CN108236611A - Two kinds of compounds, which are combined, is preparing the purposes in treating diabetes medicament - Google Patents
Two kinds of compounds, which are combined, is preparing the purposes in treating diabetes medicament Download PDFInfo
- Publication number
- CN108236611A CN108236611A CN201711429769.5A CN201711429769A CN108236611A CN 108236611 A CN108236611 A CN 108236611A CN 201711429769 A CN201711429769 A CN 201711429769A CN 108236611 A CN108236611 A CN 108236611A
- Authority
- CN
- China
- Prior art keywords
- formula
- compound
- compound represented
- pharmaceutical salt
- purposes
- 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.)
- Pending
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 88
- 206010012601 diabetes mellitus Diseases 0.000 title claims abstract description 30
- 239000003814 drug Substances 0.000 title claims abstract description 27
- 150000003839 salts Chemical class 0.000 claims description 20
- 238000011282 treatment Methods 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 229910019142 PO4 Inorganic materials 0.000 claims description 5
- 239000010452 phosphate Substances 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 229940049920 malate Drugs 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 239000008024 pharmaceutical diluent Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 229950004288 tosilate Drugs 0.000 claims description 2
- 150000008107 benzenesulfonic acids Chemical class 0.000 claims 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims 1
- 229940124531 pharmaceutical excipient Drugs 0.000 claims 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims 1
- 239000008280 blood Substances 0.000 description 30
- 210000004369 blood Anatomy 0.000 description 30
- 239000008103 glucose Substances 0.000 description 20
- 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 description 18
- 241001465754 Metazoa Species 0.000 description 14
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound 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 14
- 239000003981 vehicle Substances 0.000 description 12
- 230000000694 effects Effects 0.000 description 10
- 238000002474 experimental method Methods 0.000 description 10
- 230000002218 hypoglycaemic effect Effects 0.000 description 10
- 235000000346 sugar Nutrition 0.000 description 10
- 102000017011 Glycated Hemoglobin A Human genes 0.000 description 9
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 9
- 229940126062 Compound A Drugs 0.000 description 8
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 101800000224 Glucagon-like peptide 1 Proteins 0.000 description 7
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 7
- 102000004877 Insulin Human genes 0.000 description 7
- 102100040918 Pro-glucagon Human genes 0.000 description 7
- 229940125396 insulin Drugs 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 108010014663 Glycated Hemoglobin A Proteins 0.000 description 6
- 108090001061 Insulin Proteins 0.000 description 6
- 239000012153 distilled water Substances 0.000 description 6
- 230000002195 synergetic effect Effects 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 5
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 5
- 102100026148 Free fatty acid receptor 1 Human genes 0.000 description 5
- 101000912510 Homo sapiens Free fatty acid receptor 1 Proteins 0.000 description 5
- 206010022489 Insulin Resistance Diseases 0.000 description 5
- 235000013305 food Nutrition 0.000 description 5
- 230000007774 longterm Effects 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 239000000556 agonist Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 230000003247 decreasing effect Effects 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 239000000890 drug combination Substances 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 230000003914 insulin secretion Effects 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 230000028327 secretion Effects 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- 108091005995 glycated hemoglobin Proteins 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 210000000496 pancreas Anatomy 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- DGENZVKCTGIDRZ-UHFFFAOYSA-N 3-[4-[(3-phenoxyphenyl)methylamino]phenyl]propanoic acid Chemical class C1=CC(CCC(=O)O)=CC=C1NCC1=CC=CC(OC=2C=CC=CC=2)=C1 DGENZVKCTGIDRZ-UHFFFAOYSA-N 0.000 description 2
- 208000013016 Hypoglycemia Diseases 0.000 description 2
- 102000003746 Insulin Receptor Human genes 0.000 description 2
- 108010001127 Insulin Receptor Proteins 0.000 description 2
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000011284 combination treatment Methods 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 238000003304 gavage Methods 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 201000001421 hyperglycemia Diseases 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 208000035408 type 1 diabetes mellitus 1 Diseases 0.000 description 2
- SPFMQWBKVUQXJV-BTVCFUMJSA-N (2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanal;hydrate Chemical compound O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O SPFMQWBKVUQXJV-BTVCFUMJSA-N 0.000 description 1
- NGJOFQZEYQGZMB-KTKZVXAJSA-N (4S)-5-[[2-[[(2S,3R)-1-[[(2S)-1-[[(2S,3R)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S,3S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[2-[[(1S)-4-carbamimidamido-1-carboxybutyl]amino]-2-oxoethyl]amino]-1-oxohexan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-2-oxoethyl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-2-oxoethyl]amino]-4-[[(2S)-2-[[(2S)-2-amino-3-(1H-imidazol-4-yl)propanoyl]amino]propanoyl]amino]-5-oxopentanoic acid Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 NGJOFQZEYQGZMB-KTKZVXAJSA-N 0.000 description 1
- ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical compound O=C1CSC(=O)N1 ZOBPZXTWZATXDG-UHFFFAOYSA-N 0.000 description 1
- INGWEZCOABYORO-UHFFFAOYSA-N 2-(furan-2-yl)-7-methyl-1h-1,8-naphthyridin-4-one Chemical compound N=1C2=NC(C)=CC=C2C(O)=CC=1C1=CC=CO1 INGWEZCOABYORO-UHFFFAOYSA-N 0.000 description 1
- HVCOBJNICQPDBP-UHFFFAOYSA-N 3-[3-[3,5-dihydroxy-6-methyl-4-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyoxan-2-yl]oxydecanoyloxy]decanoic acid;hydrate Chemical compound O.OC1C(OC(CC(=O)OC(CCCCCCC)CC(O)=O)CCCCCCC)OC(C)C(O)C1OC1C(O)C(O)C(O)C(C)O1 HVCOBJNICQPDBP-UHFFFAOYSA-N 0.000 description 1
- 241001552669 Adonis annua Species 0.000 description 1
- 102000004860 Dipeptidases Human genes 0.000 description 1
- 108090001081 Dipeptidases Proteins 0.000 description 1
- 108090000194 Dipeptidyl-peptidases and tripeptidyl-peptidases Proteins 0.000 description 1
- 102000003779 Dipeptidyl-peptidases and tripeptidyl-peptidases Human genes 0.000 description 1
- 229940125827 GPR40 agonist Drugs 0.000 description 1
- 102000007446 Glucagon-Like Peptide-1 Receptor Human genes 0.000 description 1
- 108010086246 Glucagon-Like Peptide-1 Receptor Proteins 0.000 description 1
- 101800004295 Glucagon-like peptide 1(7-36) Proteins 0.000 description 1
- 229930186217 Glycolipid Natural products 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 101710092928 Insulin-like peptide-1 Proteins 0.000 description 1
- 102100024295 Maltase-glucoamylase Human genes 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- 229940123464 Thiazolidinedione Drugs 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 108010028144 alpha-Glucosidases Proteins 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 238000003149 assay kit Methods 0.000 description 1
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 230000008512 biological response Effects 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000009693 chronic damage Effects 0.000 description 1
- 229940000425 combination drug Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000002224 dissection Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000007783 downstream signaling Effects 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000004110 gluconeogenesis Effects 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 230000002641 glycemic effect Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- MGXWVYUBJRZYPE-YUGYIWNOSA-N incretin Chemical class C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=C(O)C=C1 MGXWVYUBJRZYPE-YUGYIWNOSA-N 0.000 description 1
- 239000000859 incretin Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 229940127017 oral antidiabetic Drugs 0.000 description 1
- 239000003538 oral antidiabetic agent Substances 0.000 description 1
- 238000007410 oral glucose tolerance test Methods 0.000 description 1
- 229940100688 oral solution Drugs 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- GCYXWQUSHADNBF-AAEALURTSA-N preproglucagon 78-108 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 GCYXWQUSHADNBF-AAEALURTSA-N 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000022558 protein metabolic process Effects 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000009094 second-line therapy Methods 0.000 description 1
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 description 1
- 229960004034 sitagliptin Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000007492 two-way ANOVA Methods 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
Classifications
-
- 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
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Combine the present invention relates to two kinds of compounds and preparing the purposes in treating diabetes medicament.
Description
Technical field
The present invention relates to two kinds of compound joints and its purposes in treatment diabetes medicament is prepared.
Background technology
Diabetes are a kind of inherent cause and chronic, the systemic, metabolic caused by the long-term collective effect of environmental factor
Disease, characterized by plasma glucose levels increase, mainly because of internal hypoinsulinism or effect obstacle, (insulin supports
It is anti-) caused by sugar, fat, protein metabolism is disorderly and influences a kind of disease of normal physiological activity.Chronic hyperglycemia often results in
Various internal organs, especially eye, kidney, nerve and cardiovascular long-term damage, insufficiency and failure.Diabetes are broadly divided into 1 type
(T1DM) and 2 types (T2DM), the former is also known as insulin-dependent diabetes mellitus (IDDM), and patient is with little or no secretion pancreas islet
Element；The latter is also known as Non-insulin-dependent diabetes mellitus (NIDDM), companion's insulin secretion relative deficiency based on insulin resistance,
Based on hypoinsulinism with or not with insulin resistance.Wherein, insulin resistance refers to insulin sensitive tissues such as
Muscle, liver, fat etc. can not make normal biological response to insulin, at this point, even if high concentration pancreas islet prime ring
Under border, the blood sugar decreasing effect that can not also bring into normal play.The pathogenesis of insulin resistance is more, mainly there is Expression of Insulin Receptor
Amount declines and insulin receptor mutation, but not yet discloses completely so far.Once insulin resistance occurs, i.e., it can weaken muscle
The intake, oxidation and storage to glucose are organized, upsets lipid-metabolism in adipose tissue, enhances liver gluconeogenesis, so as to cause
Body Abnormality of Glycolipid Metabolism.
The main mechanism of GPR40 agonists is the insulin secretion that glucose can be promoted to stimulate, that is, works as blood glucose level
During raising, level of insulin secretion enhancing, so as to play hypoglycemic effect；And when blood glucose level restores normal, insulin stops
It only secretes, will not also cause hypoglycemia.Therefore, GPR40 agonists not only can effectively control blood glucose, but also can make the generation wind of hypoglycemia
Danger minimizes.A kind of GPR40 agonist compounds are disclosed in WO2013104257A1 (publication date 2013.07.18), structure is such as
Shown in lower：
Research shows that DPP-IV (dipeptidyl peptidase) degradable glucagon-like-peptide-1 (GLP-1), it passes through hydrolysis
The-the third dipeptidase of group of GLP-1N- ends makes its GLP-1 (7-36) NH from active form2It is degraded to inactive GLP-1 (9-
36)NH2, therefore half-life period of the GLP-1 in blood circulation is only 2 minutes or so, and then weakens the biological effect of GLP-1.DPP-
The GLP-1 that IV inhibitor can protect endogenous even exogenous is not degraded by DPP-IV, so as to improve GLP-1 in blood circulation
Concentration greatly enhances its biological effect.It after GLP-1 secretions, can be combined with the GLP-1 receptors on beta Cell of islet, by swashing
Downstream signaling pathway living and the insulin secretion for enhancing glucose stimulation, and then achieve the effect that hypoglycemic.DPP-IV inhibitor
Play the role of to the treatment of Non-Insulin Dependent Diabetes Mellitus (NIDDM) good (US6110949).WO2009082881A1
(publication date 2009.07.09) discloses DPP-IV inhibitor, and structure is as follows：
Oral antidiabetic drug includes melbine, sulfonylureas, thiazolidinedione, Lie Nai and alpha-glucosidase and inhibits
Agent etc., but after disease continues for a long time, oral therapies (such as a line or second-line therapy, the list of most of diabetes B patients
One therapy, initial or additional combination treatment) ultimate failure, and then become dependent upon in insulin therapy, it is necessary to pancreas is injected daily
Island is plain and carries out multiple blood sugar monitoring daily, is attributed to the long-term efficacy, tolerance and administration convenience of existing hypoglycemic therapy
Limitation and long term hyperglycemia caused by complication or chronic injury.The present invention provides a kind of GPR40 agonists and presses down with DPP-IV
Preparation is combined drug, to glycemic control is related, to improve characteristic in disease related and with reducing cardiovascular morbidity and death
The relevant good effects of rate improve the combination drug of security situation simultaneously.
GPR40 agonists and DPP- are disclosed in WO2009048527A1, WO2009111056A1, WO2016016770A1
IV inhibitor combination treatment diabetes, but be unaware of being combined to whether the hypoglycemic of diabetes B has synergistic effect.Tanaka
H,et al,Novel GPR40agonist AS2575959exhibits glucose metabolism improvement
and synergistic effect with sitagliptin on insulin and incretin
Secretion.Life Sci (2013) disclose a kind of GPR40 and combine with Xi Gelieting in the experiment of normal mouse oral glucose tolerance
(OGTT) reduction blood glucose can be cooperateed in, while can cooperate with and promote insulin and GLP-1 secretions, but not in diabetes B animal
Investigate whether combination also has synergistic effect to blood glucose and glycosylated hemoglobin in model.
Invention content
The technical problem to be solved in the present invention is to provide two kinds of specific compounds in the drug for preparing treatment diabetes
Purposes, within a certain period of time, both compounds play synergistic effect when treating diabetes.
Technical scheme is as follows：
Offer formula (I) compound represented of the present invention or its pharmaceutical salt and formula (II) compound represented or its can medicine
Salt, which is combined, is preparing the purposes in treating diabetes medicament,
Preferably, the pharmaceutical salt of formula (II) compound represented is selected from phosphate, hydrochloride, mesylate, horse
Come hydrochlorate, malate, tosilate or benzene sulfonate, more preferable phosphate.
Diabetes of the present invention are diabetes B.
In said program, the usage ratio of compound shown in compound shown in the formula (I) and formula (II) for 0.001~
1000, preferably 1:2、1:4、2:1 or 4:1.
Purposes of the present invention, wherein, compound shown in the formula (I) is 0.1-1000mg.
Purposes of the present invention, wherein, compound shown in the formula (II) is 0.1-1000mg.
Dosage the present invention also provides compound shown in formula (I) for 0.1-500mg, preferably 0.5mg, 1mg, 2mg,
5mg, 10mg, 12.5mg, 15mg, 20mg, 25mg, 35mg, 40mg or 50mg, the dosage of compound shown in formula (II) are 1-
500mg, preferably 1mg, 2mg, 5mg, 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 150mg, 160mg or
200mg。
United administering mode of the present invention is selected from：It is administered simultaneously, independently prepares and be total to administration or independently prepare
And it is administered in succession.
Combine the invention further relates to compound shown in formula (I) with compound shown in formula (II) and preparing treatment diabetes
Purposes in drug, wherein, compound shown in formula (I) is recommended once a day, and compound shown in formula (II) is recommended once a day.
Significantly, compound shown in formula of the invention (I) has with compound use in conjunction shown in formula (II) cooperates with drug effect
Effect.
The pharmaceutical composition for further relating to compound shown in formula (I) and compound shown in formula (II) of the present invention, comprising optional
One or more pharmaceutical carriers, excipient and/or diluent.Described pharmaceutical composition can be made pharmaceutically acceptable
One dosage type low temperature.For example, compound shown in formula (I) and the pharmaceutical preparation of compound agent shown in formula (II) can be formulated as tablet, capsule
Agent, pill, granule, solution, suspension, syrup, injection are (including parenteral solution, injection sterile powder and injection
Concentrated solution), suppository, inhalant or spray.
In addition, the described pharmaceutical composition of the present invention can also be with any suitable administering mode, such as take orally, stomach
Outside, the modes such as rectum, transpulmonary or local administration are applied to the patient or subject for needing this treatment.When for being administered orally
When, described pharmaceutical composition can be made into oral preparation, such as oral solid formulation, such as tablet, capsule, pill, granule；
Or, oral liquid, such as oral solution, oral suspensions, syrup.When oral preparation is made, the drug system
Agent also may include suitable filler, adhesive, disintegrant, lubricant etc..
The present invention formula (I) shown in compound can be administered alone with compound medicine composition shown in formula (II) or
It is used with one or more therapeutic agents.Therefore, in certain preferred aspects, the pharmaceutical composition also contains
One or more therapeutic agents.
Each ingredient (for example, compound shown in formula (I) and compound and second therapeutic agent shown in formula (II)) to be combined can
It is administered simultaneously or sequentially separates medication successively.It for example, can be by compound shown in formula (I) of the present invention and formula (II) shownization
Prior to, concurrently with, or after closing Internet of Things use, using second therapeutic agent.In addition, each ingredient to be combined can also be with same preparation shape
Formula or the administering drug combinations in the form of separated different preparations.
In the present invention, so-called " joint or combination " is a kind of administering mode, including two kinds of drugs priorities or is administered simultaneously
Various situations, it is so-called herein to refer to give compound shown in formula (I) and formula (II) shownization in same dosage period " simultaneously "
Object is closed, such as two kinds of drugs are given in 2 days or in 1 day.So-called " successively or in succession " is administered, then is included in different dosing week
The situation of compound shown in formula (I) and compound shown in formula (II) is given in phase respectively.These administering modes, belong to the present invention
The administering drug combinations.
The present invention also provides a kind of method for treating diabetes, including being given shown in aforementioned formula (I) to cancer patient
Compound and compound shown in formula (II).
" effective quantity " of the present invention includes the amount for the symptom or illness that is enough to improve or prevent doctor's word illness.Effective quantity
Still mean that the amount for being enough to allow or promoting diagnosis.It can be according to following factor for the effective quantity of particular patient or veterinary science subject
And change：As illness to be treated, the general health of patient, the method and approach of administration and dosage and side effect are serious
Property.Effective quantity can be the maximum dose or dosage regimen for avoiding notable side effect or toxic effect.
Advantageous effect of the invention
Compared with prior art, technical scheme of the present invention has the following advantages：
(1) formula (I) compound represented of the present invention or its pharmaceutical salt and formula (II) compound represented or its can medicine
Salt drug combination can effectively reduce blood glucose, rationally control glycated hemoglobin levels, solve tolerance, complication or chronic
The problems such as damage.
(2) formula (I) compound represented of the present invention or its pharmaceutical salt and formula (II) compound represented or its can medicine
Salt drug combination has synergistic effect to the hypoglycemic of diabetes B.
Description of the drawings
Fig. 1 is the compounds of this invention A, compound B joint and blood glucose-time graph after the single-dose of one-component；
Fig. 2 be the compounds of this invention A, compound B joint with below blood glucose-time graph after the single-dose of one-component
Product, * p<0.05, compared with vehicle control group.
Specific embodiment
Exemplary tests scheme of the composition of the present invention presented below in diabetes medical usage, to show the present invention
The favorable activity or advantageous effects of composition.It is understood that following testing programs are only to the content of present invention
Example, without limiting the scope of the present invention.Those skilled in the art, can be to the present invention's under the introduction of this specification
Technical solution carries out appropriate modification or change, without departing from the spirit and scope of the invention.
The hypoglycemic effect of embodiment 1, the present composition in diabetes B ob/ob mouse
Test sample：Compound shown in formula (I) (compound B is defined as, it can be according in patent application WO2013104257A1
It is prepared by method), the phosphate of compound shown in formula (II) (be defined as compound A, can be according to patent application WO2009082881A1
In method prepare).
Experimental animal：Diabetes B ob/ob model mices, specifying information are as follows：
Control group：Solvent group.
Test solution is prepared：
Compound B：Sample accurately is weighed, a small amount of 0.5%CMC-Na and distilled water grinding is added in, is made into 20mg/mL's
Suspension (is applied alone for it and combination group is administered), then this appropriate suspension is taken to be diluted to 0.5%CMC-Na and distilled water
The suspension (be applied alone for it and combination group is administered) of 10mg/mL, is prepared at room temperature；
Compound A：Drug accurately is weighed, is completely dissolved with distilled water, is made into the colourless transparent solution of 6mg/mL, at room temperature
It prepares.
Experimental method：
(1) experiment packet：Ob/ob mouse totally 48 are divided into 6 groups according to the random blood glucose level before experiment, every group 8,
Respectively vehicle control group, compound B-50mg/kg groups, compound B-100mg/kg groups, compound A-30mg/kg groups, chemical combination
Object A-30mg/kg+ compounds B-50mg/kg combinations group and compound A-30mg/kg+ compound B-100mg/kg combination groups.
Animal packet and drug administration information are as follows：
Remarks：PO is oral, and BID is twice daily；Vehicle control group be first to portion 0.5%CMC-Na and distilled water,
Then followed by again to a distilled water.
(2) it is administered：During the experiment, animal are given solvent or test sample by group accordingly, and administration time is daily early 9:
00 and late 16:00 is each primary, and successive administration 30 days is taken twice daily, and each group is gastric infusion；
Animal gives gavage to distilled water before experiment, carries out the gavage by a definite date for 3 days and adapts to, to enhance animal to administration
The compliance of operation.
(3) Testing index includes：Blood glucose level monitor (blood glucose meter, Chinese Johnson ＆ Johnson's medical equipment Co., Ltd, model：
Lifescan；Blood sugar test paper, Johnson＆Johnson), weight and food ration measure (electronic balance, the permanent flat science of Shanghai Shun's space
Instrument Ltd., model：MP5002), biomonioring glycosylated hemoglobin (glycosylated hemoglobin assay kit, SIMENS,
Model：5035C)；
The first day is administered, the blood glucose water of 0.5,1,2,4,6,8 hour before monitoring administration and after administration after animal fasting 4 hours
It is flat；It measures within follow-up every 4 days random and fasting blood-glucose and (measures 6 hours random blood sugars after administration within the 8th, 12,16,20,24 and 28 day；
Measure 6 hours fasting blood-glucoses after administration within 1st, 5,9,13,17,21,25 and 29 day)；
During the experiment, the weight and food ration of every 4 days monitoring animals, wherein monitoring weight data records fasting respectively every time
The weight data that preceding and fasting (has surveyed fasting blood-glucose) after 6 hours；During the experiment, the random weight of each group animal and fasting 6 are small
When after weight stablize and rise, compared with vehicle control group, each administration group animal average weight there are no significant difference；Compound
A-30mg/kg+ compound B-100mg/kg combination group animals accumulation food ration from being administered the 17th day is substantially less than solvent pair
According to group (p<0.01)；Compound B-50mg/kg groups, compound B-100mg/kg groups and compound A-30mg/kg+ compounds B-
50mg/kg combination group animals accumulation food ration from being administered the 25th day is substantially less than vehicle control group (p<0.05；p<0.01)；
Compound A-30mg/kg groups animal accumulates food ration equal no difference of science of statistics compared with vehicle control group.
Last day is administered, after experiment, animal fasting is euthanized after 6 hours, dissection animal and Culling heart blood,
Retain whole blood, for the measure of glycated hemoglobin levels.
Data analysis：
All data are entered into Excel document, and are represented in a manner of Mean ± SEM.Data statistic analysis makes
With 6.0 softwares of Graphpad Prism.Using single factor test or two-way analysis of variance comparative approach, with p<0.05 as notable
The criterion of sex differernce.
Experimental result：
6 hours fasting blood-glucoses (mmol/L, mean+/-standard error) after table 1, administration
Remarks：P values refer to compared with solvent；Symbol * represents p<0.05.
Table 2, administration end of term glycosylated hemoglobin (HbA1c) level measure
Remarks：The measurement result of glycosylated hemoglobin is represented with percentage (%), refers to the blood red egg combined with glucose
The ratio of whole hemoglobins is accounted in vain.
Experiment conclusion：
After administration, blood glucose-time graph result such as Fig. 1 shows that each reagent group blood glucose level was since after administration 2 hours
There is a different degrees of reduction, but only compound A-30mg/kg+ compounds B-100mg/kg combinations group 4 hours upon administration
Blood glucose level be substantially less than vehicle control group (9.7 ± 1.49 and 18.5 ± 1.87mmol/L, p<0.05), between remaining group
Compared to equal no difference of science of statistics.Area (AUC) under blood glucose-time graph is as shown in Fig. 2, only compound A-30mg/kg+ compounds
B-100mg/kg combination groups AUC is substantially less than vehicle control group (94.5 ± 11.74 and 142.7 ± 14.07mmol/L*h, p<
0.05) equal no difference of science of statistics, is compared between remaining each group.Compared with vehicle control group, each reagent group blood glucose-time graph
The rate of descent of lower area is respectively 17.2%, 26.4%, 22.6%, 28.4% and 33.8%.
Understand that in 30 days administration process 6 hours fasting blood-glucoses of each administration group are equal compared with vehicle control group by 1 experimental result of table
Have reduces to some extent, and with the passage of administration time, and blood sugar decreasing effect enhances therewith.Compound A group fasting blood sugars
It is close with compound B-50mg/kg groups；In most of detection time point, dose dependent is presented in compound B blood sugar decreasing effects；
Combination group fasting blood sugar when being administered the 25th and the 29th day is significantly lower than vehicle control group (p<0.05)；Blood drops in two combination groups
Sugared effect is close, and is better than respective compound B to some extent and is applied alone group and compound A that group is applied alone, and illustrates chemical combination
After object B and compound A combinations, the hypoglycemic effect of superposition can be played；
After administration 30 days, blood sampling measures glycosylated hemoglobin (HbA1c) horizontal, long-term blood sugar decreasing effect is investigated, by table 2
Experimental result understands that combination group HbA1c levels are substantially less than vehicle control group, and group is applied alone less than respective compound B
And group is applied alone in compound A, illustrates there is certain synergistic effect at hypoglycemic aspect after being combined for a long time.
In conclusion the compound of the present invention B, compound A combination have superposition, diabetes reduction blood glucose and
Glycated hemoglobin levels control aspect is better than one-component compound B or compound A.
Claims (7)
1. formula (I) compound represented or its pharmaceutical salt are combined with formula (II) compound represented or its pharmaceutical salt
The purposes in treatment diabetes medicament is prepared,
2. formula (I) compound represented as described in claim 1 or its pharmaceutical salt and formula (II) compound represented or
Its pharmaceutical salt, which is combined, is preparing the purposes in treating diabetes medicament, which is characterized in that the chemical combination shown in the formula (II)
The pharmaceutical salt of object is selected from phosphate, hydrochloride, mesylate, maleate, malate, tosilate or benzene sulfonic acid
Salt, preferably phosphate.
3. formula (I) compound represented as described in claim 1 or its pharmaceutical salt and formula (II) compound represented or
Its pharmaceutical salt, which is combined, is preparing the purposes in treating diabetes medicament, and the diabetes are diabetes B.
4. formula (I) compound represented according to claim 1 or its pharmaceutical salt and formula (II) compound represented
Or its pharmaceutical salt combines the purposes in treatment diabetes medicament is prepared, which is characterized in that compound shown in the formula (I)
Usage ratio with compound shown in formula (II) is 0.001~1000, preferably 1:2、1:4、2:1 or 4:1.
5. formula (I) compound represented according to claim 1 or its pharmaceutical salt and formula (II) compound represented
Or its pharmaceutical salt combines the purposes in treatment diabetes medicament is prepared, which is characterized in that compound shown in the formula (I)
Dosage for 0.1-500mg, preferably 5mg, 10mg, 12.5mg, 15mg, 20mg, 25mg, 35mg, 40mg or 50mg.
6. formula (I) compound represented according to claim 1 or its pharmaceutical salt and formula (II) compound represented
Or its pharmaceutical salt combines the purposes in treatment diabetes medicament is prepared, feature is in the administration of compound shown in formula (II)
Dosage is 1-500mg, preferably 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 150mg, 160mg or 200mg.
7. the pharmaceutical composition containing compound shown in formula described in claim 1 (I) with compound shown in formula (II), also includes
One or more pharmaceutical excipient, diluent or carrier.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611225040 | 2016-12-27 | ||
| CN2016112250401 | 2016-12-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108236611A true CN108236611A (en) | 2018-07-03 |
Family
ID=62701205
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711429769.5A Pending CN108236611A (en) | 2016-12-27 | 2017-12-26 | Two kinds of compounds, which are combined, is preparing the purposes in treating diabetes medicament |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108236611A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120122875A1 (en) * | 2009-05-27 | 2012-05-17 | Jiangsu Hengrui Medicine Co., Ltd. | Salts of Methyl (R)-7-[3-Amino-4-(2,4,5-Trifluoro-Phenyl)-Butyryl]-3-Trifluoromethyl-5,6,7,8-Tetrahydro-Imidazo[1,5-A]Pyrazine-1-Carboxylate |
| CN103429581B (en) * | 2012-01-12 | 2015-08-26 | 江苏恒瑞医药股份有限公司 | Many lopps derivative, its preparation method and in application pharmaceutically |
-
2017
- 2017-12-26 CN CN201711429769.5A patent/CN108236611A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120122875A1 (en) * | 2009-05-27 | 2012-05-17 | Jiangsu Hengrui Medicine Co., Ltd. | Salts of Methyl (R)-7-[3-Amino-4-(2,4,5-Trifluoro-Phenyl)-Butyryl]-3-Trifluoromethyl-5,6,7,8-Tetrahydro-Imidazo[1,5-A]Pyrazine-1-Carboxylate |
| CN103429581B (en) * | 2012-01-12 | 2015-08-26 | 江苏恒瑞医药股份有限公司 | Many lopps derivative, its preparation method and in application pharmaceutically |
Non-Patent Citations (2)
| Title |
|---|
| 董志艳等: "二肽基肽酶Ⅳ抑制剂的研究进展", 《湖北科技学院学报（医学版）》 * |
| 钱晶: "游离脂肪酸受体GPR40对胰腺β细胞胰岛素合成分泌的调控及配体不依赖受体内吞机制的研究", 《万方学位论文》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI496580B (en) | Insulin long-acting formulation | |
| EP1928499B1 (en) | Use of a dpp-iv inhibitor to reduce hypoglycemic events | |
| US6652838B2 (en) | Method for treating diabetes mellitus | |
| TW201006488A (en) | Use of ultrarapid acting insulin | |
| US20240245656A1 (en) | Therapeutic uses of glucokinase activators in combination with insulin or insulin analogs | |
| Guevara‐Aguirre et al. | Oral spray insulin in treatment of type 2 diabetes: a comparison of efficacy of the oral spray insulin (Oralin) with subcutaneous (SC) insulin injection, a proof of concept study | |
| Guevara-Aguirre et al. | Beneficial effects of addition of oral spray insulin (Oralin) on insulin secretion and metabolic control in subjects with type 2 diabetes mellitus suboptimally controlled on oral hypoglycemic agents | |
| BR112020014719A2 (en) | TREATMENT OF POST-BARIATRIC HYPOGLYCEMIA USING STAINLESS GLUCAGON IN MINIDOSIS | |
| 板東浩 | Investigation for daily profile of blood glucose by the administration of canagliflozin and xultophy (Ideglira) | |
| KR20200103029A (en) | Treatment of exercise-induced hypoglycemia in type 1 diabetes and type 2 diabetes with insulin | |
| Deepak et al. | Metformin-associated lactic acidosis successfully treated with continuous renal replacement therapy | |
| CN108236611A (en) | Two kinds of compounds, which are combined, is preparing the purposes in treating diabetes medicament | |
| CN104582701A (en) | A method of weight reduction | |
| Roy | Administration of once-daily canagliflozin to a non-diabetic patient in addition to standard aerobic exercise: a case report | |
| US20200121778A1 (en) | Method and composition for treatment of hyperglycemia | |
| US20210100872A1 (en) | Pharmacological Formulation Comprising Cyclo (HIS-PRO) As Effective Ingredient For Preventing Or Treating Diabetes Mellitus | |
| Sutisnu et al. | Management of Hyperkalemia in Patients with Acute Kidney Injury Post Septic Shock: A Case Report | |
| Hompesch et al. | Glycemic exposure is affected favorably by inhaled human insulin (Exubera) as compared with subcutaneous insulin glargine (Lantus) in patients with type 2 diabetes | |
| US20260035428A1 (en) | A gip/glp1 for use in therapy | |
| Das et al. | Pathophysiology and Clinical Therapeutic Aspects of Diabetes | |
| Hiremath | Handbook Of Perioperative Care Of Adult Diabetes Patients: Diabetes Care–Before, During And After Surgery | |
| US20110060051A1 (en) | Pharmaceutical composition comprising rimeporide for treating diseases associated with insulin resistance and beta-cell dysfunction | |
| AU2023342969A1 (en) | A gip/glp1 for use in therapy | |
| Kaur et al. | Glycemic treatment of diabetes mellitus | |
| HK40042198A (en) | Therapeutic uses of glucokinase activators in combination with insulin or insulin analogs |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20180703 |
|
| WD01 | Invention patent application deemed withdrawn after publication |