SA520412473B1 - مركب أميد حلقي غير متجانس معالج بالنيتروجين واستخدامه لأغراض طبية - Google Patents

Info

Publication number

SA520412473B1

SA520412473B1 SA520412473A SA520412473A SA520412473B1 SA 520412473 B1 SA520412473 B1 SA 520412473B1 SA 520412473 A SA520412473 A SA 520412473A SA 520412473 A SA520412473 A SA 520412473A SA 520412473 B1 SA520412473 B1 SA 520412473B1

Authority

SA

Saudi Arabia

Prior art keywords

compound

methyl

acid

mixture

mhz

Prior art date

2018-02-01

Links

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• -1 Heterocyclic Amide Compound Chemical class 0.000 title description 115
• 150000001875 compounds Chemical class 0.000 claims abstract description 426
• 150000003839 salts Chemical class 0.000 claims abstract description 95
• 206010019280 Heart failures Diseases 0.000 claims abstract description 40
• 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 40
• 208000006011 Stroke Diseases 0.000 claims abstract description 37
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 31
• 201000011510 cancer Diseases 0.000 claims abstract description 31
• 208000002249 Diabetes Complications Diseases 0.000 claims abstract description 28
• 201000001421 hyperglycemia Diseases 0.000 claims abstract description 27
• 206010002383 Angina Pectoris Diseases 0.000 claims abstract description 26
• 201000001320 Atherosclerosis Diseases 0.000 claims abstract description 26
• 208000031229 Cardiomyopathies Diseases 0.000 claims abstract description 25
• 206010012655 Diabetic complications Diseases 0.000 claims abstract description 25
• 208000031225 myocardial ischemia Diseases 0.000 claims abstract description 23
• 208000012268 mitochondrial disease Diseases 0.000 claims abstract description 22
• 201000006474 Brain Ischemia Diseases 0.000 claims abstract description 21
• 238000011282 treatment Methods 0.000 claims abstract description 21
• 208000032928 Dyslipidaemia Diseases 0.000 claims abstract description 20
• 208000031773 Insulin resistance syndrome Diseases 0.000 claims abstract description 20
• 206010022562 Intermittent claudication Diseases 0.000 claims abstract description 20
• 208000017170 Lipid metabolism disease Diseases 0.000 claims abstract description 20
• 230000002490 cerebral effect Effects 0.000 claims abstract description 20
• 206010008190 Cerebrovascular accident Diseases 0.000 claims abstract description 19
• 208000007342 Diabetic Nephropathies Diseases 0.000 claims abstract description 19
• 208000001145 Metabolic Syndrome Diseases 0.000 claims abstract description 19
• 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims abstract description 19
• 208000033679 diabetic kidney disease Diseases 0.000 claims abstract description 19
• 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 19
• 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims abstract description 18
• 208000002815 pulmonary hypertension Diseases 0.000 claims abstract description 18
• 208000005764 Peripheral Arterial Disease Diseases 0.000 claims abstract description 17
• 208000030831 Peripheral arterial occlusive disease Diseases 0.000 claims abstract description 17
• 206010012689 Diabetic retinopathy Diseases 0.000 claims abstract description 16
• 230000001684 chronic effect Effects 0.000 claims abstract description 16
• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims abstract description 15
• 206010058799 Mitochondrial encephalomyopathy Diseases 0.000 claims abstract description 15
• 208000032131 Diabetic Neuropathies Diseases 0.000 claims abstract description 14
• 208000010125 myocardial infarction Diseases 0.000 claims abstract description 13
• 208000002177 Cataract Diseases 0.000 claims abstract description 10
• 208000021156 intermittent vascular claudication Diseases 0.000 claims abstract description 10
• 206010020660 Hyperlactacidaemia Diseases 0.000 claims abstract description 7
• 125000000217 alkyl group Chemical group 0.000 claims description 58
• 229910052757 nitrogen Inorganic materials 0.000 claims description 38
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 35
• 239000003795 chemical substances by application Substances 0.000 claims description 32
• 229910052799 carbon Inorganic materials 0.000 claims description 26
• 125000004429 atom Chemical group 0.000 claims description 22
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 21
• 239000008194 pharmaceutical composition Substances 0.000 claims description 19
• 229910052736 halogen Inorganic materials 0.000 claims description 15
• 150000002367 halogens Chemical class 0.000 claims description 14
• 239000008280 blood Substances 0.000 claims description 13
• 210000004369 blood Anatomy 0.000 claims description 13
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 11
• 230000036961 partial effect Effects 0.000 claims description 11
• 230000002265 prevention Effects 0.000 claims description 8
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 6
• 230000002440 hepatic effect Effects 0.000 claims description 6
• 208000037849 arterial hypertension Diseases 0.000 claims description 5
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
• 239000003937 drug carrier Substances 0.000 claims description 5
• 235000000346 sugar Nutrition 0.000 claims description 4
• 206010022489 Insulin Resistance Diseases 0.000 claims description 2
• 125000005843 halogen group Chemical group 0.000 claims description 2
• 125000004432 carbon atom Chemical group C* 0.000 claims 4
• 241000511343 Chondrostoma nasus Species 0.000 claims 1
• 241000196324 Embryophyta Species 0.000 claims 1
• 239000011800 void material Substances 0.000 claims 1
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• 230000001154 acute effect Effects 0.000 abstract description 7
• 238000011321 prophylaxis Methods 0.000 abstract description 2
• 101100463130 Arabidopsis thaliana PDK gene Proteins 0.000 abstract 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 283
• 239000000203 mixture Substances 0.000 description 174
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 171
• 239000000243 solution Substances 0.000 description 164
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 146
• 239000011541 reaction mixture Substances 0.000 description 145
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 139
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 131
• 238000001816 cooling Methods 0.000 description 127
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 109
• 239000002904 solvent Substances 0.000 description 107
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 94
• 239000002253 acid Substances 0.000 description 91
• 229920006395 saturated elastomer Polymers 0.000 description 88
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 84
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 81
• 230000002829 reductive effect Effects 0.000 description 76
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 74
• 230000000694 effects Effects 0.000 description 73
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 70
• 229910052938 sodium sulfate Inorganic materials 0.000 description 70
• 235000011152 sodium sulphate Nutrition 0.000 description 70
• 239000012044 organic layer Substances 0.000 description 69
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 67
• 102000053067 Pyruvate Dehydrogenase Acetyl-Transferring Kinase Human genes 0.000 description 67
• 101710159466 [Pyruvate dehydrogenase (acetyl-transferring)] kinase, mitochondrial Proteins 0.000 description 67
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 62
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 61
• 238000004519 manufacturing process Methods 0.000 description 61
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 57
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 57
• 238000005160 1H NMR spectroscopy Methods 0.000 description 54
• 239000011780 sodium chloride Substances 0.000 description 54
• LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 53
• 239000000706 filtrate Substances 0.000 description 52
• JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 52
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 51
• 239000002585 base Substances 0.000 description 46
• 238000006243 chemical reaction Methods 0.000 description 41
• 238000010898 silica gel chromatography Methods 0.000 description 39
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 38
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 38
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 37
• 229940076788 pyruvate Drugs 0.000 description 37
• QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 35
• LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 34
• 238000012360 testing method Methods 0.000 description 34
• 210000003470 mitochondria Anatomy 0.000 description 33
• 101710088194 Dehydrogenase Proteins 0.000 description 32
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 32
• 239000012043 crude product Substances 0.000 description 31
• QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 30
• 235000017557 sodium bicarbonate Nutrition 0.000 description 30
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 30
• LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 27
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 27
• 239000011734 sodium Substances 0.000 description 27
• 239000004310 lactic acid Substances 0.000 description 26
• 235000014655 lactic acid Nutrition 0.000 description 26
• DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 25
• 238000000034 method Methods 0.000 description 25
• 229910052708 sodium Inorganic materials 0.000 description 25
• 229940083542 sodium Drugs 0.000 description 25
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• 201000010099 disease Diseases 0.000 description 22
• ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 21
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• 108091000080 Phosphotransferase Proteins 0.000 description 21
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• 102000020233 phosphotransferase Human genes 0.000 description 21
• ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 20
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 20
• 206010061216 Infarction Diseases 0.000 description 20
• 230000015572 biosynthetic process Effects 0.000 description 20
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• VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 20
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
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• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 16
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• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
• 239000010410 layer Substances 0.000 description 14
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• VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 13
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• 230000005764 inhibitory process Effects 0.000 description 13
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 12
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• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
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• 125000000753 cycloalkyl group Chemical group 0.000 description 8
• NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 8
• HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
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• 125000001424 substituent group Chemical group 0.000 description 8
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