TWI659951B - 吡咯啶ｇｐｒ４０調節劑 - Google Patents

Info

Publication number

TWI659951B

TWI659951B TW104114493A TW104114493A TWI659951B TW I659951 B TWI659951 B TW I659951B TW 104114493 A TW104114493 A TW 104114493A TW 104114493 A TW104114493 A TW 104114493A TW I659951 B TWI659951 B TW I659951B

Authority

TW

Taiwan

Prior art keywords

alkyl

substituted

occurrence

independently selected

alkoxy

Prior art date

2014-05-07

Links

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• Global Dossier
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• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 title description 12
• 150000001875 compounds Chemical class 0.000 claims abstract description 199
• 150000003839 salts Chemical class 0.000 claims abstract description 70
• 239000003814 drug Substances 0.000 claims abstract description 41
• 125000000217 alkyl group Chemical group 0.000 claims description 147
• -1 oxalyl Diazolyl Chemical group 0.000 claims description 106
• 125000003545 alkoxy group Chemical group 0.000 claims description 78
• 229910052799 carbon Inorganic materials 0.000 claims description 51
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 51
• 229910052736 halogen Inorganic materials 0.000 claims description 47
• 150000002367 halogens Chemical class 0.000 claims description 47
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical group [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 44
• 239000003795 chemical substances by application Substances 0.000 claims description 41
• 229910052757 nitrogen Inorganic materials 0.000 claims description 38
• 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 32
• 229910052739 hydrogen Inorganic materials 0.000 claims description 32
• 125000004432 carbon atom Chemical group C* 0.000 claims description 31
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 31
• 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 30
• 229940124597 therapeutic agent Drugs 0.000 claims description 28
• 238000011282 treatment Methods 0.000 claims description 28
• 206010012601 diabetes mellitus Diseases 0.000 claims description 27
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 26
• 125000001072 heteroaryl group Chemical group 0.000 claims description 25
• 125000000623 heterocyclic group Chemical group 0.000 claims description 24
• 229910052760 oxygen Inorganic materials 0.000 claims description 24
• 229910052717 sulfur Inorganic materials 0.000 claims description 23
• 239000003472 antidiabetic agent Substances 0.000 claims description 22
• 125000005842 heteroatom Chemical group 0.000 claims description 22
• 125000001424 substituent group Chemical group 0.000 claims description 22
• 239000008194 pharmaceutical composition Substances 0.000 claims description 21
• 125000003831 tetrazolyl group Chemical group 0.000 claims description 19
• 125000004076 pyridyl group Chemical group 0.000 claims description 17
• 150000001721 carbon Chemical group 0.000 claims description 16
• 125000002837 carbocyclic group Chemical group 0.000 claims description 15
• 125000001624 naphthyl group Chemical group 0.000 claims description 15
• 125000002971 oxazolyl group Chemical group 0.000 claims description 15
• 229940125708 antidiabetic agent Drugs 0.000 claims description 14
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 13
• 239000003937 drug carrier Substances 0.000 claims description 12
• 239000001257 hydrogen Substances 0.000 claims description 12
• 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 12
• 125000004414 alkyl thio group Chemical group 0.000 claims description 11
• 239000003112 inhibitor Substances 0.000 claims description 11
• 125000000335 thiazolyl group Chemical group 0.000 claims description 11
• 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 11
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 10
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
• 125000003342 alkenyl group Chemical group 0.000 claims description 9
• 125000000392 cycloalkenyl group Chemical group 0.000 claims description 9
• 125000005843 halogen group Chemical group 0.000 claims description 9
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 9
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 8
• 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 8
• 208000032928 Dyslipidaemia Diseases 0.000 claims description 8
• 208000017170 Lipid metabolism disease Diseases 0.000 claims description 8
• 125000002541 furyl group Chemical group 0.000 claims description 8
• 238000004519 manufacturing process Methods 0.000 claims description 8
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
• 208000008589 Obesity Diseases 0.000 claims description 7
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
• 201000008980 hyperinsulinism Diseases 0.000 claims description 7
• 235000020824 obesity Nutrition 0.000 claims description 7
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 7
• 102000015779 HDL Lipoproteins Human genes 0.000 claims description 6
• 108010010234 HDL Lipoproteins Proteins 0.000 claims description 6
• 206010020772 Hypertension Diseases 0.000 claims description 6
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• 208000001145 Metabolic Syndrome Diseases 0.000 claims description 6
• 201000001421 hyperglycemia Diseases 0.000 claims description 6
• 208000017169 kidney disease Diseases 0.000 claims description 6
• 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 6
• 208000035150 Hypercholesterolemia Diseases 0.000 claims description 5
• 206010060378 Hyperinsulinaemia Diseases 0.000 claims description 5
• 208000017442 Retinal disease Diseases 0.000 claims description 5
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• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
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• 238000006467 substitution reaction Methods 0.000 claims description 5
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
• 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 4
• 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 4
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• 150000002632 lipids Chemical class 0.000 claims description 4
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• 125000003003 spiro group Chemical group 0.000 claims description 4
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• 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 3
• 206010016654 Fibrosis Diseases 0.000 claims description 3
• 208000002705 Glucose Intolerance Diseases 0.000 claims description 3
• 206010019280 Heart failures Diseases 0.000 claims description 3
• 208000031226 Hyperlipidaemia Diseases 0.000 claims description 3
• 108091006269 SLC5A2 Proteins 0.000 claims description 3
• 102000058081 Sodium-Glucose Transporter 2 Human genes 0.000 claims description 3
• 208000006011 Stroke Diseases 0.000 claims description 3
• 208000022531 anorexia Diseases 0.000 claims description 3
• 230000000879 anti-atherosclerotic effect Effects 0.000 claims description 3
• 230000007882 cirrhosis Effects 0.000 claims description 3
• 208000019425 cirrhosis of liver Diseases 0.000 claims description 3
• 230000003111 delayed effect Effects 0.000 claims description 3
• 208000033679 diabetic kidney disease Diseases 0.000 claims description 3
• 208000010706 fatty liver disease Diseases 0.000 claims description 3
• 230000003451 hyperinsulinaemic effect Effects 0.000 claims description 3
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• 230000029663 wound healing Effects 0.000 claims description 3
• 206010007559 Cardiac failure congestive Diseases 0.000 claims description 2
• 208000015943 Coeliac disease Diseases 0.000 claims description 2
• 206010009900 Colitis ulcerative Diseases 0.000 claims description 2
• 201000004624 Dermatitis Diseases 0.000 claims description 2
• 206010012438 Dermatitis atopic Diseases 0.000 claims description 2
• 229940124213 Dipeptidyl peptidase 4 (DPP IV) inhibitor Drugs 0.000 claims description 2
• 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 2
• 206010033645 Pancreatitis Diseases 0.000 claims description 2
• 201000004681 Psoriasis Diseases 0.000 claims description 2
• 208000033626 Renal failure acute Diseases 0.000 claims description 2
• 201000006704 Ulcerative Colitis Diseases 0.000 claims description 2
• 230000002159 abnormal effect Effects 0.000 claims description 2
• 201000011040 acute kidney failure Diseases 0.000 claims description 2
• 230000002253 anti-ischaemic effect Effects 0.000 claims description 2
• 239000000883 anti-obesity agent Substances 0.000 claims description 2
• 230000002946 anti-pancreatic effect Effects 0.000 claims description 2
• 239000002220 antihypertensive agent Substances 0.000 claims description 2
• 229940030600 antihypertensive agent Drugs 0.000 claims description 2
• 229940125710 antiobesity agent Drugs 0.000 claims description 2
• 201000008937 atopic dermatitis Diseases 0.000 claims description 2
• 239000003603 dipeptidyl peptidase IV inhibitor Substances 0.000 claims description 2
• 230000004217 heart function Effects 0.000 claims description 2
• 201000008383 nephritis Diseases 0.000 claims description 2
• 125000004943 pyrimidin-6-yl group Chemical group N1=CN=CC=C1* 0.000 claims description 2
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
• 208000020084 Bone disease Diseases 0.000 claims 1
• 102000004895 Lipoproteins Human genes 0.000 claims 1
• 108090001030 Lipoproteins Proteins 0.000 claims 1
• 150000001350 alkyl halides Chemical class 0.000 claims 1
• 206010003246 arthritis Diseases 0.000 claims 1
• 150000002431 hydrogen Chemical class 0.000 claims 1
• 101000912510 Homo sapiens Free fatty acid receptor 1 Proteins 0.000 abstract description 100
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• 239000012453 solvate Substances 0.000 abstract description 31
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• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 200
• 239000000243 solution Substances 0.000 description 150
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 137
• 238000004458 analytical method Methods 0.000 description 137
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 133
• 238000005481 NMR spectroscopy Methods 0.000 description 126
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 100
• 235000019439 ethyl acetate Nutrition 0.000 description 97
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 94
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 90
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• 239000000460 chlorine Substances 0.000 description 76
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• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 70
• 238000004587 chromatography analysis Methods 0.000 description 61
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 60
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• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 40
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