BR112020014177A2 - Composto de amida heterocíclica nitrogenada, e uso do mesmo para finalidades médicas - Google Patents

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Publication number

BR112020014177A2

BR112020014177A2 BR112020014177-1A BR112020014177A BR112020014177A2 BR 112020014177 A2 BR112020014177 A2 BR 112020014177A2 BR 112020014177 A BR112020014177 A BR 112020014177A BR 112020014177 A2 BR112020014177 A2 BR 112020014177A2

Authority

BR

Brazil

Prior art keywords

compound

fact

formula

pharmaceutically acceptable

acceptable salt

Prior art date

2018-02-01

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• -1 AMIDE COMPOUND Chemical class 0.000 title claims description 102
• 150000001875 compounds Chemical class 0.000 claims abstract description 496
• 150000003839 salts Chemical class 0.000 claims abstract description 114
• 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 42
• 208000002815 pulmonary hypertension Diseases 0.000 claims abstract description 36
• 206010019280 Heart failures Diseases 0.000 claims abstract description 33
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 29
• 201000011510 cancer Diseases 0.000 claims abstract description 29
• 238000011282 treatment Methods 0.000 claims abstract description 26
• 201000001421 hyperglycemia Diseases 0.000 claims abstract description 25
• 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 25
• 206010020660 Hyperlactacidaemia Diseases 0.000 claims abstract description 24
• 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims abstract description 24
• 206010002383 Angina Pectoris Diseases 0.000 claims abstract description 23
• 208000006011 Stroke Diseases 0.000 claims abstract description 23
• 230000002490 cerebral effect Effects 0.000 claims abstract description 23
• 208000010125 myocardial infarction Diseases 0.000 claims abstract description 23
• 208000031225 myocardial ischemia Diseases 0.000 claims abstract description 23
• 201000001320 Atherosclerosis Diseases 0.000 claims abstract description 22
• 201000006474 Brain Ischemia Diseases 0.000 claims abstract description 22
• 206010008120 Cerebral ischaemia Diseases 0.000 claims abstract description 22
• 206010008190 Cerebrovascular accident Diseases 0.000 claims abstract description 22
• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims abstract description 22
• 208000032928 Dyslipidaemia Diseases 0.000 claims abstract description 22
• 208000017170 Lipid metabolism disease Diseases 0.000 claims abstract description 22
• 208000001145 Metabolic Syndrome Diseases 0.000 claims abstract description 22
• 206010058799 Mitochondrial encephalomyopathy Diseases 0.000 claims abstract description 22
• 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims abstract description 22
• 208000012268 mitochondrial disease Diseases 0.000 claims abstract description 22
• 206010022562 Intermittent claudication Diseases 0.000 claims abstract description 21
• 208000005764 Peripheral Arterial Disease Diseases 0.000 claims abstract description 21
• 208000030831 Peripheral arterial occlusive disease Diseases 0.000 claims abstract description 21
• 238000011321 prophylaxis Methods 0.000 claims abstract description 21
• 208000031229 Cardiomyopathies Diseases 0.000 claims abstract description 20
• 206010008118 cerebral infarction Diseases 0.000 claims abstract description 20
• 208000031773 Insulin resistance syndrome Diseases 0.000 claims abstract description 19
• 208000032131 Diabetic Neuropathies Diseases 0.000 claims abstract description 18
• 208000007342 Diabetic Nephropathies Diseases 0.000 claims abstract description 17
• 206010012689 Diabetic retinopathy Diseases 0.000 claims abstract description 17
• 208000033679 diabetic kidney disease Diseases 0.000 claims abstract description 17
• 206010007556 Cardiac failure acute Diseases 0.000 claims abstract description 16
• 206010007558 Cardiac failure chronic Diseases 0.000 claims abstract description 16
• 239000000203 mixture Substances 0.000 claims description 173
• 229920006395 saturated elastomer Polymers 0.000 claims description 96
• 238000004519 manufacturing process Methods 0.000 claims description 58
• 229910052757 nitrogen Inorganic materials 0.000 claims description 55
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 42
• 125000000217 alkyl group Chemical group 0.000 claims description 39
• 239000003795 chemical substances by application Substances 0.000 claims description 39
• 238000000034 method Methods 0.000 claims description 39
• 208000002249 Diabetes Complications Diseases 0.000 claims description 33
• 206010012655 Diabetic complications Diseases 0.000 claims description 33
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 29
• 201000010099 disease Diseases 0.000 claims description 28
• 229910052736 halogen Inorganic materials 0.000 claims description 25
• 150000002367 halogens Chemical class 0.000 claims description 25
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 25
• 125000004432 carbon atom Chemical group C* 0.000 claims description 20
• 208000021156 intermittent vascular claudication Diseases 0.000 claims description 20
• 229910052799 carbon Inorganic materials 0.000 claims description 19
• 230000036961 partial effect Effects 0.000 claims description 17
• 239000008194 pharmaceutical composition Substances 0.000 claims description 17
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 15
• 125000000623 heterocyclic group Chemical group 0.000 claims description 14
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
• 125000001424 substituent group Chemical group 0.000 claims description 14
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 12
• 206010064911 Pulmonary arterial hypertension Diseases 0.000 claims description 12
• 125000001072 heteroaryl group Chemical group 0.000 claims description 11
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 10
• 206010007749 Cataract diabetic Diseases 0.000 claims description 10
• 201000007025 diabetic cataract Diseases 0.000 claims description 10
• 125000005842 heteroatom Chemical group 0.000 claims description 10
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
• 229910052739 hydrogen Inorganic materials 0.000 claims description 8
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 7
• 239000001257 hydrogen Substances 0.000 claims description 7
• 241000124008 Mammalia Species 0.000 claims description 6
• 125000003545 alkoxy group Chemical group 0.000 claims description 5
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 4
• 239000003937 drug carrier Substances 0.000 claims description 4
• 206010022489 Insulin Resistance Diseases 0.000 claims description 3
• 208000011580 syndromic disease Diseases 0.000 claims description 3
• 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 2
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• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 182
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 159
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 156
• 239000011541 reaction mixture Substances 0.000 description 153
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 148
• 239000000243 solution Substances 0.000 description 145
• 238000001816 cooling Methods 0.000 description 136
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 132
• 239000002904 solvent Substances 0.000 description 107
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 98
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 94
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 93
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 92
• 229910052938 sodium sulfate Inorganic materials 0.000 description 92
• 235000011152 sodium sulphate Nutrition 0.000 description 92
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 90
• 230000002829 reductive effect Effects 0.000 description 87
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 75
• 238000005160 1H NMR spectroscopy Methods 0.000 description 72
• 239000012044 organic layer Substances 0.000 description 72
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 68
• 102100039169 [Pyruvate dehydrogenase [acetyl-transferring]]-phosphatase 1, mitochondrial Human genes 0.000 description 66
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 66
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 62
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 60
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 54
• 239000000706 filtrate Substances 0.000 description 53
• 239000011780 sodium chloride Substances 0.000 description 49
• 239000002585 base Substances 0.000 description 47
• 101100463130 Arabidopsis thaliana PDK gene Proteins 0.000 description 45
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• 230000000694 effects Effects 0.000 description 42
• QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 41
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 38
• 238000010898 silica gel chromatography Methods 0.000 description 38
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 35
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• 239000012043 crude product Substances 0.000 description 29
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• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 22
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 22
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• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 16
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