AU2014379612A1 - Compositions comprising noribogaine and an excipient to facilitate transport across the blood brain barrier - Google Patents
Compositions comprising noribogaine and an excipient to facilitate transport across the blood brain barrier Download PDFInfo
- Publication number
- AU2014379612A1 AU2014379612A1 AU2014379612A AU2014379612A AU2014379612A1 AU 2014379612 A1 AU2014379612 A1 AU 2014379612A1 AU 2014379612 A AU2014379612 A AU 2014379612A AU 2014379612 A AU2014379612 A AU 2014379612A AU 2014379612 A1 AU2014379612 A1 AU 2014379612A1
- Authority
- AU
- Australia
- Prior art keywords
- noribogaine
- compound
- pharmaceutically acceptable
- patient
- pharmaceutical composition
- 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.)
- Abandoned
Links
- RAUCDOKTMDOIPF-RYRUWHOVSA-N noribogaine Chemical compound N1([C@@H]2[C@H]3C[C@H](C1)C[C@@H]2CC)CCC1=C3NC2=CC=C(O)C=C12 RAUCDOKTMDOIPF-RYRUWHOVSA-N 0.000 title claims abstract description 106
- RAUCDOKTMDOIPF-UHFFFAOYSA-N hydroxyibogamine Natural products CCC1CC(C2)CC3C1N2CCC1=C3NC2=CC=C(O)C=C12 RAUCDOKTMDOIPF-UHFFFAOYSA-N 0.000 title claims abstract description 104
- 239000000203 mixture Substances 0.000 title claims abstract description 62
- 239000000546 pharmaceutical excipient Substances 0.000 title claims abstract description 54
- 230000008499 blood brain barrier function Effects 0.000 title claims abstract description 50
- 210000001218 blood-brain barrier Anatomy 0.000 title claims abstract description 50
- 150000001875 compounds Chemical class 0.000 claims description 72
- 238000000034 method Methods 0.000 claims description 54
- 125000005647 linker group Chemical group 0.000 claims description 47
- 150000001720 carbohydrates Chemical class 0.000 claims description 37
- 229910052739 hydrogen Inorganic materials 0.000 claims description 31
- 239000001257 hydrogen Substances 0.000 claims description 31
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 31
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 28
- 235000010355 mannitol Nutrition 0.000 claims description 27
- 229930195725 Mannitol Natural products 0.000 claims description 25
- 239000000594 mannitol Substances 0.000 claims description 25
- 239000008194 pharmaceutical composition Substances 0.000 claims description 25
- 150000003839 salts Chemical class 0.000 claims description 24
- 230000035515 penetration Effects 0.000 claims description 20
- 208000002193 Pain Diseases 0.000 claims description 16
- 206010012335 Dependence Diseases 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical group OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 8
- 229920001542 oligosaccharide Polymers 0.000 claims description 8
- 150000002482 oligosaccharides Chemical class 0.000 claims description 8
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 claims description 6
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical group OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 claims description 5
- SRBFZHDQGSBBOR-SOOFDHNKSA-N D-ribopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@@H]1O SRBFZHDQGSBBOR-SOOFDHNKSA-N 0.000 claims description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 79
- 239000000243 solution Substances 0.000 description 56
- 238000002360 preparation method Methods 0.000 description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- 238000006243 chemical reaction Methods 0.000 description 29
- 210000004556 brain Anatomy 0.000 description 26
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 25
- 239000011541 reaction mixture Substances 0.000 description 21
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 239000012043 crude product Substances 0.000 description 14
- 229940079593 drug Drugs 0.000 description 14
- 239000003814 drug Substances 0.000 description 14
- -1 ethritol Chemical class 0.000 description 14
- 125000006239 protecting group Chemical group 0.000 description 13
- 238000000746 purification Methods 0.000 description 13
- 235000019439 ethyl acetate Nutrition 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 9
- SRBFZHDQGSBBOR-STGXQOJASA-N alpha-D-lyxopyranose Chemical compound O[C@@H]1CO[C@H](O)[C@@H](O)[C@H]1O SRBFZHDQGSBBOR-STGXQOJASA-N 0.000 description 9
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 9
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 9
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 9
- 238000002953 preparative HPLC Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 8
- DCBDOYDVQJVXOH-UHFFFAOYSA-N azane;1h-indole Chemical compound N.C1=CC=C2NC=CC2=C1 DCBDOYDVQJVXOH-UHFFFAOYSA-N 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 238000003776 cleavage reaction Methods 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- HSIBGVUMFOSJPD-CFDPKNGZSA-N ibogaine Chemical class N1([C@@H]2[C@H]3C[C@H](C1)C[C@@H]2CC)CCC1=C3NC2=CC=C(OC)C=C12 HSIBGVUMFOSJPD-CFDPKNGZSA-N 0.000 description 8
- 230000007017 scission Effects 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- 238000007796 conventional method Methods 0.000 description 7
- 238000003818 flash chromatography Methods 0.000 description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 210000002966 serum Anatomy 0.000 description 7
- 208000024891 symptom Diseases 0.000 description 7
- HEBKCHPVOIAQTA-QWWZWVQMSA-N D-arabinitol Chemical compound OC[C@@H](O)C(O)[C@H](O)CO HEBKCHPVOIAQTA-QWWZWVQMSA-N 0.000 description 6
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 description 6
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- PYMYPHUHKUWMLA-WDCZJNDASA-N arabinose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-WDCZJNDASA-N 0.000 description 6
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- 108090000371 Esterases Proteins 0.000 description 5
- VOXIUXZAOFEFBL-UHFFFAOYSA-N Voacangin Natural products CCC1CC2CN3CC1C(C2)(OC(=O)C)c4[nH]c5ccc(OC)cc5c4C3 VOXIUXZAOFEFBL-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 125000003545 alkoxy group Chemical group 0.000 description 5
- 230000008878 coupling Effects 0.000 description 5
- 238000010168 coupling process Methods 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000008103 glucose Substances 0.000 description 5
- OLOCMRXSJQJJPL-UHFFFAOYSA-N ibogaine Natural products CCC1CC2CC3C1N(C2)C=Cc4c3[nH]c5ccc(OC)cc45 OLOCMRXSJQJJPL-UHFFFAOYSA-N 0.000 description 5
- AREITJMUSRHSBK-UHFFFAOYSA-N ibogamine Natural products CCC1CC2C3CC1CN2CCc4c3[nH]c5ccccc45 AREITJMUSRHSBK-UHFFFAOYSA-N 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 230000032258 transport Effects 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 4
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- RIZOOQYPYGPBOC-UHFFFAOYSA-N Methyl 9-hydroxynonanoic acid Natural products COC(=O)CCCCCCCCO RIZOOQYPYGPBOC-UHFFFAOYSA-N 0.000 description 4
- 229910019142 PO4 Inorganic materials 0.000 description 4
- 108091005804 Peptidases Proteins 0.000 description 4
- 102000035195 Peptidases Human genes 0.000 description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 235000001014 amino acid Nutrition 0.000 description 4
- 229940024606 amino acid Drugs 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 206010013663 drug dependence Diseases 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- 125000001475 halogen functional group Chemical group 0.000 description 4
- 230000001965 increasing effect Effects 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 239000010452 phosphate Substances 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 229910052717 sulfur Chemical group 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 3
- MSWZFWKMSRAUBD-GASJEMHNSA-N 2-amino-2-deoxy-D-galactopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O MSWZFWKMSRAUBD-GASJEMHNSA-N 0.000 description 3
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 3
- MSWZFWKMSRAUBD-CBPJZXOFSA-N 2-amino-2-deoxy-D-mannopyranose Chemical compound N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-CBPJZXOFSA-N 0.000 description 3
- 208000019901 Anxiety disease Diseases 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 3
- 229930091371 Fructose Natural products 0.000 description 3
- 239000005715 Fructose Substances 0.000 description 3
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 3
- PNNNRSAQSRJVSB-SLPGGIOYSA-N Fucose Natural products C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C=O PNNNRSAQSRJVSB-SLPGGIOYSA-N 0.000 description 3
- SHZGCJCMOBCMKK-DHVFOXMCSA-N L-fucopyranose Chemical compound C[C@@H]1OC(O)[C@@H](O)[C@H](O)[C@@H]1O SHZGCJCMOBCMKK-DHVFOXMCSA-N 0.000 description 3
- SHZGCJCMOBCMKK-JFNONXLTSA-N L-rhamnopyranose Chemical compound C[C@@H]1OC(O)[C@H](O)[C@H](O)[C@H]1O SHZGCJCMOBCMKK-JFNONXLTSA-N 0.000 description 3
- PNNNRSAQSRJVSB-UHFFFAOYSA-N L-rhamnose Natural products CC(O)C(O)C(O)C(O)C=O PNNNRSAQSRJVSB-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 3
- 208000001294 Nociceptive Pain Diseases 0.000 description 3
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 3
- MUPFEKGTMRGPLJ-RMMQSMQOSA-N Raffinose Natural products O(C[C@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O[C@@]2(CO)[C@H](O)[C@@H](O)[C@@H](CO)O2)O1)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 MUPFEKGTMRGPLJ-RMMQSMQOSA-N 0.000 description 3
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- MUPFEKGTMRGPLJ-UHFFFAOYSA-N UNPD196149 Natural products OC1C(O)C(CO)OC1(CO)OC1C(O)C(O)C(O)C(COC2C(C(O)C(O)C(CO)O2)O)O1 MUPFEKGTMRGPLJ-UHFFFAOYSA-N 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 3
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 3
- 230000036506 anxiety Effects 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000004888 barrier function Effects 0.000 description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 3
- DLRVVLDZNNYCBX-ZZFZYMBESA-N beta-melibiose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@H](O)O1 DLRVVLDZNNYCBX-ZZFZYMBESA-N 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 230000003413 degradative effect Effects 0.000 description 3
- 238000010520 demethylation reaction Methods 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- FBPFZTCFMRRESA-GUCUJZIJSA-N galactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-GUCUJZIJSA-N 0.000 description 3
- 229930182830 galactose Natural products 0.000 description 3
- 229960002442 glucosamine Drugs 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 102000048260 kappa Opioid Receptors Human genes 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 150000002772 monosaccharides Chemical group 0.000 description 3
- 102000051367 mu Opioid Receptors Human genes 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 238000006386 neutralization reaction Methods 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 230000000149 penetrating effect Effects 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 239000011574 phosphorus Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- MUPFEKGTMRGPLJ-ZQSKZDJDSA-N raffinose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)O1 MUPFEKGTMRGPLJ-ZQSKZDJDSA-N 0.000 description 3
- HEBKCHPVOIAQTA-ZXFHETKHSA-N ribitol Chemical compound OC[C@H](O)[C@H](O)[C@H](O)CO HEBKCHPVOIAQTA-ZXFHETKHSA-N 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 239000011593 sulfur Substances 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 239000000811 xylitol Substances 0.000 description 3
- 108020001588 κ-opioid receptors Proteins 0.000 description 3
- 108020001612 μ-opioid receptors Proteins 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- UPQQXPKAYZYUKO-UHFFFAOYSA-N 2,2,2-trichloroacetamide Chemical class OC(=N)C(Cl)(Cl)Cl UPQQXPKAYZYUKO-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- USSIQXCVUWKGNF-UHFFFAOYSA-N 6-(dimethylamino)-4,4-diphenylheptan-3-one Chemical compound C=1C=CC=CC=1C(CC(C)N(C)C)(C(=O)CC)C1=CC=CC=C1 USSIQXCVUWKGNF-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- VVWPSAPZUZXYCM-UHFFFAOYSA-N 9-methoxy-9-oxononanoic acid Chemical compound COC(=O)CCCCCCCC(O)=O VVWPSAPZUZXYCM-UHFFFAOYSA-N 0.000 description 2
- 208000004998 Abdominal Pain Diseases 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 208000002881 Colic Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 244000182067 Fraxinus ornus Species 0.000 description 2
- 235000002917 Fraxinus ornus Nutrition 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 206010019233 Headaches Diseases 0.000 description 2
- GVGLGOZIDCSQPN-PVHGPHFFSA-N Heroin Chemical compound O([C@H]1[C@H](C=C[C@H]23)OC(C)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4OC(C)=O GVGLGOZIDCSQPN-PVHGPHFFSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 208000000112 Myalgia Diseases 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 206010028813 Nausea Diseases 0.000 description 2
- 108090000137 Opioid Receptors Proteins 0.000 description 2
- 102000003840 Opioid Receptors Human genes 0.000 description 2
- 208000004983 Phantom Limb Diseases 0.000 description 2
- 206010056238 Phantom pain Diseases 0.000 description 2
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 2
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- 229930182475 S-glycoside Natural products 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 206010047700 Vomiting Diseases 0.000 description 2
- LPTITAGPBXDDGR-LJIZCISZSA-N [(2r,3r,4s,5r,6r)-3,4,5,6-tetraacetyloxyoxan-2-yl]methyl acetate Chemical compound CC(=O)OC[C@H]1O[C@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O LPTITAGPBXDDGR-LJIZCISZSA-N 0.000 description 2
- WEVYAHXRMPXWCK-FIBGUPNXSA-N acetonitrile-d3 Chemical compound [2H]C([2H])([2H])C#N WEVYAHXRMPXWCK-FIBGUPNXSA-N 0.000 description 2
- WQZGKKKJIJFFOK-PQMKYFCFSA-N alpha-D-mannose Chemical compound OC[C@H]1O[C@H](O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-PQMKYFCFSA-N 0.000 description 2
- 230000009435 amidation Effects 0.000 description 2
- 238000007112 amidation reaction Methods 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 150000001719 carbohydrate derivatives Chemical class 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 239000010779 crude oil Substances 0.000 description 2
- 230000017858 demethylation Effects 0.000 description 2
- 229960002069 diamorphine Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 238000007306 functionalization reaction Methods 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 231100000869 headache Toxicity 0.000 description 2
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229960001797 methadone Drugs 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- 208000013465 muscle pain Diseases 0.000 description 2
- 239000004081 narcotic agent Substances 0.000 description 2
- 230000008693 nausea Effects 0.000 description 2
- 208000004296 neuralgia Diseases 0.000 description 2
- 230000002981 neuropathic effect Effects 0.000 description 2
- 208000021722 neuropathic pain Diseases 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 2
- 230000001766 physiological effect Effects 0.000 description 2
- 239000010695 polyglycol Substances 0.000 description 2
- 229920000151 polyglycol Polymers 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 235000019833 protease Nutrition 0.000 description 2
- 150000003214 pyranose derivatives Chemical class 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 210000000278 spinal cord Anatomy 0.000 description 2
- 230000001839 systemic circulation Effects 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 150000003569 thioglycosides Chemical class 0.000 description 2
- 210000001578 tight junction Anatomy 0.000 description 2
- ILJSQTXMGCGYMG-UHFFFAOYSA-N triacetic acid Chemical compound CC(=O)CC(=O)CC(O)=O ILJSQTXMGCGYMG-UHFFFAOYSA-N 0.000 description 2
- 230000008673 vomiting Effects 0.000 description 2
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 1
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- IDXCXSCCZNCXCL-XMADEQCMSA-N (2s)-2-[[(2s)-2-[[(2s)-1-[(2s)-2-[[(2s)-2-[[2-[[(2s,4r)-1-[(2s)-1-[(2s)-2-amino-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]-4-hydroxypyrrolidine-2-carbonyl]amino]acetyl]amino]-3-thiophen-2-ylpropanoyl]amino]-3-hydroxypropanoyl]pyrrolidine Chemical compound C1=CC(OC)=CC=C1C[C@@H](CN[C@@H](CCCN=C(N)N)C(O)=O)NC(=O)[C@H]1N(C(=O)[C@H](CO)NC(=O)[C@H](CC=2SC=CC=2)NC(=O)CNC(=O)[C@H]2N(C[C@H](O)C2)C(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCN=C(N)N)CCC1 IDXCXSCCZNCXCL-XMADEQCMSA-N 0.000 description 1
- OGOMAWHSXRDAKZ-RUOAZZEASA-N (2s,3r,4s,5r,6r)-3,4,5-tris(phenylmethoxy)-6-(phenylmethoxymethyl)oxan-2-ol Chemical compound C([C@H]1O[C@@H]([C@@H]([C@@H](OCC=2C=CC=CC=2)[C@@H]1OCC=1C=CC=CC=1)OCC=1C=CC=CC=1)O)OCC1=CC=CC=C1 OGOMAWHSXRDAKZ-RUOAZZEASA-N 0.000 description 1
- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 description 1
- YNSISDPVMBMWBJ-ZZVYKPCYSA-N (4s,5s,6r)-4,5-diacetyl-6-[(1r)-1,2-dihydroxyethyl]-4,5,6-trihydroxyoctane-2,3,7-trione Chemical compound CC(=O)C(=O)[C@@](O)(C(C)=O)[C@](O)(C(C)=O)[C@@](O)(C(C)=O)[C@H](O)CO YNSISDPVMBMWBJ-ZZVYKPCYSA-N 0.000 description 1
- 239000001124 (E)-prop-1-ene-1,2,3-tricarboxylic acid Substances 0.000 description 1
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ALVZNPYWJMLXKV-UHFFFAOYSA-N 1,9-Nonanediol Chemical compound OCCCCCCCCCO ALVZNPYWJMLXKV-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- YOWQWFMSQCOSBA-UHFFFAOYSA-N 2-methoxypropene Chemical compound COC(C)=C YOWQWFMSQCOSBA-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 108090000531 Amidohydrolases Proteins 0.000 description 1
- 102000004092 Amidohydrolases Human genes 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 206010048962 Brain oedema Diseases 0.000 description 1
- 101150041968 CDC13 gene Proteins 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical group O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 206010013654 Drug abuse Diseases 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 1
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 102000004882 Lipase Human genes 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- 108090001060 Lipase Proteins 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
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 108700031422 RMP 7 Proteins 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 229910008433 SnCU Inorganic materials 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 241001246918 Tabernanthe iboga Species 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- DRUIESSIVFYOMK-UHFFFAOYSA-N Trichloroacetonitrile Chemical compound ClC(Cl)(Cl)C#N DRUIESSIVFYOMK-UHFFFAOYSA-N 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 240000006677 Vicia faba Species 0.000 description 1
- 235000010749 Vicia faba Nutrition 0.000 description 1
- 235000002098 Vicia faba var. major Nutrition 0.000 description 1
- LPTITAGPBXDDGR-WHWZVRATSA-N [(2r,3r,4s,5s)-3,4,5,6-tetraacetyloxyoxan-2-yl]methyl acetate Chemical compound CC(=O)OC[C@H]1OC(OC(C)=O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O LPTITAGPBXDDGR-WHWZVRATSA-N 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229940091181 aconitic acid Drugs 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229940025084 amphetamine Drugs 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 239000003125 aqueous solvent 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
- 235000009697 arginine Nutrition 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- SRBFZHDQGSBBOR-TXICZTDVSA-N beta-D-ribopyranose Chemical compound O[C@@H]1CO[C@@H](O)[C@H](O)[C@@H]1O SRBFZHDQGSBBOR-TXICZTDVSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- PFYXSUNOLOJMDX-UHFFFAOYSA-N bis(2,5-dioxopyrrolidin-1-yl) carbonate Chemical compound O=C1CCC(=O)N1OC(=O)ON1C(=O)CCC1=O PFYXSUNOLOJMDX-UHFFFAOYSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004155 blood-retinal barrier Anatomy 0.000 description 1
- 230000004378 blood-retinal barrier Effects 0.000 description 1
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 1
- 239000003360 bradykinin B2 receptor agonist Substances 0.000 description 1
- 210000004781 brain capillary Anatomy 0.000 description 1
- 208000006752 brain edema Diseases 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000004858 capillary barrier Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001722 carbon compounds Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 210000004671 cell-free system Anatomy 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- GTZCVFVGUGFEME-IWQZZHSRSA-N cis-aconitic acid Chemical compound OC(=O)C\C(C(O)=O)=C\C(O)=O GTZCVFVGUGFEME-IWQZZHSRSA-N 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229960003920 cocaine Drugs 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 231100000573 exposure to toxins Toxicity 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000000819 hypertonic solution Substances 0.000 description 1
- 229940021223 hypertonic solution Drugs 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- PEECTLLHENGOKU-UHFFFAOYSA-N n,n-dimethylpyridin-4-amine Chemical compound CN(C)C1=CC=NC=C1.CN(C)C1=CC=NC=C1 PEECTLLHENGOKU-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- MYWUZJCMWCOHBA-UHFFFAOYSA-N n-methyl-1-phenylpropan-2-amine Chemical compound CNC(C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000007971 neurological deficit Effects 0.000 description 1
- 229960002715 nicotine Drugs 0.000 description 1
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- 239000003402 opiate agonist Substances 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000002337 osmotic diuretic agent Substances 0.000 description 1
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000008058 pain sensation Effects 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000003836 peripheral circulation Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- CBMSDILKECEMOT-UHFFFAOYSA-N potassium;2-methylpropan-1-olate Chemical compound [K+].CC(C)C[O-] CBMSDILKECEMOT-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 230000003016 quadriplegic effect Effects 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 239000002265 redox agent Substances 0.000 description 1
- 229940124550 renal vasodilator Drugs 0.000 description 1
- 210000001525 retina Anatomy 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 230000000392 somatic effect Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 230000000153 supplemental effect Effects 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 235000013619 trace mineral Nutrition 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- GTZCVFVGUGFEME-UHFFFAOYSA-N trans-aconitic acid Natural products OC(=O)CC(C(O)=O)=CC(O)=O GTZCVFVGUGFEME-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- JLGLQAWTXXGVEM-UHFFFAOYSA-N triethylene glycol monomethyl ether Chemical compound COCCOCCOCCO JLGLQAWTXXGVEM-UHFFFAOYSA-N 0.000 description 1
- 150000004043 trisaccharides Chemical class 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 230000009278 visceral effect Effects 0.000 description 1
- 208000009935 visceral pain 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Psychiatry (AREA)
- Dermatology (AREA)
- Addiction (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
This invention relates generally to compositions comprising noribogaine and an excipient to facilitate transport across the blood brain barrier.
Description
COMPOSITIONS COMPRISING NORIBOGAINE AND AN EXCIPIENT TO FACILITATE TRANSPORT ACROSS THE BLOOD BRAIN BARRIER
Field of the Invention [0001] This invention relates generally to compositions comprising noribogaine and an excipient to facilitate transport across the blood brain barrier.
State of the Art [0002] Noribogaine is a well known derivative of ibogaine and is sometimes referred to as 12-hydroxyibogaine. It is a metabolite of ibogaine. US Patent No. 2,813,873 claims noribogaine albeit as “12-O-demethylibogaine” while providing an incorrect structural formula for ibogaine. The structure of noribogaine has now been thoroughly evaluated and is found to combine the features of tyrptamine, tetrahydrohavaine and indolazepines. Noribogaine can be depicted by the following Formula:
[0003] Noribogaine and its pharmaceutically acceptable salts have recently received significant attention as non-addictive alkaloids useful in treating drug dependency (U.S. Patent No. 6,348,456) and as a potent analgesic (U.S. Patent No. 7,220,737).
[0004] Noribogaine is typically administered orally or intravenously and becomes systemically available to the treated patient. While noribogaine allosterically binds tightly to the μ and κ receptors, the systemic circulation of noribogaine increases the likelihood of undesirable side effects while the availability of noribogaine is limited by the efficiency of its passage across the blood brain barrier.
[0005] Accordingly, there is a need to reduce the systemic circulation of noribogaine while maintaining or increasing its concentration in the brain particularly at the μ and κ receptors.
SUMMARY OF THE INVENTION
[0006] This invention relates to increased cranial delivery of noribogaine by use of a pharmaceutically acceptable excipient to enhance blood brain barrier penetration. It is contemplated that the excipient cooperatively increases the concentration of noribogaine in the brain of the treated patient thereby reducing the systemic concentration of noribogaine in the remainder of the patient’s body. While not all drugs react cooperatively with blood brain barrier excipients, it is contemplated that noribogaine will show a significant increase in cranial concentration when used in conjunction with such an excipient. It is further contemplated that in view of such targeted delivery, the amount of noribogaine required to effect therapy will be reduced.
[0007] Accordingly, in one of its composition aspects, this invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of noribogaine, or a derivative or pharmaceutically acceptable salt thereof, and an effective amount of a pharmaceutically acceptable excipient to enhance the blood brain barrier penetration of noribogaine.
[0008] In some embodiments, the excipient which enhances the blood brain barrier penetration of noribogaine is a biocompatible dehydrating saccharide such as mannitol.
[0009] In some embodiments, at least a portion of the mannitol or other dehydrating saccharide is bound to the noribogaine via a biocompatible, cleavable linking group. It is contemplated that such compounds will reduce the concentration of the saccharide necessary to enhance the blood brain barrier penetration of noribogaine. In one such embodiment, there is provided a compound of Formula I:
I wherein is a single or double bond; R is hydrogen, alkyl, -C(0)-alkyl, or the group -L-S where L is a covalent bond or is a biocompatible, cleavable linking group and S is a dehydrating saccharide or oligosaccharide; R1 is hydrogen or the group -L-S where L is a covalent bond or is a biocompatible, cleavable linking group and S is a dehydrating saccharide or oligosaccharide; provided that at least one of R and R1 is -L-S; or a pharmaceutically acceptable salt thereof.
[0010] In another of its composition aspects, there is provided a compound of Formula I or its pharmaceutically acceptable salt.
[0011] In some embodiments, R is hydrogen and R1 is -L-S. In some embodiments, R is -C(0)-alkyl and R1 is -L-S. In some embodiments, R is -L-S and R1 is hydrogen. In some embodiments, both R and R1 are -L-S.
[0012] In another of its composition aspects, this invention is directed to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically acceptable amount of a compound of Formula I above.
[0013] In some embodiments, R is hydrogen and R1 is -L-S. In some embodiments, R is -L-S and R1 is hydrogen. In some embodiments, R is -C(0)-alkyl and R1 is -L-S. In some embodiments, both R and R1 are -L-S. In some embodiments, the pharmaceutically acceptable excipient comprises mannitol.
[0014] In one of its method aspects, there is provided a method for treating pain in a patient which method comprises administering to said patient a pharmaceutical composition comprising a therapeutically effective amount of noribogaine or a pharmaceutically acceptable salt thereof and an effective amount of a pharmaceutically acceptable excipient to enhance the blood brain barrier penetration of noribogaine.
[0015] In another of its method aspects, there is provided a method for treating addiction in a patient which method comprises administering to said patient a pharmaceutical composition comprising a therapeutically effective amount of noribogaine or a pharmaceutically acceptable salt thereof and an effective amount of a pharmaceutically acceptable excipient to enhance the blood brain barrier penetration of noribogaine.
[0016] In one of its method aspects, there is provided a method for treating pain in a patient which method comprises administering to said patient a therapeutically effective amount of a compound of Formula I or a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable excipient.
[0017] In another of its method aspects, there is provided a method for treating addiction in a patient which method comprises administering to said patient a therapeutically effective amount of a compound of Formula I or a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable excipient.
Detailed Description [0018] This invention is directed to compositions comprising noribogaine, or a derivative or pharmaceutically acceptable salt thereof, and an excipient to facilitate transport across the blood brain barrier.
[0019] It is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
[0020] It must be noted that as used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an excipient” includes a plurality of excipients. 1. Definitions [0021] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein the following terms have the following meanings.
[0022] As used herein, the term “comprising” or “comprises” is intended to mean that the compositions and methods include the recited elements, but not excluding others. “Consisting essentially of’ when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed invention. “Consisting of’ shall mean excluding more than trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention.
[0023] The term “about” when used before a numerical designation, e.g., temperature, time, amount, and concentration, including range, indicates approximations which may vary by ( + ) or ( - ) 10 %, 5 % or 1 %.
[0024] As stated above, the invention is directed to compositions comprising noribogaine, or a derivative or pharmaceutically acceptable salt thereof, and an excipient to facilitate transport across the blood brain barrier.
[0025] As used herein, the term “noribogaine” refers to the compound:
as well as its pharmaceutically acceptable salts thereof. Conventionally, noribogaine is prepared by demethylation of naturally occurring ibogaine:
which is isolated from Tabernanthe iboga, a shrub of West Africa. Demethylation may be accomplished by conventional techniques such as by reaction with boron tribromide/methylene chloride at room temperature followed by conventional purification. (See, for example, Huffman, et al., J. Org. Chem. 50:1460 (1985)). Methods for the synthesis and purification of noribogaine are disclosed in US Patent Application No. 13/104,406, entitled Methods and Compositions for Preparing and Purifying Noribogaine, filed on May 10, 2011, which is hereby incorporated by reference in its entirety. This invention is not limited to any particular chemical form of noribogaine and the drug may be given to patients either as a free base or as a pharmaceutically acceptable addition salt.
[0026] As used herein, the terms “blood-brain barrier” or “BBB” refer to the barrier between the peripheral circulation and the brain and spinal cord which is formed by tight junctions within the brain capillary endothelial plasma membranes, creating an extremely tight barrier that restricts the transport of molecules into the brain. The blood-brain barrier within the brain, the blood-spinal cord barrier within the spinal cord, and the blood-retinal barrier within the retina, are contiguous capillary barriers within the central nervous system (CNS), and are collectively referred to herein as the blood-brain barrier or BBB.
[0027] As used herein, the term “derivative” refers to derivatives of noribogaine that maintain or enhance the activity of noribogaine, or are metabolized within the patient to form noribogaine. Suitable derivatives are disclosed in US Patent Application No. 13/104,410, entitled Substituted Noribogaine, filed on May 10, 2011, which is hereby incorporated by reference in its entirety.
[0028] As used herein, the term “pharmaceutically acceptable excipient to enhance blood brain barrier penetration” refers to a substance that is capable of disrupting or penetrating the blood brain barrier. In one embodiment, the disruption is a transient disruption. The amount of pharmaceutically acceptable excipient administered with the noribogaine or derivative thereof is the amount effective to disrupt the blood brain barrier and allow noribogaine to enter the brain.
[0029] As used herein, the term “biocompatible dehydrating saccharide” refers to a saccharide or derivative thereof, having at least 6 carbon atoms (which may be linear, branched or cyclic) with an oxygen, nitrogen or sulfur atom bonded to each carbon atom. The term “biocompatible dehydrating oligosaccharides” includes oligosaccharides containing from about 2-9 monosaccharide units. Specific monosaccharides include C5 and above (preferably Cs-Cg) saccharides such as ethritol, zylitol, galactose, lactose, xylose, dulcitol, myo-insoitol, fructose, mannitol, sorbitol, glucose, arabinose, arabinose, celloboise, maltose, raffinose, rhamnose, melibiose, ribose, adonitol, arabitol, arabitol, fucose, lyxose, lyxose, lyxose, glucosamine, mannosamine, and galactosamine; di- and trisaccharides include saccharides having two or three monosaccharide units.
[0030] As used herein, the term “mannitol” refers to (2R,3R,4R,5R)-hexane-l,2,3,4,5,6-hexol
Mannitol is a polyol and has been used as an osmotic diuretic agent and a weak renal vasodilator. It was originally isolated from the secretions of the flowering ash, called manna after their resemblance to the Biblical food, and is also be referred to as mannite and manna sugar. Mannitol and derivatives thereof are readily available from commercial sources or can be synthesized using procedures known in the art. In its pyranose or condensed form, mannitol becomes a 6 membered ring saccharide (sugar) of the formula:
and is referred to as α-D-mannopyranose. As used herein, all saccharides are meant to include both their open forms as well as their pyranose forms including their naturally occurring D or L forms of the saccharide.
[0031] As used herein, the term “pharmaceutically acceptable salt” refers to salts derived from organic or inorganic acids. Examples of such acids include, without limitation, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methane sulfonic acid, phosphorous acid, nitric acid, perchloric acid, acetic acid, tartaric acid, lactic acid, succinic acid, citric acid, malic acid, maleic acid, aconitic acid, salicylic acid, thalic acid, embonic acid, enanthic acid, and the like.
[0032] As used herein, the term “biocompatible, cleavable linking group” refers to a linking group that can be attached to noribogaine at any possible position such that the linker is biocompatible (i.e. does not produce undesired side effects or have an intolerable toxicity), is readily cleaved in the body (preferably in the brain), and does not inhibit or alter the desired physiological effect of noribogaine. Specifically, the linking group should be sufficiently stable in the circulatory system (serum or blood), but is cleaved to release the noribogaine upon entry into the brain. Suitable biocompatible, cleavable linking groups comprise from 1 to 20 atoms selected from carbon, nitrogen, oxygen, sulfur, and phosphorus, and are, in general, susceptible to cleavage conditions or agents in the brain (i.e. pH, redox potential or the presence of degradative molecules such as enzymes). The biocompatible, cleavable linking group can be an ester-based cleavable linking group (-C(O)O- or -OC(O)-), an amide-based cleavable linking group (-C(0)NR-or -NRC(O)-), or a phosphate-based cleavable linking group (-P(0)(0R)-0-, -O-P(S)(0R)-0-, -0-P(S)(SR)-0-, -S-P(0)(0R)-0-, -0-P(0)(0R)-S-, -S-P(0)(0R)-S-, -0-P(S)(0R)-S-, -S-P(S)(0R)-0-, -0-P(0)(R)-0-, -0-P(S)(R)-0-, -S-P(0)(R)-0-, -S-P(S)(R)-0-, -S-P(0)(R)-S-, or -0-P(S)(R)-S-) where R can be hydrogen or alkyl.
[0033] As used herein, the term “alkyl” refers to a monovalent saturated aliphatic hydrocarbyl group having from 1 to 12 carbon atoms, or 1 to 6 carbon atoms. The term “Cx” means an alkyl group with x carbon atoms. In some embodiments, one or more of the hydrogen atoms of the alkyl group can be replaced with a functional group such as -OH, -NH2, -SH, and the like. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), t-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-). As used herein, the term “alkoxy” refers to O-alkyl.
[0034] As used herein, the term “therapeutically acceptable amount” refers to the amount of a composition of this invention that is sufficient to effect treatment, as defined herein, when administered to a subject in need of such treatment. The therapeutically effective amount will vary depending upon the subject and condition being treated, the weight and age of the subject, the severity of the condition, the particular composition or excipient chosen, the dosing regimen to be followed, timing of administration, the manner of administration and the like, all of which can be determined readily by one of ordinary skill in the art.
[0035] As used herein, the term “treatment” or “treating” means any treatment of a disease or condition in a patient, including: • preventing or protecting against the disease or condition, that is, causing the clinical symptoms not to develop, for example, in a subject at risk of suffering from such a disease or condition, thereby substantially averting onset of the disease or condition; • inhibiting the disease or condition, that is, arresting or suppressing the development of clinical symptoms; and/or • relieving the disease or condition that is, causing the regression of clinical symptoms.
[0036] As used herein, the term “pain” refers to all types of pain, including neuropathic and nociceptive pain. It is also contemplated that the compositions disclosed herein can be used to treat other types of pain such as phantom pain which is the sensation of pain from a limb or organ that has been lost or from which a person no longer receives physical signals, and is an experience almost universally reported by amputees and quadriplegics.
[0037] As used herein, the term “addiction” refers to a persistent behavioral pattern marked by physical and/or psychological dependency to a substance, particularly drugs such as narcotics, stimulants, and sedatives, including but not limited to heroin, cocaine, alcohol, nicotine, caffeine, amphetamine, desoxyephedrine, methadone and combinations thereof. As used herein, the “treatment of addiction in a patient” refers to reducing the withdrawal symptoms associated with drug dependency as well as alleviating drug cravings in addicts. Such symptoms include nausea, vomiting, anxiety, abdominal cramps, muscle pain, chills and headache.
[0038] As used herein, the term “patient” refers to mammals and includes humans and non-human mammals.
Excipients for Penetrating the Blood Brain Barrier [0039] The blood brain barrier (BBB) functions to protect the brain from exposure to toxins, both endogenous and exogenous. However, this protection severely limits the therapeutic ability of many of drugs by inhibiting their crossing from the circulatory system into the brain. In order for a drug to enter the brain and cross the BBB, molecules must either passively diffuse or be actively transported across the BBB. Water soluble or polar compounds must be actively transported across the BBB, whereas it has been shown that drugs which passively diffuse into the brain have fewer hydrogen bond donors, fewer positive charges, greater lipophilicity, lower polar surfaces, reduced flexibility, and are small (i.e. less than 400 - 500 Da) (see Pardridge Molecular Interventions, 2003, 3:2, 90-105, Deeken, et al. Clin Cancer Res, 2007, 13:6, 1663-1674 and references cited therein). However, in some instances, a pharmaceutically acceptable excipient can be used to enhance blood brain barrier penetration (see Pan, et al. Acta Pharmacol Sin, 2000, 21:7, 613-616). This invention is relates to increased cranial delivery of noribogaine by use of a pharmaceutically acceptable excipient to enhance blood brain barrier penetration.
[0040] It is contemplated that the pharmaceutically acceptable excipient cooperatively increases the concentration of noribogaine in the brain of the treated patient thereby reducing the systemic concentration of noribogaine in the remainder of the patient’s body. While not all drugs react cooperatively with blood brain barrier excipients, it is contemplated that noribogaine will show a significant increase in cranial concentration when used in conjunction with such an excipient. It is further contemplated that in view of such targeted delivery, the amount of noribogaine required to effect therapy will be reduced. In addition, it is contemplated that the compositions disclosed herein provide for an increased serum half-life when compared to noribogaine alone.
[0041] In one embodiment, the present invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of noribogaine, or a derivative or pharmaceutically acceptable salt thereof, and an effective amount of a pharmaceutically acceptable excipient to enhance the blood brain barrier penetration of noribogaine.
Methods for the synthesis and purification of noribogaine to be used in the compositions of the present invention are disclosed in US Patent Application No. 13/104,406, entitled Methods and Compositions for Preparing and Purifying Noribogaine, filed on May 10, 2011, which is hereby incorporated by reference in its entirety. Suitable derivatives are disclosed in US Patent Application No. 13/104,410, entitled Substituted Noribogaine, filed on May 10, 2011, which is hereby incorporated by reference in its entirety.
[0042] In the present invention, the composition comprises an excipient capable of transiently disrupting the BBB and allowing noribogaine to penetrate the blood brain barrier. The disrupting effects of such excipients should not produce functional neurological deficits, long-term brain edema, or brain pathology. In one embodiment, the composition comprises a hypertonic solution which transiently disrupts the BBB by causing the cells which make up the BBB to dehydrate and shrink. This dehydration and shrinkage disrupts the BBB by compromising the tight junctions between the cells and thus forming passages into the brain.
[0043] In a certain embodiment, the excipient which enhances the blood brain barrier penetration of noribogaine is a biocompatible dehydrating saccharide, such as mannitol. Suitable concentrations are known to those of skill in the art or can be readily determined using known methods. In one embodiment, it is contemplated that the concentration of mannitol in the composition is about 1.1 M. In another embodiment, mannitol is administered at a concentration of from about 0.1 mol/L to about 10 mol/L, or alternatively, at a concentration of from about 0.5 mol/L to about 5 mol/L.
[0044] Other excipients which are contemplated to be capable of enhancing penetration of noribogaine across the blood brain barrier include saccharides or saccharide derivatives (i.e. amino saccharides), bradykinin B2 receptor agonists (i.e. Cereport®), small fat-soluble molecules (i.e. ethanol or ethanol derivatives), naturally occurring or synthetic amino acids, choline, and purine bases or nucleosides or derivatives thereof. Other blood brain barrier excipients can be used that are known to those of ordinary skill in the art. Exemplary saccharides which can be used in the compositions and methods disclosed herein include, any one or more of ethritol, zylitol, galactose, lactose, xylose, dulcitol, myo-insoitol, fructose, mannitol, sorbitol, glucose, arabinose, arabinose, celloboise, maltose, raffinose, rhamnose, melibiose, ribose, adonitol, arabitol, arabitol, fucose, lyxose, lyxose, lyxose, glucosamine, mannosamine, and galactosamine. Excipients may also comprise one or more naturally occurring (endogenous or exogenous) or synthetic amino acid or derivative thereof, such as arginine, asparagine, aspartic acid, cysteine, glutamic acid, glycine, histidine, leucine, methionine, phenylalanine, proline, serine, threonine, glutamine, lysine, tryptophan, tyrosine, valine, taurine and L-dopa (a naturally occurring amino acid, dihydroxyphenyalanine, found in broad beans).
Biocompatible, Cleavable Linking Groups [0045] In one embodiment of the present invention, at least a portion of the excipient capable of enhancing blood brain barrier penetration is bound to the noribogaine via a covalent bond or a biocompatible, cleavable linking group. The covalent bond or linking group can be attached to the noribogaine at any possible position such the bond or biocompatible linker is readily cleaved in the body and does not inhibit or alter the desired physiological effect of noribogaine. Specifically, the linking group should be sufficiently stable in the circulatory system, but is cleaved to release the noribogaine upon entry into the brain. In one embodiment, the linking group is at least 2 time and preferably at least 10 times more reactive in the brain than in the circulatory system (i.e. in the blood or serum).
[0046] Suitable biocompatible, cleavable linking groups comprise a covalent bond and a linking group having from 1 to 20 atoms selected from carbon, nitrogen, oxygen, sulfur, and phosphorus, and are, in general, susceptible to cleavage conditions or agents in the brain (i.e. pH, redox potential or the presence of degradative molecules such as enzymes, e.g., proteases, lipases, etc.). Generally, the cleavage conditions or agents should be more prevalent or found at higher levels or activities in the brain than in serum or blood. Examples of degradative agents include: redox agents which are selected for particular substrates or which have no substrate specificity, including, e.g., oxidative or reductive enzymes or reductive agents such as esterases; enzymes that can hydrolyze or degrade an acid cleavable linking group by acting as a general acid, peptidases (which can be substrate specific), and phosphatases.
[0047] Biocompatible, cleavable ester-based linking groups are cleaved by enzymes such as esterases and amidases in the brain. Ester-based cleavable linking groups comprise a cleavable ester group of the general Formula -C(0)0- or -OC(O)-. Such ester-based groups can be cleaved by esterases, for example. Biocompatible, cleavable amide-based cleavable linking groups comprise amide bonds formed between amino acids and includes the amide group -C(0)NR- or -NRC(O)- where R can be hydrogen or alkyl. Amide-based cleavable linking groups can be cleaved by enzymes such as peptidases and proteases. Biocompatible, cleavable phosphate-based cleavable linking groups are cleaved by agents that degrade or hydrolyze the phosphate group, such as phosphatases. Examples of phosphate-based linking groups can include -P(0)(0R)-0-, -0-P(S)(0R)-0-, -O-P(S)(SR)-0-, -S-P(0)(0R)-0-, -0-P(0)(0R)-S-, -S-P(0)(0R)-S-, -0-P(S)(0R)-S-, -S-P(S)(0R)-0—, -0-P(0)(R)-0-, -0-P(S)(R)-0-, -S-P(0)(R)-0-, -S-P(S)(R)-0-, -S-P(0)(R)-S-, -0-P(S)(R)-S- where R can be hydrogen or alkyl. Exemplary linking groups are shown in Scheme 2.
[0048] In general, the suitability of a candidate cleavable linking group can be evaluated by testing the ability of a cleaving agent (or condition) to cleave the linking group. It will also be desirable to also test the linking group for the ability to resist cleavage in the serum, blood or when in contact with other non-target tissue. Thus one can determine the relative susceptibility to cleavage between a first and a second condition, where the first is indicative of cleavage in the brain and the second is indicative of cleavage in serum, blood or other non-target tissue. Such evaluations can be carried out in cell-free systems, in cells, in cell culture, in organ or tissue culture, or in whole animals. In preferred embodiments, the cleavable linking group is cleaved at least 2, 4, 10 or 100 times faster in the brain as compared to serum, blood or other non-target tissue.
Compounds of the Invention [0049] In one embodiment of the present invention is provided a compound of Formula I:
I wherein is a single or double bond; R is hydrogen, alkyl, -C(0)-alkyl, or the group -L-S where L is a covalent bond or is a biocompatible, cleavable linking group and S is a dehydrating saccharide or oligosaccharide; R1 is hydrogen or the group -L-S where L is a covalent bond or is a biocompatible, cleavable linking group and S is a dehydrating saccharide or oligosaccharide; provided that at least one of R and R1 is -L-S; or a pharmaceutically acceptable salt thereof.
[0050] In a certain embodiment, R is hydrogen and R1 is -L-S. In some embodiments, R is -C(0)-alkyl and R1 is -L-S. In another embodiment, R is -L-S and R1 is hydrogen. In yet another embodiment, R and R1 are -L-S.
[0051] In the present invention, S can be a saccharide or saccharide derivative such as an amino saccharide, provided that the sachharide is capable of disrupting or penetrating the BBB. For example, S can be a saccharide or amino saccharide from the group consisting of ethritol, zylitol, galactose, lactose, xylose, dulcitol, myo-insoitol, fructose, mannitol, sorbitol, glucose, arabinose, arabinose, celloboise, maltose, raffinose, rhamnose, melibiose, ribose, adonitol, arabitol, arabitol, fucose, lyxose, lyxose, lyxose, glucosamine, mannosamine, and galactosamine. In a preferred embodiment, S is mannitol. In another preferred embodiment, S is glucose.
[0052] In one embodiment of the compounds of the present invention, R is hydrogen, mannopyranose, glucopyranose, glucopyranose-0-(CH2)9C(0)-, ribofuranose, ribopyranose or mannitol. In another embodiment, R1 is hydrogen, glucopyranose-O-(CH2)8C(0)-, -C(0)0(CH2CH20)3CH3, -C02CH2CH3 or mannitol In yet another embodiment, R is hydrogen, mannopyranose, glucopyranose, glucopyranose-O-(CH2)9C(0)-, ribofuranose, ribopyranose or mannitol, and R1 is hydrogen. In yet another embodiment, R is hydrogen and R1 is hydrogen, glucopyranose-0-(CH2)8C(0)-, -C(0)0(CH2CH20)3CH3 or - C02CH2CH3 or mannitol. In yet another embodiment, R and R1 are mannitol.
[0053] In one embodiment of the compounds of the present invention, is a single bond. In another embodiment, is a double bond.
[0054] In one embodiment of the compounds of the present invention, L is a suitable biocompatible, cleavable linking group comprising from 1 to 20 atoms selected from carbon, nitrogen, oxygen, sulfur, and phosphorus, and is, in general, susceptible to cleavage conditions or agents in the brain. In one embodiment, the linking group is an ester-based linking group. In another embodiment, the linking group is an amide-based linking group. In yet another embodiment, the linking group is a phosphate-based linking group. In another embodiment of the compounds of this invention, L is a covalent bond.
[0055] Also disclosed herein is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically acceptable of a compound of Formula I. In a certain embodiment, R is hydrogen and R1 is -L-S. In some embodiments, R is -C(0)-alkyl and R1 is -L-S. In another embodiment, R is -L-S and R1 is hydrogen. In yet another embodiment, R and R1 are -L-S. In a preferred embodiment, S is mannitol. In another preferred embodiment, S is mannose. In yet another preferred embodiment, S is glucose.
[0056] Specific compounds of Formula I which exemplify the present invention are shown below in Table 1.
Table 1
[0057] Compounds of the invention can be prepared from readily available starting materials using, for example, the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
[0058] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis, 4th Edition, Wiley-Interscience, New York, 2006, and references cited therein. The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich® Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Others may be prepared by procedures, or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Supplemental (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).
[0059] Compounds of Formula I can be readily prepared from noribogaine by methods known to one of skill in the art. Noribogaine can be synthesized via ibogaine O-demethylation. This may be accomplished, for example, by reacting ibogaine with boron tribromide/methylene chloride at room temperature and then purifying the product using known procedures. In addition, noribogaine may also be obtained from the National Institute on Drug Abuse (Rockville, Md.). Ibogaine may be obtained from natural or commercial sources, or can be synthesized by methods known in the art (see Huffman, et al, J. Org. Chem. 50:1460 (1985)).
[0060] For example, as shown in Scheme 1, noribogaine can be reacted with a saccharide-linking group conjugate (LG-L-S, where LG is a leaving group such as alkoxy, halo, etc.) to form compounds of formula I. In certain embodiments (i.e. when R is H), the phenol is protected with a suitable protecting group (PG-LG where LG is a leaving group such as alkoxy, halo, etc.) such that the indole nitrogen is derivatized with -L-S. Suitable protecting groups are well known in the art (see T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis, 4th Edition, Wiley-Interscience, New York, 2006). In an alternative embodiment (i.e. when R1 is H), the indole nitrogen is protected with a suitable protecting group (PG) (see Greene et al., supra) such phenol that is derivatized with -L-S. In another alternative embodiment, both the indole nitrogen and the phenol are both derivatized with -L-S groups.
Scheme 1
[0061] Saccharide-linking group conjugates for use in the reactions depicted in Scheme 1 (LG-L-S, where LG is a leaving group such as alkoxy, halo, etc.) can be synthesized using methods known in the art. The starting compounds are commercially available from sources such as Aldrich® Chemical Company. For example, in one embodiment, the saccharide-linking group conjugate for use in the reactions depicted in Scheme 1 is of the formula S-0-(CH2)n-C0-0CH3 where S is the saccharide, n is an integer from 0 to 16 and -OCH3 is the leaving group (LG) (Scheme 2, where R is H or L-S) (see U.S. Patent No. 5,877,187). In certain embodiments, n is an integer from 5 to 10. The structures resulting from such functionalization include the following (where for illustrative purposes only a-D-mannopyranosc is used as the saccharide):
Scheme 2
[0062] Methods for preparing the compounds of Formula I wherein L is a covalent bond follow conventional saccharide chemistry. See, for example, U.S. Patent No. 5,877,187 which is incorporated herein by reference in its entirety. In one example, the anomeric carbon atom at the 1-position of a saccharide is chemically modified by conventional techniques to introduce a leaving group. Suitable leaving groups comprise halides, trichloroacetimidates, acetyl, thioglycosides, etc. The particular leaving group is selected relative to the functionality to which the saccharide is to be attached. For example, in Scheme 1, attachment of the saccharide to the indole nitrogen of noribogaine can be accomplished via the hydroxyl protected compound leaving only the amino group to couple with saccharide resulting in the formation of an N-linked sugar. Alternatively, coupling of the saccharide to the hydroxyl group would entail reacting the N-protected noribogaine with the appropriate functionalized sugar. Still further, using noribogaine and an excess of functionalized saccharides would provide for both the O- and N-functionalized noribogaine. The structures resulting from such functionalization include the following (where for illustrative purposes only α-D-mannopyranose is used as the saccharide):
[0063] Exemplary compounds of this invention wherein L is a linking group can be prepared by the synthetic protocols illustrated below in Scheme 3.
Scheme 3
[0064] Noribogaine (3-1) can be modified with a saccharide-linking group conjugate (3-2), or a protected derivative thereof (e.g., the polyacetate or polybenzylate), to form a compound of formula 1-1 under conventional amidation conditions well known in the art.
Optionally, the indole nitrogen of 3-1 or the hydroxyl groups of 3-2 can be protected using suitable protecting groups prior to the reaction of 3-1 with 3-2 and then subsequently deprotected using conditions known in the art. Compound 3-2 can be prepared from reacting at least a stoichiometric amount and preferably an excess of compound 3-4 with a suitable saccharide (3-3). The reaction can be conducted under conventional coupling conditions well known in the art as the anomeric carbon atom of the saccharide will preferably react with the hydroxyl group of the linker 3-2. In one embodiment, the reaction is conducted in a polar solvent. Upon reaction completion, the compounds 1-1 can be recovered by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration and the like; or, alternatively, used without purification and/or isolation.
[0065] Compounds 3-5 for use in the reactions depicted in Scheme 3, can be prepared by reacting compounds 3-6 (LG is preferably, but not limited to alkoxy or halo) with 3-1 under conventional esterification conditions. Optionally, the indole nitrogen of 3-1 can be protected using a suitable protecting group prior to the reaction of 3-1 with 3-6 and then subsequently deprotected using conditions known in the art. Compound 3-5 can then be modified with 3-2 to form a compound of formula 1-2 under conventional amidation conditions well known in the art. Upon reaction completion, 1-2 can be recovered by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration, and the like; or, alternatively, used without purification and/or isolation.
[0066] Methods for preparing the compounds of Formula 1-3 or 1-4 wherein L is a covalent bond follow conventional saccharide chemistry. As Shown below in Scheme 4, compounds of formula 4-1 can be prepared by the chemical modification of the anomeric carbon of 3-3 (e.g. mannose) by conventional techniques to introduce a leaving group LG (e.g. a halide, trichloroacetimidate, acetyl group, a thioglycoside, and the like). The particular leaving group is selected relative to the functionality to which 4-1 is to be attached. The coupling of 4-1 to the indole nitrogen of 3-1 or 3-5 can be accomplished using typical coupling conditions known to one of skill in the art resulting in the formation of an N-linked sugar. Further, the hydroxyl groups of 3-3 or 4-1 can be protected using a suitable protecting group and then subsequently deprotected using conditions known in the art. Upon reaction completion, 1-3 or 1-4 can be recovered by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration, and the like; or, alternatively, used without purification and/or isolation.
Scheme 4
[0067] Alternatively, as shown in Scheme 5, coupling of the saccharide to the phenol moiety of 3-1 can proceed via reacting 3-1 with the appropriately functionalized 4-1. Although not shown, it is contemplated that 3-1 may couple with the anomeric carbon atom of 3-3 under certain reaction conditions without the need for a leaving group. Optionally, the indole nitrogen of 3-1 or the hydroxyl groups of 4-1 or 3-3 can be protected using suitable protecting groups (e.g., the hydroxyl groups of 4-1 can be protected as the polyacetate or polybenzylate), and then subsequently deprotected using conditions known in the art.
Scheme 5
[0068] Chemical reactions as described above are known in the art and are exemplified in U.S. Patent Nos. 5,877,157 and 6,174,867, which are incorporated herein by reference in their entirety.
Methods of the Invention [0069] Noribogaine, a metabolite of ibogaine, has properties that are well suited to the treatment of pain and to the withdrawal symptoms associated with drug dependency or abuse. In particular, it has been discovered that noribogaine binds to two classes of opioid receptors that have been associated with pain relief, the μ and κ receptors. In the case of the μ-type receptors, it appears that noribogaine acts as a full opiate agonist. In addition, noribogaine elevates brain serotonin levels by blocking synaptic reuptake. It is believed that such levels (as well as ligand interactions at the μ and κ opiate receptors) play a role in the anxiety and drug cravings experienced by addicts during withdrawal.
Treatment of Pain [0070] One aspect of the present invention is directed to a method for treating pain in a patient. The pain can be any type of pain including, but not limited to neuropathic or nociceptive pain, and various types thereof including somatic, visceral and phantom pain. Accordingly, in one embodiment, the method comprises administering to said patient a pharmaceutical composition comprising a therapeutically effective amount of noribogaine, or a derivative or pharmaceutically acceptable salt thereof, and an effective amount of a pharmaceutically acceptable excipient to enhance the blood brain barrier penetration of noribogaine.
[0071] In another embodiment, the present invention is directed to a method for treating pain in a patient which method comprises administering to said patient a therapeutically effective amount of a compound of Formula I or a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable excipient.
Treatment of Addiction [0072] Noribogaine has been known to be used to treat patients for alleviating the symptoms associated with withdrawal from drug dependency. Accordingly, the present invention is also directed to a method for treating addiction in a patient which method comprises administering to said patient a pharmaceutical composition comprising a therapeutically effective amount of noribogaine, or a derivative or pharmaceutically acceptable salt thereof, and an effective amount of a pharmaceutically acceptable excipient to enhance the blood brain barrier penetration of noribogaine. In another embodiment, the invention is directed to a method for treating addiction in a patient which method comprises administering to said patient a therapeutically effective amount of a compound of Formula I or a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable excipient.
[0073] In certain embodiments, the treatment of addiction in a patient comprises alleviating the symptoms associated with withdrawal from drug dependency. Such symptoms include nausea, vomiting, anxiety, abdominal cramps, muscle pain, chills and headache. In addition, noribogaine treatment decreases the drug cravings normally experienced by addicts after cessation of the self administration of the abused substance.
It is contemplated that the compositions disclosed herein are especially useful in the treatment of addiction to narcotics such as heroin and methadone. However, it is also useful in treating patients addicted to cocaine, alcohol, amphetamines and combinations of these drugs.
Dosage and Routes of Administration [0074] It is contemplated that any route of administration and dosage form may be compatible with the pharmaceutical compositions and methods discussed above. As the compositions disclosed herein are designed to target the brain and penetrate the blood brain barrier, it is contemplated that the dosage of noribogaine administered to the patent can be decreased in comparison to the dose administered to a patient when using noribogaine alone. That said, the appropriate dosing regimen and route of administration can be readily determined by the attending clinician.
[0075] Although compositions suitable for oral, intravenous or intraarterial delivery will probably be used most frequently, other routes that may be used include peroral, pulmonary, rectal, nasal, vaginal, lingual, intramuscular, intraperitoneal, intracutaneous and subcutaneous routes. In addition, it is contemplated that the composition can be administered transdermally in which drug is applied as part of a cream, gel, or patch (for examples of transdermal Formulations, see U.S. Pat. Nos. 4,806,341; 5,149,538; and 4,626,539). Other dosage forms include tablets, capsules, pills, powders, aerosols, suppositories, parenterals, and oral liquids, including suspensions, solutions and emulsions. Sustained release dosage forms may also be used. All dosage forms may be prepared using methods that are standard in the art (see e.g., Remington's Pharmaceutical Sciences, 16th ed., A. Oslo editor, Easton Pa. 1980).
[0076] The compositions disclosed herein may be used in conjunction with any of the vehicles and excipients commonly employed in pharmaceutical preparations, e.g., talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous solvents, oils, paraffin derivatives, glycols, etc. Coloring and flavoring agents may also be added to preparations, particularly to those for oral administration. Solutions can be prepared using water or physiologically compatible organic solvents such as ethanol, 1,2-propylene glycol, polyglycols, dimethylsulfoxide, fatty alcohols, triglycerides, partial esters of glycerine and the like. Parenteral compositions containing noribogaine may be prepared using conventional techniques that may include sterile isotonic saline, water, 1,3-butanediol, ethanol, 1,2-propylene glycol, polyglycols mixed with water, Ringer's solution, etc.
[0077] It is contemplated that the dosage required for treating pain may differ from the dosage required for treating addiction, however, the dosing regimen can be readily determined by the attending clinician based on the desired treatment. It is contemplated that for the treatment of pain, the dosage of noribogaine administered to a patient may be from about 0.1 to about 100 mg per kg of body weight and, preferably, from about 0.1 to about 30 mg per kg of body weight. For the treatment of addiction, the dosage of noribogaine administered to a patient may be from about 0.1 to about 20 mg/ml.
Kit of Parts [0078] One aspect of the present invention is directed to a kit of parts comprising a composition as disclosed herein and a means for administering the composition to a patient in need thereof. The means for administration to a patient can include, for example, any one or combination of a syringe, a needle, an IV bag comprising the composition, a vial comprising the composition, etc. In one embodiment, the kit comprises a first and a second vial, wherein the first vial comprises the pharmaceutically acceptable excipient to enhance the blood brain barrier penetration of noribogaine and the second composition comprises a therapeutically effective amount of noribogaine, or a derivative or pharmaceutically acceptable salt thereof. In such an embodiment, the pharmaceutically acceptable excipient may be administered to the patient just prior to the noribogaine composition. In one embodiment, the pharmaceutically acceptable excipient is administered to the patient about 5 to 10 minutes prior to the noribogaine composition.
Examples [0079] The present invention is further defined by reference to the following examples.
It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the current invention.
Table 2. List of abbreviations and acronyms.
Abbreviation Meaning °C Degree Celsius A Angstrom
Ac Acetyl
Abbreviation Meaning aq. Aqueous atm Atmosphere
Bn Benzyl bs Broad singlet
Bu Butyl d Doublet DCM dichloromethane dd Doublet of doublets DMAP 4-Dimethylaminopyridine DMF Dimethylformamide
Et Ethyl g Gram h Hour HPLC High-performance liquid chromatography
Hz Hertz /-Pr Isopropyl IV Intravenous
Kg Kilogram M Molar m Multiplet M+ Mass peak
Me Methyl mg Milligram min Minute mL Milliliter mM Millimolar mmol Millimole MS Mass spectrometry N Normal
NaHDMS Sodium hexamethyldisilazane NMR Nuclear magnetic resonance PEG Polyethylene glycol
Abbreviation Meaning prep Preparative r.t./rt Room temperature s Singlet t Triplet TBS tert-Butyldimethylsilyl TBSC1 tert-Butyldimethylsilyl chloride t-Bu tert-Butyl THF Tetrahydrofuran TLC Thin layer chromatography
Ts p-Toluenesulfonyl v/v Volume/volume δ Chemical shift pL Microliter
Example 1: Preparation of Compound 1
Preparation of bromide 1-A
[00S0] To a solution of 1,2,3,4,6-penta-O-acetyl-D-mannopyranose (1 g, 2.56 mmol) in DCM (2 mL) was added HBr (33% in AcOH, 2.5 mL) dropwise at room temperature. The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with DCM, and washed with H20 and NaHC03 (3x). The organic layer was dried and concentrated. The crude 1-A (1.06 g, 100%) was pure enough to be used directly in the next step without further purification.
Preparation of 1 [0081] To a solution of noribogaine HC1 salt (30 mg, 0.09 mmol) and bromide 1-A (74 mg, 0.18 mmol) in MeOH (2 mL) was added portionwise LiOH H20 (15 mg, 0.36 mmol). The reaction mixture was stirred at room temperature for 2 h. The solution was acidified to neutral with aq. HC1 (0.5 N). The mixture was purified by prep-HPLC to give compound 1 (10 mg) as a white solid.
[0082] MS calculated for (C25H34N2O6): 458.2; MS found (M+l): 459.3. *H NMR (CD3OD) δ 8.52 (bs, 1H), 7.25 (d, 1H), 7.17 (d, 1H), 6.88 (dd, 1H), 5.38 (d, 1H), 4.02 (d, 1H), 3.93 (dd, 1H), 3.80-3.62 (m, 5H), 3.60 (m, 3H), 3.41 (m, 3H), 3.22 (m, 1H), 2.36 (t, 1H), 2.19 (m, 2H), 2.00 (m, 1H), 1.76 (dd, 1H), 1.62 (m, 2H), 1.40 (m, 1H), 1.02 (t, 3H).
Example 2: Preparation of Compound 2
Preparation of 2-A
[0083] To a solution of penta-acetyl-alpha-D-glucose (3.9 g, 10 mmol) and 1,9-nonanediol (2.4 g, 15 mmol) in DCM (35 mL) was added dropwise SnCU (15 mmol, 1M in DCM, 15 mL). The resulting mixture was stirred at 50 °C for 4 h. The reaction mixture was diluted with DCM and H20. The organic layer was separated, washed with NaHCCti, and dried and concentrated. The crude product mixture was purified by flash column chromatography (EtOAc:Hexanes/l:l) to afford compound 2-A (1.6 g, 33%).
[0084] MS calculated for (C23H38O11): 490; MS found (M+l): 491 Preparation of 2-B
[0085] To a solution of 2-A (200 mg, 0.40 mmol) and N,N’-disuccinimidyl carbonate (122 mg, 0.48 mmol) in chloroform (2 mL) was added pyridine (0.042 mL, 0.52 mmol) in one portion. The mixture was stirred at rt for 3 h. Aqueous HC1 (0.5 N) was used to quench the reaction. The reaction was diluted with DCM and Η20. The organic layer was extracted, dried and concentrated to give crude compound 2-B in quantitative yield, which used in the next step without purification.
[0086] MS calculated for (C28H41NO15): 631; MS found (M+l): 632
Preparation of 2-C
[0087] To a solution of 2-B (crude, 0.4 mmol) and noribogaine HC1 salt (35 mg, 0.08 mmol) in DCM (2 mL) was added DMAP (112 mg, 0.92 mmol) and DIPEA (60 pL, 0.36 mmol). The reaction mixture was stirred at 40 °C for 1 h. The reaction solution was diluted with DCM and H20. The organic layer was separated, dried and concentrated, and the crude product purified by prep-TLC (DCM:MeOH, 8:1) to give product 2-C (60 mg, 92%).
[0088] MS calculated for (C43H60N2013): 812; MS found (M+l): 813 Preparation of 2 [0089] To a solution of compound 2-C (20 mg, 0.024 mmol) in THF/H20 (2 mL: 1 mL) was added LiOH (6 mg, 0.143 mmol). The reaction mixture was stirred at rt for 2 h. The reaction mixture was then acidified to neutral with 1 N aq. HC1. The crude mixture was purified by HPLC to give compound 2 (9 mg).
[0090] MS calculated for (C35H52N2O9): 644.4; MS found (M+l): 645.6. ^NMR (CD3OD) δ 8.52 (bs, 1H), 7.25 (m, 2H), 6.87 (dd, 1H), 4.76 (d, 1H), 4.22 (t, 2H), 3.80-3.50 (m, 8H), 3.42-3.35 (m, 5H), 3.25-3.08 (m, 2H), 2.32 (t, 1H), 2.14 (m, 2H), 2.03 (m, 1H), 1.77-1.58 (m, 7H), 1.48-1.32 (m, 11H), 1.02 (t, 3H).
Example 3: Preparation of Compound 3
Preparation of 3-A
[0091] To a solution of penta-acetyl-alpha-D-glucose (1.0 g, 2.56 mmol) in DCM (2 mL) was added HBr (33% in AcOH, 2.5 mL) dropwise at room temperature. The reaction mixture was stirred at room temperature for 2 h. The mixture was then diluted with DCM, and washed with H20 and NaHCCT (3x). The organic layer was dried and concentrated to giver crude bromide 3-A (1.06 g, 100%), which was used directly in the next step without purification.
Preparation of 3 [0092] To a solution of noribogaine HC1 salt (30 mg, 0.09 mmol) and bromide 3-A (74 mg, 0.18 mmol) in MeOH (2 mL) was added portionwise LiOHH20 (15 mg, 0.36 mmol). The reaction mixture was stirred at room temperature for 2 h, then the solution was acidified to neutral with 0.5 N aq. HC1. The mixture was purified by prep HPLC to give compound 3(11 mg) as a white solid.
[0093] MS calculated for (C25H34N206): 458.2; MS found (M+l): 459.3. *H NMR (CD3OD) δ 8.47 (bs, 1H), 7.24 (d, 1H), 7.17 (d, 1H), 6.94 (dd, 1H), 4.84 (d, 1H), 3.94 (d, 1H), 3.70 (dd, 1H), 3.62-3.54 (m, 3H), 3.42-3.38 (m, 4H), 3.36 (m, 3H), 3.20 (m, 2H), 2.30 (t, 1H), 2.13 (m, 2H), 1.99 (m, 1H), 1.77-1.58 (m, 3H), 1.39 (m, 1H), 1.03 (t, 3H).
Example 4: Preparation of Compound 4
Preparation ofTBS-noribogaine 4-A
[0094] A suspension of noribogaine HC1 (852 mg, 2.56 mmol), TBSC1 (444 mg, 2.94 mmol) and imidazole (227 mg, 3.33 mmol) in DMF (6 mL) was stirred at room temperature for 20 h. The resulting clear solution was diluted with 10% 2-propanol/dichloromethane and washed with water (3x) and brine. The aqueous phase was extracted with EtOAc. The combined organic layers were concentrated and purified by column chromatography (EtOAc/Hexanes, v/v, 2/1). Pure 4-A (911 mg, 87%) was obtained as a white solid.
[0095] MS calculated for (C25H38N2OSi): 410, MS found (M+l): 411.
Preparation of 9-Hydroxy-nonanoic acid methyl ester 4-B
[0096] To a solution of nonanedioic acid monomethyl ester (4.80 g, 20 mmol) in THF (20 mL) at -20° C was added a solution of borane-dimethylsulfide in THF (2.0 M, 10 mL) over 10 min. The resulting mixture was stirred for an additional 10 min, and then allowed to stir at room temperature overnight. Aqueous K2C03 solution was added, and the product was extracted with ethyl ether (3x). The crude product was purified by flash column chromatography (hexane/EtOAc: 2/1) to yield 9-hydroxy-nonanoic acid methyl ester 4-B (2.0 g, 55%).
[0097] lR NMR (CDC13) δ 4.86 (bs, 1H, OH), 3.67 (s, 3H), 3.63 (t, J = 7.4 Hz, 2H), 2.29 (t, J = 7.4 Hz, 2H), 1.68-1.48 (m, 4 H), 1.40-1.24 (m, 8H).
Preparation of 4-C
[0098] A mixture of 2,3,4,6-tetra-O-benzyl-D-glucopyranose (2.0 g, 3.7 mmol), trichloroacetonitrile (2.13 g, 14.8 mmol) and K2C03 (0.66 g, 4.8 mmol) in DCM (13 mL) was stirred at room temperature for 3 days. The solid was removed by filtration and the filtrate was concentrated to provide a crude product 4-C (3.0 g, >100%) which was used without purification.
[0099] MS calculated for (CaeHaeCfiNOe): 683.2; MS found (M+Na): 708 Preparation of 4-D
[0100] A solution of SnCl4 in DCM (1.0 Μ, 1.2 mL) was slowly added into a solution of 4-B (230 mg, 1.22 mmol) and 4-C (1.25 g, 1.83 mmol) in DCM (3.5 mL) at 0° C. The resulting mixture was stirred at the temperature for 20 min, and then water was added to quench the reaction. The product was extracted with DCM, and the crude product was purified by flash column chromatography (EtOAc/hexane: 1/4) to afford 4-D (400 mg, 46%).
[0101] MS calculated for (C44H54O8): 710; MS found (M+Na): 733 Preparation of 4-E
[0102] A mixture of 4-D (400 mg, 0.56 mmol), LiOH (118 mg, 2.81 mmol) in MeOH/water/THF (2 mL/2mL/4mL) was stirred at room temperature for 16 h. The solution was acidified with 1 N aq. HC1 to pH~3.0. The product was extracted with ethyl acetate, and the combined organic layers were dried over MgSCL. After filtration and concentration, the crude product 4-E (0.39 g, quantitative) was used for next reaction without purification.
[0103] lR NMR (CDCfi) δ 7.40-7.12 (m, 17 H), 7.08-7.05 (m, 3H), 5.02-4.38 (m, 8H), 4.00-3.92 (m, 1H), 3.78-3.38 (m, 8H), 2.34 (t, J = 7.4 Hz, 2H), 1.68-1.55 (m, 4H), 1.40-1.24 (m, 8H).
Preparation of 4-F
[0104] Oxalyl chloride (59 pL, 0.68 mmol) was slowly added into a solution of acid 4-E (0.39 g, 0.57 mmol) in DCM (5 mL) at room temperature, followed by adding DMF (7 pL). The resulting mixture was stirred at the temperature for 3 h, and then concentrated. The crude product 4-F was further dried under high vacuum and used in next reaction without purification.
Preparation of 4-G
[0105] A solution of acyl chloride 4-F (104 mg, 0.25 mmol) in THF (2 mL) was cooled at -78 °C, and then 0.38 mL of 1 N NaHMDS in THF was added. After 15 min a solution of 4-A (274 mg, 0.38 mmol) in THF (3 mL) was added. The reaction mixture was stirred at -78 °C for 20 min, and then allowed to slowly warmed up to room temperature. The reaction was quenched with saturated NH4C1 solution after 2 h. The product was extracted with DCM. After combination and concentration of the extracts, the crude product was purified by prep-TLC to afford 4-G (110 mg).
[0106] MS calculated for (C68H88N208Si): 1089; MS found (M+H): 1090
Preparation of 4-H
[0107] Hydrogenation of 4-G (110 mg, 0.10 mmol) was carried in EtOAc/MeOH (2 mL/3 mL) with 10% Pd/C (80 mg) as catalyst under 1 atm of hydrogen, using HC1 (4 N in dioxane, 100 pL) to acidify the solution. After 48 h the mixture was filtered through a pad of Celite, and the organic layer concentrated. The crude product was purified by prep-TLC to give 4-H (17 mg, 27%).
[0108] MS calculated for (C4oH64N208Si): 728; MS found (M+H): 729 Preparation of 4 [0109] TBS-protected 4-H (17 mg, 0.023 mmol) was further de-protected with Bu4NF (40 mg, 1.08 mmol) in MeOH (3 mL) at 50 °C. The reaction was complete after 3 h. The crude product was purified by prep-TLC to afford the pure compound 4(12 mg).
[0110] MS calculated for (C34H5oN208): 614; MS found (M+H): 615. *HNMR (CD3OD) δ 7.56 (d, J = 8.7 Hz, 1H), 6.88 (d, J = 2.4 Hz, 1H), 6.79 (dd, J = 8.7 Hz, and 2.4 Hz, 1H), 4.78 (d, J = 2.1 Hz, 0.5 H), 4.26 (d, J = 7.8 Hz, 0.5H), 3.94-3.12 (m, 14H), 3.10-2.96 (m, 2H), 2.26-2.10 (m, 2H), 2.08-1.72 (m, 4H), 1.70-1.54 (m, 5H), 1.50-1.34 (m, 11H), 1.00 (t, J = 7.2Hz, 3H).
Example 5: Preparation of Compound 5
Preparation of 5-A
[0111] A mixture of noribogaine (17 mg, 0.06 mol), tetra-O-acetyl-P-D-ribofuranose (38 mg, 0.12 mmol) and 4Ά molecular sieves (1 g) in DCM (2 mL) was stirred at room temperature for 10 min. Boron trifluoride etherate complex (200 uL, 1.6 mmol) was added, and resulting mixture was stirred at the temperature for 2 h. The reaction mixture was diluted with DCM and then filtered to remove the solid. The filtrate was concentrated and further dried in high vacuum. The crude product was purified by flash column chromatography (EfiN/Z-PrOH/DCM: 1/10/200) to yield 7 mg of 5-A.
[0112] MS calculated for (CsoHssNzOg): 554; MS found (M+H): 555 Preparation of 5 [0113] Esterase (from porcine liver) suspension (1 drop) was added into a solution of the triacetate 5-A (7 mg, 0.013 mmol) in 10 mL of phosphate buffer (10 mM, pH 8.0). The reaction mixture was stirred at 25° C for 7 h, and then treated with 10 mL of MeOH. The resulting solution was concentrated to 3 mL and purified by prep-HPLC to yield 2.5 mg of the pure compound 5.
[0114] MS calculated for (C24H32N205): 428; MS found (M+H): 429. *HNMR (CD3OD) δ 7.16 (d, J = 8.7 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 6.81 (dd, J = 8.7 and 2.4 Hz, 1H), 5.49 (d, J = 1.2 Hz, 1H), 4.25-4.17 (m, 2H), 4.12-4.04 (m, 1H), 3.82-3.76 (m, 1H), 3.70-3.48 (m, 4H), 3.40-3.08 (m, 3H), 2.38-2.24 (m, 1H), 2.18-1.92 (m, 4H), 1.78-1.58 (m, 3H), 1.40-1.26 (m, 3H), 1.03 (t, J = 7.2 Hz, 3H).
Example 6: Preparation of Compound 6
Preparation of 6-A
[0115] A mixture of noribogaine (42 mg, 0.15 mol), 1,2,3,4-tetraacetate β-D-ribopyranose (95 mg, 0.30 mmol) and 4Ά molecular sieves (2 g) in DCM (5 mL) was stirred at room temperature for 10 min. Boron trifluoride etherate complex (500 pL, 4.0 mmol) was added, and resulting mixture was stirred at the temperature for 2 h. The reaction mixture was diluted with DCM and then filtered. The filtrate was concentrated and further dried under high vacuum. The crude product was purified by flash column chromatography (ELN/Z-PrOH/DCM: 1/10/200) to yield 6-A (30 mg).
[0116] MS calculated for (C30H38N2O8): 554; MS found (M+H): 555 Preparation of 6 [0117] Esterase (from porcine liver) suspension (1 drop) was added into a solution of the triacetate 6-A (30 mg, 0.054 mmol) in 20 mL of phosphate buffer (10 mM, pH 8.0). The reaction mixture was stirred at 25° C for 96 h, and then treated with 20 mL of MeOH. The resulting solution was concentrated to 3 mL purified by on prep HPLC to yield 7.0 mg of the pure compound 6.
[0118] MS calculated for (C24H32N205): 428; MS found (M+H): 429. ^NMR (CD3OD) δ 7.18 (d, J = 8.7 Hz, 1H), 7.16 (d, J = 2.4 Hz, 1H), 6.87 (dd, J = 8.7 and 2.1 Hz, 1H), 5.37 (d, J = 3.9 Hz, 1H), 4.03 (m, 1H), 3.96-3.50 (m, 8H), 3.43-3.08 (m, 3H), 2.38-2.24 (m, 1H), 2.18-1.96 (m, 6H), 1.80-1.58 (m, 3H), 1.46-1.26 (m, 2H), 1.05 (t, J = 7.5 Hz, 3H).
Example 7: Preparation of Compound 7
Preparation ofTBS-noribogaine-PEG 7-A
[0119] NaHMDS (0.6 mL, 1.0 M solution in THF) was added into a solution of TBS-noribogaine 4-A (164 mg, 0.4 mmol) in THF (8 mL) at -78 °C. The resulting solution was stirred for 10 min at -78 °C before a solution of 4-nitrophenyl chloroformate (126 mg, 0.6 mmol) in THF (6 mL, pre-cooled to -78 °C) was added quickly. The reaction mixture was warmed up to room temperature and stirred for 30 min before it was again cooled back to -78 °C. NaHMDS (0.8 mL, 1.0 M solution in THF) was added to a solution of triethyleneglycol methyl ether (0.125 mL, 0.8 mmol) in THF (6 mL) at -78 °C. The resulting solution was warmed up to room temperature and stirred for 10 min. This solution of deprotonated PEG alcohol was then added into the above reaction mixture at -78 °C via syringe. After stirring at room temperature for one hour, the reaction mixture was partitioned between dichloromethane and water. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine and dried over Na2SC>4. After concentration the crude product was purified by column chromatography (EtOAc/hexanes, v/v, 1/1 to pure EtOAc). The desired product 7-A (114 mg) was obtained as a yellow oil.
[0120] MS calculated for (C33H52N2O6S1): 600, MS found (M+l): 601.
Preparation of 7-B
[0121] TBAF (0.48 mL, 1.0 M solution in THF) was added to a solution of 7-A (114 mg, 0.19 mmol) in THF (5 mL) at -78 °C. The resulting solution was stirred for 15 min at -78 °C and 40 min at room temperature before it was concentrated and purified by column chromatography (dichloromethane/2-propanol/triethylamine, v/v, 10/1/0 to 100/20/1). The resulting product was further purified by prep-HPLC to give pure 7-B (68 mg) as a slightly yellow solid.
[0122] MS calculated for (C27H38N206): 486, MS found (M+l): 487. *H NMR (CD3CN) δ 10.75 (bs, 1H), 8.05 (d, 1H), 7.62 (bs, 1H), 7.03 (s, 1H), 6.95 (d, 1H), 4.55 -4.73 (m, 2H), 4.12 (dd, 1H), 3.86-4.06 (m, 3H), 3.48-3.85 (m, 11H), 3.36 (s, 3H), 3.05 - 3.25 (m, 3H), 2.63 (t, 1H), 2.20 - 2.45 (m, 4H), 1.90 - 2.20 (m, 1H), 1.76 - 1.95 (m, 2H), 1.54 (d, 1H), 1.02 - 1.18 (m, 3H).
Preparation of 7 [0123] Phenol 7-B (65 mg, 0.134 mmol), tetra-acetyl glucose bromide 3-A (110 mg, 0.267 mmol) and LiOH monohydrate (23 mg, 0.53 mmol) were dissolved in MeOH (3 mL). The solution was stirred at room temperature for one hour before more 3-A (60 mg) and LiOH monohydrate (11 mg) were added. After stirring one additional hour, the reaction was quenched by adding IN aq. HC1 (0.9 mL). Prep-HPLC purification afforded compound 7(12.9 mg) as a white solid.
[0124] MS calculated for (C33H48N2O11): 648, MS found (M+l): 649. ^NMR (CD3CN) δ 8.00 (d, 0.5 H), 7.92 (d, 0.5 H), 7.16-7.23 (m, 1H), 7.00-7.08 (m, 1H), 4.94 (d, 1H), 4.45-4.62 (m, 1 H), 3.90-4.05 (m, 2H), 3.70-3.90 (m, 3H), 3.25-3.70 (m, 22H), 3.26 (s, 3H), 3.05-3.22 (m, 3H), 2.40 - 2.58 (m, 1H), 2.18 (bs, 1H), 1.85 - 2.05 (m, 1H), 1.30-1.76 (m, 4H), 0.96 (t, 3H).
Example 8: Preparation of Compound 8
Preparation of 8-Λ [0125] A solution of compound 4-A (102 mg, 0.25 mmol) in THF (3 mL) was cooled at -78 °C, and then 0.38 mL of 1 N NaHMDS in THF was added. After 15 min, a solution of ethyl chloroformate (48 pL, 0.50 mmol) was added. The reaction mixture was stirred at -78 °C for 20 min, and then slowly warmed up to room temperature. The reaction was quenched with water after 2 h. The product was extracted with DCM, and the combined organic extracts were dried over MgSCL. Concentration of the filtrate, finally under high vacuum afforded pure compound 8-A (120 mg).
[0126] MS calculated for (C28H42N2O3S1): 482, MS found (M+l): 483.
Preparation of 8-B
[0127] A solution of B114NF in THF (1.0 M, 0.50 mL) was added into a solution of compound 8-A (0.12 mg, 0.25 mmol) in THF (5 mL) at -78° C. The resulting mixture was stirred at -78° C for 30 min and then at room temperature for 1 h. A few drops of 1 N aq. HC1 were added to quench the reaction. The reaction mixture was concentrated, and the residue was purified by chromatography on silica gel using NEt3/iPrOH/DCM (2/10/200) as eluent to give compound 8-B (69 mg, 75%).
[0128] MS calculated for (C22H28N2O3): 368, MS found (M+l): 369.
Preparation of 8 [0129] LiOH (32 mg, 0.75 mmol) was added into a solution of 8-B (69 mg, 0.19 mmol) and l-bromo-2,3,4,6-tetra-0-acetyl-glucopyranose (156 mg, 0.38 mmol) in MeOH (4 mL). The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched by adding a few drops of 1 N aq, HC1. The crude product was purified by prep-HPLC to give compound 8 (20 mg, 20%).
[0130] MS calculated for (C28H38N208): 530, MS found (M+l): 531. *H NMR (CD3OD) δ 7.95 (d, J = 9.0 Hz, 1H), 7.25 (d, J = 2.1 Hz, 1H), 7.09 (dd, J = 2.1 and 9.0 Hz, 1H), 4.49 (t, J = 7.2 Hz, 2H), 4.18-4.08 (m, 1H), 3.96-3.82 (m, 3H), 3.74-3.64 (m, 1H), 3.60-3.40 (m, 5H), 3.38-3.28 (m, 3H), 3.26-3.12 (m, 3H), 2.68-2.54 (m, 1H), 2.21 (bs, 1H), 2.14-1.96 (m, 2H), 1.72-1.42 (m, 6H), 1.05 (t, J = 7.2 Hz, 3H).
Example 9: Preparation of Compounds 9 and 10
Preparation of 9-C
[0131] A solution of 3,4-O-isopropylidene-D-mannidol 9-A (5.0 g, 22.5 mmol), 2-methoxypropene 9-B (1.62 g, 22.5 mmol) and TsOH (192 mg, 1.1 mmol) in DMF (20 mL) was stirred at room temperature for 18 hours. The reaction mixture was concentrated and purified by flash column chromatography (DCM/EtOAc, v/v, 1/1 to 1/3) to afford 9-C as a crystalline solid (3.99 g).
[0132] MS calcd for (C12H22O6): 262; MS found (M+Na): 285.
Preparation of 9-D
[0133] Benzoyl chloride (1.76 mL, 15.2 mmol) was added dropwise to a solution of 1,2,3,4-0-diisopropylidene-D-mannidol 9-C (3.99 g, 15.2 mmol) in pyridine (20 mL) and DCM (50 mL) at -78 °C. The reaction mixture was stirred for one hour and then allowed to warm up to 0 °C. After 1.5 hours, the resulting mixture was poured into 150 mL of ice-cooled aq. 5N HC1, and extracted with DCM. The organic extract was washed with water, saturated NaHC03, and brine. After drying over Na2S04 and concentration, 5.3 g of a colorless oil was obtained.
[0134] The crude oil, DMAP (186 mg, 1.52 mmol) and Et3N (2.55 mL, 18.3 mmol) were dissolved in 30 mL DCM and cooled to 0 °C. TsCl (3.19 g, 16.7 mmol) was added, and the resulting solution was stirred for one hour at 0 °C and 18 hours at room temperature. The solution was then cooled to 0 °C, and ice-cold aq. 3N HC1 (20 mL) was added. The layers were separated, and the organic extract was washed with brine and dried over Na2S04. Concentration afforded 8.3 g of a brown oil.
[0135] The crude oil was treated with K2CO3 (5.2 g) in DCM (40 mL) and MeOH (45 mL) at room temperature for 3 hours. Water (20 mL) was added into the solution. The organic layer was separated and washed with sat. NH4C1. After drying over Na2S04 and concentration, the residue was purified by flash column chromatography (EtOAc/toluene, v/v, 1/4) to afford 9-D as a white crystalline solid (1.6 g).
[0136] !H NMR (300 MHz, CDCh) δ 3.80-4.24 (m,5H), 3.10 (q, 1 H), 2.80 (d,2H), 1.41 (s, 3H), 1.39 (s, 3H), 1.38 (s, 3H), 1.34 (s, 3H).
Preparation of 9-E and 9-F
[0137] Epoxide 9-D (91 mg, 0.36 mmol) was added into a solution of noribogaine (90 mg, 0.3 mmol, free base) and i-BuOK (34 mg, 0.3 mmol) in 6 mL of DMF at room temperature. The reaction mixture was heated at 150 °C for 30 min in a microwave reactor. The resulting dark solution was diluted with DCM and washed with water (2x) and dried over Na2S04. The mixture was purified by preparative TLC (2-propanol/DCM, v/v, 1/10) to afford 9-E (25 mg) and 9-F (35 mg), both as pale white solids.
[0138] MS calcd for 9-E (C3iH44N206): 540; MS found (M+l): 541.
[0139] MS calcd for 9-F (C43H64N20ii): 784; MS found (M+l): 785.
Preparation of 9 [0140] Compound 9-E (21 mg) was treated with aq. 3N HC1 (1 mL) in MeOH (3 mL) at room temperature for 20 hours. The resulting solution was directly purified by reverse-phase preparative HPLC to afford 9 (11.3 mg) as a white solid.
[0141] MS calcd for (C^gNzOg): 460; MS found (M+l): 461. lU NMR (300 MHz, CD3OD) δ 7.17 (d, 1H), 7.00 (d, 1H), 6.80 (dd, 1H), 4.00 - 4.20 (m, 4H), 3.50-3.82 (m, 7H), 3.10-3.45 (m, 5 H), 2.30 (t, 1H), 1.90-2.20 (m, 3H), 1.55 - 1.76 (m, 3H), 1.30 - 1.42 (m, 1H), 1.04 (t, 3H).
Preparation of 10 [0142] Compound 9-F (26 mg) was treated with aq. 3N HC1 (1 mL) in MeOH (3 mL) at room temperature for 20 hours. The resulting solution was directly purified by reverse-phase preparative HPLC to afford 10(12 mg) as a white solid.
[0143] MScalcdfOT(C3iH48N2Ou): 624; MS found (M+l): 625. 1H NMR (300 MHz, CD3OD) δ 7.24 (d, 1H), 6.93 (d, 1H), 6.78 (dd, 1H), 4.40 - 4.58 (m, 1H), 4.20 - 4.30 (m, 1H), 3.90 -4.10 (m, 6H), 3.28-3.75 (m, 14H), 2.92 - 3.25 (m, 2 H), 2.34 (t, 1H), 1.95-2.12 (m, 3H), 1.40 - 1.70 (m, 3H), 1.25 - 1.40 (m, 1H), 0.97 (t, 3H).
Claims (23)
- What is claimed is:1. A pharmaceutical composition comprising a therapeutically effective amount of noribogaine, or a derivative or pharmaceutically acceptable salt thereof, and an effective amount of a pharmaceutically acceptable excipient to enhance the blood brain barrier penetration of noribogaine.
- 2. The pharmaceutical composition of claim 1, wherein the excipient which enhances the blood brain barrier penetration of noribogaine is a biocompatible dehydrating saccharide such as mannitol.
- 3. The pharmaceutical composition of claim 1, wherein at least a portion of the mannitol or other dehydrating saccharide is bound to the noribogaine via a covalent bond or a biocompatible, cleavable linking group.
- 4. A compound of Formula I:I wherein is a single or double bond; R is hydrogen, alkyl, -C(0)-alkyl, or the group -L-S where L is a covalent bond or is a biocompatible, cleavable linking group and S is a dehydrating saccharide or oligosaccharide; R1 is hydrogen or the group -L-S where L is a covalent bond or is a biocompatible, cleavable linking group and S is a dehydrating saccharide or oligosaccharide; provided that at least one of R and R1 is -L-S; or a pharmaceutically acceptable salt thereof.
- 5. The compound of claim 4, wherein R is hydrogen or -C(0)alkyl and R1 is -L-S.
- 6. The compound of claim 4, wherein R is -L-S and R1 is hydrogen.
- 7. The compound of claim 4, wherein R and R1 are -L-S.
- 8. The compound of claim 4, wherein R is hydrogen, mannopyranose, glucopyranose, glucopyranose-0-(CH2)c)C(0)-, ribofuranose, ribopyranose or mannitol.
- 9. The compound of claim 4, wherein R1 is hydrogen, glucopyranose-0-(CH2)sC(0)-, -C(0)0(CH2CH20)3CH3, -CO2CH2CH3 or mannitol.
- 10. The compound of claim 1, wherein is a single bond.
- 11. The compound of claim 1, wherein is a double bond.
- 12. The compound of claim 1, wherein the compound is selected from the group consisting of
- 13. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically acceptable amount of a compound of claim 4.
- 14. The pharmaceutical composition of claim 13, wherein R is hydrogen or -C(0)alkyl and R1 is -L-S.
- 15. The pharmaceutical composition of claim 13, wherein R is -L-S and R1 is hydrogen.
- 16. The pharmaceutical composition of claim 13, wherein both R and R1 are -L-S.
- 17. The pharmaceutical composition of claim 13, wherein the pharmaceutically acceptable excipient comprises mannitol.
- 18. A method for treating pain in a patient which method comprises administering to said patient a pharmaceutical composition comprising a therapeutically effective amount of noribogaine, or a derivative or pharmaceutically acceptable salt thereof, and an effective amount of a pharmaceutically acceptable excipient to enhance the blood brain barrier penetration of noribogaine.
- 19. A method for treating addiction in a patient which method comprises administering to said patient a pharmaceutical composition comprising a therapeutically effective amount of noribogaine, or a derivative or pharmaceutically acceptable salt thereof, and an effective amount of a pharmaceutically acceptable excipient to enhance the blood brain barrier penetration of noribogaine.
- 20. A method for treating pain in a patient which method comprises administering to said patient a therapeutically effective amount of a compound of claim 4 or a pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 4 and a pharmaceutically acceptable excipient.
- 21. A method for treating addiction in a patient which method comprises administering to said patient a therapeutically effective amount of a compound of claim 4 or a pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 4 and a pharmaceutically acceptable excipient.
- 22. A kit of parts comprising the composition of claim 1 and a means for administering the composition to a patient.
- 23. The kit of claim 22, where the means for administering the composition to a patient is a syringe or a needle.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/US2014/013063 WO2015112168A2 (en) | 2014-01-24 | 2014-01-24 | Compositions comprising noribogaine and an excipient to facilitate transport across the blood brain barrier |
Publications (1)
Publication Number | Publication Date |
---|---|
AU2014379612A1 true AU2014379612A1 (en) | 2016-08-11 |
Family
ID=53682084
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU2014379612A Abandoned AU2014379612A1 (en) | 2014-01-24 | 2014-01-24 | Compositions comprising noribogaine and an excipient to facilitate transport across the blood brain barrier |
Country Status (3)
Country | Link |
---|---|
EP (1) | EP3096794A2 (en) |
AU (1) | AU2014379612A1 (en) |
WO (1) | WO2015112168A2 (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2571696B (en) | 2017-10-09 | 2020-05-27 | Compass Pathways Ltd | Large scale method for the preparation of Psilocybin and formulations of Psilocybin so produced |
WO2020212952A1 (en) | 2019-04-17 | 2020-10-22 | Compass Pathfinder Limited | Treatment of depression and other various disorders with psilocybin |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5629307A (en) * | 1989-10-20 | 1997-05-13 | Olney; John W. | Use of ibogaine in reducing excitotoxic brain damage |
MX9701430A (en) * | 1994-07-25 | 1997-12-31 | Nda Int Inc | A method of treating chemical dependency in mammals and a composition therefor. |
US5591738A (en) * | 1994-10-14 | 1997-01-07 | Nda International, Inc. | Method of treating chemical dependency using β-carboline alkaloids, derivatives and salts thereof |
US8637648B1 (en) * | 2010-06-22 | 2014-01-28 | Demerx, Inc. | Compositions comprising noribogaine and an excipient to facilitate transport across the blood brain barrier |
-
2014
- 2014-01-24 EP EP14880182.2A patent/EP3096794A2/en not_active Withdrawn
- 2014-01-24 WO PCT/US2014/013063 patent/WO2015112168A2/en active Application Filing
- 2014-01-24 AU AU2014379612A patent/AU2014379612A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
WO2015112168A3 (en) | 2015-11-26 |
WO2015112168A2 (en) | 2015-07-30 |
EP3096794A2 (en) | 2016-11-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US8802832B2 (en) | Compositions comprising noribogaine and an excipient to facilitate transport across the blood brain barrier | |
US8637648B1 (en) | Compositions comprising noribogaine and an excipient to facilitate transport across the blood brain barrier | |
EP3260463B1 (en) | Deuterated chenodeoxycholic acid derivative and pharmaceutical composition comprising compound thereof | |
US8741891B1 (en) | N-substituted noribogaine prodrugs | |
US9586954B2 (en) | N-substituted noribogaine prodrugs | |
US6355629B2 (en) | Prodrugs with enhanced penetration into cells | |
AU2015252859B2 (en) | Bone-selective osteogenic oxysterol bisphosphonate analogs | |
BR112019021359A2 (en) | molecules, compositions, compounds, methods to administer a siren, to prepare a compound and to treat an infection, compound or salt, galnac conjugate and use of a compound | |
JP2003528146A (en) | Treatment of cerebrovascular disease | |
EP2788003A1 (en) | Phosphate esters of noribogaine | |
PT1940817E (en) | Cholinergic enhancers with improved blood-brain barrier permeability for the treatment of diseases accompanied by cognitive impairment | |
JP2021075570A (en) | Derivatives of amphotericin B | |
WO2021141969A1 (en) | Nanomaterials | |
WO2012150866A1 (en) | Phosphoribosyltransferase inhibitors and uses thereof | |
AU2014379612A1 (en) | Compositions comprising noribogaine and an excipient to facilitate transport across the blood brain barrier | |
US20130085163A1 (en) | Pyripyropene Derivative Having ACAT2 Inhibiting Activity and Stable to Metabolizing Enzymes | |
CN111417620B (en) | Creatine prodrugs, compositions thereof, and methods of use | |
JPH07121953B2 (en) | Novel pyrrolidine derivatives and salts thereof, process for producing the same, medicinal composition and preparation for transdermal administration | |
WO2023047399A1 (en) | Cannabinoid-lipid conjugates, methods for producing the same and uses thereof | |
HU224634B1 (en) | Benzoylecgonine derivatives and pharmaceutical compositions comprising thereof | |
WO2019196953A1 (en) | Ntcp inhibitors | |
WO2003087109A1 (en) | Medicaments containing glycerophosphoinositol-4-phosphate derivatives | |
WO1991016898A1 (en) | Anti-fungal bile acid derivatives | |
CN116731307A (en) | Macrolide polymer, preparation method thereof and application thereof in inhibiting effect of proinflammatory cytokines | |
WO2021033766A1 (en) | Lithocholic acid derivative having vitamin d activity |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MK4 | Application lapsed section 142(2)(d) - no continuation fee paid for the application |