JP5161226B2 - Ｃｒｆ１受容体アンタゴニストとしてのチアゾールピラゾロピリミジン - Google Patents
Ｃｒｆ１受容体アンタゴニストとしてのチアゾールピラゾロピリミジン Download PDFInfo
- Publication number
- JP5161226B2 JP5161226B2 JP2009529316A JP2009529316A JP5161226B2 JP 5161226 B2 JP5161226 B2 JP 5161226B2 JP 2009529316 A JP2009529316 A JP 2009529316A JP 2009529316 A JP2009529316 A JP 2009529316A JP 5161226 B2 JP5161226 B2 JP 5161226B2
- Authority
- JP
- Japan
- Prior art keywords
- mmol
- formula
- added
- dimethyl
- propyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 108091005471 CRHR1 Proteins 0.000 title description 11
- 239000002464 receptor antagonist Substances 0.000 title description 3
- 229940044551 receptor antagonist Drugs 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 137
- 150000003839 salts Chemical class 0.000 claims description 30
- -1 2-methyl-2H- [1,2,4] triazol-3-yl Chemical group 0.000 claims description 28
- 238000011282 treatment Methods 0.000 claims description 14
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 claims description 12
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 208000007848 Alcoholism Diseases 0.000 claims description 7
- 206010013654 Drug abuse Diseases 0.000 claims description 7
- 206010001584 alcohol abuse Diseases 0.000 claims description 7
- 208000025746 alcohol use disease Diseases 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 208000011117 substance-related disease Diseases 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 4
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- XVAWSBAQNIXMIO-UHFFFAOYSA-N tildacerfont Chemical compound CC1=NN2C(C(CC)CC)=CC(C)=NC2=C1C(=C(N=1)Cl)SC=1N1CCOCC1 XVAWSBAQNIXMIO-UHFFFAOYSA-N 0.000 claims description 2
- VOWVNYUDZKFEFL-UHFFFAOYSA-N 2-butylpyrazolo[1,5-a]pyrimidine Chemical compound N1=CC=CN2N=C(CCCC)C=C21 VOWVNYUDZKFEFL-UHFFFAOYSA-N 0.000 claims 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 216
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 144
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 98
- 238000006243 chemical reaction Methods 0.000 description 71
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 69
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 66
- 239000000203 mixture Substances 0.000 description 62
- 239000000243 solution Substances 0.000 description 55
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 54
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 50
- 235000019439 ethyl acetate Nutrition 0.000 description 49
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 48
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 38
- 238000002360 preparation method Methods 0.000 description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
- 102000012289 Corticotropin-Releasing Hormone Human genes 0.000 description 26
- 108010022152 Corticotropin-Releasing Hormone Proteins 0.000 description 26
- 239000000055 Corticotropin-Releasing Hormone Substances 0.000 description 26
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 26
- 229910052938 sodium sulfate Inorganic materials 0.000 description 26
- 235000011152 sodium sulphate Nutrition 0.000 description 26
- 239000002904 solvent Substances 0.000 description 23
- 239000010410 layer Substances 0.000 description 22
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 22
- 239000007787 solid Substances 0.000 description 21
- 102100038018 Corticotropin-releasing factor receptor 1 Human genes 0.000 description 20
- 101000878678 Homo sapiens Corticotropin-releasing factor receptor 1 Proteins 0.000 description 20
- 101000948733 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) Probable phospholipid translocase non-catalytic subunit CRF1 Proteins 0.000 description 20
- 238000003818 flash chromatography Methods 0.000 description 20
- 239000012044 organic layer Substances 0.000 description 20
- 238000009739 binding Methods 0.000 description 19
- 238000003756 stirring Methods 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 238000010992 reflux Methods 0.000 description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 17
- 230000027455 binding Effects 0.000 description 17
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 16
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 16
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 15
- 102100038019 Corticotropin-releasing factor receptor 2 Human genes 0.000 description 14
- 101000878664 Homo sapiens Corticotropin-releasing factor receptor 2 Proteins 0.000 description 14
- 238000000034 method Methods 0.000 description 13
- 239000003921 oil Substances 0.000 description 13
- 235000019198 oils Nutrition 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 12
- 239000003153 chemical reaction reagent Substances 0.000 description 12
- 239000003814 drug Substances 0.000 description 12
- 238000001914 filtration Methods 0.000 description 12
- 239000012442 inert solvent Substances 0.000 description 12
- RXNZFHIEDZEUQM-UHFFFAOYSA-N 2-bromo-1,3-thiazole Chemical compound BrC1=NC=CS1 RXNZFHIEDZEUQM-UHFFFAOYSA-N 0.000 description 11
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 11
- 230000002829 reductive effect Effects 0.000 description 11
- 238000010898 silica gel chromatography Methods 0.000 description 11
- 239000011592 zinc chloride Substances 0.000 description 11
- 235000005074 zinc chloride Nutrition 0.000 description 11
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 10
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 10
- 239000005557 antagonist Substances 0.000 description 10
- 239000012267 brine Substances 0.000 description 10
- 238000009826 distribution Methods 0.000 description 10
- 229940079593 drug Drugs 0.000 description 10
- 239000012299 nitrogen atmosphere Substances 0.000 description 10
- 238000000746 purification Methods 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- 150000001412 amines Chemical class 0.000 description 9
- 239000012298 atmosphere Substances 0.000 description 9
- 239000012043 crude product Substances 0.000 description 9
- 229910052725 zinc Inorganic materials 0.000 description 9
- 239000011701 zinc Substances 0.000 description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 8
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 8
- 238000006880 cross-coupling reaction Methods 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
- QTEPSNRIXHMSKM-UHFFFAOYSA-N 3-iodo-2h-pyrazolo[4,3-d]pyrimidine Chemical compound N1=CN=C2C(I)=NNC2=C1 QTEPSNRIXHMSKM-UHFFFAOYSA-N 0.000 description 7
- 108091005470 CRHR2 Proteins 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- 208000001145 Metabolic Syndrome Diseases 0.000 description 7
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 7
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical compound NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 description 6
- LGQMDCIHBYTQJU-UHFFFAOYSA-N 2,5-dimethyl-1h-pyrazolo[1,5-a]pyrimidin-7-one Chemical compound CC1=CC(=O)N2NC(C)=CC2=N1 LGQMDCIHBYTQJU-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 208000008589 Obesity Diseases 0.000 description 6
- 208000007913 Pituitary Neoplasms Diseases 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 210000004556 brain Anatomy 0.000 description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 6
- 229910000024 caesium carbonate Inorganic materials 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 125000000623 heterocyclic group Chemical group 0.000 description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 6
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 6
- 235000020824 obesity Nutrition 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- 208000005676 Adrenogenital syndrome Diseases 0.000 description 5
- 206010008874 Chronic Fatigue Syndrome Diseases 0.000 description 5
- 208000008448 Congenital adrenal hyperplasia Diseases 0.000 description 5
- 206010020751 Hypersensitivity Diseases 0.000 description 5
- 206010020772 Hypertension Diseases 0.000 description 5
- 208000012902 Nervous system disease Diseases 0.000 description 5
- 208000010067 Pituitary ACTH Hypersecretion Diseases 0.000 description 5
- 208000020627 Pituitary-dependent Cushing syndrome Diseases 0.000 description 5
- 208000005107 Premature Birth Diseases 0.000 description 5
- 206010036618 Premenstrual syndrome Diseases 0.000 description 5
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 5
- 201000001880 Sexual dysfunction Diseases 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 208000007107 Stomach Ulcer Diseases 0.000 description 5
- 230000007815 allergy Effects 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 210000003169 central nervous system Anatomy 0.000 description 5
- 201000005917 gastric ulcer Diseases 0.000 description 5
- 208000027866 inflammatory disease Diseases 0.000 description 5
- 208000002551 irritable bowel syndrome Diseases 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- 201000006417 multiple sclerosis Diseases 0.000 description 5
- 208000029766 myalgic encephalomeyelitis/chronic fatigue syndrome Diseases 0.000 description 5
- 230000009871 nonspecific binding Effects 0.000 description 5
- 229910052763 palladium Inorganic materials 0.000 description 5
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 5
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- 231100000872 sexual dysfunction Toxicity 0.000 description 5
- 208000019116 sleep disease Diseases 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 5
- 208000009935 visceral pain Diseases 0.000 description 5
- BHKKSKOHRFHHIN-MRVPVSSYSA-N 1-[[2-[(1R)-1-aminoethyl]-4-chlorophenyl]methyl]-2-sulfanylidene-5H-pyrrolo[3,2-d]pyrimidin-4-one Chemical compound N[C@H](C)C1=C(CN2C(NC(C3=C2C=CN3)=O)=S)C=CC(=C1)Cl BHKKSKOHRFHHIN-MRVPVSSYSA-N 0.000 description 4
- OJVAMHKKJGICOG-UHFFFAOYSA-N 2,5-hexanedione Chemical compound CC(=O)CCC(C)=O OJVAMHKKJGICOG-UHFFFAOYSA-N 0.000 description 4
- KQJDDNCSNLUGAK-UHFFFAOYSA-N 3-iodo-2,5-dimethyl-7-pentan-3-ylpyrazolo[1,5-a]pyrimidine Chemical compound CCC(CC)C1=CC(C)=NC2=C(I)C(C)=NN12 KQJDDNCSNLUGAK-UHFFFAOYSA-N 0.000 description 4
- QMHIMXFNBOYPND-UHFFFAOYSA-N 4-methylthiazole Chemical compound CC1=CSC=N1 QMHIMXFNBOYPND-UHFFFAOYSA-N 0.000 description 4
- 206010010904 Convulsion Diseases 0.000 description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 208000001640 Fibromyalgia Diseases 0.000 description 4
- 239000007818 Grignard reagent Substances 0.000 description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 4
- 208000019695 Migraine disease Diseases 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- 206010036590 Premature baby Diseases 0.000 description 4
- 108010069820 Pro-Opiomelanocortin Proteins 0.000 description 4
- 239000000683 Pro-Opiomelanocortin Substances 0.000 description 4
- 102100027467 Pro-opiomelanocortin Human genes 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000008484 agonism Effects 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- 235000019270 ammonium chloride Nutrition 0.000 description 4
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- USVZFSNDGFNNJT-UHFFFAOYSA-N cyclopenta-1,4-dien-1-yl(diphenyl)phosphane (2,3-dichlorocyclopenta-1,4-dien-1-yl)-diphenylphosphane iron(2+) Chemical compound [Fe++].c1cc[c-](c1)P(c1ccccc1)c1ccccc1.Clc1c(cc[c-]1Cl)P(c1ccccc1)c1ccccc1 USVZFSNDGFNNJT-UHFFFAOYSA-N 0.000 description 4
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 4
- BSHICDXRSZQYBP-UHFFFAOYSA-N dichloromethane;palladium(2+) Chemical compound [Pd+2].ClCCl BSHICDXRSZQYBP-UHFFFAOYSA-N 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 206010015037 epilepsy Diseases 0.000 description 4
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 4
- 150000004795 grignard reagents Chemical class 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 208000000509 infertility Diseases 0.000 description 4
- 230000036512 infertility Effects 0.000 description 4
- 231100000535 infertility Toxicity 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 229910001629 magnesium chloride Inorganic materials 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 206010027599 migraine Diseases 0.000 description 4
- LCEDQNDDFOCWGG-UHFFFAOYSA-N morpholine-4-carbaldehyde Chemical compound O=CN1CCOCC1 LCEDQNDDFOCWGG-UHFFFAOYSA-N 0.000 description 4
- 239000002858 neurotransmitter agent Substances 0.000 description 4
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 4
- MXQOYLRVSVOCQT-UHFFFAOYSA-N palladium;tritert-butylphosphane Chemical compound [Pd].CC(C)(C)P(C(C)(C)C)C(C)(C)C.CC(C)(C)P(C(C)(C)C)C(C)(C)C MXQOYLRVSVOCQT-UHFFFAOYSA-N 0.000 description 4
- 230000001817 pituitary effect Effects 0.000 description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
- 208000020016 psychiatric disease Diseases 0.000 description 4
- LDIJKUBTLZTFRG-UHFFFAOYSA-N pyrazolo[1,5-a]pyrimidine Chemical class N1=CC=CN2N=CC=C21 LDIJKUBTLZTFRG-UHFFFAOYSA-N 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- VJCHUDDPWPQOLH-UHFFFAOYSA-N trimethyl(1,3-thiazol-2-yl)silane Chemical compound C[Si](C)(C)C1=NC=CS1 VJCHUDDPWPQOLH-UHFFFAOYSA-N 0.000 description 4
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 3
- MWZDIEIXRBWPLG-UHFFFAOYSA-N 1-methyl-1,2,4-triazole Chemical compound CN1C=NC=N1 MWZDIEIXRBWPLG-UHFFFAOYSA-N 0.000 description 3
- ANNRUWYFVIGKHA-UHFFFAOYSA-N 3-[6-(dimethylamino)-4-methylpyridin-3-yl]-2,5-dimethyl-n,n-dipropylpyrazolo[1,5-a]pyrimidin-7-amine Chemical compound CC1=NN2C(N(CCC)CCC)=CC(C)=NC2=C1C1=CN=C(N(C)C)C=C1C ANNRUWYFVIGKHA-UHFFFAOYSA-N 0.000 description 3
- MTZAHLFTBUJSIJ-UHFFFAOYSA-N 4-(4-chloro-1,3-thiazol-2-yl)morpholine Chemical compound ClC1=CSC(N2CCOCC2)=N1 MTZAHLFTBUJSIJ-UHFFFAOYSA-N 0.000 description 3
- BNUTXEKPXPZAIT-UHFFFAOYSA-N 4-bromoheptane Chemical compound CCCC(Br)CCC BNUTXEKPXPZAIT-UHFFFAOYSA-N 0.000 description 3
- FYTLHYRDGXRYEY-UHFFFAOYSA-N 5-Methyl-3-pyrazolamine Chemical compound CC=1C=C(N)NN=1 FYTLHYRDGXRYEY-UHFFFAOYSA-N 0.000 description 3
- IIMLZWMRQNCPTM-UHFFFAOYSA-N 5-bromo-4-methyl-1,3-thiazole Chemical compound CC=1N=CSC=1Br IIMLZWMRQNCPTM-UHFFFAOYSA-N 0.000 description 3
- QGROGNQUPBOMJQ-UHFFFAOYSA-N 7-chloro-2,5-dimethylpyrazolo[1,5-a]pyrimidine Chemical compound N1=C(C)C=C(Cl)N2N=C(C)C=C21 QGROGNQUPBOMJQ-UHFFFAOYSA-N 0.000 description 3
- ZCUCQGFNVLUBNO-UHFFFAOYSA-N 7-heptan-4-yl-2,5-dimethylpyrazolo[1,5-a]pyrimidine Chemical compound CCCC(CCC)C1=CC(C)=NC2=CC(C)=NN12 ZCUCQGFNVLUBNO-UHFFFAOYSA-N 0.000 description 3
- 208000019901 Anxiety disease Diseases 0.000 description 3
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 3
- 229950003476 aminothiazole Drugs 0.000 description 3
- 230000036506 anxiety Effects 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 230000031709 bromination Effects 0.000 description 3
- 238000005893 bromination reaction Methods 0.000 description 3
- KMGBZBJJOKUPIA-UHFFFAOYSA-N butyl iodide Chemical compound CCCCI KMGBZBJJOKUPIA-UHFFFAOYSA-N 0.000 description 3
- 239000006260 foam Substances 0.000 description 3
- 150000003840 hydrochlorides Chemical class 0.000 description 3
- 210000000987 immune system Anatomy 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000011065 in-situ storage Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- UUSXSNJAQDJKCG-UHFFFAOYSA-N iodo(methoxy)methane Chemical compound COCI UUSXSNJAQDJKCG-UHFFFAOYSA-N 0.000 description 3
- 229910052744 lithium Inorganic materials 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 208000010916 pituitary tumor Diseases 0.000 description 3
- 230000036470 plasma concentration Effects 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 238000001269 time-of-flight mass spectrometry Methods 0.000 description 3
- 238000005292 vacuum distillation Methods 0.000 description 3
- OADLYIRTEOHBCF-UHFFFAOYSA-N 1h-pyrazolo[4,3-d]pyrimidine;1,3-thiazole Chemical class C1=CSC=N1.N1=CN=C2C=NNC2=C1 OADLYIRTEOHBCF-UHFFFAOYSA-N 0.000 description 2
- HFQXGNKAEXJTGP-UHFFFAOYSA-N 2,4-dibromo-5-(2,5-dimethyl-7-pentan-3-ylpyrazolo[1,5-a]pyrimidin-3-yl)-1,3-thiazole Chemical compound CC1=NN2C(C(CC)CC)=CC(C)=NC2=C1C=1SC(Br)=NC=1Br HFQXGNKAEXJTGP-UHFFFAOYSA-N 0.000 description 2
- HPQPXCPKTQVBPG-UHFFFAOYSA-N 2,4-dibromo-5-(7-heptan-4-yl-2,5-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)-1,3-thiazole Chemical compound CC1=NN2C(C(CCC)CCC)=CC(C)=NC2=C1C=1SC(Br)=NC=1Br HPQPXCPKTQVBPG-UHFFFAOYSA-N 0.000 description 2
- ICETWLGKJXCIDX-UHFFFAOYSA-N 2,4-dichloro-1,3-thiazole Chemical compound ClC1=CSC(Cl)=N1 ICETWLGKJXCIDX-UHFFFAOYSA-N 0.000 description 2
- WOUPIOIURYZNRU-UHFFFAOYSA-N 2-bromo-4-chloro-1,3-thiazole Chemical compound ClC1=CSC(Br)=N1 WOUPIOIURYZNRU-UHFFFAOYSA-N 0.000 description 2
- ISISZAZLEGLXEO-UHFFFAOYSA-N 2-pyridin-4-yl-1,3-thiazole Chemical compound C1=CSC(C=2C=CN=CC=2)=N1 ISISZAZLEGLXEO-UHFFFAOYSA-N 0.000 description 2
- ONZQYZKCUHFORE-UHFFFAOYSA-N 3-bromo-1,1,1-trifluoropropan-2-one Chemical compound FC(F)(F)C(=O)CBr ONZQYZKCUHFORE-UHFFFAOYSA-N 0.000 description 2
- SYQJHOHGVLZASQ-UHFFFAOYSA-N 4,5-dimethyl-2-(1H-pyrrol-2-yl)-1,3-thiazole Chemical compound Cc1nc(sc1C)-c1ccc[nH]1 SYQJHOHGVLZASQ-UHFFFAOYSA-N 0.000 description 2
- VDTIGYKLTROQAH-UHFFFAOYSA-N 4-bromo-1,3-thiazole Chemical compound BrC1=CSC=N1 VDTIGYKLTROQAH-UHFFFAOYSA-N 0.000 description 2
- RFUIPZUKDJEUSI-UHFFFAOYSA-N 4-bromo-5-(2,5-dimethyl-7-pentan-3-ylpyrazolo[1,5-a]pyrimidin-3-yl)-1,3-thiazole-2-carbaldehyde Chemical compound CC1=NN2C(C(CC)CC)=CC(C)=NC2=C1C=1SC(C=O)=NC=1Br RFUIPZUKDJEUSI-UHFFFAOYSA-N 0.000 description 2
- CQCVDIVNBYMRNY-UHFFFAOYSA-N 4-bromo-5-(2,5-dimethyl-7-pentan-3-ylpyrazolo[1,5-a]pyrimidin-3-yl)-2-(2-methyl-1,2,4-triazol-3-yl)-1,3-thiazole Chemical compound CC1=NN2C(C(CC)CC)=CC(C)=NC2=C1C(=C(N=1)Br)SC=1C1=NC=NN1C CQCVDIVNBYMRNY-UHFFFAOYSA-N 0.000 description 2
- RXMJMPNRLIALPQ-UHFFFAOYSA-N 4-bromo-5-(7-heptan-4-yl-2,5-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)-2-(2-methyl-1,2,4-triazol-3-yl)-1,3-thiazole Chemical compound CC1=NN2C(C(CCC)CCC)=CC(C)=NC2=C1C(=C(N=1)Br)SC=1C1=NC=NN1C RXMJMPNRLIALPQ-UHFFFAOYSA-N 0.000 description 2
- RTLUPHDWSUGAOS-UHFFFAOYSA-N 4-iodopyridine Chemical compound IC1=CC=NC=C1 RTLUPHDWSUGAOS-UHFFFAOYSA-N 0.000 description 2
- DWUPYMSVAPQXMS-UHFFFAOYSA-N 5-bromo-1,3-thiazole Chemical compound BrC1=CN=CS1 DWUPYMSVAPQXMS-UHFFFAOYSA-N 0.000 description 2
- WDEPLQQRIXCRQF-UHFFFAOYSA-N 5-bromo-4-(trifluoromethyl)-1,3-thiazol-2-amine;hydrobromide Chemical compound Br.NC1=NC(C(F)(F)F)=C(Br)S1 WDEPLQQRIXCRQF-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- 101150105710 CRF1 gene Proteins 0.000 description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 2
- 229910021590 Copper(II) bromide Inorganic materials 0.000 description 2
- 108010056643 Corticotropin-Releasing Hormone Receptors Proteins 0.000 description 2
- 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 2
- 208000023105 Huntington disease Diseases 0.000 description 2
- 206010062767 Hypophysitis Diseases 0.000 description 2
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 2
- 108090000189 Neuropeptides Proteins 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- 208000018737 Parkinson disease Diseases 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 241000233805 Phoenix Species 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 2
- 108010046516 Wheat Germ Agglutinins Proteins 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 2
- 210000004198 anterior pituitary gland Anatomy 0.000 description 2
- 230000007529 anxiety like behavior Effects 0.000 description 2
- 230000036528 appetite Effects 0.000 description 2
- 235000019789 appetite Nutrition 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000002567 autonomic effect Effects 0.000 description 2
- 230000006399 behavior Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 229940125692 cardiovascular agent Drugs 0.000 description 2
- 239000002327 cardiovascular agent Substances 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- OGEBRHQLRGFBNV-RZDIXWSQSA-N chembl2036808 Chemical compound C12=NC(NCCCC)=NC=C2C(C=2C=CC(F)=CC=2)=NN1C[C@H]1CC[C@H](N)CC1 OGEBRHQLRGFBNV-RZDIXWSQSA-N 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 2
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 2
- 125000005594 diketone group Chemical group 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 230000004064 dysfunction Effects 0.000 description 2
- 239000012039 electrophile Substances 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 230000002124 endocrine Effects 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 238000012224 gene deletion Methods 0.000 description 2
- 239000003365 glass fiber Substances 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 230000001900 immune effect Effects 0.000 description 2
- 230000002055 immunohistochemical effect Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- ZLIIGTFTLSZBJF-UHFFFAOYSA-N lithium;1,3-thiazole Chemical compound [Li].C1=CSC=N1 ZLIIGTFTLSZBJF-UHFFFAOYSA-N 0.000 description 2
- 230000004807 localization Effects 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 230000000116 mitigating effect Effects 0.000 description 2
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 2
- 208000015706 neuroendocrine disease Diseases 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 210000003635 pituitary gland Anatomy 0.000 description 2
- 239000013612 plasmid Substances 0.000 description 2
- 235000011056 potassium acetate Nutrition 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 201000002212 progressive supranuclear palsy Diseases 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 238000006268 reductive amination reaction Methods 0.000 description 2
- 230000001177 retroviral effect Effects 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 238000002821 scintillation proximity assay Methods 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- AOFUBOWZWQFQJU-SNOJBQEQSA-N (2r,3s,4s,5r)-2,5-bis(hydroxymethyl)oxolane-2,3,4-triol;(2s,3r,4s,5s,6r)-6-(hydroxymethyl)oxane-2,3,4,5-tetrol Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O.OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O AOFUBOWZWQFQJU-SNOJBQEQSA-N 0.000 description 1
- ZGTFNNUASMWGTM-UHFFFAOYSA-N 1,3-thiazole-2-carbaldehyde Chemical compound O=CC1=NC=CS1 ZGTFNNUASMWGTM-UHFFFAOYSA-N 0.000 description 1
- QWEWLLNSJDTOKH-UHFFFAOYSA-N 1,3-thiazole-2-carboxamide Chemical compound NC(=O)C1=NC=CS1 QWEWLLNSJDTOKH-UHFFFAOYSA-N 0.000 description 1
- ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical compound O=C1CSC(=O)N1 ZOBPZXTWZATXDG-UHFFFAOYSA-N 0.000 description 1
- AWNXKZVIZARMME-UHFFFAOYSA-N 1-[[5-[2-[(2-chloropyridin-4-yl)amino]pyrimidin-4-yl]-4-(cyclopropylmethyl)pyrimidin-2-yl]amino]-2-methylpropan-2-ol Chemical compound N=1C(NCC(C)(O)C)=NC=C(C=2N=C(NC=3C=C(Cl)N=CC=3)N=CC=2)C=1CC1CC1 AWNXKZVIZARMME-UHFFFAOYSA-N 0.000 description 1
- JWAWEQBUZOGIBZ-UHFFFAOYSA-N 1-methyltriazole Chemical compound CN1C=CN=N1 JWAWEQBUZOGIBZ-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- BUEFDJQUUGMUJO-UHFFFAOYSA-N 1h-pyrazolo[1,5-a]pyrimidin-7-one Chemical compound O=C1C=CN=C2C=CNN12 BUEFDJQUUGMUJO-UHFFFAOYSA-N 0.000 description 1
- OUYLXVQKVBXUGW-UHFFFAOYSA-N 2,3-dimethyl-1h-pyrrole Chemical compound CC=1C=CNC=1C OUYLXVQKVBXUGW-UHFFFAOYSA-N 0.000 description 1
- MKEJZKKVVUZXIS-UHFFFAOYSA-N 2,4-dibromo-1,3-thiazole Chemical compound BrC1=CSC(Br)=N1 MKEJZKKVVUZXIS-UHFFFAOYSA-N 0.000 description 1
- FXCCWSSWNZZWPQ-UHFFFAOYSA-N 2,5-dibromo-4-chloro-1,3-thiazole Chemical compound ClC=1N=C(Br)SC=1Br FXCCWSSWNZZWPQ-UHFFFAOYSA-N 0.000 description 1
- XPJACWOWEJJYRD-UHFFFAOYSA-N 2,5-dichloro-1,3-thiazole Chemical compound ClC1=CN=C(Cl)S1 XPJACWOWEJJYRD-UHFFFAOYSA-N 0.000 description 1
- YTETWZNORTXMFJ-UHFFFAOYSA-N 2,5-dimethyl-7-pentan-3-ylpyrazolo[1,5-a]pyrimidine Chemical compound CCC(CC)C1=CC(C)=NC2=CC(C)=NN12 YTETWZNORTXMFJ-UHFFFAOYSA-N 0.000 description 1
- GZEXLOIQEYXPOW-UHFFFAOYSA-N 2-(2h-triazol-4-yl)-1,3-thiazole Chemical compound C1=CSC(C=2N=NNC=2)=N1 GZEXLOIQEYXPOW-UHFFFAOYSA-N 0.000 description 1
- KNMIVNGLOLYPNT-UHFFFAOYSA-N 2-bromo-5-(2,5-dimethyl-7-pentan-3-ylpyrazolo[1,5-a]pyrimidin-3-yl)-4-(trifluoromethyl)-1,3-thiazole Chemical compound CC1=NN2C(C(CC)CC)=CC(C)=NC2=C1C=1SC(Br)=NC=1C(F)(F)F KNMIVNGLOLYPNT-UHFFFAOYSA-N 0.000 description 1
- VAQSRTGFMKWNIH-UHFFFAOYSA-N 2-iodo-1,3-thiazole Chemical compound IC1=NC=CS1 VAQSRTGFMKWNIH-UHFFFAOYSA-N 0.000 description 1
- PITHYUDHKJKJNQ-UHFFFAOYSA-N 2-propylpentanoyl chloride Chemical compound CCCC(C(Cl)=O)CCC PITHYUDHKJKJNQ-UHFFFAOYSA-N 0.000 description 1
- FZSXKNJOKINZSF-UHFFFAOYSA-N 2-pyridin-2-yl-1,3-thiazole Chemical compound C1=CSC(C=2N=CC=CC=2)=N1 FZSXKNJOKINZSF-UHFFFAOYSA-N 0.000 description 1
- VTOQFOCYBTVOJZ-UHFFFAOYSA-N 3-bromopentane Chemical compound CCC(Br)CC VTOQFOCYBTVOJZ-UHFFFAOYSA-N 0.000 description 1
- QHSGLIXDBAERBR-UHFFFAOYSA-N 4-(1,3-thiazol-2-yl)morpholine Chemical compound C1COCCN1C1=NC=CS1 QHSGLIXDBAERBR-UHFFFAOYSA-N 0.000 description 1
- YTNALFSJRHEWFY-UHFFFAOYSA-N 4-(1,3-thiazol-2-ylmethyl)morpholine Chemical compound N=1C=CSC=1CN1CCOCC1 YTNALFSJRHEWFY-UHFFFAOYSA-N 0.000 description 1
- OVMGTNMCYLZGLS-UHFFFAOYSA-N 4-(trifluoromethyl)-1,3-thiazol-2-amine Chemical compound NC1=NC(C(F)(F)F)=CS1 OVMGTNMCYLZGLS-UHFFFAOYSA-N 0.000 description 1
- VMYHAKJMZLVSMX-UHFFFAOYSA-N 4-[4-bromo-5-(7-heptan-4-yl-2,5-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)-1,3-thiazol-2-yl]morpholine Chemical compound CC1=NN2C(C(CCC)CCC)=CC(C)=NC2=C1C(=C(N=1)Br)SC=1N1CCOCC1 VMYHAKJMZLVSMX-UHFFFAOYSA-N 0.000 description 1
- ZBHSXLXGGLOAHK-UHFFFAOYSA-N 4-[4-chloro-5-(2,5-dimethyl-7-pentan-3-ylpyrazolo[1,5-a]pyrimidin-3-yl)-1,3-thiazol-2-yl]morpholine hydrochloride Chemical compound Cl.CCC(CC)c1cc(C)nc2c(c(C)nn12)-c1sc(nc1Cl)N1CCOCC1 ZBHSXLXGGLOAHK-UHFFFAOYSA-N 0.000 description 1
- LUJBSCVTFIUGDP-UHFFFAOYSA-N 4-[5-(2,5-dimethyl-7-pentan-3-ylpyrazolo[1,5-a]pyrimidin-3-yl)-4-methoxy-1,3-thiazol-2-yl]morpholine Chemical compound CC1=NN2C(C(CC)CC)=CC(C)=NC2=C1C(=C(N=1)OC)SC=1N1CCOCC1 LUJBSCVTFIUGDP-UHFFFAOYSA-N 0.000 description 1
- RNPDIOPXWTTZAF-UHFFFAOYSA-N 4-bromo-5-(2,5-dimethyl-7-pentan-3-ylpyrazolo[1,5-a]pyrimidin-3-yl)-2-pyridin-4-yl-1,3-thiazole Chemical compound CC1=NN2C(C(CC)CC)=CC(C)=NC2=C1C(=C(N=1)Br)SC=1C1=CC=NC=C1 RNPDIOPXWTTZAF-UHFFFAOYSA-N 0.000 description 1
- DLRXEPREUKUZQO-UHFFFAOYSA-N 4-chloro-1,3-thiazole Chemical compound ClC1=CSC=N1 DLRXEPREUKUZQO-UHFFFAOYSA-N 0.000 description 1
- SZOYQXBUGMXPDS-UHFFFAOYSA-N 4-chloro-5-(2,5-dimethyl-7-pentan-3-ylpyrazolo[1,5-a]pyrimidin-3-yl)-2-(2-methyl-1,2,4-triazol-3-yl)-1,3-thiazole Chemical compound CC1=NN2C(C(CC)CC)=CC(C)=NC2=C1C(=C(N=1)Cl)SC=1C1=NC=NN1C SZOYQXBUGMXPDS-UHFFFAOYSA-N 0.000 description 1
- RYDZEMDGARKSEB-UHFFFAOYSA-N 4-chloro-5-(2,5-dimethyl-7-pentan-3-ylpyrazolo[1,5-a]pyrimidin-3-yl)-2-(methoxymethyl)-1,3-thiazole Chemical compound CC1=NN2C(C(CC)CC)=CC(C)=NC2=C1C=1SC(COC)=NC=1Cl RYDZEMDGARKSEB-UHFFFAOYSA-N 0.000 description 1
- XOYXCLRIQRBYOI-UHFFFAOYSA-N 4-chloro-5-(7-heptan-4-yl-2,5-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)-n,n-dimethyl-1,3-thiazol-2-amine Chemical compound CC1=NN2C(C(CCC)CCC)=CC(C)=NC2=C1C=1SC(N(C)C)=NC=1Cl XOYXCLRIQRBYOI-UHFFFAOYSA-N 0.000 description 1
- GLCMZDPRGOZERZ-UHFFFAOYSA-N 4-methoxy-1,3-thiazole Chemical compound COC1=CSC=N1 GLCMZDPRGOZERZ-UHFFFAOYSA-N 0.000 description 1
- MGBKAPFGFOJCBK-UHFFFAOYSA-N 5-(2,5-dimethyl-7-pentan-3-ylpyrazolo[1,5-a]pyrimidin-3-yl)-2-(2,5-dimethylpyrrol-1-yl)-4-(trifluoromethyl)-1,3-thiazole Chemical compound CC1=NN2C(C(CC)CC)=CC(C)=NC2=C1C(=C(N=1)C(F)(F)F)SC=1N1C(C)=CC=C1C MGBKAPFGFOJCBK-UHFFFAOYSA-N 0.000 description 1
- GNNJEOFRNLCJFS-UHFFFAOYSA-N 5-(2,5-dimethyl-7-pentan-3-ylpyrazolo[1,5-a]pyrimidin-3-yl)-2-(2-methyl-1,2,4-triazol-3-yl)-1,3-thiazole Chemical compound CC1=NN2C(C(CC)CC)=CC(C)=NC2=C1C(S1)=CN=C1C1=NC=NN1C GNNJEOFRNLCJFS-UHFFFAOYSA-N 0.000 description 1
- UVMKVRSECQMYLW-UHFFFAOYSA-N 5-(2,5-dimethyl-7-pentan-3-ylpyrazolo[1,5-a]pyrimidin-3-yl)-2-(methoxymethyl)-1,3-thiazole Chemical compound CC1=NN2C(C(CC)CC)=CC(C)=NC2=C1C1=CN=C(COC)S1 UVMKVRSECQMYLW-UHFFFAOYSA-N 0.000 description 1
- BRLCLWWPZYDOBY-UHFFFAOYSA-N 5-(2,5-dimethyl-7-pentan-3-ylpyrazolo[1,5-a]pyrimidin-3-yl)-2-iodo-1,3-thiazole Chemical compound CC1=NN2C(C(CC)CC)=CC(C)=NC2=C1C1=CN=C(I)S1 BRLCLWWPZYDOBY-UHFFFAOYSA-N 0.000 description 1
- LQDLQLICGAUHLO-UHFFFAOYSA-N 5-(2,5-dimethyl-7-pentan-3-ylpyrazolo[1,5-a]pyrimidin-3-yl)-4-(trifluoromethyl)-1,3-thiazol-2-amine Chemical compound CC1=NN2C(C(CC)CC)=CC(C)=NC2=C1C=1SC(N)=NC=1C(F)(F)F LQDLQLICGAUHLO-UHFFFAOYSA-N 0.000 description 1
- PDZCFQFHDOXGAJ-UHFFFAOYSA-N 5-(2,5-dimethyl-7-pentan-3-ylpyrazolo[1,5-a]pyrimidin-3-yl)-4-(trifluoromethyl)-1,3-thiazol-2-amine hydroxylamine Chemical compound NO.C(C)C(CC)C1=CC(=NC=2N1N=C(C2C2=C(N=C(S2)N)C(F)(F)F)C)C PDZCFQFHDOXGAJ-UHFFFAOYSA-N 0.000 description 1
- LVEQNNRAHYRIRI-UHFFFAOYSA-N 5-(2,5-dimethyl-7-pentan-3-ylpyrazolo[1,5-a]pyrimidin-3-yl)-4-methyl-1,3-thiazole Chemical compound CC1=NN2C(C(CC)CC)=CC(C)=NC2=C1C=1SC=NC=1C LVEQNNRAHYRIRI-UHFFFAOYSA-N 0.000 description 1
- DTAVZCUKHOMGFJ-UHFFFAOYSA-N 5-(2,5-dimethyl-7-pentan-3-ylpyrazolo[1,5-a]pyrimidin-3-yl)-n,n-dimethyl-4-(trifluoromethyl)-1,3-thiazol-2-amine Chemical compound CC1=NN2C(C(CC)CC)=CC(C)=NC2=C1C=1SC(N(C)C)=NC=1C(F)(F)F DTAVZCUKHOMGFJ-UHFFFAOYSA-N 0.000 description 1
- XFDCNXIWKCIBAE-UHFFFAOYSA-N 5-bromo-1,3-thiazol-2-amine;hydrochloride Chemical compound Cl.NC1=NC=C(Br)S1 XFDCNXIWKCIBAE-UHFFFAOYSA-N 0.000 description 1
- NTVKNAYKEZCLHE-UHFFFAOYSA-N 5-bromo-2-(2,5-dimethylpyrrol-1-yl)-1,3-thiazole Chemical compound CC1=CC=C(C)N1C1=NC=C(Br)S1 NTVKNAYKEZCLHE-UHFFFAOYSA-N 0.000 description 1
- XCDSPYWINDJTSZ-UHFFFAOYSA-N 5-bromo-2-(2,5-dimethylpyrrol-1-yl)-4-(trifluoromethyl)-1,3-thiazole Chemical compound CC1=CC=C(C)N1C1=NC(C(F)(F)F)=C(Br)S1 XCDSPYWINDJTSZ-UHFFFAOYSA-N 0.000 description 1
- CFJJLEWWUVGZBE-UHFFFAOYSA-N 5-bromo-2-pyridin-4-yl-1,3-thiazole Chemical compound S1C(Br)=CN=C1C1=CC=NC=C1 CFJJLEWWUVGZBE-UHFFFAOYSA-N 0.000 description 1
- XKVUYEYANWFIJX-UHFFFAOYSA-N 5-methyl-1h-pyrazole Chemical group CC1=CC=NN1 XKVUYEYANWFIJX-UHFFFAOYSA-N 0.000 description 1
- HRWJBDKIKWXCGH-UHFFFAOYSA-N 5-propyloctane-2,4-dione Chemical compound CCCC(CCC)C(=O)CC(C)=O HRWJBDKIKWXCGH-UHFFFAOYSA-N 0.000 description 1
- UKZKRXMTBGOVRL-UHFFFAOYSA-N 7-heptan-4-yl-3-iodo-2,5-dimethylpyrazolo[1,5-a]pyrimidine Chemical compound CCCC(CCC)C1=CC(C)=NC2=C(I)C(C)=NN12 UKZKRXMTBGOVRL-UHFFFAOYSA-N 0.000 description 1
- PZASAAIJIFDWSB-CKPDSHCKSA-N 8-[(1S)-1-[8-(trifluoromethyl)-7-[4-(trifluoromethyl)cyclohexyl]oxynaphthalen-2-yl]ethyl]-8-azabicyclo[3.2.1]octane-3-carboxylic acid Chemical compound FC(F)(F)C=1C2=CC([C@@H](N3C4CCC3CC(C4)C(O)=O)C)=CC=C2C=CC=1OC1CCC(C(F)(F)F)CC1 PZASAAIJIFDWSB-CKPDSHCKSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- GCVPJPOYMINTDL-UHFFFAOYSA-N BrC1=CN=C(S1)C1=NC=NN1C.CC1=NN2C(N=C(C=C2C(CCC)CCC)C)=C1C1=CN=C(S1)C=1N(N=CN1)C Chemical compound BrC1=CN=C(S1)C1=NC=NN1C.CC1=NN2C(N=C(C=C2C(CCC)CCC)C)=C1C1=CN=C(S1)C=1N(N=CN1)C GCVPJPOYMINTDL-UHFFFAOYSA-N 0.000 description 1
- VPZCLLMCNAMHHO-UHFFFAOYSA-N BrC=1N=C(SC1C=1C(=NN2C1N=C(C=C2C(CC)CC)C)C)C=2N(N=CN2)C.CC2=CC=C(C=C2)S(=O)(=O)O Chemical compound BrC=1N=C(SC1C=1C(=NN2C1N=C(C=C2C(CC)CC)C)C)C=2N(N=CN2)C.CC2=CC=C(C=C2)S(=O)(=O)O VPZCLLMCNAMHHO-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- MLPUFXYPOGPDKG-UHFFFAOYSA-N C(C)OC(=O)C=1SC=CN1.S1C(=NC=C1)C(=O)N Chemical compound C(C)OC(=O)C=1SC=CN1.S1C(=NC=C1)C(=O)N MLPUFXYPOGPDKG-UHFFFAOYSA-N 0.000 description 1
- AKDDLTYHXXUOAL-UHFFFAOYSA-N C(CC)C(C(CC(C)=O)=O)CCC.C(CC)C(CCC)C1=CC(=NC=2N1N=C(C2)C)C Chemical compound C(CC)C(C(CC(C)=O)=O)CCC.C(CC)C(CCC)C1=CC(=NC=2N1N=C(C2)C)C AKDDLTYHXXUOAL-UHFFFAOYSA-N 0.000 description 1
- AMQMHZBQDWQFLE-UHFFFAOYSA-N C(CC)C(CCC)C1=CC(=NC=2N1N=C(C2)C)C.C(CC)C(CCC)C2=CC(=NC=1N2N=C(C1I)C)C Chemical compound C(CC)C(CCC)C1=CC(=NC=2N1N=C(C2)C)C.C(CC)C(CCC)C2=CC(=NC=1N2N=C(C1I)C)C AMQMHZBQDWQFLE-UHFFFAOYSA-N 0.000 description 1
- KMPWRDKNYNWVMO-UHFFFAOYSA-N C(CC)[N-]CCC.[Li+].C(C)C(CC)C1=CC(=NC=2N1N=C(C2C2=CN=C(S2)I)C)C Chemical compound C(CC)[N-]CCC.[Li+].C(C)C(CC)C1=CC(=NC=2N1N=C(C2C2=CN=C(S2)I)C)C KMPWRDKNYNWVMO-UHFFFAOYSA-N 0.000 description 1
- LOZFCRRNQAHOAX-UHFFFAOYSA-N C(CCC)[Li].BrC=1N=C(SC1C=1C(=NN2C1N=C(C=C2C(CC)CC)C)C)CCCC Chemical compound C(CCC)[Li].BrC=1N=C(SC1C=1C(=NN2C1N=C(C=C2C(CC)CC)C)C)CCCC LOZFCRRNQAHOAX-UHFFFAOYSA-N 0.000 description 1
- ZHNVTTUCUFJICB-UHFFFAOYSA-N CC1=NN2C(N=C(C=C2C(CCC)CCC)C)=C1C1=CN=CS1.BrC=1SC(=C(N1)Br)C=1C(=NN2C1N=C(C=C2C(CCC)CCC)C)C Chemical compound CC1=NN2C(N=C(C=C2C(CCC)CCC)C)=C1C1=CN=CS1.BrC=1SC(=C(N1)Br)C=1C(=NN2C1N=C(C=C2C(CCC)CCC)C)C ZHNVTTUCUFJICB-UHFFFAOYSA-N 0.000 description 1
- YTNWQXDAOVDOMS-UHFFFAOYSA-N CC1=NN2C(NC(=CC2=O)C)=C1.ClC1=CC(=NC=2N1N=C(C2)C)C Chemical compound CC1=NN2C(NC(=CC2=O)C)=C1.ClC1=CC(=NC=2N1N=C(C2)C)C YTNWQXDAOVDOMS-UHFFFAOYSA-N 0.000 description 1
- IQZIOXIBDFTVFI-UHFFFAOYSA-N CCC(CC)C(N1N=C2C)=CC(C)=NC1=C2C([S+](C)C(N1CCOCC1)=N1)=C1Br Chemical compound CCC(CC)C(N1N=C2C)=CC(C)=NC1=C2C([S+](C)C(N1CCOCC1)=N1)=C1Br IQZIOXIBDFTVFI-UHFFFAOYSA-N 0.000 description 1
- IQGLLDJCHFACFJ-UHFFFAOYSA-N CN1N=CN=C1C=1SC=CN1.BrC1=CN=C(S1)C1=NC=NN1C Chemical compound CN1N=CN=C1C=1SC=CN1.BrC1=CN=C(S1)C1=NC=NN1C IQGLLDJCHFACFJ-UHFFFAOYSA-N 0.000 description 1
- LQPSRBHEDUKQCF-UHFFFAOYSA-N COC(N(C)C)OC.CN1N=CN=C1C=1SC=CN1 Chemical compound COC(N(C)C)OC.CN1N=CN=C1C=1SC=CN1 LQPSRBHEDUKQCF-UHFFFAOYSA-N 0.000 description 1
- PHEUEGGZZRNZAP-UHFFFAOYSA-N C[Si](C=1SC=CN1)(C)C.CC1=NN2C(N=C(C=C2C(CCC)CCC)C)=C1C1=CN=CS1 Chemical compound C[Si](C=1SC=CN1)(C)C.CC1=NN2C(N=C(C=C2C(CCC)CCC)C)=C1C1=CN=CS1 PHEUEGGZZRNZAP-UHFFFAOYSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 101000957724 Catostomus commersonii Corticoliberin-1 Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- 208000017701 Endocrine disease Diseases 0.000 description 1
- 208000012895 Gastric disease Diseases 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- PVXSFTDOXBQOEN-UHFFFAOYSA-N N'-[5-(2,5-dimethyl-7-pentan-3-ylpyrazolo[1,5-a]pyrimidin-3-yl)-4-(trifluoromethyl)-1,3-thiazol-2-yl]ethane-1,2-diamine hydrochloride Chemical compound Cl.CCC(CC)c1cc(C)nc2c(c(C)nn12)-c1sc(NCCN)nc1C(F)(F)F PVXSFTDOXBQOEN-UHFFFAOYSA-N 0.000 description 1
- WPMASEZGBVAFQE-UHFFFAOYSA-N N-[5-(2,5-dimethyl-7-pentan-3-ylpyrazolo[1,5-a]pyrimidin-3-yl)-4-(trifluoromethyl)-1,3-thiazol-2-yl]acetamide hydroxylamine Chemical compound NO.C(C)C(CC)C1=CC(=NC=2N1N=C(C2C2=C(N=C(S2)NC(C)=O)C(F)(F)F)C)C WPMASEZGBVAFQE-UHFFFAOYSA-N 0.000 description 1
- KCTZOTUQSGYWLV-UHFFFAOYSA-N N1C=NC=C2N=CC=C21 Chemical class N1C=NC=C2N=CC=C21 KCTZOTUQSGYWLV-UHFFFAOYSA-N 0.000 description 1
- DASNRLLDMQVFEW-UHFFFAOYSA-N NC(=S)N.FC(C=1N=C(SC1)N)(F)F Chemical compound NC(=S)N.FC(C=1N=C(SC1)N)(F)F DASNRLLDMQVFEW-UHFFFAOYSA-N 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- UPTMRWGREULNAU-UHFFFAOYSA-N P(=O)(Cl)(Cl)Cl.ClC=1SC=C(N1)Cl Chemical compound P(=O)(Cl)(Cl)Cl.ClC=1SC=C(N1)Cl UPTMRWGREULNAU-UHFFFAOYSA-N 0.000 description 1
- 239000005922 Phosphane Substances 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- 101100275407 Rattus norvegicus Cotl1 gene Proteins 0.000 description 1
- 101100275979 Rattus norvegicus Csrp3 gene Proteins 0.000 description 1
- 241000219061 Rheum Species 0.000 description 1
- 238000000297 Sandmeyer reaction Methods 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- BWQWJOLXMSFBRC-UHFFFAOYSA-N [Br].BrC1=C(N=CS1)C Chemical compound [Br].BrC1=C(N=CS1)C BWQWJOLXMSFBRC-UHFFFAOYSA-N 0.000 description 1
- KYOIPUDHYRWSFO-UHFFFAOYSA-N [Br].[Li] Chemical group [Br].[Li] KYOIPUDHYRWSFO-UHFFFAOYSA-N 0.000 description 1
- HEAFLBOWLRRIHV-UHFFFAOYSA-N [Na].[P] Chemical compound [Na].[P] HEAFLBOWLRRIHV-UHFFFAOYSA-N 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 239000000883 anti-obesity agent Substances 0.000 description 1
- 229940125710 antiobesity agent Drugs 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 238000000065 atmospheric pressure chemical ionisation Methods 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- SXGBREZGMJVYRL-UHFFFAOYSA-N butan-1-amine;hydrobromide Chemical compound [Br-].CCCC[NH3+] SXGBREZGMJVYRL-UHFFFAOYSA-N 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- MOIPGXQKZSZOQX-UHFFFAOYSA-N carbonyl bromide Chemical class BrC(Br)=O MOIPGXQKZSZOQX-UHFFFAOYSA-N 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 210000001638 cerebellum Anatomy 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 230000008451 emotion Effects 0.000 description 1
- 239000006274 endogenous ligand Substances 0.000 description 1
- LBAQSKZHMLAFHH-UHFFFAOYSA-N ethoxyethane;hydron;chloride Chemical compound Cl.CCOCC LBAQSKZHMLAFHH-UHFFFAOYSA-N 0.000 description 1
- MVMPKHJUPNWMDZ-UHFFFAOYSA-N ethyl 1,3-thiazole-2-carboxylate Chemical compound CCOC(=O)C1=NC=CS1 MVMPKHJUPNWMDZ-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000002267 hypothalamic effect Effects 0.000 description 1
- 210000003016 hypothalamus Anatomy 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 239000003186 pharmaceutical solution Substances 0.000 description 1
- 229910000064 phosphane Inorganic materials 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- JUXWUYWPUDKPSD-UHFFFAOYSA-N pyrazolo[1,5-a][1,3,5]triazine Chemical compound N1=CN=CN2N=CC=C21 JUXWUYWPUDKPSD-UHFFFAOYSA-N 0.000 description 1
- 150000004943 pyrrolo[2,3-d]pyrimidines Chemical class 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000013074 reference sample Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 150000003557 thiazoles Chemical class 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- JAYKPAAGOYELFD-UHFFFAOYSA-N tris(2,4-ditert-butylphenyl)phosphane Chemical compound CC(C)(C)C1=CC(C(C)(C)C)=CC=C1P(C=1C(=CC(=CC=1)C(C)(C)C)C(C)(C)C)C1=CC=C(C(C)(C)C)C=C1C(C)(C)C JAYKPAAGOYELFD-UHFFFAOYSA-N 0.000 description 1
- KRVVVSZNTMFCON-UHFFFAOYSA-L zinc;1,3-thiazole;dibromide Chemical compound [Zn+2].[Br-].[Br-].C1=CSC=N1 KRVVVSZNTMFCON-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/06—Antiabortive agents; Labour repressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular 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
-
- 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
- A61P25/06—Antimigraine agents
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
-
- 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
- A61P25/20—Hypnotics; Sedatives
-
- 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
- A61P25/22—Anxiolytics
-
- 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
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/32—Alcohol-abuse
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/36—Opioid-abuse
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Addiction (AREA)
- Pain & Pain Management (AREA)
- Reproductive Health (AREA)
- Psychiatry (AREA)
- Endocrinology (AREA)
- Gynecology & Obstetrics (AREA)
- Pregnancy & Childbirth (AREA)
- Diabetes (AREA)
- Heart & Thoracic Surgery (AREA)
- Rheumatology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Anesthesiology (AREA)
- Immunology (AREA)
- Cardiology (AREA)
- Pulmonology (AREA)
- Child & Adolescent Psychology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Urology & Nephrology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US82626406P | 2006-09-20 | 2006-09-20 | |
| US60/826,264 | 2006-09-20 | ||
| PCT/US2007/078605 WO2008036579A1 (en) | 2006-09-20 | 2007-09-17 | Thiazole pyrazolopyrimidines as crf1 receptor antagonists |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2010504344A JP2010504344A (ja) | 2010-02-12 |
| JP2010504344A5 JP2010504344A5 (enExample) | 2010-10-28 |
| JP5161226B2 true JP5161226B2 (ja) | 2013-03-13 |
Family
ID=38924802
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2009529316A Active JP5161226B2 (ja) | 2006-09-20 | 2007-09-17 | Ｃｒｆ１受容体アンタゴニストとしてのチアゾールピラゾロピリミジン |
Country Status (33)
Families Citing this family (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2025674A1 (de) | 2007-08-15 | 2009-02-18 | sanofi-aventis | Substituierte Tetrahydronaphthaline, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel |
| TWI432435B (zh) * | 2008-10-02 | 2014-04-01 | Lilly Co Eli | 作為合成中間物之噻唑基－吡唑并嘧啶化合物及相關合成方法 |
| EP2567959B1 (en) | 2011-09-12 | 2014-04-16 | Sanofi | 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
| KR20210064407A (ko) * | 2014-01-21 | 2021-06-02 | 뉴로크린 바이오사이언시즈 인코퍼레이티드 | 선천성 부신 과형성 치료를 위한 ｃｒｆ1 수용체 길항제 |
| PL236355B1 (pl) * | 2015-04-02 | 2021-01-11 | Celon Pharma Spolka Akcyjna | Pochodne 7-(morfolin-4-ylo)pirazolo[1,5-α]pirymidyny jako inhibitory kinazy PI3 |
| EP3510029B1 (en) | 2016-09-07 | 2025-11-05 | The Regents of The University of California | Allosteric corticotropin-releasing factor receptor 1 (crfr1) antagonists that decrease p-tau and improve cognition |
| BR112020002967A2 (pt) | 2017-08-14 | 2020-08-11 | Spruce Biosciences, Inc. | antagonistas de receptor de fator de liberação de corticotropina |
| TWI803504B (zh) * | 2017-08-14 | 2023-06-01 | 美商雲杉生物科技股份有限公司 | 促皮質素釋放因子受體拮抗劑 |
| MX2020011344A (es) * | 2018-04-27 | 2021-02-09 | Spruce Biosciences Inc | Métodos para tratar tumores en reposo suprarrenales testiculares y de ovarios. |
| CN109134481B (zh) * | 2018-08-07 | 2021-05-14 | 中山大学 | 一种取代吡咯色原酮类化合物或其药学上可接受的盐及其制备方法和应用 |
| TWI714231B (zh) * | 2018-09-04 | 2020-12-21 | 美商美國禮來大藥廠 | 2,6-二胺基吡啶化合物 |
| PL3984523T3 (pl) | 2018-12-07 | 2026-02-02 | Neurocrine Biosciences, Inc. | Antagonista receptora crf1, jego formulacje farmaceutyczne i postacie stałe do leczenia wrodzonego przerostu nadnerczy |
| KR20220052927A (ko) * | 2019-07-19 | 2022-04-28 | 스프루스 바이오사이언시스 인코포레이티드 | 선천성 부신 증식증의 치료 방법 |
| US12383536B2 (en) | 2019-09-27 | 2025-08-12 | Neurocrine Biosciences, Inc. | CRF receptor antagonists and methods of use |
| ES3039926T3 (en) * | 2019-12-04 | 2025-10-27 | Neurocrine Biosciences Inc | Crf receptor antagonists and methods of use |
| GR1010096B (el) * | 2020-07-02 | 2021-10-08 | Uni-Pharma Κλεων Τσετης Φαρμακευτικα Εργαστηρια Αβεε, | Πυραζολο[1,5-a]πυριμιδινες με δραση αναστολης της αυτοταξινης |
| JP2023537598A (ja) | 2020-08-12 | 2023-09-04 | スプルース バイオサイエンシーズ，インク． | 多嚢胞性卵巣症候群を処置するための方法および組成物 |
| US20240024330A1 (en) | 2020-08-26 | 2024-01-25 | Neurocrine Biosciences, Inc. | Crf receptor antagonists and methods of use |
| BR112023018816A2 (pt) | 2021-03-19 | 2023-10-31 | Crinetics Pharmaceuticals Inc | Antagonista do receptor de melanocortina subtipo-2 (mc2r) para o tratamento de doença |
| EP4402142A4 (en) * | 2021-11-19 | 2025-07-23 | Spruce Biosciences Inc | CRYSTALLINE COMPOSITION OF TILDACERFONT AND ITS METHODS OF USE AND PREPARATION |
| US11708372B2 (en) | 2021-11-19 | 2023-07-25 | Spruce Biosciences, Inc. | Crystalline composition of tildacerfont and methods of use and preparation thereof |
| WO2023163945A1 (en) * | 2022-02-23 | 2023-08-31 | Crinetics Pharmaceuticals, Inc. | Treatment of congenital adrenal hyperplasia and polycystic ovary syndrome |
| WO2025188842A1 (en) * | 2024-03-08 | 2025-09-12 | Spruce Biosciences, Inc. | Amorphous solid dispersion of tildacerfont formulations |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BR9307646A (pt) | 1992-12-17 | 1999-05-25 | Pfizer | Pirrolopirimidinas como antagonistas de crf |
| ES2168237T3 (es) * | 1996-02-07 | 2007-04-01 | Neurocrine Biosciences, Inc. | Pirazolopirimidinas como antagonistas de receptores de crf. |
| CZ299451B6 (cs) * | 1996-07-24 | 2008-07-30 | Bristol-Myers Squibb Pharma Company | [1,5-a]-Pyrazolo-1,3,5- triaziny jejich použití afarmaceutické kompozice na jejich bázi |
| AU747708B2 (en) | 1996-07-24 | 2002-05-23 | Du Pont Pharmaceuticals Company | Azolo triazines and pyrimidines |
| PL332040A1 (en) | 1996-08-28 | 1999-08-16 | Pfizer | Substitution 6,5-heterobicyclic derivatives |
| EP1040831A3 (en) * | 1999-04-02 | 2003-05-02 | Pfizer Products Inc. | Use of corticotropin releasing factor (CRF) antagonists to prevent sudden death |
| AU4203500A (en) * | 1999-04-06 | 2000-10-23 | Du Pont Pharmaceuticals Company | Pyrazolopyrimidines as crf antagonists |
| YU23602A (sh) * | 1999-09-30 | 2004-09-03 | Neurogen Corporation | Amino supstituisani pirazolo /1,5/a/-1,5-pirimidini i pirazolo /1,5-a/-1,3,5-triazini |
| ES2282401T3 (es) | 2001-03-13 | 2007-10-16 | Bristol-Myers Squibb Pharma Company | 4-(2-butilamino)-2,7-dimetil-8-(2-metil-6-metoxipirid-3-il) pirazolo - 1,5-a-1,3,5-triazina, sus enantiomeros y sales farmaceuticamente aceptables como ligandos del receptor del factor liberador de croticotropina. |
| JP4926720B2 (ja) | 2003-12-22 | 2012-05-09 | スミスクライン ビーチャム （コーク） リミテッド | Ｃｒｆ受容体アンタゴニストおよびそれらに関連する方法 |
-
2007
- 2007-09-17 KR KR1020097005602A patent/KR101088239B1/ko not_active Expired - Fee Related
- 2007-09-17 ES ES07842582T patent/ES2350282T3/es active Active
- 2007-09-17 PL PL07842582T patent/PL2094709T3/pl unknown
- 2007-09-17 UA UAA200902216A patent/UA96458C2/ru unknown
- 2007-09-17 EP EP07842582A patent/EP2094709B1/en active Active
- 2007-09-17 MX MX2009003125A patent/MX2009003125A/es active IP Right Grant
- 2007-09-17 CN CN2007800351453A patent/CN101516887B/zh active Active
- 2007-09-17 AT AT07842582T patent/ATE481405T1/de active
- 2007-09-17 SI SI200730435T patent/SI2094709T1/sl unknown
- 2007-09-17 DK DK07842582.4T patent/DK2094709T3/da active
- 2007-09-17 AU AU2007297421A patent/AU2007297421B2/en not_active Ceased
- 2007-09-17 US US12/377,733 patent/US8030304B2/en active Active
- 2007-09-17 PT PT07842582T patent/PT2094709E/pt unknown
- 2007-09-17 DE DE602007009305T patent/DE602007009305D1/de active Active
- 2007-09-17 NZ NZ575572A patent/NZ575572A/en not_active IP Right Cessation
- 2007-09-17 MY MYPI20091067A patent/MY146388A/en unknown
- 2007-09-17 WO PCT/US2007/078605 patent/WO2008036579A1/en not_active Ceased
- 2007-09-17 EA EA200970303A patent/EA015179B1/ru active IP Right Revival
- 2007-09-17 BR BRPI0717023A patent/BRPI0717023B8/pt not_active IP Right Cessation
- 2007-09-17 RS RSP-2010/0517A patent/RS51545B/sr unknown
- 2007-09-17 HR HR20100516T patent/HRP20100516T1/hr unknown
- 2007-09-17 JP JP2009529316A patent/JP5161226B2/ja active Active
- 2007-09-17 CA CA2663511A patent/CA2663511C/en active Active
- 2007-09-18 AR ARP070104125A patent/AR062886A1/es active IP Right Grant
- 2007-09-20 TW TW096135177A patent/TWI402269B/zh not_active IP Right Cessation
- 2007-09-20 PE PE2007001271A patent/PE20081377A1/es not_active Application Discontinuation
- 2007-09-20 CL CL200702693A patent/CL2007002693A1/es unknown
-
2009
- 2009-03-16 IL IL197614A patent/IL197614A/en active IP Right Grant
- 2009-03-19 TN TN2009000095A patent/TN2009000095A1/fr unknown
- 2009-03-20 CR CR10682A patent/CR10682A/es not_active Application Discontinuation
- 2009-04-16 NO NO20091489A patent/NO20091489L/no not_active Application Discontinuation
- 2009-04-16 MA MA31794A patent/MA30798B1/fr unknown
-
2010
- 2010-10-21 CY CY20101100946T patent/CY1110854T1/el unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR101088239B1 (ko) | Ｃｒｆ１ 수용체 길항제로서의 티아졸 피라졸로피리미딘 | |
| JP5184536B2 (ja) | チオフェンピラゾロピリミジン化合物 | |
| MX2012010610A (es) | Derivados de pirrolopirazina y sus uso como inhibidores cinasa janus (jak) y tirosina cinasa del bazo (syk). | |
| US6734185B2 (en) | Pyrrolo[3,4-d]pyrimidines as corticotropin releasing factor (CRF) antagonists | |
| HK1132505B (en) | Thiazole pyrazolopyrimidines as crf1 receptor antagonists | |
| CA2631034A1 (en) | Tricyclic lactam derivatives, their manufacture and use as pharmaceutical agents | |
| HK1178534A (en) | Pyrrolopyrazine derivatives and their use as jak and syk inhibitors |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20100909 |
|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20100909 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20121204 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20121213 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 5161226 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20151221 Year of fee payment: 3 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |