WO2023198486A1 - Composés de butyrate d'urolithine - Google Patents
Composés de butyrate d'urolithine Download PDFInfo
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- WO2023198486A1 WO2023198486A1 PCT/EP2023/058610 EP2023058610W WO2023198486A1 WO 2023198486 A1 WO2023198486 A1 WO 2023198486A1 EP 2023058610 W EP2023058610 W EP 2023058610W WO 2023198486 A1 WO2023198486 A1 WO 2023198486A1
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- 150000004648 butanoic acid derivatives Chemical class 0.000 title abstract description 17
- 229930186301 urolithin Natural products 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 70
- 238000000034 method Methods 0.000 claims description 51
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 13
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- -1 picoline purine Chemical compound 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- ODINCKMPIJJUCX-UHFFFAOYSA-N Calcium oxide Chemical compound [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 239000012442 inert solvent Substances 0.000 claims description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 229940086542 triethylamine Drugs 0.000 claims description 4
- LXBGSDVWAMZHDD-UHFFFAOYSA-N 2-methyl-1h-imidazole Chemical compound CC1=NC=CN1 LXBGSDVWAMZHDD-UHFFFAOYSA-N 0.000 claims description 3
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical class CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 3
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 3
- 239000000292 calcium oxide Substances 0.000 claims description 3
- 229960001701 chloroform Drugs 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 150000002460 imidazoles Chemical class 0.000 claims description 3
- 150000002576 ketones Chemical class 0.000 claims description 3
- 229910052747 lanthanoid Inorganic materials 0.000 claims description 3
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N methylimidazole Natural products CC1=CNC=N1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 claims description 3
- 239000012454 non-polar solvent Substances 0.000 claims description 3
- 239000003880 polar aprotic solvent Substances 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 235000015320 potassium carbonate Nutrition 0.000 claims description 3
- 150000003222 pyridines Chemical class 0.000 claims description 3
- 125000005270 trialkylamine group Chemical group 0.000 claims description 3
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims 1
- MRELNEQAGSRDBK-UHFFFAOYSA-N lanthanum oxide Inorganic materials [O-2].[O-2].[O-2].[La+3].[La+3] MRELNEQAGSRDBK-UHFFFAOYSA-N 0.000 claims 1
- KTUFCUMIWABKDW-UHFFFAOYSA-N oxo(oxolanthaniooxy)lanthanum Chemical compound O=[La]O[La]=O KTUFCUMIWABKDW-UHFFFAOYSA-N 0.000 claims 1
- 229910000029 sodium carbonate Inorganic materials 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 239000000543 intermediate Substances 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- RIUPLDUFZCXCHM-UHFFFAOYSA-N Urolithin A Chemical compound OC1=CC=C2C3=CC=C(O)C=C3OC(=O)C2=C1 RIUPLDUFZCXCHM-UHFFFAOYSA-N 0.000 description 11
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 6
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 150000007529 inorganic bases Chemical class 0.000 description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 3
- YNXLOPYTAAFMTN-SBUIBGKBSA-N C([C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)C1=CC=C(O)C=C1 Chemical compound C([C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)C1=CC=C(O)C=C1 YNXLOPYTAAFMTN-SBUIBGKBSA-N 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- 108010088847 Peptide YY Proteins 0.000 description 3
- 102100029909 Peptide YY Human genes 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000003629 gastrointestinal hormone Substances 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 102000051325 Glucagon Human genes 0.000 description 1
- 108060003199 Glucagon Proteins 0.000 description 1
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 1
- 101800000224 Glucagon-like peptide 1 Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 102100040918 Pro-glucagon Human genes 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- YHASWHZGWUONAO-UHFFFAOYSA-N butanoyl butanoate Chemical compound CCCC(=O)OC(=O)CCC YHASWHZGWUONAO-UHFFFAOYSA-N 0.000 description 1
- DVECBJCOGJRVPX-UHFFFAOYSA-N butyryl chloride Chemical compound CCCC(Cl)=O DVECBJCOGJRVPX-UHFFFAOYSA-N 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000000446 fuel Substances 0.000 description 1
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 1
- 229960004666 glucagon Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 244000005709 gut microbiome Species 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- GCYXWQUSHADNBF-AAEALURTSA-N preproglucagon 78-108 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 GCYXWQUSHADNBF-AAEALURTSA-N 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 235000021391 short chain fatty acids Nutrition 0.000 description 1
- 150000004666 short chain fatty acids Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
- C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
Definitions
- the present invention relates to new specific Urolithin butyrate compounds and to the synthesis of these specific Urolithin butyrates as well as to new compounds and their use.
- Butyrate compounds are very useful compounds, either as such or as intermediates in organic synthesis.
- Butyrates are seen as very useful and healthy compounds.
- butyrates fuels colonocytes help provide an oxygen- free environment in which beneficial gut microbes thrive. This keeps inflammation in check, gut cells healthy, and gut bacteria in a good state.
- Butyrates stop some of the pro-inflammatory substances in the human body from working.
- the anti-inflammatory effect of butyrate reduces oxidative stress and controls the damage caused by free radicals.
- GLP-1 glucagon-like peptide-1
- PYY peptide YY
- butyrates can be used as intermediates in organic synthesis to produce other useful compounds.
- the main problem with the butyrates is the strong (fishy) odour. Such an odour is such that most persons are not able to swallow such a compound even in very low concentration.
- the goal of the present invention was to provide a way to produce butyrate compounds having all advantages mentioned above in a good yield and avoiding the disadvantages such as having a strong unpleasant odour.
- specific new butyrate compounds as defined by the formula below can be obtained in good yields by a new and easy process.
- the present invention relates to a compound of formula (I) wherein
- R is H or -CH 2 (CO)CH 2 CH 2 CH 3
- RI is H or -CH 2 (CO)CH 2 CH 2 CH 3 with the proviso that when R is H then Ri is not H.
- the present invention relates to a compound of formula (la)
- the present invention relates to a compound of formula (lb)
- the present invention relates to a compound of formula (Ic)
- the present invention relates to a compound of formula (la)
- the present invention relates to a compound of formula (lb)
- the present invention relates to a compound of formula (lc)
- the new compounds according to the can be produced the following way:
- the starting material is the compound of formula (II) which is Urolithin A (also known as 3,8-dihydroxy-6H-benzo[c]chromen-6-one or 3,8- dihydroxy-6H-dibenzo[b,d]pyran-6-one).
- Urolithin A also known as 3,8-dihydroxy-6H-benzo[c]chromen-6-one or 3,8- dihydroxy-6H-dibenzo[b,d]pyran-6-one.
- the compound of formula (II) is then reacted with a compound of formula (III) wherein X is a halogen (such as Cl, Br, or F), OH, or a group -O(CO)(CH 2 )2CH3.
- X is a halogen (such as Cl, Br, or F), OH, or a group -O(CO)(CH 2 )2CH3.
- the reaction is carried in the presence of at least one base.
- the present invention relates to a process (P) for producing the compounds of formula (I) wherein
- R is H or -CH 2 (CO)CH 2 CH 2 CH 3
- RI is H or -CH 2 (CO)CH 2 CH 2 CH 3 with the proviso that when R is H then Ri is not H, wherein the compound of formula (II) is reacted with a compound of formula (III) wherein
- X is a halogen (such as Cl, Br, or F), OH, or a group -O(CO)(CH2)2CH3.
- the reaction can be carried out without any solvents or in an inert solvent (or mixture of inert solvents) and preferably in the presence of at least one base.
- the process according to the present invention can be carried without any solvent or it can be carried out in at least one inert solvent.
- the solvent is usually a polar aprotic as well as non-polar solvent.
- Suitable solvents are i.e. pyridine, picolines, dichloromethane, trichloromethane, ketones, acetonitrile, xylene, and toluene as well as mixture thereof.
- the present invention relates to a process (P1 ), which is process (P), wherein the process is carried without any solvent.
- the present invention relates to a process (P2), which is process (P), wherein the process is carried in at least one inert solvent.
- the present invention relates to a process (P2’), which is process (P2), wherein the solvent (or the mixture of solvents) is a polar aprotic or non-polar solvent.
- the present invention relates to a process (P2”), which is process (P2), wherein the solvent is chosen from the group consisting of pyridine, picolines, dichloromethane, trichloromethane, ketones, acetonitrile, xylene, and toluene.
- the solvent is chosen from the group consisting of pyridine, picolines, dichloromethane, trichloromethane, ketones, acetonitrile, xylene, and toluene.
- the process according to the present invention is carried out in the presence of at least one base.
- the base can be an organic or an inorganic base.
- Suitable organic bases are nitrogen containing bases, such as pyrimidine, pyridines, picoline purine, 4-dimethylaminopyridine, imidazoles (such as methylimidazole) or trialkyl amines, (e.g. triethyl amine, tributylamine or diisopropylethyl amine).
- nitrogen containing bases such as pyrimidine, pyridines, picoline purine, 4-dimethylaminopyridine, imidazoles (such as methylimidazole) or trialkyl amines, (e.g. triethyl amine, tributylamine or diisopropylethyl amine).
- Suitable inorganic bases are Na2COs, K2CO3, NaOH, CaO, La2Os, lanthanoid carbonates (such as La2(COs)2), CaCCh and KF/AI2O3.
- the inorganic bases serve as catalyst in the reaction.
- the nitrogen containing base can serve as solvent as well as well as a catalyst.
- the present invention relates to a process (P3), which is process (P), (P1), (P2), (P2’) or (P2”), wherein the process is carried out in the presence of at least one base.
- the present invention relates to a process (P3’), which is process (P3), wherein the base is an organic or an inorganic base. Therefore, the present invention relates to a process (P3”), which is process (P3’), wherein the organic base is a nitrogen containing base.
- the present invention relates to a process (P3’”), which is process (P3), (P3’) or (P3”), wherein the base is chosen from the group consisting of pyrimidine, pyridines, picoline purine, 4-dimethylaminopyridine, imidazoles (such as methylimidazole) or trialkyl amines, (e.g. triethyl amine, tributylamine or diisopropylethyl amine), Na2COs, K2CO3, NaOH, CaO, La2Os, lanthanoid carbonates (such as La2(COs)2), CaCCh and KF/AI2O3.
- the base is chosen from the group consisting of pyrimidine, pyridines, picoline purine, 4-dimethylaminopyridine, imidazoles (such as methylimidazole) or trialkyl amines, (e.g. triethyl amine, tributylamine or
- the total amount of base, which is added to the reaction mixture, is in a molar ratio of 1 :1 to 1 :100 in view of the compound of formula (II), preferably 1 :1 to 1 :50.
- the bases used as catalysts are added are added in small amounts (in view of the compound of formula (II)).
- the present invention relates to a process (P3’”), which is process (P3), (P3’) or (P3”), wherein the at least one base is used in a molar ratio of 1 :1 to 1 : 100 in view of the compound of formula (II).
- the compound of formula (III) is used in excess in view of the compound of formula (II). It is clear that when two OH groups in compounds of formula (II) are to be acetylated the molar excess of the compound of formula (II) is more than 2.
- the molar ratio of the compound of formula (III) to the compound of formula (II) is 1 :1 to 2:1 , when one OH group in the compound of formula (II) is to be acetylated.
- the molar ratio of the compound of formula (III) to the compound of formula (II) is at least 2:1 (preferably 2:1 to 10:1 , more preferably 2:1 to 5:1), when two OH groups in the compound of formula (II) are to be acetylated.
- the present invention relates to a process (P4), which is process (P), (P1), (P2), (P2’), (P2”), (P3), (P3’), (P3”) or (P3’”), wherein the molar ratio of the compound of formula (III) to the compound of formula (II) is 1 :1 to 2:1 , when one OH group in the compound of formula (II) is to be acetylated.
- the present invention relates to a process (P4’), which is process (P), (P1), (P2), (P2’), (P2”), (P3), (P3’), (P3”) or (P3’”), wherein the molar ratio of the compound of formula (III) to the compound of formula (II) is at least 2:1 (preferably 2:1 to 10:1 , more preferably 2:1 to 5:1), when two OH groups in the compound of formula (II) are to be acetylated.
- the process according to the present invention is carried out at a temperature of -10°C to 50° C. (preferably -10°C - 40°C, -5°C - 30°C)
- the present invention relates to a process (P5), which is process (P), (P1), (P2), (P2’), (P2”), (P3), (P3’), (P3”), (P3’”), (P4) or (P4’), wherein the process is carried out at a temperature of -10°C to 50° C.
- the starting material is the compound of formula (I) and it is reacted with a compound of formula (IV) forming a compound of formula (I’) with the proviso that when R is H then Ri is not H, which is then in a further step hydrogenated (using commonly known methods) to the compound of formula (I).
- the product (compound of formula (I)) is isolated using commonly known methods. Usually using filtration.
- the product (compound of formula (I)) can the also be purified further.
- the present invention relates to compounds of formula (I’) with the proviso that when R is H then Ri is not H.
- the present invention also relates to a compound of formula (I’a)
- the present invention also relates to a compound of formula (I’b)
- the present invention also relates to a compound of formula (I’c)
- the compounds of formula (I) can be used as such or in any formulation in the field of food, feed, pharma and personal care applications.
- the compounds of formula (I) can also be used as intermediates in organic synthesis.
- the following examples illustrate the invention further without limiting it. All percentages and parts, which are given, are related to the weight and the temperatures are given in °C, and the pressures are absolute pressures when not otherwise stated.
- reaction mixture was heated to room temperature and kept stirring for a few hours, and 20 mL water was added and the suspension was filtered under vacuum.
- the filter cake was washed with 5 mL methyl tert-butyl ether (MTBE) and further dried under vacuum.
- MTBE methyl tert-butyl ether
- reaction mixture was heated to room temperature and kept stirring for a few hours, and 20 mL water was added to the mixture and the suspension was filtered under vacuum.
- the filter cake was washed with 5 mL methyl tert-butyl ether (MTBE) and further dried.
- the yield of the compound of formula (la) was 70%.
- reaction mixture was kept stirring for a few hours.
- the reaction mixture was concentrated under vacuum.
- the yield of the compound of formula (la) was 75%.
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Abstract
La présente invention concerne de nouveaux composés spécifiques de butyrate d'urolithine et la synthèse de ces butyrates d'urolithine spécifiques ainsi que de nouveaux composés et leur utilisation. Les composés de butyrate sont des composés très utiles, en tant que tels ou en tant qu'intermédiaires dans la synthèse organique.
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2015100213A2 (fr) * | 2013-12-23 | 2015-07-02 | Amazentis Sa | Synthese d'urolithines a echelle de procede |
WO2020110089A1 (fr) * | 2018-11-29 | 2020-06-04 | Warszawski Uniwersytet Medyczny | Urolithine a et composition la contenant pour utilisation externe dans des inflammations de diverses étiologies |
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- 2023-04-03 WO PCT/EP2023/058610 patent/WO2023198486A1/fr unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2015100213A2 (fr) * | 2013-12-23 | 2015-07-02 | Amazentis Sa | Synthese d'urolithines a echelle de procede |
WO2020110089A1 (fr) * | 2018-11-29 | 2020-06-04 | Warszawski Uniwersytet Medyczny | Urolithine a et composition la contenant pour utilisation externe dans des inflammations de diverses étiologies |
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