TWI354671B - Pyrazolo[3,4-b]pyridine compounds, and their use a - Google Patents

Info

Publication number

TWI354671B

TWI354671B TW092136553A TW92136553A TWI354671B TW I354671 B TWI354671 B TW I354671B TW 092136553 A TW092136553 A TW 092136553A TW 92136553 A TW92136553 A TW 92136553A TW I354671 B TWI354671 B TW I354671B

Authority

TW

Taiwan

Prior art keywords

ethyl

group

amine

alkyl

tetrahydro

Prior art date

2002-12-23

Links

• Espacenet
• Global Dossier
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• 150000005230 pyrazolo[3,4-b]pyridines Chemical class 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims description 185
• 239000000203 mixture Substances 0.000 claims description 122
• 150000003839 salts Chemical class 0.000 claims description 96
• NUKYPUAOHBNCPY-UHFFFAOYSA-N 4-aminopyridine Chemical compound NC1=CC=NC=C1 NUKYPUAOHBNCPY-UHFFFAOYSA-N 0.000 claims description 45
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 45
• 239000008194 pharmaceutical composition Substances 0.000 claims description 32
• 229960004979 fampridine Drugs 0.000 claims description 30
• 239000003814 drug Substances 0.000 claims description 27
• 241000282414 Homo sapiens Species 0.000 claims description 26
• 238000011282 treatment Methods 0.000 claims description 24
• 229940079593 drug Drugs 0.000 claims description 23
• 241000124008 Mammalia Species 0.000 claims description 20
• 230000002265 prevention Effects 0.000 claims description 14
• 241000282412 Homo Species 0.000 claims description 13
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• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 13
• 208000006673 asthma Diseases 0.000 claims description 10
• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 9
• 208000026935 allergic disease Diseases 0.000 claims description 9
• 230000002757 inflammatory effect Effects 0.000 claims description 9
• 208000027866 inflammatory disease Diseases 0.000 claims description 7
• 206010039085 Rhinitis allergic Diseases 0.000 claims description 6
• 201000010105 allergic rhinitis Diseases 0.000 claims description 6
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
• 208000028698 Cognitive impairment Diseases 0.000 claims description 5
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• 206010039073 rheumatoid arthritis Diseases 0.000 claims description 4
• 206010020751 Hypersensitivity Diseases 0.000 claims description 3
• 230000007815 allergy Effects 0.000 claims description 3
• 239000003937 drug carrier Substances 0.000 claims description 3
• WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 2
• 241000219112 Cucumis Species 0.000 claims 1
• 235000015510 Cucumis melo subsp melo Nutrition 0.000 claims 1
• 208000002720 Malnutrition Diseases 0.000 claims 1
• FJJCIZWZNKZHII-UHFFFAOYSA-N [4,6-bis(cyanoamino)-1,3,5-triazin-2-yl]cyanamide Chemical compound N#CNC1=NC(NC#N)=NC(NC#N)=N1 FJJCIZWZNKZHII-UHFFFAOYSA-N 0.000 claims 1
• 230000001071 malnutrition Effects 0.000 claims 1
• 235000000824 malnutrition Nutrition 0.000 claims 1
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• 239000000543 intermediate Substances 0.000 description 315
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 231
• 125000000217 alkyl group Chemical group 0.000 description 194
• -1 pyrazolopyridine compound Chemical class 0.000 description 119
• 235000019439 ethyl acetate Nutrition 0.000 description 111
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 109
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 77
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 73
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 73
• 239000002904 solvent Substances 0.000 description 66
• 238000000034 method Methods 0.000 description 61
• 239000000243 solution Substances 0.000 description 61
• 125000000753 cycloalkyl group Chemical group 0.000 description 60
• 125000001424 substituent group Chemical group 0.000 description 58
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 53
• 239000000463 material Substances 0.000 description 52
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 51
• 206010057190 Respiratory tract infections Diseases 0.000 description 51
• 125000003545 alkoxy group Chemical group 0.000 description 51
• 125000000623 heterocyclic group Chemical group 0.000 description 51
• OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 48
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 46
• 239000002585 base Substances 0.000 description 45
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
• 238000006243 chemical reaction Methods 0.000 description 41
• 238000004458 analytical method Methods 0.000 description 40
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• 125000004435 hydrogen atom Chemical group [H]* 0.000 description 40
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• 229910052757 nitrogen Inorganic materials 0.000 description 39
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• 239000000126 substance Substances 0.000 description 36
• 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 description 34
• 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 34
• 239000000460 chlorine Substances 0.000 description 33
• FZZMTSNZRBFGGU-UHFFFAOYSA-N 2-chloro-7-fluoroquinazolin-4-amine Chemical compound FC1=CC=C2C(N)=NC(Cl)=NC2=C1 FZZMTSNZRBFGGU-UHFFFAOYSA-N 0.000 description 31
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 30
• 239000003153 chemical reaction reagent Substances 0.000 description 28
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• 229910052731 fluorine Inorganic materials 0.000 description 27
• 239000011737 fluorine Substances 0.000 description 27
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 25
• 230000005764 inhibitory process Effects 0.000 description 25
• 239000000843 powder Substances 0.000 description 25
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 24
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• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 23
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• 125000004428 fluoroalkoxy group Chemical group 0.000 description 23
• 239000008101 lactose Substances 0.000 description 23
• 229960001375 lactose Drugs 0.000 description 23
• YSHOWEKUVWPFNR-UHFFFAOYSA-N burgess reagent Chemical compound CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC YSHOWEKUVWPFNR-UHFFFAOYSA-N 0.000 description 22
• 238000002360 preparation method Methods 0.000 description 22
• 239000000725 suspension Substances 0.000 description 22
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 21
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• 101100294106 Caenorhabditis elegans nhr-3 gene Proteins 0.000 description 20
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 20
• 239000002253 acid Substances 0.000 description 20
• 150000001412 amines Chemical class 0.000 description 20
• 125000003118 aryl group Chemical group 0.000 description 20
• 239000002158 endotoxin Substances 0.000 description 20
• 239000003112 inhibitor Substances 0.000 description 20
• 229920006008 lipopolysaccharide Polymers 0.000 description 20
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• 101000988424 Homo sapiens cAMP-specific 3',5'-cyclic phosphodiesterase 4B Proteins 0.000 description 18
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• 239000001257 hydrogen Substances 0.000 description 17
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• 210000003296 saliva Anatomy 0.000 description 17
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• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 16
• 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 16
• 238000002875 fluorescence polarization Methods 0.000 description 16
• 238000012360 testing method Methods 0.000 description 16
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
• OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 14
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• KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 13
• 125000001153 fluoro group Chemical group F* 0.000 description 13
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• 150000002431 hydrogen Chemical class 0.000 description 11
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• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 11
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• 239000012317 TBTU Substances 0.000 description 10
• CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 10
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• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 10
• JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 9
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