EA038756B1 - ФАРМАКОЛОГИЧЕСКИ АКТИВНЫЕ АЛИЦИКЛИЧЕСКИ ЗАМЕЩЕННЫЕ ПРОИЗВОДНЫЕ ПИРАЗОЛО[1,5-a]ПИРИМИДИНА - Google Patents
ФАРМАКОЛОГИЧЕСКИ АКТИВНЫЕ АЛИЦИКЛИЧЕСКИ ЗАМЕЩЕННЫЕ ПРОИЗВОДНЫЕ ПИРАЗОЛО[1,5-a]ПИРИМИДИНА Download PDFInfo
- Publication number
- EA038756B1 EA038756B1 EA201992127A EA201992127A EA038756B1 EA 038756 B1 EA038756 B1 EA 038756B1 EA 201992127 A EA201992127 A EA 201992127A EA 201992127 A EA201992127 A EA 201992127A EA 038756 B1 EA038756 B1 EA 038756B1
- Authority
- EA
- Eurasian Patent Office
- Prior art keywords
- methyl
- carboxylic acid
- pyrazolo
- trifluoromethyl
- alkyl
- Prior art date
Links
- LDIJKUBTLZTFRG-UHFFFAOYSA-N pyrazolo[1,5-a]pyrimidine Chemical class N1=CC=CN2N=CC=C21 LDIJKUBTLZTFRG-UHFFFAOYSA-N 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 122
- 238000000034 method Methods 0.000 claims abstract description 41
- 150000003839 salts Chemical class 0.000 claims abstract description 29
- 230000000694 effects Effects 0.000 claims abstract description 21
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 21
- 230000003281 allosteric effect Effects 0.000 claims abstract description 19
- 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 claims abstract description 16
- 239000003814 drug Substances 0.000 claims abstract description 16
- 238000011282 treatment Methods 0.000 claims abstract description 13
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 64
- 238000006243 chemical reaction Methods 0.000 claims description 38
- 108060003377 GABA-B receptor Proteins 0.000 claims description 30
- 102000017934 GABA-B receptor Human genes 0.000 claims description 30
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 27
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 239000002253 acid Substances 0.000 claims description 19
- -1 acetonitrile compound Chemical class 0.000 claims description 18
- 239000004480 active ingredient Substances 0.000 claims description 17
- 208000035475 disorder Diseases 0.000 claims description 17
- 125000005843 halogen group Chemical group 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 17
- XJLSEXAGTJCILF-RXMQYKEDSA-N (R)-nipecotic acid zwitterion Chemical compound OC(=O)[C@@H]1CCCNC1 XJLSEXAGTJCILF-RXMQYKEDSA-N 0.000 claims description 14
- 150000002148 esters Chemical class 0.000 claims description 14
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 12
- 229940079593 drug Drugs 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N methyl cyanide Natural products CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 10
- 208000029560 autism spectrum disease Diseases 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 229940126027 positive allosteric modulator Drugs 0.000 claims description 8
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 208000020016 psychiatric disease Diseases 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims description 4
- 208000019901 Anxiety disease Diseases 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 208000008238 Muscle Spasticity Diseases 0.000 claims description 4
- 208000002193 Pain Diseases 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 4
- 230000036506 anxiety Effects 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- 208000018198 spasticity Diseases 0.000 claims description 4
- 239000011593 sulfur Substances 0.000 claims description 4
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 4
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 3
- 206010011224 Cough Diseases 0.000 claims description 3
- 241000124008 Mammalia Species 0.000 claims description 3
- 208000008589 Obesity Diseases 0.000 claims description 3
- 206010046543 Urinary incontinence Diseases 0.000 claims description 3
- 208000006673 asthma Diseases 0.000 claims description 3
- 208000014679 binge eating disease Diseases 0.000 claims description 3
- 206010008129 cerebral palsy Diseases 0.000 claims description 3
- 208000021302 gastroesophageal reflux disease Diseases 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- 201000006417 multiple sclerosis Diseases 0.000 claims description 3
- 235000020824 obesity Nutrition 0.000 claims description 3
- 208000020431 spinal cord injury Diseases 0.000 claims description 3
- 208000011117 substance-related disease Diseases 0.000 claims description 3
- NAZGPTRCCWEEBK-MPCDZSKCSA-N CC1=NC=2N(C(=C1C(C)C)N1C[C@@](CCC1)(C(=O)O)C(C)C)N=C(C=2)[C@@H]1CC[C@H](CC1)C(F)(F)F Chemical compound CC1=NC=2N(C(=C1C(C)C)N1C[C@@](CCC1)(C(=O)O)C(C)C)N=C(C=2)[C@@H]1CC[C@H](CC1)C(F)(F)F NAZGPTRCCWEEBK-MPCDZSKCSA-N 0.000 claims description 2
- AVJDMXZYANABIA-MPCDZSKCSA-N CC1=NC=2N(C(=C1C(C)C)N1C[C@@](CCC1)(C(=O)O)CCC)N=C(C=2)[C@@H]1CC[C@H](CC1)C(F)(F)F Chemical compound CC1=NC=2N(C(=C1C(C)C)N1C[C@@](CCC1)(C(=O)O)CCC)N=C(C=2)[C@@H]1CC[C@H](CC1)C(F)(F)F AVJDMXZYANABIA-MPCDZSKCSA-N 0.000 claims description 2
- DMFLJSHKIOZINU-ULQDDVLXSA-N CC1=NC=2N(C(=C1C(C)C)N1C[C@H](CCC1)C(=O)O)N=C(C=2)[C@@H]1CC[C@H](CC1)C(F)(F)F Chemical compound CC1=NC=2N(C(=C1C(C)C)N1C[C@H](CCC1)C(=O)O)N=C(C=2)[C@@H]1CC[C@H](CC1)C(F)(F)F DMFLJSHKIOZINU-ULQDDVLXSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- RZWACFXRVLCYDS-QQMNAOGKSA-N FC[C@@]1(CN(CCC1)C1=C(C(=NC=2N1N=C(C=2)[C@@H]1CC[C@H](CC1)C(F)(F)F)C)C(C)C)C(=O)O Chemical compound FC[C@@]1(CN(CCC1)C1=C(C(=NC=2N1N=C(C=2)[C@@H]1CC[C@H](CC1)C(F)(F)F)C)C(C)C)C(=O)O RZWACFXRVLCYDS-QQMNAOGKSA-N 0.000 claims description 2
- RZWACFXRVLCYDS-SEPYTNNBSA-N FC[C@]1(CN(CCC1)C1=C(C(=NC=2N1N=C(C=2)[C@@H]1CC[C@H](CC1)C(F)(F)F)C)C(C)C)C(=O)O Chemical compound FC[C@]1(CN(CCC1)C1=C(C(=NC=2N1N=C(C=2)[C@@H]1CC[C@H](CC1)C(F)(F)F)C)C(C)C)C(=O)O RZWACFXRVLCYDS-SEPYTNNBSA-N 0.000 claims description 2
- 229940125681 anticonvulsant agent Drugs 0.000 claims description 2
- 239000001961 anticonvulsive agent Substances 0.000 claims description 2
- 239000000935 antidepressant agent Substances 0.000 claims description 2
- 229940005513 antidepressants Drugs 0.000 claims description 2
- 229940030600 antihypertensive agent Drugs 0.000 claims description 2
- 239000002220 antihypertensive agent Substances 0.000 claims description 2
- 239000000164 antipsychotic agent Substances 0.000 claims description 2
- 229940005529 antipsychotics Drugs 0.000 claims description 2
- 239000002249 anxiolytic agent Substances 0.000 claims description 2
- 230000000949 anxiolytic effect Effects 0.000 claims description 2
- 229940005530 anxiolytics Drugs 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 159000000011 group IA salts Chemical class 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 239000003368 psychostimulant agent Substances 0.000 claims description 2
- 229940125723 sedative agent Drugs 0.000 claims description 2
- 239000000932 sedative agent Substances 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 10
- 208000002740 Muscle Rigidity Diseases 0.000 claims 3
- 208000010877 cognitive disease Diseases 0.000 claims 3
- 206010015037 epilepsy Diseases 0.000 claims 3
- 210000002027 skeletal muscle Anatomy 0.000 claims 3
- 206010004716 Binge eating Diseases 0.000 claims 2
- 208000032841 Bulimia Diseases 0.000 claims 2
- WHSWIVIVQJQEEG-RXSFTSLZSA-N FC=1C(=NN2C=1N=C(C(=C2N1C[C@](CCC1)(C(=O)O)C)OC)C)[C@@H]1CC[C@H](CC1)C(F)(F)F Chemical compound FC=1C(=NN2C=1N=C(C(=C2N1C[C@](CCC1)(C(=O)O)C)OC)C)[C@@H]1CC[C@H](CC1)C(F)(F)F WHSWIVIVQJQEEG-RXSFTSLZSA-N 0.000 claims 2
- 208000001914 Fragile X syndrome Diseases 0.000 claims 2
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 claims 2
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims 2
- 150000001735 carboxylic acids Chemical class 0.000 claims 2
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 claims 2
- 201000006517 essential tremor Diseases 0.000 claims 2
- 208000002551 irritable bowel syndrome Diseases 0.000 claims 2
- 210000000111 lower esophageal sphincter Anatomy 0.000 claims 2
- 208000019906 panic disease Diseases 0.000 claims 2
- 201000000980 schizophrenia Diseases 0.000 claims 2
- 201000009032 substance abuse Diseases 0.000 claims 2
- 231100000736 substance abuse Toxicity 0.000 claims 2
- 230000001052 transient effect Effects 0.000 claims 2
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 claims 1
- XGUVQTSNLOXPQT-JOCHJYFZSA-N (3R)-1-[2-(4,4-difluorocyclohexyl)-3-fluoro-5-methyl-6-propan-2-ylpyrazolo[1,5-a]pyrimidin-7-yl]-3-methylpiperidine-3-carboxylic acid Chemical compound FC1(CCC(CC1)C1=NN2C(N=C(C(=C2N2C[C@@](CCC2)(C(=O)O)C)C(C)C)C)=C1F)F XGUVQTSNLOXPQT-JOCHJYFZSA-N 0.000 claims 1
- RUGCBFURIOPNHR-JOCHJYFZSA-N (3R)-1-[2-(4,4-difluorocyclohexyl)-5,6-diethylpyrazolo[1,5-a]pyrimidin-7-yl]-3-methylpiperidine-3-carboxylic acid Chemical compound FC1(CCC(CC1)C1=NN2C(N=C(C(=C2N2C[C@@](CCC2)(C(=O)O)C)CC)CC)=C1)F RUGCBFURIOPNHR-JOCHJYFZSA-N 0.000 claims 1
- UTYQOINWQJGILD-HSZRJFAPSA-N (3R)-1-[2-(4,4-difluorocyclohexyl)-5-methyl-6-propan-2-ylpyrazolo[1,5-a]pyrimidin-7-yl]-3-ethylpiperidine-3-carboxylic acid Chemical compound FC1(CCC(CC1)C1=NN2C(N=C(C(=C2N2C[C@@](CCC2)(C(=O)O)CC)C(C)C)C)=C1)F UTYQOINWQJGILD-HSZRJFAPSA-N 0.000 claims 1
- NPSUCBFOGBVWFQ-JOCHJYFZSA-N (3R)-1-[2-(4,4-difluorocyclohexyl)-5-methyl-6-propan-2-ylpyrazolo[1,5-a]pyrimidin-7-yl]-3-methylpiperidine-3-carboxylic acid Chemical compound FC1(CCC(CC1)C1=NN2C(N=C(C(=C2N2C[C@@](CCC2)(C(=O)O)C)C(C)C)C)=C1)F NPSUCBFOGBVWFQ-JOCHJYFZSA-N 0.000 claims 1
- UTYQOINWQJGILD-QHCPKHFHSA-N (3S)-1-[2-(4,4-difluorocyclohexyl)-5-methyl-6-propan-2-ylpyrazolo[1,5-a]pyrimidin-7-yl]-3-ethylpiperidine-3-carboxylic acid Chemical compound FC1(CCC(CC1)C1=NN2C(N=C(C(=C2N2C[C@](CCC2)(C(=O)O)CC)C(C)C)C)=C1)F UTYQOINWQJGILD-QHCPKHFHSA-N 0.000 claims 1
- NPSUCBFOGBVWFQ-QFIPXVFZSA-N (3S)-1-[2-(4,4-difluorocyclohexyl)-5-methyl-6-propan-2-ylpyrazolo[1,5-a]pyrimidin-7-yl]-3-methylpiperidine-3-carboxylic acid Chemical compound FC1(CCC(CC1)C1=NN2C(N=C(C(=C2N2C[C@](CCC2)(C(=O)O)C)C(C)C)C)=C1)F NPSUCBFOGBVWFQ-QFIPXVFZSA-N 0.000 claims 1
- 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 claims 1
- SZJRXJJYMMCDEM-XCGNWRKASA-N C(C)C=1C(=NC=2N(C=1N1C[C@@](CCC1)(C(=O)O)C)N=C(C=2)[C@@H]1CC[C@H](CC1)C(F)(F)F)C Chemical compound C(C)C=1C(=NC=2N(C=1N1C[C@@](CCC1)(C(=O)O)C)N=C(C=2)[C@@H]1CC[C@H](CC1)C(F)(F)F)C SZJRXJJYMMCDEM-XCGNWRKASA-N 0.000 claims 1
- DMFLJSHKIOZINU-BRWVUGGUSA-N CC(C)C1=C(N2N=C(C=C2N=C1C)[C@H]1CC[C@@H](CC1)C(F)(F)F)N1CCC[C@H](C1)C(O)=O Chemical compound CC(C)C1=C(N2N=C(C=C2N=C1C)[C@H]1CC[C@@H](CC1)C(F)(F)F)N1CCC[C@H](C1)C(O)=O DMFLJSHKIOZINU-BRWVUGGUSA-N 0.000 claims 1
- NAZGPTRCCWEEBK-MHPIHPPYSA-N CC(C)C1=C(N2N=C(C=C2N=C1C)[C@H]1CC[C@@H](CC1)C(F)(F)F)N1CCC[C@](C1)(C(C)C)C(O)=O Chemical compound CC(C)C1=C(N2N=C(C=C2N=C1C)[C@H]1CC[C@@H](CC1)C(F)(F)F)N1CCC[C@](C1)(C(C)C)C(O)=O NAZGPTRCCWEEBK-MHPIHPPYSA-N 0.000 claims 1
- AVJDMXZYANABIA-MHPIHPPYSA-N CC1=NC=2N(C(=C1C(C)C)N1C[C@](CCC1)(C(=O)O)CCC)N=C(C=2)[C@@H]1CC[C@H](CC1)C(F)(F)F Chemical compound CC1=NC=2N(C(=C1C(C)C)N1C[C@](CCC1)(C(=O)O)CCC)N=C(C=2)[C@@H]1CC[C@H](CC1)C(F)(F)F AVJDMXZYANABIA-MHPIHPPYSA-N 0.000 claims 1
- SHIQMGZZVCRUAO-UAVUOLJFSA-N CC[C@@]1(CCCN(C1)C1=C(C(C)C)C(C)=NC2=C(F)C(=NN12)[C@H]1CC[C@@H](CC1)C(F)(F)F)C(O)=O Chemical compound CC[C@@]1(CCCN(C1)C1=C(C(C)C)C(C)=NC2=C(F)C(=NN12)[C@H]1CC[C@@H](CC1)C(F)(F)F)C(O)=O SHIQMGZZVCRUAO-UAVUOLJFSA-N 0.000 claims 1
- SHIQMGZZVCRUAO-HOZJOUCCSA-N CC[C@]1(CCCN(C1)C1=C(C(C)C)C(C)=NC2=C(F)C(=NN12)[C@H]1CC[C@@H](CC1)C(F)(F)F)C(O)=O Chemical compound CC[C@]1(CCCN(C1)C1=C(C(C)C)C(C)=NC2=C(F)C(=NN12)[C@H]1CC[C@@H](CC1)C(F)(F)F)C(O)=O SHIQMGZZVCRUAO-HOZJOUCCSA-N 0.000 claims 1
- CHXRKXFQNDOVPF-SEPYTNNBSA-N COCCC=1C(=NC=2N(C=1N1C[C@@](CCC1)(C(=O)O)C)N=C(C=2)[C@@H]1CC[C@H](CC1)C(F)(F)F)C Chemical compound COCCC=1C(=NC=2N(C=1N1C[C@@](CCC1)(C(=O)O)C)N=C(C=2)[C@@H]1CC[C@H](CC1)C(F)(F)F)C CHXRKXFQNDOVPF-SEPYTNNBSA-N 0.000 claims 1
- AGPHNAQRSJNYHH-CKNGIIGNSA-N C[C@@]1(CN(CCC1)C=1N2C(N=C3CCCCC=13)=CC(=N2)[C@@H]1CC[C@H](CC1)C(F)(F)F)C(=O)O Chemical compound C[C@@]1(CN(CCC1)C=1N2C(N=C3CCCCC=13)=CC(=N2)[C@@H]1CC[C@H](CC1)C(F)(F)F)C(=O)O AGPHNAQRSJNYHH-CKNGIIGNSA-N 0.000 claims 1
- 206010012559 Developmental delay Diseases 0.000 claims 1
- WHSWIVIVQJQEEG-ZMOMAAQPSA-N FC=1C(=NN2C=1N=C(C(=C2N1C[C@@](CCC1)(C(=O)O)C)OC)C)[C@@H]1CC[C@H](CC1)C(F)(F)F Chemical compound FC=1C(=NN2C=1N=C(C(=C2N1C[C@@](CCC1)(C(=O)O)C)OC)C)[C@@H]1CC[C@H](CC1)C(F)(F)F WHSWIVIVQJQEEG-ZMOMAAQPSA-N 0.000 claims 1
- 229960003920 cocaine Drugs 0.000 claims 1
- 230000003533 narcotic effect Effects 0.000 claims 1
- 230000002981 neuropathic effect Effects 0.000 claims 1
- 229960002715 nicotine Drugs 0.000 claims 1
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 claims 1
- 239000000825 pharmaceutical preparation Substances 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 230000009278 visceral effect Effects 0.000 claims 1
- 230000008569 process Effects 0.000 abstract description 3
- 239000012752 auxiliary agent Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 69
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 43
- 239000000203 mixture Substances 0.000 description 42
- 239000000543 intermediate Substances 0.000 description 37
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
- 239000000243 solution Substances 0.000 description 26
- 239000011541 reaction mixture Substances 0.000 description 25
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 239000002904 solvent Substances 0.000 description 22
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 18
- 239000000047 product Substances 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
- 238000004809 thin layer chromatography Methods 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 210000004556 brain Anatomy 0.000 description 12
- 230000003287 optical effect Effects 0.000 description 12
- 239000003960 organic solvent Substances 0.000 description 12
- 102000005962 receptors Human genes 0.000 description 12
- 108020003175 receptors Proteins 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 239000002552 dosage form Substances 0.000 description 10
- 238000000605 extraction Methods 0.000 description 10
- 230000035484 reaction time Effects 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- 230000001225 therapeutic effect Effects 0.000 description 10
- 241001465754 Metazoa Species 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000000872 buffer Substances 0.000 description 9
- 238000004440 column chromatography Methods 0.000 description 9
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 9
- 230000000638 stimulation Effects 0.000 description 9
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- 241000700159 Rattus Species 0.000 description 8
- 230000027455 binding Effects 0.000 description 8
- 210000003169 central nervous system Anatomy 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 239000003446 ligand Substances 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- JNOAOWKBSHTCPM-HAQNSBGRSA-N ClC1=C(C(=NC=2N1N=C(C=2)[C@@H]1CC[C@H](CC1)C(F)(F)F)C)C(C)C Chemical compound ClC1=C(C(=NC=2N1N=C(C=2)[C@@H]1CC[C@H](CC1)C(F)(F)F)C)C(C)C JNOAOWKBSHTCPM-HAQNSBGRSA-N 0.000 description 7
- 230000008901 benefit Effects 0.000 description 7
- 230000008499 blood brain barrier function Effects 0.000 description 7
- 210000001218 blood-brain barrier Anatomy 0.000 description 7
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 7
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 7
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- YCXCRFGBFZTUSU-UHFFFAOYSA-N 1-o-tert-butyl 3-o-ethyl piperidine-1,3-dicarboxylate Chemical compound CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)C1 YCXCRFGBFZTUSU-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- KPYSYYIEGFHWSV-UHFFFAOYSA-N Baclofen Chemical compound OC(=O)CC(CN)C1=CC=C(Cl)C=C1 KPYSYYIEGFHWSV-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 229960000794 baclofen Drugs 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 230000035515 penetration Effects 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 5
- 150000007960 acetonitrile Chemical class 0.000 description 5
- 230000006399 behavior Effects 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000009835 boiling Methods 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 229960001484 edetic acid Drugs 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 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 5
- 239000012528 membrane Substances 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 4
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 150000004677 hydrates Chemical class 0.000 description 4
- 239000011261 inert gas Substances 0.000 description 4
- 230000001404 mediated effect Effects 0.000 description 4
- 239000002207 metabolite Substances 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 230000002093 peripheral effect Effects 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000000651 prodrug Substances 0.000 description 4
- 229940002612 prodrug Drugs 0.000 description 4
- 239000012453 solvate Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 208000036395 Fetal valproate spectrum disease Diseases 0.000 description 3
- 206010066485 Foetal anticonvulsant syndrome Diseases 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 102000016193 Metabotropic glutamate receptors Human genes 0.000 description 3
- 108010010914 Metabotropic glutamate receptors Proteins 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- 208000012902 Nervous system disease Diseases 0.000 description 3
- 208000025966 Neurological disease Diseases 0.000 description 3
- ODXMSJZNYXYHGQ-ZKCHVHJHSA-N O=C(CC#N)[C@@H]1CC[C@H](CC1)C(F)(F)F Chemical compound O=C(CC#N)[C@@H]1CC[C@H](CC1)C(F)(F)F ODXMSJZNYXYHGQ-ZKCHVHJHSA-N 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 3
- NIJJYAXOARWZEE-UHFFFAOYSA-N Valproic acid Chemical compound CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 239000000556 agonist Substances 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 230000003542 behavioural effect Effects 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 238000000586 desensitisation Methods 0.000 description 3
- 239000007919 dispersible tablet Substances 0.000 description 3
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- LJDQJKFMUKVEDV-UHFFFAOYSA-N ethyl 3-(fluoromethyl)piperidine-3-carboxylate hydrochloride Chemical compound Cl.FCC1(CNCCC1)C(=O)OCC LJDQJKFMUKVEDV-UHFFFAOYSA-N 0.000 description 3
- FMXSNRSXGZIOFA-UHFFFAOYSA-N ethyl 3-propylpiperidine-3-carboxylate hydrochloride Chemical compound Cl.C(CC)C1(CNCCC1)C(=O)OCC FMXSNRSXGZIOFA-UHFFFAOYSA-N 0.000 description 3
- 239000003889 eye drop Substances 0.000 description 3
- 229940012356 eye drops Drugs 0.000 description 3
- 201000004291 fetal valproate syndrome Diseases 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000012634 fragment Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical class N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 description 3
- 210000002569 neuron Anatomy 0.000 description 3
- 239000002858 neurotransmitter agent Substances 0.000 description 3
- 239000002357 osmotic agent Substances 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- 230000035939 shock Effects 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 3
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 2
- IADUEWIQBXOCDZ-VKHMYHEASA-N (S)-azetidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCN1 IADUEWIQBXOCDZ-VKHMYHEASA-N 0.000 description 2
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 2
- XAOCBPFTPYDATH-UHFFFAOYSA-N 1-o-tert-butyl 3-o-ethyl 3-ethylpiperidine-1,3-dicarboxylate Chemical compound CCOC(=O)C1(CC)CCCN(C(=O)OC(C)(C)C)C1 XAOCBPFTPYDATH-UHFFFAOYSA-N 0.000 description 2
- MXJSGZQOVOWWST-UHFFFAOYSA-N 1-o-tert-butyl 3-o-ethyl 3-methylpiperidine-1,3-dicarboxylate Chemical compound CCOC(=O)C1(C)CCCN(C(=O)OC(C)(C)C)C1 MXJSGZQOVOWWST-UHFFFAOYSA-N 0.000 description 2
- SXAMGRAIZSSWIH-UHFFFAOYSA-N 2-[3-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,2,4-oxadiazol-5-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NOC(=N1)CC(=O)N1CC2=C(CC1)NN=N2 SXAMGRAIZSSWIH-UHFFFAOYSA-N 0.000 description 2
- GNFVFPBRMLIKIM-UHFFFAOYSA-N 2-fluoroacetonitrile Chemical compound FCC#N GNFVFPBRMLIKIM-UHFFFAOYSA-N 0.000 description 2
- WYAIOGXLSXKNGX-UHFFFAOYSA-N 4-(trifluoromethyl)cyclohexane-1-carbonyl chloride Chemical compound FC(F)(F)C1CCC(C(Cl)=O)CC1 WYAIOGXLSXKNGX-UHFFFAOYSA-N 0.000 description 2
- LMEAZIIFLVDISW-UHFFFAOYSA-N 4-(trifluoromethyl)cyclohexane-1-carboxylic acid Chemical compound OC(=O)C1CCC(C(F)(F)F)CC1 LMEAZIIFLVDISW-UHFFFAOYSA-N 0.000 description 2
- GKNUVVNBWLQGQL-UHFFFAOYSA-N 5-(4,4-difluorocyclohexyl)-1h-pyrazol-3-amine Chemical compound N1N=C(N)C=C1C1CCC(F)(F)CC1 GKNUVVNBWLQGQL-UHFFFAOYSA-N 0.000 description 2
- CONKBQPVFMXDOV-QHCPKHFHSA-N 6-[(5S)-5-[[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]methyl]-2-oxo-1,3-oxazolidin-3-yl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C[C@H]1CN(C(O1)=O)C1=CC2=C(NC(O2)=O)C=C1 CONKBQPVFMXDOV-QHCPKHFHSA-N 0.000 description 2
- USVZHTBPMMSRHY-UHFFFAOYSA-N 8-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-9-[2-(2-chlorophenyl)ethyl]purin-6-amine Chemical compound C=1C=2OCOC=2C=C(Br)C=1SC1=NC=2C(N)=NC=NC=2N1CCC1=CC=CC=C1Cl USVZHTBPMMSRHY-UHFFFAOYSA-N 0.000 description 2
- PUFINDMEOIZUTI-HAQNSBGRSA-N CC1=NC=2N(C(=C1C(C)C)O)N=C(C=2)[C@@H]1CC[C@H](CC1)C(F)(F)F Chemical compound CC1=NC=2N(C(=C1C(C)C)O)N=C(C=2)[C@@H]1CC[C@H](CC1)C(F)(F)F PUFINDMEOIZUTI-HAQNSBGRSA-N 0.000 description 2
- PGHHVUYDYPBGJH-CZMCAQCFSA-N COC(=C(C#N)C#N)[C@@H]1CC[C@H](CC1)C(F)(F)F Chemical compound COC(=C(C#N)C#N)[C@@H]1CC[C@H](CC1)C(F)(F)F PGHHVUYDYPBGJH-CZMCAQCFSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 206010010904 Convulsion Diseases 0.000 description 2
- UUAZFDQKFLTTIJ-LUHQIEFSSA-N FC(C#N)C([C@@H]1CC[C@H](CC1)C(F)(F)F)=O Chemical compound FC(C#N)C([C@@H]1CC[C@H](CC1)C(F)(F)F)=O UUAZFDQKFLTTIJ-LUHQIEFSSA-N 0.000 description 2
- TWFOURUUESGAFM-LJGSYFOKSA-N FC([C@@H]1CC[C@H](CC1)C1=NNC(=C1)N)(F)F Chemical compound FC([C@@H]1CC[C@H](CC1)C1=NNC(=C1)N)(F)F TWFOURUUESGAFM-LJGSYFOKSA-N 0.000 description 2
- CWXOGNNZJCHWMZ-IZLXSQMJSA-N FC=1C(=NNC=1N)[C@@H]1CC[C@H](CC1)C(F)(F)F Chemical compound FC=1C(=NNC=1N)[C@@H]1CC[C@H](CC1)C(F)(F)F CWXOGNNZJCHWMZ-IZLXSQMJSA-N 0.000 description 2
- 108091006027 G proteins Proteins 0.000 description 2
- QGWNDRXFNXRZMB-UUOKFMHZSA-N GDP Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O QGWNDRXFNXRZMB-UUOKFMHZSA-N 0.000 description 2
- 102000030782 GTP binding Human genes 0.000 description 2
- 108091000058 GTP-Binding Proteins 0.000 description 2
- 208000004454 Hyperalgesia Diseases 0.000 description 2
- 208000035154 Hyperesthesia Diseases 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- ZLWPHGZNESYSRF-LJGSYFOKSA-N NC1=C(C(=NN1)[C@@H]1CC[C@H](CC1)C(F)(F)F)C#N Chemical compound NC1=C(C(=NN1)[C@@H]1CC[C@H](CC1)C(F)(F)F)C#N ZLWPHGZNESYSRF-LJGSYFOKSA-N 0.000 description 2
- 208000029726 Neurodevelopmental disease Diseases 0.000 description 2
- 241000700157 Rattus norvegicus Species 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 239000006172 buffering agent Substances 0.000 description 2
- OGEBRHQLRGFBNV-RZDIXWSQSA-N chembl2036808 Chemical group 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
- 239000008139 complexing agent Substances 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 239000003596 drug target Substances 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- NJJMTZFBHZYZGB-UHFFFAOYSA-N ethyl 3-(methoxymethyl)piperidine-3-carboxylate Chemical compound CCOC(=O)C1(COC)CCCNC1 NJJMTZFBHZYZGB-UHFFFAOYSA-N 0.000 description 2
- LNANFKKPVLUIBX-UHFFFAOYSA-N ethyl 3-methylpiperidine-3-carboxylate Chemical compound CCOC(=O)C1(C)CCCNC1 LNANFKKPVLUIBX-UHFFFAOYSA-N 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- QGWNDRXFNXRZMB-UHFFFAOYSA-N guanidine diphosphate Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O QGWNDRXFNXRZMB-UHFFFAOYSA-N 0.000 description 2
- 230000035863 hyperlocomotion Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 238000011813 knockout mouse model Methods 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 description 2
- 206010027175 memory impairment Diseases 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 230000001242 postsynaptic effect Effects 0.000 description 2
- 238000002953 preparative HPLC Methods 0.000 description 2
- 230000003518 presynaptic effect Effects 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 150000003217 pyrazoles Chemical class 0.000 description 2
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 2
- 150000003230 pyrimidines Chemical class 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 230000002269 spontaneous effect Effects 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000002511 suppository base Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 239000002562 thickening agent Substances 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- 238000002604 ultrasonography Methods 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 1
- 230000006269 (delayed) early viral mRNA transcription Effects 0.000 description 1
- AIZZFYPYPULRFL-DTWKUNHWSA-N 1-o-tert-butyl 3-o-ethyl (3s,4s)-4-aminopyrrolidine-1,3-dicarboxylate Chemical compound CCOC(=O)[C@H]1CN(C(=O)OC(C)(C)C)C[C@H]1N AIZZFYPYPULRFL-DTWKUNHWSA-N 0.000 description 1
- APXRHPDHORGIEB-UHFFFAOYSA-N 1H-pyrazolo[4,3-d]pyrimidine Chemical class N1=CN=C2C=NNC2=C1 APXRHPDHORGIEB-UHFFFAOYSA-N 0.000 description 1
- JVVRJMXHNUAPHW-UHFFFAOYSA-N 1h-pyrazol-5-amine Chemical compound NC=1C=CNN=1 JVVRJMXHNUAPHW-UHFFFAOYSA-N 0.000 description 1
- XLWJPQQFJNGUPA-UHFFFAOYSA-N 2,6-ditert-butyl-4-(3-hydroxy-2,2-dimethylpropyl)phenol Chemical compound OCC(C)(C)CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 XLWJPQQFJNGUPA-UHFFFAOYSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- WLAMNBDJUVNPJU-UHFFFAOYSA-N 2-methylbutyric acid Chemical compound CCC(C)C(O)=O WLAMNBDJUVNPJU-UHFFFAOYSA-N 0.000 description 1
- LGOCOBCFMCLPRZ-UHFFFAOYSA-N 3-(4,4-difluorocyclohexyl)-3-oxopropanenitrile Chemical compound FC1(F)CCC(C(=O)CC#N)CC1 LGOCOBCFMCLPRZ-UHFFFAOYSA-N 0.000 description 1
- JYLNVJYYQQXNEK-UHFFFAOYSA-N 3-amino-2-(4-chlorophenyl)-1-propanesulfonic acid Chemical compound OS(=O)(=O)CC(CN)C1=CC=C(Cl)C=C1 JYLNVJYYQQXNEK-UHFFFAOYSA-N 0.000 description 1
- OXGKEBYDILYVCG-UHFFFAOYSA-N 3-cyclohexyl-2H-pyrazolo[4,3-d]pyrimidine Chemical compound C1(CCCCC1)C1=NNC=2C=NC=NC=21 OXGKEBYDILYVCG-UHFFFAOYSA-N 0.000 description 1
- HYIUDFLDFSIXTR-UHFFFAOYSA-N 4,4-difluorocyclohexane-1-carboxylic acid Chemical compound OC(=O)C1CCC(F)(F)CC1 HYIUDFLDFSIXTR-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 206010001497 Agitation Diseases 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- 206010003805 Autism Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- CIDLXSIIKQLZLL-WWMOSFEBSA-N C[C@@]1(CN(CCC1)C=1N2C(N=C3CCC[C@@H](C=13)C)=CC(=N2)[C@@H]1CC[C@H](CC1)C(F)(F)F)C(=O)O Chemical compound C[C@@]1(CN(CCC1)C=1N2C(N=C3CCC[C@@H](C=13)C)=CC(=N2)[C@@H]1CC[C@H](CC1)C(F)(F)F)C(=O)O CIDLXSIIKQLZLL-WWMOSFEBSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 description 1
- 206010052804 Drug tolerance Diseases 0.000 description 1
- GQESBRBTACOFPO-XWEPSHTISA-N FC([C@@H]1CC[C@H](CC1)C(=O)C(C#N)C#N)(F)F Chemical compound FC([C@@H]1CC[C@H](CC1)C(=O)C(C#N)C#N)(F)F GQESBRBTACOFPO-XWEPSHTISA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 102000005915 GABA Receptors Human genes 0.000 description 1
- 108010005551 GABA Receptors Proteins 0.000 description 1
- 108090000839 GABA-A Receptors Proteins 0.000 description 1
- 108010086407 GABA-C receptor Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 108090000862 Ion Channels Proteins 0.000 description 1
- 102000004310 Ion Channels Human genes 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
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- 102000016978 Orphan receptors Human genes 0.000 description 1
- 108070000031 Orphan receptors Proteins 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 102000004257 Potassium Channel Human genes 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102000001253 Protein Kinase Human genes 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
- 241000283984 Rodentia Species 0.000 description 1
- CDGFEINVQHEUQV-UHFFFAOYSA-N [1,3]thiazolo[5,4-d]pyrimidine Chemical class N1=CN=C2SC=NC2=C1 CDGFEINVQHEUQV-UHFFFAOYSA-N 0.000 description 1
- 230000008649 adaptation response Effects 0.000 description 1
- 102000030621 adenylate cyclase Human genes 0.000 description 1
- 108060000200 adenylate cyclase Proteins 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 230000008484 agonism Effects 0.000 description 1
- 201000007930 alcohol dependence Diseases 0.000 description 1
- 230000008848 allosteric regulation Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000006254 arylation reaction Methods 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 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
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 230000009460 calcium influx Effects 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 238000005266 casting Methods 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 210000003710 cerebral cortex Anatomy 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 239000012320 chlorinating reagent Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 229940061627 chloromethyl methyl ether Drugs 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 210000003520 dendritic spine Anatomy 0.000 description 1
- AVGAIPMGSIOHFZ-UHFFFAOYSA-N dichloromethane;2-propan-2-yloxypropane Chemical compound ClCCl.CC(C)OC(C)C AVGAIPMGSIOHFZ-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 206010013663 drug dependence Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000007938 effervescent tablet Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- IPAHPPZMOMRABY-SBSPUUFOSA-N ethyl (3R)-3-methylpiperidine-3-carboxylate hydrochloride Chemical compound Cl.CCOC(=O)[C@]1(C)CCCNC1 IPAHPPZMOMRABY-SBSPUUFOSA-N 0.000 description 1
- LNANFKKPVLUIBX-SECBINFHSA-N ethyl (3r)-3-methylpiperidine-3-carboxylate Chemical compound CCOC(=O)[C@]1(C)CCCNC1 LNANFKKPVLUIBX-SECBINFHSA-N 0.000 description 1
- KUGKXJWUQADYCV-UHFFFAOYSA-N ethyl 3-ethylpiperidine-3-carboxylate Chemical compound CCOC(=O)C1(CC)CCCNC1 KUGKXJWUQADYCV-UHFFFAOYSA-N 0.000 description 1
- XJVOGXVNOKPGGJ-UHFFFAOYSA-N ethyl 3-ethylpiperidine-3-carboxylate;hydrochloride Chemical compound Cl.CCOC(=O)C1(CC)CCCNC1 XJVOGXVNOKPGGJ-UHFFFAOYSA-N 0.000 description 1
- NRLZMDBKJJSRIJ-UHFFFAOYSA-N ethyl 3-propan-2-ylpiperidine-3-carboxylate Chemical compound CC(C)C1(CNCCC1)C(=O)OCC NRLZMDBKJJSRIJ-UHFFFAOYSA-N 0.000 description 1
- IVZYPLVEPLVIMB-UHFFFAOYSA-N ethyl 3-propan-2-ylpiperidine-3-carboxylate hydrochloride Chemical compound Cl.CC(C)C1(CNCCC1)C(=O)OCC IVZYPLVEPLVIMB-UHFFFAOYSA-N 0.000 description 1
- HZZDWLBBNSDYQM-UHFFFAOYSA-N ethyl 4,4-difluorocyclohexane-1-carboxylate Chemical compound CCOC(=O)C1CCC(F)(F)CC1 HZZDWLBBNSDYQM-UHFFFAOYSA-N 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000002964 excitative effect Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000005454 flavour additive Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 230000000848 glutamatergic effect Effects 0.000 description 1
- 230000026781 habituation Effects 0.000 description 1
- 238000009474 hot melt extrusion Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 230000002102 hyperpolarization Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000005462 in vivo assay Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 230000031146 intracellular signal transduction Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 230000001057 ionotropic effect Effects 0.000 description 1
- FMKOJHQHASLBPH-UHFFFAOYSA-N isopropyl iodide Chemical compound CC(C)I FMKOJHQHASLBPH-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000010030 laminating Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 230000003020 moisturizing effect Effects 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PVWOIHVRPOBWPI-UHFFFAOYSA-N n-propyl iodide Chemical compound CCCI PVWOIHVRPOBWPI-UHFFFAOYSA-N 0.000 description 1
- 239000004081 narcotic agent Substances 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- 239000008184 oral solid dosage form Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 238000004091 panning Methods 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000006201 parenteral dosage form Substances 0.000 description 1
- 238000011458 pharmacological treatment Methods 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 208000028173 post-traumatic stress disease Diseases 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 108020001213 potassium channel Proteins 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 210000000063 presynaptic terminal Anatomy 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- NHVRIDDXGZPJTJ-UHFFFAOYSA-N skf-97,541 Chemical compound CP(O)(=O)CCCN NHVRIDDXGZPJTJ-UHFFFAOYSA-N 0.000 description 1
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 230000004960 subcellular localization Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
- 230000003956 synaptic plasticity Effects 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 210000002504 synaptic vesicle Anatomy 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 210000001779 taste bud Anatomy 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000009071 up-regulation mechanism Effects 0.000 description 1
- 229940102566 valproate Drugs 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
- UZVNCLCLJHPHIF-NOJKMYKQSA-J zinc;(1e)-2-(ethylcarbamoylamino)-n-methoxy-2-oxoethanimidoyl cyanide;manganese(2+);n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[Zn+2].[S-]C(=S)NCCNC([S-])=S.[S-]C(=S)NCCNC([S-])=S.CCNC(=O)NC(=O)C(\C#N)=N\OC UZVNCLCLJHPHIF-NOJKMYKQSA-J 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/14—Ortho-condensed systems
- C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Physical Education & Sports Medicine (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU1700108A HU231058B1 (hu) | 2017-03-13 | 2017-03-13 | Gyógyászatilag hatékony aliciklusos-szubsztituált pirazolo[1,5-a]pirimidin származékok |
| PCT/IB2018/051599 WO2018167630A1 (en) | 2017-03-13 | 2018-03-12 | PHARMACOLOGICALLY ACTIVE ALICYCLIC-SUBSTITUTED PYRAZOLO[1,5-a]PYRIMIDINE DERIVATIVES |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EA201992127A1 EA201992127A1 (ru) | 2020-02-06 |
| EA038756B1 true EA038756B1 (ru) | 2021-10-14 |
Family
ID=89992389
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EA201992127A EA038756B1 (ru) | 2017-03-13 | 2018-03-12 | ФАРМАКОЛОГИЧЕСКИ АКТИВНЫЕ АЛИЦИКЛИЧЕСКИ ЗАМЕЩЕННЫЕ ПРОИЗВОДНЫЕ ПИРАЗОЛО[1,5-a]ПИРИМИДИНА |
Country Status (32)
| Country | Link |
|---|---|
| US (1) | US11026946B2 (https=) |
| EP (1) | EP3596080B1 (https=) |
| JP (1) | JP7153662B2 (https=) |
| KR (1) | KR20190127779A (https=) |
| CN (1) | CN110431142A (https=) |
| AR (1) | AR111176A1 (https=) |
| AU (1) | AU2018235266B2 (https=) |
| BR (1) | BR112019018843A2 (https=) |
| CA (1) | CA3056185A1 (https=) |
| CL (1) | CL2019002601A1 (https=) |
| CO (1) | CO2019010120A2 (https=) |
| CY (1) | CY1124708T1 (https=) |
| DK (1) | DK3596080T3 (https=) |
| EA (1) | EA038756B1 (https=) |
| EC (1) | ECSP19072975A (https=) |
| ES (1) | ES2893824T3 (https=) |
| GE (1) | GEP20217256B (https=) |
| HR (1) | HRP20211850T1 (https=) |
| HU (2) | HU231058B1 (https=) |
| IL (1) | IL268923A (https=) |
| LT (1) | LT3596080T (https=) |
| MX (1) | MX2019011000A (https=) |
| MY (1) | MY195262A (https=) |
| PE (1) | PE20191646A1 (https=) |
| PH (1) | PH12019501968A1 (https=) |
| PL (1) | PL3596080T3 (https=) |
| PT (1) | PT3596080T (https=) |
| RS (1) | RS62533B1 (https=) |
| SG (1) | SG11201907864YA (https=) |
| SI (1) | SI3596080T1 (https=) |
| UA (1) | UA124783C2 (https=) |
| WO (1) | WO2018167630A1 (https=) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ797702A (en) | 2017-03-13 | 2026-03-27 | Lundbeck La Jolla Research Center Inc | Dual magl and faah inhibitors |
| HU231057B1 (hu) | 2017-03-13 | 2020-04-28 | Richter Gedeon Nyrt | Gyógyászatilag hatékony aril-szubsztituált pirazolo[1,5-a]pirimidin származékok |
| TWI901650B (zh) | 2020-03-26 | 2025-10-21 | 匈牙利商羅特格登公司 | 啶及吡啶并〔３，４－ｃ〕嗒衍生物 |
| TWI907472B (zh) * | 2020-08-05 | 2025-12-11 | 匈牙利商羅特格登公司 | 具藥理活性之經雜環取代的吡唑并〔１，５－ａ〕嘧啶衍生物 |
| HU231691B1 (hu) | 2021-09-29 | 2025-10-28 | Richter Gedeon Nyrt | GABAA ALFA5 receptor modulátor hatású biciklusos aminszármazékok |
| CN115872095A (zh) * | 2022-11-28 | 2023-03-31 | 南通三鑫车灯配件有限公司 | 一种汽车车灯反光罩的生产线流转装置 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007139240A1 (en) * | 2006-05-25 | 2007-12-06 | Korea Research Institute Of Chemical Technology | 7-(3,4-dialkoxyphenyl)-pyrazolo[1,5-a]pyrimidine compounds, process for preparing thereof, and pharmaceutical composition for treating or preventing asthma, chronic obstructive pulmonary disease, arthritis, atopic dermatitis, tumor and degenerative brain diseases comprising the same |
| WO2009123986A1 (en) * | 2008-03-31 | 2009-10-08 | Takeda Pharmaceutical Company Limited | Apoptosis signal-regulating kinase 1 inhibitors |
| US20160304527A1 (en) * | 2015-04-20 | 2016-10-20 | AbbVie Deutschland GmbH & Co. KG | Substituted pyrazolopyrimidines and method of use |
| WO2017069270A1 (ja) * | 2015-10-22 | 2017-04-27 | 大正製薬株式会社 | 含窒素縮合複素環化合物 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100802863B1 (ko) | 2004-03-02 | 2008-02-12 | 에프. 호프만-라 로슈 아게 | 불안증, 우울증 및 간질의 치료를 위한 ｇａｂａ 수용체리간드로서 4-(설파닐-피리미딘-4-일메틸)-모폴린 유도체및 관련 화합물 |
| GB0512844D0 (en) | 2005-06-23 | 2005-08-03 | Novartis Ag | Organic compounds |
| TWI648281B (zh) | 2013-10-17 | 2019-01-21 | 日商安斯泰來製藥股份有限公司 | 含硫二環式化合物 |
| HU231057B1 (hu) | 2017-03-13 | 2020-04-28 | Richter Gedeon Nyrt | Gyógyászatilag hatékony aril-szubsztituált pirazolo[1,5-a]pirimidin származékok |
-
2017
- 2017-03-13 HU HU1700108A patent/HU231058B1/hu not_active IP Right Cessation
-
2018
- 2018-03-12 LT LTEPPCT/IB2018/051599T patent/LT3596080T/lt unknown
- 2018-03-12 PT PT18713016T patent/PT3596080T/pt unknown
- 2018-03-12 PL PL18713016T patent/PL3596080T3/pl unknown
- 2018-03-12 KR KR1020197028833A patent/KR20190127779A/ko not_active Ceased
- 2018-03-12 BR BR112019018843A patent/BR112019018843A2/pt not_active Application Discontinuation
- 2018-03-12 RS RS20211334A patent/RS62533B1/sr unknown
- 2018-03-12 HR HRP20211850TT patent/HRP20211850T1/hr unknown
- 2018-03-12 EP EP18713016.6A patent/EP3596080B1/en active Active
- 2018-03-12 CN CN201880017859.XA patent/CN110431142A/zh active Pending
- 2018-03-12 CA CA3056185A patent/CA3056185A1/en active Pending
- 2018-03-12 PE PE2019001773A patent/PE20191646A1/es unknown
- 2018-03-12 AU AU2018235266A patent/AU2018235266B2/en not_active Ceased
- 2018-03-12 EA EA201992127A patent/EA038756B1/ru unknown
- 2018-03-12 JP JP2019549366A patent/JP7153662B2/ja active Active
- 2018-03-12 WO PCT/IB2018/051599 patent/WO2018167630A1/en not_active Ceased
- 2018-03-12 UA UAA201910328A patent/UA124783C2/uk unknown
- 2018-03-12 GE GEAP201815192A patent/GEP20217256B/en unknown
- 2018-03-12 DK DK18713016.6T patent/DK3596080T3/da active
- 2018-03-12 MY MYPI2019004947A patent/MY195262A/en unknown
- 2018-03-12 SI SI201830495T patent/SI3596080T1/sl unknown
- 2018-03-12 HU HUE18713016A patent/HUE056562T2/hu unknown
- 2018-03-12 US US16/493,453 patent/US11026946B2/en active Active
- 2018-03-12 MX MX2019011000A patent/MX2019011000A/es unknown
- 2018-03-12 SG SG11201907864YA patent/SG11201907864YA/en unknown
- 2018-03-12 ES ES18713016T patent/ES2893824T3/es active Active
- 2018-03-13 AR ARP180100580A patent/AR111176A1/es unknown
-
2019
- 2019-08-26 IL IL26892319A patent/IL268923A/en unknown
- 2019-08-27 PH PH12019501968A patent/PH12019501968A1/en unknown
- 2019-09-12 CL CL2019002601A patent/CL2019002601A1/es unknown
- 2019-09-18 CO CONC2019/0010120A patent/CO2019010120A2/es unknown
- 2019-10-10 EC ECSENADI201972975A patent/ECSP19072975A/es unknown
-
2021
- 2021-11-08 CY CY20211100964T patent/CY1124708T1/el unknown
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007139240A1 (en) * | 2006-05-25 | 2007-12-06 | Korea Research Institute Of Chemical Technology | 7-(3,4-dialkoxyphenyl)-pyrazolo[1,5-a]pyrimidine compounds, process for preparing thereof, and pharmaceutical composition for treating or preventing asthma, chronic obstructive pulmonary disease, arthritis, atopic dermatitis, tumor and degenerative brain diseases comprising the same |
| WO2009123986A1 (en) * | 2008-03-31 | 2009-10-08 | Takeda Pharmaceutical Company Limited | Apoptosis signal-regulating kinase 1 inhibitors |
| US20160304527A1 (en) * | 2015-04-20 | 2016-10-20 | AbbVie Deutschland GmbH & Co. KG | Substituted pyrazolopyrimidines and method of use |
| WO2017069270A1 (ja) * | 2015-10-22 | 2017-04-27 | 大正製薬株式会社 | 含窒素縮合複素環化合物 |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP7153662B2 (ja) | 薬理学的に活性な脂環式置換ピラゾロ［１，５－ａ］ピリミジン誘導体 | |
| JP7153661B2 (ja) | 薬理学的に活性なアリール置換ピラゾロ［１，５－ａ］ピリミジン誘導体 | |
| KR20110106450A (ko) | 바이시클릭 피라졸로-헤테로사이클 | |
| TWI907472B (zh) | 具藥理活性之經雜環取代的吡唑并〔１，５－ａ〕嘧啶衍生物 | |
| CN121127471A (zh) | 作为nlrp3抑制剂的吡唑并嘧啶衍生物 | |
| TW202035403A (zh) | 作為ｇａｂａａ ａ５受體調節子的雙環衍生物 | |
| TW202017904A (zh) | 經取代之（吖）吲哚衍生物 | |
| EA049144B1 (ru) | ФАРМАКОЛОГИЧЕСКИ АКТИВНЫЕ ЗАМЕЩЕННЫЕ ПО ГЕТЕРОЦИКЛИЧЕСКОМУ ФРАГМЕНТУ ПРОИЗВОДНЫЕ ПИРАЗОЛО[1,5-a]ПИРИМИДИНА | |
| WO2026068748A1 (en) | Novel pyrimidinedione derivatives as gaba b positive allosteric modulators | |
| JP2026514121A (ja) | Ｎｌｒｐ３阻害剤としてのピラゾロピリミジン誘導体 | |
| OA19480A (en) | Pharmacologically active alicyclicsubstituted pyrazolo [1,5-a] pyrimidine derivatives. | |
| KR19990071056A (ko) | Nmda 수용체 길항제로 작용하는 4-치환-퀴놀린-2-카복실산유도체 |