AU2012202509B2 - Noribogaine compositions - Google Patents
Noribogaine compositions Download PDFInfo
- Publication number
- AU2012202509B2 AU2012202509B2 AU2012202509A AU2012202509A AU2012202509B2 AU 2012202509 B2 AU2012202509 B2 AU 2012202509B2 AU 2012202509 A AU2012202509 A AU 2012202509A AU 2012202509 A AU2012202509 A AU 2012202509A AU 2012202509 B2 AU2012202509 B2 AU 2012202509B2
- Authority
- AU
- Australia
- Prior art keywords
- noribogaine
- compound
- group
- ibogaine
- hydrogen
- 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.)
- Ceased
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 102
- RAUCDOKTMDOIPF-UHFFFAOYSA-N hydroxyibogamine Natural products CCC1CC(C2)CC3C1N2CCC1=C3NC2=CC=C(O)C=C12 RAUCDOKTMDOIPF-UHFFFAOYSA-N 0.000 title claims abstract description 101
- 239000000203 mixture Substances 0.000 title abstract description 31
- 238000000034 method Methods 0.000 claims description 50
- 150000001875 compounds Chemical class 0.000 claims description 39
- -1 carboxyl ester Chemical group 0.000 claims description 38
- 125000003118 aryl group Chemical group 0.000 claims description 31
- 125000006239 protecting group Chemical group 0.000 claims description 29
- 125000001072 heteroaryl group Chemical group 0.000 claims description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- 239000001257 hydrogen Substances 0.000 claims description 22
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 20
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 17
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 17
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 17
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 16
- 230000008569 process Effects 0.000 claims description 14
- 239000003054 catalyst Substances 0.000 claims description 12
- 238000007363 ring formation reaction Methods 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 6
- 239000000816 peptidomimetic Substances 0.000 claims description 6
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 5
- 150000001408 amides Chemical group 0.000 claims description 4
- 229920000249 biocompatible polymer Polymers 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical group [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims description 4
- 150000002431 hydrogen Chemical group 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- HSIBGVUMFOSJPD-CFDPKNGZSA-N ibogaine Chemical compound 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 abstract description 54
- VOXIUXZAOFEFBL-UHFFFAOYSA-N Voacangin Natural products CCC1CC2CN3CC1C(C2)(OC(=O)C)c4[nH]c5ccc(OC)cc5c4C3 VOXIUXZAOFEFBL-UHFFFAOYSA-N 0.000 abstract description 53
- OLOCMRXSJQJJPL-UHFFFAOYSA-N ibogaine Natural products CCC1CC2CC3C1N(C2)C=Cc4c3[nH]c5ccc(OC)cc45 OLOCMRXSJQJJPL-UHFFFAOYSA-N 0.000 abstract description 53
- AREITJMUSRHSBK-UHFFFAOYSA-N ibogamine Natural products CCC1CC2C3CC1CN2CCc4c3[nH]c5ccccc45 AREITJMUSRHSBK-UHFFFAOYSA-N 0.000 abstract description 53
- 238000006243 chemical reaction Methods 0.000 description 37
- 239000007787 solid Substances 0.000 description 27
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 238000006114 decarboxylation reaction Methods 0.000 description 15
- 238000003786 synthesis reaction Methods 0.000 description 15
- 125000000524 functional group Chemical group 0.000 description 13
- 125000005647 linker group Chemical group 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 10
- 238000010511 deprotection reaction Methods 0.000 description 10
- 238000000746 purification Methods 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 238000010520 demethylation reaction Methods 0.000 description 9
- 229910020008 S(O) Inorganic materials 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 8
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 8
- 238000005698 Diels-Alder reaction Methods 0.000 description 7
- 150000001336 alkenes Chemical class 0.000 description 7
- 239000003638 chemical reducing agent Substances 0.000 description 7
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 229910019142 PO4 Inorganic materials 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 150000001413 amino acids Chemical class 0.000 description 6
- 125000004429 atom Chemical group 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 125000000623 heterocyclic group Chemical group 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 239000010452 phosphate Substances 0.000 description 6
- 125000004076 pyridyl group Chemical group 0.000 description 6
- 238000006268 reductive amination reaction Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- AXHVEQQLKVIZLO-UHFFFAOYSA-N 2-[4-[2-[5-(2,2-dimethylbutyl)-1h-imidazol-2-yl]ethyl]phenyl]benzoic acid Chemical compound CCC(C)(C)CC1=CNC(CCC=2C=CC(=CC=2)C=2C(=CC=CC=2)C(O)=O)=N1 AXHVEQQLKVIZLO-UHFFFAOYSA-N 0.000 description 5
- 241000196324 Embryophyta Species 0.000 description 5
- 238000006254 arylation reaction Methods 0.000 description 5
- 229940125782 compound 2 Drugs 0.000 description 5
- 230000007062 hydrolysis Effects 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- 150000002466 imines Chemical class 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 229910052763 palladium Inorganic materials 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 229910052717 sulfur Inorganic materials 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 4
- 125000006242 amine protecting group Chemical group 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 235000010290 biphenyl Nutrition 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- 238000003776 cleavage reaction Methods 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 239000011968 lewis acid catalyst Substances 0.000 description 4
- 125000002971 oxazolyl group Chemical group 0.000 description 4
- 230000036961 partial effect Effects 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 230000007017 scission Effects 0.000 description 4
- 239000012279 sodium borohydride Substances 0.000 description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- MXPCZHSTOIKVST-UHFFFAOYSA-N 1-[3-amino-2,6-di(propan-2-yl)phenyl]-3-[1-butyl-4-[3-(2-hydroxyethoxy)phenyl]-2-oxo-1,8-naphthyridin-3-yl]urea;hydrochloride Chemical compound Cl.CC(C)C=1C=CC(N)=C(C(C)C)C=1NC(=O)NC=1C(=O)N(CCCC)C2=NC=CC=C2C=1C1=CC=CC(OCCO)=C1 MXPCZHSTOIKVST-UHFFFAOYSA-N 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 239000004793 Polystyrene Substances 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [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
- 125000004423 acyloxy group Chemical group 0.000 description 3
- 229930013930 alkaloid Natural products 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 3
- 239000004305 biphenyl Substances 0.000 description 3
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 3
- 229940125898 compound 5 Drugs 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 229920001577 copolymer Polymers 0.000 description 3
- 239000002274 desiccant Substances 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 229920000747 poly(lactic acid) Polymers 0.000 description 3
- 229920002401 polyacrylamide Polymers 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 229920002223 polystyrene Polymers 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical class [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 3
- 239000011593 sulfur Chemical group 0.000 description 3
- 238000006257 total synthesis reaction Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- ASSKVPFEZFQQNQ-UHFFFAOYSA-N 2-benzoxazolinone Chemical compound C1=CC=C2OC(O)=NC2=C1 ASSKVPFEZFQQNQ-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- HNFMVVHMKGFCMB-UHFFFAOYSA-N 3-[3-[4-(1-aminocyclobutyl)phenyl]-5-phenylimidazo[4,5-b]pyridin-2-yl]pyridin-2-amine Chemical compound NC1=NC=CC=C1C1=NC2=CC=C(C=3C=CC=CC=3)N=C2N1C1=CC=C(C2(N)CCC2)C=C1 HNFMVVHMKGFCMB-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
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 2
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 239000002841 Lewis acid Substances 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
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 229920000954 Polyglycolide Polymers 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 2
- IGBXWXQEHYCEHY-VWYCJHECSA-N [(1S,4S,6R)-4-ethyl-6-formylcyclohex-2-en-1-yl] acetate Chemical compound C(C)(=O)O[C@H]1C=C[C@H](C[C@H]1C=O)CC IGBXWXQEHYCEHY-VWYCJHECSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical compound C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000003797 alkaloid derivatives Chemical class 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- DCBDOYDVQJVXOH-UHFFFAOYSA-N azane;1h-indole Chemical compound N.C1=CC=C2NC=CC2=C1 DCBDOYDVQJVXOH-UHFFFAOYSA-N 0.000 description 2
- 229910052796 boron Inorganic materials 0.000 description 2
- 125000005587 carbonate group Chemical group 0.000 description 2
- 150000001728 carbonyl compounds Chemical class 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 238000011109 contamination Methods 0.000 description 2
- 230000000875 corresponding effect Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000006911 enzymatic reaction Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 150000007517 lewis acids Chemical class 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 239000002105 nanoparticle Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- RDOWQLZANAYVLL-UHFFFAOYSA-N phenanthridine Chemical compound C1=CC=C2C3=CC=CC=C3C=NC2=C1 RDOWQLZANAYVLL-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 229910052707 ruthenium Inorganic materials 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 150000004760 silicates Chemical class 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 229920001059 synthetic polymer Polymers 0.000 description 2
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 2
- 229910052719 titanium Inorganic materials 0.000 description 2
- 239000010936 titanium Substances 0.000 description 2
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- 238000000844 transformation Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- WILBTFWIBAOWLN-UHFFFAOYSA-N triethyl(triethylsilyloxy)silane Chemical compound CC[Si](CC)(CC)O[Si](CC)(CC)CC WILBTFWIBAOWLN-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- 125000002264 triphosphate group Chemical group [H]OP(=O)(O[H])OP(=O)(O[H])OP(=O)(O[H])O* 0.000 description 1
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 231100000402 unacceptable toxicity Toxicity 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Disclosed are noribogaine compositions comprising a very high level of the 2(R), 4(S), 5(S), 6(S) and 18(R) enantiomer and less than 100 ppm of ibogaine.
Description
AUSTRALIA Regulation 3.2 Patents Act 1990 Complete Specification Standard Patent APPLICANT: DemeRx, Inc. Invention Title: NORIBOGAINE COMPOSITIONS The following statement is a full description of this invention, including the best method of performing it known to me: NORIBOGAINE COMPOSITIONS Field of the Invention 10001] This invention relates to noribogaine compositions. In one embodiment, the noribogaine compositions comprise at least 95% noribogaine having the 2(R), 4(S), 5(S), 6(S) and 18(R) configuration and having less than 100 ppm ibogaine as an impurity relative to the amount of noribogaine present in the composition. State of the Art [0002] Noribogaine is a well known member of the ibogaine family of alkaloids and is sometimes referred to as 12-hydroxyibogaine. US Patent No. 2,813,873 claims noribogaine albeit as "12-0-demethylibogaine" while providing an incorrect structural formula for ibogaine. The structure of noribogaine has now been determined and found to combine the features of tyrptamine, tetrahydrohavaine and indolazepines. Noribogaine can be depicted by the following formula: 6 8 N 19 HO 12 10 20 21 16 17 18 2 3 1315 2 14 H where the configuration at the 2, 4, 5, 6 and 18 atoms are 2(R), 4(S), 5(S), 6(S) and 18(R). 100031 Noribogaine and its pharmaceutically acceptable salts have recently received significant attention as a non-addictive alkaloid useful in treating drug dependency (U.S. Patent No. 6,348,456) and as a potent analgesic (U.S. Patent No. 7,220,737). Both of these patents are incorporated herein by reference in their entirety. [0004] Conventionally, noribogaine is prepared by 0-demethylation of naturally occurring ibogaine: 2 N Meo C2H5 N H which is isolated from Tabernanih 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. 100051 Ibogaine possesses hallucinogenic properties and is a Schedule 1-controlled substance as provided by the US Food and Drug Administration. Accordingly, methods for preparing noribogaine from ibogaine require high levels of assurance that contamination with unacceptable amounts of ibogaine is avoided. However, noribogaine so prepared has not been reported as being substantially free of ibogaine (e.g., less than 100 ppm). At best, U.S. Patent No. 6,348,456 claims an essentially pure noribogaine compound but fails to disclose any methods for purification let alone what the phrase "essentially pure" encompassed or, for that matter, the level of ibogaine remaining in the composition. The synthesis of noribogaine from ibogaine was reported in U.S. Patent No. 2,813,873. However, the '873 patent was silent as to the purity of the noribogaine obtained in that synthetic process. 100061 Accordingly, there is an ongoing need to provide a noribogaine which is enantiomerically enriched (greater than 95% of the 2(R), 4(S), 5(S), 6(S) and 18(R) enantiomer) and essentially free of ibogaine (less than 100 ppm ibogaine relative to the amount of noribogaine). Such a total synthesis should be stereoselective as undesired stereoisomers can often lead to undesired and potentially dangerous side effects when administered to a patient. Summary of the Invention [0007] This invention provides noribogaine compositions which are enantiomerically enriched and essentially free of ibogaine. Such compositions provide a significant breakthrough in the treatment of addiction and/or pain as the compositions will not contain unacceptable amounts of ibogaine and are enantiomerically enriched.
3 [00081 Accordingly, in one of its composition aspects, this invention is directed to a composition comprising noribogaine wherein at least 95% of the noribogaine is present as the 2(R), 4(S), 5(S), 6(S) and 18(R) enantiomer and further wherein said composition comprises less than 100 ppm ibogaine contamination relative to the total amount of noribogaine. [00091 In some embodiments, the amount of ibogaine contained in the noribogaine compositions is less than 50 ppm, or less than I ppm ibogaine and preferably less than 100 ppt ibogaine. [0010] In some embodiments, at least 98% of the noribogaine is present as the 2(R), 4(S), 5(S), 6(S) and 18(R) enantiomer and, preferably, at least 99%, and more preferably, at least 99.5%. [00111 In some embodiments, the noribogaine of this invention is covalently bound to an inert solid support through a cleavable linker. Detailed Description of the Invention [00121 This invention is directed to compositions comprising noribogaine and, in particular, compositions comprising highly pure noribogaine as the (R), 4(S), 5(S), 6(S) and 18(R) enantiomer. However, prior to describing this invention in greater detail, the following terms will first be defined. 100131 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. [0014] 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 "a pharmaceutically acceptable excipient" includes a plurality of such excipients. 1. Definitions [00151 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 4 belongs. As used herein the following terms have the following meanings. [0016] 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. [00171 Except as it relates to the amount of noribogaine, 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 I %. [0018] As used herein, the term "noribogaine" refers to the alkaloid noribogaine including all enantiomers thereof. Of particular interest is the enantiomer depicted by the formula: HO 12 20 21 z N 2 H where the configuration at the 2, 4, 5, 6 and 18 atoms are 2(R), 4(S), 5(S), 6(S) and 18(R). [00191 The term "inert solid support" refers to a material having a rigid or semi-rigid surface which contains or can be derivatized to contain reactive functionality which covalently links noribogaine to the surface thereof through a cleavable linker. Such materials are well known in the art and include, by way of example, silica, synthetic silicates, biogenic silicates, porous glass, hydrogels, silicate-containing minerals, synthetic polymers, polystyrene, polypropylene, polyacrylamide, polyethylene glycol, polyacrylamide and copolymers thereof including copolymers of polystyrene/polyethylene glycol and polyacrylamide/polyethylene glycol, and the like.
5 100201 As used herein, the terms "cleavable linking arms" or "cleavable linker" refer to linking arms, which are a chemical group or a covalent bond which covalently attaches at one end to a solid support and at the other end to noribogaine. At least one of the covalent bonds of the linking arm which attaches noribogaine to the solid support can be readily broken by specific chemical or enzymatic reactions, thereby providing for noribogaine free of the solid support. The chemical or enzymatic reactions employed to break the covalent bond of the linking arm are selected so as to be specific for bond breakage thereby preventing unintended reactions occurring elsewhere on the compound. The cleavable linking group is selected relative to noribogaine formed on the solid support so as to prevent premature cleavage of noribogaine from the solid support as well as not to interfere with any of the procedures employed during synthesis on the support. Suitable cleavable linking arms are well known in the art, and may include such groups as carbonate groups, carbamate groups, amide groups, and the like. In a preferred embodiment, the cleavable linker arm contains no more than 10 atoms. More preferably, the cleavable linker contains from I to 4 carbon atoms and from 2 to 4 heteroatoms selected from oxygen, nitrogen, sulfur, S(O) and S(O) 2 . 100211 As used herein, the term "reaction conditions" refers to details under which a chemical reaction proceeds. Examples of reaction conditions include, but are not limited to, one or more of following: reaction temperature, solvent, pH, pressure, reaction time, mole ratio of reactants, the presence of a base or acid, or catalyst, etc. Reaction conditions may be named after the particular chemical reaction in which the conditions are employed, such as, decarboxylation conditions, olefin arylation conditions, anhydrous reaction conditions, etc. Reaction conditions for known reactions are generally known to those skilled in the art. 10022] As used herein, the term "anhydrous reaction conditions" refers to reaction conditions wherein water is excluded. Such conditions are known to one of skill in the art, and typically comprise one or more of dry or distilled solvents and reagents, dried reaction vessels, the presence of a drying agent, such as activated molecular sieves, magnesium sulfate, sodium sulfate etc. [0023] As used herein, the term "reducing agent" refers to a reagent which can donate electrons in an oxidation-reduction reaction, allowing hydrogen to be added to a molecule.
6 Suitable reducing agents include lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, and the like. [0024] As used herein, the term "reductive amination conditions" refers to the reaction between an amine and a carbonyl compound to form an imine, which is subsequently reduced to an amine using a reducing agent. The intermediate imine can either be isolated and purified prior to the reducing step, or used in the reducing step without prior isolation or purification. [00251 As used herein, the term "cyclization catalyst" refers to a catalyst which facilitates the cyclization between a cyclohex-2-enyl ester and an amine. Such catalysts include palladium catalysts such as Pd(PPh 3
)
4 . 100261 As used herein, the term "olefin arylation conditions" refers to reaction conditions under which a covalent bond is formed between an olefin and an aryl or heteroaryl group. The reaction results in the overall reduction of the olefin and retention of the aromaticity of the aryl or heteroaryl group. Such reaction conditions include one or more catalysts such as
(CH
3
CN)
2 PdCI 2 and AgBF 4 . 100271 As used herein, the term "decarboxylation conditions" refers to reaction conditions in which a carboxylic acid or an ester is replaced by hydrogen. Typically, decarboxylation reactions result in the release of carbon dioxide. fn certain embodiments, the decarboxylation conditions first comprise hydrolysis of an ester to the corresponding carboxylic acid using e.g. sodium hydroxide. The decarboxylation can be accomplishing using standard decarboxylation reactions, such as the use of lead tetraacetate followed by hydride reduction of the resultant imine or under standard Barton reaction conditions. The decarboxylation reaction conditions can comprise heat and/or radical initiation. The art is replete with such procedures. 10028] "Alkyl" refers to groups having from I to 6 carbon atoms and more preferably I to 3 carbon atoms. The alkyl group may contain linear or branched carbon chains. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, n-pentyl and the like. The term "C alkyl" refers to an alkyl group having x carbon atoms, wherein x is an integer, for example, C 3 refers to an alkyl group having 3 carbon atoms.
7 [0029] "Aryl" refers to a monovalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-1,4-benzoxazin 3(4H)-one-7-yl, and the like) provided that the point of attachment is at an aromatic carbon atom. [0030] "Cycloalkyl" refers to cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings including, by way of example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and the like. 100311 "Heteroaryl" refers to an aromatic group of from I to 10 carbon atoms and I to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur within the ring, wherein the nitrogen and/or sulfur atom(s) of the heteroaryl are optionally oxidized (e.g., N oxide, -S(O)- or -S(O) 2 -). Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl) wherein the condensed rings may or may not be aromatic and/or contain a heteroatom provided that the point of attachment is through an atom of the aromatic heteroaryl group. Examples of heteroaryls include pyridyl, pyrrolyl, indolyl, thiophenyl, and furyl. 10032] "Heterocycle" or "heterocyclic" or "heterocycloalkyl" or "heterocyclyl" refers to a saturated or partially saturated, but not aromatic, group having from I to 10 ring carbon atoms and from 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen. Heterocycle encompasses single ring or multiple condensed rings, including fused bridged and spiro ring systems. In fused ring systems, one or more the rings can be cycloalkyl, aryl, or heteroaryl provided that the point of attachment is through the non-aromatic heterocyclic ring. In one embodiment, the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, sulfinyl, and/or sulfonyl moieties. 100331 Examples of heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, 8 phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4 tetrahydro-isoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to as thiamorpholinyl), piperidinyl, pyrrolidine, tetrahydrofuranyl, and the like. [00341 As used herein, the term "optionally substituted alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl group" refers to an alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl group as defined herein optionally substituted with I to 3 substituents selected from the group consisting of alkyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, halo, -OR 1 0 , -SR' 0 , -CN, -NO 2 , -C(O)R'4,
-C(O)OR
1 4, -NR 1 4R 10 , -S(O)R , -S(O) 2
RI
0 , -S(O) 2 0R 10 , -S(O)NR 10
R'
0 , -S(O) 2
NR
10
R
1 0 ,
-C(O)NR'
0
R
0 , - NR 1 4C(O)NR 0
R'
0 , and -NR" 0
C(S)NR
1 0
R
1 0 ; and wherein R 1 0 is independently hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl. [00351 "Halo" or "halogen" refers to fluoro, chloro, bromo and iodo and preferably is fluoro or chloro. 100361 "Carboxyl" refers to the group "-C(O)OH". [00371 "Carboxyl ester" refers to the group "-C(O)OR 9 " where R 9 is an optionally substituted alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl group. [0038] "Acyloxy" refers to the group "-OC(O)R 9 " where R 9 is an optionally substituted alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl group. [0039] "Phosphate" refers to the groups -OP(O)(OH) 2 (monophosphate),
-OP(O)(OH)OP(O)(OH)
2 (diphosphate) and -OP(O)(OH)OP(O)(OH)OP(O)(OH) 2 (triphosphate) or salts thereof including partial salts thereof including partial salts thereof. The term "phosphate ester" includes esters of the mono-, di- and tri-phosphate groups described above wherein one or more hydrogen is replaced by an R 9 , where R 9 is an optionally substituted alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl group. [0040] "Phosphonate" refers to the groups -P(O)(OH) 2 (monophosphonate),
-P(O)(OH)OP(O)(OH)
2 (diphosphonate) and -P(O)(OH)OP(O)(OH)OP(O)(OH) 2 (triphosphonate) or salts thereof including partial salts thereof including partial salts thereof. The term "phosphonate ester" includes esters of the mono-, di- and tri-phosphonate groups 9 described above wherein one or more hydrogen is replaced by an R 9 , where R 9 is an optionally substituted alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl group. [00411 "Amide" refers to the groups -C(O)NH 2 , -C(O)NHR 9 and -C(O)N(R 9
)
2 where R 9 is an optionally substituted alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl group. [00421 As used herein, the term "peptide" refers to a chain of from I to 5 a-amino acids linked by amide bonds (i.e. -NH-C(O)-). The amino acids can be naturally occurring or synthetic amino acids. 100431 As used herein, the term "peptidomimetic" refers to a peptide-like chain designed to mimic a peptide. Peptidomimetics as used herein can include one or more amino acid mimetics, such as, but are not limited to, 0-2- and p-3-amino acids, p-2,2-p-2,3, and p-3,3-disubstituted amino acids, a,a-disubstituted amino acids, D-amino acids, optionally substituted a hydroxyacids, optionally substituted p-hydroxyacids, a-aminonitriles, N-alkylamino acids, and the like. In addition, the C-terminus of the peptidomimetic might be carboxylic acid or carboxamide, or other functional group resulting from the incorporation of one of the above mentioned amino acid mimetics. 100441 As used herein, the term "biodegradable, biocompatible polymer" refers to a polymer which degrades in the body and does not itself or the degradation products thereof produce unacceptable toxicity or injurious side-effects on the biological systems of the mammal. A variety of natural and synthetic polymers have been explored for the preparation of nanoparticles, of which poly(lactic acid) (PLA), poly(glycolic acid) (PGA), and their copolymers (PLGA) have been extensively investigated because of their biocompatibility and biodegradability. Suitable biodegradable polymers for preparing a nanoparticle of the invention include, but are not limited to, poly(lactide-co-glycolides), poly(lactic acid), poly(alkylene glycol), poly(butyl)cyanoacrylate, poly(methylmethacrylate-co-methacrylic acid), poly allylamine, polyanhydride, polyhydroxybutyric acid, or polyorthoesters and the like. 10045] As used herein, the term "chiral directing group" refers to an optically active chemical moiety that is incorporated into the compound so that a chemical transformation can be carried out stereoselectively to yield the desired product having at least 95% of the desired configuration. Typically, chiral directing groups are removed and are not a part of the desired 10 final product. The chiral directing group can have more than one chiral center. Suitable chiral directing groups can be derived from, in particular, alcohols, a- or p-amino acids, carboxylic acids, and the like. Exemplary groups are shown below, where R20 and R are selected from groups such as optionally substituted alkyl (e.g., methyl, iso-propyl, tert-butyl), aryl (e.g., phenyl, biphenyls, 2,6-dimethylphenyl), heteroaryl (e.g., pyridinyl, oxazolyl, etc.), R 22 and R 23 are selected from hydrogen and groups such as optionally substituted alkyl (e.g., methyl, iso-propyl, tert-butyl), aryl (e.g., phenyl, biphenyl, 2,6-dimethylphenyl), heteroaryl (e.g., pyridinyl, oxazolyl, etc.), or two of R20 and R or R20 and R 23 together with the atom to which they are attached form an optionally substituted cycloalkyl or heterocycloalkyl ring, and further wherein
R
20 , R 2 and R 22 are different. 0 0 0 0 R 20
R
20 0 ,k.ORO O NHR OH 23 R R 0 0 1 0 N H R H H H H 10046] As used herein, the term "palladium reactive functional group" refers to functional groups which can either directly react with palladium, or a precursor to such a group, such that the functional group reacts with a cyclization catalyst under cyclization conditions. Suitable groups include, but are not limited to, acyloxy, hydroxyl, phosphate, phosphate ester,
-OS(O)
2 OH, -OS(O) 2
OR
9 where R 9 is optionally substituted alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl, or -OR 8 where R 8 is a hydroxyl protecting group. [00471 As used herein, the term "pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts of a compound of Formula I which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. [00481 As used herein, the term "protecting group" or "Pg" refers to well known functional groups which, when bound to a functional group, render the resulting protected functional group S1I inert to the reaction conditions to be conducted on other portions of the compound and which, at the appropriate time, can be reacted to regenerate the original functionality under "deprotection conditions". The identity of the protecting group is not critical and is selected to be compatible with the remainder of the molecule. In one embodiment, the protecting group is an "amino protecting group" which protects the amino functionality of ibogaine or noribogaine during the reactions described herein. Examples of conventional amino protecting groups include, for instance, benzyl, acetyl, oxyacetyl, carboxybenzyl (Cbz), and the like. In another embodiment, the protecting group is a "hydroxy protecting group" which protects the hydroxyl functionality of noribogaine. Examples of hydroxyl protecting groups include, for instance, benzyl, p methoxybenzyl, p-nitrobenzyl, allyl, trityl, dialkylsilylethers, such as dimethylsilyl ether, and trialkylsilyl ethers such as trimethylsilyl ether, triethylsilyl ether, and t-butyldimethylsilyl ether; esters such as benzoyl, acetyl, phenylacetyl, formyl, mono-, di-, and trihaloacetyl such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl; and carbonates such as methyl, ethyl, 2,2,2-trichloroethyl, allyl, benzyl, and p-nitrophenyl. Additional examples of hydroxy protecting groups may be found in standard reference works such as Greene and Wuts, Protective Groups in Organic Synthesis., 2d Ed., 1991, John Wiley & Sons, and McOmie Protective Groups in Organic Chemistry, 1975, Plenum Press. Methods for protecting and deprotecting the phenolic hydroxyl group of the compounds disclosed herein can be found in the art, and specifically in Greene and Wuts, supra, and the references cited therein. Preparation of Noribogaine [00491 Noribogaine compositions of this invention can be prepared from ibogaine or by synthesis of noribogaine by chiral directed synthetic routes. In the former case, noribogaine containing less than 100 ppm ibogaine can be prepared using solid support synthesis as described below. As this compound is prepared from the natural product ibogaine and since the reactions described below do not involve any of the stereochemical centers, noribogaine so prepared will be least 95% of the 2(R), 4(S), 5(S), 6(S) and 18(R) enantiomer and likely to be 100% of that enantiomer.
12 [0050] In the case of solid support synthesis of noribogaine, the noribogaine compositions of this invention can be prepared from readily available starting materials using 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. 100511 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 and G. M. Wuts, Protecting Groups in Organic Synthesis, Fourth Edition, Wiley, N.Y., 2007, and references cited therein. 100521 Furthermore, the compounds of this invention contain multiple chiral centers and the desired noribogaine enantiomer is the 2(R), 4(S), 5(S), 6(S) and 18(R) enantiomer. [00531 It is contemplated that noribogaine can be prepared and/or purified from ibogaine by utilizing solid support as shown in the following Schemes, where PG represents an amine protecting group, LG represents a leaving group (e.g. a halo or alcohol), L represents a cleavable linking group (e.g. a carbonyl compound such as a carbonate or carbamate) and the shaded circle represents a solid support. [00541 In the following Schemes, the O-demethylation of the aryl methoxy group to yield the corresponding phenol can be accomplishing using any suitable method known in the art. Suitable reagents include a Lewis acid (e.g. BBr 3 , AIC 3 ), a nucleophile (e.g. RS-, N 3 -, SCN-), NaCN at low pH (e.g. pH 12), and the like. In some embodiments, the 0-demethylation should be performed without affecting the linkage to the solid support or altering the stereochemistry of the stereochemical centers on the molecule. Suitable reagents can be readily ascertained by one of skill in the art and can be found, for example, in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Fourth Edition, Wiley, N.Y., 2007 (see, e.g., the reactivity charts at pages 1006-1008 and 1022-1032), and references cited therein.
13 Scheme 1 LG LG M/ eN HO 0O Nc ~N LNK N H 2012 L3 / L/ PG-LGI MN OL--O r"NN N HO N LL0 NN LG HO 2 p 0 L [00551 Noribogaine 5 can be prepared and purified from ibogaine 10 by any one of the routes shown in Scheme 1. Noribogaine, compound 5, is differentiated from ibogaine by virtue of the fact that the methoxy group of ibogaine has been converted to a hydroxyl group in noribogaine. In one embodiment, the indole amine of ibogaine can be protected using an amine protecting group to yield compound 1, followed by either tandem O-demethylation and removal of the protecting group using L-selectride@, for example, or sequential O-demethylation and removal of the protecting group to yield noribogaine 5. In addition, in one embodiment, noribogaine can be directly prepared and purified from the O-demethylation of ibogaine using methods known in the art and then purified by appending noribogaine to a solid support (compound 12 or 13), washing any contaminants, cleaving the linking group L, and recovering the noribogaine 5. In the above syntheses, one or more of the noribogaine or intermediates shown above can be purified using standard purification techniques known in the art (e.g. column chromatography, HPLC, and the like). Compounds of formula 11 are commercially available or can be synthesized in one or two steps from commercially available starting materials (see, e.g. commercially available resins from Sigma-Aldrich@).
14 [0056] In one embodiment, noribogaine can be prepared and purified from ibogaine in the manner described in Scheme 2 below: Scheme 2 N N MeO HO ) N N 1 2 Pg Pg oOAo 3 N N HO 0 N 0 N H 5 2P 4 wherein Pg is hydrogen or an amino protecting group and the shaded circle represents a solid support. [0057] Specifically, in Scheme 2, amino protected ibogaine, compound 1, is contacted with boron tribromide or other conventional demethylating agent in e.g., methylene chloride using conditions well known in the art to yield the amino protected noribogaine, compound 2. [00581 In Scheme 2, attachment of amino protected noribogaine, compound 2, to a solid support is accomplished by use of a chloroformate/solid support, compound 3, under conventional conditions to yield compound 4 wherein the carbonate group is shown for illustrative purposes only as the cleavable linking group. Other cleavable linkers can likewise be used in Scheme 2. As amino protected ibogaine does not contain a functional group reactive with compound 3, only amino protected noribogaine, compound 2, will react with the solid support and yield compound 4. Repeated washing of compound 4 will remove amino protected ibogaine contaminating the sample of amino protected noribogaine used in this reaction. Furthermore, at any time, a small portion of the solid support can be removed to provide a sample of noribogaine (after cleavage and deprotection). The sample can then be analyzed for 15 purity relative to any ibogaine present by conventional methods such as GC/MS, NMR, C" NMR, etc. 100591 Upon achieving the desired level of purity of noribogaine relative to any contaminating ibogaine, noribogaine, compound 5, can be recovered from the solid support by cleavage of the cleavable linker and subsequent deprotection of the amino group. Both cleavage and deprotection are well known in the art. [00601 As desired, exceptionally pure noribogaine, compound 5, can be obtained by repeating the process of forming the amino protected noribogaine, compound 2, binding compound 2 to a solid support via the hydroxyl group of amino protected noribogaine and washing any contaminating ibogaine from the solid support. By repeating this process as often as necessary and preferably no more than 5 times, it is contemplated that noribogaine compositions having less than 100 ppm, or less than 50 ppm, or less than 1 ppm ibogaine and preferably less than 100 ppt ibogaine relative to the amount of noribogaine present in the composition can be prepared. [00611 In one embodiment, the amount of ibogaine in a noribogaine composition can be determined by starting with a "C enriched methoxy group on ibogaine. The amount of "C over background in the final composition can be correlated to the amount of ibogaine in the noribogaine composition which can then be used to validate that the synthetic protocols employed are at or below the maximum amount of ibogaine permitted in the noribogaine composition. A 14 C enriched methoxy group on ibogaine can readily be prepared by methylating the 12-hydroxyl group of noribogaine with an enriched 4 C methylating agent. Techniques for determining the amount of a 4 C in a composition are well known in the art and detection limits are below 1 ppt. [00621 Alternatively, noribogaine can be prepared by total synthesis which ensures that ibogaine is not an intermediate during that synthesis. Such a synthetic protocol provides for noribogaine compositions having less than 100 ppm ibogaine and theoretically no ibogaine. The total synthesis is stereochemically directed such that the amount of the 2(R), 4(S), 5(S), 6(S) and 18(R) enantiomer of noribogaine in the noribogaine composition is at least 95% of all of the noribogaine enantiomer s present, preferably at least 98% and more preferably at least 99%. In 16 one embodiment, the stereochemically directed synthesis of noribogaine 5 employs compound 21a in very high enantiomeric purity, HO N N H 5 and is prepared by: a) contacting a compound of formula 21a with a compound of formula 21b, wherein X is a palladium reactive functional group or precursor thereof and R I and R are hydrogen or a protecting group and wherein 21a is at least 95% the 1S,4S,6R configuration, O X R11- 0 H
NH
2 N 12 21a 21b under reductive amination reaction conditions to yield a compound of formula 21c: R11-O NH X N 12| 21c b) contacting a compound of formula 21c with a cyclization catalyst under cyclizing conditions to yield a compound of formula 21d: 17 N 21d c) contacting a compound of formula 21d under olefin arylation conditions to yield a compound of formula 21e: R11-O N R12 21e; d) optionally contacting a compound of formula 21e under deprotection conditions to yield a compound of formula 5; and e) optionally converting compound of formula 5 to its pharmaceutically acceptable salt. [00631 In the methods disclosed above, the indole nitrogen can be protected with an amino protecting group (R1 2 ) and deprotected as required using amine protecting groups as defined herein. The amino protecting group R can be the same as the hydroxyl protecting group R" (e.g., optionally substituted benzyl) or can be an orthogonal protecting group. [00641 In some embodiments, the reductive amination conditions comprise anhydrous reaction conditions. In some embodiments, the reductive amination conditions of step a) comprise magnesium sulfate. In some embodiments, step a) further comprises low temperatures (e.g. -10 to -5 *C). [0065] In some embodiments, the reductive amination conditions of step a) comprises sodium borohydride (NaBH). In some embodiments, the reductive amination conditions of step a) comprises sodium cyanoborohydride (NaBH 3 (CN)). In some embodiments, step a) further comprises raising the temperature when the reducing agent is added (e.g. 0 *C).
18 [0066] In some embodiments, the cyclization catalyst of step b) comprises Pd(PPh 3
)
4 . In some embodiments, Pd(PPh 3
)
4 is added in an amount ranging from about 3% to about 6%. In some embodiments, step b) further comprises elevated temperatures (e.g. 70 'C). [00671 In some embodiments, the olefin arylation conditions of step c) comprises
(CH
3
CN)
2 PdC 2 and AgBF 4 . In some embodiments, step c) further comprises a base such as triethylamine. In some embodiments, step c) further comprises adding a reducing agent such as sodium borohydride (NaB14). In some embodiments, step c) further comprises elevated temperatures (e.g. 70 *C). 100681 In another of its method aspects, this invention is directed to a method for preparing noribogaine 5 from a compound of formula 22e as shown in Scheme 3. In Scheme 3, R' is selected from the group consisting of carboxyl, carboxyl ester, amide, phosphonate, phosphonate ester, a peptide, a peptidomimetic, a biodegradable, biocompatible polymer, and -C(O)R 18 where R" is -NH(CH 2 )nS(O) 2 OH, -NH(CH 2 )nOH, -C(O)R", -OC(O)R , -CH 2
C(O)R'
9 , or -CH2C(O)OR' 9 where R' 9 is optionally substituted alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl and n is 2-5, X is a palladium reactive functional group or precursor thereof (e.g., X can be acyloxy, hydroxyl, phosphate, phosphate ester, -OS(O) 2 0H, -OS(O) 2
OR'
9 where R' 9 is optionally substituted alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl, or -OR 8 where R' 8 is a hydroxyl protecting group), R" is hydrogen or a protecting group, and R' 2 is hydrogen or a protecting group.
19 Scheme 3 0 X R11-0 R R1-O R12 12 N 12 22a 22b Ril-0 R' / N R11-O R' R11-O R' N O H X N N NH - /N-R12 N N R 12 R 12 22e 22d 22c [00691 As shown above in Scheme 3, amine 22c can be prepared by reacting 22a with 22b under anhydrous conditions in a suitable solvent, such as benzene, toluene, and the like, in the presence of a drying agent such as activated molecular sieves, magnesium sulfate, sodium sulfate etc. The reaction is preferably conducted at low temperature (i.e. -10 to -5 C). The resultant imine can be used in the next step without purification or isolation. Amine 22c can be provided from the imine using a reducing agent, such as sodium borohyride at low temperature (i.e. 0 *C). Cyclization of amine 22c to yield compound 22d can proceed using a catalyst, such as Pd(PPh 3
)
4 . The cyclization reaction can be conducted in a polar solvent, such as acetonitrile, at elevated temperature (i.e. 70 C). Compound 22d can be purified using standard purification methods (i.e. liquid chromatography). Compound 22e can be provided from compound 22d using a palladium-silver catalyzed olefin arylation reaction. Suitable reaction conditions can include (CH 3
CN)
2 PdCI 2 and AgBF 4 in the presence of triethylamine in acetonitrile at elevated temperature (e.g. 70 C). A reducing agent such as sodium borohydride can be used to liberate the catalyst and yield compound 22e. Compound 22e can be purified using standard purification methods (i.e. liquid chromatography). It is contemplated that compound 22e can be further 20 purified using classical resolution (i.e. chromatography, crystallization, fractional crystallization, etc.) known in the art to provide substantially enantiomerically pure compound 22e. [0070] Both enantiomers of compounds of formula 22b can be obtained from commercial sources (Aldrich@, USA) or prepared using methods known to one of skill in the art. In some embodiments, compound 22b is of the formula 0 R11- 0 . OR 14 \
NH
2 N k12 wherein R' and R1 2 are each independently hydrogen or a protecting group and R 14 is optionally substituted alkyl or aryl. In certain embodiments, R' 4 is nitrobenzyl or bromobenzyl. 10071] It is contemplated that either the S- or R-configuration of 22b can be used in Scheme 3, above, to afford the diastereomeric compounds R-22e and S-22e, shown below, wherein R 1 and R are as described hereinabove. 0 0 R'O -OR14 R 11 -O OR 14 N N N N H H R-22e S-22e [0072] Noribogaine can be prepared from compounds of formula 22e via decarboxylation and deprotection as shown in Scheme 4, below. In Scheme 4, R' 1 is a protecting group and R' 4 is an optionally substituted alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl group, and the indole nitrogen can optionally be protected using an amine protecting group as defined herein. The decarboxylation and deprotection steps can be performed simultaneously or sequentially. In addition, the ester can be hydrolyzed to the carboxylic acid prior to decarboxylation.
21 Scheme 4 O 0 HO OR 14 HO OH / \ hydrolysis N N N N H H hydrolysis / 22g decarboxylation 23 Ideprotection decarboxylation 0 11.0 OR 14 HO / hydrolysis / N decarboxylation ,N deprotection N N N H H 22e hydrolysis decarboxylation decarboxylation deprotection O 0 R1-O OH HO OH /- N deprotection . N N N H H 22f 23 [0073] The methods disclosed herein provide for the synthesis of stereochemically enriched noribogaine having the 2R, 4S, 5S, 18R configuration. In some embodiments, the 2R, 4S, 5S, 18R noribogaine 5 is provided in at least about 95% the 2R, 4S, 5S, 18R configuration, or at least about 98% the 2R, 4S, 5S, 18R configuration, or at least about 99% the 2R, 4S, 5S, 18R configuration, or at least about 99.5% the 2R, 4S, 5S, 18R configuration. [00741 In addition, this invention provides for novel intermediates as shown below.
22 0 0 0 OO OO HO HO OH HO OH HO 'O N N N N N H H H 3 S-3 R-3 O 0 0 R"O OH R 11 O OH HO OH N N N N N N H H H 0 0 0 OR 14 OR'1 4 \ R1 HO HO HO N N N N N H H H 0 0 0
R
1 O O OR 1 4 ROO OR 4
R
1 4 OR 14 N N N N N N H H H [0075] In some embodiments, the methods disclosed herein further comprise the step of further separating two or more stereoisomers. Such methods for separating stereoisomers (including enantiomers and diastereomers) are known in the art and include chiral column chromatography, chiral resolving agents and the like. [0076] The starting materials for the above 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, Wis., USA), Bachem (Torrance, Calif., USA), Emka-Chemce or Sigma (St. Louis, Mo., USA). Others may be prepared by procedures, or obvious modifications thereof, described 23 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 Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1 40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4.sup.th Edition), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). 10077] It is contemplated that the (1S,4S,6R)-4-ethyl-6-formylcyclohex-2-enyl acetate 21a 0 0 0 R 1 0 H 21a for use in the methods disclosed herein can be prepared in at least 95% the 1 S,4S,6R configuration. However, it is preferred to have compound 21a in greater than 98%, or greater than 99%, or about 99.5%, the 1 S,4S,6R configuration. [0078] Accordingly, it is contemplated that the (1S,4S,6R)-4-ethyl-6-formylcyclohex-2-enyl acetate 21a to be used in step a) can be prepared via an asymmetric Diels-Alder reaction. The asymmetric Diels-Alder can be performed using a chiral directing group on the diene (i.e., R1 0 is a chiral directing group as defined herein). Suitable chiral directing groups can be derived from, in particular, chiral alcohols, p-amino alcohols, a- or p-amino acids, and the like. Exemplary groups are shown below, where R 20 and R 2 ' are selected from groups such as optionally substituted alkyl (e.g., methyl, iso-propyl, tert-butyl), aryl (e.g., phenyl, biphenyl, 2,6 dimethylphenyl), heteroaryl (e.g., pyridinyl, oxazolyl, etc.), and R 22 and R 23 are selected from hydrogen and groups such as optionally substituted alkyl (e.g., methyl, iso-propyl, tert-butyl), aryl (e.g., phenyl, biphenyl, 2,6-dimethylphenyl), heteroaryl (e.g., pyridinyl, oxazolyl, etc.), or two of R20 and R2 or R20 and R 23 together with the atom to which they are attached form an optionally substituted cycloalkyl or heterocycloalkyl ring, and further wherein R 20 , R 1 and R 2 are different.
24 0 0 0 0 R 2 0 0 O O O;OR23 O NHR 2 3 O O NHR23 R22 R22 1R22 RR21 H H H HR22 [0079] Typically, Diels-Alder reactions utilize a Lewis-acid catalyst. Suitable Lewis-acid catalysts are known in the art, and typically comprise aluminum, titanium, iron, ruthenium, boron, and the like. The Diels-Alder reaction is typically performed under anhydrous conditions which may include a drying agent, such as activated molecular sieves. In some embodiments, the Diels-Alder reaction is performed under pressure in a sealed vessel. 100801 Still further, the asymmetric Diels-Alder reaction can be performed using a chiral Lewis-acid catalyst or a chiral organocatalyst known or prepared by one of skill in the art. Such chiral Lewis-acid catalysts are known in the art, and typically comprise aluminum, titanium, iron, ruthenium, boron, and the like (See, Corey, E.J. Angew. Chem. Int. Ed. 2002, 41, 1650 1667). Suitable chiral organocatalysts include derivatives of proline or a-amino acid derived imidazolidinones. [00811 However, the precise identity of the chiral directing group or the chiral Lewis-acid is not critical to the present invention as such methods for performing asymmetric Diels-Alder reactions have become routine in the art. [00821 The present invention is directed to the compounds and intermediates disclosed herein, including all possible stereoisomers of compounds of formula 21b, 21c, 21d, 21e, 22b, 22c, 22d, 22e, 22f, 22g, and 23. It is contemplated that the compounds of formula 21b, 21c, 21d, 21e, 22b, 22c, 22d, 22e, 22f, 22g, and 23 can be further purified to yield at least 90%, or at least 95%, or at least 98%, of single stereoisomer using chiral resolution methods, such as chiral chromatography and/or crystallization of the diastereomeric salt using a chiral acid, such as tartaric acid, mandelic acid, lactic acid, and the like. Such methods are routine in the art. 10083] The synthetic noribogaine of the present invention is distinguished from plant derived noribogaine (i.e. noribogaine synthesized from naturally occurring ibogaine) by its 14 C content. 14 C has a half-life of about 5,730 years and is generated in the upper atmosphere as 4 C0 2 . The 25 amount of 14 C0 2 present is approximately I ppt (parts per trillion) and, through photosynthesis, accumulates in plants resulting in a 14 C content of plant material of approximately I ppt. Accordingly, plant derived noribogaine (i.e. noribogaine synthesized from naturally occurring ibogaine) is expected to have approximately 1 ppt 14 C. Conversely, the noribogaine and intermediates disclosed herein are derived from fossil fuels, which due to 14 C decay, would have a 1 4 C content of less than I ppt, or less than 0.9 ppt 14 C. Accordingly, provided herein is noribogaine having a 14 C content of less than 1 ppt, or less than 0.9 ppt, or less than 0.8 ppt, or less than 0.7 ppt, or less than 0.6 ppt, or less than 0.5 ppt, or less than 0.4 ppt, or less than 0.3 ppt, or less than 0.2 ppt, or less than 0.1 ppt. The amount of 14 C can be analyzed using methods well known in the art (i.e. radiocarbon analyses can be carried out according to the American Society for Testing Materials ASTM D6866 procedure (ASTM international, 100 Barr Harbon Drive, PO Box C700, West Conshohocken, PA 19428-2959)). Furthermore, provided is a method for distinguishing synthetic noribogaine from plant derived noribogaine based on the 14 C content. [00841 It will be apparent to those skilled in the art that many modifications of the above exemplifying methods, both to materials and methods, may be practiced without departing from the scope of the current invention. [00851 The following synthetic and biological examples are offered to illustrate this invention and are not to be construed in any way as limiting the scope of this invention. Unless otherwise stated, all temperatures are in degrees Celsius. Examples 100861 In the examples below, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning. Example 1 - Synthesis and Purification of Noribogaine from Ibogaine [0087] Example 1 illustrates one method for the synthesis and purification of noribogaine from ibogaine which method follows Scheme 5 below: 26 Scheme 5 N N MeO HO N C1 H 1) O O B7 Bz 2) BBr3 ci 0 0 N N Ho O H
-
O O Bz 100881 Specifically, in Scheme 5, ibogaine is contacted with a stoichiometric excess of benzyl chloroformate in an inert solvent such as methylene chloride. The reaction mixture further contains at least a stoichiometric equivalent of diisopropylethylamine relative to ibogaine so as to scavenge the acid generated during the reaction. The reaction is maintained at room temperature under an inert atmosphere until the reaction is substantially complete as evidenced by, for example, thin layer chromatograpy. At which time, an O-demethylation reagent (e.g. boron tribromide or aluminum trichloride), or preferably a stoichiometric excess thereof, is added to the reaction mixture which is then maintained under conditions (e.g. room temperature) wherein the methoxy group of ibogaine has been converted to the hydroxyl group of noribogaine. [00891 The hydroxyl group generated above is then employed as a complementary functionality for attachment of a solid support. In particular, an excess of chloroformate bound to a solid support is combined with N-CBZ-noribogaine under conventional conditions wherein a cleavable carbonate bond is formed. Chloroformate bound to a solid support can be prepared from a hydroxy-bearing polymer support (e.g. hydroxymethyl)polystyrene or polymer-bound benzyl alcohol, both commercially available from Sigma-Aldrich@) and carbonyl dichloride. As 27 CBZ-ibogaine does not readily react under these O-demethylation conditions, it will remain in the solution phase of the reaction mixture and can be washed from the reaction mixture by conventional techniques including placing the solid support into a column and passing excess solvent through the column. [00901 In one particular example, 1kg of solid support containing CBZ-noribogaine is loaded onto a column. The stopper of the column is partially opened so that a flow rate through the column of 0.5 liters per hour is maintained. Methylene chloride is continuously fed to the top of the column and recovered at the base of the column. The recovered methylene chloride is stripped to provide residual CBZ-ibogaine. The process is continued until the effluent from the column no longer contains CBZ-ibogaine. At which time, a portion of the solid support is loaded into a hydrogenation vessel together with methanol and a catalytic amount of palladium on carbon. Hydrogenation is continued under elevated pressure for approximately 5 hours. The reaction is then stopped and the methanol recovered and stripped, thus yielding noribogaine. Additional purification of noribogaine can be achieved by HPLC as desired. [00911 The reference to any prior art in this specification is not, and should not be taken as an acknowledgement or any form of suggestion that the referenced prior art forms part of the common general knowledge in Australia.
Claims (15)
1. A compound of formula 22d: R 11 0R' N R 1 2 22d or a salt thereof comprising a chiral acid, wherein R" is hydrogen or a hydroxyl protecting group; R 12 is hydrogen or an amino protecting group; and R' is selected from the group consisting of hydrogen, carboxyl, carboxyl ester, amide, phosphonate, phosphonate ester, a peptide, a peptidomimetic, a biodegradable, biocompatible polymer, and -C (0)R 18. R 18 is -NH(CH 2 )nS(O) 2 OH, -NH(CH 2 )nOH, -C(O)R' 9 , -OC(O)R 9 , -CH 2 C(O)R 9 , or -CH 2 C(O)OR19; R 19 is optionally substituted alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl; and n is 2-5.
2. The compound of claim 1, wherein R' is hydrogen.
3. The compound of claim 1 or 2, wherein R" is a hydroxyl protecting group.
4. The compound of any one of claims 1-3, wherein R 12 is hydrogen. 29
5. At least 90% of a single stereoisomer of the compound of any one of claims 1-4.
6. At least 95% of a single stereoisomer of the compound of any one of claims 1-5.
7. At least 98% of a single stereoisomer of the compound any one of claims 1-6.
8. A process for preparing a compound of formula 22e: R'1-O R' N RN 22e wherein R" is hydrogen or a hydroxyl protecting group; R 12 is hydrogen or an amino protecting group; and R' is selected from the group consisting of hydrogen, carboxyl, carboxyl ester, amide, phosphonate, phosphonate ester, a peptide, a peptidomimetic, a biodegradable, biocompatible polymer, and -C(O)R19' R 1 8 is -NH(CH 2 )nS(O) 2 OH, -NH(CH 2 )nOH, -C(O)R' 9 , -OC(O)R' 9 , -CH 2 C(O)R' 9 , or -CH 2 C(O)OR 19 ; R 19 is optionally substituted alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl; and n is 2-5; the process comprising contacting a compound of formula 22d: 30 R 1 -R' N 22d or a salt thereof comprising a chiral acid, wherein R", R 12 , and R' are defined as above, with a cyclization catalyst under cyclizing conditions to yield the compound of formula 22e.
9. The process of claim 8, wherein R' is hydrogen.
10. The process of claim 9, wherein R 12 is hydrogen.
11. The process of claim 10, wherein R" is a hydroxyl protecting group.
12. The process of claim 11, further comprising deprotecting the hydroxyl protecting group to provide noribogaine or a salt thereof.
13. The process of claim 12, wherein the noribogaine is provided in at least 90% in the 2R, 4S, 5S, 18R configuration.
14. The process of claim 12, wherein the noribogaine is provided in at least 95% in the 2R, 4S, 5S, 18R configuration.
15. The process of claim 12, wherein the noribogaine is provided in at least 98% in the 2R, 4S, 5S, 18R configuration.
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Title |
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Baumann, M.H. et al, "In vivo neurobiological effects of ibogaine and its Odesmethyl metabolite,12-hydroxyibogamine (noribogaine), in rats", The Journal of Pharmacology and Experimental Therapeutics, 2001, Vol. 297, No. 2, pages 531-539 * |
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