US20230265093A1 - Beta-carbolines as positive allosteric modulators of the human serotonin receptor 2c (5-ht2c) - Google Patents
Beta-carbolines as positive allosteric modulators of the human serotonin receptor 2c (5-ht2c) Download PDFInfo
- Publication number
- US20230265093A1 US20230265093A1 US18/051,300 US202218051300A US2023265093A1 US 20230265093 A1 US20230265093 A1 US 20230265093A1 US 202218051300 A US202218051300 A US 202218051300A US 2023265093 A1 US2023265093 A1 US 2023265093A1
- Authority
- US
- United States
- Prior art keywords
- compound
- methyl
- alkyl
- disorder
- pcp
- 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.)
- Pending
Links
- 101000761348 Homo sapiens 5-hydroxytryptamine receptor 2C Proteins 0.000 title abstract description 24
- AIFRHYZBTHREPW-UHFFFAOYSA-N β-carboline Chemical class N1=CC=C2C3=CC=CC=C3NC2=C1 AIFRHYZBTHREPW-UHFFFAOYSA-N 0.000 title abstract description 18
- 230000003281 allosteric effect Effects 0.000 title description 7
- 230000000694 effects Effects 0.000 claims abstract description 50
- 238000000034 method Methods 0.000 claims abstract description 44
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 41
- 208000035475 disorder Diseases 0.000 claims abstract description 20
- 201000010099 disease Diseases 0.000 claims abstract description 19
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 claims abstract description 18
- 208000012902 Nervous system disease Diseases 0.000 claims abstract description 16
- 208000025966 Neurological disease Diseases 0.000 claims abstract description 15
- 208000028698 Cognitive impairment Diseases 0.000 claims abstract description 14
- 208000010877 cognitive disease Diseases 0.000 claims abstract description 14
- 206010012335 Dependence Diseases 0.000 claims abstract description 13
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 9
- 208000008589 Obesity Diseases 0.000 claims abstract description 8
- 230000003340 mental effect Effects 0.000 claims abstract description 8
- 235000020824 obesity Nutrition 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 113
- -1 pyridine-2-yl Chemical group 0.000 claims description 64
- 102000005962 receptors Human genes 0.000 claims description 31
- 108020003175 receptors Proteins 0.000 claims description 31
- 125000000217 alkyl group Chemical group 0.000 claims description 30
- 150000003839 salts Chemical class 0.000 claims description 22
- 125000000623 heterocyclic group Chemical group 0.000 claims description 20
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 19
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
- 125000001188 haloalkyl group Chemical group 0.000 claims description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 125000005843 halogen group Chemical group 0.000 claims description 10
- 125000003342 alkenyl group Chemical group 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 208000020016 psychiatric disease Diseases 0.000 claims description 8
- 230000036528 appetite Effects 0.000 claims description 7
- 235000019789 appetite Nutrition 0.000 claims description 7
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 7
- 125000005842 heteroatom Chemical group 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 125000002883 imidazolyl group Chemical group 0.000 claims description 6
- 125000002757 morpholinyl group Chemical group 0.000 claims description 6
- 125000004193 piperazinyl group Chemical group 0.000 claims description 6
- 125000003386 piperidinyl group Chemical group 0.000 claims description 6
- 239000012453 solvate Substances 0.000 claims description 6
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000005055 alkyl alkoxy group Chemical group 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 150000003384 small molecules Chemical class 0.000 abstract description 29
- CFTOTSJVQRFXOF-UHFFFAOYSA-N 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole Chemical group N1C2=CC=CC=C2C2=C1CNCC2 CFTOTSJVQRFXOF-UHFFFAOYSA-N 0.000 abstract description 6
- BIAPMJDDPWPHOP-UHFFFAOYSA-N 2,9-dihydro-1h-pyrido[3,4-b]indole Chemical group N1C2=CC=CC=C2C2=C1CNC=C2 BIAPMJDDPWPHOP-UHFFFAOYSA-N 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 206010061428 decreased appetite Diseases 0.000 abstract description 4
- 230000003880 negative regulation of appetite Effects 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 239000000203 mixture Substances 0.000 description 60
- JTJMJGYZQZDUJJ-UHFFFAOYSA-N phencyclidine Chemical compound C1CCCCN1C1(C=2C=CC=CC=2)CCCCC1 JTJMJGYZQZDUJJ-UHFFFAOYSA-N 0.000 description 60
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
- 241000699670 Mus sp. Species 0.000 description 36
- 238000009472 formulation Methods 0.000 description 28
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 27
- 239000003981 vehicle Substances 0.000 description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 239000003814 drug Substances 0.000 description 21
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 18
- 125000003118 aryl group Chemical group 0.000 description 18
- 239000004480 active ingredient Substances 0.000 description 16
- 229940079593 drug Drugs 0.000 description 16
- 230000006742 locomotor activity Effects 0.000 description 16
- 230000007423 decrease Effects 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- 102000040125 5-hydroxytryptamine receptor family Human genes 0.000 description 12
- 108091032151 5-hydroxytryptamine receptor family Proteins 0.000 description 12
- 125000000753 cycloalkyl group Chemical group 0.000 description 12
- 239000003826 tablet Substances 0.000 description 12
- 229920002472 Starch Polymers 0.000 description 11
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Substances [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- 235000019698 starch Nutrition 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 239000000556 agonist Substances 0.000 description 10
- 125000004452 carbocyclyl group Chemical group 0.000 description 10
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 10
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- 239000008107 starch Substances 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 241000282414 Homo sapiens Species 0.000 description 8
- 238000012048 forced swim test Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 7
- 229940025084 amphetamine Drugs 0.000 description 7
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- 201000000980 schizophrenia Diseases 0.000 description 7
- 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 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 150000001408 amides Chemical class 0.000 description 6
- 125000003710 aryl alkyl group Chemical group 0.000 description 6
- 235000019359 magnesium stearate Nutrition 0.000 description 6
- 230000015654 memory Effects 0.000 description 6
- 230000003997 social interaction Effects 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 102000016979 Other receptors Human genes 0.000 description 5
- 208000028017 Psychotic disease Diseases 0.000 description 5
- 125000000304 alkynyl group Chemical group 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 239000001913 cellulose Substances 0.000 description 5
- 235000010980 cellulose Nutrition 0.000 description 5
- 229920002678 cellulose Polymers 0.000 description 5
- 239000003085 diluting agent Substances 0.000 description 5
- 229910052736 halogen Inorganic materials 0.000 description 5
- 150000002367 halogens Chemical class 0.000 description 5
- 125000001072 heteroaryl group Chemical group 0.000 description 5
- XTTZERNUQAFMOF-QMMMGPOBSA-N lorcaserin Chemical compound C[C@H]1CNCCC2=CC=C(Cl)C=C12 XTTZERNUQAFMOF-QMMMGPOBSA-N 0.000 description 5
- 229960005060 lorcaserin Drugs 0.000 description 5
- 238000001543 one-way ANOVA Methods 0.000 description 5
- 125000006413 ring segment Chemical group 0.000 description 5
- 239000000829 suppository Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 208000019901 Anxiety disease Diseases 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- 229930195725 Mannitol Natural products 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 4
- 125000003368 amide group Chemical group 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 230000036506 anxiety Effects 0.000 description 4
- 230000006399 behavior Effects 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 150000005829 chemical entities Chemical class 0.000 description 4
- 230000003247 decreasing effect Effects 0.000 description 4
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 4
- 230000001965 increasing effect Effects 0.000 description 4
- 239000000594 mannitol Substances 0.000 description 4
- 235000010355 mannitol Nutrition 0.000 description 4
- 239000004579 marble Substances 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 150000003254 radicals Chemical group 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 229940076279 serotonin Drugs 0.000 description 4
- 230000007958 sleep Effects 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 235000000346 sugar Nutrition 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000005711 Benzoic acid Substances 0.000 description 3
- VOPWNXZWBYDODV-UHFFFAOYSA-N Chlorodifluoromethane Chemical compound FC(F)Cl VOPWNXZWBYDODV-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 241000283984 Rodentia Species 0.000 description 3
- MDIGAZPGKJFIAH-UHFFFAOYSA-N Serotonin hydrochloride Chemical compound Cl.C1=C(O)C=C2C(CCN)=CNC2=C1 MDIGAZPGKJFIAH-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 206010047139 Vasoconstriction Diseases 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 150000001299 aldehydes Chemical group 0.000 description 3
- 235000010443 alginic acid Nutrition 0.000 description 3
- 229920000615 alginic acid Polymers 0.000 description 3
- 239000005557 antagonist Substances 0.000 description 3
- 239000000935 antidepressant agent Substances 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 235000010233 benzoic acid Nutrition 0.000 description 3
- 125000002619 bicyclic group Chemical group 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000007913 intrathecal administration Methods 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 230000036651 mood Effects 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 230000028016 temperature homeostasis Effects 0.000 description 3
- 230000025033 vasoconstriction Effects 0.000 description 3
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 2
- QIMOFNWSIPJEKQ-UHFFFAOYSA-N 1-pyrimidin-5-yl-9H-pyrido[3,4-b]indol-6-ol Chemical compound N1=CN=CC(C2=C3NC4=CC=C(O)C=C4C3=CC=N2)=C1 QIMOFNWSIPJEKQ-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
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- 206010011971 Decreased interest Diseases 0.000 description 2
- 208000030814 Eating disease Diseases 0.000 description 2
- 208000019454 Feeding and Eating disease Diseases 0.000 description 2
- 229930091371 Fructose Natural products 0.000 description 2
- 239000005715 Fructose Substances 0.000 description 2
- 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 2
- OWIKHYCFFJSOEH-UHFFFAOYSA-N Isocyanic acid Chemical compound N=C=O OWIKHYCFFJSOEH-UHFFFAOYSA-N 0.000 description 2
- 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 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 2
- 208000000323 Tourette Syndrome Diseases 0.000 description 2
- 208000016620 Tourette disease Diseases 0.000 description 2
- MMWCIQZXVOZEGG-HOZKJCLWSA-N [(1S,2R,3S,4S,5R,6S)-2,3,5-trihydroxy-4,6-diphosphonooxycyclohexyl] dihydrogen phosphate Chemical compound O[C@H]1[C@@H](O)[C@H](OP(O)(O)=O)[C@@H](OP(O)(O)=O)[C@H](O)[C@H]1OP(O)(O)=O MMWCIQZXVOZEGG-HOZKJCLWSA-N 0.000 description 2
- 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 2
- 150000007513 acids Chemical class 0.000 description 2
- 150000001350 alkyl halides Chemical class 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- WYTGDNHDOZPMIW-RCBQFDQVSA-N alstonine Natural products C1=CC2=C3C=CC=CC3=NC2=C2N1C[C@H]1[C@H](C)OC=C(C(=O)OC)[C@H]1C2 WYTGDNHDOZPMIW-RCBQFDQVSA-N 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 230000001430 anti-depressive effect Effects 0.000 description 2
- 229940005513 antidepressants Drugs 0.000 description 2
- 230000003190 augmentative effect Effects 0.000 description 2
- MEPJLBXTZZGXOV-UHFFFAOYSA-N azidocarbamic acid Chemical compound OC(=O)NN=[N+]=[N-] MEPJLBXTZZGXOV-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 125000001589 carboacyl group Chemical group 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 239000007910 chewable tablet Substances 0.000 description 2
- 229940110456 cocoa butter Drugs 0.000 description 2
- 235000019868 cocoa butter Nutrition 0.000 description 2
- 230000019771 cognition Effects 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 125000000392 cycloalkenyl group Chemical group 0.000 description 2
- 230000006735 deficit Effects 0.000 description 2
- 150000001982 diacylglycerols Chemical class 0.000 description 2
- 235000014632 disordered eating Nutrition 0.000 description 2
- 229960003638 dopamine Drugs 0.000 description 2
- 230000009540 excitatory neurotransmission Effects 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000019634 flavors Nutrition 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 230000005176 gastrointestinal motility Effects 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 125000004404 heteroalkyl group Chemical group 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 150000002576 ketones Chemical group 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 230000013016 learning Effects 0.000 description 2
- 208000024714 major depressive disease Diseases 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000002483 medication Methods 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000002858 neurotransmitter agent Substances 0.000 description 2
- 229960002748 norepinephrine Drugs 0.000 description 2
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 229940026197 serotonin hydrochloride Drugs 0.000 description 2
- 230000009329 sexual behaviour Effects 0.000 description 2
- 230000011273 social behavior Effects 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 239000002511 suppository base Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 1
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- 125000006710 (C2-C12) alkenyl group Chemical group 0.000 description 1
- 125000006711 (C2-C12) alkynyl group Chemical group 0.000 description 1
- 125000006564 (C4-C8) cycloalkyl group Chemical group 0.000 description 1
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- KXENLAUWLCFBBV-UHFFFAOYSA-N 1-cyclohexyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-6-ol Chemical compound C1CC(C2C=3NC4=C(C=3CCN2)C=C(C=C4)O)CCC1 KXENLAUWLCFBBV-UHFFFAOYSA-N 0.000 description 1
- HNNMNKJXEHZAKN-UHFFFAOYSA-N 1-cyclohexyl-2-prop-2-enyl-9H-pyrido[3,4-b]indol-2-ium-6-ol bromide Chemical compound [Br-].C1(CCCCC1)C1=[N+](C=CC2=C1NC1=CC=C(C=C21)O)CC=C HNNMNKJXEHZAKN-UHFFFAOYSA-N 0.000 description 1
- UIEJNSOVRSMQNL-UHFFFAOYSA-N 1-cyclohexyl-9H-pyrido[3,4-b]indol-6-ol Chemical compound C1CC(C2=C3NC4=C(C3=CC=N2)C=C(C=C4)O)CCC1 UIEJNSOVRSMQNL-UHFFFAOYSA-N 0.000 description 1
- 125000004486 1-methylpiperidin-3-yl group Chemical group CN1CC(CCC1)* 0.000 description 1
- 125000004484 1-methylpiperidin-4-yl group Chemical group CN1CCC(CC1)* 0.000 description 1
- CXHLMCAMGSKZMU-UHFFFAOYSA-N 1-phenyl-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indol-6-ol Chemical compound N1CCC=2C3=CC(O)=CC=C3NC=2C1C1=CC=CC=C1 CXHLMCAMGSKZMU-UHFFFAOYSA-N 0.000 description 1
- OVSOXEURVLXHNE-UHFFFAOYSA-N 1-phenyl-2-prop-2-enyl-9H-pyrido[3,4-b]indol-2-ium-6-ol bromide Chemical compound [Br-].OC=1C=C2C3=C(NC2=CC=1)C(=[N+](C=C3)CC=C)C1=CC=CC=C1 OVSOXEURVLXHNE-UHFFFAOYSA-N 0.000 description 1
- MLYQSDHAYSWNLS-UHFFFAOYSA-N 1-phenyl-9H-pyrido[3,4-b]indol-6-ol Chemical compound C1(C=2C=3NC4=C(C=C(C=C4)O)C=3C=CN=2)=CC=CC=C1 MLYQSDHAYSWNLS-UHFFFAOYSA-N 0.000 description 1
- ZSLYQNKUHCHSKN-UHFFFAOYSA-N 1-pyrimidin-5-yl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-6-ol Chemical compound N1=CN=CC(C2C=3NC4=CC=C(O)C=C4C=3CCN2)=C1 ZSLYQNKUHCHSKN-UHFFFAOYSA-N 0.000 description 1
- AFENDNXGAFYKQO-UHFFFAOYSA-N 2-hydroxybutyric acid Chemical compound CCC(O)C(O)=O AFENDNXGAFYKQO-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- PXACTUVBBMDKRW-UHFFFAOYSA-N 4-bromobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(Br)C=C1 PXACTUVBBMDKRW-UHFFFAOYSA-N 0.000 description 1
- OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical compound OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 102100036321 5-hydroxytryptamine receptor 2A Human genes 0.000 description 1
- 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 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010002942 Apathy Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 208000020925 Bipolar disease Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 description 1
- 125000005865 C2-C10alkynyl group Chemical group 0.000 description 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 208000015121 Cardiac valve disease Diseases 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- PTHCMJGKKRQCBF-UHFFFAOYSA-N Cellulose, microcrystalline Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC)C(CO)O1 PTHCMJGKKRQCBF-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 241000207199 Citrus Species 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 102400000739 Corticotropin Human genes 0.000 description 1
- 101800000414 Corticotropin Proteins 0.000 description 1
- 229920000858 Cyclodextrin Polymers 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
- 241000283086 Equidae Species 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 229940124602 FDA-approved drug Drugs 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229940117892 Glutamate receptor agonist Drugs 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- 229920002907 Guar gum Polymers 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 108090000543 Ligand-Gated Ion Channels Proteins 0.000 description 1
- 102000004086 Ligand-Gated Ion Channels Human genes 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102400000050 Oxytocin Human genes 0.000 description 1
- XNOPRXBHLZRZKH-UHFFFAOYSA-N Oxytocin Natural products N1C(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CC(C)C)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C(C(C)CC)NC(=O)C1CC1=CC=C(O)C=C1 XNOPRXBHLZRZKH-UHFFFAOYSA-N 0.000 description 1
- 101800000989 Oxytocin Proteins 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- 238000006929 Pictet-Spengler synthesis reaction Methods 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 102000003946 Prolactin Human genes 0.000 description 1
- 108010057464 Prolactin Proteins 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 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
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- GXBMIBRIOWHPDT-UHFFFAOYSA-N Vasopressin Natural products N1C(=O)C(CC=2C=C(O)C=CC=2)NC(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CCCN=C(N)N)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C1CC1=CC=CC=C1 GXBMIBRIOWHPDT-UHFFFAOYSA-N 0.000 description 1
- 108010004977 Vasopressins Proteins 0.000 description 1
- 102000002852 Vasopressins Human genes 0.000 description 1
- ZZXDRXVIRVJQBT-UHFFFAOYSA-M Xylenesulfonate Chemical compound CC1=CC=CC(S([O-])(=O)=O)=C1C ZZXDRXVIRVJQBT-UHFFFAOYSA-M 0.000 description 1
- BLGXFZZNTVWLAY-CCZXDCJGSA-N Yohimbine Natural products C1=CC=C2C(CCN3C[C@@H]4CC[C@@H](O)[C@H]([C@H]4C[C@H]33)C(=O)OC)=C3NC2=C1 BLGXFZZNTVWLAY-CCZXDCJGSA-N 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- PKBLNGPRDUJREH-UHFFFAOYSA-N [Br-].OC=1C=C2C3=C(NC2=CC=1)C(=[N+](C=C3)CCCOC)C1=CC=CC=C1 Chemical compound [Br-].OC=1C=C2C3=C(NC2=CC=1)C(=[N+](C=C3)CCCOC)C1=CC=CC=C1 PKBLNGPRDUJREH-UHFFFAOYSA-N 0.000 description 1
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 230000016571 aggressive behavior Effects 0.000 description 1
- 230000008484 agonism Effects 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- QVBOOBQEGOUUGN-RCBQFDQVSA-N alstonine Chemical compound C1=C[CH]C2=NC3=C(C[C@@H]4C(C(=O)OC)=CO[C@@H](C)[C@@H]4C4)[N+]4=CC=C3C2=C1 QVBOOBQEGOUUGN-RCBQFDQVSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 125000000747 amidyl group Chemical group [H][N-]* 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- KBZOIRJILGZLEJ-LGYYRGKSSA-N argipressin Chemical compound C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 KBZOIRJILGZLEJ-LGYYRGKSSA-N 0.000 description 1
- 238000005899 aromatization reaction Methods 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 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 1
- BLGXFZZNTVWLAY-UHFFFAOYSA-N beta-Yohimbin Natural products C1=CC=C2C(CCN3CC4CCC(O)C(C4CC33)C(=O)OC)=C3NC2=C1 BLGXFZZNTVWLAY-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 210000004556 brain Anatomy 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
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Inorganic materials [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 125000005518 carboxamido group Chemical group 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000009084 cardiovascular function Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 229940023913 cation exchange resins Drugs 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- KVSASDOGYIBWTA-UHFFFAOYSA-N chloro benzoate Chemical compound ClOC(=O)C1=CC=CC=C1 KVSASDOGYIBWTA-UHFFFAOYSA-N 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 235000020971 citrus fruits Nutrition 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940124301 concurrent medication Drugs 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 229960000258 corticotropin Drugs 0.000 description 1
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 description 1
- 150000001924 cycloalkanes Chemical class 0.000 description 1
- 125000002993 cycloalkylene group Chemical group 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- QKIUAMUSENSFQQ-UHFFFAOYSA-N dimethylazanide Chemical compound C[N-]C QKIUAMUSENSFQQ-UHFFFAOYSA-N 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 238000002635 electroconvulsive therapy Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- LIWAQLJGPBVORC-UHFFFAOYSA-N ethylmethylamine Chemical compound CCNC LIWAQLJGPBVORC-UHFFFAOYSA-N 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 235000019264 food flavour enhancer Nutrition 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 229940049906 glutamate Drugs 0.000 description 1
- 239000003823 glutamate receptor agonist Substances 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- KKLGDUSGQMHBPB-UHFFFAOYSA-N hex-2-ynedioic acid Chemical compound OC(=O)CCC#CC(O)=O KKLGDUSGQMHBPB-UHFFFAOYSA-N 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-M hexanoate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 description 1
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 229940060367 inert ingredients Drugs 0.000 description 1
- 230000009539 inhibitory neurotransmission Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000013227 male C57BL/6J mice Methods 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
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000006386 memory function Effects 0.000 description 1
- 125000005341 metaphosphate group Chemical group 0.000 description 1
- 229960001797 methadone Drugs 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- CWWARWOPSKGELM-SARDKLJWSA-N methyl (2s)-2-[[(2s)-2-[[2-[[(2s)-2-[[(2s)-2-[[(2s)-5-amino-2-[[(2s)-5-amino-2-[[(2s)-1-[(2s)-6-amino-2-[[(2s)-1-[(2s)-2-amino-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-5 Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)OC)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 CWWARWOPSKGELM-SARDKLJWSA-N 0.000 description 1
- IZYBEMGNIUSSAX-UHFFFAOYSA-N methyl benzenecarboperoxoate Chemical compound COOC(=O)C1=CC=CC=C1 IZYBEMGNIUSSAX-UHFFFAOYSA-N 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- MGJXBDMLVWIYOQ-UHFFFAOYSA-N methylazanide Chemical compound [NH-]C MGJXBDMLVWIYOQ-UHFFFAOYSA-N 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- 125000001620 monocyclic carbocycle group Chemical class 0.000 description 1
- 125000004312 morpholin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])OC([H])(*)C1([H])[H] 0.000 description 1
- 125000004572 morpholin-3-yl group Chemical group N1C(COCC1)* 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 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 1
- 229960003086 naltrexone Drugs 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 230000003705 neurological process Effects 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- XNOPRXBHLZRZKH-DSZYJQQASA-N oxytocin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@H](N)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(N)=O)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 XNOPRXBHLZRZKH-DSZYJQQASA-N 0.000 description 1
- 229960001723 oxytocin Drugs 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 230000018052 penile erection Effects 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 230000008447 perception Effects 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 229950010883 phencyclidine Drugs 0.000 description 1
- DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical compound CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 229950009215 phenylbutanoic acid Drugs 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004574 piperidin-2-yl group Chemical group N1C(CCCC1)* 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229940100467 polyvinyl acetate phthalate Drugs 0.000 description 1
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229920003124 powdered cellulose Polymers 0.000 description 1
- 235000019814 powdered cellulose Nutrition 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 229940097325 prolactin Drugs 0.000 description 1
- KCXFHTAICRTXLI-UHFFFAOYSA-N propane-1-sulfonic acid Chemical compound CCCS(O)(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-N 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-M propynoate Chemical compound [O-]C(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-M 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 239000000565 sealant Substances 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 230000006886 spatial memory Effects 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000008925 spontaneous activity Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical group 0.000 description 1
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- ZXLDQJLIBNPEFJ-UHFFFAOYSA-N tetrahydro-beta-carboline Natural products C1CNC(C)C2=C1C1=CC=C(OC)C=C1N2 ZXLDQJLIBNPEFJ-UHFFFAOYSA-N 0.000 description 1
- 125000004187 tetrahydropyran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 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
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 125000000165 tricyclic carbocycle group Chemical group 0.000 description 1
- 229960003726 vasopressin Drugs 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 229940071104 xylenesulfonate Drugs 0.000 description 1
- BLGXFZZNTVWLAY-SCYLSFHTSA-N yohimbine Chemical compound C1=CC=C2C(CCN3C[C@@H]4CC[C@H](O)[C@@H]([C@H]4C[C@H]33)C(=O)OC)=C3NC2=C1 BLGXFZZNTVWLAY-SCYLSFHTSA-N 0.000 description 1
- 229960000317 yohimbine Drugs 0.000 description 1
- AADVZSXPNRLYLV-UHFFFAOYSA-N yohimbine carboxylic acid Natural products C1=CC=C2C(CCN3CC4CCC(C(C4CC33)C(O)=O)O)=C3NC2=C1 AADVZSXPNRLYLV-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/36—Opioid-abuse
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
Definitions
- the field of the invention relates to novel small molecules, methods of synthesis of the small molecules, and uses of the small molecules for modulating activity of the human serotonin receptor 2C (5-HT 2c ).
- the small molecules have a substituted beta-carboline core structure, which optionally may be saturated at one or more bonds to provide a dihydro-beta-carboline core or a tetrahydro-beta-carboline core.
- the small molecules may be administered to treat and/or prevent diseases, disorder, and condition associated with human serotonin receptor 2C (5-HT 2c ) activity including psychiatric, mental, and/or neurological diseases, disorders, and conditions such as cognitive impairment, addiction, and obsessive compulsive disorder.
- Serotonin receptors are a group of G protein-coupled receptor and ligand-gated ion channels found in the central and peripheral nervous systems.
- 5-hydroxytryptamine receptors are a group of G protein-coupled receptor and ligand-gated ion channels found in the central and peripheral nervous systems.
- Serotonin receptors mediate excitatory neurotransmission and inhibitory neurotransmission.
- the serotonin receptors are activated by the neurotransmitter serotonin, which is their natural ligand.
- Serotonin receptors modulate the release of many neurotransmitters, including glutamate, GABA, dopamine, epinephrine/norepinephrine, and acetylcholine, as well as many hormones, including oxytocin, prolactin, vasopressin, cortisol, corticotropin, and substance P, among others.
- the serotonin receptors influence various biological and neurological processes such as aggression, anxiety, cognition, learning, memory, mood, appetite, nausea, sleep, and thermoregulation. (See Nichols et al., (May 2008). “Serotonin receptors.” Chem. Rev. 108(5): 1614-41; the content of which is incorporate herein by reference in its entirety).
- the 5-HT 2 family of serotonin receptors mediates excitatory neurotransmission via a G q /G 11 -protein coupled molecular mechanism that increases cellular levels of inositol triphosphate (IP 3 ) and diacylglycerol (DAG).
- the 5-HT-2 family includes three members: 5-HT 2a , 5-HT 2b , and 5-HT 2c .
- the 5-HT 2a receptor modulates addiction, anxiety, appetite, cognition, imagination, learning, memory, mood, perception, sexual behavior, sleep, thermoregulation, and vasoconstriction.
- the 5-HT 2b receptor modulates anxiety, appetite, cardiovascular function, gastrointestinal motility, sleep, and vasoconstriction.
- the 5-HT 2c receptor modulates addiction, anxiety, appetite, gastrointestinal motility, locomotion, mood, penile erection, sexual behavior, sleep, thermoregulation, and vasoconstriction.
- the 5-HT 2a , 5-HT 2b , and 5-HT 2c exhibit differing affinities for agonists and antagonists and may function as heteroreceptors for ligands other than serotonin.
- 5-HT 2c receptor is a heteroreceptor for norepinephrine and dopamine.
- novel substituted beta-carboline compounds which function as positive allosteric modulators of the human serotonin receptor 2C (5-HT 2c ).
- the disclosed small molecules preferably act selectively as positive allosteric modulators of the human serotonin receptor 2C (5-HT 2c ), relative to other 5-HT receptors such as 5-HT 2a , 5-HT 2b .
- the small molecules may be administered to treat and/or prevent diseases, disorder, and condition associated with human serotonin receptor 2C (5-HT 2c ) including psychiatric, mental, and/or neurological diseases, disorders, and conditions such as cognitive impairment, addiction, and obsessive compulsive disorder.
- novel small molecules are novel small molecules, methods of synthesis of the small molecules, and uses of the small molecules for modulating activity of the human serotonin receptor 2C (5-HT 2c ), preferably selectively.
- the small molecules have a substituted beta-carboline core structure, which optionally may be saturated at one or more bonds to provide a dihydro-beta-carboline core or a tetrahydro-beta-carboline core.
- the small molecules may be administered to treat and/or prevent diseases, disorders, and/or conditions associated with human serotonin receptor 2C (5-HT 2c ) including psychiatric, mental, and/or neurological diseases, disorders, and conditions such as cognitive impairment, addiction, and obsessive compulsive disorder (OCD).
- the disclosed small molecules also may be administered to treat and/or prevent obesity, for example, via appetite suppression.
- FIG. 1 Locomotor Activity: AJC-61 blocked amphetamine-induced increase in locomotor activity in mice. The effect of AJC-61 (2 mg/kg) on amphetamine-induced (2.5 mg/kg) increase in locomotor activity in mice. Data are presented as group means ⁇ S.E.M. for eight successive 15 minute intervals. *** p ⁇ 0.001: significant increase in LMA versus Vehicle+Vehicle; ###p ⁇ 0.001: significant decrease in LMA versus Vehicle+AJC-61 (2 mg/kg)+amphetamine (2.5 mg/kg).
- FIG. 2 Locomotor Activity: AJC-61 blocked PCP-induced increase in locomotor activity in mice. The effect of AJC-61 (2 mg/kg) on PCP-induced (10 mg/kg) increase in locomotor activity in mice. Data are presented as group means S.E.M. for eight successive 15 minute intervals. *** p ⁇ 0.001: significant increase in LMA versus Vehicle+Vehicle; ###p ⁇ 0.001: significant decrease in LMA versus Vehicle+AJC-61 (2 mg/kg)+PCP (10 mg/kg). sc-subchronic.
- DI discrimination index
- a modulator of human serotonin receptor 2C (5-HT 2 c) activity should be interpreted to mean “one or more modulators of human serotonin receptor 2C (5-HT 2 c) activity.”
- the terms “include” and “including” have the same meaning as the terms “comprise” and “comprising.”
- the terms “comprise” and “comprising” should be interpreted as being “open” transitional terms that permit the inclusion of additional components further to those components recited in the claims.
- the terms “consist” and “consisting of” should be interpreted as being “closed” transitional terms that do not permit the inclusion additional components other than the components recited in the claims.
- the term “consisting essentially of” should be interpreted to be partially closed and allowing the inclusion only of additional components that do not fundamentally alter the nature of the claimed subject matter.
- a subject may be a human subject.
- a subject may refer to a human subject having or at risk for acquiring a disease, disorder, or condition, that is associated with human serotonin receptor 2C (5-HT 2 c) activity.
- the disease, disorder, or condition is a psychiatric, mental, and/or neurological disease, disorder, or condition.
- Psychiatric, mental, and/or neurological disease, disorders, or conditions may include, but are not limited to, cognitive impairment, addiction, and obsessive compulsive disorder (OCD).
- OCD obsessive compulsive disorder
- the disclosed small molecules also may be administered to treat and/or prevent obesity, for example, via appetite suppression, where the treated and/or prevented disorder or condition is an eating disorder and/or obesity.
- modulate means decreasing or inhibiting activity and/or increasing or augmenting activity.
- modulating human serotonin receptor 2C (5-HT 2 c) activity may mean increasing or augmenting human serotonin receptor 2C (5-HT 2 c) activity and/or decreasing or inhibiting human serotonin receptor 2C (5-HT 2 c) activity.
- the disclosed novel molecules increase or augment human serotonin receptor 2C (5-HT 2 c) activity as positive allosteric ligands or agonists.
- the phrase “effective amount” shall mean that drug dosage that provides the specific pharmacological response for which the drug is administered in a significant number of patients in need of such treatment.
- An effective amount of a drug that is administered to a particular patient in a particular instance will not always be effective in treating the conditions/diseases described herein, even though such dosage is deemed to be a therapeutically effective amount by those of skill in the art.
- an asterisk “*” or a plus sign “+” may be used to designate the point of attachment for any radical group or substituent group.
- alkyl as contemplated herein includes a straight-chain or branched alkyl radical in all of its isomeric forms, such as a straight or branched group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as C1-C12 alkyl, C1-C10-alkyl, and C1-C6-alkyl, respectively.
- alkylene refers to a diradical of an alkyl group (e.g., —(CH 2 ) n — where n is an integer such as an integer between 1 and 20).
- An exemplary alkylene group is —CH 2 CH 2 —.
- haloalkyl refers to an alkyl group that is substituted with at least one halogen.
- halogen for example, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —CF 2 CF 3 , and the like.
- heteroalkyl refers to an “alkyl” group in which at least one carbon atom has been replaced with a heteroatom (e.g., an O, N, or S atom).
- a heteroatom e.g., an O, N, or S atom.
- One type of heteroalkyl group is an “alkoxy” group.
- alkenyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 2-12, 2-10, or 2-6 carbon atoms, referred to herein as C2-C12-alkenyl, C2-C10-alkenyl, and C2-C6-alkenyl, respectively.
- alkynyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond, such as a straight or branched group of 2-12, 2-10, or 2-6 carbon atoms, referred to herein as C2-C12-alkynyl, C2-C10-alkynyl, and C2-C6-alkynyl, respectively.
- cycloalkyl refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as “C4-8-cycloalkyl,” derived from a cycloalkane.
- cycloalkyl groups are optionally substituted at one or more ring positions with, for example, alkanoyl, alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halo, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl or thiocarbonyl.
- the cycloalkyl group is not substituted, i.e., it is unsubstituted.
- cycloalkylene refers to a cycloalkyl group that is unsaturated at one or more ring bonds.
- partially unsaturated carbocyclyl refers to a monovalent cyclic hydrocarbon that contains at least one double bond between ring atoms where at least one ring of the carbocyclyl is not aromatic.
- the partially unsaturated carbocyclyl may be characterized according to the number of ring carbon atoms.
- the partially unsaturated carbocyclyl may contain 5-14, 5-12, 5-8, or 5-6 ring carbon atoms, and accordingly be referred to as a 5-14, 5-12, 5-8, or 5-6 membered partially unsaturated carbocyclyl, respectively.
- the partially unsaturated carbocyclyl may be in the form of a monocyclic carbocycle, bicyclic carbocycle, tricyclic carbocycle, bridged carbocycle, spirocyclic carbocycle, or other carbocyclic ring system.
- exemplary partially unsaturated carbocyclyl groups include cycloalkenyl groups and bicyclic carbocyclyl groups that are partially unsaturated.
- partially unsaturated carbocyclyl groups are optionally substituted at one or more ring positions with, for example, alkanoyl, alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl or thiocarbonyl.
- the partially unsaturated carbocyclyl is not substituted, i.e., it is unsubstituted.
- aryl is art-recognized and refers to a carbocyclic aromatic group. Representative aryl groups include phenyl, naphthyl, anthracenyl, and the like.
- aryl includes polycyclic ring systems having two or more carbocyclic rings in which two or more carbons are common to two adjoining rings (the rings are “fused rings”) wherein at least one of the rings is aromatic and, e.g., the other ring(s) may be cycloalkyls, cycloalkenyls, cycloalkynyls, and/or aryls.
- the aromatic ring may be substituted at one or more ring positions with, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, carboxylic acid, —C(O)alkyl, —CO 2 alkyl, carbonyl, carboxyl, alkylthio, sulfonyl, sulfonamido, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl or heteroaryl moieties, —CF 3 , —CN, or the like.
- the aromatic ring is substituted at one or more ring positions with halogen, alkyl, hydroxyl, or alkoxyl. In certain other embodiments, the aromatic ring is not substituted, i.e., it is unsubstituted. In certain embodiments, the aryl group is a 6-10 membered ring structure.
- heterocyclyl and “heterocyclic group” are art-recognized and refer to saturated, partially unsaturated, or aromatic 3- to 10-membered ring structures, alternatively 3- to 7-membered rings, whose ring structures include one to four heteroatoms, such as nitrogen, oxygen, and sulfur.
- the number of ring atoms in the heterocyclyl group can be specified using 5 Cx-Cx nomenclature where x is an integer specifying the number of ring atoms.
- a C3-C7 heterocyclyl group refers to a saturated or partially unsaturated 3- to 7-membered ring structure containing one to four heteroatoms, such as nitrogen, oxygen, and sulfur.
- the designation “C3-C7” indicates that the heterocyclic ring contains a total of from 3 to 7 ring atoms, inclusive of any heteroatoms that occupy a ring atom position.
- amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines (e.g., mono-substituted amines or di-substituted amines), wherein substituents may include, for example, alkyl, cycloalkyl, heterocyclyl, alkenyl, and aryl.
- alkoxy or “alkoxyl” are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto.
- Representative alkoxy groups include methoxy, ethoxy, tert-butoxy and the like.
- an “ether” is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as may be represented by one of —O-alkyl, —O-alkenyl, —O-alkynyl, and the like.
- carbonyl refers to the radical —C(O)—.
- oxo refers to a divalent oxygen atom —O—.
- Carboxamido refers to the radical —C(O)NRR′, where R and R′ may be the same or different.
- R and R′ for example, may be independently alkyl, aryl, arylalkyl, cycloalkyl, formyl, haloalkyl, heteroaryl, or heterocyclyl.
- carboxy refers to the radical —COOH or its corresponding salts, e.g. —COONa, etc.
- amide or “amido” or “amidyl” as used herein refers to a radical of the form —R 1 C(O)N(R 2 )—, —R 1 C(O)N(R 2 )R 3 —, —C(O)NR 2 R 3 , or —C(O)NH 2 , wherein R 1 , R 2 and R 3 , for example, are each independently alkoxy, alkyl, alkenyl, alkynyl, amino, aryl, arylalkyl, carbamate, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, or nitro.
- the compounds of the disclosure may contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as geometric isomers, enantiomers or diastereomers.
- stereoisomers when used herein consist of all geometric isomers, enantiomers or diastereomers. These compounds may be designated by the symbols “R” or “S” or “+” or “ ⁇ ” depending on the configuration of substituents around the stereogenic carbon atom and or the optical rotation observed.
- Stereoisomers include enantiomers and diastereomers.
- compositions comprising, consisting essentially of, or consisting of an enantiopure compound, which composition may comprise, consist essential of, or consist of at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of a single enantiomer of a given compound (e.g., at least about 99% of an R enantiomer of a given compound).
- the compounds disclosed herein may be referred to as beta-carboline compounds and in particular, substituted beta-carboline compounds.
- the disclosed compounds may be saturated at one or more bonds to form dihydro-beta-carboline compounds or tetrahydro-beta-carboline compounds.
- the disclosed compound may be described as compounds or a salts or solvates thereof having a Formula I:
- the disclosed compounds may have a Formula Ia:
- the disclosed compound have a Formula Ib:
- R 1 may be selected from hydrogen, alkyl (e.g., methyl), alkyoxy (e.g., methoxy), and halo (e.g., chloro).
- R 1 is selected from:
- R 2 is selected from phenyl, cyclohexyl, pyridinyl (e.g., N-pyridinyl, pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl), pyrimidinyl (e.g., pyrimidin-1-yl, pyrimidin-2-yl, pyrimidin-4-yl, or pyrimidin-5-yl), imidazolyl (e.g., imidazole-1-yl, imidazol-2-yl, or imidazole-4-yl), 1-methylimidazolyl (e.g., 1-methylimidazol-2-yl, 1-methylimidazol-3-yl, 1-methylimidazol-4-yl, or 1-methylimidazol-5-yl), piperidinyl (e.g., piperidin-2-yl, or piperidin-4-yl), 1-methyl-piperidin
- —(X) n —R 2 is selected from:
- the compounds disclosed herein, including the substituted beta-carboline compounds discussed above may have several chiral centers, and stereoisomers, epimers, and enantiomers are contemplated.
- the compounds may be optically pure with respect to one or more chiral centers (e.g., some or all of the chiral centers may be completely in the S configuration; some or all of the chiral centers may be completely in the R configuration; etc.). Additionally or alternatively, one or more of the chiral centers may be present as a mixture of configurations (e.g., a racemic or another mixture of the R configuration and the S configuration).
- compositions comprising substantially purified stereoisomers, epimers, or enantiomers, or analogs or derivatives thereof are contemplated herein (e.g., a composition comprising at least about 90%, 95%, 99% or 100% pure stereoisomer, epimer, or enantiomer.)
- formulae which do not specify the orientation at one or more chiral centers are meant to encompass all orientations and mixtures thereof.
- the compounds disclosed herein preferably modulate human serotonin receptor 2C (5-HT 2 c) activity and may be administered to a subject in need thereof to modulate 5-HT 2c receptor activity.
- Modulation may include activating or increasing human serotonin receptor 2C (5-HT 2 c) activity.
- Modulation also may include inhibiting or decreasing human serotonin receptor 2C (5-HT 2 c) activity.
- 5-HT 2c receptor activity may be assessed utilizing methods known in the art and the methods disclosed herein, including the methods disclosed in the Examples provided herein.
- the compounds decrease or increase 5-HT 2 , activity relative to a control (e.g., by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000% or more (or within a range bounded by any of these values)).
- the compounds activate the 5-HT 2c receptor greater than about 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, or 100-fold, relative to a control.
- the compounds activate the 5-HT 2c receptor with a maximum activation (E max ) greater than about 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000%, 1100%, 1200%, 1300%, 1400%, or 1500% (or within a range bounded by any of these values).
- an EC 50 value for the compound in regard to activation of the 5-HT 2c receptor may be determined and preferably the compound has an EC 50 value of less than about 10 ⁇ M, 5 ⁇ M, or 1 ⁇ M, 0.5 ⁇ M, 0.1 ⁇ M, 0.05 ⁇ M, 0.01 ⁇ M, 0.005 ⁇ M, or 0.001 ⁇ M (or within a range bounded by any of these values).
- K i value for the compound in regard to activation of the 5-HT 2c receptor may be determined and preferably the compound has an K i value of less than about 10 ⁇ M, 5 ⁇ M, or 1 ⁇ M, 0.5 ⁇ M, 0.1 ⁇ M, 0.05 ⁇ M, 0.01 ⁇ M, 0.005 ⁇ M, or 0.001 ⁇ M (or within a range bounded by any of these values).
- the compounds disclosed herein do not bind to and/or activate or inhibit the 5-HT 2a receptor or the 5-HT 2b receptor or any other receptor other than the 5-HT 2c receptor. If the compounds bind to and/or activate the 5-HT 2a receptor or the 5-HT 2 b receptor or any other receptor, preferably the compounds have an EC 50 for the 5-HT 2a receptor or the 5-HT 2b receptor or any other receptor that is greater than about 0.01 ⁇ M, 0.05 ⁇ M, 0.1 ⁇ M, 0.5 ⁇ M, 1 ⁇ M, 10 ⁇ M, 20 ⁇ M, 50 ⁇ M, 100 ⁇ M, 200 ⁇ M, 500 ⁇ M, or 1000 ⁇ M If the compounds bind to and/or activate the 5-HT 2a receptor or the 5-HT 2b receptor or any other receptor, preferably the compounds have a K i , for the 5-HT 2a receptor or the 5-HT 2b receptor or any other receptor that is greater than about 0.01 ⁇ M, 0.05 ⁇ M, 0.1 ⁇ M, 0.5
- compositions may take any physical form which is pharmaceutically acceptable; illustratively, they can be orally administered pharmaceutical compositions.
- Such pharmaceutical compositions contain an effective amount of a disclosed compound, which effective amount is related to the daily dose of the compound to be administered.
- Each dosage unit may contain the daily dose of a given compound or each dosage unit may contain a fraction of the daily dose, such as one-half or one-third of the dose.
- the amount of each compound to be contained in each dosage unit can depend, in part, on the identity of the particular compound chosen for the therapy and other factors, such as the indication for which it is given.
- the pharmaceutical compositions disclosed herein may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing well known procedures.
- the compounds for use according to the methods of disclosed herein may be administered as a single compound or a combination of compounds.
- a compound that modulates the 5-HT 2c receptor activity may be administered as a single compound or in combination with another compound that modulates the 5-HT 2c receptor activity or that has a different pharmacological activity.
- pharmaceutically acceptable salts of the compounds are contemplated and also may be utilized in the disclosed methods.
- pharmaceutically acceptable salt refers to salts of the compounds which are substantially non-toxic to living organisms.
- Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds as disclosed herein with a pharmaceutically acceptable mineral or organic acid or an organic or inorganic base. Such salts are known as acid addition and base addition salts. It will be appreciated by the skilled reader that most or all of the compounds as disclosed herein are capable of forming salts and that the salt forms of pharmaceuticals are commonly used, often because they are more readily crystallized and purified than are the free acids or bases.
- Acids commonly employed to form acid addition salts may include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
- inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like
- organic acids such as p-toluenesulfonic, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
- Suitable pharmaceutically acceptable salts may include the sulfate, pyrosulfate, bisulfate, sulfite, bisulfate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleat-, butyne-.1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbuty
- Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like.
- Bases useful in preparing such salts include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like.
- the particular counter-ion forming a part of any salt of a compound disclosed herein is may not be critical to the activity of the compound, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole.
- Undesired qualities may include undesirably solubility or toxicity.
- esters and amides of the compounds can also be employed in the compositions and methods disclosed herein.
- suitable esters include alkyl, aryl, and aralkyl esters, such as methyl esters, ethyl esters, propyl esters, dodecyl esters, benzyl esters, and the like.
- suitable amides include unsubstituted amides, monosubstituted amides, and disubstituted amides, such as methyl amide, dimethyl amide, methyl ethyl amide, and the like.
- solvate forms of the compounds or salts, esters, and/or amides, thereof.
- Solvate forms may include ethanol solvates, hydrates, and the like.
- the pharmaceutical compositions may be utilized in methods of treating and/or preventing a disease, disorder, or condition associated with 5-HT 2c receptor activity.
- the pharmaceutical compositions may be utilized to treat patients having or at risk for acquiring a psychiatric disease or disorder or condition.
- Suitable patients include, for example mammals, such as humans and non-human primates (e.g., chimps) or other mammals (e.g., dogs, cats, horses, rats, and mice).
- Suitable human patients may include, for example, those who have previously been determined to be at risk of having or developing a psychiatric disease, disorder, or condition associate with 5-HT 2c receptor activity.
- an effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances.
- determining the effective amount or dose of compound administered a number of factors can be considered by the attending diagnostician, such as: the species of the subject; its size, age, and general health; the degree of involvement or the severity of the disease or disorder involved; the response of the individual subject; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.
- a typical daily dose may contain from about 0.01 mg/kg to about 100 mg/kg (such as from about 0.05 mg/kg to about 50 mg/kg and/or from about 0.1 mg/kg to about 25 mg/kg) of each compound used in the present method of treatment.
- compositions can be formulated in a unit dosage form, each dosage containing from about 1 to about 500 mg of each compound individually or in a single unit dosage form, such as from about 5 to about 300 mg, from about 10 to about 100 mg, and/or about 25 mg.
- unit dosage form refers to a physically discrete unit suitable as unitary dosages for a patient, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier, diluent, or excipient.
- Oral administration is an illustrative route of administering the compounds employed in the compositions and methods disclosed herein.
- Other illustrative routes of administration include transdermal, percutaneous, intravenous, intramuscular, intranasal, buccal, intrathecal, intracerebral, or intrarectal routes.
- the route of administration may be varied in any way, limited by the physical properties of the compounds being employed and the convenience of the subject and the caregiver.
- suitable formulations include those that are suitable for more than one route of administration.
- the formulation can be one that is suitable for both intrathecal and intracerebral administration.
- suitable formulations include those that are suitable for only one route of administration as well as those that are suitable for one or more routes of administration, but not suitable for one or more other routes of administration.
- the formulation can be one that is suitable for oral, transdermal, percutaneous, intravenous, intramuscular, intranasal, buccal, and/or intrathecal administration but not suitable for intracerebral administration.
- compositions contain from about 0.5% to about 50% of the compound in total, depending on the desired doses and the type of composition to be used.
- amount of the compound is best defined as the “effective amount”, that is, the amount of the compound which provides the desired dose to the patient in need of such treatment.
- Capsules are prepared by mixing the compound with a suitable diluent and filling the proper amount of the mixture in capsules.
- suitable diluents include inert powdered substances (such as starches), powdered cellulose (especially crystalline and microcrystalline cellulose), sugars (such as fructose, mannitol and sucrose), grain flours, and similar edible powders.
- Tablets are prepared by direct compression, by wet granulation, or by dry granulation. Their formulations usually incorporate diluents, binders, lubricants, and disintegrators (in addition to the compounds). Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts (such as sodium chloride), and powdered sugar. Powdered cellulose derivatives can also be used. Typical tablet binders include substances such as starch, gelatin, and sugars (e.g., lactose, fructose, glucose, and the like). Natural and synthetic gums can also be used, including acacia, alginates, methylcellulose, polyvinylpyrrolidine, and the like. Polyethylene glycol, ethylcellulose, and waxes can also serve as binders.
- Typical diluents include, for example, various types of starch, lactos
- Tablets can be coated with sugar, e.g., as a flavor enhancer and sealant.
- the compounds also may be formulated as chewable tablets, by using large amounts of pleasant-tasting substances, such as mannitol, in the formulation.
- Instantly dissolving tablet-like formulations can also be employed, for example, to assure that the patient consumes the dosage form and to avoid the difficulty that some patients experience in swallowing solid objects.
- a lubricant can be used in the tablet formulation to prevent the tablet and punches from sticking in the die.
- the lubricant can be chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid, and hydrogenated vegetable oils.
- Tablets can also contain disintegrators.
- Disintegrators are substances that swell when wetted to break up the tablet and release the compound. They include starches, clays, celluloses, algins, and gums. As further illustration, corn and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation-exchange resins, alginic acid, guar gum, citrus pulp, sodium lauryl sulfate, and carboxymethylcellulose can be used.
- compositions can be formulated as enteric formulations, for example, to protect the active ingredient from the strongly acid contents of the stomach.
- Such formulations can be created by coating a solid dosage form with a film of a polymer which is insoluble in acid environments and soluble in basic environments.
- Illustrative films include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose acetate succinate.
- cocoa butter is a traditional suppository base.
- the cocoa butter can be modified by addition of waxes to raise its melting point slightly.
- Water-miscible suppository bases such as polyethylene glycols of various molecular weights, can also be used in suppository formulations.
- Transdermal patches can also be used to deliver the compounds.
- Transdermal patches can include a resinous composition in which the compound will dissolve or partially dissolve; and a film which protects the composition and which holds the resinous composition in contact with the skin.
- Other, more complicated patch compositions can also be used, such as those having a membrane pierced with a plurality of pores through which the drugs are pumped by osmotic action.
- the formulation can be prepared with materials (e.g., actives excipients, carriers (such as cyclodextrins), diluents, etc.) having properties (e.g., purity) that render the formulation suitable for administration to humans.
- materials e.g., actives excipients, carriers (such as cyclodextrins), diluents, etc.
- properties e.g., purity
- the formulation can be prepared with materials having purity and/or other properties that render the formulation suitable for administration to non-human subjects, but not suitable for administration to humans.
- formulations are illustrative. These illustrative formulations may be suitable for preparing pharmaceutical compositions that include the disclosed compounds as “active ingredients.”
- active ingredients include the disclosed compounds as “active ingredients.”
- formulations is illustrative and should not be interpreted as limiting the present disclosure or claims in any way:
- Hard gelatin capsules are prepared using the following ingredients:
- Quantity (mg/capsule) Active Ingredient 250 Starch, dried 200 Magnesium stearate 10 Total 460 mg The above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities.
- Quantity (mg/tablet) Active Ingredient 250 Cellulose, microcrystalline 400 Silicon dioxide, fumed 10 Stearic acid 5 Total 665 mg The components are blended and compressed to form tablets each weighing 665 mg.
- An aerosol solution is prepared containing the following components:
- Weight % Active Ingredient 0.25 Ethanol 29.75 Propellant 22 (chlorodifluoromethane) 70.00 Total 100.00
- the active compound is mixed with ethanol and the mixture added to a portion of the Propellant 22, cooled to ⁇ 30° C. and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the remainder of the propellant. The valve units are then fitted to the container.
- Tablets each containing 60 mg of active ingredient are made as follows:
- Active Ingredient 60 mg Starch 45 mg Microcrystalline cellulose 35 mg Polyvinylpyrrolidone 4 mg Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1 mg Total 150 mg
- the active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly.
- the solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve.
- the granules so produced are dried at 50° C. and passed through a No. 18 mesh U.S. sieve.
- the sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
- Capsules each containing 80 mg medicament, are made as follows:
- Active Ingredient 80 mg Starch 59 mg Microcrystalline cellulose 59 mg Magnesium stearate 2 mg Total 200 mg The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 45 sieve, and filled into hard gelatin capsules in 200 mg quantities.
- Suppositories each containing 225 mg of active ingredient may be made as follows:
- the active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary.
- the mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool.
- the medicament is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl, cellulose and syrup to form a smooth paste.
- the benzoic acid solution, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.
- An intravenous formulation containing 100 mg of medicament per 5 ml dose can be prepared as follows:
- Embodiment 1 A compound or a salt or solvate thereof having a Formula I:
- Embodiment 2 The compound of embodiment 1 having Formula Ia:
- Embodiment 3 The compound of embodiment 1 having a Formula Ib:
- Embodiment 4 The compound of embodiment 1 having a Formula Ic:
- Embodiment 5 The compound of embodiment 1 having a Formula Id:
- Embodiment 6 The compound of embodiment 1 having a Formula Ie:
- Embodiment 7 The compound of embodiment 1, wherein R 1 is selected from hydrogen, alkyl, hydroxyl, alkyoxy, and halo.
- Embodiment 8 The compound of embodiment 4, wherein R 1 is selected from:
- Embodiment 9 The compound of embodiment 1, wherein R 2 is selected from phenyl, cyclohexyl, pyridinyl, pyrimidinyl, imidazolyl, 1-methylimidazolyl; piperidinyl, 1-methyl-piperidinyl, piperazinyl, 1-methyl-piperazinyl, tetrahydropyranyl, and morpholinyl.
- Embodiment 10 The compound of embodiment 1, wherein —(X) n —R z is selected from:
- Embodiment 11 The compound of embodiment 5, wherein —(X) n —R 2 is selected from:
- Embodiment 12 The compound of any of the foregoing embodiments with the proviso that at least one of R 1 , R 2 , and R 3 is not hydrogen.
- Embodiment 13 The compound of embodiment 1 having a formula:
- Embodiment 14 The compound of embodiment 1 having a formula selected from:
- Embodiment 15 A compound having a formula of any of the compounds of embodiments 1-14 or a compound having a formula of any compound disclosed in this application for use in treating and/or preventing a disease, disorder, or condition that is associated with 5-HT 2c receptor activity in a subject in need thereof.
- Embodiment 16 A pharmaceutical composition comprising any of the compounds of the foregoing embodiments and a pharmaceutical carrier.
- Embodiment 17 A method for treating and/or preventing a disease, disorder, or condition that is associated with 5-HT 2c receptor activity in a subject in need thereof, the method comprising administering to the subject the compound of any of embodiments 1-15 or the pharmaceutical composition of embodiment 16.
- Embodiment 18 The method of embodiment 17, wherein the disease or disorder is a psychiatric, mental, or neurological disease, disorder, or condition.
- Embodiment 19 The method of embodiment 17, wherein the disease, disorder, or condition is cognitive impairment, addiction, and/or obsessive compulsive disorder (OCD).
- OCD obsessive compulsive disorder
- Embodiment 20 The method of embodiment 17, wherein the disease, disorder, or condition is obesity and the method results in suppressing the appetite of the subject.
- Beta-carbolines as Positive Allosteric Modulators of the Human Serotonin Receptor 2c (5-HT 2c )
- the technical field of the disclosed subject matter relates to small molecule drug development.
- the disclosed small molecules provide a drug platform that has potential to treat cognitive impairment, addiction, obsessive compulsive disorder, and obesity via appetite suppression.
- the disclosed small molecules have potential for treating cognitive impairment (CI), for which there is currently no direct treatment.
- the disclosed small molecules also have potential for treating addition.
- CI cognitive impairment
- the disclosed small molecules also have potential for treating addition.
- CI cognitive impairment
- the disclosed small molecules also have potential for treating addiction.
- OCD obsessive compulsive disorder
- OCD is most often treated with antidepressant medications, but often patients do not respond to these medications. Electroconvulsive therapy can be tried in these cases, but this therapy is largely regarded as ineffective.
- Applications of the disclosed small molecules include, but are not limited to treatment of a range of neurological disorders and diseases that are associated with 5-HT 2 , activity.
- Disorders and diseases that may be treated with the disclosed small molecules may include cognitive impairment (CI), addiction, and obsessive compulsive disorder (OCD).
- CI cognitive impairment
- OCD obsessive compulsive disorder
- the disclosed small molecules also may suppress appetite and therefore may be administered to treat obesity and eating disorders.
- Small molecules have been designed having a substituted beta-carboline core and based on known yohimbine natural products alstonine and serpentine.
- the disclosed small molecuels exhibit in vivo activity consistent with agonism or positive allosteric modulation of the serotonin receptor 5-HT 2 c.
- 1-phenyl-9H-pyrido[3,4-b]indol-6-ol was synthesized according to general procedure B and was purified on 10 g silica gel, with a gradient of [10 g silica, dichloromethane to 4% methanol/96% dichloromethane to give the title product (0.359 g, 53%) as a tan solid;
- AJC-61 1-(pyrimidin-5-yl)-9H-pyrido[3,4-b]indol-6-ol (AJC-61) was synthesized according to general procedure B and was purified on 25 g silica gel, with a gradient of dichloromethane to 50% acetone/50% dichloromethane to give the title product (0.024 g, 5%) as a yellow solid;
- AJC-61 2C agonist inactive antagonist >10 ⁇ M 2A agonist inactive antagonist no data
- MJO-01-31 2C agonist 10.1 nM Emax 101% 2A agonist 54.6 nM Emax 95% MJO-01-34 2C agonist 85.9 nM Emax 103% 2A agonist 106 nM Emax 27% MJO-01-46 2C agonist 5.37 nM Emax 98% 2A agonist 11.3 nM Ernax 96%
- Mouse models were utilized to demonstrate the potential of compound AJC-61 in treating and or affecting psychotic spectrum disorder-schizophrenia including cognitive impairment of schizophrenia, negative symptoms of schizophrenia including deficit in social interaction, bipolar disorder, major depression including psychotic major depression, locomotor activity suppression-specific for positive (psychotic) symptoms of schizophrenia, psychoses of Alzheimer's disease and Parkinson's disease, obsessive compulsive disorder, Tourette's syndrome, and age-associated cognitive impairment.
- LMA Locomotor Activity
- PCP phencyclidine
- the Novel Object Recognition test in rodents is considered a valid model of spatial memory in man.
- the time spent viewing an object seen previously versus the time spent viewing a novel object i.e., the Discrimination Index (DI)
- DI Discrimination Index
- Normal mice remember for ⁇ 24 hours.
- the time to loss of the memory in aged mice can be as low as zero to less than 8 hours.
- FIG. 3 we observed a significant increase in DI in the PCP+AJC-61—treated mice versus the PCP-treated mice.
- a healthy mouse will vigorously explore a newly introduce mouse and retain the memory for that mouse for up to 24 hours.
- the loss of interest in exploring a novel mouse is considered a sign of negative symptoms.
- PCP-treatment produces a deficit in social interaction which models negative symptoms in schizophrenia. These include lack of motivation, loss of interest in activities, diminished capacity for pleasure and spontaneous activity.
- AJC-61 was tested the effect of AJC-61 on Social Interaction in mice that had been treated with PCP, including a Social Behaviors that include sniffing, following, and avoiding and Object Exploration via interaction with an inanimate object.
- sniffing we observed a significant reduction in sniffing for the PCP group versus the Vehicle group, and a significant increase in sniffing for the PCP+AJC-61 versus group versus the PCP group.
- PCP+AJC-61 a significant increase in sniffing for the PCP+AJC-61 versus group versus the PCP group.
- PCP+AJC-61 we observed no significant change, although there was non-significant reduction in following in the PCP group versus the Vehicle group.
- the Porsolt Forced Swim Test is a gold standard test for antidepressant action.
- FST The Porsolt Forced Swim Test
- normal mice become immobile after being required to swim in a tank and begin to float instead of struggling to get out of the water.
- Antidepressant drugs have been shown to increase the amount of time that a mouse will continue to swim prior to floating.
- AJC-61 could increase the swim time in a FST.
- treatment with PCP significantly increased the immobility time whereas treatment with PCP+AJC-61 significantly decreased the immobility time.
- Aged mice show a decline in memory function beginning around 13-15 month of age. Drugs which enhance memory can be assessed using the Novel Object Recognition test and determination of the Discrimination Index (DI) as discussed above.
- DI Discrimination Index
- FIG. 8 we observed a significant decrease in the DI for 22-month old mice versus the DI for 2.5 month old mice, and we observed a significant increase in the DI for 22-month old mice when the mice were treated with AJC-61.
Abstract
Disclosed are novel small molecules, methods of synthesis of the small molecules, and uses of the small molecules for modulating activity of the human serotonin receptor 2C (5-HT2c), preferably selectively. The small molecules have a substituted beta-carboline core structure, which optionally may be saturated at one or more bonds to provide a dihydro-beta-carboline core or a tetrahydro-beta-carboline core. The small molecules may be administered to treat and/or prevent diseases, disorders, and/or conditions associated with human serotonin receptor 2C (5-HT2c) including psychiatric, mental, and/or neurological diseases, disorders, and conditions such as cognitive impairment, addiction, and obsessive compulsive disorder. The disclosed small molecules also may be administered to treat and/or prevent obesity, for example, via appetite suppression.
Description
- The present application is the U.S. National Stage Entry of International Application PCT/US2019/054337, filed Oct. 2, 2019, which claims the benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 62/740,084, filed Oct. 2, 2018, the contents of which are incorporated herein by reference in their entireties.
- The field of the invention relates to novel small molecules, methods of synthesis of the small molecules, and uses of the small molecules for modulating activity of the human serotonin receptor 2C (5-HT2c). The small molecules have a substituted beta-carboline core structure, which optionally may be saturated at one or more bonds to provide a dihydro-beta-carboline core or a tetrahydro-beta-carboline core. The small molecules may be administered to treat and/or prevent diseases, disorder, and condition associated with human serotonin receptor 2C (5-HT2c) activity including psychiatric, mental, and/or neurological diseases, disorders, and conditions such as cognitive impairment, addiction, and obsessive compulsive disorder.
- Serotonin receptors, otherwise referred to as 5-hydroxytryptamine receptors or 5-HT receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in the central and peripheral nervous systems. (See Hoyer et al., (1994). “International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin)”. Pharmacol. Rev. 46 (2): 157-203. PMID 7938165; Frazer et al., “Chapter 13: Serotonin Receptors”. In Siegel et al. Basic Neurochemistry: Molecular, Cellular, and Medical Aspects. Philadelphia: Lippincott-Raven. pp. 263-292; and Beliveau et al. (2017-01-04). “A High-Resolution In Vivo Atlas of the Human Brain's Serotonin System”. Journal of Neuroscience. 37 (1): 120-128. doi:10.1523/jneurosci.2830-16.2016; the contents of which are incorporated herein by reference in their entireties). Serotonin receptors mediate excitatory neurotransmission and inhibitory neurotransmission. The serotonin receptors, as they name indicates, are activated by the neurotransmitter serotonin, which is their natural ligand. Serotonin receptors modulate the release of many neurotransmitters, including glutamate, GABA, dopamine, epinephrine/norepinephrine, and acetylcholine, as well as many hormones, including oxytocin, prolactin, vasopressin, cortisol, corticotropin, and substance P, among others. The serotonin receptors influence various biological and neurological processes such as aggression, anxiety, cognition, learning, memory, mood, appetite, nausea, sleep, and thermoregulation. (See Nichols et al., (May 2008). “Serotonin receptors.” Chem. Rev. 108(5): 1614-41; the content of which is incorporate herein by reference in its entirety).
- The 5-HT2 family of serotonin receptors mediates excitatory neurotransmission via a Gq/G11-protein coupled molecular mechanism that increases cellular levels of inositol triphosphate (IP3) and diacylglycerol (DAG). The 5-HT-2 family includes three members: 5-HT2a, 5-HT2b, and 5-HT2c. The 5-HT2a receptor modulates addiction, anxiety, appetite, cognition, imagination, learning, memory, mood, perception, sexual behavior, sleep, thermoregulation, and vasoconstriction. The 5-HT2b receptor modulates anxiety, appetite, cardiovascular function, gastrointestinal motility, sleep, and vasoconstriction. The 5-HT2c receptor modulates addiction, anxiety, appetite, gastrointestinal motility, locomotion, mood, penile erection, sexual behavior, sleep, thermoregulation, and vasoconstriction. Notably, the 5-HT2a, 5-HT2b, and 5-HT2c exhibit differing affinities for agonists and antagonists and may function as heteroreceptors for ligands other than serotonin. For example, 5-HT2c receptor is a heteroreceptor for norepinephrine and dopamine.
- Here, we disclose novel substituted beta-carboline compounds which function as positive allosteric modulators of the human serotonin receptor 2C (5-HT2c). The disclosed small molecules preferably act selectively as positive allosteric modulators of the human serotonin receptor 2C (5-HT2c), relative to other 5-HT receptors such as 5-HT2a, 5-HT2b. As such, the small molecules may be administered to treat and/or prevent diseases, disorder, and condition associated with human serotonin receptor 2C (5-HT2c) including psychiatric, mental, and/or neurological diseases, disorders, and conditions such as cognitive impairment, addiction, and obsessive compulsive disorder.
- Disclosed are novel small molecules, methods of synthesis of the small molecules, and uses of the small molecules for modulating activity of the human serotonin receptor 2C (5-HT2c), preferably selectively. The small molecules have a substituted beta-carboline core structure, which optionally may be saturated at one or more bonds to provide a dihydro-beta-carboline core or a tetrahydro-beta-carboline core. The small molecules may be administered to treat and/or prevent diseases, disorders, and/or conditions associated with human serotonin receptor 2C (5-HT2c) including psychiatric, mental, and/or neurological diseases, disorders, and conditions such as cognitive impairment, addiction, and obsessive compulsive disorder (OCD). The disclosed small molecules also may be administered to treat and/or prevent obesity, for example, via appetite suppression.
-
FIG. 1 . Locomotor Activity: AJC-61 blocked amphetamine-induced increase in locomotor activity in mice. The effect of AJC-61 (2 mg/kg) on amphetamine-induced (2.5 mg/kg) increase in locomotor activity in mice. Data are presented as group means±S.E.M. for eight successive 15 minute intervals. *** p<0.001: significant increase in LMA versus Vehicle+Vehicle; ###p<0.001: significant decrease in LMA versus Vehicle+AJC-61 (2 mg/kg)+amphetamine (2.5 mg/kg). -
FIG. 2 . Locomotor Activity: AJC-61 blocked PCP-induced increase in locomotor activity in mice. The effect of AJC-61 (2 mg/kg) on PCP-induced (10 mg/kg) increase in locomotor activity in mice. Data are presented as group means S.E.M. for eight successive 15 minute intervals. *** p<0.001: significant increase in LMA versus Vehicle+Vehicle; ###p<0.001: significant decrease in LMA versus Vehicle+AJC-61 (2 mg/kg)+PCP (10 mg/kg). sc-subchronic. -
FIG. 3 . Novel Object Recognition: Discrimination index (DI) for male C57BL/6J mice treated with Vehicle, PCP (10 mg/kg), and PCP+AJC-61 (2 mg/kg). Data are shown as mean S.E.M. of exploration time (s) n=10 mice per group. Significant differences were observed in the DI; *** p<0.001—significant decrease in DI in Vehicle versus PCP group. ###p<0.001—significant increase in DI in PCP versus PCP+AJC-61, one-way ANOVA followed by post-hoc Bonferroni. -
FIG. 4 . Social Interaction: Effect of Vehicle, PCP (10 mg/kg: i.p., 7 days: b.i.d.), and PCP+AJC-61 (2 mg/kg), on social behaviors (sniffling, following, and avoiding) and interaction with inanimate object (object exploration), in a 10-minute social interaction (SI) paradigm. Data were analyzed by one-way ANOVA comparing the effect of drug treatment on each behavior and are shown as mean±S.E.M. of time (s); n=10 pairs of mice per group. Sniffing—*** p, 0.001: Significant reduction for PCP versus Vehicle group; ###p<0.001; Significant increase for PCP+AJC-61 versus PCP group. Following—No significant change, although there was non-significant reduction in following in the PCP versus Vehicle group. Avoiding—*** p<0.001: Significant increase for PCP versus Vehicle group; ###p<0.001: Significant decrease for PCP+AJC-61 versus PCP group. Object Exploration—No significant change, although there was a non-significant increase in object exploration in the PCP versus Vehicle group. -
FIG. 5 . Porsolt Forced Swim Test (FST). Effect of Vehicle, PCP (10 mg/kg; i.p., 7 days; b.i.d.), and PCP+AJC-61 (2 mg/kg), in a 6-min Porsolt Forced Swim Test (FST). Data were analyzed by one-way ANOVA comparing the effect of drug treatment on each behavior and are shown as mean S.E.M. of time (s): n=12 pairs of mice per group. *** p<0.001: Significant increase in immobility time for PCP versus Vehicle group; ###p<0.001: Significant decrease in immobility time for PCP+AJC-16 versus PCP group. -
FIG. 6 . Marble Burying Task (MBT): Effect of Vehicle, PCP (10 mg/kg; i.p., 7 days; b.i.d.), and PCP+AJC-61 (2 mg/kg) in a 30-minute Marble Burying Task (MBT) paradigm. Data were analyzed by one-way ANOVA comparing the effect of drug treatment on each behavior and are shown as mean S.E.M. of time (s): n=12 pairs of mice per group. *** p<0.001: Significant increase in the number of marbles buried for PCP versus Vehicle group; ###p<0.001: Significant decrease in the number of marbles buried for PCP+AJC-16 versus PCP group. -
FIG. 7 . Nestlet Shredding (NS): Effect of Vehicle, PCP (10 mg/kg; i.p., 7 days; b.i.d.), and PCP+AJC-61 (2 mg/kg) in a 30-minute Nestlet Shredding (NS) paradigm. Data were analyzed by one-way ANOVA comparing the effect of drug treatment on each behavior and are shown as mean±S.E.M. of time (s): n=10 pairs of mice per group. *** p<0.001: Significant increase in the percent nestlet shredded for PCP versus Vehicle group; ###p<0.001: Significant decrease in the percent nestlet shredded for PCP+AJC-16 versus PCP group. -
FIG. 8 . Novel Object Recognition: Effect on discrimination index (DI) of Vehicle and AJC-61 (2 mg/kg) on 2.5 month old mice and 22-month old mice Data are shown as mean S.E.M. of exploration time (s): n=14 pairs of mice per group. Significant difference were observed in the DI: *** p<0.001: Significant decrease in the DI for 22-month old mice versus 2.5 month old mice; ###p<0.001: Significant increase in the DI for 22-month old mice treated with AJC-61 versus Vehicle. - The disclosed subject matter further may be described utilizing terms as defined below.
- Unless otherwise specified or indicated by context, the terms “a” “an”, and “the” mean “one or more.” For example, “a modulator of human serotonin receptor 2C (5-HT2c) activity” should be interpreted to mean “one or more modulators of human serotonin receptor 2C (5-HT2c) activity.”
- As used herein, “about”, “approximately,” “substantially,” and “significantly” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which they are used. If there are uses of the term which are not clear to persons of ordinary skill in the art given the context in which it is used, “about” and “approximately” will mean plus or minus ≤10% of the particular term and “substantially” and “significantly” will mean plus or minus >10% of the particular term.
- As used herein, the terms “include” and “including” have the same meaning as the terms “comprise” and “comprising.” The terms “comprise” and “comprising” should be interpreted as being “open” transitional terms that permit the inclusion of additional components further to those components recited in the claims. The terms “consist” and “consisting of” should be interpreted as being “closed” transitional terms that do not permit the inclusion additional components other than the components recited in the claims. The term “consisting essentially of” should be interpreted to be partially closed and allowing the inclusion only of additional components that do not fundamentally alter the nature of the claimed subject matter.
- The terms “subject,” “patient,” and “individual” may be used interchangeably herein. A subject may be a human subject. A subject may refer to a human subject having or at risk for acquiring a disease, disorder, or condition, that is associated with human serotonin receptor 2C (5-HT2c) activity. In specific embodiments, the disease, disorder, or condition is a psychiatric, mental, and/or neurological disease, disorder, or condition. Psychiatric, mental, and/or neurological disease, disorders, or conditions may include, but are not limited to, cognitive impairment, addiction, and obsessive compulsive disorder (OCD). The disclosed small molecules also may be administered to treat and/or prevent obesity, for example, via appetite suppression, where the treated and/or prevented disorder or condition is an eating disorder and/or obesity.
- As used herein, the term “modulate” means decreasing or inhibiting activity and/or increasing or augmenting activity. For example, modulating human serotonin receptor 2C (5-HT2c) activity may mean increasing or augmenting human serotonin receptor 2C (5-HT2c) activity and/or decreasing or inhibiting human serotonin receptor 2C (5-HT2c) activity. Preferably, the disclosed novel molecules increase or augment human serotonin receptor 2C (5-HT2c) activity as positive allosteric ligands or agonists.
- As used herein, the phrase “effective amount” shall mean that drug dosage that provides the specific pharmacological response for which the drug is administered in a significant number of patients in need of such treatment. An effective amount of a drug that is administered to a particular patient in a particular instance will not always be effective in treating the conditions/diseases described herein, even though such dosage is deemed to be a therapeutically effective amount by those of skill in the art.
- New Chemical Entities
- New chemical entities and uses for chemical entities are disclosed herein. The chemical entities may be described using terminology known in the art and further discussed below.
- As used herein, an asterisk “*” or a plus sign “+” may be used to designate the point of attachment for any radical group or substituent group.
- The term “alkyl” as contemplated herein includes a straight-chain or branched alkyl radical in all of its isomeric forms, such as a straight or branched group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as C1-C12 alkyl, C1-C10-alkyl, and C1-C6-alkyl, respectively.
- The term “alkylene” refers to a diradical of an alkyl group (e.g., —(CH2)n— where n is an integer such as an integer between 1 and 20). An exemplary alkylene group is —CH2CH2—.
- The term “haloalkyl” refers to an alkyl group that is substituted with at least one halogen. For example, —CH2F, —CHF2, —CF3, —CH2CF3, —CF2CF3, and the like.
- The term “heteroalkyl” as used herein refers to an “alkyl” group in which at least one carbon atom has been replaced with a heteroatom (e.g., an O, N, or S atom). One type of heteroalkyl group is an “alkoxy” group.
- The term “alkenyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 2-12, 2-10, or 2-6 carbon atoms, referred to herein as C2-C12-alkenyl, C2-C10-alkenyl, and C2-C6-alkenyl, respectively.
- The term “alkynyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond, such as a straight or branched group of 2-12, 2-10, or 2-6 carbon atoms, referred to herein as C2-C12-alkynyl, C2-C10-alkynyl, and C2-C6-alkynyl, respectively.
- The term “cycloalkyl” refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as “C4-8-cycloalkyl,” derived from a cycloalkane. Unless specified otherwise, cycloalkyl groups are optionally substituted at one or more ring positions with, for example, alkanoyl, alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halo, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl or thiocarbonyl. In certain embodiments, the cycloalkyl group is not substituted, i.e., it is unsubstituted.
- The term “cycloalkylene” refers to a cycloalkyl group that is unsaturated at one or more ring bonds.
- The term “partially unsaturated carbocyclyl” refers to a monovalent cyclic hydrocarbon that contains at least one double bond between ring atoms where at least one ring of the carbocyclyl is not aromatic. The partially unsaturated carbocyclyl may be characterized according to the number of ring carbon atoms. For example, the partially unsaturated carbocyclyl may contain 5-14, 5-12, 5-8, or 5-6 ring carbon atoms, and accordingly be referred to as a 5-14, 5-12, 5-8, or 5-6 membered partially unsaturated carbocyclyl, respectively. The partially unsaturated carbocyclyl may be in the form of a monocyclic carbocycle, bicyclic carbocycle, tricyclic carbocycle, bridged carbocycle, spirocyclic carbocycle, or other carbocyclic ring system. Exemplary partially unsaturated carbocyclyl groups include cycloalkenyl groups and bicyclic carbocyclyl groups that are partially unsaturated. Unless specified otherwise, partially unsaturated carbocyclyl groups are optionally substituted at one or more ring positions with, for example, alkanoyl, alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl or thiocarbonyl. In certain embodiments, the partially unsaturated carbocyclyl is not substituted, i.e., it is unsubstituted.
- The term “aryl” is art-recognized and refers to a carbocyclic aromatic group. Representative aryl groups include phenyl, naphthyl, anthracenyl, and the like. The term “aryl” includes polycyclic ring systems having two or more carbocyclic rings in which two or more carbons are common to two adjoining rings (the rings are “fused rings”) wherein at least one of the rings is aromatic and, e.g., the other ring(s) may be cycloalkyls, cycloalkenyls, cycloalkynyls, and/or aryls. Unless specified otherwise, the aromatic ring may be substituted at one or more ring positions with, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, carboxylic acid, —C(O)alkyl, —CO2alkyl, carbonyl, carboxyl, alkylthio, sulfonyl, sulfonamido, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl or heteroaryl moieties, —CF3, —CN, or the like. In certain embodiments, the aromatic ring is substituted at one or more ring positions with halogen, alkyl, hydroxyl, or alkoxyl. In certain other embodiments, the aromatic ring is not substituted, i.e., it is unsubstituted. In certain embodiments, the aryl group is a 6-10 membered ring structure.
- The terms “heterocyclyl” and “heterocyclic group” are art-recognized and refer to saturated, partially unsaturated, or aromatic 3- to 10-membered ring structures, alternatively 3- to 7-membered rings, whose ring structures include one to four heteroatoms, such as nitrogen, oxygen, and sulfur. The number of ring atoms in the heterocyclyl group can be specified using 5 Cx-Cx nomenclature where x is an integer specifying the number of ring atoms. For example, a C3-C7 heterocyclyl group refers to a saturated or partially unsaturated 3- to 7-membered ring structure containing one to four heteroatoms, such as nitrogen, oxygen, and sulfur. The designation “C3-C7” indicates that the heterocyclic ring contains a total of from 3 to 7 ring atoms, inclusive of any heteroatoms that occupy a ring atom position.
- The terms “amine” and “amino” are art-recognized and refer to both unsubstituted and substituted amines (e.g., mono-substituted amines or di-substituted amines), wherein substituents may include, for example, alkyl, cycloalkyl, heterocyclyl, alkenyl, and aryl.
- The terms “alkoxy” or “alkoxyl” are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxy groups include methoxy, ethoxy, tert-butoxy and the like.
- An “ether” is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as may be represented by one of —O-alkyl, —O-alkenyl, —O-alkynyl, and the like.
- The term “carbonyl” as used herein refers to the radical —C(O)—.
- The term “oxo” refers to a divalent oxygen atom —O—.
- The term “carboxamido” as used herein refers to the radical —C(O)NRR′, where R and R′ may be the same or different. R and R′, for example, may be independently alkyl, aryl, arylalkyl, cycloalkyl, formyl, haloalkyl, heteroaryl, or heterocyclyl.
- The term “carboxy” as used herein refers to the radical —COOH or its corresponding salts, e.g. —COONa, etc.
- The term “amide” or “amido” or “amidyl” as used herein refers to a radical of the form —R1C(O)N(R2)—, —R1C(O)N(R2)R3—, —C(O)NR2R3, or —C(O)NH2, wherein R1, R2 and R3, for example, are each independently alkoxy, alkyl, alkenyl, alkynyl, amino, aryl, arylalkyl, carbamate, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, or nitro.
- The compounds of the disclosure may contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as geometric isomers, enantiomers or diastereomers. The term “stereoisomers” when used herein consist of all geometric isomers, enantiomers or diastereomers. These compounds may be designated by the symbols “R” or “S” or “+” or “−” depending on the configuration of substituents around the stereogenic carbon atom and or the optical rotation observed. The present invention encompasses various stereo isomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be designated (±)” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. It is understood that graphical depictions of chemical structures, e.g., generic chemical structures, encompass all stereoisomeric forms of the specified compounds, unless indicated otherwise. Also contemplated herein are compositions comprising, consisting essentially of, or consisting of an enantiopure compound, which composition may comprise, consist essential of, or consist of at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of a single enantiomer of a given compound (e.g., at least about 99% of an R enantiomer of a given compound).
- Beta-Carboline Compounds and Uses Thereof for Modulating 5-HT2, Receptor Activity
- The compounds disclosed herein may be referred to as beta-carboline compounds and in particular, substituted beta-carboline compounds. Optionally, the disclosed compounds may be saturated at one or more bonds to form dihydro-beta-carboline compounds or tetrahydro-beta-carboline compounds.
- In some embodiments, the disclosed compound may be described as compounds or a salts or solvates thereof having a Formula I:
- where:
-
- n is 0 or 1;
- X is CH2, NH, or O;
- R1 is selected from hydrogen, hydroxyl, alkyl (e.g. methyl), alkoxy (e.g., methoxy), halo (e.g., fluoro, chloro, bromo, iodo), haloalkyl (e.g., trifluoromethyl), amino, alkylamino, and cyano;
- R2 is hydrogen, alkyl, or a 3-7 membered carbocycle or heterocycle which is saturated or unsaturated at one or more bonds and which heterocycle includes one or more heteroatoms selected from N, O, and S, optionally which carbocycle or heterocycle is substituted to include one or more non-hydrogen substituents, which non-hydrogen substituents optionally are selected from alkyl (e.g. methyl), alkoxy (e.g., methoxy), halo (e.g., fluoro, chloro, bromo, iodo), haloalkyl (e.g., trifluoromethyl), hydroxyl, phenyl, amino, and carbonyl.
- R3 is present or absent, and when R3 is present, R3 is selected from selected from hydrogen, alkyl (e.g., methyl), alkenyl (e.g. propenyl), and alkyl-alkoxy (e.g., propanyl-methoxy).
- In some embodiments, the disclosed compounds may have a Formula Ia:
- In some embodiments, the disclosed compound have a Formula Ib:
- In the disclosed compounds, in some embodiments, R1 may be selected from hydrogen, alkyl (e.g., methyl), alkyoxy (e.g., methoxy), and halo (e.g., chloro).
- In the disclosed compounds, in some embodiments R1 is selected from:
- The compound of claim 1, wherein R2 is selected from phenyl, cyclohexyl, pyridinyl (e.g., N-pyridinyl, pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl), pyrimidinyl (e.g., pyrimidin-1-yl, pyrimidin-2-yl, pyrimidin-4-yl, or pyrimidin-5-yl), imidazolyl (e.g., imidazole-1-yl, imidazol-2-yl, or imidazole-4-yl), 1-methylimidazolyl (e.g., 1-methylimidazol-2-yl, 1-methylimidazol-3-yl, 1-methylimidazol-4-yl, or 1-methylimidazol-5-yl), piperidinyl (e.g., piperidin-2-yl, or piperidin-4-yl), 1-methyl-piperidinyl (1-methyl-piperidin-2-yl, 1-methyl-piperidin-3-yl, 1-methyl-piperidin-4-yl), piperazinyl (e.g., piperazin-1-yl, piperazin-2-yl, or piperazin-4-yl), 1-methyl-piperazinyl (e.g., 1-methyl-piperazin-2-yl, 1-methyl-piperazin-3-yl, or 1-methyl-piperazin-4-yl), tetrahydropyranyl (e.g., tetrahydropyran-2-yl, tetrahydropyran-3-yl, or, tetrahydropyran-4-yl), and morpholinyl (e.g., morpholin-2-yl, morpholin-3-yl, or morpholin-4-yl).
- In the disclosed compounds, in some embodiments —(X)n—R2 is selected from:
- As noted, the compounds disclosed herein, including the substituted beta-carboline compounds discussed above may have several chiral centers, and stereoisomers, epimers, and enantiomers are contemplated. The compounds may be optically pure with respect to one or more chiral centers (e.g., some or all of the chiral centers may be completely in the S configuration; some or all of the chiral centers may be completely in the R configuration; etc.). Additionally or alternatively, one or more of the chiral centers may be present as a mixture of configurations (e.g., a racemic or another mixture of the R configuration and the S configuration). Compositions comprising substantially purified stereoisomers, epimers, or enantiomers, or analogs or derivatives thereof are contemplated herein (e.g., a composition comprising at least about 90%, 95%, 99% or 100% pure stereoisomer, epimer, or enantiomer.) As used herein, formulae which do not specify the orientation at one or more chiral centers are meant to encompass all orientations and mixtures thereof.
- Human Serotonin Receptor 2C (5-HT2c) Activity Modulation
- The compounds disclosed herein preferably modulate human serotonin receptor 2C (5-HT2c) activity and may be administered to a subject in need thereof to modulate 5-HT2c receptor activity. Modulation may include activating or increasing human serotonin receptor 2C (5-HT2c) activity. Modulation also may include inhibiting or decreasing human serotonin receptor 2C (5-HT2c) activity.
- 5-HT2c receptor activity may be assessed utilizing methods known in the art and the methods disclosed herein, including the methods disclosed in the Examples provided herein. In some embodiments, the compounds decrease or increase 5-HT2, activity relative to a control (e.g., by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000% or more (or within a range bounded by any of these values)). In other embodiments, the compounds activate the 5-HT2c receptor greater than about 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, or 100-fold, relative to a control. In other embodiments, the compounds activate the 5-HT2c receptor with a maximum activation (Emax) greater than about 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000%, 1100%, 1200%, 1300%, 1400%, or 1500% (or within a range bounded by any of these values). In other embodiments, an EC50 value for the compound in regard to activation of the 5-HT2c receptor may be determined and preferably the compound has an EC50 value of less than about 10 μM, 5 μM, or 1 μM, 0.5 μM, 0.1 μM, 0.05 μM, 0.01 μM, 0.005 μM, or 0.001 μM (or within a range bounded by any of these values). In other embodiments, Ki value for the compound in regard to activation of the 5-HT2c receptor may be determined and preferably the compound has an Ki value of less than about 10 μM, 5 μM, or 1 μM, 0.5 μM, 0.1 μM, 0.05 μM, 0.01 μM, 0.005 μM, or 0.001 μM (or within a range bounded by any of these values).
- In some embodiments, the compounds disclosed herein do not bind to and/or activate or inhibit the 5-HT2a receptor or the 5-HT2b receptor or any other receptor other than the 5-HT2c receptor. If the compounds bind to and/or activate the 5-HT2a receptor or the 5-HT2b receptor or any other receptor, preferably the compounds have an EC50 for the 5-HT2a receptor or the 5-HT2b receptor or any other receptor that is greater than about 0.01 μM, 0.05 μM, 0.1 μM, 0.5 μM, 1 μM, 10 μM, 20 μM, 50 μM, 100 μM, 200 μM, 500 μM, or 1000 μM If the compounds bind to and/or activate the 5-HT2a receptor or the 5-HT2b receptor or any other receptor, preferably the compounds have a Ki, for the 5-HT2a receptor or the 5-HT2b receptor or any other receptor that is greater than about 0.01 μM, 0.05 μM, 0.1 μM, 0.5 μM, 1 μM, 10 μM, 20 μM, 50 μM, 100 μM, 200 μM, 500 μM, or 1000 μM.
- Pharmaceutical Compositions and Methods of Administration
- The compounds employed in the compositions and methods disclosed herein may be administered as pharmaceutical compositions and, therefore, pharmaceutical compositions incorporating the compounds are considered to be embodiments of the compositions disclosed herein. Such compositions may take any physical form which is pharmaceutically acceptable; illustratively, they can be orally administered pharmaceutical compositions. Such pharmaceutical compositions contain an effective amount of a disclosed compound, which effective amount is related to the daily dose of the compound to be administered. Each dosage unit may contain the daily dose of a given compound or each dosage unit may contain a fraction of the daily dose, such as one-half or one-third of the dose. The amount of each compound to be contained in each dosage unit can depend, in part, on the identity of the particular compound chosen for the therapy and other factors, such as the indication for which it is given. The pharmaceutical compositions disclosed herein may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing well known procedures.
- The compounds for use according to the methods of disclosed herein may be administered as a single compound or a combination of compounds. For example, a compound that modulates the 5-HT2c receptor activity may be administered as a single compound or in combination with another compound that modulates the 5-HT2c receptor activity or that has a different pharmacological activity.
- As indicated above, pharmaceutically acceptable salts of the compounds are contemplated and also may be utilized in the disclosed methods. The term “pharmaceutically acceptable salt” as used herein, refers to salts of the compounds which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds as disclosed herein with a pharmaceutically acceptable mineral or organic acid or an organic or inorganic base. Such salts are known as acid addition and base addition salts. It will be appreciated by the skilled reader that most or all of the compounds as disclosed herein are capable of forming salts and that the salt forms of pharmaceuticals are commonly used, often because they are more readily crystallized and purified than are the free acids or bases.
- Acids commonly employed to form acid addition salts may include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of suitable pharmaceutically acceptable salts may include the sulfate, pyrosulfate, bisulfate, sulfite, bisulfate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleat-, butyne-.1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, alpha-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and the like.
- Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Bases useful in preparing such salts include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like.
- The particular counter-ion forming a part of any salt of a compound disclosed herein is may not be critical to the activity of the compound, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole. Undesired qualities may include undesirably solubility or toxicity.
- Pharmaceutically acceptable esters and amides of the compounds can also be employed in the compositions and methods disclosed herein. Examples of suitable esters include alkyl, aryl, and aralkyl esters, such as methyl esters, ethyl esters, propyl esters, dodecyl esters, benzyl esters, and the like. Examples of suitable amides include unsubstituted amides, monosubstituted amides, and disubstituted amides, such as methyl amide, dimethyl amide, methyl ethyl amide, and the like.
- In addition, the methods disclosed herein may be practiced using solvate forms of the compounds or salts, esters, and/or amides, thereof. Solvate forms may include ethanol solvates, hydrates, and the like.
- The pharmaceutical compositions may be utilized in methods of treating and/or preventing a disease, disorder, or condition associated with 5-HT2c receptor activity. For example, the pharmaceutical compositions may be utilized to treat patients having or at risk for acquiring a psychiatric disease or disorder or condition. Suitable patients include, for example mammals, such as humans and non-human primates (e.g., chimps) or other mammals (e.g., dogs, cats, horses, rats, and mice). Suitable human patients may include, for example, those who have previously been determined to be at risk of having or developing a psychiatric disease, disorder, or condition associate with 5-HT2c receptor activity.
- An effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances. In determining the effective amount or dose of compound administered, a number of factors can be considered by the attending diagnostician, such as: the species of the subject; its size, age, and general health; the degree of involvement or the severity of the disease or disorder involved; the response of the individual subject; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.
- A typical daily dose may contain from about 0.01 mg/kg to about 100 mg/kg (such as from about 0.05 mg/kg to about 50 mg/kg and/or from about 0.1 mg/kg to about 25 mg/kg) of each compound used in the present method of treatment.
- Compositions can be formulated in a unit dosage form, each dosage containing from about 1 to about 500 mg of each compound individually or in a single unit dosage form, such as from about 5 to about 300 mg, from about 10 to about 100 mg, and/or about 25 mg. The term “unit dosage form” refers to a physically discrete unit suitable as unitary dosages for a patient, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier, diluent, or excipient.
- Oral administration is an illustrative route of administering the compounds employed in the compositions and methods disclosed herein. Other illustrative routes of administration include transdermal, percutaneous, intravenous, intramuscular, intranasal, buccal, intrathecal, intracerebral, or intrarectal routes. The route of administration may be varied in any way, limited by the physical properties of the compounds being employed and the convenience of the subject and the caregiver.
- As one skilled in the art will appreciate, suitable formulations include those that are suitable for more than one route of administration. For example, the formulation can be one that is suitable for both intrathecal and intracerebral administration. Alternatively, suitable formulations include those that are suitable for only one route of administration as well as those that are suitable for one or more routes of administration, but not suitable for one or more other routes of administration. For example, the formulation can be one that is suitable for oral, transdermal, percutaneous, intravenous, intramuscular, intranasal, buccal, and/or intrathecal administration but not suitable for intracerebral administration.
- The inert ingredients and manner of formulation of the pharmaceutical compositions are conventional. The usual methods of formulation used in pharmaceutical science may be used here. All of the usual types of compositions may be used, including tablets, chewable tablets, capsules, solutions, parenteral solutions, intranasal sprays or powders, troches, suppositories, transdermal patches, and suspensions. In general, compositions contain from about 0.5% to about 50% of the compound in total, depending on the desired doses and the type of composition to be used. The amount of the compound, however, is best defined as the “effective amount”, that is, the amount of the compound which provides the desired dose to the patient in need of such treatment. The activity of the compounds employed in the compositions and methods disclosed herein are not believed to depend greatly on the nature of the composition, and, therefore, the compositions can be chosen and formulated primarily or solely for convenience and economy.
- Capsules are prepared by mixing the compound with a suitable diluent and filling the proper amount of the mixture in capsules. The usual diluents include inert powdered substances (such as starches), powdered cellulose (especially crystalline and microcrystalline cellulose), sugars (such as fructose, mannitol and sucrose), grain flours, and similar edible powders.
- Tablets are prepared by direct compression, by wet granulation, or by dry granulation. Their formulations usually incorporate diluents, binders, lubricants, and disintegrators (in addition to the compounds). Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts (such as sodium chloride), and powdered sugar. Powdered cellulose derivatives can also be used. Typical tablet binders include substances such as starch, gelatin, and sugars (e.g., lactose, fructose, glucose, and the like). Natural and synthetic gums can also be used, including acacia, alginates, methylcellulose, polyvinylpyrrolidine, and the like. Polyethylene glycol, ethylcellulose, and waxes can also serve as binders.
- Tablets can be coated with sugar, e.g., as a flavor enhancer and sealant. The compounds also may be formulated as chewable tablets, by using large amounts of pleasant-tasting substances, such as mannitol, in the formulation. Instantly dissolving tablet-like formulations can also be employed, for example, to assure that the patient consumes the dosage form and to avoid the difficulty that some patients experience in swallowing solid objects.
- A lubricant can be used in the tablet formulation to prevent the tablet and punches from sticking in the die. The lubricant can be chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid, and hydrogenated vegetable oils.
- Tablets can also contain disintegrators. Disintegrators are substances that swell when wetted to break up the tablet and release the compound. They include starches, clays, celluloses, algins, and gums. As further illustration, corn and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation-exchange resins, alginic acid, guar gum, citrus pulp, sodium lauryl sulfate, and carboxymethylcellulose can be used.
- Compositions can be formulated as enteric formulations, for example, to protect the active ingredient from the strongly acid contents of the stomach. Such formulations can be created by coating a solid dosage form with a film of a polymer which is insoluble in acid environments and soluble in basic environments. Illustrative films include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose acetate succinate.
- When it is desired to administer the compound as a suppository, conventional bases can be used. Illustratively, cocoa butter is a traditional suppository base. The cocoa butter can be modified by addition of waxes to raise its melting point slightly. Water-miscible suppository bases, such as polyethylene glycols of various molecular weights, can also be used in suppository formulations.
- Transdermal patches can also be used to deliver the compounds. Transdermal patches can include a resinous composition in which the compound will dissolve or partially dissolve; and a film which protects the composition and which holds the resinous composition in contact with the skin. Other, more complicated patch compositions can also be used, such as those having a membrane pierced with a plurality of pores through which the drugs are pumped by osmotic action.
- As one skilled in the art will also appreciate, the formulation can be prepared with materials (e.g., actives excipients, carriers (such as cyclodextrins), diluents, etc.) having properties (e.g., purity) that render the formulation suitable for administration to humans. Alternatively, the formulation can be prepared with materials having purity and/or other properties that render the formulation suitable for administration to non-human subjects, but not suitable for administration to humans.
- The following list of formulations is illustrative. These illustrative formulations may be suitable for preparing pharmaceutical compositions that include the disclosed compounds as “active ingredients.” The following list of formulations is illustrative and should not be interpreted as limiting the present disclosure or claims in any way:
-
Formulation 1 - Hard gelatin capsules are prepared using the following ingredients:
-
Quantity (mg/capsule) Active Ingredient 250 Starch, dried 200 Magnesium stearate 10 Total 460 mg
The above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities. -
Formulation 2 -
Quantity (mg/tablet) Active Ingredient 250 Cellulose, microcrystalline 400 Silicon dioxide, fumed 10 Stearic acid 5 Total 665 mg
The components are blended and compressed to form tablets each weighing 665 mg. - Formulation 3
- An aerosol solution is prepared containing the following components:
-
Weight % Active Ingredient 0.25 Ethanol 29.75 Propellant 22 (chlorodifluoromethane) 70.00 Total 100.00
The active compound is mixed with ethanol and the mixture added to a portion of thePropellant 22, cooled to −30° C. and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the remainder of the propellant. The valve units are then fitted to the container. - Formulation 4
- Tablets each containing 60 mg of active ingredient are made as follows:
-
Active Ingredient 60 mg Starch 45 mg Microcrystalline cellulose 35 mg Polyvinylpyrrolidone 4 mg Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1 mg Total 150 mg
The active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50° C. and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg. -
Formulation 5 - Capsules, each containing 80 mg medicament, are made as follows:
-
Active Ingredient 80 mg Starch 59 mg Microcrystalline cellulose 59 mg Magnesium stearate 2 mg Total 200 mg
The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 45 sieve, and filled into hard gelatin capsules in 200 mg quantities. - Formulation 6
- Suppositories each containing 225 mg of active ingredient may be made as follows:
-
Active Ingredient 225 mg Saturated fatty acid glycerides 2,000 mg Total 2,225 mg
The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool. - Formulation 7
- Suspensions each containing 50 mg of medicament per 5 ml dose are made as follows:
-
Active Ingredient 50 mg Sodium carboxymethyl cellulose 50 mg Syrup 1.25 ml Benzoic acid solution 0.10 ml Flavor q.v. Color q.v. Purified water to total 5 ml
The medicament is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl, cellulose and syrup to form a smooth paste. The benzoic acid solution, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume. - Formulation 8
- An intravenous formulation containing 100 mg of medicament per 5 ml dose can be prepared as follows:
-
Active Ingredient 100 mg Mannitol 100 mg 5N Sodium hydroxide 200 ml Purified water to total 5 ml - The followings Embodiments are illustrative only and are not intended to limit the scope of the claimed subject matter.
- Embodiment 1. A compound or a salt or solvate thereof having a Formula I:
- wherein:
-
- n is 0-3;
- X is CH2, NH, or O;
- R1 is selected from hydrogen, hydroxyl, alkyl, alkoxy, halo, haloalkyl, amino, and cyano;
- R2 is hydrogen, or alkyl, or a 3-7 membered carbocycle or heterocycle which is saturated or unsaturated at one or more bonds and which heterocycle includes one or more heteroatoms selected from N, O, and S, optionally which carbocycle or heterocycle is substituted to include one or more non-hydrogen substituents, which non-hydrogen substituents optionally are selected from hydroxyl, alkyl, halo, haloalkyl, phenyl, amino, and carbonyl.
- R3 is present or absent, and when R3 is present, R3 is selected from selected from hydrogen, alkyl, alkenyl, and alkyl-alkoxy.
- Embodiment 2. The compound of embodiment 1 having Formula Ia:
- Embodiment 3. The compound of embodiment 1 having a Formula Ib:
- Embodiment 4. The compound of embodiment 1 having a Formula Ic:
- Embodiment 5. The compound of embodiment 1 having a Formula Id:
- Embodiment 6. The compound of embodiment 1 having a Formula Ie:
- Embodiment 7. The compound of
embodiment 1, wherein R1 is selected from hydrogen, alkyl, hydroxyl, alkyoxy, and halo. - Embodiment 8. The compound of embodiment 4, wherein R1 is selected from:
- Embodiment 9. The compound of
embodiment 1, wherein R2 is selected from phenyl, cyclohexyl, pyridinyl, pyrimidinyl, imidazolyl, 1-methylimidazolyl; piperidinyl, 1-methyl-piperidinyl, piperazinyl, 1-methyl-piperazinyl, tetrahydropyranyl, and morpholinyl. - Embodiment 10. The compound of embodiment 1, wherein —(X)n—Rz is selected from:
- Embodiment 11. The compound of embodiment 5, wherein —(X)n—R2 is selected from:
- Embodiment 12. The compound of any of the foregoing embodiments with the proviso that at least one of R1, R2, and R3 is not hydrogen.
- Embodiment 13. The compound of embodiment 1 having a formula:
- Embodiment 14. The compound of embodiment 1 having a formula selected from:
-
Embodiment 15. A compound having a formula of any of the compounds of embodiments 1-14 or a compound having a formula of any compound disclosed in this application for use in treating and/or preventing a disease, disorder, or condition that is associated with 5-HT2c receptor activity in a subject in need thereof. - Embodiment 16. A pharmaceutical composition comprising any of the compounds of the foregoing embodiments and a pharmaceutical carrier.
- Embodiment 17. A method for treating and/or preventing a disease, disorder, or condition that is associated with 5-HT2c receptor activity in a subject in need thereof, the method comprising administering to the subject the compound of any of embodiments 1-15 or the pharmaceutical composition of embodiment 16.
- Embodiment 18. The method of embodiment 17, wherein the disease or disorder is a psychiatric, mental, or neurological disease, disorder, or condition.
- Embodiment 19. The method of embodiment 17, wherein the disease, disorder, or condition is cognitive impairment, addiction, and/or obsessive compulsive disorder (OCD).
-
Embodiment 20. The method of embodiment 17, wherein the disease, disorder, or condition is obesity and the method results in suppressing the appetite of the subject. - The followings Examples are illustrative only and are not intended to limit the scope of the claimed subject matter.
- Beta-carbolines as Positive Allosteric Modulators of the Human Serotonin Receptor 2c (5-HT2c)
- The technical field of the disclosed subject matter relates to small molecule drug development. The disclosed small molecules provide a drug platform that has potential to treat cognitive impairment, addiction, obsessive compulsive disorder, and obesity via appetite suppression.
- Abstract
- We disclose novel small molecules having a substituted beta-carboline core. The disclosed small molecules have potential for treating cognitive impairment (CI), for which there is currently no direct treatment. The disclosed small molecules also have potential for treating addition. Although there are several drug options for treating addiction depending on the addiction, many are inadequate. For example, the current opioid epidemic exists despite the existence of treatment options that include methadone, buprenorphinem and naltrexone. The disclosed small molecules also have potential for treating obsessive compulsive disorder (OCD). OCD is most often treated with antidepressant medications, but often patients do not respond to these medications. Electroconvulsive therapy can be tried in these cases, but this therapy is largely regarded as ineffective.
- Applications
- Applications of the disclosed small molecules include, but are not limited to treatment of a range of neurological disorders and diseases that are associated with 5-HT2, activity. Disorders and diseases that may be treated with the disclosed small molecules may include cognitive impairment (CI), addiction, and obsessive compulsive disorder (OCD). The disclosed small molecules also may suppress appetite and therefore may be administered to treat obesity and eating disorders.
- Advantages
- There currently is only one FDA-approved drug that acts selectively on 5-HT2c, Lorcaserin, which currently is approved only for weight loss. However, Lorcaserin is associated with two dangerous side effects: cancer and cardiac valvulopathy. While Lorcaserin demonstrates selectivity for 5-HT2c, Lorcaserin nonetheless exhibit activity for 5-HT2a and 5-HT2b.
-
Receptor EC50 [nM] Ki[nM] 5-HT2C 39 13 5-HT2B 2380 147 5-HT2A 553 92 - While Lorcaserin's selectivity for 5-HT2, (Ki=39 nM) over 5-HT2a (Ki=92 nM) and 5-HT2b (Ki=147 nM) is good, selectivity can be improved upon because positive allosteric modulators have been known to bind less conserved sites.
- Brief Summary of the Technology
- Small molecules have been designed having a substituted beta-carboline core and based on known yohimbine natural products alstonine and serpentine. The disclosed small molecuels exhibit in vivo activity consistent with agonism or positive allosteric modulation of the serotonin receptor 5-HT2c.
- Compound Synthesis
- General Procedure A: Pictet-Spengler reaction of serotonin-HCl and aldehydes to give tetrahydro-β-carbolines. To a solution of serotonin hydrochloride (1 equiv) in N,N-dimethylformamide (4.5 mL/mmol serotonin hydrochloride) was added the appropriate aldehyde (1.1 equiv). The resulting solution was stirred at 60° C. overnight (16-20 hours). After this time the reaction was allowed to cool to room temperature, neutralized with saturated sodium bicarbonate (equal volume to N,N-dimethylformamide), and was extracted with ethyl acetate (3×equal volumes of the total mixture). The combined organic layers were washed with additional water (1 equal volume), washed with saturated sodium chloride (1 equal volume), dried over magnesium sulfate, filtered, and concentrated to dryness. The resulting residue was purified via column chromatography.
- General Procedure B: Palladium on carbon aromatization of tetrahydro-p-carbolines to give β-carbolines. To a flask containing dry tetrahydro-β-carboline (1 equiv) and palladium on carbon (10 wt %, 0.1 equiv) was added anisole (15 mL/mmol of tetrahydro-p-carboline). The resulting mixture was heated at reflux overnight (16-20 hours). If the reaction had not proceeded sufficiently, minimal amounts of methanol were added to aid with solubility, and the reaction was resubmitted to the previous conditions. After this time the reaction was allowed to cool to room temperature, filtered through Celite® (rinsing with methanol), and concentrated to dryness. The resulting residue was purified via column chromatography.
- General Procedure C: Alkylation of β-carbolines to give N-alkyl β-carbolines. To a solution of β-carboline (1 equiv) in N,N-dimethylformamide (7 mL/mmol of β-carboline) was added the appropriate alkyl halide (1.1 equiv). The resulting mixture was heated at 85° C. overnight (16-20 hours). After this time the reaction was allowed to cool to room temperature. If starting material was not consumed, additional alkyl halide would be added and resubmitted to the previous conditions. After this time, the reaction was concentrated to dryness. The resulting residue was purified via column chromatography.
- 1-phenyl-1H,2H,3H,4H,9H-pyrido[3,4-b]indol-6-ol was synthesized according to general procedure A and was purified on 10 g silica gel, with a gradient of dichloromethane to 6% methanol/94% dichloromethane to give the title product (0.120 g, 32%) as an off-white solid; H NMR (500 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.51 (s, 1H), 7.37-7.21 (m, 6H), 7.16 (dd, J=18.3, 7.3 Hz, 1H), 6.99 (d, J=8.5 Hz, 1H), 6.72 (s, 1H), 6.50 (dd, J=8.5, 2.2 Hz, 1H), 5.02 (s, 1H), 3.05-3.01 (m, 1H), 2.93-2.88 (m, 1H), 2.67-2.62 (m, 1H), 2.59-2.54 (m, 1H). 13C NMR (126 MHz, DMSO) δ 150.15, 143.31, 135.85, 130.36, 128.38, 128.03, 127.51, 127.07, 111.25, 110.36, 107.43, 101.82, 56.65, 41.25, 21.05. MS (ESI) calculated for C17H17N2O [M+H]+: 265.1, Found: 265.2.
- 1-phenyl-9H-pyrido[3,4-b]indol-6-ol was synthesized according to general procedure B and was purified on 10 g silica gel, with a gradient of [10 g silica, dichloromethane to 4% methanol/96% dichloromethane to give the title product (0.359 g, 53%) as a tan solid; 1H NMR (500 MHz, DMSO-d6) δ 11.18 (s, 1H), 9.15 (s, 1H), 8.37 (d, J=5.1 Hz, 1H), 8.00 (dd, J=10.9, 6.4 Hz, 3H), 7.60 (t, J=7.5 Hz, 2H), 7.55-7.42 (m, 3H), 7.07 (dd, J=8.7, 2.2 Hz, 1H). 13C NMR (126 MHz, DMSO) δ 151.03, 141.96, 138.53, 137.56, 137.34, 135.17, 133.55, 128.83, 128.66, 128.38, 128.26, 121.43, 118.26, 112.96, 105.41. MS (ESI) calculated for C17H13N2O [M+H]+: 261.1, Found: 262.1.
- 6-hydroxy-1-phenyl-2-(prop-2-en-1-yl)-9H-pyrido[3,4-b]indol-2-ium bromide was synthesized according to general procedure C and was purified on 25 g silica gel, with a gradient of dichloromethane to 7% methanol/93% dichloromethane to give the title product (0.143 g, 64%) as a dark yellow solid; 1H NMR (500 MHz, DMSO-d6) δ 11.98 (s, 1H), 9.69 (s, 1H), 8.80 (d, J=6.6 Hz, 1H), 8.69 (d, J=6.6 Hz, 1H), 7.76 (m, 6H), 7.53 (d, J=8.9 Hz, 1H), 7.33 (dd, J=8.9, 2.4 Hz, 1H), 6.20-5.73 (m, 1H), 5.26 (d, J=10.5 Hz, 1H), 5.08 (d, J=5.2 Hz, 2H), 4.95 (d, J=17.2 Hz, 1H). 13C NMR (126 MHz, DMSO) δ 152.55, 140.09, 139.09, 135.27, 132.53, 132.43, 131.74, 131.35, 129.66, 129.40, 128.23, 123.16, 120.33, 119.23, 117.22, 113.92, 105.91, 58.69. MS (ESI) calculated for C20H17N2O [M]+: 301.1, Found: 301.3.
- 6-hydroxy-2-(3-methoxypropyl)-1-phenyl-9H-pyrido[3,4-b]indol-2-ium bromide was synthesized according to general procedure C and was purified on 10 g silica gel, with a gradient of dichloromethane to 20% methanol/80% dichloromethane to give the title product (0.045 g, 28%) as a dark brown solid; 1H NMR (500 MHz, DMSO-d6) δ 11.90 (s, 1H), 9.67 (s, 1H), 8.78-8.73 (m, 2H), 7.79-7.74 (q, J=17.8, 11.1 Hz, 6H), 7.52 (d, J=8.9 Hz, 1H), 7.32 (dd, J=8.9, 2.3 Hz, 1H), 4.49 (t, J=7.4 Hz, 2H), 3.22 (t, J=5.8 Hz, 2H), 3.06 (s, 3H), 1.98 (p, J=6.1 Hz, 2H). 13C NMR (126 MHz, DMSO) δ 152.51, 139.98, 138.91, 135.27, 132.50, 131.47, 131.25, 129.69, 129.51, 128.38, 123.00, 120.30, 117.09, 113.88, 105.91, 68.16, 57.68, 54.57, 30.32. MS (ESI) calculated for C21H21N2O2 [M]+: 333.2, Found: 333.3.
- 1-cyclohexyl-1H,2H,3H,4H,9H-pyrido[3,4-b]indol-6-ol was synthesized according to general procedure A and was purified on 10 g silica gel, with a gradient of dichloromethane to 20% methanol/80% dichloromethane to give the title product (0.083 g, 22%) as a tan solid; 1H NMR (500 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.70 (s, 1H), 7.48-6.95 (m, 1H), 6.73 (s, 1H), 6.62-6.60 (m, 1H), 4.43 (s, 1H), 3.48-3.46 (m, 1H), 3.25-3.15 (m, 1H), 2.98-2.73 (m, 2H), 2.20-2.10 (m, 1H), 1.82-1.65 (m, 4H), 1.38-1.10 (m, 7H). 13C NMR (126 MHz, DMSO) δ 150.65, 130.66, 130.06, 126.69, 111.64, 111.57, 105.93, 101.93, 57.36, 41.84, 29.23, 26.66, 26.08, 25.71, 18.58. MS (ESI) calculated for C17H23N2O [M+H]+: 271.2, Found: 271.0.
- 1-cyclohexyl-9H-pyrido[3,4-b]indol-6-ol was synthesized according to general procedure B and was purified on 50 g silica gel, with a gradient of dichloromethane to acetone to give the title product (0.093 g, 31%) as a beige solid; 1H NMR (500 MHz, DMSO-d6) δ 11.17 (s, 1H), 9.06 (s, 1H), 8.15 (d, J=5.2 Hz, 1H), 7.77 (d, J=5.2 Hz, 1H), 7.44 (d, J=2.2 Hz, 1H), 7.40 (d, J=8.7 Hz, 1H), 7.04 (dd, J=8.7, 2.4 Hz, 1H), 3.28-3.20 (m, 1H), 1.91-1.82 (m, 2H), 1.81-1.66 (m, 3H), 1.56-1.41 (m, 2H), 1.39-1.25 (m, 1H). 13C NMR (126 MHz, DMSO) δ 150.68, 149.74, 136.68, 134.39, 133.78, 126.82, 121.75, 117.77, 112.38, 112.37, 105.43, 40.80, 31.31, 26.24, 25.84. MS (ESI) calculated for C17H19N2O [M+H]+: 267.2, Found: 267.4.
- 1-cyclohexyl-6-hydroxy-2-(prop-2-en-1-yl)-9H-pyrido[3,4-b]indol-2-ium bromide was synthesized according to general procedure C and was purified on 10 g silica gel, with a gradient of dichloromethane to acetone to give the title product (0.066 g, 46%) as a dark yellow solid; 1H NMR (500 MHz, DMSO-d6) δ 12.00 (s, 1H), 9.65 (s, 1H), 8.63 (d, J=6.5 Hz, 1H), 8.56 (d, J=6.2 Hz, 1H), 7.73 (d, J=8.9 Hz, 1H), 7.68 (d, J=2.2 Hz, 1H), 7.36 (dd, J=8.9, 2.4 Hz, 1H), 6.25-6.17 (m, 1H), 5.51 (s, 2H), 5.36 (d, J=10.6 Hz, 1H), 5.02 (d, J=17.3 Hz, 1H), 3.50-3.39 (m, 1H), 2.35-2.16 (m, 2H), 2.01-1.62 (m, 6H), 1.53-1.40 (m, 2H). 13C NMR (126 MHz, DMSO) δ 152.51, 146.40, 138.08, 133.81, 133.21, 133.15, 132.32, 123.06, 119.76, 118.00, 116.14, 113.94, 105.56, 59.72, 48.58, 27.96, 25.71, 23.96. MS (ESI) calculated for C20H23N2O [M]+: 307.2, Found: 307.3.
- 1-(pyrimidin-5-yl)-1H,2H,3H,4H,9H-pyrido[3,4-b]indol-6-ol was synthesized according to general procedure A and was purified on 10 g silica gel, with a gradient of dichloromethane to 10% methanol/90% dichloromethane to give the title product (0.137 g, 37%) as an off-white solid; 1H NMR (500 MHz, DMSO-d6) δ 10.23 (s, 1H), 9.12 (s, 1H), 8.67 (s, 2H), 8.58 (s, 1H), 7.02 (d, J=8.5 Hz, 1H), 6.75 (d, J=2.0 Hz, 1H), 6.55 (dd, J=8.5, 2.2 Hz, 1H), 5.14 (s, 1H), 3.14-2.92 (m, 3H), 2.74-2.64 (m, 1H), 2.64-2.55 (m, 2H). 13C NMR (126 MHz, DMSO) δ 157.33, 156.69, 150.36, 136.39, 134.06, 130.45, 127.44, 111.35, 110.84, 108.06, 102.01, 52.39, 41.38, 22.03. MS (ESI) calculated for C15H15N4O [M+H]+: 267.1, Found: 267.2.
- 1-(pyrimidin-5-yl)-9H-pyrido[3,4-b]indol-6-ol (AJC-61) was synthesized according to general procedure B and was purified on 25 g silica gel, with a gradient of dichloromethane to 50% acetone/50% dichloromethane to give the title product (0.024 g, 5%) as a yellow solid; 1H NMR (500 MHz, DMSO-d6) δ 11.54 (s, 1H), 9.40 (s, 2H), 9.32 (s, 1H), 9.23 (s, 1H), 8.51-8.40 (m, 1H), 8.19-8.06 (m, 1H), 7.57 (s, 1H), 7.47 (d, J=8.7 Hz, 1H), 7.11 (d, J=8.6 Hz, 1H). 13C NMR (126 MHz, DMSO) δ 157.83, 156.08, 151.29, 138.05, 136.13, 135.29, 134.04, 132.02, 129.36, 121.28, 118.76, 115.10, 112.96, 105.64. MS (ESI) calculated for C15H11N4O [M+H]−: 263.1, Found: 263.1.
-
TABLE 1 Activity of Selected Compounds. AJC-61 2C agonist inactive antagonist >10 μM 2A agonist inactive antagonist no data MJO-01-31 2C agonist 10.1 nM Emax 101% 2A agonist 54.6 nM Emax 95% MJO-01-34 2C agonist 85.9 nM Emax 103% 2A agonist 106 nM Emax 27% MJO-01-46 2C agonist 5.37 nM Emax 98% 2A agonist 11.3 nM Ernax 96% - Biological Activity of AJC-61
- Mouse models were utilized to demonstrate the potential of compound AJC-61 in treating and or affecting psychotic spectrum disorder-schizophrenia including cognitive impairment of schizophrenia, negative symptoms of schizophrenia including deficit in social interaction, bipolar disorder, major depression including psychotic major depression, locomotor activity suppression-specific for positive (psychotic) symptoms of schizophrenia, psychoses of Alzheimer's disease and Parkinson's disease, obsessive compulsive disorder, Tourette's syndrome, and age-associated cognitive impairment.
- The ability of a test drug to block the increase in Locomotor Activity (LMA) produced by amphetamine or the glutamate receptor agonist, phencyclidine (PCP), has a high predictive value for the antipsychotic efficacy of the test drug for treating schizophrenia. Administration of amphetamine or PCP to man has been shown to produce psychotic state in a significant percentage of previously normal humans. Treatment of mice with PCP for one week has been shown to produce a robust model of schizophrenia. As such, we tested the effect of AJC-61 on reducing LMA in mice that had been treated with amphetamine or PCP to increase LMA activity. As shown in
FIG. 1 , AJC-61 blocked the amphetamine-induced increase in LMA in mice, and as shown inFIG. 2 , AJC-61 blocked the PCP-induced increase in LAM in mice. - The Novel Object Recognition test in rodents is considered a valid model of spatial memory in man. The time spent viewing an object seen previously versus the time spent viewing a novel object (i.e., the Discrimination Index (DI)) provides an indirect measure of assessing retention of the memory of the object that had previously been shown to the rodent. Normal mice remember for ˜24 hours. The time to loss of the memory in aged mice can be as low as zero to less than 8 hours. As such, we tested the effect of AJC-61 on reducing the DI in mice that had been treated with PCP to reduce the DI. As shown in
FIG. 3 , we observed a significant increase in DI in the PCP+AJC-61—treated mice versus the PCP-treated mice. - A healthy mouse will vigorously explore a newly introduce mouse and retain the memory for that mouse for up to 24 hours. The loss of interest in exploring a novel mouse is considered a sign of negative symptoms.
- PCP-treatment produces a deficit in social interaction which models negative symptoms in schizophrenia. These include lack of motivation, loss of interest in activities, diminished capacity for pleasure and spontaneous activity. We tested the effect of AJC-61 on Social Interaction in mice that had been treated with PCP, including a Social Behaviors that include sniffing, following, and avoiding and Object Exploration via interaction with an inanimate object. As illustrated in
FIG. 4 , regarding sniffing we observed a significant reduction in sniffing for the PCP group versus the Vehicle group, and a significant increase in sniffing for the PCP+AJC-61 versus group versus the PCP group. Regarding following, we observed no significant change, although there was non-significant reduction in following in the PCP group versus the Vehicle group. Regarding avoiding, we observed a significant increase for the PCP versus group versus the Vehicle group, and a significant decrease in avoiding for the PCP+AJC-61 group versus the PCP group. Regarding object exploration, we observed no significant change, although there was a non-significant increase in object exploration in the PCP group versus the Vehicle group. - The Porsolt Forced Swim Test (FST) is a gold standard test for antidepressant action. In the FST, normal mice become immobile after being required to swim in a tank and begin to float instead of struggling to get out of the water. Antidepressant drugs have been shown to increase the amount of time that a mouse will continue to swim prior to floating. As such, we tested whether AJC-61 could increase the swim time in a FST. As illustrated in
FIG. 5 , treatment with PCP significantly increased the immobility time whereas treatment with PCP+AJC-61 significantly decreased the immobility time. - Marble Burying (MB) and extent of shredding a standard type of rodent bedding (i.e., Nestlet Shredding) are both proven methods for assessing drug efficacy to treat obsessive-compulsive disorder and Tourette's syndrome. As such, we tested the effect on AJC-61 on Marble Burying and Nestlet Shredding. As illustrated in
FIG. 6 , we observed a significant increase in the number of marbles buried for the PCP group versus the Vehicle group, and we observed a significant decrease in the number of marbles buried for the PCP+AJC-16 group versus the PCP group. As illustrated inFIG. 7 , we observed a significant increase in the percent nestlet shredded for the PCP group versus the Vehicle group, and we observed a significant decrease in the percent nestlet shredded for the PCP+AJC-16 group versus the PCP group. - Aged mice show a decline in memory function beginning around 13-15 month of age. Drugs which enhance memory can be assessed using the Novel Object Recognition test and determination of the Discrimination Index (DI) as discussed above. As such, we tested whether AJC-61 could improve the DI for aged mice (i.e., 22-month old mice) versus young mice (i.e., 2.5 month old mice). As illustrated in
FIG. 8 , we observed a significant decrease in the DI for 22-month old mice versus the DI for 2.5 month old mice, and we observed a significant increase in the DI for 22-month old mice when the mice were treated with AJC-61. - It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention. Thus, it should be understood that although the present invention has been illustrated by specific embodiments and optional features, modification and/or variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention.
- Citations to a number of patent and non-patent references are made herein. The cited references are incorporated by reference herein in their entireties. In the event that there is an inconsistency between a definition of a term in the specification as compared to a definition of the term in a cited reference, the term should be interpreted based on the definition in the specification.
Claims (21)
1.-20. (canceled)
21. A compound or a salt or solvate thereof having a Formula I:
wherein:
n is 0-3;
X is CH2, NH, or O;
R1 is selected from hydrogen, hydroxyl, alkyl, alkoxy, halo, haloalkyl, amino, and cyano;
R2 is hydrogen, or alkyl, or a 3-7 membered carbocycle or heterocycle which is saturated or unsaturated at one or more bonds and which heterocycle includes one or more heteroatoms selected from N, O, and S, optionally which carbocycle or heterocycle is substituted to include one or more non-hydrogen substituents, which non-hydrogen substituents optionally are selected from hydroxyl, alkyl, halo, haloalkyl, phenyl, amino, and carbonyl.
R3 is present or absent, and when R3 is present, R3 is selected from selected from hydrogen, alkyl, alkenyl, and alkyl-alkoxy.
22. The compound of claim 21 , wherein R2 is selected from phenyl, cyclohexyl, pyridine-2-yl, pyridine-3-yl, imidazolyl, 1-methylimidazolyl; piperidinyl, 1-methyl-piperidinyl, piperazinyl, 1-methyl-piperazinyl, tetrahydropyranyl, and morpholinyl.
24. The compound of claim 21 , wherein —(X)n—R2 is selected from phenyl and cyclohexyl.
27. The compound of claim 26 , wherein R2 is selected from phenyl, cyclohexyl, pyridin-2-yl, pyridin-3-yl, imidazolyl, 1-methylimidazolyl; piperidinyl, 1-methyl-piperidinyl, piperazinyl, 1-methyl-piperazinyl, tetrahydropyranyl, and morpholinyl.
29. The compound of claim 21 , wherein R1 is selected from hydroxyl, halo, methyl, and hydrogen.
30. The compound of claim 29 , wherein R2 is selected from phenyl, cyclohexyl, pyridinyl, imidazolyl, 1-methylimidazolyl; piperidinyl, 1-methyl-piperidinyl, piperazinyl, 1-methyl-piperazinyl, tetrahydropyranyl, and morpholinyl.
33. The compound of claim 32 , wherein R2 is selected from phenyl, cyclohexyl, pyridinyl, imidazolyl, 1-methylimidazolyl; piperidinyl, 1-methyl-piperidinyl, piperazinyl, 1-methyl-piperazinyl, tetrahydropyranyl, and morpholinyl.
35. The compound of claim 32 , wherein R1 is hydroxyl.
36. A pharmaceutical composition comprising the compound of claim 21 and a pharmaceutical carrier.
37. A method for treating and/or preventing a disease, disorder, or condition that is associated with 5-HT2c receptor activity in a subject in need thereof, the method comprising administering to the subject the compound of claim 21 .
38. The method of claim 37 , wherein the disease or disorder is a psychiatric, mental, or neurological disease, disorder, or condition.
39. The method of claim 37 , wherein the disease, disorder, or condition is cognitive impairment, addiction, and/or obsessive compulsive disorder.
40. The method of claim 37 , wherein the disease, disorder, or condition is obesity and the method results in suppressing the appetite of the subject.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US18/051,300 US20230265093A1 (en) | 2018-10-02 | 2022-10-31 | Beta-carbolines as positive allosteric modulators of the human serotonin receptor 2c (5-ht2c) |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201862740084P | 2018-10-02 | 2018-10-02 | |
PCT/US2019/054337 WO2020072675A1 (en) | 2018-10-02 | 2019-10-02 | Beta-carbolines as positive allosteric modulators of the human serotonin receptor 2c (5-ht2c) |
US202016766217A | 2020-05-21 | 2020-05-21 | |
US18/051,300 US20230265093A1 (en) | 2018-10-02 | 2022-10-31 | Beta-carbolines as positive allosteric modulators of the human serotonin receptor 2c (5-ht2c) |
Related Parent Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2019/054337 Continuation WO2020072675A1 (en) | 2018-10-02 | 2019-10-02 | Beta-carbolines as positive allosteric modulators of the human serotonin receptor 2c (5-ht2c) |
US16/766,217 Continuation US11485734B2 (en) | 2018-10-02 | 2019-10-02 | Beta-carbolines as positive allosteric modulators of the human serotonin receptor 2C (5-HT2C) |
Publications (1)
Publication Number | Publication Date |
---|---|
US20230265093A1 true US20230265093A1 (en) | 2023-08-24 |
Family
ID=70055878
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US16/766,217 Active US11485734B2 (en) | 2018-10-02 | 2019-10-02 | Beta-carbolines as positive allosteric modulators of the human serotonin receptor 2C (5-HT2C) |
US18/051,300 Pending US20230265093A1 (en) | 2018-10-02 | 2022-10-31 | Beta-carbolines as positive allosteric modulators of the human serotonin receptor 2c (5-ht2c) |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US16/766,217 Active US11485734B2 (en) | 2018-10-02 | 2019-10-02 | Beta-carbolines as positive allosteric modulators of the human serotonin receptor 2C (5-HT2C) |
Country Status (3)
Country | Link |
---|---|
US (2) | US11485734B2 (en) |
EP (1) | EP3860996A4 (en) |
WO (1) | WO2020072675A1 (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11639340B2 (en) | 2019-07-08 | 2023-05-02 | Northwestern University | Substituted chromanes, analogs thereof, and methods of use and synthesis |
CN113307806A (en) * | 2021-05-22 | 2021-08-27 | 陈冬寅 | Beta-carboline selective monoamine oxidase B inhibitor and pharmaceutical application thereof |
Family Cites Families (78)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2182915A1 (en) | 1972-03-30 | 1973-12-14 | Nelson Res & Dev | Substd indoles, benzimidazoles - as anti-immune agents , antitumour agents, serotonin inhibitors, hypnotics |
US3915990A (en) | 1973-03-13 | 1975-10-28 | Nelson Res & Dev | Tryptamines |
JPS57123180A (en) | 1980-12-17 | 1982-07-31 | Schering Ag | 3-substituted beta-carboline, manufacture and psychotropic drug containing same |
DE3240514A1 (en) | 1982-10-29 | 1984-05-03 | Schering AG, 1000 Berlin und 4709 Bergkamen | SS-CARBOLINE, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATIONS CONTAINING THE SAME |
US4631149A (en) * | 1983-07-25 | 1986-12-23 | University Of Illinois | Antiviral eudistomins from a marine tunicate |
DK240084D0 (en) | 1984-05-15 | 1984-05-15 | Ferrosan As | NEW BETA-CARBOLINE-3-OXADIAZOLYL DERIVATIVES |
WO1988000826A1 (en) | 1986-08-05 | 1988-02-11 | Harbor Branch Oceanographic Institution, Inc. | Antitumor compositions and their methods of use |
GB9819035D0 (en) | 1998-09-01 | 1998-10-28 | Cerebrus Res Ltd | Chemical compounds VII |
FR2796644B1 (en) | 1999-07-23 | 2001-09-07 | Adir | NOVEL BETA-CARBOLINE DERIVATIVES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
US6890933B1 (en) | 2000-02-24 | 2005-05-10 | President And Fellows Of Harvard College | Kinesin inhibitors |
JP5000828B2 (en) | 2000-03-15 | 2012-08-15 | サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | Substituted beta-carboline having IkB kinase inhibitory activity |
WO2001068648A1 (en) | 2000-03-15 | 2001-09-20 | Aventis Pharma Deutschland Gmbh | Substituted beta-carbolines with ikb-kinase inhibiting activity |
EP1442039A1 (en) | 2001-10-31 | 2004-08-04 | Bayer HealthCare AG | Pyrimido (4,5-b) indole derivatives |
DE60316672T2 (en) * | 2002-04-03 | 2008-07-17 | Orion Corp. | POLYCYCLIC COMPOUNDS AS POTENTIAL ALPHA2 ADRENOCEPTOR ANTAGONISTS |
US6953787B2 (en) | 2002-04-12 | 2005-10-11 | Arena Pharmaceuticals, Inc. | 5HT2C receptor modulators |
ES2427166T3 (en) | 2003-06-23 | 2013-10-29 | Ono Pharmaceutical Co., Ltd. | Novel tricyclic heterocyclic compound |
TW200510324A (en) | 2003-08-11 | 2005-03-16 | Lilly Co Eli | 6-(2,2,2-trifluoroethylamino)-7-chiloro-2, 3, 4, 5-tetrahydro-1h-benzo[d]azepine as a 5-ht2c receptor agonist |
EP1706404A2 (en) | 2004-01-23 | 2006-10-04 | Chiron Corporation | Tetrahydrocarboline compounds as anticancer agents |
US7767689B2 (en) | 2004-03-15 | 2010-08-03 | Ptc Therapeutics, Inc. | Carboline derivatives useful in the treatment of cancer |
MXPA06010543A (en) * | 2004-03-15 | 2007-03-26 | Ptc Therapeutics Inc | Carboline derivatives useful in the inhibition of angiogenesis. |
US8076352B2 (en) | 2004-03-15 | 2011-12-13 | Ptc Therapeutics, Inc. | Administration of carboline derivatives useful in the treatment of cancer and other diseases |
EP1799640A4 (en) | 2004-09-27 | 2009-09-02 | Organix Inc | Indole compounds useful as serotonin selective agents |
WO2006116151A1 (en) | 2005-04-22 | 2006-11-02 | Wyeth | Benzofuranyl alkanamine derivatives and uses thereof as 5-ht2c agonists |
US20090203750A1 (en) | 2005-08-24 | 2009-08-13 | Alan Kozikowski | 5-HT2C Receptor Agonists as Anorectic Agents |
FR2898358B1 (en) * | 2006-03-08 | 2008-05-30 | Macef Sa | ASSOCIATION OF 5HT2 RECEPTOR ANTAGONIST AND 5HT2 RECEPTOR ACTIVATOR BY ALLOSTERIC MODULATION AND USES THEREOF AS MEDICAL PRODUCTS |
US7732447B2 (en) | 2006-06-22 | 2010-06-08 | Cephalon, Inc. | Fused [d]pyridazin-7-ones |
KR20090121358A (en) | 2007-03-23 | 2009-11-25 | 화이자 리미티드 | Pyrimido [4,5-d] azepine derivatives as 5-ht2c agonists |
US20090143363A1 (en) | 2007-10-15 | 2009-06-04 | Concert Pharmaceuticals, Inc. | Deuterated lorcaserin |
AU2009214724A1 (en) | 2008-02-11 | 2009-08-20 | Organix Inc. | Indole compounds and methods of use thereof |
PE20140609A1 (en) | 2008-06-11 | 2014-05-22 | Genentech Inc | DIAZACARBAZOLES AND METHODS OF USE |
AR072084A1 (en) | 2008-06-12 | 2010-08-04 | Sanofi Aventis | DERIVATIVES OF AZACARBOLINAS, ITS PREPARATION AND ITS THERAPEUTIC USE AS INHIBITORS OF PIM KINASES |
WO2010042933A2 (en) | 2008-10-10 | 2010-04-15 | Northwestern University | Inhibition and treatment of prostate cancer metastasis |
RU2470934C1 (en) | 2008-11-11 | 2012-12-27 | Дзе Ил Фармасьютикал Ко., Лтд. | Novel tricyclic derivative and pharmaceutically acceptable salts thereof, method for production thereof and pharmaceutical composition containing said derivative |
US8329723B2 (en) | 2009-04-24 | 2012-12-11 | John K Buolamwini | 1-aryl- or 1-heteroaryl-pyrido[B]indoles and uses thereof in treating cancers |
US8927570B2 (en) | 2009-04-24 | 2015-01-06 | John K. Buolamwini | 1-naphthyl-or 1-dihydroacenaphthenyl-pyrido[B]indoles and uses thereof in treating cancers |
CN102480957A (en) | 2009-05-27 | 2012-05-30 | Ptc医疗公司 | Methods For Treating Cancer And Non-neoplastic Conditions |
FR2953838B1 (en) | 2009-12-10 | 2012-02-24 | Sanofi Aventis | TRISUBSTITUTED 9H-BETA-CARBOLINE (OR 9H-PYRIDINO [3,4-B] INDOLE) DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE |
FR2953837B1 (en) | 2009-12-10 | 2012-03-09 | Sanofi Aventis | DISUBSTITUTED 9H-PYRIDINO [3,4-B] INDOLE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE |
US20110183938A1 (en) | 2009-12-16 | 2011-07-28 | Genentech, Inc. | 1,7-diazacarbazoles and methods of use |
AU2011212930B2 (en) | 2010-02-04 | 2016-02-11 | The Board Of Trustees Of The University Of Illinois | Highly selective 5-HT(2C) receptor agonists having antagonist activity at the 5-HT(2B) receptor |
EP3485878A1 (en) | 2010-09-01 | 2019-05-22 | Arena Pharmaceuticals, Inc. | Modified-release dosage forms of 5-ht2c agonists useful for weight management |
SG10201506865WA (en) | 2010-09-01 | 2015-10-29 | Arena Pharm Inc | Non-hygroscopic salts of 5-ht2c agonists |
EP2455378A1 (en) | 2010-11-03 | 2012-05-23 | Philip Morris Products S.A. | Carbazole and carboline derivatives, and preparation and therapeutic applications thereof |
CN111012779A (en) | 2011-10-25 | 2020-04-17 | 新疆华世丹药物研究有限责任公司 | Application of harmine derivative in preparation of antibacterial drugs |
EP2809156B1 (en) | 2011-12-08 | 2017-05-24 | The Board of Regents of The University of Texas System | Allosteric modulators of 5-hydroxytryptamine 2c receptor (5-ht2cr) |
US9090634B2 (en) | 2012-05-08 | 2015-07-28 | Northwestern University | Azolium metal-organic frameworks |
EP2924042A4 (en) | 2012-11-26 | 2016-08-17 | Xinjiang Huashidan Pharmaceutical Res Co Ltd | Bis- -carboline compound and preparation method, pharmaceutical composition and use thereof |
US8912341B2 (en) | 2013-01-16 | 2014-12-16 | Northwestern University | Enantioselective N-heterocyclic carbene-catalyzed annulation reactions with imidazolidinones |
WO2014145576A2 (en) | 2013-03-15 | 2014-09-18 | Northwestern University | Substituted pyrrolo(2,3-d)pyrimidines for the treatment of cancer |
US9643947B2 (en) | 2013-08-28 | 2017-05-09 | Northwestern University | 7-membered fused heterocycles and methods of their synthesis |
US9260564B2 (en) | 2014-03-03 | 2016-02-16 | Dow Global Technologies Llc | Catalyst for non-isocyanate based polyurethane |
US9527812B2 (en) | 2014-05-01 | 2016-12-27 | Northwestern University | N-heterocyclic carbene-catalyzed synthesis of 2-aryl indoles |
US9309217B2 (en) | 2014-05-01 | 2016-04-12 | Northwestern University | Catalytic enantioselective synthesis of 2-aryl chromenes and related phosphoramidite ligands and catalyst compounds |
CN104003988A (en) | 2014-06-05 | 2014-08-27 | 中国药科大学 | CDK2 (cyclin-dependent kinase 2) kinase inhibitor based on 3-amino-beta-carboline and derivatives thereof, as well as preparation method and application of CDK2 kinase inhibitor |
CN111978319B (en) * | 2014-06-27 | 2023-08-11 | 诺格拉制药有限公司 | Aryl receptor modulators and methods of making and using the same |
US9334297B2 (en) | 2014-09-15 | 2016-05-10 | Northwestern University | Chiral imidazolium salts for asymmetric catalysis |
US10472355B2 (en) | 2014-09-26 | 2019-11-12 | Texas Tech University System | Cancer treatment utilizing SP-141 to bind with MDM2 and act as an inhibitor of MDM2 expression |
US9839625B2 (en) | 2014-11-06 | 2017-12-12 | Northwestern University | Inhibition of cancer cell motility |
CN107810175B (en) | 2015-01-29 | 2021-06-15 | 伊利诺伊大学评议会 | Cyclopropylmethylamines as selective 5-HT (2C) receptor agonists |
WO2016179184A2 (en) | 2015-05-04 | 2016-11-10 | Northwestern University | Enantioselective syntheses of heteroyohimbine natural product intermediates |
WO2017087534A1 (en) | 2015-11-16 | 2017-05-26 | Cigall Kadoch | Compounds and methods for treating synovial sarcomas |
US20170212992A1 (en) | 2016-01-26 | 2017-07-27 | Northwestern University | Systems and methods for generating high resolution probabilistic raster maps for electronic health record and other data associated with a geographical region |
EP3500570B1 (en) | 2016-08-19 | 2022-10-05 | Arena Pharmaceuticals, Inc. | 5-ht2c receptor agonists and compositions and methods of use |
EP3318563A1 (en) | 2016-11-07 | 2018-05-09 | Sanofi | Substituted pyrido[3,4-b]indoles for the treatment of cartilage disorders |
US20180170941A1 (en) | 2016-12-19 | 2018-06-21 | Agenebio, Inc. | Benzodiazepine derivatives, compositions, and methods for treating cognitive impairment |
CN106957301A (en) | 2017-05-09 | 2017-07-18 | 浙江工业大学 | A kind of preparation method of the hydroxycarbazole class compound of N heteroaryls 2 |
WO2018206537A1 (en) | 2017-05-11 | 2018-11-15 | Merck Patent Gmbh | Carbazole-based bodipys for organic electroluminescent devices |
CN107141285B (en) | 2017-05-26 | 2019-12-03 | 广西师范大学 | 1- pyridine -6- methoxyl group -9- methyl benzyl-B-carboline and its synthesis and application |
US10544152B2 (en) | 2017-07-28 | 2020-01-28 | The Board Of Regents Of The University Of Texas System | 5-HT2CR agonist analogs |
US11225483B2 (en) | 2018-03-07 | 2022-01-18 | Northwestern University | Substituted fused pyrrolo-diazepinones and uses thereof |
CN108409732B (en) | 2018-03-09 | 2019-08-27 | 温州大学 | A kind of green synthesis method of B-carboline heterocyclic compound |
US10781172B2 (en) | 2018-06-21 | 2020-09-22 | Northwestern University | Catalysts and methods for enantioselective conjugate additions of amines to unsaturated electrophiles |
US11174238B2 (en) | 2018-12-11 | 2021-11-16 | Northwestern University | Enantioselective cross dehydrogenative coupling reactions and compounds synthesized by the reactions |
US11370770B2 (en) | 2019-06-24 | 2022-06-28 | Northwestern University | 3-arylindazoles as selective MEK4 inhibitors |
US11440892B2 (en) | 2019-07-03 | 2022-09-13 | Northwestern University | Substituted dihydrobenzoxazinones, dihydroquinolones, and methods of their use and synthesis |
US11639340B2 (en) | 2019-07-08 | 2023-05-02 | Northwestern University | Substituted chromanes, analogs thereof, and methods of use and synthesis |
US11479558B2 (en) | 2019-07-09 | 2022-10-25 | Northwestern University | Substituted tetrahydropyranoindoles, derivatives thereof, and their methods of synthesis and use |
US11518750B2 (en) | 2019-08-06 | 2022-12-06 | Northwestern University | 3-methylideneoxan-4-one compounds and substituted derivatives thereof as inhibitors of telomerase |
-
2019
- 2019-10-02 WO PCT/US2019/054337 patent/WO2020072675A1/en unknown
- 2019-10-02 EP EP19868885.5A patent/EP3860996A4/en active Pending
- 2019-10-02 US US16/766,217 patent/US11485734B2/en active Active
-
2022
- 2022-10-31 US US18/051,300 patent/US20230265093A1/en active Pending
Also Published As
Publication number | Publication date |
---|---|
WO2020072675A1 (en) | 2020-04-09 |
US20210214352A1 (en) | 2021-07-15 |
US11485734B2 (en) | 2022-11-01 |
EP3860996A1 (en) | 2021-08-11 |
EP3860996A4 (en) | 2022-08-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20230265093A1 (en) | Beta-carbolines as positive allosteric modulators of the human serotonin receptor 2c (5-ht2c) | |
US10160747B2 (en) | Compounds and methods for kinase modulation, and indications therefor | |
CN109820853B (en) | Use of substituted heterocyclic compounds for the treatment of cancer | |
AU2017331345A1 (en) | Compounds and methods for IDO and TDO modulation, and indications therefor | |
EP3137081B1 (en) | Buprenorphine dimer and its use in treatment of gastrointestinal disorders | |
US11312721B2 (en) | Benzodiazepine derivatives, compositions, and methods for treating cognitive impairment | |
ES2232168T3 (en) | PIRROLOQUINOLINAS FOR THE TREATMENT OF OBESITY. | |
EP1988898A2 (en) | Pharmaceutical compositions for the treatment of attention deficit hyperactivity disorder comprising flibanserin | |
EA006604B1 (en) | Combination of serotonin agonist (5-ht) and antagonist (5-ht) as pharmaceutical formulation | |
US20070225278A1 (en) | Methods for treating cognitive and other disorders | |
US20230096978A1 (en) | Mor receptor agonist compound, preparation method therefor, and use thereof | |
BR112019016827A2 (en) | 5-membered azaheterocyclic delta-opioid receptor modulating compounds, methods of use and production thereof | |
JP2022535744A (en) | Methods and compositions for treating epilepsy | |
US20220151990A1 (en) | Formulations and methods for treating acute cannabinoid overdose | |
JPWO2008001885A1 (en) | AbI kinase inhibitor | |
RU2652992C2 (en) | Novel crystalline salt form 3-(1,2,4-triazolo[4,3-a]pyridin-3-ylethynyl)-4-methyl-n-(4-((4-methylpiperazin-1-yl)methyl)-3-trifluoromethylphenyl) benzamide for medical application | |
CA2786072A1 (en) | Sulfone compounds as 5-ht6 receptor ligands | |
JPWO2006132192A1 (en) | New 2-quinolone derivatives | |
AU2018221705A1 (en) | 7-membered aza-heterocyclic containing delta-opioid receptor modulating compounds, methods of using and making the same | |
US20170305895A1 (en) | Substituted aminothiazoles for the treatment of tuberculosis | |
JP2022554159A (en) | Treatment of epileptic conditions with GABAA receptor modulators | |
WO2016025652A1 (en) | Combinations of an erk inhibitor and a bcl-2 pathway modulator and related methods | |
US10800776B2 (en) | Fluorine-containing triazolopyridine, and manufacturing method, pharmaceutical composition, and application thereof | |
US7973075B2 (en) | Kainate receptor-selective epimeric analogs of dysiherbaine | |
US8263611B2 (en) | Hydrochloride salt of an azabicyclo[3.2.1]octane derivative |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: NORTHWESTERN UNIVERSITY, ILLINOIS Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:SCHEIDT, KARL A.;MELTZER, HERBERT Y.;CSAKAI, ADAM J.;SIGNING DATES FROM 20191216 TO 20191226;REEL/FRAME:062310/0323 |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION |