JP2020521002A - テトラメチルピラジンニトロン誘導体の糖尿病合併症疾患の予防と治療における応用 - Google Patents
テトラメチルピラジンニトロン誘導体の糖尿病合併症疾患の予防と治療における応用 Download PDFInfo
- Publication number
- JP2020521002A JP2020521002A JP2020515801A JP2020515801A JP2020521002A JP 2020521002 A JP2020521002 A JP 2020521002A JP 2020515801 A JP2020515801 A JP 2020515801A JP 2020515801 A JP2020515801 A JP 2020515801A JP 2020521002 A JP2020521002 A JP 2020521002A
- Authority
- JP
- Japan
- Prior art keywords
- tetramethylpyrazine
- derivative
- diabetic
- group
- drug
- Prior art date
- 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.)
- Granted
Links
- FINHMKGKINIASC-UHFFFAOYSA-N tetramethyl-pyrazine Natural products CC1=NC(C)=C(C)N=C1C FINHMKGKINIASC-UHFFFAOYSA-N 0.000 title claims abstract description 84
- -1 tetramethylpyrazine nitrone derivative Chemical class 0.000 title claims abstract description 23
- 208000002249 Diabetes Complications Diseases 0.000 title claims abstract description 12
- 206010012655 Diabetic complications Diseases 0.000 title claims abstract description 12
- 230000002265 prevention Effects 0.000 title claims abstract description 8
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims abstract description 58
- 208000033679 diabetic kidney disease Diseases 0.000 claims abstract description 58
- 239000003814 drug Substances 0.000 claims abstract description 23
- 230000002207 retinal effect Effects 0.000 claims abstract description 21
- 230000003902 lesion Effects 0.000 claims abstract description 20
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
- 239000002552 dosage form Substances 0.000 claims abstract description 5
- 239000003937 drug carrier Substances 0.000 claims abstract description 5
- 229940079593 drug Drugs 0.000 claims description 17
- 238000002347 injection Methods 0.000 claims description 10
- 239000007924 injection Substances 0.000 claims description 10
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 claims description 6
- 208000010837 Diabetic eye disease Diseases 0.000 claims description 5
- 208000010412 Glaucoma Diseases 0.000 claims description 4
- 208000002177 Cataract Diseases 0.000 claims description 3
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 claims description 3
- 239000011724 folic acid Substances 0.000 claims description 3
- 229960000304 folic acid Drugs 0.000 claims description 3
- 235000019152 folic acid Nutrition 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- 239000005541 ACE inhibitor Substances 0.000 claims description 2
- 229940125364 angiotensin receptor blocker Drugs 0.000 claims description 2
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 239000000725 suspension Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 101710129690 Angiotensin-converting enzyme inhibitor Proteins 0.000 claims 1
- 101710086378 Bradykinin-potentiating and C-type natriuretic peptides Proteins 0.000 claims 1
- 239000002220 antihypertensive agent Substances 0.000 claims 1
- 229940127088 antihypertensive drug Drugs 0.000 claims 1
- 230000036772 blood pressure Effects 0.000 claims 1
- 210000005036 nerve Anatomy 0.000 claims 1
- 239000000825 pharmaceutical preparation Substances 0.000 claims 1
- 229940127557 pharmaceutical product Drugs 0.000 claims 1
- 231100001028 renal lesion Toxicity 0.000 claims 1
- 241000700159 Rattus Species 0.000 abstract description 43
- 210000004369 blood Anatomy 0.000 abstract description 14
- 239000008280 blood Substances 0.000 abstract description 14
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 abstract description 14
- 102000004169 proteins and genes Human genes 0.000 abstract description 12
- 108090000623 proteins and genes Proteins 0.000 abstract description 12
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 abstract description 10
- 239000008103 glucose Substances 0.000 abstract description 10
- PNNCWTXUWKENPE-UHFFFAOYSA-N [N].NC(N)=O Chemical compound [N].NC(N)=O PNNCWTXUWKENPE-UHFFFAOYSA-N 0.000 abstract description 8
- 210000002966 serum Anatomy 0.000 abstract description 8
- 229940109239 creatinine Drugs 0.000 abstract description 7
- 210000002700 urine Anatomy 0.000 abstract description 6
- 230000003247 decreasing effect Effects 0.000 abstract description 5
- 238000010586 diagram Methods 0.000 abstract 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 24
- 230000000694 effects Effects 0.000 description 22
- 206010012601 diabetes mellitus Diseases 0.000 description 17
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 10
- 230000002485 urinary effect Effects 0.000 description 10
- 230000001225 therapeutic effect Effects 0.000 description 9
- 230000037396 body weight Effects 0.000 description 7
- 210000003734 kidney Anatomy 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 201000010099 disease Diseases 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 235000012000 cholesterol Nutrition 0.000 description 5
- 239000003642 reactive oxygen metabolite Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 5
- 230000002292 Radical scavenging effect Effects 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- 208000030533 eye disease Diseases 0.000 description 4
- 230000037406 food intake Effects 0.000 description 4
- 235000012631 food intake Nutrition 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- SQDFHQJTAWCFIB-UHFFFAOYSA-N n-methylidenehydroxylamine Chemical group ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 description 4
- 230000001681 protective effect Effects 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 230000006909 anti-apoptosis Effects 0.000 description 3
- 230000003064 anti-oxidating effect Effects 0.000 description 3
- 230000002526 effect on cardiovascular system Effects 0.000 description 3
- 230000029142 excretion Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 210000001508 eye Anatomy 0.000 description 3
- 201000001421 hyperglycemia Diseases 0.000 description 3
- 230000001771 impaired effect Effects 0.000 description 3
- 208000017169 kidney disease Diseases 0.000 description 3
- 230000003907 kidney function Effects 0.000 description 3
- 230000037356 lipid metabolism Effects 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 210000005084 renal tissue Anatomy 0.000 description 3
- 239000002083 C09CA01 - Losartan Substances 0.000 description 2
- 206010016654 Fibrosis Diseases 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- RXUWDKBZZLIASQ-UHFFFAOYSA-N Puerarin Natural products OCC1OC(Oc2c(O)cc(O)c3C(=O)C(=COc23)c4ccc(O)cc4)C(O)C(O)C1O RXUWDKBZZLIASQ-UHFFFAOYSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 235000021050 feed intake Nutrition 0.000 description 2
- 230000004761 fibrosis Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical group N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 230000000302 ischemic effect Effects 0.000 description 2
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 description 2
- 229960004773 losartan Drugs 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- 208000030159 metabolic disease Diseases 0.000 description 2
- 230000007102 metabolic function Effects 0.000 description 2
- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 description 2
- 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 description 2
- 206010036067 polydipsia Diseases 0.000 description 2
- HKEAFJYKMMKDOR-VPRICQMDSA-N puerarin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=C(O)C=CC(C2=O)=C1OC=C2C1=CC=C(O)C=C1 HKEAFJYKMMKDOR-VPRICQMDSA-N 0.000 description 2
- 238000011552 rat model Methods 0.000 description 2
- 210000000952 spleen Anatomy 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 231100000027 toxicology Toxicity 0.000 description 2
- 230000003442 weekly effect Effects 0.000 description 2
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 208000012639 Balance disease Diseases 0.000 description 1
- 102000015735 Beta-catenin Human genes 0.000 description 1
- 108060000903 Beta-catenin Proteins 0.000 description 1
- 229940123208 Biguanide Drugs 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010010071 Coma Diseases 0.000 description 1
- 102000000634 Cytochrome c oxidase subunit IV Human genes 0.000 description 1
- 108090000365 Cytochrome-c oxidases Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102000003779 Dipeptidyl-peptidases and tripeptidyl-peptidases Human genes 0.000 description 1
- 108090000194 Dipeptidyl-peptidases and tripeptidyl-peptidases Proteins 0.000 description 1
- 102000004366 Glucosidases Human genes 0.000 description 1
- 108010056771 Glucosidases Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 229940122199 Insulin secretagogue Drugs 0.000 description 1
- 206010023379 Ketoacidosis Diseases 0.000 description 1
- 208000007976 Ketosis Diseases 0.000 description 1
- FFFHZYDWPBMWHY-VKHMYHEASA-N L-homocysteine Chemical compound OC(=O)[C@@H](N)CCS FFFHZYDWPBMWHY-VKHMYHEASA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 206010067633 Peripheral nerve lesion Diseases 0.000 description 1
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 1
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 description 1
- 102000003923 Protein Kinase C Human genes 0.000 description 1
- 108090000315 Protein Kinase C Proteins 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- 229940123464 Thiazolidinedione Drugs 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000002253 anti-ischaemic effect Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 210000000702 aorta abdominal Anatomy 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 150000004283 biguanides Chemical class 0.000 description 1
- 210000004155 blood-retinal barrier Anatomy 0.000 description 1
- 230000004378 blood-retinal barrier Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000035487 diastolic blood pressure Effects 0.000 description 1
- 208000016097 disease of metabolism Diseases 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 208000028208 end stage renal disease Diseases 0.000 description 1
- 201000000523 end stage renal failure Diseases 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 210000000585 glomerular basement membrane Anatomy 0.000 description 1
- 206010061989 glomerulosclerosis Diseases 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 230000036252 glycation Effects 0.000 description 1
- 230000000004 hemodynamic effect Effects 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- RQKFOGXUTRDQPB-UHFFFAOYSA-N hydron;2,3,5,6-tetramethylpyrazine;chloride Chemical compound Cl.CC1=NC(C)=C(C)N=C1C RQKFOGXUTRDQPB-UHFFFAOYSA-N 0.000 description 1
- 230000002727 hyperosmolar Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000034727 intrinsic apoptotic signaling pathway Effects 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000006996 mental state Effects 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 230000004065 mitochondrial dysfunction Effects 0.000 description 1
- 210000001700 mitochondrial membrane Anatomy 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000006654 negative regulation of apoptotic process Effects 0.000 description 1
- 230000010046 negative regulation of endothelial cell proliferation Effects 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- BNYHRGTXRPWASY-UHFFFAOYSA-N nonylsulfonylurea Chemical compound CCCCCCCCCS(=O)(=O)NC(N)=O BNYHRGTXRPWASY-UHFFFAOYSA-N 0.000 description 1
- 208000013441 ocular lesion Diseases 0.000 description 1
- 210000001328 optic nerve Anatomy 0.000 description 1
- 229940127017 oral antidiabetic Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000004792 oxidative damage Effects 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 201000001474 proteinuria Diseases 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000008085 renal dysfunction Effects 0.000 description 1
- 230000010410 reperfusion Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000001210 retinal vessel Anatomy 0.000 description 1
- 238000000518 rheometry Methods 0.000 description 1
- 230000002000 scavenging effect Effects 0.000 description 1
- PTLRDCMBXHILCL-UHFFFAOYSA-M sodium arsenite Chemical compound [Na+].[O-][As]=O PTLRDCMBXHILCL-UHFFFAOYSA-M 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 208000032598 susceptibility microvascular complications of diabetes Diseases 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 230000035488 systolic blood pressure Effects 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
- XPFJYKARVSSRHE-UHFFFAOYSA-K trisodium;2-hydroxypropane-1,2,3-tricarboxylate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].[Na+].OC(=O)CC(O)(C(O)=O)CC(O)=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O XPFJYKARVSSRHE-UHFFFAOYSA-K 0.000 description 1
- 230000002227 vasoactive effect Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/10—Ophthalmic agents for accommodation disorders, e.g. myopia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/12—Ophthalmic agents for cataracts
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Ophthalmology & Optometry (AREA)
- Diabetes (AREA)
- Epidemiology (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Urology & Nephrology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
1. モデルの作製
SDラット(200±10g)をモデル動物として、注射前に12h禁食させ、注射時にクエン酸バッファーを用いて1%の濃度でSTZを溶解し、禁食後のラットの体重を測定した後、55mg/kg STZを腹腔内注射して、ラットをケージに入れ、ラットに24h十分に飲水させた。STZを注射するときに、10min以内で素早く注射すべきである。正常対照群には、pH4.5のクエン酸−クエン酸ナトリウムバッファーを等体積で注射した。動物の状態(多飲多尿が認められる)を観察し、STZ注射3週間後、尾静脈から採血して、測定した空腹時血糖≧16.7mmol/Lをラット糖尿病性腎臓病モデルの作製完成基準とした。
2. 群分け
DKDラットをランダムに6群に分け、それぞれ異なる医薬品を投与し、投与6週間後、実験を停止し、医薬品によるDKDラットへの保護作用を観察した。
毎週、作製されたモデルラットの一般的な状況及び体重の変化を観察し、一般的な状況には、ラットの活動状況、精神状態、毛色、摂食、飲水量や尿量などが含まれる。毎週、飲水量及び飼料摂取量を記録した。
テトラメチルピラジン誘導体による、STZ誘発糖尿病性腎臓病ラットの体重への影響については、図1aに示されるように、TBN及びTN−2は、糖尿病性腎臓病ラットの体重にもほとんど影響がなく、糖尿病性腎臓病ラットの飲水量及び飼料摂取量の変化については、それぞれ図1b及び図1cに示されるように、TBN及びTN−2を投与した治療群のDKDラットでは、飲水量及び摂食がモデル群のそれよりも有意に低く、それは、TBN及びTN−2がDKDラット糖尿病の進行を遅らせて、DKDラットの多飲多食の糖尿病症状を改善できることを示した。
実験には、毎日投与するときにラット網膜病変の状況を観察し、群別にラットの網膜病変の発症日を記録した。
網膜病変は、糖尿病性腎臓病の一般的な合併症の1つであり、糖尿病性腎臓病との相関性が高かった。テトラメチルピラジン誘導体による、STZ誘発DKDラット網膜病変への影響については、表1に示されるように、TBN及びTN−2を投与することで治療を施した後、DKDラットでは、網膜病変の発症例数が減少し、網膜病変の発症時刻が遅くなり、研究結果から明らかなように、テトラメチルピラジン誘導体TBN及びTN−2が網膜病変の発生を減少させ、且つ遅らせることができた。
実験には、モデル作製後及び投与後に、それぞれラットの血糖をモニタリングして、24hの尿を1回収集して、尿タンパク質を検出した。
テトラメチルピラジン誘導体による、STZ誘発DKDラットの血糖への影響については、図2aに示されるように、ラットでは、STZにより誘発されてから3週間後、血糖が有意に上昇し、TBN及びTN−2の投与により治療を施してから6週間後、血糖が有意に低下した。TBN及びTN−2によるSTZ誘発DKDラットの尿タンパク質への影響については、図2bに示されるように、TBN及びTN−2の投与により治療を施した後、DKDラットの尿中の尿タンパク質の含有量が大幅に低下し、且つ、TBNとロサルタンを併用する場合は、TBN単独投与による治療の場合及びロサルタン単独投与による治療の場合よりも好ましかった。
投与6週間後、ラットを麻酔して腹部大動脈から採血し、1h静置後、3000rmpで10min遠心処理し、−70℃で保存した。自動生化学分析装置を使用して、血清クレアチニン、尿素窒素、コレステロール及びトリグリセリドのレベルを測定した。
血清クレアチニン、尿素窒素、コレステロール及びトリグリセリドのレベルは、体の脂質代謝、糖類の代謝や腎臓機能などの状況を反映できる。テトラメチルピラジン誘導体による、STZ誘発DKDラットの血清クレアチニン、尿素窒素、コレステロール及びトリグリセリドの影響については、図3に示されるように、TBN及びTN−2は、血清におけるクレアチニン(図3a)、尿素窒素(図3b)、コレステロール(図3c)及びトリグリセリド(図3d)のレベルを用量依存的に大幅に低下させることができ、STZ誘発糖尿病性腎臓病ラットの脂質代謝、糖類の代謝や腎臓機能を改善する作用を示した。
投与6週間後、オートクレーブで滅菌した手術器具を用いて腹腔を開いて腎臓組織を一括して摘出し、生理食塩水で洗浄し、ろ紙で水を吸い取った後、精密天びんで重量を量り、次に使用時まで−80℃の冷蔵庫で保存した。腎臓指数(相対腎臓重量)は、腎臓重量(mg)/体重(g)=BW/KWであった。
糖尿病性腎臓病の病理学的プロセスの進行に伴い、糸球体基底膜が徐々に厚くなり、メサンギウムがより広くなり、最終的に腎限局性尿細管萎縮及び間質性線維化まで進行し、腎不全の段階に入り、腎臓指数は、糖尿病性腎臓病の病理学的状況をある程度で反映できた。テトラメチルピラジン誘導体によるSTZ誘発DKDラットの腎臓指数への影響については、図4に示されるように、TBN及びTN−2は、DKDラットの腎臓指数を大幅に低下させ、それは、TBN及びTN−2が糖尿病性腎臓病の進行を遅らせることを示した。
Claims (12)
- テトラメチルピラジンニトロン誘導体の医薬品の調製における応用であって、
前記医薬品は、前記誘導体又はその医薬組成物を含み、糖尿病合併症疾患の予防と治療に用いられ、前記誘導体は、下記一般式(I)の構造を有する応用。
- 前記C1−C6アルキル基は、メチル基、エチル基、n−プロピル基、イソプロピル基、n−ブチル基、イソブチル基、t−ブチル基又はn−ペンチル基である請求項1に記載の応用。
- 前記誘導体は、下記構造式を有する請求項1に記載の応用。
- 前記糖尿病合併症は、糖尿病性腎臓病である請求項1に記載の応用。
- 前記糖尿病合併症は、糖尿病性眼疾患、腎臓病変又は神経病変である請求項1に記載の応用。
- 前記糖尿病性眼疾患は、網膜病変、緑内障又は白内障である請求項5に記載の応用。
- 前記医薬組成物は、治療有効用量の前記誘導体又はその薬学的に許容可能な塩、及び薬学的に許容可能な担体を含む請求項1に記載の応用。
- 前記誘導体を含む医薬品は、単独で使用してもよく、又はほかの医薬品と組み合わせて使用してもよい請求項1に記載の応用。
- 前記組み合わせるほかの医薬品は、血圧降下薬である請求項8に記載の応用。
- 前記血圧降下薬は、アンジオテンシン受容体遮断薬、アンジオテンシン変換酵素阻害薬又は葉酸である請求項9に記載の応用。
- 前記誘導体は、薬学的に許容可能な担体とともに各種の剤形を調製でき、前記剤形は、錠剤、顆粒剤、注射剤、粉末剤、カプセル剤又は懸濁剤である請求項7に記載の応用。
- 前記有効用量は、0.001〜2g/kgである請求項7に記載の応用。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710392539.X | 2017-05-27 | ||
CN201710392539.XA CN107157999A (zh) | 2017-05-27 | 2017-05-27 | 川芎嗪硝酮衍生物在预防和治疗糖尿病并发症疾病中的应用 |
PCT/CN2018/000194 WO2018218961A1 (zh) | 2017-05-27 | 2018-05-25 | 川芎嗪硝酮衍生物在预防和治疗糖尿病并发症疾病中的应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2020521002A true JP2020521002A (ja) | 2020-07-16 |
JP6954698B2 JP6954698B2 (ja) | 2021-10-27 |
Family
ID=59821915
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2020515801A Active JP6954698B2 (ja) | 2017-05-27 | 2018-05-25 | テトラメチルピラジンニトロン誘導体の糖尿病合併症疾患の予防と治療における応用 |
Country Status (7)
Country | Link |
---|---|
US (1) | US11197855B2 (ja) |
EP (1) | EP3632440A4 (ja) |
JP (1) | JP6954698B2 (ja) |
CN (3) | CN115887460A (ja) |
AU (1) | AU2018276686B2 (ja) |
CA (1) | CA3064976C (ja) |
WO (1) | WO2018218961A1 (ja) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115887460A (zh) * | 2017-05-27 | 2023-04-04 | 青岛海蓝医药有限公司 | 川芎嗪硝酮衍生物在预防和治疗糖尿病并发症疾病中的应用 |
CN116003334A (zh) * | 2019-04-01 | 2023-04-25 | 广州喜鹊医药有限公司 | 硝酮嗪晶型、制备方法及应用 |
CN114344304B (zh) * | 2020-10-14 | 2023-06-30 | 广州喜鹊医药有限公司 | 川芎嗪硝酮化合物在制备预防和/或治疗肾性贫血药物中的应用 |
CN116650411A (zh) * | 2022-02-25 | 2023-08-29 | 广州喜鹊医药有限公司 | 一种注射用硝酮嗪药物组合物及其制备方法 |
WO2023165479A1 (zh) * | 2022-03-02 | 2023-09-07 | 广州喜鹊医药有限公司 | 硝酮化合物或其在药学上可接受的盐与sglt-2抑制剂联合应用 |
CN116850188A (zh) * | 2023-05-29 | 2023-10-10 | 广州喜鹊医药有限公司 | 川芎嗪硝酮衍生物在制备预防或治疗2型糖尿病药物中的应用 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101468970A (zh) * | 2008-04-25 | 2009-07-01 | 暨南大学 | 一种硝酮类化合物及其制备方法和在制药中的应用 |
JP2013529656A (ja) * | 2010-07-05 | 2013-07-22 | ジナン・ユニバーシティ | ピラジン誘導体、その製造方法及びその医薬用途 |
CN107157999A (zh) * | 2017-05-27 | 2017-09-15 | 青岛海蓝医药有限公司 | 川芎嗪硝酮衍生物在预防和治疗糖尿病并发症疾病中的应用 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101816655A (zh) * | 2009-12-16 | 2010-09-01 | 成都百康医药工业药理毒理研究院 | 包含瑞格列奈和川芎嗪药物制剂及在糖尿病并发症中用途 |
CN102552267A (zh) * | 2012-02-17 | 2012-07-11 | 上海市中医医院 | 川芎嗪在制备治疗造影剂肾病药物中的应用 |
CN105017165B (zh) * | 2015-07-07 | 2018-04-03 | 广州喜鹊医药有限公司 | 一种新的吡嗪衍生物及其制备方法和医药应用 |
CN105963298B (zh) * | 2016-05-06 | 2019-07-09 | 广州喜鹊医药有限公司 | 川芎嗪衍生物硝酮嗪在预防和治疗脑损伤疾病中的应用 |
-
2017
- 2017-05-27 CN CN202211727058.7A patent/CN115887460A/zh active Pending
- 2017-05-27 CN CN202211673444.2A patent/CN116637115A/zh active Pending
- 2017-05-27 CN CN201710392539.XA patent/CN107157999A/zh active Pending
-
2018
- 2018-05-25 AU AU2018276686A patent/AU2018276686B2/en active Active
- 2018-05-25 WO PCT/CN2018/000194 patent/WO2018218961A1/zh active Application Filing
- 2018-05-25 US US16/602,714 patent/US11197855B2/en active Active
- 2018-05-25 CA CA3064976A patent/CA3064976C/en active Active
- 2018-05-25 JP JP2020515801A patent/JP6954698B2/ja active Active
- 2018-05-25 EP EP18809367.8A patent/EP3632440A4/en active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101468970A (zh) * | 2008-04-25 | 2009-07-01 | 暨南大学 | 一种硝酮类化合物及其制备方法和在制药中的应用 |
JP2011518789A (ja) * | 2008-04-25 | 2011-06-30 | 曁南大学 | ニトロン化合物、その製造方法およびその医薬用途 |
JP2013529656A (ja) * | 2010-07-05 | 2013-07-22 | ジナン・ユニバーシティ | ピラジン誘導体、その製造方法及びその医薬用途 |
CN107157999A (zh) * | 2017-05-27 | 2017-09-15 | 青岛海蓝医药有限公司 | 川芎嗪硝酮衍生物在预防和治疗糖尿病并发症疾病中的应用 |
Non-Patent Citations (1)
Title |
---|
日本臨床(増刊), vol. 第70巻, 増刊号5, JPN6020036540, 2012, pages 411 - 418, ISSN: 0004490770 * |
Also Published As
Publication number | Publication date |
---|---|
CN115887460A (zh) | 2023-04-04 |
JP6954698B2 (ja) | 2021-10-27 |
CA3064976C (en) | 2022-06-28 |
EP3632440A4 (en) | 2021-02-17 |
EP3632440A1 (en) | 2020-04-08 |
CN116637115A (zh) | 2023-08-25 |
US20200155548A1 (en) | 2020-05-21 |
CA3064976A1 (en) | 2018-12-06 |
AU2018276686B2 (en) | 2021-01-21 |
AU2018276686A1 (en) | 2019-12-19 |
US11197855B2 (en) | 2021-12-14 |
CN107157999A (zh) | 2017-09-15 |
WO2018218961A1 (zh) | 2018-12-06 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6954698B2 (ja) | テトラメチルピラジンニトロン誘導体の糖尿病合併症疾患の予防と治療における応用 | |
WO2008053982A1 (fr) | Composition pour le traitement de l'allergie | |
Chao | A paradigm shift in diabetes therapy—dapagliflozin and other SGLT2 inhibitors | |
CN108025007A (zh) | 曲美他嗪在制备防治肝病的药物中的用途 | |
EP2891499A1 (en) | Combination of sglt2 inhibitor and anti-hypertension drug | |
US20080249168A1 (en) | Pharmaceutical composition for gout | |
JP5680412B2 (ja) | レオヌリンの使用およびその組成物 | |
US20220202812A1 (en) | Use of ligustrazine nitrone derivatives in treatment and prevention of diabetic complication diseases | |
JP2014527506A (ja) | 糖尿病治療のための組み合わせ | |
CN101273994A (zh) | 用于治疗糖尿病性视网膜病变的药物组合物及其制备方法 | |
JP2004534760A (ja) | 腎線維症の治療 | |
CN101229373B (zh) | 治疗糖尿病肾病的药物组合物 | |
EP0063973A1 (fr) | Composition pour collyre à base de sulfate de chondroitine A | |
US10918612B2 (en) | Combinations with 2-aminoethanesulfonic acid | |
JP7344422B2 (ja) | 糖尿病予防・治療用の医薬品組成物及びその用途 | |
Savant et al. | Herbal Drugs used in the Management of Diabetic Nephropathy | |
CN102161619B (zh) | 一种阿魏酸降糖复盐及其制备方法和用途 | |
CN111067910B (zh) | 一种用于预防和治疗糖尿病的药物组合物及其应用 | |
RU2461386C1 (ru) | Применение югланэкса как средства, нормализующего липидный, углеводный и белковый обмены | |
CN105030806A (zh) | 一种治疗糖尿病的药物组合物及其用途 | |
CN1883541A (zh) | 一种治疗心脑血管疾病的中药制剂及其制备方法和用途 | |
Abdelrahman et al. | Sodium Glucose Co-transporter 2 Inhibitors: Pharmacology, Mechanism of Action and Efficacy in Non-diabetic Kidney Disease from Bench to Bed-Side | |
RU2495663C1 (ru) | Твердая лекарственная форма таурина с улучшенными фармакологическими свойствами | |
TWI331530B (en) | Pharmaceutical composition for treating aristolochic acid nephropathy | |
WO2008025450A1 (en) | Methods of lowering glucose levels |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20191125 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20200929 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20201224 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20210427 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20210726 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20210831 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20210922 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6954698 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |