AU2021204158B2 - Deuterated compounds - Google Patents
Deuterated compounds Download PDFInfo
- Publication number
- AU2021204158B2 AU2021204158B2 AU2021204158A AU2021204158A AU2021204158B2 AU 2021204158 B2 AU2021204158 B2 AU 2021204158B2 AU 2021204158 A AU2021204158 A AU 2021204158A AU 2021204158 A AU2021204158 A AU 2021204158A AU 2021204158 B2 AU2021204158 B2 AU 2021204158B2
- Authority
- AU
- Australia
- Prior art keywords
- compound
- dimethyltryptamine
- deuterated
- composition
- formula
- 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.)
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- 150000001875 compounds Chemical class 0.000 title claims description 202
- 239000000203 mixture Substances 0.000 claims description 202
- DMULVCHRPCFFGV-UHFFFAOYSA-N N,N-dimethyltryptamine Chemical class C1=CC=C2C(CCN(C)C)=CNC2=C1 DMULVCHRPCFFGV-UHFFFAOYSA-N 0.000 claims description 171
- -1 deuterated N,N-dimethyltryptamine compound Chemical class 0.000 claims description 98
- 238000000034 method Methods 0.000 claims description 76
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 75
- 239000007822 coupling agent Substances 0.000 claims description 67
- 229910010084 LiAlH4 Inorganic materials 0.000 claims description 66
- 150000003839 salts Chemical class 0.000 claims description 66
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical group OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 32
- 210000003494 hepatocyte Anatomy 0.000 claims description 30
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 28
- 239000000654 additive Substances 0.000 claims description 26
- 150000001412 amines Chemical class 0.000 claims description 26
- 230000000996 additive effect Effects 0.000 claims description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 17
- 238000003556 assay Methods 0.000 claims description 16
- 150000001718 carbodiimides Chemical class 0.000 claims description 15
- 208000020016 psychiatric disease Diseases 0.000 claims description 15
- 208000012902 Nervous system disease Diseases 0.000 claims description 13
- 239000012445 acidic reagent Substances 0.000 claims description 12
- 208000019901 Anxiety disease Diseases 0.000 claims description 11
- 208000024714 major depressive disease Diseases 0.000 claims description 11
- 208000020401 Depressive disease Diseases 0.000 claims description 10
- 238000002560 therapeutic procedure Methods 0.000 claims description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 claims description 6
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 claims description 5
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 5
- 208000029028 brain injury Diseases 0.000 claims description 5
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 claims description 5
- 201000009032 substance abuse Diseases 0.000 claims description 5
- 206010002942 Apathy Diseases 0.000 claims description 4
- 231100000736 substance abuse Toxicity 0.000 claims description 4
- 208000011117 substance-related disease Diseases 0.000 claims description 4
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 claims description 3
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 3
- LCFXLZAXGXOXAP-UHFFFAOYSA-N ethyl 2-cyano-2-hydroxyiminoacetate Chemical compound CCOC(=O)C(=NO)C#N LCFXLZAXGXOXAP-UHFFFAOYSA-N 0.000 claims description 3
- 208000028552 Treatment-Resistant Depressive disease Diseases 0.000 claims description 2
- 201000000980 schizophrenia Diseases 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims 4
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 claims 2
- HJBLUNHMOKFZQX-UHFFFAOYSA-N 3-hydroxy-1,2,3-benzotriazin-4-one Chemical compound C1=CC=C2C(=O)N(O)N=NC2=C1 HJBLUNHMOKFZQX-UHFFFAOYSA-N 0.000 claims 1
- 239000006201 parenteral dosage form Substances 0.000 claims 1
- 239000007909 solid dosage form Substances 0.000 claims 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 64
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 60
- 239000002904 solvent Substances 0.000 description 41
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- 239000000243 solution Substances 0.000 description 35
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 33
- 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 33
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 32
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 30
- 102000010909 Monoamine Oxidase Human genes 0.000 description 25
- 108010062431 Monoamine oxidase Proteins 0.000 description 25
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
- 229910052805 deuterium Inorganic materials 0.000 description 24
- 239000000047 product Substances 0.000 description 23
- 238000004128 high performance liquid chromatography Methods 0.000 description 22
- DMULVCHRPCFFGV-BNEYPBHNSA-N 1-deuterio-2-(1H-indol-3-yl)-N,N-dimethylethanamine Chemical class [2H]C(Cc1c[nH]c2ccccc12)N(C)C DMULVCHRPCFFGV-BNEYPBHNSA-N 0.000 description 21
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 21
- 238000000338 in vitro Methods 0.000 description 21
- 238000003756 stirring Methods 0.000 description 20
- 239000000725 suspension Substances 0.000 description 19
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 17
- 230000002503 metabolic effect Effects 0.000 description 17
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 17
- 239000007787 solid Substances 0.000 description 16
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 15
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 15
- 230000008859 change Effects 0.000 description 14
- 238000001914 filtration Methods 0.000 description 14
- 239000003112 inhibitor Substances 0.000 description 14
- 230000005445 isotope effect Effects 0.000 description 14
- 229910001868 water Inorganic materials 0.000 description 14
- 238000004458 analytical method Methods 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 13
- 229910052799 carbon Inorganic materials 0.000 description 13
- 210000004027 cell Anatomy 0.000 description 13
- 230000000694 effects Effects 0.000 description 13
- SEOVTRFCIGRIMH-UHFFFAOYSA-N indole-3-acetic acid Chemical class C1=CC=C2C(CC(=O)O)=CNC2=C1 SEOVTRFCIGRIMH-UHFFFAOYSA-N 0.000 description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 13
- 239000003638 chemical reducing agent Substances 0.000 description 12
- 210000004185 liver Anatomy 0.000 description 12
- 230000002438 mitochondrial effect Effects 0.000 description 12
- 239000002899 monoamine oxidase inhibitor Substances 0.000 description 12
- 208000024891 symptom Diseases 0.000 description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 11
- 229940082992 antihypertensives mao inhibitors Drugs 0.000 description 11
- 229940125904 compound 1 Drugs 0.000 description 11
- 239000001530 fumaric acid Substances 0.000 description 11
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 10
- 208000035475 disorder Diseases 0.000 description 10
- 239000012458 free base Substances 0.000 description 10
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 10
- 229940011051 isopropyl acetate Drugs 0.000 description 10
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 10
- 239000000546 pharmaceutical excipient Substances 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- 206010026749 Mania Diseases 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 9
- 239000012071 phase Substances 0.000 description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 9
- 238000001953 recrystallisation Methods 0.000 description 9
- 230000009467 reduction Effects 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 description 8
- JFBZPFYRPYOZCQ-UHFFFAOYSA-N [Li].[Al] Chemical compound [Li].[Al] JFBZPFYRPYOZCQ-UHFFFAOYSA-N 0.000 description 8
- 238000009472 formulation Methods 0.000 description 8
- 230000004060 metabolic process Effects 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 239000008194 pharmaceutical composition Substances 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- 230000008878 coupling Effects 0.000 description 7
- 238000010168 coupling process Methods 0.000 description 7
- 238000005859 coupling reaction Methods 0.000 description 7
- 230000007423 decrease Effects 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- 238000010189 synthetic method Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 208000020925 Bipolar disease Diseases 0.000 description 6
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
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- 239000007864 aqueous solution Substances 0.000 description 6
- 239000003637 basic solution Substances 0.000 description 6
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 6
- 229940125898 compound 5 Drugs 0.000 description 6
- 125000004431 deuterium atom Chemical group 0.000 description 6
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- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 description 6
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- 238000002098 selective ion monitoring Methods 0.000 description 6
- MEZLKOACVSPNER-GFCCVEGCSA-N selegiline Chemical compound C#CCN(C)[C@H](C)CC1=CC=CC=C1 MEZLKOACVSPNER-GFCCVEGCSA-N 0.000 description 6
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 6
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- ROSDSFDQCJNGOL-UHFFFAOYSA-N protonated dimethyl amine Natural products CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 5
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- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 4
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- 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 3
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Applications Claiming Priority (19)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US16/890,664 US11771681B2 (en) | 2019-06-03 | 2020-06-02 | Therapeutic compounds |
| PCT/EP2020/065244 WO2020245133A1 (en) | 2019-06-03 | 2020-06-02 | Therapeutic compositions comprising deuterated or partially deuterated n,n-dimethyltryptamine compounds |
| US16/890,664 | 2020-06-02 | ||
| GB2008303.6A GB2585978B (en) | 2019-06-03 | 2020-06-02 | Therapeutic compositions |
| AUPCT/EP2020/065244 | 2020-06-02 | ||
| GB2008303.6 | 2020-06-02 | ||
| GB2018955.1 | 2020-12-01 | ||
| US17/108,679 US20220168274A1 (en) | 2020-12-01 | 2020-12-01 | Parenteral Formulation |
| GBGB2018955.1A GB202018955D0 (en) | 2020-12-01 | 2020-12-01 | Compositions and compounds for bioanalysis |
| US17/108,679 | 2020-12-01 | ||
| US17/108,938 | 2020-12-01 | ||
| US17/108,938 US20220169606A1 (en) | 2020-12-01 | 2020-12-01 | Compositions and compounds for bioanalysis |
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| WO2020245133A1 (en) * | 2019-06-03 | 2020-12-10 | Small Pharma Ltd | Therapeutic compositions comprising deuterated or partially deuterated n,n-dimethyltryptamine compounds |
| WO2021089872A1 (en) * | 2019-11-07 | 2021-05-14 | Small Pharma Ltd | Compounds |
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| WO2020245133A1 (en) * | 2019-06-03 | 2020-12-10 | Small Pharma Ltd | Therapeutic compositions comprising deuterated or partially deuterated n,n-dimethyltryptamine compounds |
| WO2021089872A1 (en) * | 2019-11-07 | 2021-05-14 | Small Pharma Ltd | Compounds |
| WO2021089873A1 (en) * | 2019-11-07 | 2021-05-14 | Small Pharma Ltd | Method of synthesis |
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| US11771681B2 (en) | Therapeutic compounds | |
| AU2020381103B2 (en) | Compounds | |
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