulators and methods of use thereof |
| MX361653B (en) * | 2012-10-26 | 2018-12-13 | Intercept Pharmaceuticals Inc | Process for preparing bile acid derivatives. |
-
2015
- 2015-01-05 CN CN201510002830.2A patent/CN104672290B/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN104672290A (en) | 2015-06-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104672290B (en) | A kind of medicine of disease for preventing or treating FXR mediations and its production and use | |
| CN102282157B (en) | TGR5 Modulators and Methods of Use Thereof | |
| CN102675403B (en) | Synthesis of anti-hepatitis B medicine LQC-X and application thereof | |
| CN106232612B (en) | Bone selectivity osteogenic oxygen sterol diphosphonate is similar to object | |
| Yi et al. | Enhanced oral bioavailability and tissue distribution of a new potential anticancer agent, Flammulina velutipes sterols, through liposomal encapsulation | |
| CN108137482A (en) | Orient the prodrug of lymph | |
| CN106478759A (en) | Shellfish chlolic acid derivatives difficult to understand and its production and use | |
| CN102603861A (en) | Tanshinone derivatives, medicine compositions thereof, and purposes thereof in medicine | |
| CN107428792A (en) | For treating the phosphamide of hepatitis type B virus | |
| CN101434625A (en) | Anoectochilus roxburghii glycosides, derivatives thereof, preparation and use | |
| CN105732381A (en) | Compounds from antrodia camphorata, method for preparing the same and use thereof | |
| CN101823956B (en) | Diisopropylamine fenofibrate, preparation method of same, medicinal composition and use of same | |
| CN106866609A (en) | A kind of preparation method and application of noval chemical compound in Sabia parviflora Wall.ex Roxb | |
| CN101434635A (en) | Water-soluble phenolic triterpenoid with antineoplastic activity and preparation thereof | |
| Bandgar et al. | Synthesis and biological evaluation of ester prodrugs of benzafibrate as orally active hypolipidemic agents | |
| CN106518708B (en) | The synthesis and application of new FXR activators | |
| CN111116684B (en) | Liver targeting compound with thyroid hormone receptor agonist characteristic and pharmaceutical composition thereof | |
| CN102643316B (en) | A kind of acylated glycosides compound and its preparation method and application | |
| CN101134769A (en) | Ursodeoxycholic acid entecavir acidamide and preparation method and use thereof | |
| CN101307076A (en) | Prodrug with liver-targeted anti-HBV effect | |
| CN101792478A (en) | Light affinity labelling small molecular probe based on maslinic acid and preparation method thereof | |
| CN103073560A (en) | Sauchinone derivative and preparing method and application thereof | |
| CN105085391B (en) | Cyclopropyl unsaturated quionoline compound and application as LTRA | |
| CN101541780A (en) | Fibrate carboxylate compounds, preparation methods and uses thereof | |
| CN114315855A (en) | Curcumenol derivatives, preparation method and application thereof in preparation of anti-inflammatory drugs |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20170606 |