CN112752760B - 杂环化合物 - Google Patents
杂环化合物 Download PDFInfo
- Publication number
- CN112752760B CN112752760B CN201980063261.9A CN201980063261A CN112752760B CN 112752760 B CN112752760 B CN 112752760B CN 201980063261 A CN201980063261 A CN 201980063261A CN 112752760 B CN112752760 B CN 112752760B
- Authority
- CN
- China
- Prior art keywords
- group
- groups
- atom
- compound
- examples
- 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.)
- Active
Links
- 150000002391 heterocyclic compounds Chemical class 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 221
- 206010010774 Constipation Diseases 0.000 claims abstract description 52
- -1 [1,3] oxazin-6-yl Chemical group 0.000 claims description 307
- 239000003814 drug Substances 0.000 claims description 78
- 150000003839 salts Chemical class 0.000 claims description 71
- 238000000034 method Methods 0.000 claims description 60
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 52
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 51
- 125000005843 halogen group Chemical group 0.000 claims description 40
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 32
- 125000000217 alkyl group Chemical group 0.000 claims description 29
- 125000003545 alkoxy group Chemical group 0.000 claims description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
- 230000001713 cholinergic effect Effects 0.000 claims description 17
- 125000004429 atom Chemical group 0.000 claims description 14
- 229940126027 positive allosteric modulator Drugs 0.000 claims description 14
- 229940124597 therapeutic agent Drugs 0.000 claims description 13
- 102000007207 Muscarinic M1 Receptor Human genes 0.000 claims description 12
- 108010008406 Muscarinic M1 Receptor Proteins 0.000 claims description 12
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 125000005842 heteroatom Chemical group 0.000 claims description 11
- 125000004434 sulfur atom Chemical group 0.000 claims description 11
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 125000002950 monocyclic group Chemical group 0.000 claims description 9
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 230000000069 prophylactic effect Effects 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 6
- 230000003281 allosteric effect Effects 0.000 claims description 3
- 238000006467 substitution reaction Methods 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 150000002367 halogens Chemical class 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 84
- 125000001424 substituent group Chemical group 0.000 description 74
- 235000002639 sodium chloride Nutrition 0.000 description 65
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 60
- 229940079593 drug Drugs 0.000 description 54
- 125000003118 aryl group Chemical group 0.000 description 45
- 230000000694 effects Effects 0.000 description 42
- 239000003795 chemical substances by application Substances 0.000 description 35
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 34
- 238000011282 treatment Methods 0.000 description 30
- 239000003153 chemical reaction reagent Substances 0.000 description 29
- 238000009472 formulation Methods 0.000 description 27
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 26
- 235000019441 ethanol Nutrition 0.000 description 25
- 125000000623 heterocyclic group Chemical group 0.000 description 25
- 208000024827 Alzheimer disease Diseases 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- 239000002904 solvent Substances 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- 201000000980 schizophrenia Diseases 0.000 description 22
- 229940126585 therapeutic drug Drugs 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- 125000003277 amino group Chemical group 0.000 description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 17
- 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 17
- 230000002829 reductive effect Effects 0.000 description 17
- 238000012360 testing method Methods 0.000 description 17
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 16
- 208000018737 Parkinson disease Diseases 0.000 description 16
- 239000002585 base Substances 0.000 description 16
- 125000006517 heterocyclyl carbonyl group Chemical group 0.000 description 16
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 15
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 15
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 15
- 125000006239 protecting group Chemical group 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- 201000010099 disease Diseases 0.000 description 14
- 230000003287 optical effect Effects 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 12
- 229920002472 Starch Polymers 0.000 description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- 239000008107 starch Substances 0.000 description 12
- 235000019698 starch Nutrition 0.000 description 12
- 239000000126 substance Substances 0.000 description 12
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 11
- 239000002253 acid Substances 0.000 description 11
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 11
- 238000005886 esterification reaction Methods 0.000 description 11
- 239000007924 injection Substances 0.000 description 11
- 238000002347 injection Methods 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- 208000002193 Pain Diseases 0.000 description 10
- 125000003710 aryl alkyl group Chemical group 0.000 description 10
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 10
- 239000001768 carboxy methyl cellulose Substances 0.000 description 10
- 150000002430 hydrocarbons Chemical group 0.000 description 10
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- 238000010898 silica gel chromatography Methods 0.000 description 10
- 208000019116 sleep disease Diseases 0.000 description 10
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 9
- 102100033350 ATP-dependent translocase ABCB1 Human genes 0.000 description 9
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 108010047230 Member 1 Subfamily B ATP Binding Cassette Transporter Proteins 0.000 description 9
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 9
- 241000700159 Rattus Species 0.000 description 9
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 9
- 229960004373 acetylcholine Drugs 0.000 description 9
- 239000000872 buffer Substances 0.000 description 9
- 239000003054 catalyst Substances 0.000 description 9
- 125000004093 cyano group Chemical group *C#N 0.000 description 9
- 230000032050 esterification Effects 0.000 description 9
- 125000001153 fluoro group Chemical group F* 0.000 description 9
- 235000010355 mannitol Nutrition 0.000 description 9
- 229920000609 methyl cellulose Polymers 0.000 description 9
- 235000010981 methylcellulose Nutrition 0.000 description 9
- 239000001923 methylcellulose Substances 0.000 description 9
- 229960002900 methylcellulose Drugs 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 230000035699 permeability Effects 0.000 description 9
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
- 208000011580 syndromic disease Diseases 0.000 description 9
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 9
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 description 8
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 8
- 125000005915 C6-C14 aryl group Chemical group 0.000 description 8
- 125000005974 C6-C14 arylcarbonyl group Chemical group 0.000 description 8
- 201000002832 Lewy body dementia Diseases 0.000 description 8
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 239000005557 antagonist Substances 0.000 description 8
- 229910052731 fluorine Inorganic materials 0.000 description 8
- 235000019253 formic acid Nutrition 0.000 description 8
- 229910052751 metal Inorganic materials 0.000 description 8
- 239000002184 metal Substances 0.000 description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 7
- 102000017927 CHRM1 Human genes 0.000 description 7
- 101150073075 Chrm1 gene Proteins 0.000 description 7
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 7
- 206010067889 Dementia with Lewy bodies Diseases 0.000 description 7
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 7
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 7
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 125000005099 aryl alkyl carbonyl group Chemical group 0.000 description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- 150000001924 cycloalkanes Chemical class 0.000 description 7
- 239000008187 granular material Substances 0.000 description 7
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 7
- 239000003112 inhibitor Substances 0.000 description 7
- 238000001990 intravenous administration Methods 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 150000007522 mineralic acids Chemical class 0.000 description 7
- 201000006417 multiple sclerosis Diseases 0.000 description 7
- 150000007524 organic acids Chemical class 0.000 description 7
- 239000008194 pharmaceutical composition Substances 0.000 description 7
- 102000005962 receptors Human genes 0.000 description 7
- 108020003175 receptors Proteins 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 6
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 241000124008 Mammalia Species 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 6
- 125000004414 alkyl thio group Chemical group 0.000 description 6
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 6
- 150000004945 aromatic hydrocarbons Chemical group 0.000 description 6
- 239000011230 binding agent Substances 0.000 description 6
- 210000004556 brain Anatomy 0.000 description 6
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 6
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 6
- 229940105329 carboxymethylcellulose Drugs 0.000 description 6
- 210000003169 central nervous system Anatomy 0.000 description 6
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 6
- 125000000753 cycloalkyl group Chemical group 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- 150000007529 inorganic bases Chemical class 0.000 description 6
- 239000007951 isotonicity adjuster Substances 0.000 description 6
- 239000012528 membrane Substances 0.000 description 6
- 150000007530 organic bases Chemical class 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical class ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- 239000003755 preservative agent Substances 0.000 description 6
- 150000003254 radicals Chemical class 0.000 description 6
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 6
- 208000020431 spinal cord injury Diseases 0.000 description 6
- 235000000346 sugar Nutrition 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 208000019901 Anxiety disease Diseases 0.000 description 5
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 5
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 5
- 108010010803 Gelatin Proteins 0.000 description 5
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 5
- 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 5
- 239000002841 Lewis acid Substances 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 230000002378 acidificating effect Effects 0.000 description 5
- 125000005115 alkyl carbamoyl group Chemical group 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 5
- 125000003725 azepanyl group Chemical group 0.000 description 5
- 125000002619 bicyclic group Chemical group 0.000 description 5
- 229920002678 cellulose Polymers 0.000 description 5
- 239000001913 cellulose Substances 0.000 description 5
- 235000010980 cellulose Nutrition 0.000 description 5
- 238000007796 conventional method Methods 0.000 description 5
- 206010012601 diabetes mellitus Diseases 0.000 description 5
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 5
- 239000007884 disintegrant Substances 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 239000008273 gelatin Substances 0.000 description 5
- 229920000159 gelatin Polymers 0.000 description 5
- 235000019322 gelatine Nutrition 0.000 description 5
- 235000011852 gelatine desserts Nutrition 0.000 description 5
- 230000002140 halogenating effect Effects 0.000 description 5
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 5
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
- 150000007517 lewis acids Chemical class 0.000 description 5
- 239000000314 lubricant Substances 0.000 description 5
- 235000019359 magnesium stearate Nutrition 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 125000003367 polycyclic group Chemical group 0.000 description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 5
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 229940002612 prodrug Drugs 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 5
- 239000000454 talc Substances 0.000 description 5
- 229910052623 talc Inorganic materials 0.000 description 5
- 235000012222 talc Nutrition 0.000 description 5
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 5
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 4
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 4
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 208000007848 Alcoholism Diseases 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- 241000282472 Canis lupus familiaris Species 0.000 description 4
- 239000004215 Carbon black (E152) Substances 0.000 description 4
- 208000019888 Circadian rhythm sleep disease Diseases 0.000 description 4
- 229920002261 Corn starch Polymers 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- 208000012902 Nervous system disease Diseases 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- 239000002202 Polyethylene glycol Substances 0.000 description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 4
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 4
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 239000000556 agonist Substances 0.000 description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 4
- 150000001350 alkyl halides Chemical class 0.000 description 4
- 238000007112 amidation reaction Methods 0.000 description 4
- 150000001413 amino acids Chemical group 0.000 description 4
- 239000003963 antioxidant agent Substances 0.000 description 4
- 235000006708 antioxidants Nutrition 0.000 description 4
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000008120 corn starch Substances 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 description 4
- 238000010575 fractional recrystallization Methods 0.000 description 4
- 230000002496 gastric effect Effects 0.000 description 4
- 230000005176 gastrointestinal motility Effects 0.000 description 4
- 229930195733 hydrocarbon Natural products 0.000 description 4
- 239000003999 initiator Substances 0.000 description 4
- 208000002551 irritable bowel syndrome Diseases 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000000018 receptor agonist Substances 0.000 description 4
- 229940044601 receptor agonist Drugs 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 4
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 239000000375 suspending agent Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- 230000032258 transport Effects 0.000 description 4
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 4
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 description 3
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 description 3
- 125000006717 (C3-C10) cycloalkenyl group Chemical group 0.000 description 3
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 3
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- FQTFHMSZCSUVEU-QRPNPIFTSA-N 4-[(1r)-2-amino-1-hydroxyethyl]benzene-1,2-diol;hydrochloride Chemical compound Cl.NC[C@H](O)C1=CC=C(O)C(O)=C1 FQTFHMSZCSUVEU-QRPNPIFTSA-N 0.000 description 3
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 208000020925 Bipolar disease Diseases 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 3
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 3
- 206010012289 Dementia Diseases 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LTMHDMANZUZIPE-AMTYYWEZSA-N Digoxin Natural products O([C@H]1[C@H](C)O[C@H](O[C@@H]2C[C@@H]3[C@@](C)([C@@H]4[C@H]([C@]5(O)[C@](C)([C@H](O)C4)[C@H](C4=CC(=O)OC4)CC5)CC3)CC2)C[C@@H]1O)[C@H]1O[C@H](C)[C@@H](O[C@H]2O[C@@H](C)[C@H](O)[C@@H](O)C2)[C@@H](O)C1 LTMHDMANZUZIPE-AMTYYWEZSA-N 0.000 description 3
- 102100035102 E3 ubiquitin-protein ligase MYCBP2 Human genes 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 239000007821 HATU Substances 0.000 description 3
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 3
- 208000001456 Jet Lag Syndrome Diseases 0.000 description 3
- 206010026749 Mania Diseases 0.000 description 3
- 208000026139 Memory disease Diseases 0.000 description 3
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 description 3
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 3
- 229940127450 Opioid Agonists Drugs 0.000 description 3
- 101150003085 Pdcl gene Proteins 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- 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 3
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 3
- 239000012190 activator Substances 0.000 description 3
- 201000007930 alcohol dependence Diseases 0.000 description 3
- 150000004703 alkoxides Chemical class 0.000 description 3
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 125000005116 aryl carbamoyl group Chemical group 0.000 description 3
- 125000005129 aryl carbonyl group Chemical group 0.000 description 3
- 150000001540 azides Chemical class 0.000 description 3
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 3
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 3
- 235000019445 benzyl alcohol Nutrition 0.000 description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 229910000019 calcium carbonate Inorganic materials 0.000 description 3
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 3
- 235000013539 calcium stearate Nutrition 0.000 description 3
- 239000008116 calcium stearate Substances 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 235000012000 cholesterol Nutrition 0.000 description 3
- 239000003086 colorant Substances 0.000 description 3
- 238000006482 condensation reaction Methods 0.000 description 3
- 235000005687 corn oil Nutrition 0.000 description 3
- 239000002285 corn oil Substances 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 208000010643 digestive system disease Diseases 0.000 description 3
- LTMHDMANZUZIPE-PUGKRICDSA-N digoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)[C@H](O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O LTMHDMANZUZIPE-PUGKRICDSA-N 0.000 description 3
- 229960005156 digoxin Drugs 0.000 description 3
- LTMHDMANZUZIPE-UHFFFAOYSA-N digoxine Natural products C1C(O)C(O)C(C)OC1OC1C(C)OC(OC2C(OC(OC3CC4C(C5C(C6(CCC(C6(C)C(O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)CC2O)C)CC1O LTMHDMANZUZIPE-UHFFFAOYSA-N 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 125000002541 furyl group Chemical group 0.000 description 3
- 230000007661 gastrointestinal function Effects 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 208000003532 hypothyroidism Diseases 0.000 description 3
- 230000002989 hypothyroidism Effects 0.000 description 3
- 206010022437 insomnia Diseases 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 235000010445 lecithin Nutrition 0.000 description 3
- 239000000787 lecithin Substances 0.000 description 3
- 229940067606 lecithin Drugs 0.000 description 3
- 230000003902 lesion Effects 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 208000030159 metabolic disease Diseases 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- JJYKJUXBWFATTE-UHFFFAOYSA-N mosher's acid Chemical compound COC(C(O)=O)(C(F)(F)F)C1=CC=CC=C1 JJYKJUXBWFATTE-UHFFFAOYSA-N 0.000 description 3
- 230000001272 neurogenic effect Effects 0.000 description 3
- 239000002858 neurotransmitter agent Substances 0.000 description 3
- 229910017604 nitric acid Inorganic materials 0.000 description 3
- 235000006408 oxalic acid Nutrition 0.000 description 3
- 229940116315 oxalic acid Drugs 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 208000020016 psychiatric disease Diseases 0.000 description 3
- 125000004076 pyridyl group Chemical group 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000008159 sesame oil Substances 0.000 description 3
- 235000011803 sesame oil Nutrition 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 229960002920 sorbitol Drugs 0.000 description 3
- 208000011117 substance-related disease Diseases 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 125000001544 thienyl group Chemical group 0.000 description 3
- 125000002053 thietanyl group Chemical group 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 239000008215 water for injection Substances 0.000 description 3
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 2
- 125000004845 (C1-C6) alkylsulfonylamino group Chemical group 0.000 description 2
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 2
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 description 2
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical group COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 2
- RXBYRTSOWREATF-UHFFFAOYSA-N 1,2,3,4-tetrahydroacridine Chemical compound C1=CC=C2C=C(CCCC3)C3=NC2=C1 RXBYRTSOWREATF-UHFFFAOYSA-N 0.000 description 2
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 2
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 2
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 2
- VDFVNEFVBPFDSB-UHFFFAOYSA-N 1,3-dioxane Chemical group C1COCOC1 VDFVNEFVBPFDSB-UHFFFAOYSA-N 0.000 description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 2
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
- HBEDSQVIWPRPAY-UHFFFAOYSA-N 2,3-dihydrobenzofuran Chemical compound C1=CC=C2OCCC2=C1 HBEDSQVIWPRPAY-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- YGZFYDFBHIDIBH-UHFFFAOYSA-N 2-[bis(2-hydroxyethyl)amino]icosan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCC(CO)N(CCO)CCO YGZFYDFBHIDIBH-UHFFFAOYSA-N 0.000 description 2
- ABFPKTQEQNICFT-UHFFFAOYSA-M 2-chloro-1-methylpyridin-1-ium;iodide Chemical compound [I-].C[N+]1=CC=CC=C1Cl ABFPKTQEQNICFT-UHFFFAOYSA-M 0.000 description 2
- BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- AHOUBRCZNHFOSL-UHFFFAOYSA-N 3-(1,3-benzodioxol-5-yloxymethyl)-4-(4-fluorophenyl)piperidine Chemical compound C1=CC(F)=CC=C1C1C(COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- AEDQNOLIADXSBB-UHFFFAOYSA-N 3-(dodecylazaniumyl)propanoate Chemical compound CCCCCCCCCCCCNCCC(O)=O AEDQNOLIADXSBB-UHFFFAOYSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- RTRHCNVUWOOTES-UHFFFAOYSA-N 4-(bromomethyl)-2-fluoro-N-(2-methoxyethyl)benzamide Chemical compound BrCC1=CC(=C(C(=O)NCCOC)C=C1)F RTRHCNVUWOOTES-UHFFFAOYSA-N 0.000 description 2
- WSTLFAWLFXOZKC-UHFFFAOYSA-N 4-(bromomethyl)-2-fluorobenzoic acid Chemical compound OC(=O)C1=CC=C(CBr)C=C1F WSTLFAWLFXOZKC-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- FBXGQDUVJBKEAJ-UHFFFAOYSA-N 4h-oxazin-3-one Chemical group O=C1CC=CON1 FBXGQDUVJBKEAJ-UHFFFAOYSA-N 0.000 description 2
- FPBBFDNGMKYTGR-UHFFFAOYSA-N 7-bromo-4-hydroxy-2,3-dihydro-1-benzofuran-5-carboxylic acid Chemical compound BrC1=CC(=C(C=2CCOC=21)O)C(=O)O FPBBFDNGMKYTGR-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 208000000103 Anorexia Nervosa Diseases 0.000 description 2
- 102100033367 Appetite-regulating hormone Human genes 0.000 description 2
- 206010003591 Ataxia Diseases 0.000 description 2
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 description 2
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 description 2
- 206010003805 Autism Diseases 0.000 description 2
- 208000020706 Autistic disease Diseases 0.000 description 2
- 239000004342 Benzoyl peroxide Substances 0.000 description 2
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- 125000005947 C1-C6 alkylsulfonyloxy group Chemical group 0.000 description 2
- 125000005914 C6-C14 aryloxy group Chemical group 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 229940127291 Calcium channel antagonist Drugs 0.000 description 2
- 241000282693 Cercopithecidae Species 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 206010008874 Chronic Fatigue Syndrome Diseases 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- 206010010539 Congenital megacolon Diseases 0.000 description 2
- 241000699800 Cricetinae Species 0.000 description 2
- 239000004375 Dextrin Substances 0.000 description 2
- 229920001353 Dextrin Polymers 0.000 description 2
- 201000003066 Diffuse Scleroderma Diseases 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 208000030814 Eating disease Diseases 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
- 208000019454 Feeding and Eating disease Diseases 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 208000018522 Gastrointestinal disease Diseases 0.000 description 2
- 101800001586 Ghrelin Proteins 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- 208000004592 Hirschsprung disease Diseases 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 101001017818 Homo sapiens ATP-dependent translocase ABCB1 Proteins 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 2
- 208000037147 Hypercalcaemia Diseases 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 208000019025 Hypokalemia Diseases 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 206010027439 Metal poisoning Diseases 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 208000019695 Migraine disease Diseases 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 101100400865 Mus musculus Abcb1b gene Proteins 0.000 description 2
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 208000025966 Neurological disease Diseases 0.000 description 2
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 2
- 102000019315 Nicotinic acetylcholine receptors Human genes 0.000 description 2
- 108050006807 Nicotinic acetylcholine receptors Proteins 0.000 description 2
- 208000030053 Opioid-Induced Constipation Diseases 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- WYNCHZVNFNFDNH-UHFFFAOYSA-N Oxazolidine Chemical compound C1COCN1 WYNCHZVNFNFDNH-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- 241001494479 Pecora Species 0.000 description 2
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 2
- 206010034912 Phobia Diseases 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Natural products P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- 241000097929 Porphyria Species 0.000 description 2
- 208000010642 Porphyrias Diseases 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 2
- 208000028017 Psychotic disease Diseases 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- FTALBRSUTCGOEG-UHFFFAOYSA-N Riluzole Chemical compound C1=C(OC(F)(F)F)C=C2SC(N)=NC2=C1 FTALBRSUTCGOEG-UHFFFAOYSA-N 0.000 description 2
- 206010039710 Scleroderma Diseases 0.000 description 2
- 208000026214 Skeletal muscle atrophy Diseases 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 2
- 201000009594 Systemic Scleroderma Diseases 0.000 description 2
- 206010042953 Systemic sclerosis Diseases 0.000 description 2
- 208000008548 Tension-Type Headache Diseases 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 208000000323 Tourette Syndrome Diseases 0.000 description 2
- 208000016620 Tourette disease Diseases 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 2
- 201000004810 Vascular dementia Diseases 0.000 description 2
- 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 2
- 102000002852 Vasopressins Human genes 0.000 description 2
- 108010004977 Vasopressins Proteins 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- 150000001241 acetals Chemical group 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical compound C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 2
- 150000008046 alkali metal hydrides Chemical class 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 description 2
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 description 2
- 230000002152 alkylating effect Effects 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 229940087168 alpha tocopherol Drugs 0.000 description 2
- PAZJSJFMUHDSTF-UHFFFAOYSA-N alprenolol Chemical compound CC(C)NCC(O)COC1=CC=CC=C1CC=C PAZJSJFMUHDSTF-UHFFFAOYSA-N 0.000 description 2
- 229960002213 alprenolol Drugs 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 206010002022 amyloidosis Diseases 0.000 description 2
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 239000002249 anxiolytic agent Substances 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 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 2
- 125000001691 aryl alkyl amino group Chemical group 0.000 description 2
- 125000001769 aryl amino group Chemical group 0.000 description 2
- 125000004658 aryl carbonyl amino group Chemical group 0.000 description 2
- 125000005199 aryl carbonyloxy group Chemical group 0.000 description 2
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 2
- 125000004657 aryl sulfonyl amino group Chemical group 0.000 description 2
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000002567 autonomic effect Effects 0.000 description 2
- 125000002393 azetidinyl group Chemical group 0.000 description 2
- 125000004069 aziridinyl group Chemical group 0.000 description 2
- QXNDZONIWRINJR-UHFFFAOYSA-N azocane Chemical compound C1CCCNCCC1 QXNDZONIWRINJR-UHFFFAOYSA-N 0.000 description 2
- 159000000009 barium salts Chemical class 0.000 description 2
- 229960000686 benzalkonium chloride Drugs 0.000 description 2
- 229960001950 benzethonium chloride Drugs 0.000 description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical group C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 2
- 239000012964 benzotriazole Chemical group 0.000 description 2
- 235000019400 benzoyl peroxide Nutrition 0.000 description 2
- 229960002903 benzyl benzoate Drugs 0.000 description 2
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 230000008499 blood brain barrier function Effects 0.000 description 2
- 210000001218 blood-brain barrier Anatomy 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 230000031709 bromination Effects 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 235000019437 butane-1,3-diol Nutrition 0.000 description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 235000001465 calcium Nutrition 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- 150000001718 carbodiimides Chemical class 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 150000001728 carbonyl compounds Chemical class 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 150000001793 charged compounds Chemical class 0.000 description 2
- OGEBRHQLRGFBNV-RZDIXWSQSA-N chembl2036808 Chemical compound C12=NC(NCCCC)=NC=C2C(C=2C=CC(F)=CC=2)=NN1C[C@H]1CC[C@H](N)CC1 OGEBRHQLRGFBNV-RZDIXWSQSA-N 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 239000000812 cholinergic antagonist Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 description 2
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 2
- 208000010877 cognitive disease Diseases 0.000 description 2
- 229960001338 colchicine Drugs 0.000 description 2
- 239000008119 colloidal silica Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 125000000000 cycloalkoxy group Chemical group 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical compound C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 230000013872 defecation Effects 0.000 description 2
- 235000019258 dehydroacetic acid Nutrition 0.000 description 2
- PGRHXDWITVMQBC-UHFFFAOYSA-N dehydroacetic acid Chemical compound CC(=O)C1C(=O)OC(C)=CC1=O PGRHXDWITVMQBC-UHFFFAOYSA-N 0.000 description 2
- 239000003405 delayed action preparation Substances 0.000 description 2
- 235000019425 dextrin Nutrition 0.000 description 2
- 125000002576 diazepinyl group Chemical group N1N=C(C=CC=C1)* 0.000 description 2
- 229960001259 diclofenac Drugs 0.000 description 2
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 2
- 235000014632 disordered eating Nutrition 0.000 description 2
- 229960003530 donepezil Drugs 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- 206010013663 drug dependence Diseases 0.000 description 2
- 208000024732 dysthymic disease Diseases 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 208000030172 endocrine system disease Diseases 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- JRURYQJSLYLRLN-BJMVGYQFSA-N entacapone Chemical compound CCN(CC)C(=O)C(\C#N)=C\C1=CC(O)=C(O)C([N+]([O-])=O)=C1 JRURYQJSLYLRLN-BJMVGYQFSA-N 0.000 description 2
- 229960003337 entacapone Drugs 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 125000001033 ether group Chemical group 0.000 description 2
- 125000006125 ethylsulfonyl group Chemical group 0.000 description 2
- 230000005496 eutectics Effects 0.000 description 2
- 230000002964 excitative effect Effects 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 239000007941 film coated tablet Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 235000011087 fumaric acid Nutrition 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- ASUTZQLVASHGKV-JDFRZJQESA-N galanthamine Chemical compound O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 ASUTZQLVASHGKV-JDFRZJQESA-N 0.000 description 2
- 210000004211 gastric acid Anatomy 0.000 description 2
- 208000018685 gastrointestinal system disease Diseases 0.000 description 2
- GNKDKYIHGQKHHM-RJKLHVOGSA-N ghrelin Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)CN)COC(=O)CCCCCCC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C1=CC=CC=C1 GNKDKYIHGQKHHM-RJKLHVOGSA-N 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 229940075507 glyceryl monostearate Drugs 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 238000005658 halogenation reaction Methods 0.000 description 2
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 2
- 208000010501 heavy metal poisoning Diseases 0.000 description 2
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 2
- 229920000669 heparin Polymers 0.000 description 2
- 229960001008 heparin sodium Drugs 0.000 description 2
- 125000005553 heteroaryloxy group Chemical group 0.000 description 2
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 102000053576 human ABCB1 Human genes 0.000 description 2
- 229960002163 hydrogen peroxide Drugs 0.000 description 2
- 229920001477 hydrophilic polymer Polymers 0.000 description 2
- RCBVKBFIWMOMHF-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O RCBVKBFIWMOMHF-UHFFFAOYSA-L 0.000 description 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 2
- 229940071826 hydroxyethyl cellulose Drugs 0.000 description 2
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 2
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 2
- 230000000148 hypercalcaemia Effects 0.000 description 2
- 208000030915 hypercalcemia disease Diseases 0.000 description 2
- 208000033065 inborn errors of immunity Diseases 0.000 description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000010255 intramuscular injection Methods 0.000 description 2
- 239000007927 intramuscular injection Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 208000033915 jet lag type circadian rhythm sleep disease Diseases 0.000 description 2
- 210000002429 large intestine Anatomy 0.000 description 2
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 2
- 239000000347 magnesium hydroxide Substances 0.000 description 2
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 2
- 159000000003 magnesium salts Chemical class 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-N mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 229960004640 memantine Drugs 0.000 description 2
- LDDHMLJTFXJGPI-UHFFFAOYSA-N memantine hydrochloride Chemical compound Cl.C1C(C2)CC3(C)CC1(C)CC2(N)C3 LDDHMLJTFXJGPI-UHFFFAOYSA-N 0.000 description 2
- 230000006371 metabolic abnormality Effects 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- HYRURJQQQURGQC-UHFFFAOYSA-N methyl 4-hydroxy-1-benzofuran-5-carboxylate Chemical compound COC(=O)C1=CC=C2OC=CC2=C1O HYRURJQQQURGQC-UHFFFAOYSA-N 0.000 description 2
- GELDXVDZNHGLQD-UHFFFAOYSA-N methyl 4-hydroxy-2,3-dihydro-1-benzofuran-5-carboxylate Chemical compound OC1=C(C=CC2=C1CCO2)C(=O)OC GELDXVDZNHGLQD-UHFFFAOYSA-N 0.000 description 2
- DEIFTKOOBRKBBF-UHFFFAOYSA-N methyl 4-oxo-6,7-dihydro-5h-1-benzofuran-5-carboxylate Chemical compound O=C1C(C(=O)OC)CCC2=C1C=CO2 DEIFTKOOBRKBBF-UHFFFAOYSA-N 0.000 description 2
- QYZCFMHIPHNKBL-UHFFFAOYSA-N methyl 7-bromo-4-hydroxy-2,3-dihydro-1-benzofuran-5-carboxylate Chemical compound BrC1=CC(=C(C=2CCOC=21)O)C(=O)OC QYZCFMHIPHNKBL-UHFFFAOYSA-N 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 2
- 239000003094 microcapsule Substances 0.000 description 2
- 206010027599 migraine Diseases 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- 230000003387 muscular Effects 0.000 description 2
- 208000029766 myalgic encephalomeyelitis/chronic fatigue syndrome Diseases 0.000 description 2
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 2
- 238000005648 named reaction Methods 0.000 description 2
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- 230000004770 neurodegeneration Effects 0.000 description 2
- 208000015122 neurodegenerative disease Diseases 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 235000008390 olive oil Nutrition 0.000 description 2
- 125000001979 organolithium group Chemical group 0.000 description 2
- 125000003566 oxetanyl group Chemical group 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 125000004043 oxo group Chemical group O=* 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- RDOWQLZANAYVLL-UHFFFAOYSA-N phenanthridine Chemical compound C1=CC=C2C3=CC=CC=C3C=NC2=C1 RDOWQLZANAYVLL-UHFFFAOYSA-N 0.000 description 2
- 125000006678 phenoxycarbonyl group Chemical group 0.000 description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
- 208000028591 pheochromocytoma Diseases 0.000 description 2
- 208000019899 phobic disease Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 2
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 description 2
- 230000000865 phosphorylative effect Effects 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 230000004962 physiological condition Effects 0.000 description 2
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 238000002600 positron emission tomography Methods 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 2
- 208000024896 potassium deficiency disease Diseases 0.000 description 2
- 238000000634 powder X-ray diffraction Methods 0.000 description 2
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 208000028529 primary immunodeficiency disease Diseases 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 125000005554 pyridyloxy group Chemical group 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 229960004181 riluzole Drugs 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 2
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 230000025185 skeletal muscle atrophy Effects 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 2
- 239000007901 soft capsule Substances 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 235000010199 sorbic acid Nutrition 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 238000004885 tandem mass spectrometry Methods 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 2
- 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 description 2
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 2
- 229930192474 thiophene Natural products 0.000 description 2
- 229960000984 tocofersolan Drugs 0.000 description 2
- 230000000472 traumatic effect Effects 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 description 2
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- JOYRKODLDBILNP-UHFFFAOYSA-N urethane group Chemical group NC(=O)OCC JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 2
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229960003726 vasopressin Drugs 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- UAYWVJHJZHQCIE-UHFFFAOYSA-L zinc iodide Chemical compound I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 description 2
- 239000002076 α-tocopherol Substances 0.000 description 2
- 235000004835 α-tocopherol Nutrition 0.000 description 2
- AIFRHYZBTHREPW-UHFFFAOYSA-N β-carboline Chemical compound N1=CC=C2C3=CC=CC=C3NC2=C1 AIFRHYZBTHREPW-UHFFFAOYSA-N 0.000 description 2
- RQEUFEKYXDPUSK-ZETCQYMHSA-N (1S)-1-phenylethanamine Chemical compound C[C@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-ZETCQYMHSA-N 0.000 description 1
- BKPRVQDIOGQWTG-FKXFVUDVSA-N (1r,2s)-2-phenylcyclopropan-1-amine;sulfuric acid Chemical compound OS(O)(=O)=O.N[C@@H]1C[C@H]1C1=CC=CC=C1.N[C@@H]1C[C@H]1C1=CC=CC=C1 BKPRVQDIOGQWTG-FKXFVUDVSA-N 0.000 description 1
- ZERWDZDNDJBYKA-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O ZERWDZDNDJBYKA-UHFFFAOYSA-N 0.000 description 1
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 1
- QXWYKJLNLSIPIN-YUMQZZPRSA-N (2s,3s)-2-azaniumyl-3-(3,4-dihydroxyphenyl)-3-hydroxypropanoate Chemical compound [O-]C(=O)[C@@H]([NH3+])[C@@H](O)C1=CC=C(O)C(O)=C1 QXWYKJLNLSIPIN-YUMQZZPRSA-N 0.000 description 1
- PDVFSPNIEOYOQL-UHFFFAOYSA-N (4-methylphenyl)sulfonyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OS(=O)(=O)C1=CC=C(C)C=C1 PDVFSPNIEOYOQL-UHFFFAOYSA-N 0.000 description 1
- GBBSUAFBMRNDJC-MRXNPFEDSA-N (5R)-zopiclone Chemical compound C1CN(C)CCN1C(=O)O[C@@H]1C2=NC=CN=C2C(=O)N1C1=CC=C(Cl)C=N1 GBBSUAFBMRNDJC-MRXNPFEDSA-N 0.000 description 1
- 125000006624 (C1-C6) alkoxycarbonylamino group Chemical group 0.000 description 1
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 description 1
- IWYDHOAUDWTVEP-SSDOTTSWSA-N (R)-mandelic acid Chemical compound OC(=O)[C@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-SSDOTTSWSA-N 0.000 description 1
- BGRJTUBHPOOWDU-NSHDSACASA-N (S)-(-)-sulpiride Chemical compound CCN1CCC[C@H]1CNC(=O)C1=CC(S(N)(=O)=O)=CC=C1OC BGRJTUBHPOOWDU-NSHDSACASA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- LRGZZEOWQURWFK-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7-octahydroisoquinoline Chemical compound C1NCCC2CCCC=C21 LRGZZEOWQURWFK-UHFFFAOYSA-N 0.000 description 1
- ZCZVGQCBSJLDDS-UHFFFAOYSA-N 1,2,3,4-tetrahydro-1,8-naphthyridine Chemical compound C1=CC=C2CCCNC2=N1 ZCZVGQCBSJLDDS-UHFFFAOYSA-N 0.000 description 1
- WXRSSOIHEAVYLL-UHFFFAOYSA-N 1,2,3,4-tetrahydrocinnoline Chemical compound C1=CC=C2NNCCC2=C1 WXRSSOIHEAVYLL-UHFFFAOYSA-N 0.000 description 1
- JBHCHNYONQSXLP-UHFFFAOYSA-N 1,2,3,4-tetrahydrophenanthridine Chemical compound N1=CC2=CC=CC=C2C2=C1CCCC2 JBHCHNYONQSXLP-UHFFFAOYSA-N 0.000 description 1
- IMSHIOJKUPGIOQ-UHFFFAOYSA-N 1,2,3,4-tetrahydrophenazine Chemical compound C1=CC=C2N=C(CCCC3)C3=NC2=C1 IMSHIOJKUPGIOQ-UHFFFAOYSA-N 0.000 description 1
- STIWEDICJHIFJT-UHFFFAOYSA-N 1,2,3,4-tetrahydrophthalazine Chemical compound C1=CC=C2CNNCC2=C1 STIWEDICJHIFJT-UHFFFAOYSA-N 0.000 description 1
- JQIZHNLEFQMDCQ-UHFFFAOYSA-N 1,2,3,4-tetrahydropyridazine Chemical compound C1CC=CNN1 JQIZHNLEFQMDCQ-UHFFFAOYSA-N 0.000 description 1
- OTPDWCMLUKMQNO-UHFFFAOYSA-N 1,2,3,4-tetrahydropyrimidine Chemical compound C1NCC=CN1 OTPDWCMLUKMQNO-UHFFFAOYSA-N 0.000 description 1
- PKORYTIUMAOPED-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinazoline Chemical compound C1=CC=C2NCNCC2=C1 PKORYTIUMAOPED-UHFFFAOYSA-N 0.000 description 1
- HORKYAIEVBUXGM-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoxaline Chemical compound C1=CC=C2NCCNC2=C1 HORKYAIEVBUXGM-UHFFFAOYSA-N 0.000 description 1
- BBVIDBNAYOIXOE-UHFFFAOYSA-N 1,2,4-oxadiazole Chemical compound C=1N=CON=1 BBVIDBNAYOIXOE-UHFFFAOYSA-N 0.000 description 1
- 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 description 1
- YGTAZGSLCXNBQL-UHFFFAOYSA-N 1,2,4-thiadiazole Chemical compound C=1N=CSN=1 YGTAZGSLCXNBQL-UHFFFAOYSA-N 0.000 description 1
- 125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 description 1
- CSNIZNHTOVFARY-UHFFFAOYSA-N 1,2-benzothiazole Chemical compound C1=CC=C2C=NSC2=C1 CSNIZNHTOVFARY-UHFFFAOYSA-N 0.000 description 1
- KTZQTRPPVKQPFO-UHFFFAOYSA-N 1,2-benzoxazole Chemical compound C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 description 1
- CIISBYKBBMFLEZ-UHFFFAOYSA-N 1,2-oxazolidine Chemical compound C1CNOC1 CIISBYKBBMFLEZ-UHFFFAOYSA-N 0.000 description 1
- CZSRXHJVZUBEGW-UHFFFAOYSA-N 1,2-thiazolidine Chemical compound C1CNSC1 CZSRXHJVZUBEGW-UHFFFAOYSA-N 0.000 description 1
- FKASFBLJDCHBNZ-UHFFFAOYSA-N 1,3,4-oxadiazole Chemical compound C1=NN=CO1 FKASFBLJDCHBNZ-UHFFFAOYSA-N 0.000 description 1
- 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 description 1
- MBIZXFATKUQOOA-UHFFFAOYSA-N 1,3,4-thiadiazole Chemical compound C1=NN=CS1 MBIZXFATKUQOOA-UHFFFAOYSA-N 0.000 description 1
- 125000004520 1,3,4-thiadiazolyl group Chemical group 0.000 description 1
- BGJSXRVXTHVRSN-UHFFFAOYSA-N 1,3,5-trioxane Chemical compound C1OCOCO1 BGJSXRVXTHVRSN-UHFFFAOYSA-N 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 1
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- FLBAYUMRQUHISI-UHFFFAOYSA-N 1,8-naphthyridine Chemical compound N1=CC=CC2=CC=CN=C21 FLBAYUMRQUHISI-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- MNCMBBIFTVWHIP-UHFFFAOYSA-N 1-anthracen-9-yl-2,2,2-trifluoroethanone Chemical group C1=CC=C2C(C(=O)C(F)(F)F)=C(C=CC=C3)C3=CC2=C1 MNCMBBIFTVWHIP-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- LVZIWKFQFKNSMO-UHFFFAOYSA-N 1-chlorobutan-1-ol Chemical class CCCC(O)Cl LVZIWKFQFKNSMO-UHFFFAOYSA-N 0.000 description 1
- 125000006039 1-hexenyl group Chemical group 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- 125000001088 1-naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000006023 1-pentenyl group Chemical group 0.000 description 1
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 description 1
- TZMSYXZUNZXBOL-UHFFFAOYSA-N 10H-phenoxazine Chemical compound C1=CC=C2NC3=CC=CC=C3OC2=C1 TZMSYXZUNZXBOL-UHFFFAOYSA-N 0.000 description 1
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- 125000005955 1H-indazolyl group Chemical group 0.000 description 1
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 1
- ZKAMEFMDQNTDFK-UHFFFAOYSA-N 1h-imidazo[4,5-b]pyrazine Chemical compound C1=CN=C2NC=NC2=N1 ZKAMEFMDQNTDFK-UHFFFAOYSA-N 0.000 description 1
- AMFYRKOUWBAGHV-UHFFFAOYSA-N 1h-pyrazolo[4,3-b]pyridine Chemical compound C1=CN=C2C=NNC2=C1 AMFYRKOUWBAGHV-UHFFFAOYSA-N 0.000 description 1
- XWIYUCRMWCHYJR-UHFFFAOYSA-N 1h-pyrrolo[3,2-b]pyridine Chemical compound C1=CC=C2NC=CC2=N1 XWIYUCRMWCHYJR-UHFFFAOYSA-N 0.000 description 1
- UTQNKKSJPHTPBS-UHFFFAOYSA-N 2,2,2-trichloroethanone Chemical group ClC(Cl)(Cl)[C]=O UTQNKKSJPHTPBS-UHFFFAOYSA-N 0.000 description 1
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- DKASUYIOUPPQSY-UHFFFAOYSA-N 2,3,3a,4-tetrahydrothieno[2,3-c]pyridine Chemical compound C1C=NC=C2SCCC21 DKASUYIOUPPQSY-UHFFFAOYSA-N 0.000 description 1
- MZBVNYACSSGXID-UHFFFAOYSA-N 2,3,4,5-tetrahydro-1h-1-benzazepine Chemical compound N1CCCCC2=CC=CC=C21 MZBVNYACSSGXID-UHFFFAOYSA-N 0.000 description 1
- CFTOTSJVQRFXOF-UHFFFAOYSA-N 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole Chemical compound N1C2=CC=CC=C2C2=C1CNCC2 CFTOTSJVQRFXOF-UHFFFAOYSA-N 0.000 description 1
- XKLNOVWDVMWTOB-UHFFFAOYSA-N 2,3,4,9-tetrahydro-1h-carbazole Chemical compound N1C2=CC=CC=C2C2=C1CCCC2 XKLNOVWDVMWTOB-UHFFFAOYSA-N 0.000 description 1
- LCXSFEMSLWDBJG-UHFFFAOYSA-N 2,3,4,9-tetrahydro-1h-thioxanthene Chemical compound C1C2=CC=CC=C2SC2=C1CCCC2 LCXSFEMSLWDBJG-UHFFFAOYSA-N 0.000 description 1
- HRCMXYXVAWHBTH-UHFFFAOYSA-N 2,3-dihydro-1,3-benzoxazole Chemical compound C1=CC=C2OCNC2=C1 HRCMXYXVAWHBTH-UHFFFAOYSA-N 0.000 description 1
- VEPOHXYIFQMVHW-XOZOLZJESA-N 2,3-dihydroxybutanedioic acid (2S,3S)-3,4-dimethyl-2-phenylmorpholine Chemical compound OC(C(O)C(O)=O)C(O)=O.C[C@H]1[C@@H](OCCN1C)c1ccccc1 VEPOHXYIFQMVHW-XOZOLZJESA-N 0.000 description 1
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 1
- JECYNCQXXKQDJN-UHFFFAOYSA-N 2-(2-methylhexan-2-yloxymethyl)oxirane Chemical group CCCCC(C)(C)OCC1CO1 JECYNCQXXKQDJN-UHFFFAOYSA-N 0.000 description 1
- HUHXLHLWASNVDB-UHFFFAOYSA-N 2-(oxan-2-yloxy)oxane Chemical group O1CCCCC1OC1OCCCC1 HUHXLHLWASNVDB-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 1
- CILPHQCEVYJUDN-VWYCJHECSA-N 2-[(1s,2s,5r)-5-methyl-2-propan-2-ylcyclohexyl]oxyacetic acid Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1OCC(O)=O CILPHQCEVYJUDN-VWYCJHECSA-N 0.000 description 1
- 125000005999 2-bromoethyl group Chemical group 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- ALFWHEYHCZRVLO-UHFFFAOYSA-N 2-fluoro-4-methylbenzoic acid Chemical compound CC1=CC=C(C(O)=O)C(F)=C1 ALFWHEYHCZRVLO-UHFFFAOYSA-N 0.000 description 1
- ASUDFOJKTJLAIK-UHFFFAOYSA-N 2-methoxyethanamine Chemical compound COCCN ASUDFOJKTJLAIK-UHFFFAOYSA-N 0.000 description 1
- 125000006020 2-methyl-1-propenyl group Chemical group 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- BZSXEZOLBIJVQK-UHFFFAOYSA-N 2-methylsulfonylbenzoic acid Chemical compound CS(=O)(=O)C1=CC=CC=C1C(O)=O BZSXEZOLBIJVQK-UHFFFAOYSA-N 0.000 description 1
- 125000001216 2-naphthoyl group Chemical group C1=C(C=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000006024 2-pentenyl group Chemical group 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- VSWICNJIUPRZIK-UHFFFAOYSA-N 2-piperideine Chemical compound C1CNC=CC1 VSWICNJIUPRZIK-UHFFFAOYSA-N 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical compound C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 description 1
- YWPMKTWUFVOFPL-UHFFFAOYSA-N 3,4-dihydro-2h-isoquinolin-1-one Chemical group C1=CC=C2C(=O)NCCC2=C1 YWPMKTWUFVOFPL-UHFFFAOYSA-N 0.000 description 1
- WPWNEKFMGCWNPR-UHFFFAOYSA-N 3,4-dihydro-2h-thiochromene Chemical compound C1=CC=C2CCCSC2=C1 WPWNEKFMGCWNPR-UHFFFAOYSA-N 0.000 description 1
- DNNVRTZJRKIUFK-UHFFFAOYSA-N 3,4-dihydroquinoline Chemical compound C1=CC=C2N=CCCC2=C1 DNNVRTZJRKIUFK-UHFFFAOYSA-N 0.000 description 1
- GGNCUSDIUUCNKE-RSAXXLAASA-N 3-(1,3-benzodioxol-5-yloxy)-n-[[(3s)-2,3-dihydro-1,4-benzodioxin-3-yl]methyl]propan-1-amine;hydrochloride Chemical compound Cl.C1=C2OCOC2=CC(OCCCNC[C@@H]2OC3=CC=CC=C3OC2)=C1 GGNCUSDIUUCNKE-RSAXXLAASA-N 0.000 description 1
- OTHCIGKQBMKICB-UHFFFAOYSA-N 3-(3-silylpropoxy)propane-1,2-diol Chemical compound OCC(O)COCCC[SiH3] OTHCIGKQBMKICB-UHFFFAOYSA-N 0.000 description 1
- ZPZDIFSPRVHGIF-UHFFFAOYSA-N 3-aminopropylsilicon Chemical compound NCCC[Si] ZPZDIFSPRVHGIF-UHFFFAOYSA-N 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- MEAPRSDUXBHXGD-UHFFFAOYSA-N 3-chloro-n-(4-propan-2-ylphenyl)propanamide Chemical compound CC(C)C1=CC=C(NC(=O)CCCl)C=C1 MEAPRSDUXBHXGD-UHFFFAOYSA-N 0.000 description 1
- 125000006041 3-hexenyl group Chemical group 0.000 description 1
- VFXXTYGQYWRHJP-UHFFFAOYSA-N 4,4'-azobis(4-cyanopentanoic acid) Chemical compound OC(=O)CCC(C)(C#N)N=NC(C)(CCC(O)=O)C#N VFXXTYGQYWRHJP-UHFFFAOYSA-N 0.000 description 1
- GLQPTZAAUROJMO-UHFFFAOYSA-N 4-(3,4-dimethoxyphenyl)benzaldehyde Chemical compound C1=C(OC)C(OC)=CC=C1C1=CC=C(C=O)C=C1 GLQPTZAAUROJMO-UHFFFAOYSA-N 0.000 description 1
- NZBKIOJQXNGENQ-UHFFFAOYSA-N 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium Chemical compound COC1=NC(OC)=NC([N+]2(C)CCOCC2)=N1 NZBKIOJQXNGENQ-UHFFFAOYSA-N 0.000 description 1
- GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical compound C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 0.000 description 1
- 125000003119 4-methyl-3-pentenyl group Chemical group [H]\C(=C(/C([H])([H])[H])C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- FGBFEFJZYZDLSZ-UHFFFAOYSA-N 5,7-dimethoxy-2,3-dimethyl-2,3-dihydroinden-1-one Chemical compound COC1=CC(OC)=CC2=C1C(=O)C(C)C2C FGBFEFJZYZDLSZ-UHFFFAOYSA-N 0.000 description 1
- 125000006043 5-hexenyl group Chemical group 0.000 description 1
- RXQZLSRIOOYKLF-UHFFFAOYSA-N 5H-pyrazolo[4,3-d]triazine Chemical compound N1=NN=C2C=NNC2=C1 RXQZLSRIOOYKLF-UHFFFAOYSA-N 0.000 description 1
- KDOPAZIWBAHVJB-UHFFFAOYSA-N 5h-pyrrolo[3,2-d]pyrimidine Chemical compound C1=NC=C2NC=CC2=N1 KDOPAZIWBAHVJB-UHFFFAOYSA-N 0.000 description 1
- DXWQOYPYNPSVRL-UHFFFAOYSA-N 6,7-dihydro-5h-1-benzofuran-4-one Chemical compound O=C1CCCC2=C1C=CO2 DXWQOYPYNPSVRL-UHFFFAOYSA-N 0.000 description 1
- VATIMCNDILNPMW-UHFFFAOYSA-N 7-chloro-1h-diazepine Chemical compound ClC1=CC=CC=NN1 VATIMCNDILNPMW-UHFFFAOYSA-N 0.000 description 1
- 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 1
- NPNNLGXEAGTSRN-UHFFFAOYSA-N 9-bromo-10-(10-bromoanthracen-9-yl)anthracene Chemical compound C12=CC=CC=C2C(Br)=C(C=CC=C2)C2=C1C1=C(C=CC=C2)C2=C(Br)C2=CC=CC=C12 NPNNLGXEAGTSRN-UHFFFAOYSA-N 0.000 description 1
- 206010000117 Abnormal behaviour Diseases 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 208000017194 Affective disease Diseases 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- KHOITXIGCFIULA-UHFFFAOYSA-N Alophen Chemical compound C1=CC(OC(=O)C)=CC=C1C(C=1N=CC=CC=1)C1=CC=C(OC(C)=O)C=C1 KHOITXIGCFIULA-UHFFFAOYSA-N 0.000 description 1
- KFYRPLNVJVHZGT-UHFFFAOYSA-N Amitriptyline hydrochloride Chemical compound Cl.C1CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 KFYRPLNVJVHZGT-UHFFFAOYSA-N 0.000 description 1
- 208000000044 Amnesia Diseases 0.000 description 1
- 206010002869 Anxiety symptoms Diseases 0.000 description 1
- 229940088872 Apoptosis inhibitor Drugs 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- CEUORZQYGODEFX-UHFFFAOYSA-N Aripirazole Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl CEUORZQYGODEFX-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 1
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 1
- 102100034605 Atrial natriuretic peptide receptor 3 Human genes 0.000 description 1
- 208000037157 Azotemia Diseases 0.000 description 1
- UYIFTLBWAOGQBI-BZDYCCQFSA-N Benzhormovarine Chemical compound C([C@@H]1[C@@H](C2=CC=3)CC[C@]4([C@H]1CC[C@@H]4O)C)CC2=CC=3OC(=O)C1=CC=CC=C1 UYIFTLBWAOGQBI-BZDYCCQFSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 206010069632 Bladder dysfunction Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 208000032841 Bulimia Diseases 0.000 description 1
- 206010006550 Bulimia nervosa Diseases 0.000 description 1
- ZYUZLEUJKZZXNN-UHFFFAOYSA-N C1=CC(CC(N)C(O)=O)=CC=C1OS(=O)(=O)C1=CC=C(C=CC=C2)C2=C1 Chemical group C1=CC(CC(N)C(O)=O)=CC=C1OS(=O)(=O)C1=CC=C(C=CC=C2)C2=C1 ZYUZLEUJKZZXNN-UHFFFAOYSA-N 0.000 description 1
- 125000003320 C2-C6 alkenyloxy group Chemical group 0.000 description 1
- 229940124802 CB1 antagonist Drugs 0.000 description 1
- SSUFDOMYCBCHML-UHFFFAOYSA-N CCCCC[S](=O)=O Chemical group CCCCC[S](=O)=O SSUFDOMYCBCHML-UHFFFAOYSA-N 0.000 description 1
- 102000017923 CHRM5 Human genes 0.000 description 1
- 101150064612 CHRM5 gene Proteins 0.000 description 1
- KORNTPPJEAJQIU-KJXAQDMKSA-N Cabaser Chemical compound C1=CC([C@H]2C[C@H](CN(CC=C)[C@@H]2C2)C(=O)N(CCCN(C)C)C(=O)NCC)=C3C2=CNC3=C1 KORNTPPJEAJQIU-KJXAQDMKSA-N 0.000 description 1
- 229940123613 Calcium receptor antagonist Drugs 0.000 description 1
- 102100024633 Carbonic anhydrase 2 Human genes 0.000 description 1
- 101710167917 Carbonic anhydrase 2 Proteins 0.000 description 1
- 206010007269 Carcinogenicity Diseases 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 206010048610 Cardiotoxicity Diseases 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- XTEGARKTQYYJKE-UHFFFAOYSA-M Chlorate Chemical class [O-]Cl(=O)=O XTEGARKTQYYJKE-UHFFFAOYSA-M 0.000 description 1
- 108010062745 Chloride Channels Proteins 0.000 description 1
- 102000011045 Chloride Channels Human genes 0.000 description 1
- 102000009660 Cholinergic Receptors Human genes 0.000 description 1
- 108010009685 Cholinergic Receptors Proteins 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 208000017164 Chronobiology disease Diseases 0.000 description 1
- 241000725101 Clea Species 0.000 description 1
- 208000028698 Cognitive impairment Diseases 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 206010010071 Coma Diseases 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 239000005749 Copper compound Substances 0.000 description 1
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 description 1
- 239000005751 Copper oxide Substances 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- 208000011990 Corticobasal Degeneration Diseases 0.000 description 1
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 1
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 1
- 208000020406 Creutzfeldt Jacob disease Diseases 0.000 description 1
- 208000003407 Creutzfeldt-Jakob Syndrome Diseases 0.000 description 1
- 208000010859 Creutzfeldt-Jakob disease Diseases 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 1
- 239000004287 Dehydroacetic acid Substances 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- 201000010374 Down Syndrome Diseases 0.000 description 1
- 206010013710 Drug interaction Diseases 0.000 description 1
- 206010013980 Dyssomnias Diseases 0.000 description 1
- VMZUTJCNQWMAGF-UHFFFAOYSA-N Etizolam Chemical compound S1C(CC)=CC2=C1N1C(C)=NN=C1CN=C2C1=CC=CC=C1Cl VMZUTJCNQWMAGF-UHFFFAOYSA-N 0.000 description 1
- 206010057671 Female sexual dysfunction Diseases 0.000 description 1
- 208000001640 Fibromyalgia Diseases 0.000 description 1
- LFMYNZPAVPMEGP-PIDGMYBPSA-N Fluvoxamine maleate Chemical compound OC(=O)\C=C/C(O)=O.COCCCC\C(=N/OCCN)C1=CC=C(C(F)(F)F)C=C1 LFMYNZPAVPMEGP-PIDGMYBPSA-N 0.000 description 1
- 208000001914 Fragile X syndrome Diseases 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- 201000011240 Frontotemporal dementia Diseases 0.000 description 1
- 108091006027 G proteins Proteins 0.000 description 1
- 102000004300 GABA-A Receptors Human genes 0.000 description 1
- 108090000839 GABA-A Receptors Proteins 0.000 description 1
- 102000030782 GTP binding Human genes 0.000 description 1
- 108091000058 GTP-Binding Proteins 0.000 description 1
- 208000001613 Gambling Diseases 0.000 description 1
- 206010052405 Gastric hypomotility Diseases 0.000 description 1
- 208000017228 Gastrointestinal motility disease Diseases 0.000 description 1
- 208000011688 Generalised anxiety disease Diseases 0.000 description 1
- 201000004311 Gilles de la Tourette syndrome Diseases 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 241001320695 Hermas Species 0.000 description 1
- 101000924488 Homo sapiens Atrial natriuretic peptide receptor 3 Proteins 0.000 description 1
- 101000841267 Homo sapiens Long chain 3-hydroxyacyl-CoA dehydrogenase Proteins 0.000 description 1
- 101001090860 Homo sapiens Myeloblastin Proteins 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010021067 Hypopituitarism Diseases 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 208000015814 Intrinsic Sleep disease Diseases 0.000 description 1
- 108090000862 Ion Channels Proteins 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- PWWVAXIEGOYWEE-UHFFFAOYSA-N Isophenergan Chemical compound C1=CC=C2N(CC(C)N(C)C)C3=CC=CC=C3SC2=C1 PWWVAXIEGOYWEE-UHFFFAOYSA-N 0.000 description 1
- 208000012659 Joint disease Diseases 0.000 description 1
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 1
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- 102000004016 L-Type Calcium Channels Human genes 0.000 description 1
- 108090000420 L-Type Calcium Channels Proteins 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 208000009829 Lewy Body Disease Diseases 0.000 description 1
- 206010024419 Libido decreased Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 102100029107 Long chain 3-hydroxyacyl-CoA dehydrogenase Human genes 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 206010057672 Male sexual dysfunction Diseases 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- ZRVUJXDFFKFLMG-UHFFFAOYSA-N Meloxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=C(C)S1 ZRVUJXDFFKFLMG-UHFFFAOYSA-N 0.000 description 1
- 208000027530 Meniere disease Diseases 0.000 description 1
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 1
- 208000001145 Metabolic Syndrome Diseases 0.000 description 1
- 102000016193 Metabotropic glutamate receptors Human genes 0.000 description 1
- 108010010914 Metabotropic glutamate receptors Proteins 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 238000006845 Michael addition reaction Methods 0.000 description 1
- 208000019022 Mood disease Diseases 0.000 description 1
- 102000057413 Motilin receptors Human genes 0.000 description 1
- 108700040483 Motilin receptors Proteins 0.000 description 1
- 208000005314 Multi-Infarct Dementia Diseases 0.000 description 1
- 235000003805 Musa ABB Group Nutrition 0.000 description 1
- 240000008790 Musa x paradisiaca Species 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- 102100034681 Myeloblastin Human genes 0.000 description 1
- OKIZCWYLBDKLSU-UHFFFAOYSA-M N,N,N-Trimethylmethanaminium chloride Chemical compound [Cl-].C[N+](C)(C)C OKIZCWYLBDKLSU-UHFFFAOYSA-M 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 102000004129 N-Type Calcium Channels Human genes 0.000 description 1
- 108090000699 N-Type Calcium Channels Proteins 0.000 description 1
- YLXDSYKOBKBWJQ-LBPRGKRZSA-N N-[2-[(8S)-2,6,7,8-tetrahydro-1H-cyclopenta[e]benzofuran-8-yl]ethyl]propanamide Chemical compound C1=C2OCCC2=C2[C@H](CCNC(=O)CC)CCC2=C1 YLXDSYKOBKBWJQ-LBPRGKRZSA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 108010025020 Nerve Growth Factor Proteins 0.000 description 1
- 102000007072 Nerve Growth Factors Human genes 0.000 description 1
- 208000009668 Neurobehavioral Manifestations Diseases 0.000 description 1
- 206010029333 Neurosis Diseases 0.000 description 1
- 102000010410 Nogo Proteins Human genes 0.000 description 1
- 108010077641 Nogo Proteins Proteins 0.000 description 1
- QMGVPVSNSZLJIA-UHFFFAOYSA-N Nux Vomica Natural products C1C2C3C4N(C=5C6=CC=CC=5)C(=O)CC3OCC=C2CN2C1C46CC2 QMGVPVSNSZLJIA-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 206010034010 Parkinsonism Diseases 0.000 description 1
- 206010034158 Pathological gambling Diseases 0.000 description 1
- 206010034972 Photosensitivity reaction Diseases 0.000 description 1
- PIJVFDBKTWXHHD-UHFFFAOYSA-N Physostigmine Natural products C12=CC(OC(=O)NC)=CC=C2N(C)C2C1(C)CCN2C PIJVFDBKTWXHHD-UHFFFAOYSA-N 0.000 description 1
- 235000015266 Plantago major Nutrition 0.000 description 1
- 229920000148 Polycarbophil calcium Polymers 0.000 description 1
- 206010054048 Postoperative ileus Diseases 0.000 description 1
- 201000009916 Postpartum depression Diseases 0.000 description 1
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 description 1
- 208000024777 Prion disease Diseases 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 101100288143 Rattus norvegicus Klkb1 gene Proteins 0.000 description 1
- 206010074268 Reproductive toxicity Diseases 0.000 description 1
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 1
- 206010038678 Respiratory depression Diseases 0.000 description 1
- 208000005793 Restless legs syndrome Diseases 0.000 description 1
- 208000006289 Rett Syndrome Diseases 0.000 description 1
- XSVMFMHYUFZWBK-NSHDSACASA-N Rivastigmine Chemical compound CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 XSVMFMHYUFZWBK-NSHDSACASA-N 0.000 description 1
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 description 1
- SKZKKFZAGNVIMN-UHFFFAOYSA-N Salicilamide Chemical compound NC(=O)C1=CC=CC=C1O SKZKKFZAGNVIMN-UHFFFAOYSA-N 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 208000032140 Sleepiness Diseases 0.000 description 1
- 206010041250 Social phobia Diseases 0.000 description 1
- 108010052164 Sodium Channels Proteins 0.000 description 1
- 102000018674 Sodium Channels Human genes 0.000 description 1
- 102100033927 Sodium- and chloride-dependent GABA transporter 1 Human genes 0.000 description 1
- 101710104414 Sodium- and chloride-dependent GABA transporter 1 Proteins 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 208000013200 Stress disease Diseases 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- 208000034972 Sudden Infant Death Diseases 0.000 description 1
- 206010042440 Sudden infant death syndrome Diseases 0.000 description 1
- 208000001871 Tachycardia Diseases 0.000 description 1
- 102000003141 Tachykinin Human genes 0.000 description 1
- 206010043189 Telangiectasia Diseases 0.000 description 1
- 206010043269 Tension headache Diseases 0.000 description 1
- YPWFISCTZQNZAU-UHFFFAOYSA-N Thiane Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- GNVMUORYQLCPJZ-UHFFFAOYSA-M Thiocarbamate Chemical compound NC([S-])=O GNVMUORYQLCPJZ-UHFFFAOYSA-M 0.000 description 1
- 208000030886 Traumatic Brain injury Diseases 0.000 description 1
- 229940123445 Tricyclic antidepressant Drugs 0.000 description 1
- 206010044688 Trisomy 21 Diseases 0.000 description 1
- 240000000581 Triticum monococcum Species 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 238000005874 Vilsmeier-Haack formylation reaction Methods 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- 238000006734 Wohl-Ziegler bromination reaction Methods 0.000 description 1
- BFPLMTPHDFFMTG-UHFFFAOYSA-N [1,3]oxazolo[5,4-b]pyridine Chemical compound C1=CN=C2OC=NC2=C1 BFPLMTPHDFFMTG-UHFFFAOYSA-N 0.000 description 1
- BRIOKNPDCPJCOD-UHFFFAOYSA-N [1,3]oxazolo[5,4-d]pyrimidine Chemical compound N1=CN=C2OC=NC2=C1 BRIOKNPDCPJCOD-UHFFFAOYSA-N 0.000 description 1
- WFIHKLWVLPBMIQ-UHFFFAOYSA-N [1,3]thiazolo[5,4-b]pyridine Chemical compound C1=CN=C2SC=NC2=C1 WFIHKLWVLPBMIQ-UHFFFAOYSA-N 0.000 description 1
- 206010000059 abdominal discomfort Diseases 0.000 description 1
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 150000003869 acetamides Chemical group 0.000 description 1
- 230000000397 acetylating effect Effects 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 239000002313 adhesive film Substances 0.000 description 1
- 239000000674 adrenergic antagonist Substances 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 206010001584 alcohol abuse Diseases 0.000 description 1
- 208000025746 alcohol use disease Diseases 0.000 description 1
- 208000029650 alcohol withdrawal Diseases 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 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
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000006323 alkenyl amino group Chemical group 0.000 description 1
- 125000005090 alkenylcarbonyl group Chemical group 0.000 description 1
- 125000005108 alkenylthio group Chemical group 0.000 description 1
- 150000003973 alkyl amines Chemical group 0.000 description 1
- 150000004791 alkyl magnesium halides Chemical class 0.000 description 1
- 125000005103 alkyl silyl group Chemical group 0.000 description 1
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 125000005336 allyloxy group Chemical group 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 1
- 229960003805 amantadine Drugs 0.000 description 1
- 230000002862 amidating effect Effects 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- QXAITBQSYVNQDR-ZIOPAAQOSA-N amitraz Chemical compound C=1C=C(C)C=C(C)C=1/N=C/N(C)\C=N\C1=CC=C(C)C=C1C QXAITBQSYVNQDR-ZIOPAAQOSA-N 0.000 description 1
- 229960002587 amitraz Drugs 0.000 description 1
- 229960005119 amitriptyline hydrochloride Drugs 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 125000002078 anthracen-1-yl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C([*])=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 125000000748 anthracen-2-yl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C([H])=C([*])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 230000003092 anti-cytokine Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 239000000883 anti-obesity agent Substances 0.000 description 1
- 229940082992 antihypertensives mao inhibitors Drugs 0.000 description 1
- 229940045985 antineoplastic platinum compound Drugs 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 229940005530 anxiolytics Drugs 0.000 description 1
- 208000008784 apnea Diseases 0.000 description 1
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 1
- 229960004046 apomorphine Drugs 0.000 description 1
- 239000000158 apoptosis inhibitor Substances 0.000 description 1
- ATALOFNDEOCMKK-OITMNORJSA-N aprepitant Chemical compound O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NNC(=O)N1 ATALOFNDEOCMKK-OITMNORJSA-N 0.000 description 1
- 229960001372 aprepitant Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- GLGAUBPACOBAMV-DOFZRALJSA-N arachidonylcyclopropylamide Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(=O)NC1CC1 GLGAUBPACOBAMV-DOFZRALJSA-N 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229960004372 aripiprazole Drugs 0.000 description 1
- 238000013528 artificial neural network Methods 0.000 description 1
- 125000005126 aryl alkyl carbonyl amino group Chemical group 0.000 description 1
- 125000004659 aryl alkyl thio group Chemical group 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- 150000004792 aryl magnesium halides Chemical class 0.000 description 1
- 125000005135 aryl sulfinyl group Chemical group 0.000 description 1
- 125000005110 aryl thio group Chemical group 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 238000000065 atmospheric pressure chemical ionisation Methods 0.000 description 1
- 229960005370 atorvastatin Drugs 0.000 description 1
- MXWJVTOOROXGIU-UHFFFAOYSA-N atrazine Chemical compound CCNC1=NC(Cl)=NC(NC(C)C)=N1 MXWJVTOOROXGIU-UHFFFAOYSA-N 0.000 description 1
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 description 1
- 125000002785 azepinyl group Chemical group 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- BNQDCRGUHNALGH-UHFFFAOYSA-N benserazide Chemical compound OCC(N)C(=O)NNCC1=CC=C(O)C(O)=C1O BNQDCRGUHNALGH-UHFFFAOYSA-N 0.000 description 1
- 229960000911 benserazide Drugs 0.000 description 1
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 229960003872 benzethonium Drugs 0.000 description 1
- MXMZCLLIUQEKSN-UHFFFAOYSA-N benzimidazoline Chemical compound C1=CC=C2NCNC2=C1 MXMZCLLIUQEKSN-UHFFFAOYSA-N 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 1
- AWNLOVXXKLDDSM-UHFFFAOYSA-N benzo[a]anthracen-1-yl(silyl)silane Chemical compound C1(=CC=CC2=CC=C3C=C4C=CC=CC4=CC3=C12)[SiH2][SiH3] AWNLOVXXKLDDSM-UHFFFAOYSA-N 0.000 description 1
- CYKIHIBNSFRKQP-UHFFFAOYSA-N benzo[f][1]benzothiole Chemical compound C1=CC=C2C=C(SC=C3)C3=CC2=C1 CYKIHIBNSFRKQP-UHFFFAOYSA-N 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 description 1
- 150000003938 benzyl alcohols Chemical class 0.000 description 1
- PUJDIJCNWFYVJX-UHFFFAOYSA-N benzyl carbamate Chemical group NC(=O)OCC1=CC=CC=C1 PUJDIJCNWFYVJX-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
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- LUFPJJNWMYZRQE-UHFFFAOYSA-N benzylsulfanylmethylbenzene Chemical group C=1C=CC=CC=1CSCC1=CC=CC=C1 LUFPJJNWMYZRQE-UHFFFAOYSA-N 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- YSXKPIUOCJLQIE-UHFFFAOYSA-N biperiden Chemical compound C1C(C=C2)CC2C1C(C=1C=CC=CC=1)(O)CCN1CCCCC1 YSXKPIUOCJLQIE-UHFFFAOYSA-N 0.000 description 1
- 229960003003 biperiden Drugs 0.000 description 1
- 208000028683 bipolar I disease Diseases 0.000 description 1
- 208000025307 bipolar depression Diseases 0.000 description 1
- 229960000503 bisacodyl Drugs 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 1
- 238000005271 boronizing Methods 0.000 description 1
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 1
- OZVBMTJYIDMWIL-AYFBDAFISA-N bromocriptine Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=C(Br)NC3=C1 OZVBMTJYIDMWIL-AYFBDAFISA-N 0.000 description 1
- 229960002802 bromocriptine Drugs 0.000 description 1
- LHMHCLYDBQOYTO-UHFFFAOYSA-N bromofluoromethane Chemical compound FCBr LHMHCLYDBQOYTO-UHFFFAOYSA-N 0.000 description 1
- QWCRAEMEVRGPNT-UHFFFAOYSA-N buspirone Chemical compound C1C(=O)N(CCCCN2CCN(CC2)C=2N=CC=CN=2)C(=O)CC21CCCC2 QWCRAEMEVRGPNT-UHFFFAOYSA-N 0.000 description 1
- 229960001768 buspirone hydrochloride Drugs 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- BMQGVNUXMIRLCK-OAGWZNDDSA-N cabazitaxel Chemical compound O([C@H]1[C@@H]2[C@]3(OC(C)=O)CO[C@@H]3C[C@@H]([C@]2(C(=O)[C@H](OC)C2=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=3C=CC=CC=3)C[C@]1(O)C2(C)C)C)OC)C(=O)C1=CC=CC=C1 BMQGVNUXMIRLCK-OAGWZNDDSA-N 0.000 description 1
- 229960001573 cabazitaxel Drugs 0.000 description 1
- 229960004596 cabergoline Drugs 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate 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
- 244000309466 calf Species 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229930003827 cannabinoid Natural products 0.000 description 1
- 239000003557 cannabinoid Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- QTAOMKOIBXZKND-PPHPATTJSA-N carbidopa Chemical compound O.NN[C@@](C(O)=O)(C)CC1=CC=C(O)C(O)=C1 QTAOMKOIBXZKND-PPHPATTJSA-N 0.000 description 1
- 229960004205 carbidopa Drugs 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 125000005587 carbonate group Chemical group 0.000 description 1
- 125000005392 carboxamide group Chemical group NC(=O)* 0.000 description 1
- 150000007942 carboxylates Chemical group 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 1
- 230000007670 carcinogenicity Effects 0.000 description 1
- 231100000260 carcinogenicity Toxicity 0.000 description 1
- 229940082638 cardiac stimulant phosphodiesterase inhibitors Drugs 0.000 description 1
- 231100000259 cardiotoxicity Toxicity 0.000 description 1
- 230000007681 cardiovascular toxicity Effects 0.000 description 1
- 238000005266 casting Methods 0.000 description 1
- 239000003543 catechol methyltransferase inhibitor Substances 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- 239000013553 cell monolayer Substances 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 206010008129 cerebral palsy Diseases 0.000 description 1
- 208000013677 cerebrovascular dementia Diseases 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 229940125400 channel inhibitor Drugs 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- PJGJQVRXEUVAFT-UHFFFAOYSA-N chloroiodomethane Chemical compound ClCI PJGJQVRXEUVAFT-UHFFFAOYSA-N 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- QBWCMBCROVPCKQ-UHFFFAOYSA-N chlorous acid Chemical class OCl=O QBWCMBCROVPCKQ-UHFFFAOYSA-N 0.000 description 1
- ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 1
- 229960001076 chlorpromazine Drugs 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 239000011651 chromium Substances 0.000 description 1
- 230000007665 chronic toxicity Effects 0.000 description 1
- 231100000160 chronic toxicity Toxicity 0.000 description 1
- KMPWYEUPVWOPIM-LSOMNZGLSA-N cinchonine Chemical compound C1=CC=C2C([C@@H]([C@H]3N4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-LSOMNZGLSA-N 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- WCZVZNOTHYJIEI-UHFFFAOYSA-N cinnoline Chemical compound N1=NC=CC2=CC=CC=C21 WCZVZNOTHYJIEI-UHFFFAOYSA-N 0.000 description 1
- 229960001564 clomipramine hydrochloride Drugs 0.000 description 1
- DGBIGWXXNGSACT-UHFFFAOYSA-N clonazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1Cl DGBIGWXXNGSACT-UHFFFAOYSA-N 0.000 description 1
- 229960003120 clonazepam Drugs 0.000 description 1
- 229960004170 clozapine Drugs 0.000 description 1
- QZUDBNBUXVUHMW-UHFFFAOYSA-N clozapine Chemical compound C1CN(C)CCN1C1=NC2=CC(Cl)=CC=C2NC2=CC=CC=C12 QZUDBNBUXVUHMW-UHFFFAOYSA-N 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 150000001869 cobalt compounds Chemical class 0.000 description 1
- 238000002288 cocrystallisation Methods 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 150000001880 copper compounds Chemical class 0.000 description 1
- 229910000431 copper oxide Inorganic materials 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 150000001925 cycloalkenes Chemical class 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000006310 cycloalkyl amino group Chemical group 0.000 description 1
- 125000006254 cycloalkyl carbonyl group Chemical group 0.000 description 1
- 125000005366 cycloalkylthio group Chemical group 0.000 description 1
- CFBGXYDUODCMNS-UHFFFAOYSA-N cyclobutene Chemical compound C1CC=C1 CFBGXYDUODCMNS-UHFFFAOYSA-N 0.000 description 1
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 description 1
- ZXIJMRYMVAMXQP-UHFFFAOYSA-N cycloheptene Chemical compound C1CCC=CCC1 ZXIJMRYMVAMXQP-UHFFFAOYSA-N 0.000 description 1
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- NKLCHDQGUHMCGL-UHFFFAOYSA-N cyclohexylidenemethanone Chemical group O=C=C1CCCCC1 NKLCHDQGUHMCGL-UHFFFAOYSA-N 0.000 description 1
- 125000002933 cyclohexyloxy group Chemical group C1(CCCCC1)O* 0.000 description 1
- WJTCGQSWYFHTAC-UHFFFAOYSA-N cyclooctane Chemical compound C1CCCCCCC1 WJTCGQSWYFHTAC-UHFFFAOYSA-N 0.000 description 1
- 239000004914 cyclooctane Substances 0.000 description 1
- URYYVOIYTNXXBN-UPHRSURJSA-N cyclooctene Chemical compound C1CCC\C=C/CC1 URYYVOIYTNXXBN-UPHRSURJSA-N 0.000 description 1
- 239000004913 cyclooctene Substances 0.000 description 1
- 125000000522 cyclooctenyl group Chemical group C1(=CCCCCCC1)* 0.000 description 1
- 125000004410 cyclooctyloxy group Chemical group C1(CCCCCCC1)O* 0.000 description 1
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- OOXWYYGXTJLWHA-UHFFFAOYSA-N cyclopropene Chemical compound C1C=C1 OOXWYYGXTJLWHA-UHFFFAOYSA-N 0.000 description 1
- 125000000298 cyclopropenyl group Chemical group [H]C1=C([H])C1([H])* 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 229940061632 dehydroacetic acid Drugs 0.000 description 1
- 201000001098 delayed sleep phase syndrome Diseases 0.000 description 1
- 208000033921 delayed sleep phase type circadian rhythm sleep disease Diseases 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- XAEWZDYWZHIUCT-UHFFFAOYSA-N desipramine hydrochloride Chemical compound [H+].[Cl-].C1CC2=CC=CC=C2N(CCCNC)C2=CC=CC=C21 XAEWZDYWZHIUCT-UHFFFAOYSA-N 0.000 description 1
- 229960003829 desipramine hydrochloride Drugs 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- NIJJYAXOARWZEE-UHFFFAOYSA-N di-n-propyl-acetic acid Natural products CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 description 1
- 229960003529 diazepam Drugs 0.000 description 1
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 1
- KJGHYQZXEYTDSW-UHFFFAOYSA-N diazocane Chemical compound C1CCCNNCC1 KJGHYQZXEYTDSW-UHFFFAOYSA-N 0.000 description 1
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical group C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 1
- VBXDEEVJTYBRJJ-UHFFFAOYSA-N diboronic acid Chemical compound OBOBO VBXDEEVJTYBRJJ-UHFFFAOYSA-N 0.000 description 1
- FJBFPHVGVWTDIP-UHFFFAOYSA-N dibromomethane Chemical compound BrCBr FJBFPHVGVWTDIP-UHFFFAOYSA-N 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 125000000723 dihydrobenzofuranyl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 description 1
- 125000005435 dihydrobenzoxazolyl group Chemical group O1C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004655 dihydropyridinyl group Chemical group N1(CC=CC=C1)* 0.000 description 1
- NZZFYRREKKOMAT-UHFFFAOYSA-N diiodomethane Chemical compound ICI NZZFYRREKKOMAT-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 description 1
- QKIUAMUSENSFQQ-UHFFFAOYSA-N dimethylazanide Chemical group C[N-]C QKIUAMUSENSFQQ-UHFFFAOYSA-N 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- VDCSGNNYCFPWFK-UHFFFAOYSA-N diphenylsilane Chemical compound C=1C=CC=CC=1[SiH2]C1=CC=CC=C1 VDCSGNNYCFPWFK-UHFFFAOYSA-N 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 229960001104 droxidopa Drugs 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 201000002491 encephalomyelitis Diseases 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 229950002007 estradiol benzoate Drugs 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- NQIZCDQCNYCVAS-RQBPZYBGSA-N ethyl 2-[[(7s)-7-[[(2r)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-5,6,7,8-tetrahydronaphthalen-2-yl]oxy]acetate;hydron;chloride Chemical compound Cl.C1([C@@H](O)CN[C@H]2CCC3=CC=C(C=C3C2)OCC(=O)OCC)=CC=CC(Cl)=C1 NQIZCDQCNYCVAS-RQBPZYBGSA-N 0.000 description 1
- MHYCRLGKOZWVEF-UHFFFAOYSA-N ethyl acetate;hydrate Chemical compound O.CCOC(C)=O MHYCRLGKOZWVEF-UHFFFAOYSA-N 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 229960004404 etizolam Drugs 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000003940 fatty acid amidase inhibitor Substances 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 210000003191 femoral vein Anatomy 0.000 description 1
- 229940125753 fibrate Drugs 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 229960001258 fluphenazine hydrochloride Drugs 0.000 description 1
- 229960002107 fluvoxamine maleate Drugs 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- YRTCKZIKGWZNCU-UHFFFAOYSA-N furo[3,2-b]pyridine Chemical compound C1=CC=C2OC=CC2=N1 YRTCKZIKGWZNCU-UHFFFAOYSA-N 0.000 description 1
- JUQAECQBUNODQP-UHFFFAOYSA-N furo[3,2-d]pyrimidine Chemical compound C1=NC=C2OC=CC2=N1 JUQAECQBUNODQP-UHFFFAOYSA-N 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 229960003980 galantamine Drugs 0.000 description 1
- ASUTZQLVASHGKV-UHFFFAOYSA-N galanthamine hydrochloride Natural products O1C(=C23)C(OC)=CC=C2CN(C)CCC23C1CC(O)C=C2 ASUTZQLVASHGKV-UHFFFAOYSA-N 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 208000001288 gastroparesis Diseases 0.000 description 1
- 208000029364 generalized anxiety disease Diseases 0.000 description 1
- 230000007674 genetic toxicity Effects 0.000 description 1
- 231100000025 genetic toxicology Toxicity 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000003163 gonadal steroid hormone Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 150000002366 halogen compounds Chemical class 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 229960003878 haloperidol Drugs 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 125000000268 heptanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004468 heterocyclylthio group Chemical group 0.000 description 1
- 125000005935 hexyloxycarbonyl group Chemical group 0.000 description 1
- 239000000938 histamine H1 antagonist Substances 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 125000005597 hydrazone group Chemical group 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- JUMYIBMBTDDLNG-OJERSXHUSA-N hydron;methyl (2r)-2-phenyl-2-[(2r)-piperidin-2-yl]acetate;chloride Chemical compound Cl.C([C@@H]1[C@H](C(=O)OC)C=2C=CC=CC=2)CCCN1 JUMYIBMBTDDLNG-OJERSXHUSA-N 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- ZQDWXGKKHFNSQK-UHFFFAOYSA-N hydroxyzine Chemical compound C1CN(CCOCCO)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZQDWXGKKHFNSQK-UHFFFAOYSA-N 0.000 description 1
- 229960003220 hydroxyzine hydrochloride Drugs 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 210000003405 ileum Anatomy 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000004857 imidazopyridinyl group Chemical group N1C(=NC2=C1C=CC=N2)* 0.000 description 1
- XZZXIYZZBJDEEP-UHFFFAOYSA-N imipramine hydrochloride Chemical compound [Cl-].C1CC2=CC=CC=C2N(CCC[NH+](C)C)C2=CC=CC=C21 XZZXIYZZBJDEEP-UHFFFAOYSA-N 0.000 description 1
- 229960002102 imipramine hydrochloride Drugs 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 208000000509 infertility Diseases 0.000 description 1
- 231100000535 infertility Toxicity 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 230000002601 intratumoral effect Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000026045 iodination Effects 0.000 description 1
- 238000006192 iodination reaction Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 238000000752 ionisation method Methods 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 208000033923 irregular sleep wake type circadian rhythm sleep disease Diseases 0.000 description 1
- 125000005929 isobutyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])OC(*)=O 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- XTBAPWCYTNCZTO-UHFFFAOYSA-N isoindol-1-one Chemical group C1=CC=C2C(=O)N=CC2=C1 XTBAPWCYTNCZTO-UHFFFAOYSA-N 0.000 description 1
- GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical compound C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 description 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 238000004898 kneading Methods 0.000 description 1
- JCQLYHFGKNRPGE-FCVZTGTOSA-N lactulose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 JCQLYHFGKNRPGE-FCVZTGTOSA-N 0.000 description 1
- 229960000511 lactulose Drugs 0.000 description 1
- PFCRQPBOOFTZGQ-UHFFFAOYSA-N lactulose keto form Natural products OCC(=O)C(O)C(C(O)CO)OC1OC(CO)C(O)C(O)C1O PFCRQPBOOFTZGQ-UHFFFAOYSA-N 0.000 description 1
- PYZRQGJRPPTADH-UHFFFAOYSA-N lamotrigine Chemical compound NC1=NC(N)=NN=C1C1=CC=CC(Cl)=C1Cl PYZRQGJRPPTADH-UHFFFAOYSA-N 0.000 description 1
- 229960001848 lamotrigine Drugs 0.000 description 1
- 239000008141 laxative Substances 0.000 description 1
- 230000002475 laxative effect Effects 0.000 description 1
- ACKFDYCQCBEDNU-UHFFFAOYSA-J lead(2+);tetraacetate Chemical compound [Pb+2].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O ACKFDYCQCBEDNU-UHFFFAOYSA-J 0.000 description 1
- 229960004502 levodopa Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000011981 lindlar catalyst Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- 229940008015 lithium carbonate Drugs 0.000 description 1
- 229910001416 lithium ion Inorganic materials 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- WGFOBBZOWHGYQH-MXHNKVEKSA-N lubiprostone Chemical compound O1[C@](C(F)(F)CCCC)(O)CC[C@@H]2[C@@H](CCCCCCC(O)=O)C(=O)C[C@H]21 WGFOBBZOWHGYQH-MXHNKVEKSA-N 0.000 description 1
- 229960000345 lubiprostone Drugs 0.000 description 1
- 229960000816 magnesium hydroxide Drugs 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- 229960000869 magnesium oxide Drugs 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 208000024714 major depressive disease Diseases 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 150000004667 medium chain fatty acids Chemical class 0.000 description 1
- 229960001929 meloxicam Drugs 0.000 description 1
- 230000006984 memory degeneration Effects 0.000 description 1
- 208000023060 memory loss Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- AFCCDDWKHLHPDF-UHFFFAOYSA-M metam-sodium Chemical compound [Na+].CNC([S-])=S AFCCDDWKHLHPDF-UHFFFAOYSA-M 0.000 description 1
- 229960001252 methamphetamine Drugs 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- TWXDDNPPQUTEOV-FVGYRXGTSA-N methamphetamine hydrochloride Chemical compound Cl.CN[C@@H](C)CC1=CC=CC=C1 TWXDDNPPQUTEOV-FVGYRXGTSA-N 0.000 description 1
- 229960002532 methamphetamine hydrochloride Drugs 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical group CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- IZDROVVXIHRYMH-UHFFFAOYSA-N methanesulfonic anhydride Chemical compound CS(=O)(=O)OS(C)(=O)=O IZDROVVXIHRYMH-UHFFFAOYSA-N 0.000 description 1
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical group CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- NSPJNIDYTSSIIY-UHFFFAOYSA-N methoxy(methoxymethoxy)methane Chemical group COCOCOC NSPJNIDYTSSIIY-UHFFFAOYSA-N 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 238000006063 methoxycarbonylation reaction Methods 0.000 description 1
- SIGOIUCRXKUEIG-UHFFFAOYSA-N methyl 2-dimethoxyphosphorylacetate Chemical compound COC(=O)CP(=O)(OC)OC SIGOIUCRXKUEIG-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical group 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 229960001033 methylphenidate hydrochloride Drugs 0.000 description 1
- 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 description 1
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- YHXISWVBGDMDLQ-UHFFFAOYSA-N moclobemide Chemical compound C1=CC(Cl)=CC=C1C(=O)NCCN1CCOCC1 YHXISWVBGDMDLQ-UHFFFAOYSA-N 0.000 description 1
- 229960004644 moclobemide Drugs 0.000 description 1
- 239000002899 monoamine oxidase inhibitor Substances 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 230000003551 muscarinic effect Effects 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- GRTPAOVVVLZLDP-UHFFFAOYSA-N n-benzylbenzenesulfonamide Chemical compound C=1C=CC=CC=1S(=O)(=O)NCC1=CC=CC=C1 GRTPAOVVVLZLDP-UHFFFAOYSA-N 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
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 239000004081 narcotic agent Substances 0.000 description 1
- 239000003887 narcotic antagonist Substances 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 229960002362 neostigmine Drugs 0.000 description 1
- LULNWZDBKTWDGK-UHFFFAOYSA-M neostigmine bromide Chemical compound [Br-].CN(C)C(=O)OC1=CC=CC([N+](C)(C)C)=C1 LULNWZDBKTWDGK-UHFFFAOYSA-M 0.000 description 1
- 210000000715 neuromuscular junction Anatomy 0.000 description 1
- 230000004031 neuronal differentiation Effects 0.000 description 1
- 208000015238 neurotic disease Diseases 0.000 description 1
- 239000003900 neurotrophic factor Substances 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 150000002816 nickel compounds Chemical class 0.000 description 1
- KFBKRCXOTTUAFS-UHFFFAOYSA-N nickel;triphenylphosphane Chemical compound [Ni].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 KFBKRCXOTTUAFS-UHFFFAOYSA-N 0.000 description 1
- 229960003966 nicotinamide Drugs 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 208000013651 non-24-hour sleep-wake syndrome Diseases 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 125000004930 octahydroisoquinolinyl group Chemical group C1(NCCC2CCCC=C12)* 0.000 description 1
- KVWDHTXUZHCGIO-UHFFFAOYSA-N olanzapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 description 1
- 229960005017 olanzapine Drugs 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 229940005483 opioid analgesics Drugs 0.000 description 1
- 229940124636 opioid drug Drugs 0.000 description 1
- 239000006191 orally-disintegrating tablet Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 239000012285 osmium tetroxide Substances 0.000 description 1
- 229910000489 osmium tetroxide Inorganic materials 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000005968 oxazolinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 150000002923 oximes Chemical group 0.000 description 1
- 125000000466 oxiranyl group Chemical group 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 229960001834 oxprenolol hydrochloride Drugs 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 150000002941 palladium compounds Chemical class 0.000 description 1
- ULYNIEUXPCUIEL-UHFFFAOYSA-L palladium(2+);triethylphosphane;dichloride Chemical compound [Cl-].[Cl-].[Pd+2].CCP(CC)CC.CCP(CC)CC ULYNIEUXPCUIEL-UHFFFAOYSA-L 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 230000002465 palmitoylating effect Effects 0.000 description 1
- 208000019906 panic disease Diseases 0.000 description 1
- 230000001734 parasympathetic effect Effects 0.000 description 1
- 229960005183 paroxetine hydrochloride Drugs 0.000 description 1
- 239000004031 partial agonist Substances 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000001148 pentyloxycarbonyl group Chemical group 0.000 description 1
- 208000000689 peptic esophagitis Diseases 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical class OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004851 pergolide Drugs 0.000 description 1
- YYPWGCZOLGTTER-MZMPZRCHSA-N pergolide Chemical compound C1=CC=C2[C@H]3C[C@@H](CSC)CN(CCC)[C@@H]3CC3=CN=C1[C]32 YYPWGCZOLGTTER-MZMPZRCHSA-N 0.000 description 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical class OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000008855 peristalsis Effects 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 230000010363 phase shift Effects 0.000 description 1
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 229950000688 phenothiazine Drugs 0.000 description 1
- 125000005954 phenoxathiinyl group Chemical group 0.000 description 1
- IPBVNPXQWQGGJP-UHFFFAOYSA-N phenyl acetate Chemical group CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 1
- 229940067157 phenylhydrazine Drugs 0.000 description 1
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- AQSJGOWTSHOLKH-UHFFFAOYSA-N phosphite(3-) Chemical class [O-]P([O-])[O-] AQSJGOWTSHOLKH-UHFFFAOYSA-N 0.000 description 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 150000004714 phosphonium salts Chemical class 0.000 description 1
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 description 1
- XUYJLQHKOGNDPB-UHFFFAOYSA-N phosphonoacetic acid Chemical class OC(=O)CP(O)(O)=O XUYJLQHKOGNDPB-UHFFFAOYSA-N 0.000 description 1
- 125000005499 phosphonyl group Chemical group 0.000 description 1
- 208000007578 phototoxic dermatitis Diseases 0.000 description 1
- 231100000018 phototoxicity Toxicity 0.000 description 1
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- PIJVFDBKTWXHHD-HIFRSBDPSA-N physostigmine Chemical compound C12=CC(OC(=O)NC)=CC=C2N(C)[C@@H]2[C@@]1(C)CCN2C PIJVFDBKTWXHHD-HIFRSBDPSA-N 0.000 description 1
- 229960001697 physostigmine Drugs 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- NKJQZSDCCLDOQH-UHFFFAOYSA-N piroheptine Chemical compound CC1N(CC)CCC1=C1C2=CC=CC=C2CCC2=CC=CC=C21 NKJQZSDCCLDOQH-UHFFFAOYSA-N 0.000 description 1
- 229950009232 piroheptine Drugs 0.000 description 1
- 150000003058 platinum compounds Chemical class 0.000 description 1
- 229950005134 polycarbophil Drugs 0.000 description 1
- 229920000139 polyethylene terephthalate Polymers 0.000 description 1
- 239000005020 polyethylene terephthalate Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Chemical class 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 208000028173 post-traumatic stress disease Diseases 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- FASDKYOPVNHBLU-ZETCQYMHSA-N pramipexole Chemical compound C1[C@@H](NCCC)CCC2=C1SC(N)=N2 FASDKYOPVNHBLU-ZETCQYMHSA-N 0.000 description 1
- 229960003089 pramipexole Drugs 0.000 description 1
- 229960002965 pravastatin Drugs 0.000 description 1
- 229960001495 pravastatin sodium Drugs 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 description 1
- 229960001233 pregabalin Drugs 0.000 description 1
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 201000002212 progressive supranuclear palsy Diseases 0.000 description 1
- 229960003910 promethazine Drugs 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 229960004604 propranolol hydrochloride Drugs 0.000 description 1
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol hydrochloride Natural products C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000005030 pyridylthio group Chemical group N1=C(C=CC=C1)S* 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229960005197 quetiapine fumarate Drugs 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000007154 radical cyclization reaction Methods 0.000 description 1
- 229960001150 ramelteon Drugs 0.000 description 1
- RUOKEQAAGRXIBM-GFCCVEGCSA-N rasagiline Chemical compound C1=CC=C2[C@H](NCC#C)CCC2=C1 RUOKEQAAGRXIBM-GFCCVEGCSA-N 0.000 description 1
- 229960000245 rasagiline Drugs 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000006215 rectal suppository Substances 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000007696 reproductive toxicity Effects 0.000 description 1
- 231100000372 reproductive toxicity Toxicity 0.000 description 1
- 150000003284 rhodium compounds Chemical class 0.000 description 1
- FCQRKDSALKMOGU-UHFFFAOYSA-K rhodium(3+);triphenylphosphane;trichloride Chemical compound Cl[Rh](Cl)Cl.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 FCQRKDSALKMOGU-UHFFFAOYSA-K 0.000 description 1
- JZCPYUJPEARBJL-UHFFFAOYSA-N rimonabant Chemical compound CC=1C(C(=O)NN2CCCCC2)=NN(C=2C(=CC(Cl)=CC=2)Cl)C=1C1=CC=C(Cl)C=C1 JZCPYUJPEARBJL-UHFFFAOYSA-N 0.000 description 1
- 229960003015 rimonabant Drugs 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 description 1
- 229960001534 risperidone Drugs 0.000 description 1
- 229960004136 rivastigmine Drugs 0.000 description 1
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 description 1
- 229960000371 rofecoxib Drugs 0.000 description 1
- 229960001879 ropinirole Drugs 0.000 description 1
- UHSKFQJFRQCDBE-UHFFFAOYSA-N ropinirole Chemical compound CCCN(CCC)CCC1=CC=CC2=C1CC(=O)N2 UHSKFQJFRQCDBE-UHFFFAOYSA-N 0.000 description 1
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 description 1
- 229960000672 rosuvastatin Drugs 0.000 description 1
- 229960003179 rotigotine Drugs 0.000 description 1
- KFQYTPMOWPVWEJ-INIZCTEOSA-N rotigotine Chemical compound CCCN([C@@H]1CC2=CC=CC(O)=C2CC1)CCC1=CC=CS1 KFQYTPMOWPVWEJ-INIZCTEOSA-N 0.000 description 1
- 229960000581 salicylamide Drugs 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 208000012672 seasonal affective disease Diseases 0.000 description 1
- 125000005930 sec-butyloxycarbonyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- MEZLKOACVSPNER-GFCCVEGCSA-N selegiline Chemical compound C#CCN(C)[C@H](C)CC1=CC=CC=C1 MEZLKOACVSPNER-GFCCVEGCSA-N 0.000 description 1
- 229960003946 selegiline Drugs 0.000 description 1
- 229940124513 senna glycoside Drugs 0.000 description 1
- 229930186851 sennoside Natural products 0.000 description 1
- IPQVTOJGNYVQEO-KGFNBKMBSA-N sennoside A Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC=CC2=C1C(=O)C1=C(O)C=C(C(O)=O)C=C1[C@@H]2[C@H]1C2=CC(C(O)=O)=CC(O)=C2C(=O)C2=C(O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O)C=CC=C21 IPQVTOJGNYVQEO-KGFNBKMBSA-N 0.000 description 1
- 239000003369 serotonin 5-HT3 receptor antagonist Substances 0.000 description 1
- 239000000387 serotonin 5-HT4 receptor agonist Substances 0.000 description 1
- 229960003660 sertraline hydrochloride Drugs 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 229960002855 simvastatin Drugs 0.000 description 1
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 1
- 201000002859 sleep apnea Diseases 0.000 description 1
- 230000005586 smoking cessation Effects 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 description 1
- 229960002218 sodium chlorite Drugs 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 description 1
- 229940084026 sodium valproate Drugs 0.000 description 1
- 235000021127 solid diet Nutrition 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 150000003398 sorbic acids Chemical class 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000004059 squalene synthase inhibitor Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([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])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 210000000470 submucous plexus Anatomy 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 125000000565 sulfonamide group Chemical group 0.000 description 1
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 1
- 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide-pyridine complex Substances O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 description 1
- 229960004940 sulpiride Drugs 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000006794 tachycardia Effects 0.000 description 1
- 108060008037 tachykinin Proteins 0.000 description 1
- 229950000505 tandospirone Drugs 0.000 description 1
- DMLGUJHNIWGCKM-DPFKZJTMSA-N tandospirone citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.O=C([C@@H]1[C@H]2CC[C@H](C2)[C@@H]1C1=O)N1CCCCN(CC1)CCN1C1=NC=CC=N1 DMLGUJHNIWGCKM-DPFKZJTMSA-N 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 208000009056 telangiectasis Diseases 0.000 description 1
- DNHPDWGIXIMXSA-CXNSMIOJSA-N tenapanor Chemical compound C12=CC(Cl)=CC(Cl)=C2CN(C)C[C@H]1C1=CC=CC(S(=O)(=O)NCCOCCOCCNC(=O)NCCCCNC(=O)NCCOCCOCCNS(=O)(=O)C=2C=C(C=CC=2)[C@H]2C3=CC(Cl)=CC(Cl)=C3CN(C)C2)=C1 DNHPDWGIXIMXSA-CXNSMIOJSA-N 0.000 description 1
- 229950007506 tenapanor Drugs 0.000 description 1
- WZWYJBNHTWCXIM-UHFFFAOYSA-N tenoxicam Chemical compound O=C1C=2SC=CC=2S(=O)(=O)N(C)C1=C(O)NC1=CC=CC=N1 WZWYJBNHTWCXIM-UHFFFAOYSA-N 0.000 description 1
- 229960002871 tenoxicam Drugs 0.000 description 1
- 125000006633 tert-butoxycarbonylamino group Chemical group 0.000 description 1
- XKXIQBVKMABYQJ-UHFFFAOYSA-M tert-butyl carbonate Chemical group CC(C)(C)OC([O-])=O XKXIQBVKMABYQJ-UHFFFAOYSA-M 0.000 description 1
- FGTJJHCZWOVVNH-UHFFFAOYSA-N tert-butyl-[tert-butyl(dimethyl)silyl]oxy-dimethylsilane Chemical group CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C FGTJJHCZWOVVNH-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 1
- KBLZDCFTQSIIOH-UHFFFAOYSA-M tetrabutylazanium;perchlorate Chemical compound [O-]Cl(=O)(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC KBLZDCFTQSIIOH-UHFFFAOYSA-M 0.000 description 1
- 229940127228 tetracyclic antidepressant Drugs 0.000 description 1
- 125000006337 tetrafluoro ethyl group Chemical group 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
- 150000003527 tetrahydropyrans Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 150000008634 thiazolopyrimidines Chemical class 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- DBDCNCCRPKTRSD-UHFFFAOYSA-N thieno[3,2-b]pyridine Chemical compound C1=CC=C2SC=CC2=N1 DBDCNCCRPKTRSD-UHFFFAOYSA-N 0.000 description 1
- RBNBDIMXFJYDLQ-UHFFFAOYSA-N thieno[3,2-d]pyrimidine Chemical compound C1=NC=C2SC=CC2=N1 RBNBDIMXFJYDLQ-UHFFFAOYSA-N 0.000 description 1
- 229940125670 thienopyridine Drugs 0.000 description 1
- 239000002175 thienopyridine Substances 0.000 description 1
- XSROQCDVUIHRSI-UHFFFAOYSA-N thietane Chemical compound C1CSC1 XSROQCDVUIHRSI-UHFFFAOYSA-N 0.000 description 1
- VOVUARRWDCVURC-UHFFFAOYSA-N thiirane Chemical compound C1CS1 VOVUARRWDCVURC-UHFFFAOYSA-N 0.000 description 1
- 125000001730 thiiranyl group Chemical group 0.000 description 1
- 125000004149 thio group Chemical group *S* 0.000 description 1
- DUYAAUVXQSMXQP-UHFFFAOYSA-M thioacetate Chemical group CC([S-])=O DUYAAUVXQSMXQP-UHFFFAOYSA-M 0.000 description 1
- 238000005936 thiocarbonylation reaction Methods 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 239000005495 thyroid hormone Substances 0.000 description 1
- 229940036555 thyroid hormone Drugs 0.000 description 1
- YUKARLAABCGMCN-PKLMIRHRSA-N tiagabine hydrochloride Chemical compound Cl.C1=CSC(C(=CCCN2C[C@@H](CCC2)C(O)=O)C2=C(C=CS2)C)=C1C YUKARLAABCGMCN-PKLMIRHRSA-N 0.000 description 1
- 229960002410 tiagabine hydrochloride Drugs 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 229960003797 tranylcypromine sulfate Drugs 0.000 description 1
- 230000009529 traumatic brain injury Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- JOFWLTCLBGQGBO-UHFFFAOYSA-N triazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1Cl JOFWLTCLBGQGBO-UHFFFAOYSA-N 0.000 description 1
- 229960003386 triazolam Drugs 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-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
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 1
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 1
- LALRXNPLTWZJIJ-UHFFFAOYSA-N triethylborane Chemical compound CCB(CC)CC LALRXNPLTWZJIJ-UHFFFAOYSA-N 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- BXDAOUXDMHXPDI-UHFFFAOYSA-N trifluoperazine hydrochloride Chemical compound [H+].[H+].[Cl-].[Cl-].C1CN(C)CCN1CCCN1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C21 BXDAOUXDMHXPDI-UHFFFAOYSA-N 0.000 description 1
- 229960000315 trifluoperazine hydrochloride Drugs 0.000 description 1
- WTVXIBRMWGUIMI-UHFFFAOYSA-N trifluoro($l^{1}-oxidanylsulfonyl)methane Chemical group [O]S(=O)(=O)C(F)(F)F WTVXIBRMWGUIMI-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- XQKBFQXWZCFNFF-UHFFFAOYSA-K triiodosamarium Chemical compound I[Sm](I)I XQKBFQXWZCFNFF-UHFFFAOYSA-K 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- HUYHHHVTBNJNFM-UHFFFAOYSA-N trimethylsilylsilicon Chemical compound C[Si](C)(C)[Si] HUYHHHVTBNJNFM-UHFFFAOYSA-N 0.000 description 1
- BZVJOYBTLHNRDW-UHFFFAOYSA-N triphenylmethanamine Chemical group C=1C=CC=CC=1C(C=1C=CC=CC=1)(N)C1=CC=CC=C1 BZVJOYBTLHNRDW-UHFFFAOYSA-N 0.000 description 1
- SJHCUXCOGGKFAI-UHFFFAOYSA-N tripropan-2-yl phosphite Chemical compound CC(C)OP(OC(C)C)OC(C)C SJHCUXCOGGKFAI-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229940046728 tumor necrosis factor alpha inhibitor Drugs 0.000 description 1
- 239000002451 tumor necrosis factor inhibitor Substances 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 238000004724 ultra fast liquid chromatography Methods 0.000 description 1
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 1
- 208000009852 uremia Diseases 0.000 description 1
- 229940045145 uridine Drugs 0.000 description 1
- 239000006216 vaginal suppository Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000009278 visceral effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 229960001475 zolpidem Drugs 0.000 description 1
- ZAFYATHCZYHLPB-UHFFFAOYSA-N zolpidem Chemical compound N1=C2C=CC(C)=CN2C(CC(=O)N(C)C)=C1C1=CC=C(C)C=C1 ZAFYATHCZYHLPB-UHFFFAOYSA-N 0.000 description 1
- UBQNRHZMVUUOMG-UHFFFAOYSA-N zonisamide Chemical compound C1=CC=C2C(CS(=O)(=O)N)=NOC2=C1 UBQNRHZMVUUOMG-UHFFFAOYSA-N 0.000 description 1
- 229960002911 zonisamide Drugs 0.000 description 1
- 229960000820 zopiclone Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/10—Laxatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
本发明的目的是提供一种可用于预防或治疗便秘等的化合物。本发明提供了一种由下式(I)表示的化合物或其盐:
Description
技术领域
本发明涉及一种杂环化合物,其可能具有胆碱能毒蕈碱M1受体正向变构调节剂活性,并且可能用作药物,如用于便秘等的预防或治疗药物。如本文所用,所述正向变构调节剂活性是指一种通过与内源性激活剂(对于此受体为乙酰胆碱)所结合的部分不同的部分结合来增强受体功能的作用。
(背景技术)
乙酰胆碱是一种神经递质,其在中枢神经***和神经肌肉连接(副交感神经和运动神经)中诱导信号转导。在胃肠道中,肌间神经丛、粘膜下神经丛等形成神经网络并且控制胃肠功能。其中,乙酰胆碱是胃肠功能中的主要神经递质,并且在胃肠运动性中起关键作用。
乙酰胆碱受体被分类为配体依赖性离子通道(胆碱能烟碱受体)和G蛋白缀合受体(胆碱能毒蕈碱受体)。胆碱能毒蕈碱受体是兴奋性神经递质乙酰胆碱的一种受体,并且是基于毒蕈碱对所述受体的选择性激活而命名的。毒蕈碱受体进一步分类为M1至M5的亚型,并且已知M1受体主要广泛分布在大脑中。在另一方面,M1受体在胃肠神经丛中的表达也是已知的,并且已指出了其调节胃肠道功能的作用(非专利文献1)。从近年来的研究中,也有胆碱能M1受体激动剂促进胃肠运动性的报道。
通常,胃肠道的蠕动由相邻部位的协调收缩和松弛组成。还已知胆碱能M1受体在胃肠神经丛中的兴奋性神经和抑制性神经两者中均表达(非专利文献1)。
WO 2010/059773(专利文献1)公开了具有胆碱能毒蕈碱M1受体正向变构调节剂(M1PAM)活性并且可用于治疗阿尔茨海默病、精神***症等的以下化合物。
其中每个符号如所述文献中所定义。
WO 2010/096338(专利文献2)公开了具有M1PAM活性并且可用于治疗阿尔茨海默病、精神***症等的以下化合物。
其中每个符号如所述文献中所定义。
WO 2010/123716(专利文献3)公开了具有M1PAM活性并且可用于治疗阿尔茨海默病、精神***症等的以下化合物。
其中每个符号如所述文献中所定义。
WO 2011/025851(专利文献4)公开了具有M1PAM活性并且可用于治疗阿尔茨海默病、精神***症等的以下化合物。
其中每个符号如所述文献中所定义。
WO 2011/049731(专利文献5)公开了具有M1PAM活性并且可用于治疗阿尔茨海默病、精神***症等的以下化合物。
其中每个符号如所述文献中所定义。
WO 2011/075371(专利文献6)公开了具有M1PAM活性并且可用于治疗阿尔茨海默病、精神***症等的以下化合物。
其中每个符号如所述文献中所定义。
WO 2011/084371(专利文献7)公开了具有M1PAM活性并且可用于治疗阿尔茨海默病、精神***症等的以下化合物。
其中每个符号如所述文献中所定义。
WO 2011/159553(专利文献8)公开了具有M1PAM活性并且可用于治疗阿尔茨海默病、精神***症等的以下化合物。
其中每个符号如所述文献中所定义。
WO 2012/003147(专利文献9)公开了具有M1PAM活性并且可用于治疗阿尔茨海默病、精神***症等的以下化合物。
其中每个符号如所述文献中所定义。
WO 2012/047702(专利文献10)公开了具有M1PAM活性并且可用于治疗阿尔茨海默病、精神***症等的以下化合物。
其中每个符号如所述文献中所定义。
WO 2013/129622(专利文献11)公开了具有M1PAM活性并且可用于治疗阿尔茨海默病、精神***症、疼痛、睡眠障碍等的以下化合物。
其中每个符号如所述文献中所定义。
WO 2014/077401(专利文献12)公开了具有M1PAM活性并且可用于治疗阿尔茨海默病、精神***症、疼痛、睡眠障碍等的以下化合物。
其中每个符号如所述文献中所定义。
WO 2015/174534(专利文献13)公开了具有M1PAM活性并且可用于治疗阿尔茨海默病、精神***症、疼痛、睡眠障碍、帕金森病、痴呆、路易体痴呆等的以下化合物。
其中每个符号如所述文献中所定义。
WO 2015/163485(专利文献14)公开了具有M1PAM活性并且可用于治疗阿尔茨海默病、精神***症、疼痛、睡眠障碍、帕金森病、痴呆、路易体痴呆等的以下化合物。
其中每个符号如所述文献中所定义。
WO 2016/208775(专利文献15)公开了具有M1PAM活性并且可用于治疗阿尔茨海默病、精神***症、疼痛、睡眠障碍、帕金森病、痴呆、路易体痴呆等的以下化合物。
其中每个符号如所述文献中所定义。
WO 2015/190564(专利文献16)公开了具有M1PAM活性并且可用于治疗阿尔茨海默病、精神***症、疼痛、睡眠障碍、帕金森病、痴呆、路易体痴呆等的以下化合物。
其中每个符号如所述文献中所定义。
WO 2017/069173(专利文献17)公开了具有M1PAM活性并且可用于治疗阿尔茨海默病、精神***症、疼痛、睡眠障碍、帕金森病、痴呆、路易体痴呆等的以下化合物。
其中每个符号如所述文献中所定义。
WO 2017/155050(专利文献18)公开了具有M1PAM活性并且可用于治疗阿尔茨海默病、精神***症、疼痛、睡眠障碍、帕金森病、痴呆、路易体痴呆等的以下化合物。
其中每个符号如所述文献中所定义。
文献列表
专利文献
专利文献1:WO 2010/059773
专利文献2:WO 2010/096338
专利文献3:WO 2010/123716
专利文献4:WO 2011/025851
专利文献5:WO 2011/049731
专利文献6:WO 2011/075371
专利文献7:WO 2011/084371
专利文献8:WO 2011/159553
专利文献9:WO 2012/003147
专利文献10:WO 2012/047702
专利文献11:WO 2013/129622
专利文献12:WO 2014/077401
专利文献13:WO 2015/174534
专利文献14:WO 2015/163485
专利文献15:WO 2016/208775
专利文献16:WO 2015/190564
专利文献17:WO 2017/069173
专利文献18:WO 2017/155050
非专利文献
非专利文献1:Journal of Chemical Neuroanatomy,2007年7月,33(4),193-201
发明内容
本发明要解决的问题
需要开发一种化合物,其具有胆碱能毒蕈碱M1受体(M1受体)正向变构调节剂活性并且可用作用于便秘(例如,与神经***疾病(例如,帕金森病、脊髓损伤、多发性硬化症)相关的便秘、特发性便秘、与年龄相关的便秘、阿片类药物引起的便秘等)的预防或治疗剂。如本文所用,所述正向变构调节剂活性意指一种与内源性激活剂(在此受体中为乙酰胆碱)所结合的位点不同的位点结合并增强受体功能的作用。
解决问题的手段
为了解决上述问题,本发明人进行了深入研究,并且发现由下式(I)表示的化合物可能具有胆碱能毒蕈碱M1受体正向变构调节剂活性,从而导致完成了本发明。
因此,本发明涉及以下内容。
[1]一种由式(I)表示的化合物:
其中
X是O或CH2;
Y是N或CR5;
R1和R2各自独立地是氢原子或卤素原子;
R3、R4和R5各自独立地是氢原子、卤素原子、羟基基团、任选取代的C1-6烷基基团、或任选取代的C1-6烷氧基基团;
R3和R4之一任选地与R5一起形成任选取代的环;并且
环A是任选地进一步取代的环,
或其盐。
[2]上述[1]中所述的化合物,其中
X是O;
Y是CR5;
R1和R2各自是氢原子;
R3是氢原子;
R4是任选取代的C1-6烷基基团;
R5是卤素原子;并且
环A是任选取代的3至14元非芳族杂环基团,
或其盐。
[3]上述[1]中所述的化合物,其中
X是O;
Y是CR5;
R1和R2各自是氢原子;
R3是氢原子;
R4是C1-6烷基基团,其任选地被选自C1-6烷氧基基团和3至14元非芳族杂环基团的1或2个取代基取代;
R5是卤素原子;并且
环A是任选地被1至3个羟基基团取代的3至14元非芳族杂环基团,
或其盐。
[4]上述[1]中所述的化合物,其中
X是O;
Y是CR5;
R1和R2各自是氢原子;
R3是氢原子;
R4是任选地被C1-6烷氧基基团取代的C1-6烷基基团;
R5是卤素原子;并且
环A是任选地被1至3个羟基基团取代的3至14元非芳族杂环基团,
或其盐。
[5]上述[1]中所述的化合物,其中
环A是
或其盐。
[6]上述[1]中所述的化合物,其中
R3是氢原子;并且
R4是C1-6烷基基团,其任选地被选自C1-6烷氧基基团和3至14元非芳族杂环基团的1或2个取代基取代,
或其盐。
[7]2-氟-4-((3-((3R,4S)-3-羟基四氢-2H-吡喃-4-基)-4-氧代-3,4,8,9-四氢-2H-苯并呋喃并[5,4-e][1,3]噁嗪-6-基)甲基)-N-(2-甲氧基乙基)苯甲酰胺,或其盐。
[8]2-氟-4-((3-((3R,4S)-3-羟基四氢-2H-吡喃-4-基)-4-氧代-3,4,8,9-四氢-2H-苯并呋喃并[5,4-e][1,3]噁嗪-6-基)甲基)-N-甲基苯甲酰胺,或其盐。
[9]2-氟-4-((3-((3R,4S)-3-羟基四氢-2H-吡喃-4-基)-4-氧代-3,4,8,9-四氢-2H-苯并呋喃并[5,4-e][1,3]噁嗪-6-基)甲基)-N-(((S)-四氢呋喃-2-基)甲基)苯甲酰胺,或其盐。
[10]2-氟-4-((3-((3R,4S)-3-羟基四氢-2H-吡喃-4-基)-4-氧代-3,4,8,9-四氢-2H-苯并呋喃并[5,4-e][1,3]噁嗪-6-基)甲基)-N-(((R)-四氢呋喃-2-基)甲基)苯甲酰胺,或其盐。
[11]一种包含上述[1]中所述的化合物的药物或其盐。
[12]上述[11]中所述的药物,其是一种胆碱能毒蕈碱M1受体正向变构调节剂。
[13]上述[11]中所述的药物,其是一种用于便秘的预防或治疗剂。
[14]一种在哺乳动物中的胆碱能毒蕈碱M1受体正向变构调节的方法,其包括向所述哺乳动物施用有效量的上述[1]中所述的化合物或其盐。
[15]一种在哺乳动物中预防或治疗便秘的方法,其包括向所述哺乳动物施用有效量的上述[1]中所述的化合物或其盐。
[16]上述[1]中所述的化合物或其盐在产生用于便秘的预防或治疗剂方面的用途。
[17]上述[1]中所述的化合物或其盐,所述化合物或其盐用于预防或治疗便秘。
发明效果
本发明的化合物可以具有胆碱能毒蕈碱M1受体正向变构调节剂活性,并且可以用作药物,如用于例如,便秘(如与神经***疾病(例如,帕金森病、脊髓损伤、多发性硬化症)相关的便秘、特发性便秘、与年龄相关的便秘、阿片类药物引起的便秘等)的预防或治疗药物。
(具体实施方式)
以下详细地描述了本说明书中使用的各取代基的定义。除非另有说明,否则每个取代基具有以下定义。
在本说明书中,“卤素原子”的例子包括氟、氯、溴和碘。
在本说明书中,“C1-6烷基基团”的例子包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、1-乙基丙基、己基、异己基、1,1-二甲基丁基、2,2-二甲基丁基、3,3-二甲基丁基和2-乙基丁基。
在本说明书中,“任选卤化的C1-6烷基基团”的例子包括任选地具有1至7个,优选1至5个卤素原子的C1-6烷基基团。其具体例子包括甲基、氯甲基、二氟甲基、三氯甲基、三氟甲基、乙基、2-溴乙基、2,2,2-三氟乙基、四氟乙基、五氟乙基、丙基、2,2-二氟丙基、3,3,3-三氟丙基、异丙基、丁基、4,4,4-三氟丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、5,5,5-三氟戊基、己基和6,6,6-三氟己基。
在本说明书中,“C2-6烯基基团”的例子包括乙烯基、1-丙烯基、2-丙烯基、2-甲基-1-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、3-甲基-2-丁烯基、1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、4-甲基-3-戊烯基、1-己烯基、3-己烯基和5-己烯基。
在本说明书中,“C2-6炔基基团”的例子包括乙炔基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、3-丁炔基、1-戊炔基、2-戊炔基、3-戊炔基、4-戊炔基、1-己炔基、2-己炔基、3-己炔基、4-己炔基、5-己炔基和4-甲基-2-戊炔基。
在本说明书中,“C3-10环烷基基团”的例子包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基、双环[2.2.1]庚基、双环[2.2.2]辛基、双环[3.2.1]辛基和金刚烷基。
在本说明书中,“任选卤化的C3-10环烷基基团”的例子包括任选地具有1至7个,优选1至5个卤素原子的C3-10环烷基基团。其具体例子包括环丙基、2,2-二氟环丙基、2,3-二氟环丙基、环丁基、二氟环丁基、环戊基、环己基、环庚基和环辛基。
在本说明书中,“C3-10环烯基基团”的例子包括环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基和环辛烯基。
在本说明书中,“C6-14芳基基团”的例子包括苯基、1-萘基、2-萘基、1-蒽基、2-蒽基和9-蒽基。
在本说明书中,“C7-16芳烷基基团”的例子包括苄基、苯乙基、萘基甲基和苯基丙基。
在本说明书中,“C1-6烷氧基基团”的例子包括甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基、戊氧基和己氧基。
在本说明书中,“任选卤化的C1-6烷氧基基团”的例子包括任选地具有1至7个,优选1至5个卤素原子的C1-6烷氧基基团。其具体例子包括甲氧基、二氟甲氧基、三氟甲氧基、乙氧基、2,2,2-三氟乙氧基、丙氧基、异丙氧基、丁氧基、4,4,4-三氟丁氧基、异丁氧基、仲丁氧基、戊氧基和己氧基。
在本说明书中,“C3-10环烷氧基基团”的例子包括环丙氧基、环丁氧基、环戊氧基、环己氧基、环庚氧基和环辛氧基。
在本说明书中,“C1-6烷硫基基团”的例子包括甲硫基、乙硫基、丙硫基、异丙基硫基、丁硫基、仲丁硫基、叔丁硫基、戊硫基和己硫基。
在本说明书中,“任选卤化的C1-6烷硫基基团”的例子包括任选地具有1至7个,优选1至5个卤素原子的C1-6烷硫基基团。其具体例子包括甲硫基、二氟甲硫基、三氟甲硫基、乙硫基、丙硫基、异丙基硫基、丁硫基、4,4,4-三氟丁基硫基、戊硫基和己硫基。
在本说明书中,“C1-6烷基-羰基基团”的例子包括乙酰基、丙酰基、丁酰基、2-甲基丙酰基、戊酰基、3-甲基丁酰基、2-甲基丁酰基、2,2-二甲基丙酰基、己酰基和庚酰基。
在本说明书中,“任选卤化的C1-6烷基-羰基基团”的例子包括任选地具有1至7个,优选1至5个卤素原子的C1-6烷基-羰基基团。其具体例子包括乙酰基、氯乙酰基、三氟乙酰基、三氯乙酰基、丙酰基、丁酰基、戊酰基和己酰基。
在本说明书中,“C1-6烷氧基-羰基基团”的例子包括甲氧羰基、乙氧羰基、丙氧羰基、异丙氧羰基、丁氧羰基、异丁氧羰基、仲丁氧羰基、叔丁氧羰基、戊氧羰基和己氧羰基。
在本说明书中,“C6-14芳基-羰基基团”的例子包括苯甲酰基、1-萘甲酰基和2-萘甲酰基。
在本说明书中,“C7-16芳烷基-羰基基团”的例子包括苯基乙酰基和苯基丙酰基。
在本说明书中,“5至14元芳族杂环基羰基基团”的例子包括烟碱基、异烟碱基、噻吩甲酰基和呋喃甲酰基。
在本说明书中,“3至14元非芳族杂环基羰基基团”的例子包括吗啉基羰基、哌啶基羰基和吡咯烷基羰基。
在本说明书中,“单或二C1-6烷基-氨基甲酰基基团”的例子包括甲基氨基甲酰基、乙基氨基甲酰基、二甲基氨基甲酰基、二乙基氨基甲酰基和N-乙基-N-甲基氨基甲酰基。
在本说明书中,“单或二C7-16芳烷基-氨基甲酰基基团”的例子包括苄基氨基甲酰基和苯乙基氨基甲酰基。
在本说明书中,“C1-6烷基磺酰基基团”的例子包括甲基磺酰基、乙基磺酰基、丙基磺酰基、异丙基磺酰基、丁基磺酰基、仲丁基磺酰基和叔丁基磺酰基。
在本说明书中,“任选卤化的C1-6烷基磺酰基基团”的例子包括任选地具有1至7个,优选1至5个卤素原子的C1-6烷基磺酰基。其具体例子包括甲基磺酰基、二氟甲基磺酰基、三氟甲基磺酰基、乙基磺酰基、丙基磺酰基、异丙基磺酰基、丁基磺酰基、4,4,4-三氟丁基磺酰基、戊基磺酰基和己基磺酰基。
在本说明书中,“C6-14芳基磺酰基基团”的例子包括苯磺酰基、1-萘基磺酰基和2-萘基磺酰基。
在本说明书中,“取代基”的例子包括卤素原子、氰基基团、硝基基团、任选取代的烃基团、任选取代的杂环基团、酰基基团、任选取代的氨基基团、任选取代的氨基甲酰基基团、任选取代的硫代氨基甲酰基基团、任选取代的氨磺酰基基团、任选取代的羟基基团、任选取代的磺酰基(SH)基团和任选取代的甲硅烷基基团。
在本说明书中,“烃基团”(包括“任选取代的烃基团”的“烃基团”)的例子包括C1-6烷基基团、C2-6烯基基团、C2-6炔基基团、C3-10环烷基基团、C3-10环烯基基团、C6-14芳基和C7-16芳烷基基团。
在本说明书中,“任选取代的烃基团”的例子包括任选地具有选自以下取代基团A的一个或多个取代基的烃基团。
[取代基团A]
(1)卤素原子,
(2)硝基基团,
(3)氰基基团,
(4)氧代基团,
(5)羟基基团,
(6)任选卤化的C1-6烷氧基基团,
(7)C6-14芳氧基基团(例如,苯氧基、萘氧基),
(8)C7-16芳烷氧基基团(例如,苄氧基),
(9)5至14元芳族杂环氧基基团(例如,吡啶氧基),
(10)3至14元非芳族杂环氧基基团(例如,吗啉氧基、哌啶氧基),
(11)C1-6烷基-羰基氧基基团(例如,乙酰氧基、丙酰氧基),
(12)C6-14芳基-羰基氧基基团(例如,苯甲酰氧基、1-萘氧基、2-萘氧基),
(13)C1-6烷氧基-羰基氧基基团(例如,甲氧基羰基氧基、乙氧基羰基氧基、丙氧基羰基氧基、丁氧基羰基氧基),
(14)单或二-C1-6烷基-氨基甲酰氧基基团(例如,甲基氨基甲酰氧基、乙基氨基甲酰氧基、二甲基氨基甲酰氧基、二乙基氨基甲酰氧基),
(15)C6-14芳基-氨基甲酰氧基基团(例如,苯基氨基甲酰氧基、萘基氨基甲酰氧基),
(16)5至14元芳族杂环基羰基氧基基团(例如,烟酰氧基),
(17)3至14元非芳族杂环基羰基氧基基团(例如,吗啉基羰基氧基、哌啶基羰基氧基),
(18)任选卤化的C1-6烷基磺酰氧基基团(例如,甲磺酰氧基、三氟甲基磺酰氧基),
(19)任选地被C1-6烷基取代的C6-14芳基磺酰氧基基团(例如,苯基磺酰氧基、甲苯磺酰氧基),
(20)任选卤化的C1-6烷硫基基团,
(21)5至14元芳族杂环基团,
(22)3至14元非芳族杂环基团,
(23)甲酰基基团,
(24)羧基基团,
(25)任选卤化的C1-6烷基-羰基基团,
(26)C6-14芳基-羰基基团,
(27)5至14元芳族杂环基羰基基团,
(28)3至14元非芳族杂环基羰基基团,
(29)C1-6烷氧基-羰基基团,
(30)C6-14芳氧基-羰基基团(例如,苯氧基羰基、1-萘氧基羰基、2-萘氧基羰基),
(31)C7-16芳烷氧基-羰基基团(例如,苄氧基羰基、苯乙基氧基羰基),
(32)氨基甲酰基基团,
(33)硫代氨基甲酰基基团,
(34)单或二C1-6烷基-氨基甲酰基基团,
(35)C6-14芳基-氨基甲酰基基团(例如,苯基氨基甲酰基),
(36)5至14元芳族杂环基氨基甲酰基基团(例如,吡啶基氨基甲酰基、噻吩基氨基甲酰基),
(37)3至14元非芳族杂环基氨基甲酰基基团(例如,吗啉基氨基甲酰基、哌啶基氨基甲酰基),
(38)任选卤化的C1-6烷基磺酰基基团,
(39)C6-14芳基磺酰基基团,
(40)5至14元芳族杂环基磺酰基基团(例如,吡啶基磺酰基、噻吩基磺酰基),
(41)任选卤化的C1-6烷基亚磺酰基基团,
(42)C6-14芳基亚磺酰基基团(例如,苯基亚磺酰基、1-萘基亚磺酰基、2-萘基亚磺酰基),
(43)5至14元芳族杂环基亚磺酰基基团(例如,吡啶基亚磺酰基、噻吩基亚磺酰基),
(44)氨基基团,
(45)单或二C1-6烷基氨基基团(例如,甲基氨基、乙基氨基、丙基氨基、异丙基氨基、丁基氨基、二甲基氨基、二乙基氨基、二丙基氨基、二丁基氨基、N-乙基-N-甲基氨基),
(46)单或二C6-14芳基氨基基团(例如,苯基氨基),
(47)5至14元芳族杂环基氨基基团(例如,吡啶基氨基),
(48)C7-16芳烷基氨基基团(例如,苄基氨基),
(49)甲酰氨基基团,
(50)C1-6烷基-羰基氨基基团(例如,乙酰氨基、丙酰氨基、丁酰氨基),
(51)(C1-6烷基)(C1-6烷基-羰基)氨基基团(例如,N-乙酰基-N-甲基氨基),
(52)C6-14芳基-羰基氨基基团(例如,苯基羰基氨基、萘基羰基氨基),
(53)C1-6烷氧基-羰基氨基基团(例如,甲氧基羰基氨基、乙氧基羰基氨基、丙氧基羰基氨基、丁氧基羰基氨基、叔丁氧基羰基氨基),
(54)C7-16芳烷氧基-羰基氨基基团(例如,苄氧基羰基氨基),
(55)C1-6烷基磺酰基氨基基团(例如,甲基磺酰基氨基、乙基磺酰基氨基),
(56)任选地被C1-6烷基基团取代的C6-14芳基磺酰基氨基基团(例如,苯基磺酰基氨基、甲苯磺酰基氨基),
(57)任选卤化的C1-6烷基基团,
(58)C2-6烯基基团,
(59)C2-6炔基基团,
(60)C3-10环烷基基团,
(61)C3-10环烯基基团和
(62)C6-14芳基基团。
“任选取代的烃基团”中的上述取代基的数目是例如,1至5,优选1至3。当取代基的数目是两个或更多个时,各个取代基可以相同或不同。
在本说明书中,“杂环基团”(包括“任选取代的杂环基团”的“杂环基团”)的例子包括:(i)芳族杂环基团,(ii)非芳族杂环基团和(iii)7至10元桥接杂环基团,各自含有选自氮原子、硫原子和氧原子的1至4个杂原子作为除碳原子之外的环构成原子。
在本说明书中,“芳族杂环基团”(包括“5至14元芳族杂环基团”)的例子包括5至14元(优选5至10元)芳族杂环基团,其含有选自氮原子、硫原子和氧原子的1至4个杂原子作为除碳原子之外的环构成原子。
“芳族杂环基团”的优选例子包括5或6元单环芳族杂环基团,如噻吩基、呋喃基、吡咯基、咪唑基、吡唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、1,2,4-噁二唑基、1,3,4-噁二唑基、1,2,4-噻二唑基、1,3,4-噻二唑基、***基、四唑基、三嗪基等;以及
8至14元稠合多环(优选双环或三环)芳族杂环基团,如苯并噻吩基、苯并呋喃基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噻唑基、苯并异噻唑基、苯并***基、咪唑并吡啶基、噻吩并吡啶基、呋喃并吡啶基、吡咯并吡啶基、吡唑并吡啶基、噁唑并吡啶基、噻唑并吡啶基、咪唑并吡嗪基、咪唑并嘧啶基、噻吩并嘧啶基、呋喃并嘧啶基、吡咯并嘧啶基、吡唑并嘧啶基、噁唑并嘧啶基、噻唑并嘧啶基、吡唑并三嗪基、萘并[2,3-b]噻吩基、吩噁噻基(phenoxathiinyl)、吲哚基、异吲哚基、1H-吲唑基、嘌呤基、异喹啉基、喹啉基、酞嗪基、萘并嘧啶基、喹喔啉基、喹唑啉基、噌啉基(cinnolinyl)、咔唑基、β-咔啉基、菲啶基、吖啶基、吩嗪基、吩噻嗪基、吩噁嗪基(phenoxazinyl)等。
在本说明书中,“非芳族杂环基团”(包括“3至14元非芳族杂环基团”)的例子包括3至14元(优选4至10元)非芳族杂环基团,其含有选自氮原子、硫原子和氧原子的1至4个杂原子作为除碳原子之外的环构成原子。
“非芳族杂环基团”的优选例子包括3至8元单环非芳族杂环基团,如氮丙啶基、环氧乙烷基、硫杂环丙基(thiiranyl)、氮杂环丁烷基(azetidinyl)、氧杂环丁基(oxetanyl)、硫杂环丁烷基(thietanyl)、四氢噻吩基、四氢呋喃基、吡咯啉基、吡咯烷基、咪唑啉基、咪唑烷基、噁唑啉基、噁唑烷基、吡唑啉基、吡唑烷基、噻唑啉基、噻唑烷基、四氢异噻唑基、四氢噁唑基、四氢异噁唑基、哌啶基、哌嗪基、四氢吡啶基、二氢吡啶基、二氢噻喃基、四氢嘧啶基、四氢哒嗪基、二氢吡喃基、四氢吡喃基、四氢噻喃基、吗啉基、硫代吗啉基、氮杂环庚烷基(azepanyl)、二氮杂环庚烷基(diazepanyl)、氮杂卓基(azepinyl)、氧杂环庚烷基(oxepanyl)、氮杂环辛烷基(azocanyl)、二氮杂环辛烷基(diazocanyl)等;以及
9至14元稠合多环(优选双环或三环)非芳族杂环基团,如二氢苯并呋喃基、二氢苯并咪唑基、二氢苯并噁唑基、二氢苯并噻唑基、二氢苯并异噻唑基、二氢苯并[2,3-b]噻吩基、四氢异喹啉基、四氢喹啉基、4H-喹啉基、吲哚基、异吲哚啉基、四氢噻吩并[2,3-c]吡啶基、四氢苯并氮杂卓基(tetrahydrobenzazepinyl)、四氢喹喔啉基、四氢菲啶基、六氢吩噻嗪基、六氢吩噁嗪基、四氢酞嗪基、四氢萘啶基、四氢喹唑啉基、四氢噌啉基、四氢咔唑基、四氢-β-咔啉基、四氢吖啶基(tetrahydroacrydinyl)、四氢吩嗪基、四氢噻吨基、八氢异喹啉基等。
在本说明书中,“7至10元桥接杂环基团”的优选例子包括奎宁环基和7-氮杂双环[2.2.1]庚烷基。
在本说明书中,“含氮杂环基团”的例子包括含有至少一个氮原子作为环构成原子的“杂环基团”。
在本说明书中,“任选取代的杂环基团”的例子包括任选地具有选自上述取代基团A的一个或多个取代基的杂环基团。
“任选取代的杂环基团”中的取代基的数目是例如,1至3。当取代基的数目是两个或更多个时,各个取代基可以相同或不同。
在本说明书中,“酰基基团”的例子包括甲酰基基团、羧基基团、氨基甲酰基基团、硫代氨基甲酰基基团、亚磺基基团、磺基基团、氨磺酰基基团和膦酰基基团,各自任选地具有“选自C1-6烷基基团、C2-6烯基基团,C3-10环烷基基团、C3-10环烯基基团、C6-14芳基基团、C7-16芳烷基基团、5至14元芳族杂环基团和3至14元非芳族杂环基团的1或2个取代基,每个任选地具有选自卤素原子、任选卤化的C1-6烷氧基基团、羟基基团、硝基基团、氰基基团、氨基基团和氨基甲酰基基团的1至3个取代基”。
“酰基基团”的例子还包括烃-磺酰基基团、杂环基磺酰基基团、烃-亚磺酰基基团和杂环基亚磺酰基基团。
在此,所述烃-磺酰基意指烃基团键合的磺酰基基团,所述杂环基磺酰基基团意指杂环基团键合的磺酰基基团,所述烃-亚磺酰基基团意指烃基团键合的亚磺酰基基团,并且所述杂环基亚磺酰基基团意指杂环基团键合的亚磺酰基基团。
“酰基基团”的优选例子包括甲酰基基团、羧基基团、C1-6烷基-羰基基团、C2-6烯基-羰基基团(例如,巴豆酰基)、C3-10环烷基-羰基基团(例如,环丁烷羰基、环戊烷羰基、环己烷羰基、环庚烷羰基)、C3-10环烯基-羰基基团(例如,2-环己烯羰基)、C6-14芳基-羰基基团、C7-16芳烷基-羰基基团、5至14元芳族杂环基羰基基团、3至14元非芳族杂环基羰基基团、C1-6烷氧基-羰基基团、C6-14芳氧基羰基基团(例如,苯氧羰基、萘氧羰基)、C7-16芳烷氧基-羰基基团(例如,苄氧基羰基、苯乙基氧基羰基)、氨基甲酰基基团、单或二C1-6烷基-氨基甲酰基基团、单或二C2-6烯基-氨基甲酰基基团(例如,二烯丙基氨基甲酰基)、单或二C3-10环烷基-氨基甲酰基基团(例如,环丙基氨基甲酰基)、单或二C6-14芳基-氨基甲酰基基团(例如,苯基氨基甲酰基)、单或二C7-16芳烷基-氨基甲酰基基团、5至14元芳族杂环基氨基甲酰基基团(例如,吡啶基氨基甲酰基)、硫代氨基甲酰基基团、单或二C1-6烷基-硫代氨基甲酰基基团(例如,甲基硫代氨基甲酰基、N-乙基-N-甲基硫代氨基甲酰基)、单或二C2-6烯基-硫代氨基甲酰基基团(例如,二烯丙基硫代氨基甲酰基)、单或二C3-10环烷基-硫代氨基甲酰基基团(例如,环丙基硫代氨基甲酰基、环己基硫代氨基甲酰基)、单或二C6-14芳基-硫代氨基甲酰基基团(例如,苯基硫代氨基甲酰基)、单或二C7-16芳烷基-硫代氨基甲酰基基团(例如,苄基硫代氨基甲酰基、苯乙基硫代氨基甲酰基)、5至14元芳族杂环基硫代氨基甲酰基基团(例如,吡啶基硫代氨基甲酰基)、亚磺基基团、C1-6烷基亚磺酰基基团(例如,甲基亚磺酰基、乙基亚磺酰基)、磺基基团、C1-6烷基磺酰基基团、C6-14芳基磺酰基基团、膦酰基基团和单或二C1-6烷基膦酰基基团(例如,二甲基膦酰基、二乙基膦酰基、二异丙基膦酰基、二丁基膦酰基)。
在本说明书中,“任选取代的氨基基团”的例子包括任选地具有以下的氨基基团:“选自C1-6烷基基团、C2-6烯基基团、C3-10环烷基基团、C6-14芳基基团、C7-16芳烷基基团、C1-6烷基-羰基基团、C6-14芳基羰基基团、C7-16芳烷基-羰基基团、5至14元芳族杂环基羰基基团、3至14元非芳族杂环基羰基基团、C1-6烷氧基-羰基基团、5至14元芳族杂环基团、氨基甲酰基基团、单或二C1-6烷基-氨基甲酰基基团、单或二C7-16芳烷基-氨基甲酰基基团、C1-6烷基磺酰基基团和C6-14芳基磺酰基基团的1或2个取代基,它们各自任选地具有选自取代基团A的1至3个取代基”。
任选取代的氨基基团的优选例子包括氨基基团、单或二(任选卤化的C1-6烷基)氨基基团(例如,甲基氨基、三氟甲基氨基、二甲基氨基、乙基氨基、二乙基氨基、丙基氨基、二丁基氨基)、单或二C2-6烯基氨基基团(例如,二烯丙基氨基)、单或二C3-10环烷基氨基基团(例如,环丙基氨基、环己基氨基)、单或二C6-14芳基氨基基团(例如,苯基氨基)、单或二C7-16芳烷基氨基基团(例如,苄基氨基、二苄基氨基)、单或二(任选卤化的C1-6烷基)-羰基氨基基团(例如,乙酰氨基、丙酰氨基)、单或二C6-14芳基-羰基氨基基团(例如,苯甲酰基氨基)、单或二C7-16芳烷基-羰基氨基基团(例如,苄基羰基氨基)、单或二5至14元芳族杂环基羰基氨基基团(例如,烟酰氨基、异烟酰氨基)、单或二3至14元非芳族杂环基羰基氨基基团(例如,哌啶基羰基氨基)、单或二C1-6烷氧基-羰基氨基基团(例如,叔丁氧基羰基氨基)、5至14元芳族杂环基氨基基团(例如,吡啶基氨基)、氨基甲酰基氨基基团、(单或二C1-6烷基-氨基甲酰基)氨基基团(例如,甲基氨基甲酰基氨基)、(单或二C7-16芳烷基-氨基甲酰基)氨基基团(例如,苄基氨基甲酰基氨基)、C1-6烷基磺酰基氨基基团(例如,甲基磺酰基氨基、乙基磺酰基氨基)、C6-14芳基磺酰基氨基基团(例如,苯基磺酰基氨基)、(C1-6烷基)(C1-6烷基-羰基)氨基基团(例如,N-乙酰基-N-甲基氨基)和(C1-6烷基)(C6-14芳基-羰基)氨基基团(例如,N-苯甲酰基-N-甲基氨基)。
在本说明书中,“任选取代的氨基甲酰基基团”的例子包括任选地具有以下的氨基甲酰基基团:“选自C1-6烷基基团、C2-6烯基基团、C3-10环烷基基团、C6-14芳基基团、C7-16芳烷基基团、C1-6烷基-羰基基团、C6-14芳基-羰基基团、C7-16芳烷基-羰基基团、5至14元芳族杂环基羰基基团、3至14元非芳族杂环基羰基基团、C1-6烷氧基羰基基团、5至14元芳族杂环基基团、氨基甲酰基基团、单或二C1-6烷基-氨基甲酰基基团和单或二C7-16芳烷基-氨基甲酰基基团的1或2个取代基,它们各自任选地具有选自取代基团A的1至3个取代基”。
任选取代的氨基甲酰基基团的优选例子包括氨基甲酰基基团、单或二C1-6烷基-氨基甲酰基基团、单或二C2-6烯基-氨基甲酰基基团(例如,二烯丙基氨基甲酰基)、单或二C3-10环烷基-氨基甲酰基基团(例如,环丙基氨基甲酰基,环己基氨基甲酰基)、单或二C6-14芳基-氨基甲酰基基团(例如,苯基氨基甲酰基)、单或二C7-16芳烷基-氨基甲酰基基团、单或二C1-6烷基-羰基-氨基甲酰基基团(例如,乙酰基氨基甲酰基、丙酰基氨基甲酰基)、单或二C6-14芳基-羰基-氨基甲酰基基团(例如,苯甲酰基氨基甲酰基)和5至14元芳族杂环基氨基甲酰基基团(例如,吡啶基氨基甲酰基)。
在本说明书中,“任选取代的硫代氨基甲酰基基团”的例子包括任选地具有以下的硫代氨基甲酰基基团:“选自C1-6烷基基团、C2-6烯基基团、C3-10环烷基基团、C6-14芳基基团、C7-16芳烷基基团、C1-6烷基-羰基基团、C6-14芳基-羰基基团、C7-16芳烷基-羰基基团、5至14元芳族杂环基羰基基团、3至14元非芳族杂环基羰基基团、C1-6烷氧基羰基基团、5至14元芳族杂环基团、氨基甲酰基基团、单或二C1-6烷基-氨基甲酰基基团和单或二C7-16芳烷基-氨基甲酰基基团的1或2个取代基,它们各自任选地具有选自取代基团A的1至3个取代基”。
任选取代的硫代氨基甲酰基基团的优选例子包括硫代氨基甲酰基基团、单或二C1-6烷基硫代氨基甲酰基基团(例如,甲基硫代氨基甲酰基、乙基硫代氨基甲酰基、二甲基硫代氨基甲酰基、二乙基硫代氨基甲酰基、N-乙基-N-甲基硫代氨基甲酰基)、单或二C2-6烯基-硫代氨基甲酰基基团(例如,二烯丙基硫代氨基甲酰基)、单或二C3-10环烷基-硫代氨基甲酰基基团(例如,环丙基硫代氨基甲酰基、环己基硫代氨基甲酰基)、单或二C6-14芳基-硫代氨基甲酰基基团(例如,苯基硫代氨基甲酰基)、单或二C7-16芳烷基-硫代氨基甲酰基基团(例如,苄基硫代氨基甲酰基、苯乙基硫代氨基甲酰基)、单或二C1-6烷基-羰基-硫代氨基甲酰基基团(例如,乙酰基硫代氨基甲酰基、丙酰基硫代氨基甲酰基)、单或二C6-14芳基-羰基-硫代氨基甲酰基基团(例如,苯甲酰基硫代氨基甲酰基)和5至14元芳族杂环基硫代氨基甲酰基基团(例如,吡啶基硫代氨基甲酰基)。
在本说明书中,“任选取代的氨磺酰基基团”的例子包括任选地具有以下的氨磺酰基基团:“选自C1-6烷基基团、C2-6烯基基团、C3-10环烷基基团、C6-14芳基基团、C7-16芳烷基基团、C1-6烷基-羰基基团、C6-14芳基-羰基基团、C7-16芳烷基-羰基基团、5至14元芳族杂环基羰基基团、3至14元非芳族杂环基羰基基团、C1-6烷氧基羰基基团、5至14元芳族杂环基基团、氨基甲酰基基团、单或二C1-6烷基-氨基甲酰基基团和单或二C7-16芳烷基-氨基甲酰基基团的1或2个取代基,它们各自任选地具有选自取代基团A的1至3个取代基”。
任选取代的氨磺酰基基团的优选例子包括氨磺酰基基团、单或二C1-6烷基-氨磺酰基基团(例如,甲基氨磺酰基、乙基氨磺酰基、二甲基氨磺酰基、二乙基氨磺酰基、N-乙基-N-甲基氨磺酰基)、单或二C2-6烯基-氨磺酰基基团(例如,二烯丙基氨磺酰基)、单或二C3-10环烷基-氨磺酰基基团(例如,环丙基氨磺酰基、环己基氨磺酰基)、单或二C6-14芳基-氨磺酰基基团(例如,苯基氨磺酰基)、单或二C7-16芳烷基-氨磺酰基基团(例如,苄基氨磺酰基、苯乙基氨磺酰基)、单或二C1-6烷基-羰基-氨磺酰基基团(例如,乙酰基氨磺酰基、丙酰基氨磺酰基)、单或二C6-14芳基-羰基-氨磺酰基基团(例如,苯甲酰基氨磺酰基)和5至14元芳族杂环基氨磺酰基基团(例如,吡啶基氨磺酰基)。
在本说明书中,“任选取代的羟基基团”的例子包括任选地具有以下的羟基基团:“选自C1-6烷基基团、C2-6烯基基团、C3-10环烷基基团、C6-14芳基基团、C7-16芳烷基基团、C1-6烷基-羰基基团、C6-14芳基羰基基团、C7-16芳烷基-羰基基团、5至14元芳族杂环基羰基基团、3至14元非芳族杂环基羰基基团、C1-6烷氧基羰基基团、5至14元芳族杂环基团、氨基甲酰基基团、单或二C1-6烷基-氨基甲酰基基团、单或二C7-16芳烷基-氨基甲酰基基团、C1-6烷基磺酰基基团和C6-14芳基磺酰基基团的取代基,它们各自任选地具有选自取代基团A的1至3个取代基”。
任选取代的羟基基团的优选例子包括羟基基团、C1-6烷氧基基团、C2-6烯氧基基团(例如、烯丙氧基、2-丁烯氧基、2-戊烯氧基、3-己烯氧基)、C3-10环烷氧基基团(例如,环己氧基)、C6-14芳氧基基团(例如,苯氧基、萘氧基)、C7-16芳烷氧基基团(例如,苄氧基、苯乙氧基)、C1-6烷基-羰基氧基基团(例如,乙酰氧基、丙酰氧基、丁酰氧基、异丁酰氧基、新戊酰氧基)、C6-14芳基-羰基氧基基团(例如、苯甲酰氧基)、C7-16芳烷基-羰基氧基基团(例如,苄基羰基氧基)、5至14元芳族杂环基羰基氧基基团(例如,烟酰氧基)、3至14元非芳族杂环基羰基氧基基团(例如,哌啶基羰基氧基)、C1-6烷氧基-羰基氧基基团(例如,叔丁氧基羰基氧基)、5至14元芳族杂环氧基基团(例如,吡啶基氧基)、氨基甲酰氧基基团、C1-6烷基-氨基甲酰氧基基团(例如,甲基氨基甲酰氧基)、C7-16芳烷基-氨基甲酰氧基基团(例如,苄基氨基甲酰氧基)、C1-6烷基磺酰氧基基团(例如,甲基磺酰氧基、乙基磺酰氧基)和C6-14芳基磺酰氧基基团(例如,苯基磺酰氧基)。
在本说明书中,“任选取代的磺酰基基团”的例子包括任选地具有以下的磺酰基基团:“选自C1-6烷基基团、C2-6烯基基团、C3-10环烷基基团、C6-14芳基基团、C7-16芳烷基基团、C1-6烷基-羰基基团、C6-14芳基-羰基基团和5至14元芳族杂环基基团的取代基,它们各自任选地具有选自取代基团A的1至3个取代基”和卤代磺酰基基团。
任选取代的磺酰基基团的优选例子包括硫酰基(-SH)基团、C1-6烷硫基基团、C2-6烯基硫基基团(例如,烯丙基硫基、2-丁烯基硫基、2-戊烯基硫基、3-己烯基硫基)、C3-10环烷基硫基基团(例如,环己基硫基)、C6-14芳基硫基基团(例如,苯硫基、萘硫基)、C7-16芳烷基硫基基团(例如,苄基硫基、苯乙基硫基)、C1-6烷基-羰基硫基基团(例如,乙酰硫基、丙硫基、丁硫基、异丁硫基、新戊酰硫基)、C6-14芳基-羰基硫基基团(例如,苯甲酰基硫基)、5至14元芳族杂环基硫基基团(例如,吡啶基硫基)和卤代硫基基团(例如,五氟硫基)。
在本说明书中,“任选取代的甲硅烷基基团”的例子包括任选地具有以下的甲硅烷基基团:“选自C1-6烷基基团、C2-6烯基基团、C3-10环烷基基团、C6-14芳基基团和C7-16芳烷基基团的1至3个取代基,它们各自任选地具有选自取代基团A的1至3个取代基”。
任选取代的甲硅烷基基团的优选例子包括三-C1-6烷基甲硅烷基基团(例如,三甲基甲硅烷基、叔丁基(二甲基)甲硅烷基)。
在本说明书中,“烃环”的例子包括C6-14芳族烃环、C3-10环烷烃和C3-10环烷烃。
在本说明书中,“C6-14芳族烃环”的例子包括苯和萘。
在本说明书中,“C3-10环烷烃”的例子包括环丙烷、环丁烷、环戊烷、环己烷、环庚烷和环辛烷。
在本说明书中,“C3-10环烯烃”的例子包括环丙烯、环丁烯、环戊烯、环己烯、环庚烯和环辛烯。
在本说明书中,“杂环基团”的例子包括芳族杂环基团和非芳族杂环基团,各自含有选自氮原子、硫原子和氧原子的1至4个杂原子作为除碳原子之外的环构成原子。
在本说明书中,“芳族杂环基团”的例子包括5至14元(优选5至10元)芳族杂环,其含有选自氮原子、硫原子和氧原子的1至4个杂原子作为除碳原子之外的环构成原子。“芳族杂环”的优选例子包括5或6元单环芳族杂环,如噻吩、呋喃、吡咯、咪唑、吡唑、噻唑、异噻唑、噁唑、异噁唑、吡啶、吡嗪、嘧啶、哒嗪、1,2,4-噁二唑、1,3,4-噁二唑、1,2,4-噻二唑、1,3,4-噻二唑、***、四唑、三嗪等;以及
8至14元稠合多环(优选双环或三环)芳族杂环,如苯并噻吩、苯并呋喃、苯并咪唑、苯并噁唑、苯并异噁唑、苯并噻唑、苯并异噻唑、苯并***、咪唑并吡啶、噻吩并吡啶、呋喃并吡啶、吡咯并吡啶、吡唑并吡啶、噁唑并吡啶、噻唑并吡啶、咪唑并吡嗪、咪唑并嘧啶、噻吩并嘧啶、呋喃并嘧啶、吡咯并嘧啶、吡唑并嘧啶、噁唑并嘧啶、噻唑并嘧啶、吡唑并嘧啶、吡唑并三嗪、萘并[2,3-b]噻吩、吩噁噻、吲哚、异吲哚、1H-吲唑、嘌呤、异喹啉、喹啉、酞嗪、萘啶、喹喔啉、喹唑啉、噌啉、咔唑、β-咔啉、菲啶、吖啶、吩嗪、吩噻嗪、吩噁嗪等。
在本说明书中,“非芳族杂环”的例子包括3至14元(优选4至10元)非芳族杂环,其含有选自氮原子、硫原子和氧原子的1至4个杂原子作为除碳原子之外的环构成原子。“非芳族杂环”的优选例子包括3至8元单环非芳族杂环基团,如氮丙啶、环氧乙烷、环硫乙烷、氮杂环丁烷、氧杂环丁烷、硫杂环丁烷、四氢噻吩、四氢呋喃、吡咯烷、吡咯烷、咪唑啉、咪唑烷、噁唑啉、噁唑烷、吡唑啉、吡唑烷、噻唑啉,噻唑烷、四氢异噻唑、四氢噁唑、四氢异噁唑、哌啶、哌嗪、四氢吡啶、二氢吡啶、二氢噻喃、四氢嘧啶、四氢哒嗪、二氢吡喃、四氢吡喃、四氢硫代吡喃、吗啉、硫代吗啉、azepanine、二氮杂、氮杂、氮杂环辛烷(azocane)、二氮杂环辛烷、环氧己烷等;和9至14元稠合多环(优选双环或三环)非芳族杂环,如二氢苯并呋喃、二氢苯并咪唑、二氢苯并噁唑、二氢苯并噻唑、二氢苯并异噻唑、二氢萘并[2,3-b]噻吩、四氢异喹啉、四氢喹啉、4H-喹啉、吲哚啉、异吲哚啉、四氢噻吩并[2,3-c]吡啶、四氢苯并氮杂、四氢喹喔啉、四氢菲啶、六氢吩噻嗪、六氢吩噁嗪、四氢酞嗪、四氢萘啶、四氢喹唑啉、四氢噌啉、四氢咔唑、四氢-β-咔啉、四氢吖啶、四氢吩嗪、四氢噻吨、八氢异喹啉等。
在本说明书中,“含氮杂环”的例子包括含有至少一个氮原子作为环构成原子的“杂环”。
下面解释式(I)中的每个符号。
X是O或CH2。
在本发明的一个实施方案中,X优选地是O。
在本发明的另一个实施方案中,X优选地是CH2。
Y是N或CR5。
在本发明的一个实施方案中,Y优选地是CR5。
在本发明的另一个实施方案中,Y优选地是N。
环A是任选地进一步取代的环。
作为环A的“任选地进一步取代的环”,可以提及任选地进一步取代的杂环和任选地进一步取代的非芳族烃环。
作为环A的“任选地进一步取代的杂环”的“杂环”,3至14元非芳族杂环(例如,四氢吡喃)是优选的。作为其取代基,1至3个(优选1个)羟基基团是优选的。
作为环A的“任选地进一步取代的非芳族烃环”的“非芳族烃环”,C3-10环烷烃(例如,环丁烷、环戊烷、环己烷)是优选的。作为取代基,选自羟基基团和卤素原子(例如,氟原子)的1至3个(优选1个)取代基是优选的。
环A优选地是
(1)任选地进一步取代的3至14元非芳族杂环,或
(2)任选地进一步取代的C3-10环烷烃。
环A更优选地是
(1)3至14元非芳族杂环(例如,四氢吡喃),任选地被1至3个(优选1个)羟基基团取代,或
(2)C3-10环烷烃(例如,环丁烷、环戊烷、环己烷),任选地被选自羟基基团和卤素原子(例如,氟原子)的1至3个(优选1个)取代基取代。
环A进一步优选地是
(1)被一个羟基基团取代的3至14元非芳族杂环(例如,四氢吡喃),或
(2)C3-10环烷烃(例如,环己烷),被选自羟基基团和卤素原子(例如,氟原子)的1至3个(优选1个)取代基取代。
此外,环A优选地是被一个羟基基团取代的3至14元非芳族杂环(例如,四氢吡喃)。
在本发明的另一个实施方案中,环A优选地是由以下表示的环
更优选地,由以下表示的环
进一步优选地,由以下表示的环
特别优选地,由以下表示的环
在本发明的另一个实施方案中,环A优选地是由以下表示的环
更优选地,由以下表示的环
进一步优选地,由以下表示的环
此外,优选地,由以下表示的环
特别优选地,由以下表示的环
R1和R2各自独立地是氢原子或卤素原子。
作为R1或R2的卤素原子,可以提及氟原子、氯原子和溴原子。
在本发明的一个实施方案中,R1和R2各自优选地是氢原子。
在本发明的另一个实施方案中,R1是氢原子,并且R2是氢原子或卤素原子(例如,氟原子)。
R3、R4和R5各自独立地是氢原子、卤素原子、羟基基团、任选取代的C1-6烷基基团、或任选取代的C1-6烷氧基基团。
R3和R4之一任选地与R5一起形成任选取代的环。
作为R3、R4或R5的卤素原子,可以提及氟原子、氯原子或溴原子。
R3、R4或R5的“任选取代的C1-6烷基基团”的“C1-6烷基基团”任选地在一个或多个可取代位置处具有1至5个(优选1至3个)取代基。这样的取代基的例子包括前述的“取代基”和“取代基团A”。当存在多个取代基时,各个取代基可以相同或不同。
R3、R4或R5的“任选取代的C1-6烷氧基基团”的“C1-6烷氧基基团”任选地在一个或多个可取代位置处具有1至5个(优选1至3个)取代基。这样的取代基的例子包括前述的“取代基”和“取代基团A”。当存在多个取代基时,各个取代基可以相同或不同。
R3、R4或R5的“任选取代的C1-6烷基基团”和“任选取代的C1-6烷氧基基团”的取代基的例子包括1至3个(优选1或2个,更优选1个)选自以下的取代基
(i)卤素原子,
(ii)氰基基团,
(iii)羟基基团,
(iv)C1-6烷氧基基团(例如,甲氧基、乙氧基、叔丁氧基),任选地被选自卤素原子和C1-6烷氧基基团的1至3个取代基取代,
(v)C3-10环烷基基团,
(vi)3至14元非芳族杂环基团(例如,四氢呋喃基),
(vii)C6-14芳基基团(例如,苯基),任选地被选自羟基基团、C1-6烷硫基基团和C1-6烷基磺酰基基团的1至3个取代基取代,
(viii)5至14元芳族杂环基团(例如,呋喃基、吡啶基),任选地被1至3个C1-6烷氧基基团取代,
(ix)C1-6烷氧基-羰基基团,
(x)C1-6烷硫基基团,
(xi)C1-6烷基磺酰基基团,
(xii)单或二C1-6烷基-氨基甲酰基基团,
(xiii)3至14元非芳族杂环基羰基基团(例如,吗啉-4-基羰基),以及
(xiv)C1-6烷基-羰基氨基基团等。
作为由R3和R4之一与R5一起形成的“任选取代的环”的“环”,可以提及与苯环稠合以形成9至14元稠合多环(优选双环)非芳族杂环(例如,异吲哚酮环、二氢异喹啉酮环)的环。例如,在式(I)中,由下式表示的部分
是由下式表示的部分
可以提及(在上述式中,R3与R5一起形成环)。
由R3和R4之一与R5一起形成的“环”任选地在一个或多个可取代位置处具有1至5个(优选1至3个)取代基。这样的取代基的例子包括前述的“取代基”和“取代基团A”。当存在多个取代基时,各个取代基可以相同或不同。这种取代基的例子包括1至5个(优选1至3个)选自以下的取代基:卤素原子、硝基基团、氰基基团、氧代基团、羟基基团、任选取代的C1-6烷基基团和任选取代的C1-6烷氧基基团。
R5优选地是氢原子、卤素原子(例如,氟原子)、羟基基团、C1-6烷基基团(例如,甲基)或C1-6烷氧基基团(例如,甲氧基),更优选地,氢原子或卤素原子(例如,氟原子)。
R3和R4优选地各自独立地是
(1)氢原子,
(2)卤素原子,
(3)羟基基团,
(4)C1-6烷基基团,任选地被选自以下的1至3个(优选1或2个,更优选1个)取代基取代
(i)卤素原子,
(ii)氰基基团,
(iii)羟基基团,
(iv)C1-6烷氧基基团(例如,甲氧基、乙氧基、叔丁氧基),任选地被选自卤素原子和C1-6烷氧基基团的1至3个取代基取代,
(v)C3-10环烷基基团,
(vi)3至14元非芳族杂环基团(例如,四氢呋喃基),
(vii)C6-14芳基基团(例如,苯基),任选地被选自羟基基团、C1-6烷硫基基团和C1-6烷基磺酰基基团的1至3个取代基取代,
(viii)5至14元芳族杂环基团(例如,呋喃基、吡啶基),任选地被1至3个C1-6烷氧基基团取代,
(ix)C1-6烷氧基-羰基基团,
(x)C1-6烷硫基基团,
(xi)C1-6烷基磺酰基基团,
(xii)单或二C1-6烷基-氨基甲酰基基团,
(xiii)3至14元非芳族杂环基羰基基团(例如,吗啉-4-基羰基),以及
(xiv)C1-6烷基-羰基氨基基团,或
(4)C1-6烷氧基基团;以及
R3和R4之一任选地与R5一起形成任选取代的环。
在本发明的另一个实施方案中,R3优选地是氢原子;
R4优选地是C1-6烷基基团(例如,甲基、乙基、丙基),任选地被选自C1-6烷氧基基团(例如,甲氧基、乙氧基、叔丁氧基)和3至14元非芳族杂环基团(例如,四氢呋喃基、四氢吡喃基)的1或2个(优选1个)取代基取代。
作为化合物(I)的优选实施方案,可以提及以下化合物。
[化合物I-1]
化合物(I)其中
X是O;
Y是CR5;
R1和R2各自是氢原子;
R3是氢原子;
R4是C1-6烷基基团(例如,甲基、乙基、丙基),任选地被选自C1-6烷氧基基团(例如,甲氧基、乙氧基、叔丁氧基)和3至14元非芳族杂环基团(例如,四氢呋喃基、四氢吡喃基)的1或2个(优选1个)取代基取代;
R5是卤素原子(例如,氟原子);并且
环A是任选地被1至3个(优选1个)羟基基团取代的3至14元非芳族杂环基团(例如,四氢吡喃基)。
[化合物I-2]
化合物(I)其中
X是O;
Y是CR5;
R1和R2各自是氢原子;
R3是氢原子;
R4是任选地被C1-6烷氧基基团(例如,甲氧基、乙氧基、叔丁氧基)取代的C1-6烷基基团(例如,甲基、乙基、丙基);
R5是卤素原子(例如,氟原子);并且
环A是任选地被1至3个(优选1个)羟基基团取代的3至14元非芳族杂环基团(例如,四氢吡喃基)。
具体地,由式(I)表示的化合物的优选例子包括实施例1至4的化合物或其盐。
当化合物(I)呈盐的形式时,这种盐的例子包括与无机碱形成的盐、铵盐、与有机碱形成的盐、与无机酸形成的盐、与有机酸形成的盐、与碱性或酸性氨基酸形成的盐等。
与无机碱形成的盐的优选例子包括碱金属盐,如钠盐、钾盐等;碱土金属盐,如钙盐、镁盐、钡盐等;铝盐等。
与有机碱形成的盐的优选例子包括与以下形成的盐:三甲胺、三乙胺、吡啶、甲基吡啶、乙醇胺、二乙醇胺、三乙醇胺、二环己胺、N,N-二苄基乙二胺等。
与无机酸形成的盐的优选例子包括与以下形成的盐:盐酸、氢溴酸、硝酸、硫酸、磷酸等。
与有机酸形成的盐的优选例子包括与以下形成的盐:甲酸、乙酸、三氟乙酸、富马酸、草酸、酒石酸、马来酸、柠檬酸、琥珀酸、苹果酸、甲磺酸、苯磺酸、对甲苯磺酸等。
与碱性氨基酸形成的盐的优选例子包括与以下形成的盐:精氨酸、赖氨酸、鸟氨酸等。
与酸性氨基酸形成的盐的优选例子包括与以下形成的盐:天冬氨酸、谷氨酸等。
在这些盐中,药学上可接受的盐是优选的。当化合物具有碱性官能团时,优选的药学上可接受的盐的例子包括与无机酸如盐酸、氢溴酸、硝酸、硫酸、磷酸等形成的盐,以及与有机酸如乙酸、邻苯二甲酸、富马酸、草酸、酒石酸、马来酸、柠檬酸、琥珀酸、甲磺酸、对甲苯磺酸等形成的盐。此外,当化合物具有酸性官能团时,其例子包括无机盐如碱金属盐(例如,钠盐、钾盐等)、碱土金属盐(例如,钙盐、镁盐、钡盐等)等、铵盐等。
化合物(I)可以是晶体,并且单晶和晶体混合物两者均包括在化合物(I)中。
化合物(I)可以是药学上可接受的共晶或共晶盐。在此,共晶或共晶盐意指由在室温下为固体的两种或更多种特殊物质组成的结晶物质,每种特殊物质均具有不同的物理特性(例如,结构、熔点、熔化热、吸湿性、溶解性、稳定性等)。所述共晶和共晶盐可以通过本身已知的共结晶方法来产生。
化合物(I)包括在其范围内的溶剂化物(例如,水合物)和非溶剂化物。化合物(I)可以是被同位素(例如,2H、3H、11C、14C、18F、35S、125I)标记或取代的化合物。被同位素标记或取代的化合物可以用作例如,用于正电子发射断层扫描(PET)的示踪剂(PET示踪剂),并且可用于医学诊断等领域。
当本发明的化合物(I)具有不对称中心时,可以存在异构体,如对映体、非对映体等。此类异构体及其混合物均包括在本发明的范围内。当由于构象或互变异构而形成异构体时,此类异构体及其混合物也包括在本发明的化合物(I)中。
以下解释了本发明的化合物的产生方法。
以下产生方法中各步骤中所使用的起始材料和试剂以及所获得的化合物各自可以形成盐。所述盐的例子包括与前述本发明的化合物的盐等类似的那些盐。
当在每个步骤中获得的化合物是游离化合物时,可以通过本身已知的方法将其转化为所需的盐。相反,当在每个步骤中获得的化合物是盐时,可以通过本身已知的方法将其转化为游离形式或所需的其他种类的盐。
在每个步骤中获得的化合物还可以作为其反应混合物或在获得其粗产物之后用于下一个反应。可替代地,在每个步骤中获得的化合物可以根据常规方法通过分离手段(如浓缩、结晶、重结晶、蒸馏、溶剂萃取、分馏、色谱等)从反应混合物分离和/或纯化。
当每个步骤的起始材料和试剂化合物都可商购时,所述可商购的产品可以按原样使用。
在每个步骤的反应中,尽管反应时间根据待使用的试剂和溶剂而改变,但除非另有说明,一般为1min-48h,优选10min-8h。
在每个步骤的反应中,尽管反应温度根据待使用的试剂和溶剂而改变,但除非另有说明,一般为-78℃至300℃,优选-78℃至150℃。
在每个步骤的反应中,尽管压力根据待使用的试剂和溶剂而改变,但除非另有说明,一般为1atm-20atm,优选1atm-3atm。
在每个步骤的反应中,例如,有时使用微波合成器,如由Biotage制造的引发器等。尽管反应温度根据待使用的试剂和溶剂而改变,但除非另有说明,一般为室温-300℃,优选50℃-250℃。尽管反应时间根据待使用的试剂和溶剂而改变,但除非另有说明,一般为1min-48h,优选1min-8h。
在每个步骤的反应中,除非另有说明,否则相对于底物以0.5当量-20当量,优选0.8当量-5当量使用试剂。当使用试剂作为催化剂时,相对于底物以0.001当量-1当量,优选0.01当量-0.2当量使用所述试剂。当所述试剂也是反应溶剂时,以溶剂量使用所述试剂。
在每个步骤的反应中,除非另有说明,否则在没有溶剂的情况下或者通过溶解或悬浮于合适的溶剂中进行。所述溶剂的具体例子包括实施例和以下所述的那些。
醇:甲醇、乙醇、叔丁醇、2-甲氧基乙醇等;
醚类:***、二苯醚、四氢呋喃、1,2-二甲氧基乙烷等;
芳烃:氯苯、甲苯、二甲苯等;
饱和烃:环己烷、己烷等;
酰胺类:N,N-二甲基甲酰胺、N-甲基吡咯烷酮等;
卤代烃:二氯甲烷、四氯化碳等;
腈类:乙腈等;
亚砜:二甲基亚砜等;
芳族有机碱:吡啶等;
酸酐:乙酸酐等;
有机酸:甲酸、乙酸、三氟乙酸等;
无机酸:盐酸、硫酸等;
酯:乙酸乙酯等;
酮:丙酮、甲乙酮等;和
水。
通过以适当的比率混合,可以使用两种或更多种上述溶剂。
当在每个步骤的反应中使用碱时,例如,使用以下所示的碱或实施例中所述的碱。
无机碱:氢氧化钠、氢氧化镁、碳酸钠、碳酸钙、碳酸氢钠等;
有机碱:三乙胺、二乙胺、吡啶、4-二甲基氨基吡啶、N,N-二甲基苯胺、1,4-二氮杂双环[2.2.2]辛烷、1,8-二氮杂双环[5.4.0]-7-十一碳烯、咪唑、哌啶等;
金属醇盐:乙醇钠、叔丁醇钾等;
碱金属氢化物:氢化钠等;
金属酰胺:氨基钠、二异丙基氨基锂、六甲基二硅基氨基锂等;和
有机锂:正丁基锂等。
当在每个步骤的反应中使用酸或酸性催化剂时,例如,使用以下所示的酸或酸性催化剂或实施例中所述的那些。
无机酸:盐酸、硫酸、硝酸、氢溴酸、磷酸等;
有机酸:乙酸、三氟乙酸、柠檬酸、对甲苯磺酸、10-樟脑磺酸等;
路易斯酸:三氟化硼***络合物、碘化锌、无水氯化铝、无水氯化锌、无水氯化铁等。
除非另有说明,否则每个步骤的反应均根据本身已知的方法进行,例如,描述于以下中的方法:Jikken Kagaku Kouza第5版,第13卷-第19卷(The Chemical Society ofJapan编辑);Shinjikken Kagaku Kouza(实验化学课程),第14卷-第15卷(The ChemicalSociety of Japan编辑);Fine Organic Chemistry rev.第2版(L.F.Tietze,Th.Eicher,NANKODO);rev.Organic Name Reactions,Their Mechanism and Essence(Hideo Togo,Kodansha);ORGANIC SYNTHESES Collective Volume I-VII(John Wiley&Sons Inc);Modern Organic Synthesis in the Laboratory,A Collection of StandardExperimental Procedures(Jie Jack Li,OXFORD UNIVERSITY);ComprehensiveHeterocyclic Chemistry III,第1卷-第14卷(Elsevier Japan KK);StrategicApplications of Named Reactions in Organic Synthesis(translation supervisorKiyoshi Tomioka,KAGAKUDOJIN);Comprehensive Organic Transformations(VCHPublishers Inc.),1989等,或描述于实施例中的方法。
在每个步骤中,官能团的保护或脱保护反应通过本身已知的方法进行,例如,描述于以下中的方法:“Protective Groups in Organic Synthesis,第4版”(TheodoraW.Greene,Peter G.M.Wuts)Wiley-Interscience,2007;“Protecting Groups第3版”(P.J.Kocienski)Thieme,2004等,或描述于实施例中的方法。
醇等的羟基基团和酚羟基基团的保护基团的例子包括醚保护基团,如甲氧基甲基醚、苄基醚、叔丁基二甲基甲硅烷基醚、四氢吡喃基醚等;羧酸酯保护基团,如乙酸酯等;磺酸酯保护基团,如甲磺酸酯等;碳酸酯保护基团,如碳酸叔丁基酯等,等等。
醛的羰基基团的保护基团的例子包括缩醛保护基团,如二甲基缩醛等;环状缩醛保护基团,如1,3-二氧六环等,等等。
酮的羰基基团的保护基团的例子包括缩酮保护基团,如二甲基缩酮等;环状缩酮保护基团,如1,3-二氧六环等;肟保护基团,如O-甲基肟等;腙保护基团,如N,N-二甲基腙等,等等。
羧基保护基团的例子包括酯保护基团,如甲酯等;酰胺保护基团,如N,N-二甲基酰胺等,等等。
硫醇保护基团的例子包括醚保护基团,如苄基硫醚等;酯保护基团,如硫代乙酸酯、硫代碳酸酯、硫代氨基甲酸酯等,等等。
氨基基团和芳族杂环(如咪唑、吡咯、吲哚等)的保护基团的例子包括氨基甲酸酯保护基团,如氨基甲酸苄酯等;酰胺保护基团,如乙酰胺等;烷基胺保护基团,如N-三苯基甲胺等;磺酰胺保护基团,如甲磺酰胺等,等等。
所述保护基团可以通过本身已知的方法去除,例如,使用酸、碱、紫外光、肼、苯肼、N-甲基二硫代氨基甲酸钠、四丁基氟化铵、乙酸钯、三烷基甲硅烷基卤化物(例如,三甲基甲硅烷基碘化物、三甲基甲硅烷基溴化物)的方法;还原方法等。
当在每个步骤中进行还原反应时,待使用的还原剂的例子包括金属氢化物,如氢化铝锂、三乙酰氧基硼氢化钠、氰基硼氢化钠、二异丁基氢化铝(DIBAL-H)、硼氢化钠、三乙酰氧基硼氢化氢四甲基铵等;硼烷,如硼烷四氢呋喃络合物等;雷尼镍;雷尼钴;氢;甲酸;三乙基硅烷等。当碳-碳双键或三键被还原时,使用了使用催化剂(如钯-碳、Lindlar催化剂等)的方法。
当在每个步骤中进行氧化反应时,待使用的氧化剂的例子包括过酸,如间氯过苯甲酸(mCPBA)、过氧化氢、叔丁基过氧化氢等;高氯酸盐,如四丁基高氯酸铵等;氯酸盐,如氯酸钠等;亚氯酸盐,如亚氯酸钠等;高碘酸,如高碘酸钠等;高价碘试剂,如亚碘酰苯等;含锰试剂,如二氧化锰、高锰酸钾等;铅,如四乙酸铅等;含铬试剂,如氯铬酸吡啶鎓(PCC)、重铬酸吡啶鎓(PDC)、琼斯试剂等;卤素化合物,如N-溴代琥珀酰亚胺(NBS)等;氧气;臭氧;三氧化硫吡啶络合物;四氧化锇;二氧化硒;2,3-二氯-5,6-二氰基-1,4-苯醌(DDQ)等。
当在每个步骤中进行自由基环化反应时,待使用的自由基引发剂的例子包括偶氮化合物,如偶氮二异丁腈(AIBN)等;水溶性自由基引发剂,如4,4'-偶氮二-4-氰基戊酸(ACPA)等;空气或氧气存在下的三乙基硼;过氧化苯甲酰等。此外,待使用的自由基反应剂的例子包括三丁基锡烷、三三甲基甲硅烷基硅烷、1,1,2,2-四苯基二硅烷、二苯基硅烷、碘化钐等。
当在每个步骤中进行维蒂希反应时,待使用的维蒂希试剂的例子包括亚烷基膦等。亚烷基膦可以通过本身已知的方法制备,例如通过使鏻盐与强碱反应。
当在每个步骤中进行霍纳尔-埃蒙斯(Horner-Emmons)反应时,待使用的试剂的例子包括膦酰基乙酸酯,如二甲基膦酰基乙酸甲酯、二乙基膦酰基乙酸乙酯等;以及碱,如碱金属氢化物、有机锂等。
当在每个步骤中进行弗里德尔-克拉夫茨(Friedel-Crafts)反应时,待使用的试剂的例子包括路易斯酸和酰氯的组合、路易斯酸和烷基化剂(例如,烷基卤、醇、烯烃等)的组合。可替代地,也可以使用有机酸和无机酸来代替路易斯酸,并且也可以使用酸酐(如乙酸酐等)来代替酰氯。
当在每个步骤中进行芳族亲核取代反应时,使用亲核试剂(例如,胺、咪唑等)和碱(例如,有机碱等)作为试剂。
当在每个步骤中进行与碳负离子的亲核加成反应、与碳负离子的亲核1,4-加成反应(迈克尔加成反应)或与碳负离子的亲核取代反应时,待用于形成碳负离子的碱的例子包括有机锂、金属醇盐、无机碱、有机碱等。
当在每个步骤中进行格氏反应时,格氏试剂的例子包括芳基卤化镁,如苯基溴化镁等;和烷基卤化镁,如甲基溴化镁等。格氏试剂可以通过本身已知的方法制备,例如,通过使烷基卤或芳基卤与金属镁在作为溶剂的醚或四氢呋喃中反应。
当在每个步骤中进行克诺维纳盖尔(Knoevenagel)缩合反应时,使用保持在两个吸电子基团(例如,丙二酸、丙二酸二乙酯、丙二腈等)之间的活性亚甲基化合物和碱(例如,有机碱、金属醇盐、无机碱)作为试剂。
当在每个步骤中进行维尔斯迈尔-哈克(Vilsmeier-Haack)反应时,使用磷酰氯和酰胺衍生物(例如,N,N-二甲基甲酰胺等)作为试剂。
当在每个步骤中进行醇、烷基卤或磺酸酯的叠氮化反应时,待使用的叠氮化剂的例子包括二苯基磷酰基叠氮化物(DPPA)、三甲基甲硅烷基叠氮化物、叠氮化钠等。例如,当叠氮化醇时,可以采用使用二苯基磷酰基叠氮化物和1,8-二氮杂双环[5,4,0]十一碳-7-烯(DBU)的方法、使用三甲基甲硅烷基叠氮化物和路易斯酸等的方法。
当在每个步骤中进行还原胺化反应时,待使用的还原剂的例子包括三乙酰氧基硼氢化钠、氰基硼氢化钠、氢气、甲酸等。当所述底物是胺化合物时,除了对甲醛之外,待使用的羰基化合物的例子包括醛,如乙醛等;酮,如环己酮等。当所述底物是羰基化合物时,待使用的胺的例子包括氨、伯胺,如甲胺等;仲胺,如二甲胺等,等等。
当在每个步骤中进行光延反应时,使用偶氮二甲酸酯(例如,偶氮二甲酸二乙酯(DEAD)、偶氮二甲酸二异丙基酯(DIAD)等)和三苯基膦作为试剂。
当在每个步骤中进行酯化反应、酰胺化反应或脲化反应时,待使用的试剂的例子包括酰基卤,如酰氯、酸溴化物等;和激活的羧酸,如酸酐、活性酯形式、硫酸酯形式等。羧酸激活剂的例子包括碳二亚胺缩合剂,如1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐(WSCD)等;三嗪缩合剂,如4-(4,6-二甲氧基-1,3,5-三嗪-2-基)-4-甲基吗啉鎓氯化物-n-水合物(DMT-MM)等;碳酸酯缩合剂,如1,1-羰基二咪唑(CDI)等;二苯基磷酰基叠氮化物(DPPA);苯并***-1-基氧基-三二甲基氨基磷酸盐(BOP试剂);2-氯-1-甲基-吡啶盐碘化物(向山试剂);亚硫酰氯;低级烷基卤代甲酸酯,如氯甲酸乙酯等;O-(7-氮杂苯并***-1-基)-N,N,N',N’-四甲基脲六氟磷酸盐(HATU);硫酸;它们的组合等。当使用碳二亚胺缩合剂时,可以向反应中进一步添加添加剂,如1-羟基苯并***(HOBt)、N-羟基琥珀酰亚胺(HOSu)、二甲基氨基吡啶(DMAP)等。
当在每个步骤中进行偶联反应时,待使用的金属催化剂的例子包括钯化合物,如乙酸钯(II)、四(三苯基膦)钯(0)、二氯双(三苯基膦)钯(II)、二氯双(三乙基膦)钯(II)、三(二亚苄基丙酮)二钯(0)、1,1'-双(二苯基膦基)二茂铁氯化钯(II)等;镍化合物,如四(三苯基膦)镍(0)等;铑化合物,如三(三苯基膦)氯化铑(III)等;钴化合物;铜化合物,如氧化铜、碘化铜(I)等;铂化合物等。可以将碱进一步添加至反应中,并且这种碱的例子包括无机碱等。
当在每个步骤中进行硫羰基化反应时,代表性地使用五硫化二磷作为硫羰基化剂。除了五硫化二磷之外,还可以使用具有1,3,2,4-二硫杂二磷杂环丁烷-2,4-二硫化物结构的试剂,如2,4-双(4-甲氧基苯基-1,3,2,4-二硫杂二磷杂环丁烷-2,4-二硫化物(劳森试剂)等。
当在每个步骤中进行伏尔-齐格勒(Wohl-Ziegler)反应时,待使用的卤化剂的例子包括N-碘代琥珀酰亚胺、N-溴代琥珀酰亚胺(NBS)、N-氯代琥珀酰亚胺(NCS)、溴、硫酰氯等。此外,可以通过向反应中添加热、光、自由基引发剂(如过氧化苯甲酰、偶氮二异丁腈等)来加速反应。
当在每个步骤中进行羟基基团的卤化反应时,待使用的卤化剂的例子包括氢卤酸和无机酸的酰卤;具体地,用于氯化的盐酸、亚硫酰氯、三氯氧磷等,以及用于溴化的48%氢溴酸等。此外,可以使用通过与三苯基膦和四氯化碳或四溴化碳等反应从醇获得烷代卤形式的方法。可替代地,也可以使用经由两步反应合成烷基卤形式的方法,所述两步反应包括将醇转化为磺酸酯,并使其与溴化锂、氯化锂或碘化钠反应。
当在每个步骤中进行阿尔布佐夫反应时,待使用的试剂的例子包括烷基卤,如溴乙酸乙酯等;和亚磷酸酯,如亚磷酸三乙酯、亚磷酸三(异丙基)酯等。
当在每个步骤中进行磺酸酯化反应时,待使用的磺酰化剂的例子包括甲磺酰氯、对甲苯磺酰氯、甲磺酸酐、对甲苯磺酸酐等。
当在每个步骤中进行水解反应时,使用酸或碱作为试剂。此外,当进行叔丁酯的酸水解反应时,有时添加甲酸、三乙基硅烷等以还原捕集副产的叔丁基阳离子。
当在每个步骤中进行脱水反应时,待使用的脱水剂的例子包括硫酸、五氧化二磷、三氯氧化磷、N,N'-二环己基碳二亚胺、氧化铝、多磷酸等。
当在每个步骤中进行卤化时,待使用的卤化剂是用于氯化的N-氯代琥珀酰亚胺(NCS)、硫酰氯等,用于溴化的N-溴代琥珀酰亚胺(NBS)、溴等,以及用于碘化的N-碘代琥珀酰亚胺(NIS)、碘等。
当在每个步骤中进行水杨酰胺的噁嗪酮环形成反应时,所述试剂包括例如甲醛、对甲醛、1,3,5-三噁烷、二溴甲烷、二碘甲烷、氯碘甲烷等。待使用的酸是例如甲酸、对甲苯磺酸、樟脑磺酸等,并且待使用的碱是例如碳酸铯等。
化合物(I)可以通过以下方案中所示的方法或与其类似的方法或实施例中所述的方法产生。
化合物(I)可以通过以下方法由化合物(1)产生。
在反应式中,R10是低级烷基基团,R6和R7各自是卤素原子,P是保护基团,并且R1-R4、X、Y和环A的含义与上述相同。
化合物(2)可以通过化合物(1)的还原反应来产生。
化合物(3)可以通过用卤化剂(如NBS、NIS等)将化合物(2)进行卤化来产生。
化合物(4)可以通过化合物(3)的水解来产生。
化合物(6)可以通过化合物(4)和化合物(5)的酰胺化反应来产生。
化合物(7)可以通过化合物(6)的噁嗪酮环形成反应来产生。
化合物(8)可以通过在化合物(7)中引入保护基团来产生。
化合物(9)可以通过化合物(8)和联硼酸频那醇酯在金属催化剂存在下的偶联反应来产生。
化合物(I)可以通过化合物(9)和化合物(10)在金属催化剂存在下的偶联反应和保护基团P的脱保护来产生。
在化合物(I)的产生中,在一些情况下可能不需要引入上述方案中的保护基团及其脱保护步骤。
化合物(I)也可以通过以下方法由化合物(9)产生。
在反应式中,R8是低级烷基基团,R9是卤素原子,并且P、R1-R4、X、Y和环A的含义与上述相同。
化合物(12)可以通过化合物(9)和化合物(11)在金属催化剂存在下的偶联反应来产生。
化合物(I)可以通过使化合物(12)水解、与化合物(13)进行酰胺化反应,并且然后使保护基团P脱保护来产生。
用作生产化合物(I)的起始材料的化合物(1)、化合物(5)、化合物(10)、化合物(11)、化合物(13)、NBS、NIS和联硼酸频那醇酯可以是可商购获得的产品或可以根据本身已知的方法来产生。
当化合物(I)具有光学异构体、立体异构体、位置异构体或旋转异构体时,这些也包括在化合物(I)中,并且可以根据本身已知的合成和分离方法作为单一产物获得。例如,当化合物(I)含有光学异构体时,从所述化合物分解的光学异构体也包括在化合物(I)中。
光学异构体可以根据本身已知的方法来产生。具体地,使用光学活性的合成中间体,或者根据常规方法对最终的外消旋体产物进行光学拆分,以得到光学异构体。
例如,光学拆分的方法可以是本身已知的方法,如分级重结晶法、手性柱法、非对映体法等。
1)分级重结晶法
一种方法,其中用光学活性化合物(例如,(+)-扁桃酸、(-)-扁桃酸、(+)-酒石酸、(-)-酒石酸、(+)-l-苯乙胺、(-)-1-苯乙胺、辛可宁、(-)-辛可宁定、马钱子碱等)形成了具有外消旋体的盐,将其通过分级重结晶法分离,并且如果需要,通过中和步骤以得到游离的光学异构体。
2)手性柱法
一种方法,其中将外消旋体或其盐施加到用于分离光学异构体的柱(手性柱)以允许分离。在液相色谱的情况下,例如,将光学异构体的混合物施加到手性柱(如ENANTIO-OVM(由Tosoh公司制造)、由Daicel公司制造的CHIRAL系列等)并且用水、各种缓冲液(例如,磷酸盐缓冲液等)和有机溶剂(例如,乙醇、甲醇、异丙醇、乙腈、三氟乙酸、二乙胺等)(单独或以其混合溶液的形式)显影,以分离光学异构体。
3)非对映体法
一种如下方法,其中将外消旋混合物通过与光学活性试剂的化学反应制备成非对映体混合物,将其通过典型的分离手段(例如,分级重结晶法、色谱法等)等制成单一物质,并且进行化学处理(如水解反应等)以去除光学活性试剂部分,从而获得光学异构体。例如,当化合物(I)在分子内含有羟基基团或伯氨基或仲氨基时,所述化合物和光学活性有机酸(例如,MTPA[α-甲氧基-α-(三氟甲基)苯乙酸]、(-)-薄荷氧基乙酸等)等进行缩合反应,以分别得到酯化合物或酰胺化合物的非对映体。当化合物(I)具有羧酸基团时,将此化合物和光学活性胺或光学活性醇试剂进行缩合反应,以分别得到酰胺化合物或酯化合物的非对映体。通过酸水解或碱水解反应将分离出的非对映体转化为原始化合物的光学异构体。
当获得作为游离化合物的化合物(I)时,可以根据本身已知的方法或与其类似的方法将所述化合物转化为目标盐。相反,当作为盐获得时,可以通过本身已知的方法或与其类似的方法将所述盐转化为游离形式或其他目标盐。
化合物(I)可以是前药,并且化合物(I)的前药是指在体内生理条件下,由于与酶、胃酸等反应而转化为化合物(I)的化合物,因此是进行酶的氧化、还原、水解等转化为化合物(I)的化合物和通过胃酸等进行水解等以转化为化合物(I)的化合物。
化合物(I)的前药的例子包括
通过使化合物(I)中的氨基基团进行酰化、烷基化或磷酸化而获得的化合物(例如,通过使化合物(I)中的氨基基团进行二十碳酰化、丙氨酰化、戊基氨基羰基化、(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)甲氧基羰基化、四氢呋喃基化、吡咯烷基甲基化、新戊氧基甲基化、叔丁基化等而获得的化合物);
通过使化合物(I)中的羟基基团进行酰化、烷基化、磷酸化或硼化而获得的化合物(例如,通过使化合物(I)中的羟基基团进行乙酰化、棕榈酰化、丙酰化、新戊酰化、琥珀酰化、富马酰化、丙氨酰化或二甲基氨基甲基羰基化等而获得的化合物);
通过使化合物(I)中的羧基基团进行酯化或酰胺化而获得的化合物(例如,通过使化合物(I)中的羧基基团进行乙基酯化、苯基酯化、羧甲基酯化、二甲基氨基甲基酯化、新戊酰氧基甲基酯化、乙氧基羰基氧基乙基酯化、酞基酯化、(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)甲基酯化、环己氧基羰基乙基酯化或甲基酰胺化等而获得的化合物)等。这些化合物中的任一种均可以根据本身已知的方法由化合物(I)产生。
化合物(I)的前药也可以是在如“IYAKUHIN no KAIHATSU(Development ofPharmaceuticals)”,第7卷,Design of Molecules,第163-198页(HIROKAWA SHOTEN)中所述的生理条件下转化为化合物(I)的前药。
化合物(I)可以用于预防或治疗疾病,例如,
(1)便秘,例如,神经源性便秘(与如帕金森病、多发性硬化症、脊髓损伤,阿尔茨海默病、先天性巨结肠综合征、恰加斯氏病等疾病相关的便秘)、特发性便秘、功能性便秘、弛缓性便秘、伴有便秘的肠易激综合征、可能并发于其他疾病(帕金森病、脊髓损伤、多发性硬化症等)的便秘、与年龄相关的便秘、各种药物引起的便秘(阿片激动剂引起的便秘等)、原发性慢性便秘、药物引起的便秘(阿片类药物、抗胆碱能剂、钙拮抗剂、抗癌剂、重金属中毒等)、与基础疾病(如内分泌疾病或代谢异常(垂体功能减退、甲状腺功能减退、嗜铬细胞瘤等))相关的便秘、肌肉异常疾病(家族性内脏骨骼肌萎缩、硬皮病、淀粉样变性、进行性***性硬化症等)、代谢性疾病(糖尿病、卟啉症、***、低钾血症、高钙血症等)等,
(2)消化性疾病[例如,胃溃疡、十二指肠溃疡、胃动力减退如胃麻痹等、术后胃肠麻痹、上胃肠动力障碍和不适、恶心、呕吐、反流性食管炎、抗炎剂(非甾体抗炎药)诱导的胃肠障碍、肠易激综合征、炎性肠病、溃疡性结肠炎、克罗恩病、应激性胃肠障碍、腹泻、术后肠梗阻],
(3)精神疾病[例如,抑郁症、重度抑郁症、双相抑郁症、心境恶劣障碍、情感障碍(季节性情感障碍等)、复发性抑郁症、产后抑郁症、应激障碍、抑郁症状、躁狂症、广泛性焦虑障碍、焦虑综合征、恐慌性障碍、恐惧症、社交恐惧症、社交焦虑障碍、强迫性障碍、创伤后应激综合征、创伤后应激障碍、妥瑞综合征(Tourette syndrome)、自闭症、自闭症谱系综合征、脆性X综合征、雷特综合征(Rett syndrome)、适应障碍、双相障碍、神经症、精神***症(例如,阳性症状、阴性症状、认知症状)、与精神***症相关的认知损害、慢性疲劳综合征、焦虑性神经症、强迫性神经症、癫痫、焦虑症状、焦虑精神状态、情绪异常、循环性精神病、神经异常兴奋、昏厥、成瘾、低***、注意缺陷多动障碍(ADHD)、精神病性重度抑郁症、难治性重度抑郁症、抗治疗性抑郁症],
(4)神经退行性疾病[例如,阿尔茨海默病、阿尔茨海默型老年性痴呆、帕金森病、帕金森病痴呆、亨廷顿病、多发性梗塞性痴呆、额颞叶痴呆、额颞叶痴呆帕金森病、进行性核上性麻痹、皮克综合征、尼曼-匹克综合征、皮质基底节变性、唐氏综合征、血管性痴呆、脑炎后型帕金森综合征、路易体痴呆、HIV痴呆、肌萎缩性侧索硬化症(ALS)、运动神经发生疾病(MND)、克雅氏病或朊病毒病、脑瘫、多发性硬化症],
(5)与年龄相关的认知和记忆障碍[例如,与年龄相关的记忆障碍、老年性痴呆],
(6)睡眠障碍[例如,内在睡眠障碍(例如,心理生理性失眠等)、外在睡眠障碍、昼夜节律障碍(例如,时区变化综合征(时差)、轮班工作睡眠障碍、不规则的睡眠-觉醒模式、延迟睡眠期综合征、睡眠时相前移综合征、非24小时睡眠-觉醒等)、深眠状态、与内科或精神障碍(例如,慢性阻塞性肺疾病、阿尔茨海默病、帕金森病、脑血管痴呆、精神***症、抑郁症、焦虑神经症)相关的睡眠障碍、应激性失眠、失眠症、失眠神经症、睡眠呼吸暂停综合征],
(7)由***、创伤性疾病或神经退行性疾病等引起的呼吸抑制,
(8)创伤性脑损伤、脑中风、神经性厌食症、进食障碍、神经性厌食、食欲过盛、其他进食障碍、酒精依赖、酒精滥用、酒精性失忆症、酒精性偏执、酒精偏好、酒精戒断、酒精性精神错乱、酒精中毒、酒精性嫉妒、酒精性躁狂、酒精依赖型精神障碍、酒精性精神错乱、嗜药症、药物恐怖、药物癖、药物戒断、偏头痛、应激性头痛、紧张性头痛、糖尿病性神经病、肥胖症、糖尿病、肌肉痉挛、梅尼埃病、自主性共济失调、脱发、青光眼、高血压、心脏病、心动过速、充血性心力衰竭、呼吸过度、支气管哮喘、呼吸暂停、婴儿猝死综合征、炎性疾病、过敏性疾病、阳痿、更年期障碍、***症、癌症、HIV感染引起的免疫缺陷综合征、由应激引起的免疫缺陷综合征、脑脊髓膜炎、肢端肥大症、代谢综合征、骨质疏松、失禁、排尿困难、膀胱功能障碍,
(9)哺乳动物(例如,小鼠、大鼠、仓鼠、兔子、猫、狗、牛、绵羊、猴子、人等)的疼痛等。特别优选地,化合物(I)可以用于预防或治疗神经源性便秘(与如帕金森病、多发性硬化症、脊髓损伤、阿尔茨海默病、先天性巨结肠综合征、恰加斯氏病等疾病相关的便秘)、特发性便秘、功能性便秘、弛缓性便秘、伴有便秘的肠易激综合征、可能并发于其他疾病(帕金森病、脊髓损伤、多发性硬化症等)的便秘、与年龄相关的便秘、各种药物引起的便秘(阿片激动剂引起的便秘等)、原发性慢性便秘、药物引起的便秘(阿片类药物、抗胆碱能剂、钙拮抗剂、抗癌剂、重金属中毒等)、与基础疾病(如内分泌疾病或代谢异常(垂体功能减退、甲状腺功能减退、嗜铬细胞瘤等))相关的便秘、肌肉异常疾病(家族性内脏骨骼肌萎缩、硬皮病、淀粉样变性、进行性***性硬化症等)、代谢性疾病(糖尿病、卟啉症、***、低钾血症、高钙血症等)等。
由于化合物(I)可能具有胆碱能毒蕈碱M1受体正向变构调节剂活性,因此它有望为上述疾病提供出色的预防或治疗效果。
通常,期望用于便秘的治疗药物在施用后立即展现出效果,并且然后所述效果迅速消失。预期化合物(I)作为便秘的治疗药物显示出优异的药代动力学,并且可以预期在例如施用后3h、优选在施用后2h、进一步优选在施用后1h内展现出效果,并且可以预期所述效果在之后迅速消失。
已知胆碱能毒蕈碱M1受体在大脑和胃肠神经丛中表达。预期化合物(I)显示出低的中枢神经***渗透性,在外周有效地发挥作用,并且作为便秘的治疗药物显示出优异的效果。关于中枢神经***渗透性,例如,在MDR1膜渗透性测试中,MDR1的校正流出比率优选地不小于2.0、更优选不小于3.0并且进一步优选不小于5.0。
由于预期化合物(I)在水中具有优异的溶解性,因此在药代动力学(例如,血浆药物半衰期、代谢稳定性、CYP抑制)方面优异的日本药典溶出试验第2流体或日本药典崩解试验第2流体显示出低毒性(例如,作为药物在急性毒性、慢性毒性、遗传毒性、生殖毒性、心脏毒性、药物相互作用、致癌性、光毒性等方面更优异),并且还可以具有作为药物产品的优异特性,如一些副作用等,它可以安全地口服或胃肠外施用至哺乳动物(例如,小鼠、大鼠、仓鼠、兔子、猫、狗、牛、绵羊、猴子、人等)。“肠胃外”的例子包括静脉内、肌内、皮下、器官内、鼻内、皮内、滴注、脑内、直肠内、***内、腹膜内和肿瘤内施用、对肿瘤等附近的施用和对病变的直接施用。
含有化合物(I)的药物(在本说明书中有时简称为“本发明的药物”)可以具有固体制剂的任何形式(制剂形式)(如粉末、颗粒、片剂、胶囊、口服可崩解膜剂等)或液体剂(如糖浆、乳剂、注射剂等)。
本发明的药物可以根据制剂的形式通过常规方法(如共混、捏合、造粒、压片、包衣、灭菌处理、乳化等)来产生。关于制剂的产生,例如,可以参考日本药典制剂总则等的每一项。此外,本发明的药物可以形成为含有活性成分和生物可降解高分子化合物的缓释制剂。所述缓释制剂可以根据JP-A-9-263545所述的方法产生。
在本发明的药物中,化合物(I)的含量根据制剂的形式而改变,但通常是按重量计0.01%至100%、优选按重量计0.1%至50%、更优选按重量计0.5%至20%,作为化合物(I)相对于整个制剂(整个药物)的量。
化合物(I)可以单独使用,或者与合适的、药理学上可接受的载体(例如赋形剂(例如,淀粉、乳糖、绵白糖、碳酸钙、磷酸钙等)、粘合剂(例如,淀粉、***胶、羧甲基纤维素、羟丙基纤维素、结晶纤维素、藻酸、明胶、聚乙烯吡咯烷酮等)、润滑剂(例如,硬脂酸、硬脂酸镁、硬脂酸钙、滑石等)、崩解剂(例如,羧甲基纤维素钙、滑石等)、稀释剂(例如,注射用水、生理盐水等))并且如果需要,与添加剂(例如,稳定剂、防腐剂、着色剂、香料、增溶剂、乳化剂、缓冲液、等渗剂等)等混合使用,通过常规方法将其加工成固体药剂的剂型(如粉末、细颗粒、颗粒、片剂、胶囊等)或液体形式(如注射剂等),并且口服或肠胃外施用。当化合物(I)形成为用于局部施用的制剂时,它也可以直接施用至关节疾病的受影响部分。在这种情况下,注射是优选的。也可以将化合物(I)作为用于局部施用的肠胃外药剂(例如,肌内注射、皮下注射、器官注射、注射至关节附近等;固体制剂,如植入物、颗粒、粉末等;液体,如悬浮液等;软膏等)等施用。
为了配制成注射剂,例如,将化合物(I)配制成具有以下的水性悬浮液:分散剂(例如,表面活性剂,如吐温80、HCO-60等;多糖,如羧甲基纤维素、藻酸钠、透明质酸等;聚山梨醇酯等)、防腐剂(例如,对羟基苯甲酸甲酯、对羟基苯甲酸丙酯等)、等渗剂(例如,氯化钠、甘露醇、山梨醇、葡萄糖等)、缓冲液(例如,碳酸钙等)、pH调节剂(例如,磷酸钠、磷酸钾等)等,以得到实际的注射制剂。此外,可以通过将所述化合物与植物油(如芝麻油、玉米油等)或其与磷脂(如卵磷脂等)或中链脂肪酸甘油三酯(例如,miglyol 812等)的混合物一起分散来获得油状悬浮液,以得到待实际使用的注射剂。
化合物(I)的剂量根据施用受试者、施用途径和症状而改变,并且没有特别限制。例如,对于口服施用至患有便秘的成人患者(成人体重40至80kg,例如60kg),所述剂量以化合物(I)的形式可以是例如0.001至1000mg/kg体重/天,优选0.01至100mg/kg体重/天,更优选0.1至10mg/kg体重/天。此量可以每天以一至三份施用。
根据作为药物制剂的生产方法的本身已知的方法(例如,日本药典等中描述的方法),本发明的药物可以能够单独使用化合物(I),或者作为化合物(I)与药理学上可接受的载体混合的药物组合物使用。本发明的药物可以以例如以下的形式安全地口服或肠胃外(例如,静脉内、肌内、皮下、器官内、鼻内、皮内、滴注、脑内、直肠内、***内、腹膜内、病变等)施用:药物组合物,如片剂(包括糖衣片、膜衣片、舌下片、口腔崩解片、颊片等)、丸剂、粉末、颗粒、胶囊(包括软胶囊、微胶囊)、锭剂、糖浆、液体、乳剂、悬浮液、控释制剂(例如,速释制剂、缓释制剂、缓释微胶囊)、气雾剂、膜剂(例如,口腔崩解膜剂、口腔粘膜-粘附膜剂)、注射剂(例如,皮下注射剂、静脉内注射剂、肌内注射剂、腹膜内注射剂)、滴注、透皮吸收型制剂、软膏、洗剂、胶粘剂制剂、栓剂(例如,直肠栓剂、***栓剂)、微丸、鼻制剂、肺制剂(吸入剂)、滴眼剂等。
作为前述“药理学上可接受的载体”,可以使用常规地用作制备材料(起始材料)的各种有机或无机载体。例如,赋形剂、润滑剂、粘合剂、崩解剂等可以用于固体制剂,并且溶剂、增溶剂、悬浮剂、等渗剂、缓冲液、舒缓剂等可以用于液体制剂。必要时,也可以使用制备添加剂,如防腐剂、抗氧化剂、着色剂、甜味剂等。
所述赋形剂的例子包括乳糖、绵白糖、D-甘露醇、淀粉、玉米淀粉、结晶纤维素、轻质无水硅酸等。
所述润滑剂的例子包括硬脂酸镁、硬脂酸钙、滑石、胶体二氧化硅等。
所述粘合剂的例子包括结晶纤维素、绵白糖、D-甘露醇、糊精、羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮、淀粉、蔗糖、明胶、甲基纤维素、羧甲基纤维素钠等。
所述崩解剂的例子包括淀粉、羧甲基纤维素、羧甲基纤维素钙、羧甲基淀粉钠、L-羟丙基纤维素等。
所述溶剂的例子包括注射用水、醇、丙二醇、聚乙二醇、芝麻油、玉米油、橄榄油等。
所述增溶剂的例子包括聚乙二醇、丙二醇、D-甘露醇、苯甲酸苄酯、乙醇、三氨基甲烷、胆固醇、三乙醇胺、碳酸钠、柠檬酸钠等。
所述悬浮剂的例子包括表面活性剂,如硬脂酰三乙醇胺、月桂基硫酸钠、月桂基氨基丙酸、卵磷脂、苯扎氯铵、苄索氯铵(benzetonium chloride)、单硬脂酸甘油酯等;亲水性聚合物,如聚乙烯醇、聚乙烯吡咯烷酮、羧甲基纤维素钠、甲基纤维素、羟甲基纤维素、羟乙基纤维素、羟丙基纤维素等;等等。
所述等渗剂的例子包括葡萄糖、D-山梨醇、氯化钠、甘油、D-甘露醇等。
所述缓冲液的例子包括缓冲溶液,如磷酸盐、乙酸盐、碳酸盐、柠檬酸盐等。
所述舒缓剂的例子包括苯甲醇等。
所述防腐剂的例子包括对羟基苯甲酸酯、氯丁醇、苯甲醇、苯乙醇、脱氢乙酸、山梨酸等。
所述抗氧化剂的例子包括亚硫酸盐、抗坏血酸、α-生育酚等。
虽然药物组合物根据剂型、施用方法、载体等而改变,但它可以根据常规方法通过以通常为所述制剂总量0.01%-100%(w/w)、优选0.1%-95%(w/w)的比例添加化合物(I)来产生。
化合物(I)可以与其他活性成分(以下简称为伴随药物)组合使用。
伴随药物的例子包括以下。
促动力药(胆碱酯酶抑制剂(新斯的明、毒扁豆碱等)、5-HT4激动剂、饥饿素(ghrelin)激动剂(卡莫瑞林等)、胃动素受体激动剂(卡米西纳(camicinal)、红霉素等)、阿片类拮抗剂(纳曲酮(naltrexone)、纳洛昔醇(naloxegol)等)、肠水分泌促进剂(鸟苷酸环化酶C激动剂(利那洛肽等)、氯离子通道2开放剂(鲁比前列酮等)、钠/质子交换剂3抑制剂(替那帕诺(tenapanor)等))、抗便秘药物(番泻苷、氧化镁、氢氧化镁、比沙可啶、聚卡波非钙、泻药糖(乳果糖等)、laxoberon、具有抗便秘作用的天然药物(车前草等)等)、苯二氮卓类药物(利眠宁(chlordiazepoxide)、***、二甲氯氮卓、劳拉西泮、氯硝西泮、阿普***等)、L型钙通道抑制剂(普瑞巴林等)、三环或四环抗抑郁药(盐酸丙咪嗪、盐酸阿米替林、盐酸地昔帕明、盐酸氯米帕明等)、选择性5-羟色胺再摄取抑制剂(马来酸氟伏沙明、盐酸氟西汀、氢溴酸西酞普兰、盐酸舍曲林、盐酸帕罗西汀、草酸艾司西酞普兰等)、5-羟色胺-去甲肾上腺素再摄取抑制剂(盐酸文拉法辛、盐酸度洛西汀、盐酸地文拉法辛等)、去甲肾上腺素再摄取抑制剂(甲磺酸瑞波西汀等)、去甲肾上腺素-多巴胺再摄取抑制剂(盐酸安非他酮等)、米氮平、***唑酮、盐酸奈法唑酮、盐酸丁氨苯丙酮、马来酸司普替林、5-HT1A激动剂(盐酸丁螺环酮、枸橼酸坦度螺酮、盐酸奥沙莫唑坦(osemozotan hydrochloride)等)、5-HT3拮抗剂(氰美马嗪等)、非心脏选择性β受体阻滞剂(盐酸***、盐酸氧烯洛尔等)、组胺H1拮抗剂(盐酸羟嗪等)、精神***症治疗药物(氯丙嗪、氟哌啶醇、舒必利、氯氮平、盐酸三氟拉嗪、盐酸氟奋乃静、奥氮平、富马酸喹硫平、利培酮、阿立哌唑等)、CRF拮抗剂、其他抗焦虑药物(甲丙氨酯等)、速激肽拮抗剂(阿瑞匹坦、沙瑞度坦等)、作用于代谢型谷氨酸受体的药物、CCK拮抗剂、β3肾上腺素拮抗剂(盐酸阿米拜龙(amibegron hydrochloride)等)、GAT-1抑制剂(盐酸噻加宾等)、N型钙通道抑制剂、碳酸酐酶II抑制剂、NMDA甘氨酸部分激动剂、NMDA拮抗剂(美金刚等)、外周苯二氮卓类受体激动剂、血管加压素拮抗剂、血管加压素V1b拮抗剂、血管加压素V1a拮抗剂、磷酸二酯酶抑制剂、阿片激动剂、尿苷、烟碱酸受体激动剂、甲状腺激素(T3、T4)、TSH、TRH、MAO抑制剂(硫酸苯乙肼、硫酸反苯环丙胺、吗氯贝胺等)、5-HT2A拮抗剂、5-HT2A反向激动剂、COMT抑制剂(恩他卡朋等)、双相障碍的治疗药物(碳酸锂、丙戊酸钠、拉莫三嗪、利鲁唑、非尔氨酯等)、***素CB1拮抗剂(利莫那班等)、FAAH抑制剂、钠通道抑制剂、抗ADHD药物(盐酸哌甲酯、盐酸甲基***等)、酒精中毒的治疗药物、自闭症的治疗药物、慢性疲劳综合征的治疗药物、惊厥的治疗药物、纤维肌痛综合征的治疗药物、头痛的治疗药物、失眠的治疗药物(依替***、佐匹克隆、***仑、唑吡坦、雷美替胺、茚地普隆等)、戒烟的治疗药物、重症肌无力的治疗药物、脑梗死的治疗药物、躁狂症的治疗药物、嗜睡症的治疗药物、疼痛的治疗药物、心境恶劣的治疗药物、自主性共济失调的治疗药物、男性和女性性功能障碍的治疗药物、偏头痛的治疗药物、病态赌徒的治疗药物、不宁腿综合征的治疗药物、物质成瘾的治疗药物、酒精相关综合征的治疗药物、肠易激综合征的治疗药物、阿尔茨海默病的治疗药物(多奈哌齐、加兰他敏、美金刚、卡巴拉汀等)、帕金森病的治疗药物(左旋多巴、卡比多巴、苄丝肼、司来吉兰、雷沙吉兰、唑尼沙胺、恩他卡朋、金刚烷胺、他利克索、普拉克索、罗匹尼罗、罗替戈汀、阿扑***、卡麦角林、培高利特、溴麦角环肽、伊曲茶碱、苯海索、比哌立登、吡咯庚汀(piroheptine)、普罗吩胺、异丙嗪、屈昔多巴、那些药物的组合等)、帕金森病痴呆的治疗药物(卡巴拉汀)、路易体痴呆的治疗药物(多奈哌齐)、ALS的治疗药物(利鲁唑、神经营养因子等)、脂质异常的治疗药物(如降胆固醇药物)(他汀类药物系列(普伐他汀钠、阿托伐他汀、辛伐他汀、罗素伐他汀等)、贝特类(安妥明等)、角鲨烯合成酶抑制剂)、行为异常的治疗药物或由于痴呆引起的漫游癖的抑制药(镇静剂、抗焦虑药等)、凋亡抑制剂、抗肥胖症药物、糖尿病的治疗药物、高血压的治疗药物、低血压的治疗药物、风湿病的治疗药物(DMARD)、抗癌剂、甲状腺功能减退的治疗药物(PTH)、钙受体拮抗剂、性激素或其衍生物(孕酮、***、苯甲酸***等)、神经元分化促进剂、神经再生促进剂、非甾体类抗炎药(美洛昔康、替诺昔康、吲哚美辛、布洛芬、塞来昔布、罗非考昔、阿司匹林等)、类固醇(***、醋酸可的松等)、抗细胞因子药物(TNF抑制剂、MAP激酶抑制剂等)、抗体药物、核酸或核酸衍生物、适体药物、阿片类药物(例如,***、羟考酮、芬太尼、哌替啶、可待因、二氢可待因、曲马多、丁丙诺啡、喷他佐辛、依他佐辛、***、他喷他多、洛哌丁胺等)等。
通过将化合物(I)和伴随药物组合,可以实现优异的效果,如
(1)与化合物(I)或伴随药物的单一施用相比,可以减少剂量,
(2)可以根据患者的病情(轻症、重症等)选择待与化合物(I)组合的药物,
(3)可以通过选择与化合物(I)具有不同作用和机理的伴随药物来设定更长的治疗期,
(4)可以通过选择与化合物(I)具有不同作用和机理的伴随药物来设计持续的治疗效果,
(5)通过组合使用化合物(I)和伴随药物可以获得协同效应,等等。
以下,将用于组合的化合物(I)和伴随药物称为“本发明的组合药剂”。
当使用本发明的组合药剂时,化合物(I)和伴随药物的施用时间不受限制,并且化合物(I)或其药物组合物和伴随药物或其药物组合物可以同时施用至施用受试者,或者可以在不同的时间施用。伴随药物的剂量可以根据临床上使用的剂量来确定,并且可以取决于施用受试者、施用途径、疾病、组合等适当地选择。
本发明的组合药剂的施用方式没有特别限制,并且化合物(I)和伴随药物在施用时组合就足够了。施用方式的例子包括以下方法:
(1)施用通过同时加工化合物(I)和伴随药物获得的单一制剂,(2)通过相同的施用途径同时施用已分别产生的化合物(I)和伴随药物的两种制剂,(3)通过相同的施用途径以交错方式施用已分别产生的化合物(I)和伴随药物的两种制剂,(4)通过不同的施用途径同时施用已分别产生的化合物(I)和伴随药物的两种制剂,(5)通过不同的施用途径以交错方式(例如,按化合物(I)和伴随药物的顺序或按相反的顺序施用)施用已分别产生的化合物(I)和伴随药物的两种制剂等。
可以预期本发明的组合药剂显示出低毒性。例如,化合物(I)或(和)前述伴随药物可以根据已知方法与药理学上可接受的载体组合以制备药物组合物,如片剂(包括糖衣片和膜衣片)、粉末、颗粒、胶囊(包括软胶囊)、液体、注射剂、栓剂、缓释剂等。这些组合物可以安全地口服或非口服施用(例如,局部施用、直肠施用、静脉内施用等)。注射可以是静脉内、肌内、皮下施用或通过器官内施用或直接对病变进行施用。
作为用于产生本发明结合剂的药理学上可接受的载体,可以使用常规用作制备材料的各种有机或无机载体物质。对于固体制剂,例如,可以使用赋形剂、润滑剂、粘合剂和崩解剂。对于液体制剂,例如,可以使用溶剂、增溶剂、悬浮剂、等渗剂、缓冲剂、舒缓剂等。必要时,可适当使用适量的常规防腐剂、抗氧化剂、着色剂、甜味剂、吸附剂、润湿剂等。
所述赋形剂的例子包括乳糖、绵白糖、D-甘露醇、淀粉、玉米淀粉、结晶纤维素、轻质无水硅酸等。
所述润滑剂的例子包括硬脂酸镁、硬脂酸钙、滑石、胶体二氧化硅等。
所述粘合剂的例子包括结晶纤维素、绵白糖、D-甘露醇、糊精、羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮、淀粉、蔗糖、明胶、甲基纤维素、羧甲基纤维素钠等。
所述崩解剂的例子包括淀粉、羧甲基纤维素、羧甲基纤维素钙、羧甲基淀粉钠、L-羟丙基纤维素等。
所述溶剂的例子包括注射用水、醇、丙二醇、聚乙二醇、芝麻油、玉米油、橄榄油等。
所述增溶剂的例子包括聚乙二醇、丙二醇、D-甘露醇、苯甲酸苄酯、乙醇、三氨基甲烷、胆固醇、三乙醇胺、碳酸钠、柠檬酸钠等。
所述悬浮剂的例子包括表面活性剂,如硬脂酰三乙醇胺、月桂基硫酸钠、月桂基氨基丙酸、卵磷脂、苯扎氯铵、苄索氯铵、单硬脂酸甘油酯等;亲水性聚合物,如聚乙烯醇、聚乙烯吡咯烷酮、羧甲基纤维素钠、甲基纤维素、羟甲基纤维素、羟乙基纤维素、羟丙基纤维素等;等等。
所述等渗剂的例子包括葡萄糖、D-山梨醇、氯化钠、甘油、D-甘露醇等。
所述缓冲液的例子包括缓冲溶液,如磷酸盐、乙酸盐、碳酸盐、柠檬酸盐等。
所述舒缓剂的例子包括苯甲醇等。
所述防腐剂的例子包括对氧基苯甲酸酯、氯丁醇、苯甲醇、苯乙醇、脱氢乙酸、山梨酸等。
所述抗氧化剂的例子包括亚硫酸盐、抗坏血酸、α-生育酚等。
本发明的组合药剂中化合物(I)与伴随药物的混合比率可以根据施用受试者、施用途径、疾病等适当地选择。
例如,本发明的组合药剂中化合物(I)的含量取决于制剂的形式而不同,并且基于整个制剂,通常为约0.01wt%至100wt%、优选约0.1wt%至50wt%、进一步优选约0.5wt%至20wt%。
本发明的组合药剂中伴随药物的含量根据制剂的形式而不同,并且基于整个制剂,通常为约0.01wt%至100wt%、优选约0.1wt%至50wt%、进一步优选约0.5wt%至20wt%。
本发明的组合药剂中添加剂(如载体等)的含量根据制剂的形式而不同,并且基于整个制剂,通常为约1wt%至99.99wt%、优选约10wt%至90wt%。
当化合物(I)和伴随药物分别被配制成制剂时,其含量与上述相似。
实施例
下面通过参考实施例、实验实施例和配制品实施例对本发明进行详细解释,这些实施例、实验实施例和配制品实施例不应被解释为限制性的,并且本发明可以在本发明的范围内改变。
在以下实施例中,“室温”通常意指约10℃至约35℃。除非另有说明,否则针对混合溶剂指示的比率是体积混合比率。除非另有说明,否则%意指wt%。
除非特别指示,否则实施例中的柱色谱洗脱是在TLC(薄层色谱)的观察下进行的。在TLC观察中,将由Merck制造的60F254用作TLC板,并将在柱色谱中用作洗脱剂的溶剂用作洗脱溶剂。为了进行检测,采用了UV检测器。在硅胶柱色谱中,NH的指示意指使用氨基丙基硅烷键合的硅胶,并且二醇的指示意指使用3-(2,3-二羟基丙氧基)丙基硅烷键合的硅胶。在制备型HPLC(高效液相色谱)中,C18的指示意指使用十八烷基键合的硅胶。除非另有说明,否则洗脱溶剂的比率是体积混合比率。
为了分析1H NMR,使用ACD/SpecManager(商品名)软件等。可能没有描述羟基基团、氨基基团等质子的非常温和的峰。
通过LC/MS测量MS。作为电离方法,使用ESI方法或APCI方法。数据表明发现的那些。通常,观察到分子离子峰,但有时可能观察为碎片离子。在盐的情况下,通常观察到游离形式的分子离子峰或碎片离子峰。
通过旋光度([α]D)测定的样品浓度(c)的单位是g/100mL。
元素分析值(Anal.)显示计算值(Calcd)和测量值(Found)。
实施例中的粉末X射线衍射的峰意指在室温下使用Cu Kα射线作为辐射源和Ultima IV(Rigaku Corporation,日本)测得的峰。测量条件如下。
电压/电流:40kV/50mA
扫描速度:6度/分钟
2θ的扫描范围:2-35度
通过Hermans方法计算了实施例中依据粉末X射线衍射的结晶度。
在实施例中,使用以下缩写。
mp:熔点
MS:质谱
M:摩尔浓度
N:归一化
CDCl3:氘代氯仿
DMSO-d6:六氘代二甲基亚砜
1H NMR:质子核磁共振
LC/MS:液相色谱质谱仪
ESI:电喷雾电离
APCI:大气压化学电离
AIBN:2,2'-偶氮二(异丁腈)
DDQ:2,3-二氯-5,6-二氰基-1,4-苯醌
DIPEA:N,N-二异丙基乙胺
DME:1,2-二甲氧基乙烷
DMF:N,N-二甲基甲酰胺
DMSO:二甲基亚砜
HATU:O-(7-氮杂苯并***-1-基)-N,N,N',N'-四甲基脲六氟磷酸酯
MeOH:甲醇
NBS:N-溴代琥珀酰亚胺
PdCl2(dppf):[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)
THF:四氢呋喃
实施例1
1,5-脱水-2,3-二脱氧-3-[6-({3-氟-4-[(2-甲氧基乙基)氨基甲酰基]苯基}甲基)-4-氧代-8,9-二氢-2H-呋喃并[2,3-h][1,3]苯并噁嗪-3(4H)-基]-L-苏-戊糖醇
(同义词)2-氟-4-((3-((3R,4S)-3-羟基四氢-2H-吡喃-4-基)-4-氧代-3,4,8,9-四氢-2H-苯并呋喃并[5,4-e][1,3]噁嗪-6-基)甲基)-N-(2-甲氧基乙基)苯甲酰胺
A)4-(溴甲基)-2-氟苯甲酸
在室温下,向2-氟-4-甲基苯甲酸(50g)、AIBN(5.33g)和三氟甲苯(500mL)的混合物中添加NBS(63.5g),并且将混合物在79℃-87℃的内部温度下搅拌1h。在冷却至室温后,通过过滤收集沉淀的晶体,并将其用三氟甲苯(750mL)洗涤。将获得的粗产物和水(500mL)的混合物在室温下搅拌过夜。通过过滤收集沉淀的晶体,以得到标题化合物(46.2g)。
1H NMR(300MHz,DMSO-d6)δ4.73(2H,s),7.35-7.45(2H,m),7.86(1H,t,J=7.9Hz),13.31(1H,brs)。
B)4-(溴甲基)-2-氟-N-(2-甲氧基乙基)苯甲酰胺
将4-(溴甲基)-2-氟苯甲酸(51.2g)和亚硫酰氯(200mL)的混合物回流30min。在减压下浓缩混合物,并且在减压下使用甲苯将残余物共沸浓缩3次。将获得的油溶解在THF(250mL)中,并且将其在1h内于0℃下滴加到2-甲氧基乙胺(16.50g)在THF(500mL)中的溶液中。将混合物在0℃下搅拌2h,在0℃下添加水(800mL),并且将混合物用乙酸乙酯(800mL)萃取两次。分离有机层,将其用饱和碳酸氢钠水溶液、1M盐酸和饱和盐水洗涤,经无水硫酸钠干燥,并在减压下浓缩。将残余物通过硅胶柱色谱(乙酸乙酯/己烷)纯化,并且从乙酸乙酯/己烷结晶所获得的油(56g),以得到标题化合物(41.4g)。
1H NMR(300MHz,DMSO-d6)δ3.27(3H,s),3.37-3.47(4H,m),4.72(2H,s),7.32-7.41(2H,m),7.58(1H,t,J=7.6Hz),8.34(1H,brs)。
C)4-氧代-4,5,6,7-四氢-1-苯并呋喃-5-甲酸甲酯
在0℃下,向60%氢化钠(7.35g)和DME(200mL)的混合物中添加6,7-二氢-1-苯并呋喃-4(5H)-酮(10.0g)。将反应混合物在0℃下搅拌30min,添加碳酸二甲酯(9.93g),并且将混合物在85℃下搅拌8h。向混合物中添加饱和氯化铵水溶液,并且用乙酸乙酯萃取混合物。分离有机层,将其用水和饱和盐水洗涤,经无水硫酸钠干燥,并且在减压下浓缩,以得到标题化合物(6.5g)。不进行进一步纯化,并将所述化合物用于下一步。
MS:[M+H]+195.02。
D)4-羟基-1-苯并呋喃-5-甲酸甲酯
在室温下,向4-氧代-4,5,6,7-四氢-1-苯并呋喃-5-甲酸甲酯(13.0g)和1,4-二氧六环(130mL)的混合物中添加DDQ(16.73g),并且将混合物在100℃下搅拌6h。将混合物用乙酸乙酯稀释,通过硅藻土过滤掉不溶性物质,并且在减压下浓缩滤液。将获得的残余物在乙酸乙酯-水之间分配,并将有机层用亚硫酸钠水溶液、水和饱和盐水洗涤,经无水硫酸钠干燥,并在减压下浓缩。将残余物通过硅胶柱色谱(乙酸乙酯/石油醚)纯化,以得到标题化合物(9.5g)。
1H NMR(400MHz,CDCl3)δ3.97(3H,s),6.98(1H,dd,J=2.0,0.8Hz),7.04(1H,dd,J=9.2,0.8Hz),7.56(1H,d,J=2.4Hz),7.78(1H,d,J=8.8Hz),11.47(1H,s)。
E)4-羟基-2,3-二氢-1-苯并呋喃-5-甲酸甲酯
将4-羟基-1-苯并呋喃-5-甲酸甲酯(9.5g)、钯-碳(1.5g)和MeOH(150mL)的混合物在50psi氢气气氛下于室温下搅拌24h。将混合物用MeOH稀释,过滤掉催化剂,并且在减压下浓缩滤液。将残余物通过硅胶柱色谱(乙酸乙酯/石油醚)纯化,以得到标题化合物(8.0g)。
MS:[M+H]+195.1。
F)7-溴-4-羟基-2,3-二氢-1-苯并呋喃-5-甲酸甲酯
在0℃下,向4-羟基-2,3-二氢-1-苯并呋喃-5-甲酸甲酯(10g)和乙腈(120mL)的混合物中添加NBS(3.52g),并且将混合物在室温下搅拌过夜。将混合物用乙酸乙酯稀释,用水洗涤,经无水硫酸钠干燥,并且在减压下浓缩。将残余物通过硅胶柱色谱(乙酸乙酯/己烷)纯化,以得到标题化合物(8.17g)。
1H NMR(400MHz,DMSO-d6)δ3.24(2H,t,J=8.8Hz),3.87(3H,s),4.76(2H,t,J=9.0Hz),7.76(1H,s),10.70(1H,brs)。
G)7-溴-4-羟基-2,3-二氢-1-苯并呋喃-5-甲酸
向7-溴-4-羟基-2,3-二氢-1-苯并呋喃-5-甲酸甲酯(2.0g)和混合溶剂(MeOH/THF/H2O=2:2:1,40mL)的混合物中添加氢氧化钠(880mg),并且将混合物在50℃下搅拌12h。在冷却至室温后,将混合物用水(200mL)稀释,并用10%柠檬酸水溶液中和。通过过滤收集沉淀,将其用水洗涤两次,并在减压下干燥,以得到标题化合物(1.76g)。
1H NMR(400MHz,DMSO-d6):δ3.23(2H,t,J=9.6Hz),4.76(2H,t,J=9.2Hz),7.74(1H,s),11.52(1H,brs),13.85(1H,brs)。
H)1,5-脱水-3-[(7-溴-4-羟基-2,3-二氢-1-苯并呋喃-5-羰基)氨基]-2,3-二脱氧-L-苏-戊糖醇
在0℃下,向7-溴-4-羟基-2,3-二氢-1-苯并呋喃-5-甲酸(2.46g)和DMF(40mL)的混合物中添加HATU(4.15g)和DIPEA(4.98mL),并且将混合物在室温下搅拌30min。向混合物中添加(3R,4S)-4-氨基四氢-2H-吡喃-3-醇盐酸盐(1.459g),并且将混合物在室温下搅拌3天。在室温下将反应混合物倒入水中,并将其用乙酸乙酯萃取两次。将有机层分离,用饱和盐水洗涤,经无水硫酸钠干燥,并且在减压下浓缩。将残余物通过硅胶柱色谱(乙酸乙酯/己烷)纯化,以得到标题化合物(2.0g)。
MS,测量值:358.0、360.1。
I)1,5-脱水-3-(6-溴-4-氧代-8,9-二氢-2H-呋喃并[2,3-h][1,3]苯并噁嗪-3(4H)-基)-2,3-二脱氧-L-苏-戊糖醇
将1,5-脱水-3-[(7-溴-4-羟基-2,3-二氢-1-苯并呋喃-5-羰基)氨基]-2,3-二脱氧-L-苏-戊糖醇(2g)、对甲醛(503mg)、对甲苯磺酸一水合物(212mg)和甲苯(25mL)的混合物在60℃下搅拌15h。在0℃下用饱和碳酸氢钠水溶液中和混合物,并用乙酸乙酯和THF的混合溶剂萃取3次。过滤掉不溶性物质,并将有机层分离,用水和饱和盐水洗涤,经无水硫酸镁干燥,并且在减压下浓缩,以得到标题化合物(1.9g)。不进行进一步纯化,并将所述化合物用于下一步。
MS,测量值:370.1、372.1。
J)1,5-脱水-3-(6-溴-4-氧代-8,9-二氢-2H-呋喃并[2,3-h][1,3]苯并噁嗪-3(4H)-基)-2-O-[叔丁基(二甲基)甲硅烷基]-3,4-二脱氧-L-苏-戊糖醇
在0℃下,向1,5-脱水-3-(6-溴-4-氧代-8,9-二氢-2H-呋喃并[2,3-h][1,3]苯并噁嗪-3(4H)-基)-2,3-二脱氧-L-苏-戊糖醇(1.90g)、1H-咪唑(769mg)和DMF(50mL)的混合物中添加叔丁基二甲基氯硅烷(1.16g)。将混合物在室温下搅拌过夜,添加水,并且将混合物用乙酸乙酯萃取。将有机层分离,用水和饱和盐水洗涤,经无水硫酸镁干燥,并且在减压下浓缩。将残余物通过硅胶柱色谱(乙酸乙酯/己烷)纯化,以得到标题化合物(2.256g)。
MS,测量值:484.1、486.1。
K)1,5-脱水-2-O-[叔丁基(二甲基)甲硅烷基]-3,4-二脱氧-3-[4-氧代-6-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-8,9-二氢-2H-呋喃并[2,3-h][1,3]苯并噁嗪-3(4H)-基]-L-苏-戊糖醇
向1,5-脱水-3-(6-溴-4-氧代-8,9-二氢-2H-呋喃并[2,3-h][1,3]苯并噁嗪-3(4H)-基)-2-O-[叔丁基(二甲基)甲硅烷基]-3,4-二脱氧-L-苏-戊糖醇(2.25g)、联硼酸频那醇酯(2.359g)、乙酸钾(1.367g)和甲苯(50mL)的混合物中添加PdCl2(dppf)(340mg),并且将混合物在氮气气氛下于85℃下搅拌过夜。将混合物在减压下浓缩并且将残余物通过硅胶柱色谱(乙酸乙酯/己烷)纯化,以得到标题化合物(1.62g)。
MS:[M+H]+523.3。
L)1,5-脱水-2-O-[叔丁基(二甲基)甲硅烷基]-3,4-二脱氧-3-[6-({3-氟-4-[(2-甲氧基乙基)氨基甲酰基]苯基}甲基)-4-氧代-8,9-二氢-2h-呋喃并[2,3-h][1,3]苯并噁嗪-3(4H)-基]-L-苏-戊糖醇
在室温下,向1,5-脱水-2-O-[叔丁基(二甲基)甲硅烷基]-3,4-二脱氧-3-[4-氧代-6-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-8,9-二氢-2H-呋喃并[2,3-h][1,3]苯并噁嗪-3(4H)-基]-L-苏-戊糖醇(1.62g)、4-(溴甲基)-2-氟-N-(2-甲氧基乙基)苯甲酰胺(1.061g)、2M碳酸钠水溶液(4.57mL)和DME(20mL)的混合物中添加PdCl2(dppf)(223mg),并且使混合物在85℃下经受微波辐照1h。在室温下向混合物中添加水,并用乙酸乙酯萃取混合物。将有机层分离,用水和饱和盐水洗涤,经无水硫酸镁干燥,并且在减压下浓缩。将残余物通过硅胶柱色谱(NH,乙酸乙酯/己烷)和硅胶柱色谱(乙酸乙酯/己烷)纯化,以得到标题化合物(950mg)。
MS:[M+H]+615.3。
M)1,5-脱水-2,3-二脱氧-3-[6-({3-氟-4-[(2-甲氧基乙基)氨基甲酰基]苯基}甲基)-4-氧代-8,9-二氢-2H-呋喃并[2,3-h][1,3]苯并噁嗪-3(4H)-基]-L-苏-戊糖醇
(同义词)2-氟-4-((3-((3R,4S)-3-羟基四氢-2H-吡喃-4-基)-4-氧代-3,4,8,9-四氢-2H-苯并呋喃并[5,4-e][1,3]噁嗪-6-基)甲基)-N-(2-甲氧基乙基)苯甲酰胺
向1,5-脱水-2-O-[叔丁基(二甲基)甲硅烷基]-3,4-二脱氧-3-[6-({3-氟-4-[(2-甲氧基乙基)氨基甲酰基]苯基}甲基)-4-氧代-8,9-二氢-2H-呋喃并[2,3-h][1,3]苯并噁嗪-3(4H)-基]-L-苏-戊糖醇(950mg)和THF(15mL)的混合物中添加1M四正丁基氟化铵THF溶液(1.854mL),并且将混合物在室温下搅拌2h。向混合物中添加饱和盐水和水,并用乙酸乙酯萃取混合物。将有机层分离,用水和饱和盐水洗涤,经无水硫酸镁干燥,并且在减压下浓缩。从乙醇/庚烷结晶所获得的固体,以得到标题化合物(571mg)。
1H NMR(400MHz,DMSO-d6):δ1.63(1H,brs),1.89(1H,qd,J=12.5,4.5Hz),3.00(1H,t,J=10.4Hz),3.14(2H,t,J=8.8Hz),3.26(3H,s),3.30-3.46(5H,m),3.65(1H,d,J=5.4Hz),3.84(2H,dt,J=10.8,5.4Hz),3.89(2H,s),4.09(1H,brs),4.68(2H,t,J=8.9Hz),5.03(1H,d,J=5.6Hz),5.24(1H,d,J=8.8Hz),5.33(1H,d,J=8.8Hz),7.05-7.15(2H,m),7.48-7.54(2H,m),8.12-8.23(1H,m,J=2.9Hz)。
MS:[M+H]+501.3(测量值)。
实施例的化合物如下表所示。下表中的实施例2至4的化合物可以通过与实施例1类似的方法或其相似方法产生。
[表1]
配制品实施例1
/>
使在实施例1中获得的化合物(10.0g)、乳糖(60.0g)和玉米淀粉(35.0g)的混合物通过1mm网筛,并通过使用10wt%明胶水溶液(30mL)(明胶为3.0g)造粒,并且将颗粒在40℃下干燥并再次过筛。将获得的颗粒与硬脂酸镁(2.0g)混合,并将混合物压缩。将获得的核心片剂用蔗糖、二氧化钛、滑石和***树胶的水性悬浮液的糖衣进行包衣。将包衣的片剂用蜂蜡上釉,以得到1000个包衣的片剂。
配制品实施例2
使用水溶性淀粉溶液(70mL)(可溶性淀粉为7.0g)对在实施例1中获得的化合物(10.0g)和硬脂酸镁(3.0g)进行造粒,将其干燥并与乳糖(70.0g)和玉米淀粉(50.0g)混合。将混合物压缩以得到1000个片剂。
实验实施例1
M1受体正向变构调节剂(M1PAM)活性的测量
在存在乙酰胆碱的情况下提供最大活性作用的约20%的EC20浓度下的测试化合物的活性被测量为PAM活性。其方法如下。向384孔白板(Greiner)中添加4μL的如下测试化合物,所述测试化合物经包含含有80nM乙酰胆碱的0.1%不含脂肪酸的BSA的IP1刺激缓冲液(CisBio)稀释。用含有0.1%不含脂肪酸的BSA的IP1刺激缓冲液(CisBio)制备稳定表达人M1受体(hCHRM1)的CHO-K1细胞的冷冻储备溶液,添加4μL(10,000个细胞/孔)的所述冷冻储备溶液,并将混合物在5%CO2培养箱中于37℃下培养1h。添加4μL含有IP1-d2和抗IP1-穴状化合物Tb缀合物的溶液(CisBio),将混合物在室温下孵育1h,并在Envision板读取器(PerkinElmer)上测量时间分辨的荧光信号。通过将乙酰胆碱以20μM的最终浓度添加时的值定义为100%且在无乙酰胆碱条件下添加DMSO代替测试化合物时的值定义为0%来计算测试化合物的活性(%),并且将EC50值计算为测试化合物的浓度依赖性曲线的50%的值。结果显示于表2中。
[表2]
实施例编号 | EC50值(nM) |
1 | 0.31 |
实验实施例2
大鼠排便实验
在约1周的驯化期后,使用雄性SD大鼠(5-6周龄)。将测试药物(1mg/kg或3mg/kg)悬浮于0.5%甲基纤维素溶液中,并以5mL/kg的体积口服施用,并且在2h后计算粪便的数量。仅向溶剂施用组施用0.5%甲基纤维素。
结果显示于表3中。结果显示平均值±标准误差。
[表3]
实验实施例3
大鼠PK测试
作为大鼠,使用了8周龄的雄性SD大鼠(Japan SLC,Inc.)。向它们喂食可商购的固体饮食(CE-2,CLEA Japan,Inc.),并允许自由摄取作为饮用水的自来水。通过以下方法制备用于大鼠的静脉内施用溶液:将测试化合物称重,将其溶解在二甲基乙酰胺(DMA)(WakoPure Chemical Industries,Ltd.)中,添加相同体积的1,3-丁二醇(Wako Pure ChemicalIndustries,Ltd.),并通过搅拌混合以得到DMA:1,3-丁二醇(1:1,v/v)溶液。通过以下方法制备口服施用溶液:将测试化合物称重,将其在玛瑙研钵中研磨,并逐渐添加0.5w/v%甲基纤维素水溶液,以得到悬浮液。对于静脉内施用,将溶液以0.1mg/0.5mL/kg(盐转化为游离形式)施用至大鼠的股静脉中。对于口服施用,将悬浮液以1mg/5mL/kg(盐转化为游离形式)施用至大鼠。将盒式给药方法用于这两种施用途径,并且按以下方式施用测试化合物。
实施例1的化合物(静脉内:10个化合物盒式施用,口服:5个化合物盒式施用)
在静脉内施用的情况下,在施用后5min、10min、15min、30min、1h、2h、4h、8h从尾静脉采集血样,用肝素钠(Shimizu Pharmaceutical Co.,Ltd.)进行抗凝处理,并且在离心后收集血浆并进行药物浓度的测量。在口服施用的情况下,在施用后15min、30min、1h、2h、4h、8h从尾静脉采集血样,用肝素钠进行抗凝处理,并且在离心后收集血浆并进行药物浓度的测量。
通过LC-MS/MS分析测量所有药物浓度。对于药代动力学测试,将血浆(50μL)置于试管中,添加含乙腈(150μL)的内标溶液,并使它们在涡旋混合器上混合。此后,将混合物离心(5000rpm,5min,4℃)。将离心后的上清液(60μL)添加至更早添加的10mmol/L甲酸铵(160μL)中,并与之混合。将此样品注入LC/MS。使用的HPLC***是Shimadzu LC-20A(ShimadzuCorporation),使用的柱是在50℃下的Unison UK-C18 HT(3.0μm,2.0×20mm,Imtakt),并且10mmol/L甲酸铵、0.2%甲酸作为流动相A以及乙腈、0.2%甲酸作为流动相B在(B浓度:0min→0.1min,5%,0.1→0.75min,5%-99%,0.75→1.15min,99%,1.15→1.16min,5%,1.16→1.5min,5%)的梯度条件下以1.2mL/min的流速各自进料。使用的MS/MS是AB SciexTQ5500-MPX(Applied Biosystems)。
结果显示于表4中。
Tmax:达到最大血浆浓度的时间
MRT:平均停留时间
iv:静脉内施用
CL总计:总清除率
[表4]
实验实施例4
MDR1膜渗透性测试
当MDR1在作为极性细胞的LLC-PK1细胞中过量表达时,MDR1位于顶端膜(A),由此促进从基底膜侧(B)向方向A的跨细胞运输。当取与反方向的跨细胞运输的比率,并进一步取与已引入模拟载体的对照细胞的比率时,计算MDR1与简单扩散的流出比率(校正的流出比率)。类似地,当将Mdr1(-/-)小鼠的脑/血浆浓度比除以野生型小鼠的脑/血浆浓度比时,计算出Mdr1与血脑屏障(BBB)中简单扩散的流出比率(Kp,脑比率,较高的值意味着较低的中枢神经***渗透性)。Adachi Y.等人(参考文献1)已报道了校正的流出比率与Kp,脑比率(图5(C)),以及MDR1表达细胞中的流出比率与Kp,脑比率(图5(B))之间的正相关。也就是说,所述报告表明,MDR1在体外较高的流出比率导致较低的中枢神经***渗透性。
为了证实本发明化合物的中枢神经***渗透性,通过以下方法进行MDR1膜渗透性测试。
地高辛和荧光黄(LY)购自Sigma-Aldrich,双氯芬酸、秋水仙碱和阿普洛尔购自Wako Pure Chemical Industries,Ltd.,并且使用的其他试剂是特殊等级的可商购产品。
根据Takeuchi等人(参考文献2)的报道培养表达人MDR1的LLC-PK1细胞。将表达人MDR1的LLC-PK1细胞在10%胎牛血清(Invitrogen)、500μg/ml G418(Invitrogen)、150ng/ml含秋水仙碱的M199培养基(Invitrogen)中在5%CO2条件下于37℃下培养。
根据Sugimoto等人(参考文献3)的报道进行了跨细胞运输。将细胞在HTSTranswell(注册商标)96孔渗透性支持物(孔径0.4μm,0.143cm2表面积,Corning LifeSciences)上培养3天,所述支持物具有聚对苯二甲酸乙二醇酯膜,细胞以3.45×104个细胞/孔已接种在膜上。在M199培养基(10mmol/LHEPES,1%BSA,pH 7.4)中预孵育30min后,将溶解在M199培养基中的药物溶液(10μmol/L地高辛、200μmol/L LY、10μmol/L测试化合物)分别以75或250μL添加至Transwell的顶侧或基底外侧,并且将细胞在5%CO2条件下于37℃下培养。在1h后,从与添加药物溶液的一侧相对的一侧收集样品,并通过LC-MS/MS测量测试化合物的浓度。作为内标物质,使用100ng/mL的阿普洛尔和双氯芬酸。分析条件如下。
LC:UFLC LC-20(Shimadzu)
MS/MS:API4000(AB Sciex仪器)
LC条件:梯度法
[表5]
时间(min) | 泵B(%) |
0.02 | 5 |
0.40 | 95 |
0.80 | 95 |
0.81 | 5 |
1.50 | 停止 |
柱:Unison UK-C18 HT(3.0μm,2.0×20mm)
柱温:50℃
流速:0.7mL/min(对于1.5min运行)、1.0mL/min(对于1.0min运行)
流动相A:50mM CH3COONH4:MeCN:水=1:1:8
流动相B:50mM CH3COONH4:MeCN=1:9
注射体积:1-20μL
通过荧光板读取器(Fluoroskan Ascent FL)测量LY。
由式(1)计算Papp(A至B)和Papp(B至A)(表观渗透性),并且由式(2)计算流出比率(ER)。
量:运输的地高辛量/孔
面积:细胞单层的表面积(0.143cm2)
C0:添加的药物溶液的浓度
时间:孵育时间
结果显示于表6中。
[表6]
实施例编号 | 流出比率(ER) |
1 | 15 |
实验实施例5
犬的胃肠运动性实验
在手术后15天的驯化期后,使用雄性比格犬,每只均配备有四个压力传感器(回肠中一个且大肠中三个)。将实施例1的化合物(0.03mg/kg)悬浮于0.5%甲基纤维素溶液中,并以10mL/kg的体积口服施用。仅向溶剂施用组施用0.5%甲基纤维素。
使用胃肠运动性遥测仪(GTS-850,STARMEDICAL)计算施用后8h的HAPC(高幅传播性收缩的缩写,其意指排便时从大肠的口腔侧传播至***侧的强烈收缩。在正常排便期间观察到的肠收缩模式。)。
作为结果,与溶剂施用组相比,在施用实施例1的化合物的组中观察到肠道中HAPC的数量增加。
参考文献
1.Adachi Y.et al.,Comparative studies on in vitro methods forevaluating in vivo function of MDR1 P-glycoprotein,Pharm.Res.18:1660-1668,2001
2.Takeuchi T.,Yoshitomi S.,Higuchi T.,Ikemoto K.,Niwa S.,Ebihara T.,Katoh M.,Yokoi T.and Asahi S.,Establishment and characterization of thetransformants stably-expressing MDR1 derived from various animal species inLLC-PK1,Pharm.Res.,23(7):1460-1472,2006
3.Sugimoto H.,Hirabayashi H.,Kimura Y.,Furuta A.,Amano N.and MoriwakiT.,Quantitative investigation of the impact of P-glycoprotein inhibition ondrug transport across blood-brain barrier in rats,Drug Metab.Dispos.,39(1):8-14,2011
工业实用性
本发明的化合物可以具有胆碱能毒蕈碱M1受体正向变构调节剂活性,并且可以用作药物,如用于预防或治疗便秘等的药剂。
本申请基于在日本提交的专利申请号2018-184966,将其全部内容通过引用并入本文。
Claims (15)
1.一种由式(I)表示的化合物:
其中
X是O;
Y是CR5;
R1和R2各自是氢原子;
R3是氢原子;
R4是C1-6烷基基团,其任选地被C1-6烷氧基基团或3至8元单环非芳族杂环基团取代,所述非芳族杂环基团含有选自硫原子和氧原子的一个杂原子作为除碳原子之外的环构成原子;
R5是卤素原子;
环A是被1-3个羟基基团取代的3至8元单环非芳族杂环基团,其含有选自硫原子和氧原子的一个杂原子作为除碳原子之外的环构成原子,或其盐。
2.根据权利要求1所述的化合物,其中
X是O;
Y是CR5;
R1和R2各自是氢原子;
R3是氢原子;
R4是C1-6烷基基团,其任选地被C1-6烷氧基基团取代;
R5是卤素原子;并且
环A是被1-3个羟基基团取代的3至8元单环非芳族杂环基团,其含有选自硫原子和氧原子的一个杂原子作为除碳原子之外的环构成原子,或其盐。
3.根据权利要求1所述的化合物,其中
X是O;
Y是CR5;
R1和R2各自是氢原子;
R3是氢原子;
R4是C1-6烷基基团,其任选地被3至8元单环非芳族杂环基团取代,所述非芳族杂环基团含有选自硫原子和氧原子的一个杂原子作为除碳原子之外的环构成原子;
R5是卤素原子;并且
环A是被1-3个羟基基团取代的3至8元单环非芳族杂环基团,其含有选自硫原子和氧原子的一个杂原子作为除碳原子之外的环构成原子,或其盐。
4.根据权利要求1所述的化合物,其中
X是O;
Y是CR5;
R1和R2各自是氢原子;
R3是氢原子;
R4是任选地被C1-6烷氧基基团取代的C1-6烷基基团;
R5是卤素原子;并且
环A是被1-3个羟基基团取代的3至8元单环非芳族杂环基团,其含有氧原子作为除碳原子之外的环构成原子,
或其盐。
5.根据权利要求1所述的化合物,其中
环A是
或其盐。
6.根据权利要求1所述的化合物,其中
R3是氢原子;并且
R4是C1-6烷基基团,其任选地被C1-6烷氧基基团或四氢呋喃基取代,或其盐。
7.2-氟-4-((3-((3R,4S)-3-羟基四氢-2H-吡喃-4-基)-4-氧代-3,4,8,9-四氢-2H-苯并呋喃并[5,4-e][1,3]噁嗪-6-基)甲基)-N-(2-甲氧基乙基)苯甲酰胺,或其盐。
8.2-氟-4-((3-((3R,4S)-3-羟基四氢-2H-吡喃-4-基)-4-氧代-3,4,8,9-四氢-2H-苯并呋喃并[5,4-e][1,3]噁嗪-6-基)甲基)-N-甲基苯甲酰胺,或其盐。
9.2-氟-4-((3-((3R,4S)-3-羟基四氢-2H-吡喃-4-基)-4-氧代-3,4,8,9-四氢-2H-苯并呋喃并[5,4-e][1,3]噁嗪-6-基)甲基)-N-(((S)-四氢呋喃-2-基)甲基)苯甲酰胺,或其盐。
10.2-氟-4-((3-((3R,4S)-3-羟基四氢-2H-吡喃-4-基)-4-氧代-3,4,8,9-四氢-2H-苯并呋喃并[5,4-e][1,3]噁嗪-6-基)甲基)-N-(((R)-四氢呋喃-2-基)甲基)苯甲酰胺,或其盐。
11.一种药物,其包含根据权利要求1所述的化合物或其盐。
12.根据权利要求11所述的药物,其是胆碱能毒蕈碱M1受体正向变构调节剂。
13.根据权利要求11所述的药物,其是用于便秘的预防或治疗剂。
14.根据权利要求1-10中任一项所述的化合物或其盐在制备用于胆碱能毒蕈碱M1受体正向变构调节的药物中的用途。
15.根据权利要求1-10中任一项所述的化合物或其盐在产生用于便秘的预防或治疗剂方面的用途。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2018184966 | 2018-09-28 | ||
JP2018-184966 | 2018-09-28 | ||
PCT/JP2019/038228 WO2020067455A1 (ja) | 2018-09-28 | 2019-09-27 | 複素環化合物 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN112752760A CN112752760A (zh) | 2021-05-04 |
CN112752760B true CN112752760B (zh) | 2024-01-19 |
Family
ID=69953171
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201980063261.9A Active CN112752760B (zh) | 2018-09-28 | 2019-09-27 | 杂环化合物 |
Country Status (10)
Country | Link |
---|---|
US (1) | US20210347786A1 (zh) |
EP (1) | EP3858838A4 (zh) |
JP (1) | JP7416537B2 (zh) |
KR (1) | KR20210068025A (zh) |
CN (1) | CN112752760B (zh) |
AU (1) | AU2019351469A1 (zh) |
BR (1) | BR112021005759A2 (zh) |
CA (1) | CA3113227A1 (zh) |
MX (1) | MX2021003481A (zh) |
WO (1) | WO2020067455A1 (zh) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017069173A1 (ja) * | 2015-10-20 | 2017-04-27 | 武田薬品工業株式会社 | 複素環化合物 |
WO2017155816A1 (en) * | 2016-03-09 | 2017-09-14 | Merck Sharp & Dohme Corp. | Quinazoline compounds useful as m1 receptor positive allosteric modulators |
WO2018005249A1 (en) * | 2016-06-28 | 2018-01-04 | Merck Sharp & Dohme Corp. | Benzoisoquinolinone m1 receptor positive allosteric modulators |
WO2018042362A1 (en) * | 2016-09-02 | 2018-03-08 | Suven Life Sciences Limited | Muscarinic m1 receptor positive allosteric modulators |
CN107922403A (zh) * | 2015-06-26 | 2018-04-17 | 武田药品工业株式会社 | 作为胆碱能毒蕈碱m1受体的调节剂的2,3‑二氢‑4h‑1,3‑苯并噁嗪‑4‑酮衍生物 |
Family Cites Families (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2992677B2 (ja) | 1995-06-05 | 1999-12-20 | 武田薬品工業株式会社 | 骨形成促進医薬組成物 |
MY162502A (en) | 2008-11-20 | 2017-06-15 | Merck Sharp & Dohme | Aryl methyl benzoquinazolinone m1 receptor positive allosteric modulators |
JP2012518640A (ja) | 2009-02-23 | 2012-08-16 | メルク・シャープ・エンド・ドーム・コーポレイション | ピラゾロ[4,3−c]シンノリン−3−オンM1受容体陽性アロステリックモジュレーター |
US8293744B2 (en) | 2009-04-20 | 2012-10-23 | Merck Sharp & Dohme Corp. | Heterocyclic fused cinnoline M1 receptor positive allosteric modulators |
HUE026296T2 (en) | 2009-08-31 | 2016-06-28 | Merck Sharp & Dohme | Positive allosteric pyranyl arylmethyl benzoquinazolinone M1 receptor modulators |
US8895580B2 (en) | 2009-10-21 | 2014-11-25 | Merck Sharp & Dohme Corp. | Quinolinone-pyrazolone M1 receptor positive allosteric modulators |
EP2512245B1 (en) | 2009-12-14 | 2014-07-23 | Merck Sharp & Dohme Corp. | Pyridoquinazolinone m1 receptor positive allosteric modulators |
WO2011084371A1 (en) | 2009-12-21 | 2011-07-14 | Merck Sharp & Dohme Corp. | Aminobenzoquinazolinone m1 receptor positive allosteric modulators |
EP2582241B1 (en) | 2010-06-15 | 2016-04-06 | Merck Sharp & Dohme Corp. | Heterocyclic fused phenanthrolinone m1 receptor positive allosteric modulators |
WO2012003147A1 (en) | 2010-07-01 | 2012-01-05 | Merck Sharp & Dohme Corp. | Isoindolone m1 receptor positive allosteric modulators |
US8664234B2 (en) | 2010-10-04 | 2014-03-04 | Merck Sharp & Dohme Corp. | Dihydrobenzoquinazolinone M1 receptor positive allosteric modulators |
US9403802B2 (en) | 2012-03-02 | 2016-08-02 | Takeda Pharmaceutical Company Limited | Heterocyclic compound and use therefor |
WO2014077401A1 (ja) | 2012-11-19 | 2014-05-22 | 武田薬品工業株式会社 | 含窒素複素環化合物 |
AU2015250610B2 (en) | 2014-04-23 | 2019-02-07 | Takeda Pharmaceutical Company Limited | Isoindoline-1-one derivatives as cholinergic muscarinic M1 receptor positive alloesteric modulator activity for the treatment of Alzheimers disease |
US10208046B2 (en) | 2014-05-16 | 2019-02-19 | Takeda Pharmaceutical Company Limited | Nitrogen-containing heterocyclic compound |
US10214508B2 (en) | 2014-06-13 | 2019-02-26 | Takeda Pharmaceutical Company Limited | Nitrogen-containing heterocyclic compound |
EP3428150B1 (en) | 2016-03-11 | 2023-07-12 | Takeda Pharmaceutical Company Limited | Aromatic ring compound having a cholinergic muscarine m1 receptor positive allosteric modulator activity |
JP6889019B2 (ja) | 2017-04-24 | 2021-06-18 | ダイダン株式会社 | 二重配管用スペーサーおよび二重配管組立方法 |
-
2019
- 2019-09-27 WO PCT/JP2019/038228 patent/WO2020067455A1/ja unknown
- 2019-09-27 EP EP19866638.0A patent/EP3858838A4/en active Pending
- 2019-09-27 KR KR1020217008979A patent/KR20210068025A/ko unknown
- 2019-09-27 US US17/280,634 patent/US20210347786A1/en active Pending
- 2019-09-27 JP JP2020549452A patent/JP7416537B2/ja active Active
- 2019-09-27 CA CA3113227A patent/CA3113227A1/en active Pending
- 2019-09-27 AU AU2019351469A patent/AU2019351469A1/en active Pending
- 2019-09-27 MX MX2021003481A patent/MX2021003481A/es unknown
- 2019-09-27 BR BR112021005759A patent/BR112021005759A2/pt unknown
- 2019-09-27 CN CN201980063261.9A patent/CN112752760B/zh active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107922403A (zh) * | 2015-06-26 | 2018-04-17 | 武田药品工业株式会社 | 作为胆碱能毒蕈碱m1受体的调节剂的2,3‑二氢‑4h‑1,3‑苯并噁嗪‑4‑酮衍生物 |
WO2017069173A1 (ja) * | 2015-10-20 | 2017-04-27 | 武田薬品工業株式会社 | 複素環化合物 |
WO2017155816A1 (en) * | 2016-03-09 | 2017-09-14 | Merck Sharp & Dohme Corp. | Quinazoline compounds useful as m1 receptor positive allosteric modulators |
WO2018005249A1 (en) * | 2016-06-28 | 2018-01-04 | Merck Sharp & Dohme Corp. | Benzoisoquinolinone m1 receptor positive allosteric modulators |
WO2018042362A1 (en) * | 2016-09-02 | 2018-03-08 | Suven Life Sciences Limited | Muscarinic m1 receptor positive allosteric modulators |
Also Published As
Publication number | Publication date |
---|---|
JP7416537B2 (ja) | 2024-01-17 |
EP3858838A4 (en) | 2022-06-29 |
CA3113227A1 (en) | 2020-04-02 |
MX2021003481A (es) | 2021-06-18 |
JPWO2020067455A1 (ja) | 2021-08-30 |
CN112752760A (zh) | 2021-05-04 |
US20210347786A1 (en) | 2021-11-11 |
KR20210068025A (ko) | 2021-06-08 |
AU2019351469A1 (en) | 2021-04-15 |
BR112021005759A2 (pt) | 2021-07-06 |
EP3858838A1 (en) | 2021-08-04 |
WO2020067455A1 (ja) | 2020-04-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2020158762A1 (ja) | 複素環化合物 | |
JP7145875B2 (ja) | アセチルコリン受容体のモジュレーターとして有用な複素環化合物 | |
US20220017530A1 (en) | Heterocyclic compound | |
JP7250686B2 (ja) | 複素環化合物 | |
JP7250687B2 (ja) | 複素環化合物 | |
KR102658949B1 (ko) | 헤테로시클릭 화합물 | |
CN112752760B (zh) | 杂环化合物 | |
RU2806347C2 (ru) | Гетероциклическое соединение | |
US11970483B2 (en) | Heterocyclic compound | |
JP7446232B2 (ja) | 縮合環化合物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |