JP4180365B2 - ピペラジン誘導体 - Google Patents

Info

Publication number

JP4180365B2

JP4180365B2 JP2002515898A JP2002515898A JP4180365B2 JP 4180365 B2 JP4180365 B2 JP 4180365B2 JP 2002515898 A JP2002515898 A JP 2002515898A JP 2002515898 A JP2002515898 A JP 2002515898A JP 4180365 B2 JP4180365 B2 JP 4180365B2

Authority

JP

Japan

Prior art keywords

pyrazino

indole

methyl

hexahydro

compound

Prior art date

2000-07-31

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.)

Expired - Fee Related

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• 150000004885 piperazines Chemical class 0.000 title description 2
• 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims description 419
• 238000000034 method Methods 0.000 claims description 223
• 239000000203 mixture Substances 0.000 claims description 135
• -1 1H-pyrrolo (2,3-b) pyridin-3-ylmethyl Chemical group 0.000 claims description 130
• 125000000217 alkyl group Chemical group 0.000 claims description 80
• 239000001257 hydrogen Substances 0.000 claims description 75
• 229910052739 hydrogen Inorganic materials 0.000 claims description 75
• 150000002431 hydrogen Chemical class 0.000 claims description 50
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 45
• QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims description 30
• 238000011282 treatment Methods 0.000 claims description 28
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 25
• 150000003839 salts Chemical class 0.000 claims description 24
• 208000008589 Obesity Diseases 0.000 claims description 21
• 235000020824 obesity Nutrition 0.000 claims description 21
• AHLBNYSZXLDEJQ-FWEHEUNISA-N orlistat Chemical group CCCCCCCCCCC[C@H](OC(=O)[C@H](CC(C)C)NC=O)C[C@@H]1OC(=O)[C@H]1CCCCCC AHLBNYSZXLDEJQ-FWEHEUNISA-N 0.000 claims description 18
• 229960001243 orlistat Drugs 0.000 claims description 17
• 239000003814 drug Substances 0.000 claims description 16
• 150000002148 esters Chemical class 0.000 claims description 16
• 229910052736 halogen Inorganic materials 0.000 claims description 16
• 150000002367 halogens Chemical class 0.000 claims description 16
• 125000000623 heterocyclic group Chemical group 0.000 claims description 15
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 14
• 238000004519 manufacturing process Methods 0.000 claims description 14
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
• 229940086609 Lipase inhibitor Drugs 0.000 claims description 13
• 230000009467 reduction Effects 0.000 claims description 13
• 125000003545 alkoxy group Chemical group 0.000 claims description 12
• 208000035475 disorder Diseases 0.000 claims description 12
• 125000001188 haloalkyl group Chemical group 0.000 claims description 12
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 12
• 239000003638 chemical reducing agent Substances 0.000 claims description 11
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
• 239000008194 pharmaceutical composition Substances 0.000 claims description 11
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 10
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
• 125000003118 aryl group Chemical group 0.000 claims description 9
• 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 9
• 208000015114 central nervous system disease Diseases 0.000 claims description 9
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
• IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 claims description 8
• 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 8
• 229940079593 drug Drugs 0.000 claims description 8
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
• XTQKZPARPUBXCZ-LDYMZIIASA-N (4r,10ar)-7-chloro-4-methyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole Chemical compound C1=C(Cl)C=C2N3[C@H](C)CNC[C@H]3CC2=C1 XTQKZPARPUBXCZ-LDYMZIIASA-N 0.000 claims description 7
• 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims description 7
• 125000005110 aryl thio group Chemical group 0.000 claims description 7
• 125000004104 aryloxy group Chemical group 0.000 claims description 7
• 230000003542 behavioural effect Effects 0.000 claims description 7
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
• 125000005242 carbamoyl alkyl group Chemical group 0.000 claims description 7
• 210000003169 central nervous system Anatomy 0.000 claims description 7
• 230000006378 damage Effects 0.000 claims description 7
• 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
• OFZCNKHDZGJKCK-VXGBXAGGSA-N (4r,10ar)-7-bromo-4-ethyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole Chemical compound C1=C(Br)C=C2N3[C@H](CC)CNC[C@H]3CC2=C1 OFZCNKHDZGJKCK-VXGBXAGGSA-N 0.000 claims description 6
• ZFJVQQQPMHYSOA-NEPJUHHUSA-N (4r,10as)-4,6,9-trimethyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole Chemical compound CC1=CC=C(C)C2=C1N1[C@H](C)CNC[C@@H]1C2 ZFJVQQQPMHYSOA-NEPJUHHUSA-N 0.000 claims description 6
• TVNXTKSDLQSLAY-KOLCDFICSA-N (4r,10as)-6-chloro-4,7-dimethyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole Chemical compound C1=C(C)C(Cl)=C2N3[C@H](C)CNC[C@@H]3CC2=C1 TVNXTKSDLQSLAY-KOLCDFICSA-N 0.000 claims description 6
• SZWVUASESVZMCY-KCJUWKMLSA-N (4r,10as)-7-chloro-4,6-dimethyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole Chemical compound C1=C(Cl)C(C)=C2N3[C@H](C)CNC[C@@H]3CC2=C1 SZWVUASESVZMCY-KCJUWKMLSA-N 0.000 claims description 6
• 208000024172 Cardiovascular disease Diseases 0.000 claims description 6
• 125000004414 alkyl thio group Chemical group 0.000 claims description 6
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 6
• 125000004432 carbon atom Chemical group C* 0.000 claims description 6
• 125000004438 haloalkoxy group Chemical group 0.000 claims description 6
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
• 239000012453 solvate Substances 0.000 claims description 6
• XWXVGQFTZHFUNL-LDYMZIIASA-N (4r,10ar)-7-bromo-4-methyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole Chemical compound C1=C(Br)C=C2N3[C@H](C)CNC[C@H]3CC2=C1 XWXVGQFTZHFUNL-LDYMZIIASA-N 0.000 claims description 5
• 208000018522 Gastrointestinal disease Diseases 0.000 claims description 5
• 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 5
• 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 5
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 5
• 125000005129 aryl carbonyl group Chemical group 0.000 claims description 5
• 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 5
• 239000003795 chemical substances by application Substances 0.000 claims description 5
• 125000004473 dialkylaminocarbonyl group Chemical group 0.000 claims description 5
• 208000015181 infectious disease Diseases 0.000 claims description 5
• 230000002458 infectious effect Effects 0.000 claims description 5
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
• 238000011321 prophylaxis Methods 0.000 claims description 5
• 239000000018 receptor agonist Substances 0.000 claims description 5
• 231100000331 toxic Toxicity 0.000 claims description 5
• 230000002588 toxic effect Effects 0.000 claims description 5
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
• NGNJCNYNDBMXSG-ZWNOBZJWSA-N (4r,10ar)-4,6,7-trimethyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole Chemical compound C1=C(C)C(C)=C2N3[C@H](C)CNC[C@H]3CC2=C1 NGNJCNYNDBMXSG-ZWNOBZJWSA-N 0.000 claims description 4
• OTCYUUXMBOVVSQ-ZYHUDNBSSA-N (4r,10ar)-4,6-dimethyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole Chemical compound C1=CC(C)=C2N3[C@H](C)CNC[C@H]3CC2=C1 OTCYUUXMBOVVSQ-ZYHUDNBSSA-N 0.000 claims description 4
• GKCUTGZGZISWAV-MWLCHTKSSA-N (4r,10ar)-4,8-dimethyl-7-(trifluoromethyl)-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole Chemical compound CC1=C(C(F)(F)F)C=C2N3[C@H](C)CNC[C@H]3CC2=C1 GKCUTGZGZISWAV-MWLCHTKSSA-N 0.000 claims description 4
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 4
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
• 239000003937 drug carrier Substances 0.000 claims description 4
• 229940044601 receptor agonist Drugs 0.000 claims description 4
• 208000024891 symptom Diseases 0.000 claims description 4
• SYNUFLXJJGLJER-BXKDBHETSA-N (4r,10ar)-4-methyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole-6-carbonitrile Chemical compound C1=CC(C#N)=C2N3[C@H](C)CNC[C@H]3CC2=C1 SYNUFLXJJGLJER-BXKDBHETSA-N 0.000 claims description 3
• 208000007848 Alcoholism Diseases 0.000 claims description 3
• 208000000103 Anorexia Nervosa Diseases 0.000 claims description 3
• 208000019901 Anxiety disease Diseases 0.000 claims description 3
• 208000020925 Bipolar disease Diseases 0.000 claims description 3
• 208000032841 Bulimia Diseases 0.000 claims description 3
• 206010006550 Bulimia nervosa Diseases 0.000 claims description 3
• 206010008874 Chronic Fatigue Syndrome Diseases 0.000 claims description 3
• 206010012289 Dementia Diseases 0.000 claims description 3
• 208000019695 Migraine disease Diseases 0.000 claims description 3
• 208000027626 Neurocognitive disease Diseases 0.000 claims description 3
• 208000021384 Obsessive-Compulsive disease Diseases 0.000 claims description 3
• 206010036618 Premenstrual syndrome Diseases 0.000 claims description 3
• 208000028017 Psychotic disease Diseases 0.000 claims description 3
• 201000001880 Sexual dysfunction Diseases 0.000 claims description 3
• 206010041250 Social phobia Diseases 0.000 claims description 3
• 208000007536 Thrombosis Diseases 0.000 claims description 3
• 102100026383 Vasopressin-neurophysin 2-copeptin Human genes 0.000 claims description 3
• 230000010933 acylation Effects 0.000 claims description 3
• 238000005917 acylation reaction Methods 0.000 claims description 3
• 230000002152 alkylating effect Effects 0.000 claims description 3
• 208000025748 atypical depressive disease Diseases 0.000 claims description 3
• 238000010511 deprotection reaction Methods 0.000 claims description 3
• 201000010064 diabetes insipidus Diseases 0.000 claims description 3
• 206010013663 drug dependence Diseases 0.000 claims description 3
• 206010014599 encephalitis Diseases 0.000 claims description 3
• 206010015037 epilepsy Diseases 0.000 claims description 3
• 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 claims description 3
• 125000002140 imidazol-4-yl group Chemical group [H]N1C([H])=NC([*])=C1[H] 0.000 claims description 3
• 208000014674 injury Diseases 0.000 claims description 3
• 206010027175 memory impairment Diseases 0.000 claims description 3
• 206010027599 migraine Diseases 0.000 claims description 3
• 208000029766 myalgic encephalomeyelitis/chronic fatigue syndrome Diseases 0.000 claims description 3
• 230000004770 neurodegeneration Effects 0.000 claims description 3
• 208000015122 neurodegenerative disease Diseases 0.000 claims description 3
• 208000022821 personality disease Diseases 0.000 claims description 3
• 201000000484 premenstrual tension Diseases 0.000 claims description 3
• 230000002265 prevention Effects 0.000 claims description 3
• 201000000980 schizophrenia Diseases 0.000 claims description 3
• 231100000872 sexual dysfunction Toxicity 0.000 claims description 3
• 201000002859 sleep apnea Diseases 0.000 claims description 3
• 208000019116 sleep disease Diseases 0.000 claims description 3
• 208000020685 sleep-wake disease Diseases 0.000 claims description 3
• 208000011117 substance-related disease Diseases 0.000 claims description 3
• 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 claims description 3
• 125000003831 tetrazolyl group Chemical group 0.000 claims description 3
• 230000008733 trauma Effects 0.000 claims description 3
• 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 3
• 206010022773 Intracranial pressure increased Diseases 0.000 claims description 2
• 201000009906 Meningitis Diseases 0.000 claims description 2
• 208000002193 Pain Diseases 0.000 claims description 2
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
• 239000013543 active substance Substances 0.000 claims description 2
• 125000005081 alkoxyalkoxyalkyl group Chemical group 0.000 claims description 2
• 208000010643 digestive system disease Diseases 0.000 claims description 2
• 230000004064 dysfunction Effects 0.000 claims description 2
• 230000005176 gastrointestinal motility Effects 0.000 claims description 2
• 208000018685 gastrointestinal system disease Diseases 0.000 claims description 2
• 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 2
• 208000020016 psychiatric disease Diseases 0.000 claims description 2
• 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
• 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims 4
• 206010010904 Convulsion Diseases 0.000 claims 1
• 206010019233 Headaches Diseases 0.000 claims 1
• 125000001246 bromo group Chemical group Br* 0.000 claims 1
• 125000002837 carbocyclic group Chemical group 0.000 claims 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 204
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 180
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 117
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 115
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 113
• 239000007787 solid Substances 0.000 description 90
• 239000000243 solution Substances 0.000 description 86
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 76
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 68
• 235000019439 ethyl acetate Nutrition 0.000 description 68
• 238000004587 chromatography analysis Methods 0.000 description 63
• 239000000741 silica gel Substances 0.000 description 63
• 229910002027 silica gel Inorganic materials 0.000 description 63
• 239000002904 solvent Substances 0.000 description 55
• 238000002451 electron ionisation mass spectrometry Methods 0.000 description 52
• 239000012074 organic phase Substances 0.000 description 49
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 46
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 45
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 44
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 42
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 39
• 239000012267 brine Substances 0.000 description 38
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 36
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 34
• 239000000047 product Substances 0.000 description 31
• 239000003921 oil Substances 0.000 description 28
• 235000019198 oils Nutrition 0.000 description 28
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 26
• 125000006239 protecting group Chemical group 0.000 description 26
• 239000011541 reaction mixture Substances 0.000 description 26
• 239000000543 intermediate Substances 0.000 description 25
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 24
• 235000002639 sodium chloride Nutrition 0.000 description 22
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
• 235000019441 ethanol Nutrition 0.000 description 19
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
• 238000002844 melting Methods 0.000 description 18
• 230000008018 melting Effects 0.000 description 18
• 239000012071 phase Substances 0.000 description 18
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 17
• 235000019341 magnesium sulphate Nutrition 0.000 description 17
• 238000007429 general method Methods 0.000 description 16
• BRGKFDMYQYKVHU-UHFFFAOYSA-N tert-butyl oxathiazolidine-3-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCOS1 BRGKFDMYQYKVHU-UHFFFAOYSA-N 0.000 description 16
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
• 239000002253 acid Substances 0.000 description 15
• 239000002585 base Substances 0.000 description 15
• 102000005962 receptors Human genes 0.000 description 15
• 108020003175 receptors Proteins 0.000 description 15
• 238000010992 reflux Methods 0.000 description 15
• 238000003756 stirring Methods 0.000 description 13
• 239000000725 suspension Substances 0.000 description 13
• ZGFOJWQAHCHOLG-LURJTMIESA-N tert-butyl (5s)-5-methyl-2,2-dioxooxathiazolidine-3-carboxylate Chemical compound C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1 ZGFOJWQAHCHOLG-LURJTMIESA-N 0.000 description 13
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
• 239000008346 aqueous phase Substances 0.000 description 12
• 239000012230 colorless oil Substances 0.000 description 12
• 239000000843 powder Substances 0.000 description 12
• 238000006722 reduction reaction Methods 0.000 description 12
• 229910000104 sodium hydride Inorganic materials 0.000 description 12
• 238000001816 cooling Methods 0.000 description 11
• 239000013078 crystal Substances 0.000 description 11
• 230000000694 effects Effects 0.000 description 11
• 239000003480 eluent Substances 0.000 description 11
• 239000012280 lithium aluminium hydride Substances 0.000 description 11
• UOUFRTFWWBCVPV-UHFFFAOYSA-N tert-butyl 4-(2,4-dioxo-1H-thieno[3,2-d]pyrimidin-3-yl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(CC1)n1c(=O)[nH]c2ccsc2c1=O UOUFRTFWWBCVPV-UHFFFAOYSA-N 0.000 description 11
• XXRCUYVCPSWGCC-UHFFFAOYSA-N Ethyl pyruvate Chemical compound CCOC(=O)C(C)=O XXRCUYVCPSWGCC-UHFFFAOYSA-N 0.000 description 10
• 238000006243 chemical reaction Methods 0.000 description 10
• 229940117360 ethyl pyruvate Drugs 0.000 description 10
• 239000000706 filtrate Substances 0.000 description 10
• 239000011734 sodium Substances 0.000 description 10
• 235000017557 sodium bicarbonate Nutrition 0.000 description 10
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 10
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
• 235000012631 food intake Nutrition 0.000 description 9
• 229910000027 potassium carbonate Inorganic materials 0.000 description 9
• 230000002829 reductive effect Effects 0.000 description 9
• 229920006395 saturated elastomer Polymers 0.000 description 9
• PTDZGJNEPIRDTH-UHFFFAOYSA-N (2-methylpropan-2-yl)oxycarbonylsulfamic acid Chemical compound CC(C)(C)OC(=O)NS(O)(=O)=O PTDZGJNEPIRDTH-UHFFFAOYSA-N 0.000 description 8
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 8
• 229910052799 carbon Inorganic materials 0.000 description 8
• 235000015165 citric acid Nutrition 0.000 description 8
• 229920001971 elastomer Polymers 0.000 description 8
• 239000006260 foam Substances 0.000 description 8
• 230000037406 food intake Effects 0.000 description 8
• 150000002475 indoles Chemical class 0.000 description 8
• 239000012044 organic layer Substances 0.000 description 8
• 239000012279 sodium borohydride Substances 0.000 description 8
• 229910000033 sodium borohydride Inorganic materials 0.000 description 8
• 239000012312 sodium hydride Substances 0.000 description 8
• 239000003826 tablet Substances 0.000 description 8
• VHFVKMTVMIZMIK-UHFFFAOYSA-N 1-(3-chlorophenyl)piperazine Chemical compound ClC1=CC=CC(N2CCNCC2)=C1 VHFVKMTVMIZMIK-UHFFFAOYSA-N 0.000 description 7
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 7
• 241000700159 Rattus Species 0.000 description 7
• 150000001721 carbon Chemical group 0.000 description 7
• 238000003818 flash chromatography Methods 0.000 description 7
• 150000003840 hydrochlorides Chemical class 0.000 description 7
• MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 7
• 238000002360 preparation method Methods 0.000 description 7
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• AGRYNMDAWIYGNJ-LLVKDONJSA-N ethyl 4,6-dichloro-1-[(2r)-1-[(2-methylpropan-2-yl)oxycarbonylamino]propan-2-yl]indole-2-carboxylate Chemical compound C1=C(Cl)C=C2N([C@H](C)CNC(=O)OC(C)(C)C)C(C(=O)OCC)=CC2=C1Cl AGRYNMDAWIYGNJ-LLVKDONJSA-N 0.000 description 2
• PLWDLOJYWDOVEE-OAHLLOKOSA-N ethyl 4,6-dimethyl-1-[(2r)-1-[(2-methylpropan-2-yl)oxycarbonylamino]propan-2-yl]indole-2-carboxylate Chemical compound C1=C(C)C=C2N([C@H](C)CNC(=O)OC(C)(C)C)C(C(=O)OCC)=CC2=C1C PLWDLOJYWDOVEE-OAHLLOKOSA-N 0.000 description 2
• IGQVZYUDZAZINC-LLVKDONJSA-N ethyl 4,7-difluoro-1-[(2r)-1-[(2-methylpropan-2-yl)oxycarbonylamino]propan-2-yl]indole-2-carboxylate Chemical compound C1=CC(F)=C2N([C@H](C)CNC(=O)OC(C)(C)C)C(C(=O)OCC)=CC2=C1F IGQVZYUDZAZINC-LLVKDONJSA-N 0.000 description 2
• KPMMXXNDHSLVKM-OAHLLOKOSA-N ethyl 4,7-dimethyl-1-[(2r)-1-[(2-methylpropan-2-yl)oxycarbonylamino]propan-2-yl]indole-2-carboxylate Chemical compound C1=CC(C)=C2N([C@H](C)CNC(=O)OC(C)(C)C)C(C(=O)OCC)=CC2=C1C KPMMXXNDHSLVKM-OAHLLOKOSA-N 0.000 description 2
• WOXZXFHKNUXCFA-UHFFFAOYSA-N ethyl 4-bromo-1-(cyanomethyl)indole-2-carboxylate Chemical compound C1=CC=C2N(CC#N)C(C(=O)OCC)=CC2=C1Br WOXZXFHKNUXCFA-UHFFFAOYSA-N 0.000 description 2
• ACGHZCMAXSMPRH-GFCCVEGCSA-N ethyl 4-chloro-1-[(2r)-1-[(2-methylpropan-2-yl)oxycarbonylamino]propan-2-yl]indole-2-carboxylate Chemical compound C1=CC=C2N([C@H](C)CNC(=O)OC(C)(C)C)C(C(=O)OCC)=CC2=C1Cl ACGHZCMAXSMPRH-GFCCVEGCSA-N 0.000 description 2
• LSGNITUKEBVOTR-LLVKDONJSA-N ethyl 4-chloro-7-fluoro-1-[(2r)-1-[(2-methylpropan-2-yl)oxycarbonylamino]propan-2-yl]indole-2-carboxylate Chemical compound C1=CC(F)=C2N([C@H](C)CNC(=O)OC(C)(C)C)C(C(=O)OCC)=CC2=C1Cl LSGNITUKEBVOTR-LLVKDONJSA-N 0.000 description 2
• WBOYVWVJGBZKEG-GFCCVEGCSA-N ethyl 5-fluoro-1-[(2r)-1-[(2-methylpropan-2-yl)oxycarbonylamino]propan-2-yl]indole-2-carboxylate Chemical compound FC1=CC=C2N([C@H](C)CNC(=O)OC(C)(C)C)C(C(=O)OCC)=CC2=C1 WBOYVWVJGBZKEG-GFCCVEGCSA-N 0.000 description 2
• NONXIADLXCZUQU-CYBMUJFWSA-N ethyl 5-fluoro-6-methyl-1-[(2r)-1-[(2-methylpropan-2-yl)oxycarbonylamino]propan-2-yl]indole-2-carboxylate Chemical compound FC1=C(C)C=C2N([C@H](C)CNC(=O)OC(C)(C)C)C(C(=O)OCC)=CC2=C1 NONXIADLXCZUQU-CYBMUJFWSA-N 0.000 description 2
• QHMRETDVOPIVAM-CQSZACIVSA-N ethyl 5-methyl-1-[(2r)-1-[(2-methylpropan-2-yl)oxycarbonylamino]propan-2-yl]indole-2-carboxylate Chemical compound CC1=CC=C2N([C@H](C)CNC(=O)OC(C)(C)C)C(C(=O)OCC)=CC2=C1 QHMRETDVOPIVAM-CQSZACIVSA-N 0.000 description 2
• WQHIUDDIDWTRBI-UHFFFAOYSA-N ethyl 5-methyl-6-(trifluoromethyl)-1h-indole-2-carboxylate Chemical compound CC1=C(C(F)(F)F)C=C2NC(C(=O)OCC)=CC2=C1 WQHIUDDIDWTRBI-UHFFFAOYSA-N 0.000 description 2
• CFZCWHAKGSCQLC-UHFFFAOYSA-N ethyl 6,7-difluoro-1h-indole-2-carboxylate Chemical compound C1=C(F)C(F)=C2NC(C(=O)OCC)=CC2=C1 CFZCWHAKGSCQLC-UHFFFAOYSA-N 0.000 description 2
• MIBFONNBTQRYGN-UHFFFAOYSA-N ethyl 6-(trifluoromethyl)-1h-indole-2-carboxylate Chemical compound C1=C(C(F)(F)F)C=C2NC(C(=O)OCC)=CC2=C1 MIBFONNBTQRYGN-UHFFFAOYSA-N 0.000 description 2
• IKSUHXBPFTYQJQ-GFCCVEGCSA-N ethyl 6-bromo-1-[(2r)-1-[(2-methylpropan-2-yl)oxycarbonylamino]propan-2-yl]indole-2-carboxylate Chemical compound C1=C(Br)C=C2N([C@H](C)CNC(=O)OC(C)(C)C)C(C(=O)OCC)=CC2=C1 IKSUHXBPFTYQJQ-GFCCVEGCSA-N 0.000 description 2
• FVMZWWFKRMBNSZ-UHFFFAOYSA-N ethyl 6-bromo-1h-indole-2-carboxylate Chemical compound C1=C(Br)C=C2NC(C(=O)OCC)=CC2=C1 FVMZWWFKRMBNSZ-UHFFFAOYSA-N 0.000 description 2
• CWMMDFDMQCDTAB-UHFFFAOYSA-N ethyl 6-bromo-4-fluoro-1h-indole-2-carboxylate Chemical compound C1=C(Br)C=C2NC(C(=O)OCC)=CC2=C1F CWMMDFDMQCDTAB-UHFFFAOYSA-N 0.000 description 2
• UJPSFZNFNLMHIV-UHFFFAOYSA-N ethyl 6-chloro-1-(1-cyanoethyl)indole-2-carboxylate Chemical compound C1=C(Cl)C=C2N(C(C)C#N)C(C(=O)OCC)=CC2=C1 UJPSFZNFNLMHIV-UHFFFAOYSA-N 0.000 description 2
• FSMZLIBWSAMADK-UHFFFAOYSA-N ethyl 6-chloro-1h-indole-2-carboxylate Chemical compound C1=C(Cl)C=C2NC(C(=O)OCC)=CC2=C1 FSMZLIBWSAMADK-UHFFFAOYSA-N 0.000 description 2
• PPRAPJONRYJDFE-LLVKDONJSA-N ethyl 6-chloro-5-fluoro-1-[(2r)-1-[(2-methylpropan-2-yl)oxycarbonylamino]propan-2-yl]indole-2-carboxylate Chemical compound FC1=C(Cl)C=C2N([C@H](C)CNC(=O)OC(C)(C)C)C(C(=O)OCC)=CC2=C1 PPRAPJONRYJDFE-LLVKDONJSA-N 0.000 description 2
• GCHIGJXRRNHXRV-LLVKDONJSA-N ethyl 6-chloro-7-fluoro-1-[(2r)-1-[(2-methylpropan-2-yl)oxycarbonylamino]propan-2-yl]indole-2-carboxylate Chemical compound C1=C(Cl)C(F)=C2N([C@H](C)CNC(=O)OC(C)(C)C)C(C(=O)OCC)=CC2=C1 GCHIGJXRRNHXRV-LLVKDONJSA-N 0.000 description 2
• RXTPBFBVTOXJHO-UHFFFAOYSA-N ethyl 6-chloro-7-fluoro-1h-indole-2-carboxylate Chemical compound C1=C(Cl)C(F)=C2NC(C(=O)OCC)=CC2=C1 RXTPBFBVTOXJHO-UHFFFAOYSA-N 0.000 description 2
• BVQWOGVOYYEQPB-GFCCVEGCSA-N ethyl 6-chloro-7-methyl-1-[(2r)-1-[(2-methylpropan-2-yl)oxycarbonylamino]propan-2-yl]indole-2-carboxylate Chemical compound C1=C(Cl)C(C)=C2N([C@H](C)CNC(=O)OC(C)(C)C)C(C(=O)OCC)=CC2=C1 BVQWOGVOYYEQPB-GFCCVEGCSA-N 0.000 description 2
• MWMVPKZJEBCEFZ-GFCCVEGCSA-N ethyl 6-fluoro-7-methyl-1-[(2r)-1-[(2-methylpropan-2-yl)oxycarbonylamino]propan-2-yl]indole-2-carboxylate Chemical compound C1=C(F)C(C)=C2N([C@H](C)CNC(=O)OC(C)(C)C)C(C(=O)OCC)=CC2=C1 MWMVPKZJEBCEFZ-GFCCVEGCSA-N 0.000 description 2
• FNQPUXSVCJWKBO-UHFFFAOYSA-N ethyl 7-(trifluoromethoxy)-1h-indole-2-carboxylate Chemical compound C1=CC(OC(F)(F)F)=C2NC(C(=O)OCC)=CC2=C1 FNQPUXSVCJWKBO-UHFFFAOYSA-N 0.000 description 2
• MAZVDDKFMWFTBT-GFCCVEGCSA-N ethyl 7-bromo-1-[(2r)-1-[(2-methylpropan-2-yl)oxycarbonylamino]propan-2-yl]indole-2-carboxylate Chemical compound C1=CC(Br)=C2N([C@H](C)CNC(=O)OC(C)(C)C)C(C(=O)OCC)=CC2=C1 MAZVDDKFMWFTBT-GFCCVEGCSA-N 0.000 description 2
• UXQODLHHBWTHRQ-LLVKDONJSA-N ethyl 7-bromo-5-fluoro-1-[(2r)-1-[(2-methylpropan-2-yl)oxycarbonylamino]propan-2-yl]indole-2-carboxylate Chemical compound FC1=CC(Br)=C2N([C@H](C)CNC(=O)OC(C)(C)C)C(C(=O)OCC)=CC2=C1 UXQODLHHBWTHRQ-LLVKDONJSA-N 0.000 description 2
• LLWGGHFPDPDGBB-UHFFFAOYSA-N ethyl 7-bromo-6-methyl-1h-indole-2-carboxylate Chemical compound C1=C(C)C(Br)=C2NC(C(=O)OCC)=CC2=C1 LLWGGHFPDPDGBB-UHFFFAOYSA-N 0.000 description 2
• LROVGXRQNHHZPC-CYBMUJFWSA-N ethyl 7-chloro-5-methyl-1-[(2r)-1-[(2-methylpropan-2-yl)oxycarbonylamino]propan-2-yl]indole-2-carboxylate Chemical compound CC1=CC(Cl)=C2N([C@H](C)CNC(=O)OC(C)(C)C)C(C(=O)OCC)=CC2=C1 LROVGXRQNHHZPC-CYBMUJFWSA-N 0.000 description 2
• MXQDPJDKGXHPGI-CYBMUJFWSA-N ethyl 7-chloro-6-methyl-1-[(2r)-1-[(2-methylpropan-2-yl)oxycarbonylamino]propan-2-yl]indole-2-carboxylate Chemical compound C1=C(C)C(Cl)=C2N([C@H](C)CNC(=O)OC(C)(C)C)C(C(=O)OCC)=CC2=C1 MXQDPJDKGXHPGI-CYBMUJFWSA-N 0.000 description 2
• MSAFHAPZXWNMSH-UHFFFAOYSA-N ethyl 7-chloro-6-methyl-1h-indole-2-carboxylate Chemical compound C1=C(C)C(Cl)=C2NC(C(=O)OCC)=CC2=C1 MSAFHAPZXWNMSH-UHFFFAOYSA-N 0.000 description 2
• RQHCZSXKZCFWDO-GFCCVEGCSA-N ethyl 7-fluoro-1-[(2r)-1-[(2-methylpropan-2-yl)oxycarbonylamino]propan-2-yl]indole-2-carboxylate Chemical compound C1=CC(F)=C2N([C@H](C)CNC(=O)OC(C)(C)C)C(C(=O)OCC)=CC2=C1 RQHCZSXKZCFWDO-GFCCVEGCSA-N 0.000 description 2
• IBPOGSPFWFEXSK-CYBMUJFWSA-N ethyl 7-fluoro-4-methyl-1-[(2r)-1-[(2-methylpropan-2-yl)oxycarbonylamino]propan-2-yl]indole-2-carboxylate Chemical compound C1=CC(F)=C2N([C@H](C)CNC(=O)OC(C)(C)C)C(C(=O)OCC)=CC2=C1C IBPOGSPFWFEXSK-CYBMUJFWSA-N 0.000 description 2
• ABBOXOMUELWNEB-UHFFFAOYSA-N ethyl 7-fluoro-4-methyl-1h-indole-2-carboxylate Chemical compound C1=CC(F)=C2NC(C(=O)OCC)=CC2=C1C ABBOXOMUELWNEB-UHFFFAOYSA-N 0.000 description 2
• LQFBVARIHIMSAC-CYBMUJFWSA-N ethyl 7-fluoro-6-methyl-1-[(2r)-1-[(2-methylpropan-2-yl)oxycarbonylamino]propan-2-yl]indole-2-carboxylate Chemical compound C1=C(C)C(F)=C2N([C@H](C)CNC(=O)OC(C)(C)C)C(C(=O)OCC)=CC2=C1 LQFBVARIHIMSAC-CYBMUJFWSA-N 0.000 description 2
• KURXPNVVFATLMH-UHFFFAOYSA-N ethyl 7-fluoro-6-methyl-1h-indole-2-carboxylate Chemical compound C1=C(C)C(F)=C2NC(C(=O)OCC)=CC2=C1 KURXPNVVFATLMH-UHFFFAOYSA-N 0.000 description 2
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• IMTWCOLMLKHDJT-UHFFFAOYSA-N ethyl 4,7-dimethyl-1h-indole-2-carboxylate Chemical compound C1=CC(C)=C2NC(C(=O)OCC)=CC2=C1C IMTWCOLMLKHDJT-UHFFFAOYSA-N 0.000 description 1
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• XWNVSPGTJSGNPU-UHFFFAOYSA-N ethyl 4-chloro-1h-indole-2-carboxylate Chemical compound C1=CC=C2NC(C(=O)OCC)=CC2=C1Cl XWNVSPGTJSGNPU-UHFFFAOYSA-N 0.000 description 1
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• AYZHLERWRPSCIT-CYBMUJFWSA-N ethyl 5-methyl-1-[(2r)-1-[(2-methylpropan-2-yl)oxycarbonylamino]propan-2-yl]-6-(trifluoromethyl)indole-2-carboxylate Chemical compound CC1=C(C(F)(F)F)C=C2N([C@H](C)CNC(=O)OC(C)(C)C)C(C(=O)OCC)=CC2=C1 AYZHLERWRPSCIT-CYBMUJFWSA-N 0.000 description 1
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