CN112638911A - 拉尼兰诺的氘代衍生物 - Google Patents
拉尼兰诺的氘代衍生物 Download PDFInfo
- Publication number
- CN112638911A CN112638911A CN201980049453.4A CN201980049453A CN112638911A CN 112638911 A CN112638911 A CN 112638911A CN 201980049453 A CN201980049453 A CN 201980049453A CN 112638911 A CN112638911 A CN 112638911A
- Authority
- CN
- China
- Prior art keywords
- deuterated
- deuterated derivative
- group
- pharmaceutically acceptable
- derivative according
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 13
- 201000010099 disease Diseases 0.000 claims abstract description 11
- 230000003176 fibrotic effect Effects 0.000 claims abstract description 10
- 230000001225 therapeutic effect Effects 0.000 claims abstract description 7
- 239000000203 mixture Substances 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 12
- 239000012453 solvate Substances 0.000 claims description 10
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 8
- 229910052805 deuterium Inorganic materials 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- -1 1, 3-benzothiazol-6-ylsulfonyl Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 4
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 4
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 4
- 208000004930 Fatty Liver Diseases 0.000 claims description 2
- 206010019708 Hepatic steatosis Diseases 0.000 claims description 2
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 claims description 2
- 150000004652 butanoic acids Chemical class 0.000 claims description 2
- 208000020832 chronic kidney disease Diseases 0.000 claims description 2
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 2
- 208000035475 disorder Diseases 0.000 claims description 2
- 208000010706 fatty liver disease Diseases 0.000 claims description 2
- 208000036971 interstitial lung disease 2 Diseases 0.000 claims description 2
- 208000005069 pulmonary fibrosis Diseases 0.000 claims description 2
- 201000003086 pulmonary systemic sclerosis Diseases 0.000 claims description 2
- 231100000240 steatosis hepatitis Toxicity 0.000 claims description 2
- 125000004431 deuterium atom Chemical group 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 238000002360 preparation method Methods 0.000 description 29
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 20
- 239000000243 solution Substances 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 150000001875 compounds Chemical group 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 13
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 11
- 239000000047 product Substances 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 description 8
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 235000019439 ethyl acetate Nutrition 0.000 description 8
- 238000003818 flash chromatography Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 239000007832 Na2SO4 Substances 0.000 description 5
- 238000000668 atmospheric pressure chemical ionisation mass spectrometry Methods 0.000 description 5
- 239000007795 chemical reaction product Substances 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 3
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical class C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- VPFMEXRVUOPYRG-UHFFFAOYSA-N hex-5-ynoic acid Chemical compound OC(=O)CCCC#C VPFMEXRVUOPYRG-UHFFFAOYSA-N 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- OQDQIFQRNZIEEJ-NMFSSPJFSA-N 4-[1-(1,3-benzothiazol-6-ylsulfonyl)-5-chloroindol-2-yl]-2,2,3,3,4,4-hexadeuteriobutanoic acid Chemical compound S1C=NC2=C1C=C(C=C2)S(=O)(=O)N1C(=CC2=CC(=CC=C12)Cl)C(C(C(C(=O)O)([2H])[2H])([2H])[2H])([2H])[2H] OQDQIFQRNZIEEJ-NMFSSPJFSA-N 0.000 description 2
- OQDQIFQRNZIEEJ-UHFFFAOYSA-N 4-[1-(1,3-benzothiazol-6-ylsulfonyl)-5-chloroindol-2-yl]butanoic acid Chemical compound C1=C2N=CSC2=CC(S(=O)(=O)N2C3=CC=C(Cl)C=C3C=C2CCCC(=O)O)=C1 OQDQIFQRNZIEEJ-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 206010048554 Endothelial dysfunction Diseases 0.000 description 2
- 208000035150 Hypercholesterolemia Diseases 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 201000009594 Systemic Scleroderma Diseases 0.000 description 2
- 206010042953 Systemic sclerosis Diseases 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 2
- 150000001975 deuterium Chemical group 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000008694 endothelial dysfunction Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 208000006575 hypertriglyceridemia Diseases 0.000 description 2
- 238000010348 incorporation Methods 0.000 description 2
- 125000002249 indol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([*])=C([H])C2=C1[H] 0.000 description 2
- 208000027866 inflammatory disease Diseases 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 230000004770 neurodegeneration Effects 0.000 description 2
- 208000015122 neurodegenerative disease Diseases 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000013612 plasmid Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- FAYAYUOZWYJNBD-UHFFFAOYSA-N 1,3-benzothiazol-6-amine Chemical class NC1=CC=C2N=CSC2=C1 FAYAYUOZWYJNBD-UHFFFAOYSA-N 0.000 description 1
- KRRLILAOGRCMFH-UHFFFAOYSA-N 1,3-benzothiazole-6-sulfonamide Chemical class NS(=O)(=O)C1=CC=C2N=CSC2=C1 KRRLILAOGRCMFH-UHFFFAOYSA-N 0.000 description 1
- XQOLJTWXFUSVOR-UHFFFAOYSA-N 1,3-benzothiazole-6-sulfonyl chloride Chemical class ClS(=O)(=O)C1=CC=C2N=CSC2=C1 XQOLJTWXFUSVOR-UHFFFAOYSA-N 0.000 description 1
- GTUOMTZFCNDDBA-SPLBAYPWSA-N 2-(1,1,2,2,3,3,4,4-octadeuterio-4-iodobutoxy)oxane Chemical compound [2H]C([2H])(I)C([2H])([2H])C([2H])([2H])C([2H])([2H])OC1CCCCO1 GTUOMTZFCNDDBA-SPLBAYPWSA-N 0.000 description 1
- FLEJOBRWKBPUOX-UHFFFAOYSA-N 4-chloro-2-iodoaniline Chemical compound NC1=CC=C(Cl)C=C1I FLEJOBRWKBPUOX-UHFFFAOYSA-N 0.000 description 1
- QLUFBCVWKTWKBF-UHFFFAOYSA-N 6-nitro-1,3-benzothiazole Chemical class [O-][N+](=O)C1=CC=C2N=CSC2=C1 QLUFBCVWKTWKBF-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- 208000032928 Dyslipidaemia Diseases 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 229940126032 IVA-337 Drugs 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 239000003810 Jones reagent Substances 0.000 description 1
- 208000017170 Lipid metabolism disease Diseases 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 108060001084 Luciferase Proteins 0.000 description 1
- 239000005089 Luciferase Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- 108010028924 PPAR alpha Proteins 0.000 description 1
- 102000023984 PPAR alpha Human genes 0.000 description 1
- 108010015181 PPAR delta Proteins 0.000 description 1
- 108010016731 PPAR gamma Proteins 0.000 description 1
- 102000000536 PPAR gamma Human genes 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 240000002834 Paulownia tomentosa Species 0.000 description 1
- 235000010678 Paulownia tomentosa Nutrition 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 229940122054 Peroxisome proliferator-activated receptor delta agonist Drugs 0.000 description 1
- 229940080774 Peroxisome proliferator-activated receptor gamma agonist Drugs 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- VGTCWWMCIQYNFC-UHFFFAOYSA-N acetylene;lithium Chemical class [Li].C#C VGTCWWMCIQYNFC-UHFFFAOYSA-N 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 238000000065 atmospheric pressure chemical ionisation Methods 0.000 description 1
- 229960003237 betaine Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical class [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 235000011116 calcium hydroxide Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000023852 carbohydrate metabolic process Effects 0.000 description 1
- 235000021256 carbohydrate metabolism Nutrition 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229910000365 copper sulfate Inorganic materials 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000002405 diagnostic procedure Methods 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000012254 magnesium hydroxide Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- ILOZGGRPYUTYCT-UHFFFAOYSA-N n-(4-chloro-2-iodophenyl)-1,3-benzothiazole-6-sulfonamide Chemical compound IC1=CC(Cl)=CC=C1NS(=O)(=O)C1=CC=C(N=CS2)C2=C1 ILOZGGRPYUTYCT-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000023603 positive regulation of transcription initiation, DNA-dependent Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000007423 screening assay Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/428—Thiazoles condensed with carbocyclic rings
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Gastroenterology & Hepatology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及拉尼兰诺的氘代衍生物,特别是用于治疗用途、尤其是用于治疗纤维化疾病用途的拉尼兰诺的氘代衍生物。
Description
技术领域
本发明涉及拉尼兰诺(lanifibranor)的氘代衍生物,特别是用于其治疗用途、尤其是用于治疗纤维化疾病用途的拉尼兰诺的氘代衍生物。
背景技术
拉尼兰诺或4-(1-(1,3-苯并噻唑-6-基磺酰基)-5-氯-吲哚-2-基)-丁酸是PPAR受体激动剂,特别适用于在系统性硬化症(SSc)和非酒精性脂肪性肝炎(NASH)的治疗中使用。在专利申请WO 2007/026097中特别对拉尼兰诺与其它吲哚衍生物进行了描述,特别是用于预防或治疗高甘油三酯血症、高胆固醇血症,更普遍地,用于在脂质和碳水化合物代谢被打乱的过程中重新建立正常参数,以及用于治疗内皮功能障碍、炎性疾病或神经退行性疾病的情况。
使用氘化分子的兴趣被认为是一种通过改善其代谢稳定性对其代谢进行修饰的手段,并可能改善其细胞渗透特性(Maehr等,J.Med.Chem.2013,56,3878-3888;Kerekes等,J.Med.Chem.2011,54,201-210;Harbeson&Tung,Medchem News 2014,29-22;Gant,J.Med.Chem.2014,57,3595-3611;DeWitt&Maryanoff,Biochemistry 2018,57,472-473;WO2017/136375;WO 2018/039521)。氘化药物的合成也在几篇文章中进行了描述(Modutwa等,J.Label Compd.Radiopharm 2010,53 686-692;Junk等,J.Label Compd.Radiopharm1997,39 625-630)。
然而,已经认识到氢被氘取代对化学物质代谢的影响仍然是不可预测的,并且对于许多作者来说,药物的氘化不被认为是可靠的调控手段(Foster,AB,Adv Drug Res1985,14:1-40;Fisher,MB等,Curr Opin Drug Discov Devel,2006,9:101-09;Katsnelson,Nature Medecine 2013,19 6656)。
发明内容
本发明涉及式(I)的拉尼兰诺的氘代衍生物:
其中,基团R1至R7中的至少一者是氘原子(D),且R1至R7的其它基团是氢原子(H)。
本发明还涉及包含至少一种式(I)的氘代衍生物的组合物、特别是药物组合物。
本发明还涉及用于其治疗用途、特别是用于纤维化疾病的治疗用途的式(I)的氘代衍生物。
具体实施方式
本发明涉及式(I)的拉尼兰诺的氘代衍生物,及其药学上可接受的盐和溶剂化物:
其中,基团R1至R7中的至少一者是氘原子,且R1至R7的其它基团是氢原子。
根据本发明的第一实施方式,至少基团R1是D。
特别地,拉尼兰诺的氘代衍生物是4-(1-(2-氘代-1,3-苯并噻唑-6-基)磺酰基)-5-氯-1H-吲哚-2-基)丁酸。
根据本发明的另一实施方式,基团R2至R7中的至少一者是D。更优选地,基团R2和R3中的至少一者和/或基团R4和R5中的至少一者和/或基团R6和R7中的至少一者是D。甚至更优选地,R2、R3、R4、R5、R6和R7是D。
特别地,拉尼兰诺的氘代衍生物是4-[1-(1,3-苯并噻唑-6-基磺酰基)-5-氯-吲哚-2-基]-2,2,3,3,4,4-六氘代丁酸。
根据本发明的氘代衍生物的药学上可接受的盐与拉尼兰诺的药学上可接受的盐相同,特别是通过将酸与药学上可接受的无毒的无机碱或有机碱结合。在无机碱中,可以使用例如钠、钾、镁或钙的氢氧化物。在有机碱中,可以使用例如胺、氨基醇、碱性氨基酸(例如赖氨酸或精氨酸)或带有季铵官能团的化合物(例如甜菜碱或胆碱)。
根据本发明的化合物是根据制备拉尼兰诺的常用方法制备的,例如专利申请WO2007/026097中所述的方法,氘代合成中间体替代了在这些常规方法中使用的相同的同位素未富集的中间体。
本发明还涉及一种组合物,所述组合物包含根据本发明的氘代衍生物或其盐或溶剂化物之一,特别是药学上可接受的盐或溶剂化物,以及适合其使用的载体。
为了在治疗中使用,根据本发明的组合物有利地是药物组合物,载体包括药典的常规赋形剂,所述赋形剂根据设想的给药方式进行选择。
此类组合物是本领域技术人员已知的,并且特别在专利申请WO 2007/026097和WO2015/189401中进行描述。
对于口服给药,例如以片剂、胶囊剂、锭剂、凝胶剂、糖浆剂、口服混悬剂的形式,根据本发明的药物组合物有利地包含1mg至1000mg的式(I)的氘代衍生物,例如1mg、5mg、10mg、50mg、100mg、200mg、500mg或1000mg。
本发明还涉及用于其治疗用途的式(I)的氘代衍生物或其药学上可接受的盐或溶剂化物。
根据本发明的氘代衍生物的不同治疗用途是拉尼兰诺及其类似物已知的那些用途,例如专利申请WO 2007/026097和WO 2015/189401中所述的那些用途。
因此,本发明涉及用于对抗以下疾病的用途的式(I)的氘代衍生物、或其药学上可接受的盐或溶剂化物:高胆固醇血症、高脂血症、高甘油三酯血症、血脂异常、胰岛素抵抗、糖尿病或肥胖症以及由血清脂蛋白失衡引起的心血管疾病。根据本发明的化合物也可用作药物的有效成分,所述药物旨在预防或治疗与内皮功能障碍、动脉粥样硬化、心肌梗塞、高血压、脑血管疾病、某些炎性疾病(例如类风湿性关节炎)、神经退行性疾病(例如特别是阿尔茨海默氏病或帕金森氏病)有关的疾病。
本发明特别涉及用于治疗纤维化疾病的用途的式(I)的氘代衍生物。在一个实施方案中,纤维化疾病是影响可发展出纤维化的任何器官的病症,所述器官例如心脏、肺、肝脏、肾脏、胃肠道、皮肤、肌肉等。纤维化疾病特别选自:肝纤维化、脂肪肝、非酒精性脂肪性肝炎、慢性肾病、诸如特发性肺纤维化的肺纤维化紊乱和系统性硬化症。
本发明还涉及在等待此类治疗的患者中对如上定义的纤维化疾病进行治疗的方法,所述方法包括向该患者给予式(I)的氘代衍生物,特别是通过药物组合物的方式,所述药物组合物包含适合于所选给药方式的形式的所述式(I)的氘代衍生物。
有利地,已通过任何适当的用于检测待治疗的纤维化疾病的诊断方法预先确定了患者治疗的需要,特别是通过分析待治疗的患者的纤维化组织中PPAR受体的表达水平。
实施例
缩略语
APCI=大气压化学电离
DCM=二氯甲烷
DMSO=二甲亚砜
eq.=当量
EtOAc=乙酸乙酯
EtOH=乙醇
h=小时
HPLC=高效液相色谱
LCMS=液相色谱与质谱联用
MeOH=甲醇
min=分钟
Pd(PPh3)4=四(三苯基膦)钯(0)
pTsOH=对甲苯磺酸
NMR=核磁共振
THF=四氢呋喃
实施例1:4-[5-氯-1-[(2-氘代-1,3-苯并噻唑-6-基)磺酰基)]吲哚-2-基]丁酸
制备例1:2-氘代-1,3-苯并噻唑
将正丁基锂(37.0mL,92.5mmol,2.5当量,2.5M己烷溶液)滴加到溶于THF(80mL)的1,3-苯并噻唑(5.0g,36.9mmol,1.0当量)中,冷却至-78℃。添加完毕后,在-78℃下将D2O(4mL,222mmol,6.0当量)添加至反应混合物中,全部搅拌30分钟,然后使其升至室温。通过LCMS分析监测反应。然后将反应混合物用饱和NH4Cl水溶液处理,并将全部用DCM萃取3次。合并有机相,经MgSO4干燥,然后过滤,减压蒸馏,得到粗产物,通过快速色谱纯化(洗脱剂:0至40%EtOAc的正庚烷溶液),作为棕色油状物得到制备例1的化合物(3.22g,产率64%)。APCI MS m/z 137[M+H]+;HPLC-MS(220-254nm)纯度:99%.1H NMR(300MHz DMSO-d6):δ7.46-7.58(2H,m);8.08-8.19(2H,m)。
制备例2:2-氘代-6-硝基-1,3-苯并噻唑
在0℃下,将2-氘代-1,3-苯并噻唑(制备例1,2.9g,21.3mmol,1.0当量)缓慢添加至硫酸溶液(13mL)中,然后滴加硝酸(6.4mL),同时温度保持在0℃以下。然后将反应混合物升至室温并搅拌12h,随后在冰水混合物上水解。滤出黄色沉淀,用水洗涤并在乙醇中结晶,得到黄色结晶形式的所需产物(制备例2,1.4g,产率37%)。APCI MS m/z182[M+H]+;HPLC-MS(220-254nm)纯度>99%.1H NMR(300MHz DMSO-d6):δ8.27-8.38(2H,m);9.25(1H,d,J=2.3Hz)。
制备例3:2-氘代-1,3-苯并噻唑-6-胺
将氯化锡粉末(7.3g,38.6mmol,3.5当量)加入溶解在1:1EtOH-EtOAc混合物(60mL)中的制备例2的化合物(2.0g,11.0mmol,1.0当量)中,将溶液在室温下搅拌4小时。在反应结束时,将反应混合物通过CeliteTM柱过滤,并用饱和Na2CO3溶液萃取。合并有机相,经MgSO4干燥,然后过滤并减压蒸馏,得到的粗产物,通过快速色谱纯化(洗脱剂:0至20%MeOH的DCM溶液),作为褐色结晶得到所需化合物(制备例3,970mg,产率58%)。APCI MS m/z 152[M+H]+;HPLC-MS(220-254nm)纯度:97%.1H NMR(300MHz DMSO-d6):δ5.38(2H,s);6.8(1H,dd,J=8.7Hz以及J=2.2Hz);7.11(1H,d,J=2.2Hz);7.7(1H,d,J=8.7Hz)。
制备例4:2-氘代-1,3-苯并噻唑-6-磺酰氯
在0℃下制备亚硫酰氯(1.1mL)的水溶液(4.5mL),并在4℃下保存过夜。在-10℃下向该溶液中加入氯化铜(I)(0.05当量)。将制备例3的化合物(450mg,2.9mmol,1.0当量)溶解于盐酸(3.5mL)中,同时保持温度低于25℃,然后将后一溶液冷却至-10℃,在温度不超过-2℃的条件下添加亚硝酸钠溶液(3.3mmol,0.7mL,1.1当量)。将如此获得的混合物在-2℃下搅拌15分钟,然后在-5℃下滴加到亚硫酰氯第一溶液中。然后将反应混合物在-5℃下搅拌3小时,然后使反应在水中水解。过滤形成的沉淀物,然后用水洗涤以产生呈浅棕色结晶形式的所需产物(制备例4,255mg,产率37%)。该化合物无需纯化即用于下一步。HPLC-MS(220-254nm)纯度:94%。
制备例5:N-(4-氯-2-碘代苯基)-2-氘代-1,3-苯并噻唑-6-磺酰胺
在氩气下,将4-氯-2-碘苯胺(564mg,2.2mmol,1.0当量)溶解在无水吡啶(8mL)中,并加入制备例4的化合物(600mg,2.5mmol,1.15当量)。然后将溶液在室温搅拌2小时。蒸馏溶剂,并将反应粗产物通过快速色谱纯化(洗脱剂:0至30%EtOAc的正庚烷溶液),得到呈棕色结晶形式的所需产物(制备例5,0.73g,产率73%)。APCI MS m/z 452[M+H]+;HPLC-MS(220-254nm)纯度:94%.1H NMR(300MHz DMSO-d6):δ7.01(1H,d,J=8.5Hz);7.4(1H,dd,J=8.5Hz以及J=2.3Hz);7.82(1H,dd,J=8.7Hz以及J=1.8Hz);7.88(1H,d,J=2.4Hz);8.26(1H,d,J=8.7Hz);8.6(1H,d,J=1.5Hz);10.03(1H,s)。
制备例6:4-[5-氯-1-[(2-氘代-1,3-苯并噻唑-6-基)磺酰基)]吲哚-2-基]丁酸
在氩气下,将制备例5的化合物(1.31g,2.9mmol,1.0当量)溶解于无水DMF(30mL)中,然后加入5-己炔酸(360mg,3.2mmol,1.1当量)、碘化铜(56mg,0.3mmol,0.1当量)、Pd(PPh3)4(168mg,0.15mmol,0.05当量)和三乙胺(606μL,4.4mmol,1.5当量),并将反应混合物在80℃搅拌2小时。反应结束时,将混合物置于1N盐酸水溶液中,并用乙酸乙酯萃取两次。合并有机相,经MgSO4干燥,然后过滤并减压蒸馏,得到粗产物,通过快速色谱纯化(洗脱剂:0至5%MeOH的DCM溶液),得到呈棕色结晶形式的所需产物(实施例1,1.05g,产率83%)。APCIMS m/z 452[M+H]+;HPLC-MS(220-254nm)纯度:94%.1H NMR(300MHz DMSO-d6):δ1.86-2.01(2H,m);2.29-2.41(2H,m);3.08(2H,t,J=7.2Hz);6.61(1H,s);7.31(1H,dd,J=8.7Hz以及J=2.0Hz);7.51(1H,d,J=2.0Hz);7.84(1H,dd,J=8.7Hz以及J=1.8Hz);8.08(1H,d,J=8.7Hz);8.19(1H,d,J=8.7Hz);8.97(1H,d,J=1.8Hz);12.13(1H,s)。通过500MHz NMR测定的氘掺入率:98%。
实施例2:4-[1-(1,3-苯并噻唑-6-基磺酰基)-5-氯-吲哚-2-基]-2,2,3,3,4,4-六氘代丁酸
制备例7:2-(1,1,2,2,3,3,4,4-八氘代-4-碘-丁氧基)四氢吡喃
在0℃下将三甲基碘硅烷(25g,125mmol,1当量)加入到THF-D8(10g,125mmol,1当量)中。在0℃下搅拌2小时后,加入乙醚(80mL)和水(20mL)。将混合物搅拌3小时,然后倒出。然后将有机相经MgSO4干燥,过滤并在减压下浓缩。在0℃下,将如此获得的反应粗产物置于DCM(100mL)中,然后加入二氢吡喃(12.5mL,150mmol,1.2当量)和pTsOH(50mg,0.2mmol,0.002当量)。然后将反应混合物在0℃下搅拌过夜。该溶液依次用饱和NaHCO3溶液(3×15mL)洗涤,然后用盐水洗涤,然后经Na2SO4干燥,然后减压浓缩。将反应粗产物通过快速色谱纯化(洗脱剂:1:20至1:5的EtOAc:己烷),得到无色油状物形式的所需产物(制备例7,23g,产率62%),将其直接用于下一步。
制备例8:2-(1,1,2,2,3,3,4,4-八氘代己-5-炔氧基)四氢吡喃
在5℃下,向处于新蒸馏的DMSO(60mL)中的乙炔锂(19.94g,186.3mmol,1当量)溶液中滴加处于DMSO(30mL)中的制备例7的化合物(30g,102.7mmol,0.55当量)溶液。将如此获得的溶液搅拌2小时,然后在0℃下用NH4Cl溶液水解。然后将该混合物用己烷萃取,依次用硫酸铜溶液(5%,20mL)和盐水(20mL)洗涤。合并有机相并经Na2SO4干燥,然后减压浓缩,得到黄色油状物形式的所需产物(制备例8,10.7g,产率55%),其无需任何纯化即直接用于下一步。
制备例9:1,1,2,2,3,3,4,4-八氘代己-5-炔-1-醇
在0℃下,向处于THF(12.5mL)和MeOH(350mL)的混合物中的制备例8的化合物(10.7g,56.2mmol,1当量)溶液中分批加入pTsOH(360mg,1.82mmol,0.03当量),将如此获得的反应混合物搅拌过夜。然后将混合物用NaHCO3饱和溶液(3×15mL)和盐水(15mL)洗涤,然后经Na2SO4干燥,然后减压浓缩。将反应粗产物通过快速色谱纯化(洗脱剂:1:20至1:5的EtOAc:己烷),得到无色油状物形式的所需产物(制备例9,5g,产率82%),将其直接用于下一步。
制备例10:2,2,3,3,4,4-六氘代己-5-炔酸
在搅拌下,在0℃下历时5分钟向处于丙酮(87mL)中的制备例9的化合物(9.25g,87mmol,1当量)的溶液中加入琼斯试剂(处于10N H2SO4(218mL)中的CrO3(17.45g,174.5mmol,2当量))。然后将反应混合物搅拌1h,然后减压浓缩。然后立即加入乙醚(130mL)和水(4mL)。滤出获得的固体,并将滤液用乙醚(6×100mL)萃取。合并有机相并用水洗涤,然后经Na2SO4干燥,然后过滤并在减压下浓缩,得到橙色油状物形式的所需产物(制备例10,9.17g,产率89%),将其直接用于下一步而无需任何纯化。
制备例11:4-[1-(1,3-苯并噻唑-6-基磺酰基)-5-氯-吲哚-2-基]-2,2,3,3,4,4-六氘代丁酸
在110℃、氮气下,将苯并噻唑-6-磺酸(4-氯-2-碘-苯基)-酰胺(16g,35.5mmol,1当量)、己-5-炔酸(制备例10,5.2g,44mmol,1.24当量)、碘化铜(335mg,1.75mmol,0.05当量)、二氯双(三苯基膦)钯(1.24g,1.72mmol,0.05当量)、三乙胺(130mL)和N,N-二甲基甲酰胺(130mL)的混合物搅拌1小时。然后将反应混合物用1M HCl溶液稀释并用乙酸乙酯萃取,滤出不溶物,并将滤液经Na2SO4干燥,然后减压浓缩。通过快速色谱纯化反应粗产物,然后从DCM重结晶,得到白色固体形式的所需产物(实施例2,2.3g,产率15%)。通过500MHz NMR测定的氘掺入率:>99%。1H NMR(400MHz,DMSO-d6)δ6.62(1H,d,J=0.6Hz),7.32(1H,dd,J=8.9以及2.2Hz),7.57(1H,d,J=2.1Hz),7.85(1H,dd,J=8.7以及2.1Hz),8.10(1H,d,J=8.9Hz),8.20(1H,d,J=8.7Hz),8.99(1H,s),9.66(1H,s),12.15(1H,s)。
实施例3:药理活性
对本发明的化合物进行生物学测试,以评估其治疗或预防某些疾病的潜力。首先,对化合物作为PPAR核受体活化剂的能力进行测量。
将反式激活试验用作主要的筛选试验。用表达鼠或人受体PPAR-Gal4(受体PPARα-Gal4或PPARδ-Gal4或PPARγ-Gal4)嵌合体的质粒和报告质粒5Gal4pGL3 TK Luc转染Cos-7细胞。使用化学试剂(Jet PEI)进行转染。
将转染的细胞分配到384孔板中,并静置24小时。
在24小时,更换培养基。将待测试的产物(终浓度在10-4和3.10-10M之间)添加到培养基中。孵育过夜后,根据制造商(Promega)的说明,在添加“SteadyGlo”后对荧光素酶表达进行测量。
将10-5M的非诺贝酸(PPARα激动剂)、10-8M的GW501516(PPARδ激动剂)和10-6M的罗格列酮(PPARγ激动剂)用作参照。
结果表示为相对于基础水平的诱导率(次数),以适当参照(参照=100%)的活性百分比表示。使用Assay Explorer(MDL)软件计算作用-浓度曲线和EC50。
表1
从上表可以看出,拉尼兰诺的氘代衍生物激活了PPAR受体的三种亚型(PPARα、PPARγ和PPARδ),每种亚型的EC50均小于2.5μM。还应注意,两种PPAR亚型的EC50之比小于100或大于0.01。
参考文献
1.DeWitt&Maryanoff,Biochemistry 2018,57,472-473
2.Fisher et al,Curr Opin Drug Discov Devel,2006,9:101-09
3.Foster,Adv Drug Res 1985,14∶1-40
4.Gant,J.Med.Chem.2014,57,3595-3611
5.Harbeson&Tung,Medchem News 2014,29-22
6.Junk&al.,J.Label Compd.Radiopharm 1997,39625-630
7.Katsnelson,Nature Medecine 2013,196656
8.Kerekes&al.,J.Med.Chem.2011,54,201-210
9.Maehr&al.,J.Med.Chem.2013,56,3878-3888
10.Modutwa&a.,J.Label Compd.Radiopharm 2010,53686-692
11.WO 2007/026097
12.WO 2015/189401
13.WO 2017/136375
14.WO 2018/039521
Claims (10)
2.根据权利要求1所述的氘代衍生物,其中,至少所述基团R1是D。
3.根据权利要求2的所述氘代衍生物,所述氘代衍生物为4-(1-(2-氘代-1,3-苯并噻唑-6-基)磺酰基)-5-氯-1H-吲哚-2-基)丁酸。
4.根据权利要求1所述的氘代衍生物,其中,所述基团R2至R7中的至少一者是D。
5.根据权利要求4所述的氘代衍生物,其中,所述基团R2和R3中的至少一者和/或基团R4和R5中的至少一者和/或基团R6和R7中的至少一者是D。
6.根据权利要求5所述的氘代衍生物,所述氘代衍生物是4-[1-(1,3-苯并噻唑-6-基磺酰基)-5-氯-吲哚-2-基]-2,2,3,3,4,4-六氘代丁酸。
7.一种组合物,所述组合物包含权利要求1-6中任一项所述的氘代衍生物或其盐或溶剂化物之一,以及合适的载体。
8.一种药物组合物,所述药物组合物包含权利要求1-6中任一项所述的氘代衍生物或其药学上可接受的盐或溶剂化物,以及药学上可接受的载体。
9.用于治疗用途的权利要求1-6中任一项所述的氘代衍生物或其药学上可接受的盐或溶剂化物。
10.用于治疗纤维化疾病的用途的权利要求1-6中任一项所述的氘代衍生物或其药学上可接受的盐或溶剂化物,所述纤维化疾病特别选自:肝纤维化、脂肪肝、非酒精性脂肪性肝炎、慢性肾病、诸如特发性肺纤维化的肺纤维化紊乱、以及系统性硬化症。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR1857021 | 2018-07-27 | ||
FR1857021A FR3084254B1 (fr) | 2018-07-27 | 2018-07-27 | Derives deuteres du lanifibranor |
PCT/FR2019/051860 WO2020021215A1 (fr) | 2018-07-27 | 2019-07-26 | Derives deuteres du lanifibranor |
Publications (1)
Publication Number | Publication Date |
---|---|
CN112638911A true CN112638911A (zh) | 2021-04-09 |
Family
ID=63684156
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201980049453.4A Pending CN112638911A (zh) | 2018-07-27 | 2019-07-26 | 拉尼兰诺的氘代衍生物 |
Country Status (16)
Country | Link |
---|---|
US (1) | US20210300913A1 (zh) |
EP (2) | EP4331584A1 (zh) |
JP (2) | JP7434278B2 (zh) |
CN (1) | CN112638911A (zh) |
DK (1) | DK3830085T3 (zh) |
ES (1) | ES2970597T3 (zh) |
FI (1) | FI3830085T3 (zh) |
FR (1) | FR3084254B1 (zh) |
HR (1) | HRP20240157T1 (zh) |
HU (1) | HUE065045T2 (zh) |
LT (1) | LT3830085T (zh) |
PL (1) | PL3830085T3 (zh) |
PT (1) | PT3830085T (zh) |
RS (1) | RS65095B1 (zh) |
SI (1) | SI3830085T1 (zh) |
WO (1) | WO2020021215A1 (zh) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR102199640B1 (ko) * | 2020-01-06 | 2021-01-07 | 브렉소젠 주식회사 | 라니피브라노르를 포함하는 줄기세포 유래 엑소좀 생성 촉진 및 줄기세포기능 강화용 조성물 |
EP4000616A1 (en) | 2020-11-17 | 2022-05-25 | Inventiva | Combination therapy for the treatment of a liver disease |
WO2022143479A1 (zh) * | 2020-12-29 | 2022-07-07 | 广东东阳光药业有限公司 | 一种化合物的固体形式及其制备方法和用途 |
WO2023016319A1 (zh) * | 2021-08-12 | 2023-02-16 | 苏州科睿思制药有限公司 | Lanifibranor的晶型及其制备方法和用途 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101248044A (zh) * | 2005-08-30 | 2008-08-20 | 实验室富尼耶公司 | 新的吲哚化合物 |
CN106573058A (zh) * | 2014-06-13 | 2017-04-19 | 伊文蒂瓦公司 | 用于纤维化疾病的治疗用途的ppar化合物 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017136375A1 (en) | 2016-02-05 | 2017-08-10 | Concert Pharmaceuticals, Inc. | Deuterated tozadenant |
WO2018039521A1 (en) | 2016-08-26 | 2018-03-01 | Concert Pharmaceuticals, Inc. | Deuterated cenicriviroc |
US11504380B2 (en) * | 2019-11-08 | 2022-11-22 | Inventiva | Method of treatment of cirrhosis |
-
2018
- 2018-07-27 FR FR1857021A patent/FR3084254B1/fr active Active
-
2019
- 2019-07-26 PT PT197596588T patent/PT3830085T/pt unknown
- 2019-07-26 EP EP23201458.9A patent/EP4331584A1/fr active Pending
- 2019-07-26 RS RS20240090A patent/RS65095B1/sr unknown
- 2019-07-26 PL PL19759658.8T patent/PL3830085T3/pl unknown
- 2019-07-26 HU HUE19759658A patent/HUE065045T2/hu unknown
- 2019-07-26 JP JP2021504431A patent/JP7434278B2/ja active Active
- 2019-07-26 FI FIEP19759658.8T patent/FI3830085T3/fi active
- 2019-07-26 EP EP19759658.8A patent/EP3830085B1/fr active Active
- 2019-07-26 WO PCT/FR2019/051860 patent/WO2020021215A1/fr active Application Filing
- 2019-07-26 LT LTEPPCT/FR2019/051860T patent/LT3830085T/lt unknown
- 2019-07-26 ES ES19759658T patent/ES2970597T3/es active Active
- 2019-07-26 US US17/261,938 patent/US20210300913A1/en active Pending
- 2019-07-26 HR HRP20240157TT patent/HRP20240157T1/hr unknown
- 2019-07-26 DK DK19759658.8T patent/DK3830085T3/da active
- 2019-07-26 CN CN201980049453.4A patent/CN112638911A/zh active Pending
- 2019-07-26 SI SI201930700T patent/SI3830085T1/sl unknown
-
2024
- 2024-02-07 JP JP2024017170A patent/JP2024036611A/ja active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101248044A (zh) * | 2005-08-30 | 2008-08-20 | 实验室富尼耶公司 | 新的吲哚化合物 |
CN106573058A (zh) * | 2014-06-13 | 2017-04-19 | 伊文蒂瓦公司 | 用于纤维化疾病的治疗用途的ppar化合物 |
Non-Patent Citations (2)
Title |
---|
ALLA KATSNELSON: "Heavy drugs draw heavy interest from pharma backers", 《NATURE MEDICINE》, vol. 19, no. 6, pages 656, XP055387255, DOI: 10.1038/nm0613-656 * |
BENAÏSSA BOUBIA等: "Design, Synthesis, and Evaluation of a Novel Series of Indole Sulfonamide Peroxisome Proliferator Activated Receptor (PPAR) α/γ/δ Triple Activators: Discovery of Lanifibranor, a New Antifibrotic Clinical Candidate", 《JOURNAL OD MEDICINAL CHEMISTRY》, vol. 61, pages 2246 - 2265, XP002790345, DOI: 10.1021/acs.jmedchem.7b01285 * |
Also Published As
Publication number | Publication date |
---|---|
FI3830085T3 (fi) | 2024-01-17 |
US20210300913A1 (en) | 2021-09-30 |
JP2021533101A (ja) | 2021-12-02 |
RS65095B1 (sr) | 2024-02-29 |
PT3830085T (pt) | 2024-01-24 |
EP4331584A1 (fr) | 2024-03-06 |
WO2020021215A1 (fr) | 2020-01-30 |
JP7434278B2 (ja) | 2024-02-20 |
PL3830085T3 (pl) | 2024-04-15 |
EP3830085A1 (fr) | 2021-06-09 |
HRP20240157T1 (hr) | 2024-04-12 |
FR3084254A1 (fr) | 2020-01-31 |
DK3830085T3 (da) | 2024-01-22 |
ES2970597T3 (es) | 2024-05-29 |
HUE065045T2 (hu) | 2024-04-28 |
JP2024036611A (ja) | 2024-03-15 |
SI3830085T1 (sl) | 2024-03-29 |
LT3830085T (lt) | 2024-02-12 |
EP3830085B1 (fr) | 2023-11-08 |
FR3084254B1 (fr) | 2020-10-23 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN112638911A (zh) | 拉尼兰诺的氘代衍生物 | |
CN108602811B (zh) | Fxr受体激动剂 | |
NL1028947C2 (nl) | Gesubstitueerde methylaryl- of heteroarylamideverbindingen. | |
JP6424231B2 (ja) | ファルネソイドx受容体をモジュレートするための組成物および方法 | |
KR20200010483A (ko) | Fxr 수용체 작용제로서 락탐 화합물 | |
BRPI0414130B1 (pt) | Compostos de fenilamida ou piridilamida, seu uso e composições farmacêuticas que os compreendem | |
BRPI0611853A2 (pt) | derivados de n-(piridin-2-il)-sulfonamida | |
JP2012503595A (ja) | 代謝病の治療用の化合物 | |
JP7065081B2 (ja) | Gpr120モジュレーターとして有用な二環式化合物 | |
EP1981842A2 (fr) | Derives de sulfonamides, leur preparation et leur application en therapeutique | |
JP6754828B2 (ja) | ピリジン及びピリミジン誘導体 | |
JP5396650B2 (ja) | パーキンソン病を治療するためのnurr−1活性化剤としてのインドール誘導体の使用 | |
WO2002020462A1 (fr) | Derives d'acide benzoique et medicaments possedant ces derniers comme principe actif | |
JPS6330914B2 (zh) | ||
JP2020506226A (ja) | アミド化合物およびその使用 | |
JP2020508981A (ja) | ビアリール化合物、その製造方法及び用途 | |
WO2023138599A1 (zh) | 芳香并环类Nav1.8抑制剂及其用途 | |
KR20080023758A (ko) | 비만 및 관련 질환의 치료를 위한 신규한 아미노산 유도체 | |
CN107434789B (zh) | 苯并三氮唑类衍生物、及其制法和药物组合物与用途 | |
CN111793066B (zh) | 苯并五元杂环磺酰胺类化合物、其制备方法、药物组合物及应用 | |
RU2793266C2 (ru) | Изоксазол в качестве агонистов fxr-рецептора | |
WO2005016255A2 (en) | Substituted tetrahydroquinolines, phenylacetic acids and benzoic acids as hepatocyte nuclear factor 4 (hnf-4 ) modulator compounds | |
EP3823960B1 (en) | Isoxazole as fxr receptor agonists |
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 | ||
EE01 | Entry into force of recordation of patent licensing contract | ||
EE01 | Entry into force of recordation of patent licensing contract |
Application publication date: 20210409 Assignee: CHIA TAI TIANQING PHARMACEUTICAL GROUP Co.,Ltd. Assignor: INVENTIVA Contract record no.: X2022990000980 Denomination of invention: Deuterium derivatives of lanilano License type: Exclusive License Record date: 20221210 |