CA2579889A1 - Thiazole derivatives having vap-1 inhibitory activity - Google Patents

Info

Publication number

CA2579889A1

CA2579889A1 CA002579889A CA2579889A CA2579889A1 CA 2579889 A1 CA2579889 A1 CA 2579889A1 CA 002579889 A CA002579889 A CA 002579889A CA 2579889 A CA2579889 A CA 2579889A CA 2579889 A1 CA2579889 A1 CA 2579889A1

Authority

CA

Canada

Prior art keywords

ethyl

disease

amino

methyl

acetamide

Prior art date

2004-09-09

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.)

Abandoned

Links

• Espacenet
• Global Dossier
• CIPO
• Discuss

• 230000002401 inhibitory effect Effects 0.000 title description 5
• 101000774560 Crotalus atrox Zinc metalloproteinase-disintegrin-like VAP1 Proteins 0.000 title 1
• 150000007979 thiazole derivatives Chemical class 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 145
• 102100027159 Membrane primary amine oxidase Human genes 0.000 claims abstract description 82
• 101710132836 Membrane primary amine oxidase Proteins 0.000 claims abstract description 80
• 201000010099 disease Diseases 0.000 claims abstract description 53
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 53
• 239000003112 inhibitor Substances 0.000 claims abstract description 53
• 150000003839 salts Chemical class 0.000 claims abstract description 53
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 52
• 238000000034 method Methods 0.000 claims abstract description 49
• -1 -OH Chemical group 0.000 claims abstract description 46
• 208000001344 Macular Edema Diseases 0.000 claims abstract description 37
• 206010025415 Macular oedema Diseases 0.000 claims abstract description 37
• 201000010230 macular retinal edema Diseases 0.000 claims abstract description 37
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 22
• 239000001257 hydrogen Substances 0.000 claims abstract description 22
• 125000002947 alkylene group Chemical group 0.000 claims abstract description 17
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 17
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 8
• 150000003557 thiazoles Chemical class 0.000 claims abstract description 6
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 4
• 206010012601 diabetes mellitus Diseases 0.000 claims description 58
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• 201000001320 Atherosclerosis Diseases 0.000 claims description 18
• 208000027866 inflammatory disease Diseases 0.000 claims description 18
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• 206010012688 Diabetic retinal oedema Diseases 0.000 claims description 16
• 201000011190 diabetic macular edema Diseases 0.000 claims description 16
• VXAPNCLMTSOGLM-UHFFFAOYSA-N n-[4-[2-[4-[(2-amino-1h-imidazol-5-yl)methyl]phenyl]ethyl]-1,3-thiazol-2-yl]acetamide Chemical compound S1C(NC(=O)C)=NC(CCC=2C=CC(CC=3N=C(N)NC=3)=CC=2)=C1 VXAPNCLMTSOGLM-UHFFFAOYSA-N 0.000 claims description 15
• 208000017442 Retinal disease Diseases 0.000 claims description 14
• 238000011282 treatment Methods 0.000 claims description 14
• 230000002792 vascular Effects 0.000 claims description 14
• LSBXWMQLLHVMMW-UHFFFAOYSA-N 2-[5-[2-(2-acetamido-1,3-thiazol-4-yl)ethyl]thiophen-2-yl]-n-(diaminomethylidene)acetamide Chemical compound S1C(NC(=O)C)=NC(CCC=2SC(CC(=O)NC(N)=N)=CC=2)=C1 LSBXWMQLLHVMMW-UHFFFAOYSA-N 0.000 claims description 12
• 206010020772 Hypertension Diseases 0.000 claims description 12
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• DTAMEVWADAHQQN-UHFFFAOYSA-N n-[4-[2-[5-[(diaminomethylideneamino)methyl]thiophen-2-yl]ethyl]-1,3-thiazol-2-yl]acetamide Chemical compound S1C(NC(=O)C)=NC(CCC=2SC(CNC(N)=N)=CC=2)=C1 DTAMEVWADAHQQN-UHFFFAOYSA-N 0.000 claims description 8
• 238000011321 prophylaxis Methods 0.000 claims description 8
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• 230000002093 peripheral effect Effects 0.000 claims description 6
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• 206010035114 pityriasis rosea Diseases 0.000 claims description 6
• 206010035116 pityriasis rubra pilaris Diseases 0.000 claims description 6
• 201000006292 polyarteritis nodosa Diseases 0.000 claims description 6
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• 230000007824 polyneuropathy Effects 0.000 claims description 6
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• 208000002574 reactive arthritis Diseases 0.000 claims description 6
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• 208000009852 uremia Diseases 0.000 claims description 6
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• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 5
• 206010014954 Eosinophilic fasciitis Diseases 0.000 claims description 5
• 206010017969 Gastrointestinal inflammatory conditions Diseases 0.000 claims description 5
• 208000017189 Gastrointestinal inflammatory disease Diseases 0.000 claims description 5
• 208000007048 Polymyalgia Rheumatica Diseases 0.000 claims description 5
• 208000012947 ischemia reperfusion injury Diseases 0.000 claims description 5
• 239000004480 active ingredient Substances 0.000 claims description 4
• 208000027496 Behcet disease Diseases 0.000 claims 2
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 212
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 162
• 238000004519 manufacturing process Methods 0.000 description 154
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 141
• 238000005160 1H NMR spectroscopy Methods 0.000 description 117
• 239000000243 solution Substances 0.000 description 108
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 95
• 239000000203 mixture Substances 0.000 description 93
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 72
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 71
• 239000011541 reaction mixture Substances 0.000 description 69
• 239000007787 solid Substances 0.000 description 60
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 55
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 48
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 48
• 229960001701 chloroform Drugs 0.000 description 44
• 238000003786 synthesis reaction Methods 0.000 description 43
• 230000015572 biosynthetic process Effects 0.000 description 41
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• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 39
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 38
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 36
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 36
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
• 239000012299 nitrogen atmosphere Substances 0.000 description 33
• 239000000741 silica gel Substances 0.000 description 33
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• 229960001866 silicon dioxide Drugs 0.000 description 33
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 31
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• YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 26
• 125000003118 aryl group Chemical group 0.000 description 26
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• 239000000706 filtrate Substances 0.000 description 24
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 23
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• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 19
• 125000004432 carbon atom Chemical group C* 0.000 description 16
• 238000001816 cooling Methods 0.000 description 16
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 16
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