EP3164402A1 - N-substituted noribogaine prodrugs - Google Patents
N-substituted noribogaine prodrugsInfo
- Publication number
- EP3164402A1 EP3164402A1 EP14890017.8A EP14890017A EP3164402A1 EP 3164402 A1 EP3164402 A1 EP 3164402A1 EP 14890017 A EP14890017 A EP 14890017A EP 3164402 A1 EP3164402 A1 EP 3164402A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- substituted
- compound
- group
- alkyl
- heterocyclic
- 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.)
- Withdrawn
Links
- RAUCDOKTMDOIPF-RYRUWHOVSA-N noribogaine Chemical class 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 abstract description 56
- RAUCDOKTMDOIPF-UHFFFAOYSA-N hydroxyibogamine Natural products CCC1CC(C2)CC3C1N2CCC1=C3NC2=CC=C(O)C=C12 RAUCDOKTMDOIPF-UHFFFAOYSA-N 0.000 title abstract description 49
- 239000000651 prodrug Substances 0.000 title abstract description 17
- 229940002612 prodrug Drugs 0.000 title abstract description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 205
- 238000000034 method Methods 0.000 claims abstract description 79
- 208000002193 Pain Diseases 0.000 claims abstract description 22
- 230000036407 pain Effects 0.000 claims abstract description 21
- 206010012335 Dependence Diseases 0.000 claims abstract description 16
- 125000000623 heterocyclic group Chemical group 0.000 claims description 145
- 239000001257 hydrogen Substances 0.000 claims description 85
- 229910052739 hydrogen Inorganic materials 0.000 claims description 85
- 125000000217 alkyl group Chemical group 0.000 claims description 80
- 125000001072 heteroaryl group Chemical group 0.000 claims description 79
- -1 aryi Chemical group 0.000 claims description 78
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 74
- 125000003118 aryl group Chemical group 0.000 claims description 58
- 239000000203 mixture Substances 0.000 claims description 55
- 125000000304 alkynyl group Chemical group 0.000 claims description 51
- 125000003342 alkenyl group Chemical group 0.000 claims description 45
- 125000004426 substituted alkynyl group Chemical group 0.000 claims description 44
- 125000003107 substituted aryl group Chemical group 0.000 claims description 44
- 150000003839 salts Chemical class 0.000 claims description 42
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 42
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 40
- 239000012453 solvate Substances 0.000 claims description 40
- 125000005017 substituted alkenyl group Chemical group 0.000 claims description 39
- 125000005647 linker group Chemical group 0.000 claims description 30
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 21
- 239000003814 drug Substances 0.000 claims description 20
- 229910052757 nitrogen Inorganic materials 0.000 claims description 20
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- 229910052760 oxygen Inorganic materials 0.000 claims description 16
- 229910052717 sulfur Inorganic materials 0.000 claims description 14
- 150000001720 carbohydrates Chemical class 0.000 claims description 13
- 229940079593 drug Drugs 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 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 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 229920001542 oligosaccharide Polymers 0.000 claims description 11
- 150000002482 oligosaccharides Chemical class 0.000 claims description 11
- 239000000126 substance Substances 0.000 claims description 11
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 7
- 208000028173 post-traumatic stress disease Diseases 0.000 claims description 7
- 125000005415 substituted alkoxy group Chemical group 0.000 claims description 7
- 208000019901 Anxiety disease Diseases 0.000 claims description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
- 230000036506 anxiety Effects 0.000 claims description 6
- 125000004429 atom Chemical group 0.000 claims description 6
- 229960003920 cocaine Drugs 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 239000011593 sulfur Substances 0.000 claims description 5
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 4
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 claims description 4
- 229960001948 caffeine Drugs 0.000 claims description 4
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 235000002637 Nicotiana tabacum Nutrition 0.000 claims description 3
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 3
- 229940049706 benzodiazepine Drugs 0.000 claims description 3
- 229910052698 phosphorus Inorganic materials 0.000 claims description 3
- 239000011574 phosphorus Substances 0.000 claims description 3
- 238000012216 screening Methods 0.000 claims description 3
- 238000011287 therapeutic dose Methods 0.000 claims description 3
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 claims description 2
- 229940025084 amphetamine Drugs 0.000 claims description 2
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 claims 1
- 241000208125 Nicotiana Species 0.000 claims 1
- 229960001252 methamphetamine Drugs 0.000 claims 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- 239000000243 solution Substances 0.000 description 44
- 239000011541 reaction mixture Substances 0.000 description 34
- 238000011282 treatment Methods 0.000 description 30
- 125000000392 cycloalkenyl group Chemical group 0.000 description 29
- 238000006243 chemical reaction Methods 0.000 description 26
- 238000002360 preparation method Methods 0.000 description 26
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- 235000019439 ethyl acetate Nutrition 0.000 description 20
- 239000007787 solid Substances 0.000 description 19
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 16
- 239000000546 pharmaceutical excipient Substances 0.000 description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- 125000001424 substituent group Chemical group 0.000 description 15
- 210000004556 brain Anatomy 0.000 description 14
- 125000005843 halogen group Chemical group 0.000 description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 13
- 208000024891 symptom Diseases 0.000 description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- 238000005481 NMR spectroscopy Methods 0.000 description 12
- 239000002253 acid Substances 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 12
- 230000002829 reductive effect Effects 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 11
- 125000005366 cycloalkylthio group Chemical group 0.000 description 11
- 238000009472 formulation Methods 0.000 description 11
- 125000006239 protecting group Chemical group 0.000 description 11
- 210000002966 serum Anatomy 0.000 description 11
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 10
- 125000004414 alkyl thio group Chemical group 0.000 description 10
- 230000008499 blood brain barrier function Effects 0.000 description 10
- 238000003776 cleavage reaction Methods 0.000 description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
- 125000005553 heteroaryloxy group Chemical group 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- 230000007017 scission Effects 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 125000005110 aryl thio group Chemical group 0.000 description 9
- 125000004104 aryloxy group Chemical group 0.000 description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 9
- 239000012043 crude product Substances 0.000 description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 9
- 125000005368 heteroarylthio group Chemical group 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- 229920006395 saturated elastomer Polymers 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- 239000012267 brine Substances 0.000 description 8
- 201000010099 disease Diseases 0.000 description 8
- 239000004615 ingredient Substances 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 238000002953 preparative HPLC Methods 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 150000003573 thiols Chemical class 0.000 description 8
- 239000008346 aqueous phase Substances 0.000 description 7
- 238000004587 chromatography analysis Methods 0.000 description 7
- 125000004093 cyano group Chemical group *C#N 0.000 description 7
- 125000002346 iodo group Chemical group I* 0.000 description 7
- 229960004592 isopropanol Drugs 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- 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 7
- 230000035882 stress Effects 0.000 description 7
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 7
- 229940124597 therapeutic agent Drugs 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 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 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000002252 acyl group Chemical group 0.000 description 6
- 210000001218 blood-brain barrier Anatomy 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 125000000524 functional group Chemical group 0.000 description 6
- 208000014674 injury Diseases 0.000 description 6
- 239000008101 lactose Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 208000024714 major depressive disease Diseases 0.000 description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- 208000011117 substance-related disease Diseases 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 230000008733 trauma Effects 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- 206010019233 Headaches Diseases 0.000 description 5
- 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 5
- 229910006069 SO3H Inorganic materials 0.000 description 5
- 230000001154 acute effect Effects 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 229940125782 compound 2 Drugs 0.000 description 5
- 238000007796 conventional method Methods 0.000 description 5
- 125000004122 cyclic group Chemical group 0.000 description 5
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 231100000869 headache Toxicity 0.000 description 5
- 230000004048 modification Effects 0.000 description 5
- 238000012986 modification Methods 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 201000009032 substance abuse Diseases 0.000 description 5
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 5
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 5
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- 208000020401 Depressive disease Diseases 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 206010028813 Nausea Diseases 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 4
- 125000004423 acyloxy group Chemical group 0.000 description 4
- 239000000443 aerosol Substances 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 125000001246 bromo group Chemical group Br* 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- 229940125878 compound 36 Drugs 0.000 description 4
- 235000019788 craving Nutrition 0.000 description 4
- 125000000000 cycloalkoxy group Chemical group 0.000 description 4
- 206010013663 drug dependence Diseases 0.000 description 4
- 230000002996 emotional effect Effects 0.000 description 4
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 4
- 125000001183 hydrocarbyl group Chemical group 0.000 description 4
- 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 4
- 238000001727 in vivo Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 150000002772 monosaccharides Chemical class 0.000 description 4
- 230000008693 nausea Effects 0.000 description 4
- 229940005483 opioid analgesics Drugs 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 229960004063 propylene glycol Drugs 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 4
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 3
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 3
- 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 3
- 208000004998 Abdominal Pain Diseases 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- OJRUSAPKCPIVBY-KQYNXXCUSA-N C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N Chemical compound C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N OJRUSAPKCPIVBY-KQYNXXCUSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- 208000002881 Colic Diseases 0.000 description 3
- 229940127007 Compound 39 Drugs 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 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 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 3
- 206010022998 Irritability Diseases 0.000 description 3
- 208000000112 Myalgia Diseases 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- 208000001294 Nociceptive Pain Diseases 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- VOXIUXZAOFEFBL-UHFFFAOYSA-N Voacangin Natural products CCC1CC2CN3CC1C(C2)(OC(=O)C)c4[nH]c5ccc(OC)cc5c4C3 VOXIUXZAOFEFBL-UHFFFAOYSA-N 0.000 description 3
- 206010047700 Vomiting Diseases 0.000 description 3
- 125000004442 acylamino group Chemical group 0.000 description 3
- 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 3
- 125000006598 aminocarbonylamino group Chemical group 0.000 description 3
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 3
- DCBDOYDVQJVXOH-UHFFFAOYSA-N azane;1h-indole Chemical compound N.C1=CC=C2NC=CC2=C1 DCBDOYDVQJVXOH-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
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 3
- 210000003169 central nervous system 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
- 238000011260 co-administration Methods 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 229940125758 compound 15 Drugs 0.000 description 3
- 229940127573 compound 38 Drugs 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 230000003413 degradative effect Effects 0.000 description 3
- 229960002069 diamorphine Drugs 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 125000004468 heterocyclylthio group Chemical group 0.000 description 3
- OLOCMRXSJQJJPL-UHFFFAOYSA-N ibogaine Natural products CCC1CC2CC3C1N(C2)C=Cc4c3[nH]c5ccc(OC)cc45 OLOCMRXSJQJJPL-UHFFFAOYSA-N 0.000 description 3
- AREITJMUSRHSBK-UHFFFAOYSA-N ibogamine Natural products CCC1CC2C3CC1CN2CCc4c3[nH]c5ccccc45 AREITJMUSRHSBK-UHFFFAOYSA-N 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 102000048260 kappa Opioid Receptors Human genes 0.000 description 3
- 238000011866 long-term treatment Methods 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 3
- 229960001797 methadone Drugs 0.000 description 3
- 208000013465 muscle pain Diseases 0.000 description 3
- 238000006386 neutralization reaction Methods 0.000 description 3
- 229960002715 nicotine Drugs 0.000 description 3
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 3
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 229940124531 pharmaceutical excipient Drugs 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000002035 prolonged effect Effects 0.000 description 3
- 231100000736 substance abuse Toxicity 0.000 description 3
- 125000005338 substituted cycloalkoxy group Chemical group 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 125000003441 thioacyl group Chemical group 0.000 description 3
- 229920002554 vinyl polymer Polymers 0.000 description 3
- 230000008673 vomiting Effects 0.000 description 3
- 108020001588 κ-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
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 2
- IOQORVDNYPOZPL-VQTJNVASSA-N (5S,6R)-5-(4-chlorophenyl)-6-cyclopropyl-3-[6-methoxy-5-(4-methylimidazol-1-yl)pyridin-2-yl]-5,6-dihydro-2H-1,2,4-oxadiazine Chemical compound ClC1=CC=C(C=C1)[C@@H]1NC(=NO[C@@H]1C1CC1)C1=NC(=C(C=C1)N1C=NC(=C1)C)OC IOQORVDNYPOZPL-VQTJNVASSA-N 0.000 description 2
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 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 2
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 2
- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 206010008479 Chest Pain Diseases 0.000 description 2
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 2
- HEBKCHPVOIAQTA-QWWZWVQMSA-N D-arabinitol Chemical compound OC[C@@H](O)C(O)[C@H](O)CO HEBKCHPVOIAQTA-QWWZWVQMSA-N 0.000 description 2
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 2
- 206010013654 Drug abuse Diseases 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- 206010026749 Mania Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 150000001204 N-oxides Chemical class 0.000 description 2
- 244000061176 Nicotiana tabacum Species 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- 102000035195 Peptidases Human genes 0.000 description 2
- 208000004983 Phantom Limb Diseases 0.000 description 2
- 206010056238 Phantom pain Diseases 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
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-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
- 229920002472 Starch Polymers 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 241001061127 Thione Species 0.000 description 2
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 2
- ABRVLXLNVJHDRQ-UHFFFAOYSA-N [2-pyridin-3-yl-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound FC(C1=CC(=CC(=N1)C=1C=NC=CC=1)CN)(F)F ABRVLXLNVJHDRQ-UHFFFAOYSA-N 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 150000007513 acids Chemical class 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
- 239000004480 active ingredient Substances 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- UCTWMZQNUQWSLP-UHFFFAOYSA-N adrenaline Chemical compound CNCC(O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 125000004682 aminothiocarbonyl group Chemical group NC(=S)* 0.000 description 2
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 2
- 230000003542 behavioural effect Effects 0.000 description 2
- 150000001557 benzodiazepines Chemical class 0.000 description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 2
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 229910052796 boron Inorganic materials 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 239000007975 buffered saline Substances 0.000 description 2
- 239000003557 cannabinoid Substances 0.000 description 2
- 229930003827 cannabinoid Natural products 0.000 description 2
- 229940065144 cannabinoids Drugs 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 150000001722 carbon compounds Chemical class 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 229940126142 compound 16 Drugs 0.000 description 2
- 229940126540 compound 41 Drugs 0.000 description 2
- 230000000994 depressogenic effect Effects 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 229940088679 drug related substance Drugs 0.000 description 2
- 208000024732 dysthymic disease Diseases 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 238000007429 general method Methods 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 150000002334 glycols Chemical class 0.000 description 2
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 description 2
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000007972 injectable composition Substances 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- 238000001990 intravenous administration 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
- 238000012423 maintenance Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 2
- 102000051367 mu Opioid Receptors Human genes 0.000 description 2
- UZHSEJADLWPNLE-GRGSLBFTSA-N naloxone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C UZHSEJADLWPNLE-GRGSLBFTSA-N 0.000 description 2
- 229960004127 naloxone Drugs 0.000 description 2
- DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 description 2
- 229960003086 naltrexone Drugs 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 239000006199 nebulizer Substances 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
- BFLJLOKFWZLUTR-STGWVFMRSA-N noribogaine hydrochloride Chemical compound Cl.C([C@@H](C1)C[C@H]2CC)C3C2N1CCC1=C3NC2=CC=C(O)C=C12 BFLJLOKFWZLUTR-STGWVFMRSA-N 0.000 description 2
- 239000000014 opioid analgesic Substances 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000006053 organic reaction Methods 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 230000002085 persistent effect Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 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
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 210000002345 respiratory system Anatomy 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 230000001568 sexual effect Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 210000000278 spinal cord Anatomy 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 230000000153 supplemental effect Effects 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 230000001839 systemic circulation Effects 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 229930192474 thiophene Natural products 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 238000000844 transformation Methods 0.000 description 2
- 150000003626 triacylglycerols Chemical class 0.000 description 2
- APJYDQYYACXCRM-UHFFFAOYSA-N tryptamine Chemical compound C1=CC=C2C(CCN)=CNC2=C1 APJYDQYYACXCRM-UHFFFAOYSA-N 0.000 description 2
- 235000013311 vegetables Nutrition 0.000 description 2
- 108020001612 μ-opioid receptors Proteins 0.000 description 2
- 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
- 239000001124 (E)-prop-1-ene-1,2,3-tricarboxylic acid Substances 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
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 1
- 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 1
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 description 1
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Substances C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 1
- VEPOHXYIFQMVHW-XOZOLZJESA-N 2,3-dihydroxybutanedioic acid (2S,3S)-3,4-dimethyl-2-phenylmorpholine Chemical compound OC(C(O)C(O)=O)C(O)=O.C[C@H]1[C@@H](OCCN1C)c1ccccc1 VEPOHXYIFQMVHW-XOZOLZJESA-N 0.000 description 1
- 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 1
- 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 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- GDRVFDDBLLKWRI-UHFFFAOYSA-N 4H-quinolizine Chemical compound C1=CC=CN2CC=CC=C21 GDRVFDDBLLKWRI-UHFFFAOYSA-N 0.000 description 1
- FHCSBLWRGCOVPT-UHFFFAOYSA-N AZD2858 Chemical compound C1CN(C)CCN1S(=O)(=O)C1=CC=C(C=2N=C(C(N)=NC=2)C(=O)NC=2C=NC=CC=2)C=C1 FHCSBLWRGCOVPT-UHFFFAOYSA-N 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- 206010050012 Bradyphrenia Diseases 0.000 description 1
- 235000002568 Capsicum frutescens Nutrition 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 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 1
- 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 1
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 description 1
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 1
- 206010011971 Decreased interest Diseases 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
- 206010012735 Diarrhoea Diseases 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical group O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 206010013496 Disturbance in attention Diseases 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- 206010016275 Fear Diseases 0.000 description 1
- 206010016754 Flashback Diseases 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- 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 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 1
- 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 1
- PNNNRSAQSRJVSB-UHFFFAOYSA-N L-rhamnose Natural products CC(O)C(O)C(O)C(O)C=O PNNNRSAQSRJVSB-UHFFFAOYSA-N 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- 108090001060 Lipase Proteins 0.000 description 1
- 102000004882 Lipase Human genes 0.000 description 1
- 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 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001024304 Mino Species 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- UIQMVEYFGZJHCZ-SSTWWWIQSA-N Nalorphine Chemical compound C([C@@H](N(CC1)CC=C)[C@@H]2C=C[C@@H]3O)C4=CC=C(O)C5=C4[C@@]21[C@H]3O5 UIQMVEYFGZJHCZ-SSTWWWIQSA-N 0.000 description 1
- 206010057852 Nicotine dependence Diseases 0.000 description 1
- 206010029412 Nightmare Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 description 1
- 206010057342 Onychophagia Diseases 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 206010034912 Phobia Diseases 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 206010037180 Psychiatric symptoms Diseases 0.000 description 1
- 206010071368 Psychological trauma Diseases 0.000 description 1
- 208000001431 Psychomotor Agitation Diseases 0.000 description 1
- 206010037211 Psychomotor hyperactivity Diseases 0.000 description 1
- 206010037213 Psychomotor retardation Diseases 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 1
- 206010041243 Social avoidant behaviour Diseases 0.000 description 1
- 206010042209 Stress Diseases 0.000 description 1
- 208000013200 Stress disease Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose 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)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 206010042458 Suicidal ideation Diseases 0.000 description 1
- 206010042464 Suicide attempt Diseases 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
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 208000025569 Tobacco Use disease Diseases 0.000 description 1
- 208000031674 Traumatic Acute Stress disease Diseases 0.000 description 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
- ZEEBGORNQSEQBE-UHFFFAOYSA-N [2-(3-phenylphenoxy)-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound C1(=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)C1=CC=CC=C1 ZEEBGORNQSEQBE-UHFFFAOYSA-N 0.000 description 1
- SAHIZENKTPRYSN-UHFFFAOYSA-N [2-[3-(phenoxymethyl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound O(C1=CC=CC=C1)CC=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 SAHIZENKTPRYSN-UHFFFAOYSA-N 0.000 description 1
- VVGPECAOVDZTLZ-UHFFFAOYSA-N [N]NC(N)=N Chemical group [N]NC(N)=N VVGPECAOVDZTLZ-UHFFFAOYSA-N 0.000 description 1
- QKNDAUTYSODFJV-UHFFFAOYSA-N [dimethyl-(trimethylsilylamino)silyl]methane;sodium Chemical compound [Na].C[Si](C)(C)N[Si](C)(C)C QKNDAUTYSODFJV-UHFFFAOYSA-N 0.000 description 1
- GPWHDDKQSYOYBF-UHFFFAOYSA-N ac1l2u0q Chemical compound Br[Br-]Br GPWHDDKQSYOYBF-UHFFFAOYSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 229940091181 aconitic acid Drugs 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 208000026345 acute stress disease Diseases 0.000 description 1
- 230000006389 acute stress response Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 201000007930 alcohol dependence Diseases 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 1
- 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 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
- 150000001412 amines Chemical class 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- PYMYPHUHKUWMLA-WDCZJNDASA-N arabinose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-WDCZJNDASA-N 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 150000001556 benzimidazoles Chemical class 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004155 blood-retinal barrier Anatomy 0.000 description 1
- 230000004378 blood-retinal barrier Effects 0.000 description 1
- 210000004781 brain capillary Anatomy 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 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
- 230000004858 capillary barrier Effects 0.000 description 1
- 239000007963 capsule composition Substances 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 210000004027 cell Anatomy 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
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000010568 chiral column chromatography Methods 0.000 description 1
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-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
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 229940125877 compound 31 Drugs 0.000 description 1
- 230000010485 coping Effects 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 125000004465 cycloalkenyloxy group Chemical group 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 229960002887 deanol Drugs 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical group [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000012972 dimethylethanolamine Substances 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 230000009429 distress Effects 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000001544 dysphoric effect Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000013213 extrapolation Methods 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- 125000004438 haloalkoxy group Chemical group 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 208000022119 inability to concentrate Diseases 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- LPAGFVYQRIESJQ-UHFFFAOYSA-N indoline Chemical compound C1=CC=C2NCCC2=C1 LPAGFVYQRIESJQ-UHFFFAOYSA-N 0.000 description 1
- HOBCFUWDNJPFHB-UHFFFAOYSA-N indolizine Chemical compound C1=CC=CN2C=CC=C21 HOBCFUWDNJPFHB-UHFFFAOYSA-N 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000003434 inspiratory effect 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
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000010410 layer Substances 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
- 239000006193 liquid solution Substances 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 230000007774 longterm Effects 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
- 239000011159 matrix material Substances 0.000 description 1
- 230000015654 memory Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229940087646 methanolamine Drugs 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000003595 mist Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 230000036651 mood Effects 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 230000003387 muscular Effects 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
- 229960000938 nalorphine Drugs 0.000 description 1
- 239000004081 narcotic agent Substances 0.000 description 1
- 239000003887 narcotic antagonist Substances 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
- 238000006396 nitration reaction Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000003401 opiate antagonist Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 230000008058 pain sensation Effects 0.000 description 1
- 208000019906 panic disease Diseases 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
- 239000000312 peanut oil Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 230000007903 penetration ability Effects 0.000 description 1
- 230000003836 peripheral circulation Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229950000688 phenothiazine Drugs 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- KTNLYTNKBOKXRW-UHFFFAOYSA-N phenyliodanium Chemical compound [IH+]C1=CC=CC=C1 KTNLYTNKBOKXRW-UHFFFAOYSA-N 0.000 description 1
- 208000019899 phobic disease Diseases 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- CPNGPNLZQNNVQM-UHFFFAOYSA-N pteridine Chemical compound N1=CN=CC2=NC=CN=C21 CPNGPNLZQNNVQM-UHFFFAOYSA-N 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 230000003016 quadriplegic effect Effects 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 239000002265 redox agent Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 230000003938 response to stress Effects 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 210000001525 retina Anatomy 0.000 description 1
- HEBKCHPVOIAQTA-ZXFHETKHSA-N ribitol Chemical compound OC[C@H](O)[C@H](O)[C@H](O)CO HEBKCHPVOIAQTA-ZXFHETKHSA-N 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 125000005920 sec-butoxy group Chemical group 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
- 229940125723 sedative agent Drugs 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 230000000392 somatic effect Effects 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 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
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 210000001578 tight junction Anatomy 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- 235000013619 trace mineral Nutrition 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
- 230000007704 transition Effects 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 150000004043 trisaccharides Chemical class 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000009278 visceral effect Effects 0.000 description 1
- 208000009935 visceral pain Diseases 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/18—Bridged systems
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- 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
- A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
Definitions
- This invention relates generally to prodrugs of noribogaine or noribogaine derivatives.
- This invention also relates to pharmaceutical compositions comprising the prodrugs of noribogaine or noribogaine derivatives as well as methods of treating pain, addiction and or stress using such compounds and/or pharmaceutical compositions.
- Noribogaine is a metabolite of ibogaine and is sometimes referred to as 12- hydroxyibogamine.
- 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 no w been thoroughly evaluated and is found to combine the features of tryptamine, tetrahydrohavairie and indoiazepines.
- Noribogaine can be depicted the following formula:
- 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).
- Noribogaine is typically administered orally or intravenously and becomes systemically available to the treated patient. While noribogaine allostericaily binds tightly to the ⁇ and ⁇ 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.
- the invention relates, in part, to a class of noribogaine prodrugs which, after administration, release noribogaine in vivo.
- the prodrug moiety is selected to be readily cleavable either by a cleavable linking ami or by cleavage of the prodrug entity that binds to noribogaine such that noribogaine is generated in vivo.
- the prodrug moiety Is selected to facilitate binding to the ⁇ and or ⁇ receptors in the brain either by facilitating passage across the blood brain barrier or by targeting brain receptors other than the ⁇ and/or receptors.
- This invention also relates, in part, to a class of prodrugs of noribogaine derivatives.
- this invention is directed to compounds which are represented by Formula I or II below:
- L is selected from the group consisting of a covending bond and a cleavable linker group
- R is selected from the group consisting of hydrogen, a hydrolysabie group selected from the group consisting of ⁇ C(0)R 2 , -C(0)NR 3 R 4 and -C(0)OR 5 , where R 2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyi, substituted alkenyi, alkynyl and substituted alkynyl,
- R 3 and R 4 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyi. substituted alkenyi, alkynyl, substituted alkynyl, aryl. substituted ary!, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic,
- R 3 is selected from the group consisting of alkyl, substituted alkyl, alkenyi, substituted alkenyi, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic provided that R is not a saccharide or an oligosaccharide: ' is selected from the group consisting of hydrogen, aiky!, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkyuyl, aryl, substituted aryl, eycloalkyl, substituted cycioalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic provided that R 1 is not a saccharide or an oligosaccharide;
- R l ' is hydrogen or -OR
- R n is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, (CH 2 ) m OC(0)aikyL (CH 2 ) m OH, (CH 2 )n,Oalkyl, CH2-X-CH 3 or
- R 1 is hydrogen, then either R is selected from the group consisting of ⁇ C(0)NR 3 R and -C(0)OR 5 or R a is not alky!;
- R H is selected from the group consisting of hydrogen, C1-C3 alkyl, substituted C1 -C3 alkyl, C1-C3 alkoxy and substituted alkoxy,
- R' 1 is H.
- R 1 1 is C 1 -C3 alkyl, such as ethyl, In one embodiment.
- R is C3 ⁇ 4C3 ⁇ 4OH, in one embodiment,
- R ! 1 is CH 2 CH 2 OCH 3 .
- R 1 1 is CH2CH2OCH2PI1.
- Ph represents a phenyl group.
- R u is CH 2 CH 2 OC(0)aIkyL such as CH 2 CH 2 OC(0)(CH2)ioCH3.
- R u is CH 2 CH 2 0(CH 2 ) p O(CH2) «0(CH 2 ) r CH 3 .
- R 11 is C 1 -C3 alkyl optionally substituted with YH, YR 12 , YC(0)R 12 , C(0)YR i2 s C(0)NH 2 , C(0) HR 12 , C(0)NR 12 R 13 , N3 ⁇ 4.
- R ! 5 is C1-C3 alkoxy optionally substituted with. YH, YR ! ? .
- R is hydrogen and L is a cleavable group.
- R is hydrogen
- L is a -C(G)-, -C(0)0 ⁇ , or -C(0)NH-
- R ! is substituted alkyl.
- R ! is alkyl substituted with -NR 6 R 7 where R 6 and R' are independently selected from the group consisting of hydrogen, alkyl, alkenyl substituted aikenyl, aikynyl, substituted aikynyl, aryl, substituted aryl, cycloalkyl, substituted cycloaikyl, heteroaryJ, substituted heleroaryl, heterocyclic, and substituted heterocyclic.
- R is selected from the group consisting of - € G)NR " 'R 4 and -CiC ⁇ OR 5 and R 1 is hydrogen,
- a compound of Formula II which is selected from those as set ibrth in Table I below or a pharmaceutically acceptable salt and/or solvate thereof:
- the compound of Formula I is a compound wherein R i0 is H, L and R ! are as defined in Table 1 above, and R' ' is C1-C3 alkyl optionally substituted with YH, YR' ⁇ YC(0)R 12 , C(0)YR !2 , C(0)N3 ⁇ 4, C(0)NHR ,2 9 C(0)NR L2 R 13 , NH 2 , NHPJ 2 , NR I2 R 13 , NHC(Q)R !2 , or NR L 2 C(0)R 13 , where Y is O or S, R 12 and R 13 are independently C,-C 3 alkyl, or a pliarmaceuticaiiy acceptable salt and/or solvate thereof.
- the compound of Formula I is a compound wherein R I 0 is -OR, R, L and R 1 are as defined in Table ⁇ above, and R 1 1 is Cj-C 3 alkyl optionally substituted with YH, YR 12 , YC(0)R !2 , C(0)YR I 2 , C(0)NH 2 , C(0)NHR 12 , C(0)NR ,2 R 13 , H 2 , NHR 12 ,
- NR ,2 R 13 NHC(0)R n or NR ! 2 C(0)R ! 3 5
- Y is O or S
- R ! 2 and R 13 are independently C C 3 alkyl, or a pharmaceutically acceptable salt and/or solvate thereof.
- this invention is directed to a pharmaceutical composition comprising a pharmaceutically acceptable excipieni and a therapeutically effective amount of a compound of Formula I or ⁇ or Table I above.
- this invention is directed to a method for treating addiction in a patient which method comprises administering to the patient a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of Formula I or II or Table I above.
- this invention is directed to a method for treating pain, addition and/or stress in a patient which method comprises administering to the patient a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of Formula I or II or Table ⁇ above.
- 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.
- the invention is directed to compositions comprising the prodrugs described herein and an excipierit to facilitate transport across the blood brain barrier.
- Alkyl refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and preferably 1 to 6 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), w-propyl (CH 3 CH 2 CH 2 -), isopropyl ((CH 3 ) 2 CH-), n-butyl (CH 3 CH 2 CH 2 CH 2 -), isobutyl ((CH 3 ) 2 CHCH ), .sec-butyl ((CH 3 )(CH 3 CH 2 )CH-), /-butyl ((CH 3 ) 3 C-), n-pentyl
- Alkynyl refers to straight or branched monovalent hydrocarbyl groups having from 2 to 6 carbon atoms and preferably 2 to 3 carbon atoms and having at least 1 and preferably from 1 to 2 sites of acetylenic (-OC-) unsaturation.
- Substituted alkyl refers to an alkyl group having from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl,
- Substituted alkenyl refers to alkenyl groups having from 1 to 3 substituents, and preferably i to 2 substituents, selected from the group consisting of aikoxy, substituted aikoxy, acyl. aeylamino, acyioxy, amino, substituted amino, aminocarbonyl,
- heterocyciyloxy heterocvclylthio, substituted heterocyciylthio, nitro, SO 3 H, substituted sulfonyl, sulfonyloxy, thioacyi, thiol, alkylthio, and substituted aikylthio, wherein said substituents are defined herein and with the proviso that any hydroxy or thiol substitution is not attached to a vinyl (unsaturated) carbon atom.
- Substituted alkynyl refers to alkynyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of aikoxy, substituted aikoxy, acyl, aeylamino, acyioxy, amino, substituted amino, aminocarbonyl,
- arninothiocarbonyl aminocarboriylamino, aminothiocarbonylamino, aminocarbonyioxy, aminosul fonyl, aminosuifonyloxy, aminosulfbnylamino, arnidino, aryi, substituted ar l.
- aryloxy substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyi ester, (carboxyl ester)amtno, (carboxyi ester)oxy, cyano, cycioalkyl, substituted cycioalkyl, cycloaikyloxy, substituted cycloaikyloxy, cycloalkylthio, substituted cycloalkylthio, cycloaikenvl, substituted cycloaikenvl, cvcloaikenyloxy, substituted cvcloaikenyloxy, cycioaikenylthio, substituted cycioaikenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryi, substituted heteroaryi.
- heteroaryloxy substituted heteroaryloxy, heteroarylthio, substituted heieroarytthio, heterocyclic, substituted heterocyclic, heteroeyclyloxy, substituted heteroeyclyloxy, heterocyclyithio, substituted heterocyelylthio, nitro, SO 3 H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkyithio, arid substituted alkylthio, wherein said substituents are defined herein and with the proviso that any hydroxy or thiol substitution is not attached to an acetylenic carbon atom.
- '"Aikoxy refers to the group -O-a!kyl wherein alkyS is defined herein, Aikoxy includes, by way of example, methoxy, ethoxy, H-propoxy, isopropoxy, «-butoxy, -butoxy, sec-butoxy, and w-pentoxy,
- Substituted aikoxy refers to the group -0-(substituted afkyl) wherein substituted aikyi is defined herein.
- Acyl refers to the groups H-C(O)-, alkyl-C(0 , substituted aikyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(0)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyi ⁇ C(0)-, substituted cycloalkyl-C(O)-, eyeloalkenyi-C(O)-, substituted cyeloalkenyl-C(O)-, aryl-C(O)-, substituted ary!-C(O)-, heteroary!-C(O)-, substituted heteroaryl-C(0)-, heterocyctic-C(O)-, and substituted heteroeyciic-C(O)-.
- aikyi, substituted alkyl, aikenyl, substituted aikenyl, alkynyi, substituted alkynyl, cycloalkyi. substituted cycloalkyi, cycloalkenyl, substituted cycloalkenyl, aryi, substituted aryi, heteroaryi, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein, Acyl includes the "acetyl" group CHjCtQ)-.
- Acylamino refers to the groups -NR 17 C(0)alkyl, -NR 17 C(0)substituted alkyl, -NR l7 C(0)cycloalkyl, -NR i7 C(0)substiiuted cycloalkyi, -NR l7 C(0)cycloalkenyi s
- R 17 is hydrogen or aikyi and wherein alkyl, substituted a!kyi, aikenyl, substituted aikenyl, alkynyl, substituted alkynyi, cycloalkyi, substituted cycloalkyi, cycloalkenyl, substituted cycloalkenyl, aryi, substituted aryi, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein,
- Acyloxy refers to the groups a!kyl-C(0)0 ⁇ , substituted a!kyl ⁇ €( €))0-, alkenyl-C(0)0-, substituted a!kcnyj-UOKK aikynyi-C(0)0 ⁇ , substituted alkynyi - €(0)0 ⁇ , aryl-C(0)0-, substituted aryl-C(0)0- s cycloalkyl-C(O)C ) -, substituted eycioaikyhC(0)0-, cycloalkenyI-C(0)0-, substituted cycloalkenyl-C(0)0-, heteroaryi ⁇ C(O)0 ⁇ , substituted heteroaryl-C(0)0-, heterocycHc-C(0)0-, and substituted heterocyciic-C(0)0- wherein alky!, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyi, cycl
- Amino refers to the group -NH 2 .
- Substituted amino refers to the group -NR'*R 19 where R' 8 and R i 9 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyi, substituted cycloalkyi, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -S0 2 -alky], ⁇ S0 2 -subsiituied alkyl, -SCb-alkenyl, -SG 2 -substituted alkenyl, -S02-cycloalkyl, -S0 2 -substituted cylcoaikyl, -SOycycloalkenyl, -S0 2 -substituted c
- R !S and R ,v are optionally joined, together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, provided that R 1 * and R !S are both not hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyi, substituted alkynyl, cycloalkyi, substituted cycloalkyi, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
- R' 8 is hydrogen and R' 9 is alkyl
- the substituted amino group is sometimes referred to herein as alkyl amino.
- R S and R 19 are alkyl, the substituted amino group is sometimes referred to herein as dialkylaniino.
- a monosubstituted amino it is meant that either R 1$ or R h ⁇ is hydrogen but not both.
- R 1 S nor R 19 it is meant that neither R 1 S nor R 19 are hydrogen.
- Aminocarbonyl refers to the group -C(O)NR 20 R z l where R i0 and R 2 ' are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyi, substituted alkynyl, aryl, substituted aryl, cycloalkyi, substituted cycloalkyi, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 20 and R 21 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substi tuted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyi, substituted cycloalkyi, cycloalkenyl, substituted cyclo
- Aminothiocarbonyl refers to the group -C(S)NR 20 R 2 (where i ° and R 21 are independently selected from the group consisting of hydrogen, alkyi, substituted alkyl.
- alkenyl substituted alkenyl , alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloaikenyl, substituted cycloaikenyl, heteroaryl.
- substituted heteroaryl, heterocyclic, and substituted heterocyclic where R 0 and R 2 i are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloaikenyl, substituted cycloaikenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
- Aminocarbonylamino refers to the group -NR ! 'C(O)NR 20 R 21 where R' 7 is hydrogen or alkyi and R 20 and R *1 are independently selected from the group consisting of hydrogen, alkyi, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloaikenyl, substituted
- cycloaikenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic where R 2 and R 2 ' are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloaikenyl, substituted cycloaikenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
- AiiJtnothiocarbonylamino refers to the group -NR 1 'C(S)NR 20 R 2! where R 17 is hydrogen or alkyi and R 20 and R 2! are independenily selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloaikenyl, substituted
- cycloaikenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic where R 20 and R 2 ' are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloaikenyl, substituted cycloaikenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
- Arninocarbonyloxy refers to the group -O-C(Q)NR 2 R 2i where R 20 and 2i axe independently selected from the group consisting of hydrogen, alkyl, substituted alky!, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl.
- cycloalkyl substituted cycloalkyl, cycloaikenyl, substituted cyc!oaikenyl, heteroaryi, substituted heteroaryi, heterocyclic, and substituted heterocyclic and where R 20 and R ai are optionally- joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl substituted alkenyl, alkynyl, substituted alkynyl cycloalkyl, substituted cycloalkyl, cycloaikenyl, substituted cycloaikenyl, aryi, substituted aryl, heteroaryi, substituted heteroaryi, heterocyclic, and substituted heterocyclic are as defined herein.
- Aminosulfonyl refers to the group -SO 2 NR 20 R 25 where R 20 and R 2i are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloaikenyl, substituted cycloaikenyl, heteroaryi, substituted heteroaryi, heterocyclic, and substituted heterocyclic and where R 20 and R 2 ' are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloaikenyl, substituted cyclo
- Aminosulfonyloxy refers to the group -OSG 2 NR 2(3 R 21 where R 20 and R 2 i are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted aikynyl, aryl substituted aryl, cycloalkyl, substituted cycloalkyl, cycloaikenyl, substituted cycloaikenyl, heteroaryi, substituted heteroaryi, heterocyclic, and substituted heterocyclic and where R 20 and R 2i are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloaikenyl, substituted
- Aminosulfonylamino refers to the group - R 1 '-3C3 ⁇ 4NR 20 R i where R 17 is hydrogen or alkyl and R 20 and R 21 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aikynyl, substituted alkynyl, aryl, substituted aryl, cycloaikyi, substituted cycloaikyi cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R i0 and R S are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloaikyi, substituted cyclo
- Aryl refers to a monovalent aromatic carbocyciie group of from 6 to 1 carbon atoms having a single ring ⁇ e.g. , phenyl) or multiple condensed rings ⁇ e.g., naphthyl or ant ryl) which condensed rings may or may not be aromatic (e.g., 2-benzoxazolmone, 2H-1 ,4-henzoxazin-3(4H)-one-7-yl, and the like) provided that the point of attachment is at an aromatic carbon atom, Preferred aryl groups include phenyl and naphthyl.
- Substituted aryl refers to aryl groups which are substituted with I to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkyl, substituted alky!, alkenyl, substituted alkenyl.
- alkynyl substituted alkynyl, alkoxy, substituted alkoxy, acyi, acyiamino, acyloxy, amino, substituted amino, amlnocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylantino, aminocarbonyloxy, amtnosu!fonyl, aminosulfonyloxy, arninosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, aryithio, substituted arylihio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloaikyi, substituted cycloaikyi, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substitute
- Aryloxy refers to the group -O-aryl, where aryl is as defined herein, that includes, by way of example, phenoxy and naphthoxy.
- Substituted aryioxy refers to the group -Q-(substituted ary!) where substituted aryl is as defined herein.
- Arylthio refers to the group -S-aryi, where aryi is as defined herein.
- Substituted arylthio refers to the group -S-(substituted aryi), where substituted aryi is as defined herein.
- Carboxy or “carboxyl” refers to -COOH or salts thereof.
- Carboxyl ester or “carboxy ester” refers to the groups -C(0)0-alkyl
- alkyl or hydrogen is alkyl or hydrogen, and wherein alkyl, substituted aikyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cyeioalkyl, substituted cycloalkyl, cycloaikenyl, substituted cycloaikenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
- (Carboxyl ester)oxy refers to the group -0-C(0)0-aIkyl, substituted
- cycloaikenyl -0-C(0)0-heteroaryl, -0-C(0)0-substituted heteroaryl, -0-C(0)0-heterocyclic ( and -0-C(0)0-substituted heterocyclic wherein alkyi, substituted alkyi alkenyl, substituted alkenyl. alkynyl, substituted alkynyl, cycloalkyl substituted cycloalkyl, cycloaikenyl, substituted cycloaikenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
- Cyano refers to the group -CN.
- Cycloalkyl refers to cyclic alkyi groups of from 3 to 10 carbon atoms having single or multiple cyclic rings including fused, bridged, and spiro ring systems. One or more of the rings can be aryl, heteroaryl, or heterocyclic provided that the point of attachment is through the non-aromatic, non-heterocyclic ring carbocyclic ring.
- suitable cycloalkyl groups include, for instance, adaciantyi, cyclopropyl, cyelohutyL cyelopentyl, and cyclooctyl.
- Other examples of cycloalkyl groups include bicyele[2,2,2,]oetanyl, norbornyl, and spirobicyclo groups such as spiro[4.5]dec-8-yl:
- Substituted cycloalkyl and “substituted cycloaikenyl” refers to a cycloalkyl or cycloaikenyl group having from 1 to 5 or preferably 1 to 3 substituents selected from the group consisting ofoso, thione, alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy.
- cycloalkylthio cyeloalkenyi, substituted cyeloalkenyi cycloaikenyioxy, substituted cycloaikenyioxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryi, substituted heteroarvl. heteroaryioxy, substituted heteroaryloxy, heteroarylthio.
- substituted heteroarylthio heterocyclic, substituted heterocyclic, heterocyclyioxy, substituted heterocyelyioxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol alky!thio, and substituted alkylthio, wherein said substituents are defined herein.
- Substituted cycloalkyloxy refers to -0 ⁇ (substituted cycloalkyl).
- Cycloalkylthio refers to -S-cycioalky!.
- Substituted cycloalkylthio refers to -S-(substituted cycloalkyi).
- Substituted cycloaikenyioxy refers to -0-(substituted cyeloalkenyi).
- Cycloalkenylthio refers to -S-cycloalkenyl.
- Substituted cycloalkenylthio refers to -S-(subsiituted cyeloalkenyi ⁇ .
- Substituted guanidino refers to -NR 2i C(" R 2jl )N(R- J ) 2 where each R 2i is independently selected from the group consisting of hydrogen, alkyl substituted aiky!, aryl, substituted aryl heteroaryi, substituted heteroaryi, heterocyclic, and substituted heterocyclic and two R 23 groups attached to a common guanidino nitrogen atom are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, provided that at least one R 2j is not hydrogen, and wherein said substituents are as defined herein,
- Halo or "halogen” refers to fluoro, chloro, bromo and iodo and preferabl is fluoro or chloro.
- Haloaikyl refers to alkyl groups substituted with 1 to 5, 1 to 3, or I to 2 halo groups, wherein alkyl and halo are as defined herein.
- Haloalkoxy refers to aikoxy groups substituted with 1 to 5, 1 to 3, or I to 2 halo groups, wherein aikoxy and halo are as defined herein,
- Haloalky!thio refers to alkylthio groups substituted with 1 to 5, 1 to 3, or 1 to 2 halo groups, wherein alkylthio and halo are as defined herein,
- Heieroaryl refers to an aromatic group of from 1 to 10 carbon atoms and I to 4 heteroaioms selected from the group consisting of oxygen, nitrogen and sulfur within the ring.
- Such heieroaryl groups can have a single ring (e.g. , pyridinyl or furyl) or multiple condensed rings (e.g.
- indolizinyl or benzothienyi wherein the condensed rings may or may not be aromatic and/or contain a heteroatora provided that the point of attachment is through an atom of the aromatic heieroaryl group, in one embodiment, the nitrogen and/or the sulfur ring atom(s) of the heieroaryl group are optionally oxidized to provide for the N-oxide (N ⁇ 0), suifmyl, and/or su!fonyl moieties.
- Preferred heteroaryls include pyridinyl pyrroiyl, mdolyi, thiophenyl, and furanyl.
- Substituted heieroaryl refers to heieroaryl groups that are substituted with from 1 to 5. preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of the same group of substituents defined for substituted aryi.
- Heteroaryloxy refers to -O-heteroaryl
- Substituted heteroaryloxy refers to the group -0-(substituted heteroaryi),
- Heieroarylthio refers to the group -S-heteroaryl.
- Substituted heieroarylthio refers to the group -S-(substituted heteroaryi).
- 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 heteroaioms 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, ary , or heteroaryi provided that the point of attachment is through the
- the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, suifmyl, and/or sutforryl moieties.
- OOSSj “Substituted heterocyclic” or “substituted heterocycloalkyl” or “substituted heterocyclyP refers to heterocyclyl groups that are substituted with from 1 to 5 or preferably I to 3 of the same substituems as defined for substituted cyeloalkyl
- Heteroeyclylosy refers to the group -O-heterocycyl.
- Substituted heteroeycl loxy refers to the group -G ⁇ (substituted heterocycyl).
- Heterocyelylthio refers to the group -S-heterocycyl.
- Substituted heterocyclylthio refers to the group -S-(substituted heterocycyl),
- heterocycle and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazoie, pyridine, pyrazine, pyrimidine, pyridazme, indolizine, isoindo!e, indole, dihydroindole, indazoie, purine, quinolizine, isoquinoline, quinoline, phthalaz e, naphihylpyridine, qumoxaltne, quinazoline, cinnoiine, pteridine.
- carhazole carboline, phenanthridine, acridine, p enanthroline, isoibiazole, phenazine, isoxazole, phenoxazme, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, p haiirnide, i ,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetehydrobenzoj3 ⁇ 4]thiophene, thiazole, thiazoJidine, thiophene, benzofbjthiophene, morpholinyl, thiomorpholinyl (also referred to as
- Ne refers to the group -N0 2 .
- Oxo refers to the atom (-0) or (-0 " ).
- Substituted suifonyl refers to the group -S0 2 -aikyI, -SOa-substitoted aikyl, -SOralkenyl, -SOj-substituted aikenyl, -SOj-cycloalkyl, -SOa-substituted cylcoaikyi, -SOa-eyeloalkenyl, -SC3 ⁇ 4-substiiuted cylcoalkenyl, -SOj-aryL -SOs-substituted aryS,
- heterocyclic wherein alkyl, substituted alkyl, aikenyl, substituted aikenyl, aikynyl, substituted aikynyl, cyeloalkyl, substituted cyeloalkyl, cycloalkenyl, substituted cyeloalkenyi, aryl, substituted aryl, heteroaryl substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
- Substituted sulfonyl includes groups such as methyl - SO - phenyl-S0 2 - s a d 4-methylphenyl-SQ2-.
- alkyisulfonyl refers to -SCh-alkyl.
- '3 ⁇ 4aioalkylsttlfonyl refers to -SCh-haloalkyl where haloalkyl is defined herein.
- (substituted suifonybamino) * refers to -NHisubstituted sulfonyi), and the term
- alkyl, substituted alkyl, alkenyl, substituted alkenyl, . alkynyl, substituted aikynyl, cycioalkyi, substituted cycioalkyi,, cycioaikenyl, substituted cycioaikenyl, aryl, substituted aryl, heteroaryi, substituted heteroaryi, heterocyclic, and substituted heterocyclic are as defined herein,
- Thioacyt refers to the groups H-C(S)-, alkyl-C(S)-, substituted alkyl-C(S)-, aikeny!- (S ⁇ -. substituted alkenyl-C(S)-, aikynyl-C(S)- s substituted alkynyi-C(S)-, cycIoaikyl ⁇ C(S) ⁇ ⁇ substituted cycloalkyi-C(S)-, cydoaikeny!-C(S)-, substituted
- Alkylthio refers to the group -S-aikyl wherein alkyl is as defined herein.
- Substituted alkylthio refers to the group -S-fsubstituted alkyl) wherein substituted alkyl is as defined herein.
- Steps or “stereoisomers'” refer to compounds thai differ in the ebirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers.
- noribogaine refers to the compound:
- noribogaine is prepared by demethylation of naturally occurring ibogaine:
- the term "pharmaceutically acceptable salt” refers to salts derived from organic or inorganic acids.
- examples of such acids include, without limitation, hydrochloric acid, hydrobromie 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, cmbonic acid, enanthie acid, and the like.
- solvate refers to a solid form of a compound that crystallizes with solvent molecules trapped inside and includes, but is not limited to, complexes of a compound of the invention with less than one, one or more solvent molecules. or from about 0, 1 to about 100, or about 1 to about 10, or about 0.5, 1, 2, 3 or 4 solvent molecules,
- a "pharmaceutically acceptable solvate" of a compound of the invention refers to a solvate complex that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
- solvents that cars be used to create solvates include, but are certainly not limited to, water, methanol, ethanol, isopropanol, butanol, C1 -C6 alcohols in general (and optionally substituted), tefrahydrofuran, acetone, ethylene glycol, propylene glycol, acetic acid, formic acid, water, and solvent mixtures thereof.
- Other biocompatible solvents which may aid in making a pharmaceutically acceptable solvate are well known in the art and applicable to the present invention.
- various organic and inorganic adds and bases can be added or used alone as the solvent to create a desired solvate. Such acids and bases are known in the art.
- the solvate is referred to as hydrate, such as hemihydrate (two compound molecules are complexed with one water molecule), monohydrate (one compound molecule is complexed with one water molecule) or dehydrate (one compound molecule is complexed with two water molecules).
- the term "therapeutically effective 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 exeipient 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,
- treatment means any treatment of a disease or condition in a patient, including:
- 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.
- 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.
- the "treatment of addiction in a patient” refers to reducing the withdrawal symptoms associated with drag dependency as well as alleviating drug cravings in addicts. Such symptoms include nausea, vomiting, anxiety, abdominal cramps, muscle pain, chills and headache.
- blood-brain barrier refers 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.
- the term "cleavable linking group” refers to a linking group that can be attached to noribogaine or a derivative at any possible position.
- 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 or derivative.
- the linking group is preferably sufficiently stable in the circulatory system (serum or blood), but is cleaved to release the noribogaine or derivative 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. H, 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(0)0- or -OC(O)-), an amide-based cleavable linking group (-C(0) R 9 - or -NR 9 C(0)-), or a phosphate-based cleavable linking group (-P(O)(OR 9 )-0-, -0-P(S)(OR 9 )-0-, -0-P(S)(SR)- 0-, -S-P(0)(OR 9 )-0-, -O-PCOXOR ⁇ -S-, -S-P ⁇ 0)(OR 9 )-S- s -0 ⁇ P(5)(OR 9 )-S-, -S-P(S)(GR 9 )- C.k.
- R 9 can be hydrogen or alkyi.
- saccharide or ''monosaccharide refers to a saccharide or derivative thereof, having at least 6 carbon atoms (which may be linear, branched or cyclic) with aii oxygen, nitrogen or sulfur atom bonded to each carbon atom.
- oligosaccharides includes oligosaccharides containing from about 2-9 monosaccharide units.
- Specific monosaccharides include C5 and above (preferably Cs-Cg) saccharides such as etbritol, zylitol, galactose, lactose, xylose, dulcitoi, myo-insoitol, fructose, mannitoi, sorbitol, glucose, arabmose, arabinose, celloboise, maltose, raffmose, rhamnose, nielibiose, ribose, adonitol, arabitol, arabitol, fxteose, lyxose, lyxose, glucosamine, mannosamine, and gaiactosamine; di- and trisaccharides include saccharides having two or three
- the term "patient” refers io mammals and includes humans and non-human mammals.
- this invention is directed to compounds which are represented by Formula I below:
- L is selected from the group consisting of a covalent bond and a cleavab!e linker group
- R 1 is selected from the group consisting of hydrogen, alkyl, substituted alkyi, alkenyi, substituted alkenyi, alkynyl, substituted alkynyl, ary!, substituted aryi cyeloaikyl, substituted cyeloaikyl, heteroaryi, substituted heteroaryi, heterocyclic, and substituted heterocyclic provided thai R ! is not a saccharide or an oligosaccharide;
- R i0 is hydrogen or -OR
- R 1 ' is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, (CH 2 )mOC(0)alkyl, (CH 2 ) m OH, (CH 2 ) m Oalkyl, CH 2 -X-alkyl or
- R is selected from the group consisting of hydrogen, a hydrolysaMe group selected from the group consisting of -C(0)R 2 , -C(0)NR J R 4 and -C(0)OR 5 , where R 2 is selected from the group consisting of hydrogen, alkyi, substituted alkyi, aikenyl, substituted aikenyl, alkynyl and substituted alkynyl,
- R 3 and R 4 are independently selected from the group consisting of hydrogen, alkyi, substituted alkyi, aikenyl, substituted aikenyl, alkynyl, substituted alkynyl, aryl, substituted aryh heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and
- R" is selected from the group consisting of alkyi, substituted alkyi, aikenyl, substituted aikenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic provided that R is not a saccharide or an oligosaccharide;
- R is selected from the group consisting of -C(0)NR 3 R and -C(0)OR s ;
- R 1 is not hydrogen
- R 1 1 is selected from the group consisting of hydrogen, C 1 -C3 alkyi, substituted Ci-Cs alkyi, C1 -C3 alkoxy and substituted C-. -C3 alkoxy.
- R f f is H.
- R" is C 1 -C3 alkyi, such as ethyl.
- R H is C%CH 2 OH.
- R" is CH2CH2OCH3.
- R" is ⁇ 3 ⁇ 4 ⁇ 3 ⁇ 40 € ⁇ 2 ⁇ 1 ⁇ , in one embodiment, R' 1 is CH 2 CH 2 OC(0)alky], such as CH 2 CH 2 OC(0)(CH2)ioCH3.
- R i l is CH2-X-CH3.
- R n is CH 2 CH20(C3 ⁇ 4) p O(CH 2 ) q O(CH 2 ) f CH 3 .
- R ! 1 is C 1 -C3 alkyi optionally substituted with YH, YR 12 , YC(0)R i2 , C(0)YR 12 , C(0)N13 ⁇ 4, C(C))NHR !2 , C(0)NR , 2 R , NH 2 , NHR 12 , NR 12 R U , NHC(0)R i2 , or NR 12 C(0)R 13 , where Y is 0 or S, R 12 and R 13 are independently C r C 3 alky! ,
- R 1 1 is C1-C3 alkoxy optionally substituted with YH, YR' 2 , YC(0)R 12 , C(0)YR !2 , C(0)NH 2 , C(0)NHR ! 2 s C(0)NR 12 R 13 , NH 2 , NHR 12 , NR 12 R 13 ,
- NHC(0)R 12 or R ,2 C(0)R 13 , where Y is O or S, R 12 and R 13 are independently C C 3 alkyi.
- L is a suitable biocompatible, eleavable linking group described herein. [0126] In one embodiment, L is -C(0) ⁇ . In another embodiment, L is - €(0)0-, In still another embodiment, I, is -C(0)NR-, where R is hydrogen or alkyl
- L is selected from the group consisting of -P(0)(OR 9 )-0-, -O- P(S)(OR 9 )-0-, -0-P(S)(SR 9 ).0- 5 -S-P(0) ⁇ OR 9 )-0., -0.p(0)(OR 9 )-S ⁇ 5 -S-P(0)(OR 9 )-S- ; -0-P(S)(OR 9 )-8-, ⁇ 5-P(S)(OE 9 ) ⁇ 0 ⁇ , -0-P ⁇ 0)(R*)-0- s ⁇ 0- ⁇ S K R -S-P(0)(R 9 )-0-, -S-P(S)(R 9 )-0- s -S-P ⁇ 0)(R 9 )-S- s and -0-P(S)(R 9 )-S-, where R 9 Is hydrogen or alkyl.
- R is hydrogen.
- L is a cova!ent bond or - ( .. ' (( ) ⁇ -. and R s is substituted alkyl.
- R f is alkyl substituted with -NR 6 R'' where R 6 and R ' are independently selected from the group consisting of hydrogen, alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkyny], aryl, substituted aryl, eyeioalkyl, substituted cycioaikyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic,
- R is selected from the group consisting of ⁇ C(0)NR 3 R 4 and -C(0)OR 5 and R ! is hydrogen.
- the compound of Formula I is a compound wherein R 1 is H, L and R 1 are as defined in Table II below, and R I ! is Cp3 ⁇ 4 alkyl optionally substituted with YH, YR 12 , YC(0)R 12 , C(0)YR !2 , C(0) 13 ⁇ 4, C(0)NHR 12 , C(0)NR% 13 , NH 2 , NHR 12 , NR 12 R°, NHC(0)R 12 , or NR ,2 C(0)R 13 , where Y is O or S, R 12 and R 13 are independently C,- C3 ⁇ 4 alkyl, or a pharmaceutically acceptable salt and/or solvate thereof.
- the compound of Formula ⁇ is a compound wherein R i( ' is H, L and R* are as defined in Table II below, and R 11 is selected from H, CH2CH2OH,
- the compound of Formula 1 is a compound wherein R s0 is -OR, R, L and R 1 are as defined in Table II below, and R 11 is C r (3 ⁇ 4 alkyl optionally substituted with YH, YR 12 , YC(0)R n , C(0)YR 12 , C(0)NH 2 , C(0)NHR 12 , C(0) R I2 R t3 , H3 ⁇ 4 NHR 12 , NR I2 R 13 , NHC(0)R 12 , or NR ,2 C(0)R 13 , where Y is O or 8, R 12 and R are independently C r C3 a!kyl, or a pharmaceutically acceptable salt and/or solvate thereof.
- the compound of Formula I is a compound wherein R s0 is -OR, R. L and R 1 are as defined in Table II below, and R l ! is selected from H. CH 2 CH 2 OH,
- the compound of Formula I is a compound wherein R'° is -OR, R, L and R 1 are as defined in Table II below, and R ! 1 is selected from H, CH2CH2OH,
- the compound of Formula I is a compound wherein R.” J is -OR, R, L and R 3 are as defined in Table II below, and R ! 1 is H, or a pharmaceutically acceptable salt and/or solvate thereof.
- the compound of Formula I is a compound wherein R'° is -OR, R » L and R 3 ⁇ 4 are as defined in Table II below, and R 1 ' is CH2CH2OH, or a pharmaceuticaliy acceptable salt and/or solvate thereof.
- the compound of Formula I is a compound wherein R ! 0 is -OR, R, L and R 1 are as defined in Table II below, and R' 1 is CH 2 CH 2 OCH3, or a pharmaceuticaliy acceptable salt and/or solvate thereof.
- the compound of Formula 1 is a compound wherein R 10 is -OR, R, L and R 1 are as defined in Table II below, and R" is CH2OCH3, or a pharmaceutically acceptable salt and/or solvate thereof,
- the compound of Formula I is a compound wherein R 10 is -OR, R. L and R 1 are as defined in Table 11. below, and R n is ( ⁇ i 2 0 fTX'i Ph.. or a
- the compound of Formula I is a compound wherein R i0 is -OK, R, L and R 1 are as defined in Table II below, and R ! ! is CH2CH20C(0)alk l, such as C i2 alkyi, or a pharmaceutically acceptable salt and/or solvate thereof.
- the compound of Formula I is a compound wherein R Uj is -OR, R, L and R 1 are as defined in Table ⁇ below, aid R ! ! is
- the compound of Formula ⁇ is a compound wherein R i 0 is -OR, R, L and R 1 are as defined in Tabie II below, and R 1 1 is methyl or a pharmaceutically acceptable salt and/or solvate thereof.
- the compound of Formula I is a compound wherein R'° is -OR, R, L and R 1 are as defined in Table II below, and R f 1 is C ⁇ alkyi, or a pharmaceutically acceptable salt and/or solvate thereof.
- R is selected from the group consisting of hydrogen, a hydrolysable group selected from the group consisting of -C(0)R ⁇ -C(0)NR 3 R 4 and -C(0)OR ⁇ where R 2 is selected from the group consisting of hydrogen, alkyL substituted aikyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl, R J and R 4 are independently selected from the group consisting of hydrogen, aikyl, substituted aikyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, R 5 is selected from the group consisting of aikyl, substituted alkyf, alkenyl, substituted alkenyl. alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and
- L is selected from the group consisting of a covending bond and a eleavab!e linker group
- R ! is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyi, substituted alkenyi, a!kynyh substituted alkynyi, aryl, substituted aryi, cycioalkyl, substituted cycloalkyi, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, provided that R ! is not a saccharide or an oligosaccharide;
- R is selected from the group consisting of -C(0)NR. 3 R 4 and -C(0)OR 5 ;
- R is hydrogen or -C(0)R z and L, is a covending bond, then R ! is not hydrogen,
- R is hydrogen and L is a cleavable group
- L is a suitable biocompatible, cleavable linking group.
- Suitable biocompatible, cleavable linking groups comprise a covending 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. H, redox potential or the presence of degradative molecules such as enzymes, e.g., proteases, lipases, etc.).
- the cleavage conditions or agents should be more prevalent or found at higher levels or activities in the brain than in serum or b!ood.
- 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 cleavabie linking group by acting as a general acid, peptidases (which can be substrate specific), and phosphatases.
- 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 cleavabie linking group by acting as a general acid, peptidases (which can be substrate specific), and phosphatases.
- 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.
- a cleaving agent or condition
- the linking group for the ability to resist cleavage in the serum, blood or when in contact with other non-target tissue.
- 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 cova!ent bond.
- L is -C(0) « , In another embodiment, L is - €(0)0-. In still • another embodiment, h is -C(0)NR-, where R is hydrogen or alkyL
- L is seiected from the group consisting of -P(0)(OR 9 ) ⁇ 0-, -O- P(5) ⁇ OR 9 )-Q-, -G-P(S) ⁇ 8R 9 )- ⁇ , -S-P(0) ⁇ OR 9 )-C)-, ⁇ 0-P(G)(GR 9 )-g-, ⁇ 8 ⁇ P(0)(OR 9 )-S ⁇ , .0-P(S)iC)R 9 ) ⁇ S ⁇ ; -S-P($)(OR' 0-.
- R is hydrogen
- L is a covalent bond or -C(0)- s
- R 1 is substituted alkyl.
- R 1 is alkyl substituted with -NR 6 R ; where R 6 and R' are independently selected from the group consisting of hydrogen, alkyl, alkenyl, substituted aikenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, hetefoatyl, substituted heteroaiyi, heterocyclic, and substituted heterocyclic,
- R is selected from the group consisting of -C(0)NR 3 R 4 and -C(0)OR 3 and R 1 is hydrogen.
- the compound of Formula II is a compound as set forth in Table I below or a pharmaceutically acceptable salt and or solvate thereof- Table I
- Compounds of this invention are contemplated to be useful in treating pain and/or addiction as an active ingredient or a prodrug, in some embodiments, the compounds of this invention are prodrugs whose and/or -i>R J groups are cleaved in vtvo to produce nori oga ne or a noribogaine derivative.
- the compound is at least 2, 5 or 10 times more stable in serum plasma than in the central nervous system, such as the brain, in a more preferred embodiment, the prodrugs have improved BBB penetration property as compared with noribogaine or the noribogaine derivative, for example, the compounds of this invention have at least 20 %, 50 % or 100 % more BBB penetration ability than noribogaine or the noribogaine derivative,
- the present invention is directed to a method for treating a pain in a patient which method comprises administering to said patient a compound of this invention or a pharmaceutically acceptable salt and/or solvate thereof or a
- 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.
- the use of noribogaine for treatment of pain is described, for example, in U.S. Provisional Patent Application Serial No. 61/952,738, filed on March 13, 2014 and titled "USE OF NORIBOGAINE FOR THE TREATMENT OF PAIN", which is incorporated herein by reference is its entirety.
- the present invention is directed to a method for reducing tolerance to opioid analgesics in a patient undergoing treatment for pain.
- the use of noribogaine for reducing tolerance to opioid analgesics is described, for example, in U.S. Provisional Patent Application Serial No. 61/952,74!, filed on March 13, 2014 and tided "METHODS AND COMPOSITIONS FOR REDUCING TOLERANCE TO OPIOID
- the present invention is directed to a method for treating addiction in a patient which method comprises administering to said patient a compound of this invention or a pharmaceutically acceptable salt and or solvate thereof or a composition comprising a compound of this invention and a pharmaceutically acceptable excipient.
- 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.
- treatment with a compound of this invention decreases the drug cravings normally experienced by addicts after cessation of the self-administration of the abused substance.
- the compositions disclosed herein are especially useful in the treatment of addiction to opioids such as heroin and methadone.
- the invention is also directed to a method for treating drag addiction (involving drag dependency or drug abuse) during withdrawal therapy by administering a compound of this invention to a patient at a dosage sufficient to reduce or eliminate one or more symptoms associated with withdrawal.
- Symptoms of acute withdrawal include nausea, vomiting, anxiety, abdominal cramps, muscle pain, chilis and headache.
- treatment with a compound of this invention is contemplated to decrease the drug cravings normally experienced by addicts after cessation of the self-administration of the abused substance, for example, opioids such as heroin and methadone,
- opioids such as heroin and methadone
- compounds of this invention are contemplated to be also useful in treating patients addicted to other substances, cocaine, alcohol, amphetamines, tobacco, caffeine, opioid-like drugs, cannabinoids, benzodiazepines, and any other illicit, prescription, or generally available addictive substance, as well as combinations of these drugs.
- Compounds of this invention may be administered to patients suffering from drug dependence or abuse in conjunction with an opioid antagonist such as naloxone, naltrexone or nalorphine, for example, at a concentration of between 0, 15 mg and 0.5 mg for each mg of the compound of this invention administered.
- the invention is also directed to a method for preventing relapse to drag use after drug use has been stopped (e.g., after treatment to ameliorate drag abuse), by administering a compound of this invention to a patient at a dosage sufficient to reduce or eliminate one or more symptoms associated with post-acute withdrawal, including cravings.
- the compound may be administered at a lower (e.g., "maintenance") dose compared to that used for treatment of addiction and acute withdrawal symptoms.
- the present invention is directed to a method for treating depressive disorders in a patient in need of the treatment, which method comprises administering to said patient a compound of this invention or a pharmaceutically acceptable salt and/or solvate thereof or a composition comprising a compound of this invention and a pharmaceutically acceptable excipient.
- Depressive disorders include major depressive disorder and dysthymic disorder (American Psychiatric Association, 1994a; American Psychiatric Association, 1 94b).
- Major depressive disorder is characterized by the occurrence of one or more major depressive episodes without manic or hypomanic episodes,
- a major depressive episode is defined as a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearl every day for at least 2 weeks): it can include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation.
- Dysthymic disorder involves a type of depression that is not severe enough to be called a major depressive episode, but that lasts much longer than major depressive disorder, without high phases.
- noribogaine for treatment of depression is described, for example, in U.S. Provisional Patent Application Serial No. 61/952,733, filed on March 13, 2014 and titled “METHODS AND COMPOSITIONS FOR TREATING DEPRESSION", which is incorporated herein by reference in its entirety.
- the present invention is directed to a method for treating stress, such as post-traumatic stress disorder, in a patient in need of the treatment, which method comprises administering to said patient a compound of this invention or a pharmaceutically acceptable salt and/or sol vate thereof or a composition comprising a compound of this invention and a pharmaceutically acceptable excipient.
- stress such as post-traumatic stress disorder
- Stress or anxiety refers to the consequence when a patient fails to respond appropriately to emotional or physical threats, which may be actual or imagined. Stress symptoms or conditions may be cognitive, emotional, physical or behavioral, including, but not limited to a state of alarm and adrenaline production, short-term resistance as a coping mechanism, exhaustion, irritability, muscular tension, inability to concentrate, poor judgment, a genera!
- PTSD is a severe stress disorder that can develop after exposure to an event which results in psychological trauma. Such events usually involve death of someone else, threat of death to oneself or to someone else, or trauma to the physical, sexual, or psychological integrity of one's own or someone else. PTSD may be an acute stress response or a long term stress response to such an event when it overwhelms one's ability to cope.
- Symptoms of PTSD include some or all of the following; recurrent re-experiencing of the trauma, for example, intrusive, upsetting memories of the event, flashbacks of the traumatic events (acting or feeling like the event is happening again), recurring nightmares (either of the event or of other frightening things); feelings of intense distress and/or intense physical reactions when reminded of the trauma; avoidance to the point of having a phobia of places, people, and experiences that remind the sufferer of the trauma and a general numbing of emotional responsiveness; inability to remember important aspects of the trauma; and physical signs of hyperarousal, including sleep problems, trouble concentrating, irritability, anger, poor concentration, blackouts or difficulty remembering things, increased tendency and reaction to being startled, and hypervigilanee to threat.
- Other symptoms include anbedonia, lack of interest in activities that used to be enjoyed, emotional deadness, distancing oneself from people, and/or a sense of a limited future (for example, not being able to think about the future or make future plans, not believing one will live much longer), guilt, shame, self-blame, depression and hopelessness, suicidal thoughts and feelings, feeling alienated and alone, headaches, stomach problems, chest pain and substance abuse.
- co-administration can be in any manner in which the pharmacological effects of both are manifest in the patient at the same time.
- co-administration does not require that a single pharmaceutical composition, the same dosage form, or even the same route of administration be used for administration of both the compound of this invention and the other agent or that the two agents be administered at precisely the same time.
- co-administration will be accomplished most conveniently by the same dosage form and the same route of administration, at substantially the same time. Obviously, such administration most advantageously proceeds by delivering both active ingredients simultaneously in a novel pharmaceutical composition in accordance with the present invention.
- a compound of this invention can be used as an adjunct to conventional drug withdrawal therapy, specifically providing for the administration of a compound of this invention with one or more opioid antagonists,
- this invention is also directed to pharmaceutical compositions comprising a pharmaceutically acceptable excipient and a compound of this invention or mixtures of one or more of such compounds.
- compositions suitable for oral, intravenous or intraarterial delivery will probably be used most frequently, oilier routes that may be used include peroral, pulmonary, rectal, nasal, vaginal, lingual, intramuscular, intraperitoneal, intracutaneous and subcutaneous routes.
- the composition can be administered transdermal!' 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).
- 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, for example, in a transdermal patch form. All dosage forms may be prepared using methods that are standard in the art (see e.g., Remington's Pharmaceutical Sciences, 16th ed. 5 A. Oslo editor, Easton Pa. 1 80). Intranasal administration is an effective method for delivering a therapeutic agent directly to the respiratory tract, where the therapeutic agent may be quickly absorbed,
- compositions are comprised of in general, a compound of this invention or a mixture thereof in combination with at least one pharmaceutically acceptable exeipient.
- excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of this invention.
- excipients may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous exeipient that is generally available to one of skill in the art.
- Pharmaceutical compositions in accordance with the invention are prepared by conventional means using methods known in the art.
- Solid pharmaceutical excipients include starch, cellulose, tale, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
- Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
- Preferred liquid carriers, particularly for injectable solutions include water, saline, aqueous dextrose, and glycols.
- Compressed gases may be used to disperse a compound of this invention in aerosol form.
- Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
- Other suitable pharmaceutical excipients and their formulations are described in Remington's
- compositions disclosed herein may be used in conjunction, with any of the vehicles and excipients commonly employed in pharmaceutical preparations, e.g., talc, guro arable, 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.
- vehicles and excipients commonly employed in pharmaceutical preparations, e.g., talc, guro arable, 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, poiyglycols, dimethyisulfoxi.de, fatty alcohols, triglycerides, partial esters of glycerine and the like.
- Parenteral compositions containing the compounds described herein may be prepared using conventional techniques that may include sterile isotonic saline, water, 1,3- butanediol, ethanol, 1,2 -propylene glycol, poiyglycols mixed with water, Ringer's solution, etc.
- the amount of the compound in a formulation can vary within the full range employed by those skilled in the art, Typically, the formulation will contain, on a weight percent (wt %) basis, from about 0.01 to 99.99 wt % of a compound of this invention based on the total formulation, with the balance being one or more suitable pharmaceutical excipients.
- the compound is present at a level of about 1 to 80 wt %.
- a compound of this invention should generally be present in such compositions at a concentration of between about 0.1 and 20 rng/rnl.
- naloxone or naltrexone When either naloxone or naltrexone is combined with a compound of this invention, they should be present at 0,05 to 0.5 mg for each mg of the compound of this invention.
- the choice of formulation depends on various factors such as the mode of drug administration and bioavailability of the drug substance.
- the compound can be formulated as liquid solution, suspensions, aerosol propellents or dry powder and loaded into a suitable dispenser for administration.
- suitable dispenser for administration There are several types of pharmaceutical inhalation devices-nebulizer inhalers, metered dose inhalers (MDi) and dry powder inhalers (DPI).
- MDI metered dose inhalers
- DPI dry powder inhalers
- Nebulizer devices produce a stream of high velocity air that causes the therapeutic agents (which are formulated in a liquid form) to spray as a mist that is carried into the patient's respiratory tract.
- MDI's typically are formulation packaged with a compressed gas.
- the device Upon actuation, the device discharges a measured amount of therapeutic agent by compressed gas, thus affording a reliable method of administering a set amount of agent.
- DPI dispenses therapeutic agents in the form of a free flowing powder that can be dispersed in the patient's inspiratory air-stream during breathing by the device.
- the therapeutic agent In order to achieve a free flowing powder, the therapeutic agent is formulated with an excipient such as lactose, A measured amount of the therapeutic agent is stored in a capsule form and is dispensed with each actuation,
- U.S. Patent No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparfieles (average particle size of 400 Mi) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably hig bioavailability.
- a narrow therapeutic dose of a compound of the invention is administered to a patient such that the patient's QT interval is not prolonged to unacceptable levels.
- patients are administered therapeutic doses of the compound in a clinical setting with cardiac monitoring, in some embodiments, the patient will, be pre-screened to evaluate tolerance for prolongation of QT interval, e.g., to determine whether the patient has any pre-existing cardiac conditions which would disqualify them from treatment with the compound.
- the patient's QT interval is not prolonged by more than about 50 ms, preferably, not more than about 30 ms, and more preferably, not more than about 20 ms.
- the patient's QT interval does not exceed about 500 ms, preferably, does not exceed about 450 ms, and more preferably does not exceed about 420 ms.
- the dosage of a compound of this invention that is administered to the patient is sufficient to provide an average serum concentration of about 50 Bg/mL to about 850 ng mL (area under the curve/24 hours, AUC/24 h), or any subrange or subvalue there between,
- the dose of noribogame, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof administered to the patient provides an average serum concentration of about 50 ng/mL to about 400 ng mL (AUC/24 h),
- the compound of this invention is administered in an effective amount It is contemplated that the dosage required for treating pain or addiction, or a combination thereof may differ according to the condition(s) being treated, however, the dosing regimen can be readily determined by the attending clinician based on the desired treatment, it is contemplated that generally, the aggregate dosage of a compound of this invention administered to a patient may be from about 1 to about 8 mg per kg of body weight per day (rag/kg/day), or from about 1 to about 4 mg kg day, preferably, from about 1 to about 3 mg kg day.
- the dosage range would preferably be about 70 to 210 mg per day,
- a lower dosage of a compound of this invention is administered, for example from about 50 ng to less than 10 pg per kg of body weight per day.
- a maintenance dosage of a compound of this invention is administered, for example approximately 80% or less of the
- therapeutically effective dose may be effective for prevention of relapse of drug use in an addicted patient treated to ameliorate their substance abuse.
- a patient is pre-screened with a compound of the invention to determine whether the patient is a candidate for treatment with the compound, for example whether the patient's QT interval will be prolonged to an unacceptable level by treatment with the compound.
- the patient is treated with a sub-therapeutic dosage of the compound, for example about 50% to about 90% of the therapeutically effective dosage of compound, and the patient's response to the compound is monitored.
- the patient's QT interval is monitored before and during treatment with the compound.
- the present invention is directed to a pharmaceutical composition, preferably in unit dose form, comprising a compound of this invention.
- a pharmaceutical composition preferably in unit dose form, comprising a compound of this invention.
- one or more unit doses provide an amount of a compound of this invention effective to treat a disease or condition as described above, including pain, depression, stress, and/or addiction,
- composition administered will depend on a number of factors, including but not limited to the desired final concentration of the compound, the
- the active compound is effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual, compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
- compositions are administered in one dosing of a single formulation and in other embodiments, compositions are administered in multiple dosing of a single formulation within a specified time period, in some embodiments, the time period is between about 3 hours to about 6 hours. In other embodiments, the time period is between about 6 hours and 12 hours, in additional embodiments, the time period is between about 12 hours and 24 hours. In yet further embodiments, the time period is between about 24 hours and 48 hours,
- the administration of separate formulations can be simultaneous or staged throughout a specified time period, such thai all ingredients are administered within the specified time period,
- the compounds 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 reaetants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reaetants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
- the compounds of this invention will typically contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisorner-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this invention, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.
- the starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof.
- many of the staiting 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).
- noribogaine can react with LO-R where LG is a leaving group such as hydroxy, alkoxy, halo, etc, to give compound 1-1, which may further react with LG-L-R' to form compound 1-2.
- the phenol is protected by reaction with a suitable protecting group, PG-LG, where LG is a Leaving group such as defined above, such that the indole nitrogen is derivatized with L-R 1 .
- suitable protecting groups are well known in the art (see T. W. Greene. P. G. M. Wuts, Protective
- compounds of this invention wherein L-R is not hydrogen may be prepared by reacting ibogaine with LG-L-R 5 to give compound 2-1.
- Compound 2-1 can be demethvlated by methods known in the art, such as reaction with boron tribromide/methyleiie chloride at room temperature to give compound 1-4. which may further react with LG-R to give compound J -2.
- Scheme 2
- Compound 3-2 can be de-car oxylated by methods described herein or known in the art. such as using refluxing hydrazine, or hydrolyzing the -COOCH3 group to an acid, and reacting the corresponding sodium or lithium salt with aqueous mineral acid to give compound 3-3.
- An exemplifying decarboxylation procedure for preparing an intermediate 7- 3 is illustrated in Scheme 7 below, which includes a procedure for preparing an
- Intermediate 7-3 when the starting material 7-1 is a racemic mixture or when racemization occurs during redeutton.
- Intermediate 7-3 can react with LG-L-R 1 to give compounds of ibis invention.
- Compound 4-1 is halogenated to compound 4-2.
- X is iodo
- the iodo group can be conveniently incorporated into the indole ring by reacting compound 4-1 , e.g. and without limitation, with N-iodosuce nimide (NTS).
- NTS N-iodosuce nimide
- the iodo group can be also incorporated using a phenyl iodonium intermediate by reaction with PhI(OH)OTs, followed by removal of the phenyl group through reaction with OH " .
- the iodo or the bromo group can be incorporated by nitration to form a nitro intermediate, foilowed by reducing the nitro group to an amino group, diazotizing the amino group to form a diazonium group, and reacting the diazonium compound with Cul or CuBr.
- Exemplifying halogenation procedures are illustrated in Scheme 6 below?.
- Compound 4-2 is then converted to compound 4-3 b reacting with ROH or RO " , e.g., in presence of a copper catalyst such as Cwl and a ligand, such as tetramethyi phenanthroline (see, for example.
- 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, 4* Edition, Wiley-Interscience, New York, 2006, and references cited therein.
- the stalling 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.
- Compound 1 may be prepared by reacting noribogaine with at least two equivalents of (CH3) 2 NCH ? .CH 2 C(0)C1 in the presence of a base in a suitable solvent.
- reaction is conducted in a polar solvent.
- compound 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.
- Compound 2 may prepared by reacting noribogaine with at least one equivalent of (CH 3 ) 2 NC3 ⁇ 4CH 2 CC0)C1 in the presence of a base in a suitable solvent to give an intermediate product.
- the reaction is conducted in a polar' solvent
- the intermediate product can be demethylated by reaction with boron iribromide/methyiene chloride at room temperature to give compound 2,
- compound 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.
- Compound 3 may prepared by reacting noribogaine with one equivalent of
- reaction mixture was then cooled to -78 °C, and sodium ⁇ , ⁇ -dimethylethanolamine solution (1.4 mL, 1.4 mmo!, 1 M in THF) was added.
- the reaction mixture was allowed to wans to rt and stirred for 30 min. Water (5 mL) was added, and the reaction mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were concentrated under reduced pressure, and the crude product was purified by Flash Chromatography (ethyl
- the following example illustrates how to treat an opioid addicted patient having an immediate craving for the opioid.
- a 65 kg cocaine addicted male patient presenting with an immediate craving for a cocaine "fix” is administered a bolus comprising 0.1 % weight volume of a compound of this invention in sterile buffered saline.
- the aqueous composition is administered in an i,v, format and the serum concentrations of the compound of Formula II and noribogaine which is produced by in vivo cleavage of the compound of this invention are monitored.
- a sufficient amount of the compound is administered until a therapeutic serum concentration of the compound and or noribogaine is achieved.
- the patient is then monitored until the craving is diminished or relieved.
- the following example illustrates how to treat severe pain in a patient.
- a 80 kg male patient presenting severe trauma due to several gunshots to the chest and legs is administered a bolus comprising 1 gm of a compound of Formula II in 10 niL of sterile buffered saline.
- the aqueous composition is injected into the patient to provide immediate analgesia for the pain.
- a transdermal patch is then placed on the patient's back.
- the patch contains a sufficient amount of the compound in a sustained release fonn wherein the amount of noribogaine released is sufficient to maintain serum concentration of the compound or noribogaine which is produced by in vivo cleavage of the compound of this invention in the patient for a period of 48 hours.
- a suppository of total weight 2.5 g is prepared by mixing the compound of the invention with Witepsol® H-15 ⁇ triglycerides of saturated vegetable fatty acid;
Abstract
Description
Claims
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/US2014/034826 WO2015163844A1 (en) | 2014-04-21 | 2014-04-21 | N-substituted noribogaine prodrugs |
Publications (1)
Publication Number | Publication Date |
---|---|
EP3164402A1 true EP3164402A1 (en) | 2017-05-10 |
Family
ID=54332877
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP14890017.8A Withdrawn EP3164402A1 (en) | 2014-04-21 | 2014-04-21 | N-substituted noribogaine prodrugs |
Country Status (3)
Country | Link |
---|---|
EP (1) | EP3164402A1 (en) |
CA (1) | CA2983727A1 (en) |
WO (1) | WO2015163844A1 (en) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014143201A1 (en) | 2013-03-15 | 2014-09-18 | Demerx, Inc. | Method for noribogaine treatment of addiction in patients on methadone |
US9561232B2 (en) | 2014-02-18 | 2017-02-07 | Demerx, Inc. | Low dose noribogaine for treating nicotine addiction and preventing relapse of nicotine use |
US9561233B2 (en) * | 2014-03-13 | 2017-02-07 | Demerx, Inc. | Use of ibogaine for the treatment of pain |
US9592239B2 (en) | 2014-09-12 | 2017-03-14 | Demerx, Inc. | Methods and compositions for ibogaine treatment of impulse control disorder, anxiety-related disorders, violence and/or anger, or regulating food intake |
EP4279134A1 (en) | 2014-11-26 | 2023-11-22 | DemeRx, Inc. | Methods and compostions for potentiating the action of opioid analgesics using iboga alkaloids |
WO2017184531A1 (en) * | 2016-04-18 | 2017-10-26 | Demerx, Inc. | Treatment of movement-related disorders using noribogaine |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7220737B1 (en) * | 1997-09-04 | 2007-05-22 | Novoneuron, Inc | Noribogaine in the treatment of pain and drug addiction |
US20030153552A1 (en) * | 2002-02-14 | 2003-08-14 | Mash Deborah C. | Method of treating chemical dependency in mammals and a composition therefor |
US8362007B1 (en) * | 2010-05-11 | 2013-01-29 | Demerx, Inc. | Substituted noribogaine |
US8637648B1 (en) * | 2010-06-22 | 2014-01-28 | Demerx, Inc. | Compositions comprising noribogaine and an excipient to facilitate transport across the blood brain barrier |
US8741891B1 (en) * | 2010-06-22 | 2014-06-03 | Demerx, Inc. | N-substituted noribogaine prodrugs |
WO2013085922A1 (en) * | 2011-12-09 | 2013-06-13 | Demerx, Inc. | Phosphate esters of noribogaine |
WO2013148572A1 (en) * | 2012-03-27 | 2013-10-03 | Albany Medical College | Blocking of cue-induced drug reinstatement |
-
2014
- 2014-04-21 CA CA2983727A patent/CA2983727A1/en not_active Abandoned
- 2014-04-21 EP EP14890017.8A patent/EP3164402A1/en not_active Withdrawn
- 2014-04-21 WO PCT/US2014/034826 patent/WO2015163844A1/en active Application Filing
Also Published As
Publication number | Publication date |
---|---|
CA2983727A1 (en) | 2015-10-29 |
WO2015163844A1 (en) | 2015-10-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US9586954B2 (en) | N-substituted noribogaine prodrugs | |
US8741891B1 (en) | N-substituted noribogaine prodrugs | |
EP3164402A1 (en) | N-substituted noribogaine prodrugs | |
US9051343B2 (en) | Phosphate esters of noribogaine | |
US4831155A (en) | Physostigmine derivatives with acetylcholinesterase inhibition properties, and manufacture | |
CA3087263A1 (en) | Benzamide compounds | |
US8853201B2 (en) | Sulfate esters of noribogaine | |
US9133195B2 (en) | Quaternary ammonium salt compounds of spirocyclopiperazines, preparation methods and uses thereof | |
ES2289159T3 (en) | REPLACED TETRACICLIC DERIVATIVES OF PIRROLOQUINOLONA USED AS PHOSPHODIESTERASE INHIBITORS. | |
ES2297217T3 (en) | SUBSTITUTED DERIVATIVES OF 2,4-DIHIDRO-PIRROLO (3,4-B) QUINOLIN-9-ONA USED AS PHOSPHODESTERASE INHIBITORS. | |
TW541307B (en) | 1,4-diazabicyclo [3.2.2] nonabenzoxazole, -benzothiazole and -benzimidazole derivatives, their preparation and their therapeutic application | |
WO2023023347A1 (en) | Prodrugs and derivatives of psilocin and uses thereof | |
CA3235603A1 (en) | Small molecule inhibitors of ubiquitin specific protease 1 (usp1) and uses thereof | |
JP2010505747A (en) | Selective antagonist of A2A adenosine receptor | |
JPH09508635A (en) | Aza cyclic derivative | |
US4940789A (en) | 10,11-dihydro-5-alkyl-12-substituted-10,5-(iminomethano)-5H-dibenzo[a,d]cycloheptenes as neuroprotectant agents | |
PT86776B (en) | PROCESS FOR THE PREPARATION OF PIPERAZINOCARBOXYLIC ACID AND OF PHARMACEUTICAL COMPOSITIONS CONTAINING IT | |
JPS6043348B2 (en) | Novel compounds or physiologically acceptable salts thereof and methods for producing them | |
ES2935615T3 (en) | Azetidine substituted dihydrothienopyridines and their use as phosphodiesterase inhibitors | |
ES2235475T3 (en) | 2-AMINOPIRIDINES CONTAINING SUBSTITUTES OF CONDENSED RINGS AS INHIBITORS OF NITRICO SINTASA OXIDE. | |
PT2291380E (en) | Nalmefene prodrugs | |
CN108409728B (en) | Phenyloctahydro-1H-pyrido [1,2-a ] pyrazine derivatives and uses thereof | |
CN106065018B (en) | Substituted indole compounds, methods of use and uses thereof | |
US8557842B2 (en) | Cocaine analogs and methods of preparation and uses thereof | |
AU2014379612A1 (en) | Compositions comprising noribogaine and an excipient to facilitate transport across the blood brain barrier |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE |
|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE |
|
17P | Request for examination filed |
Effective date: 20170314 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
AX | Request for extension of the european patent |
Extension state: BA ME |
|
DAX | Request for extension of the european patent (deleted) | ||
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
18D | Application deemed to be withdrawn |
Effective date: 20181101 |