CN104478880B - 作为dpp-iv抑制剂的双胍衍生物 - Google Patents
作为dpp-iv抑制剂的双胍衍生物 Download PDFInfo
- Publication number
- CN104478880B CN104478880B CN201410831183.1A CN201410831183A CN104478880B CN 104478880 B CN104478880 B CN 104478880B CN 201410831183 A CN201410831183 A CN 201410831183A CN 104478880 B CN104478880 B CN 104478880B
- Authority
- CN
- China
- Prior art keywords
- compound
- dpp
- compounds
- formula
- preparation
- 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.)
- Active
Links
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 title claims abstract description 32
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 title claims abstract description 31
- 239000003112 inhibitor Substances 0.000 title description 6
- 150000004283 biguanides Chemical class 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 103
- 201000010099 disease Diseases 0.000 claims abstract description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 11
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims description 30
- 238000002360 preparation method Methods 0.000 claims description 27
- 238000011282 treatment Methods 0.000 claims description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- 201000001320 Atherosclerosis Diseases 0.000 claims description 2
- 206010061218 Inflammation Diseases 0.000 claims description 2
- 208000001145 Metabolic Syndrome Diseases 0.000 claims description 2
- 208000008589 Obesity Diseases 0.000 claims description 2
- 208000001132 Osteoporosis Diseases 0.000 claims description 2
- 208000017442 Retinal disease Diseases 0.000 claims description 2
- 206010038923 Retinopathy Diseases 0.000 claims description 2
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 2
- 230000001684 chronic effect Effects 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 230000004054 inflammatory process Effects 0.000 claims description 2
- 208000017169 kidney disease Diseases 0.000 claims description 2
- 230000007823 neuropathy Effects 0.000 claims description 2
- 201000001119 neuropathy Diseases 0.000 claims description 2
- 235000020824 obesity Nutrition 0.000 claims description 2
- 208000033808 peripheral neuropathy Diseases 0.000 claims description 2
- 201000010065 polycystic ovary syndrome Diseases 0.000 claims description 2
- 201000001421 hyperglycemia Diseases 0.000 claims 2
- 206010048554 Endothelial dysfunction Diseases 0.000 claims 1
- 208000002705 Glucose Intolerance Diseases 0.000 claims 1
- 208000035150 Hypercholesterolemia Diseases 0.000 claims 1
- 206010020772 Hypertension Diseases 0.000 claims 1
- 206010056997 Impaired fasting glucose Diseases 0.000 claims 1
- 206010033307 Overweight Diseases 0.000 claims 1
- 230000008694 endothelial dysfunction Effects 0.000 claims 1
- 208000006575 hypertriglyceridemia Diseases 0.000 claims 1
- 208000001921 latent autoimmune diabetes in adults Diseases 0.000 claims 1
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims 1
- 201000009104 prediabetes syndrome Diseases 0.000 claims 1
- 230000009885 systemic effect Effects 0.000 claims 1
- 208000024891 symptom Diseases 0.000 abstract description 4
- 208000002249 Diabetes Complications Diseases 0.000 abstract description 3
- 206010012655 Diabetic complications Diseases 0.000 abstract description 3
- 229940124213 Dipeptidyl peptidase 4 (DPP IV) inhibitor Drugs 0.000 abstract 1
- -1 amino, pyrrolidin-1-yl Chemical group 0.000 description 58
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 38
- 235000002639 sodium chloride Nutrition 0.000 description 29
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 239000011541 reaction mixture Substances 0.000 description 21
- 229940075420 xanthine Drugs 0.000 description 19
- 238000000921 elemental analysis Methods 0.000 description 16
- 238000004949 mass spectrometry Methods 0.000 description 16
- 239000000203 mixture Substances 0.000 description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 14
- 230000000694 effects Effects 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 235000019441 ethanol Nutrition 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 125000006504 o-cyanobenzyl group Chemical group [H]C1=C([H])C(C#N)=C(C([H])=C1[H])C([H])([H])* 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 description 11
- 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 11
- 102100040918 Pro-glucagon Human genes 0.000 description 11
- 210000004369 blood Anatomy 0.000 description 11
- 239000008280 blood Substances 0.000 description 11
- 239000012453 solvate Substances 0.000 description 11
- 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 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 10
- 239000008103 glucose Substances 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 9
- QGBSISYHAICWAH-UHFFFAOYSA-N dicyandiamide Chemical compound NC(N)=NC#N QGBSISYHAICWAH-UHFFFAOYSA-N 0.000 description 9
- 229910052739 hydrogen Inorganic materials 0.000 description 9
- 239000001257 hydrogen Substances 0.000 description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 9
- 125000006239 protecting group Chemical group 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 239000013078 crystal Substances 0.000 description 8
- 229940090124 dipeptidyl peptidase 4 (dpp-4) inhibitors for blood glucose lowering Drugs 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 230000002218 hypoglycaemic effect Effects 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- 239000000969 carrier Substances 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- 230000001276 controlling effect Effects 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 239000000546 pharmaceutical excipient Substances 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 208000013016 Hypoglycemia Diseases 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 239000012876 carrier material Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 206010012601 diabetes mellitus Diseases 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 230000009471 action Effects 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 239000003085 diluting agent Substances 0.000 description 5
- 150000002431 hydrogen Chemical class 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 230000001376 precipitating effect Effects 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- 230000002411 adverse Effects 0.000 description 4
- HIMXGTXNXJYFGB-UHFFFAOYSA-N alloxan Chemical compound O=C1NC(=O)C(=O)C(=O)N1 HIMXGTXNXJYFGB-UHFFFAOYSA-N 0.000 description 4
- SIONIIVXRCVHFL-OAHLLOKOSA-N benzyl (3r)-3-[(2-methylpropan-2-yl)oxycarbonylamino]piperidine-1-carboxylate Chemical compound C1[C@H](NC(=O)OC(C)(C)C)CCCN1C(=O)OCC1=CC=CC=C1 SIONIIVXRCVHFL-OAHLLOKOSA-N 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 210000001035 gastrointestinal tract Anatomy 0.000 description 4
- 150000004677 hydrates Chemical class 0.000 description 4
- 229920005862 polyol Polymers 0.000 description 4
- 150000003077 polyols Chemical class 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 4
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 3
- NAGNVTUFQFDPRC-PIJUOVFKSA-N C(C)(C)(C)OC(=O)C1[C@H](N(CCC1)N)CCCC Chemical compound C(C)(C)(C)OC(=O)C1[C@H](N(CCC1)N)CCCC NAGNVTUFQFDPRC-PIJUOVFKSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- 102000051325 Glucagon Human genes 0.000 description 3
- 108060003199 Glucagon Proteins 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000007884 disintegrant Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 230000003914 insulin secretion Effects 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 239000006225 natural substrate Substances 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 230000028327 secretion Effects 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 239000001993 wax Substances 0.000 description 3
- 230000004584 weight gain Effects 0.000 description 3
- 235000019786 weight gain Nutrition 0.000 description 3
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 description 2
- DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 description 2
- MPPPKRYCTPRNTB-UHFFFAOYSA-N 1-bromobutane Chemical compound CCCCBr MPPPKRYCTPRNTB-UHFFFAOYSA-N 0.000 description 2
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 2
- NNAYPIDFVQLEDK-UHFFFAOYSA-N 2-(bromomethyl)quinoline Chemical compound C1=CC=CC2=NC(CBr)=CC=C21 NNAYPIDFVQLEDK-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- XNCOSPRUTUOJCJ-UHFFFAOYSA-N Biguanide Chemical class NC(N)=NC(N)=N XNCOSPRUTUOJCJ-UHFFFAOYSA-N 0.000 description 2
- 229940123208 Biguanide Drugs 0.000 description 2
- 0 C*(C(CCC1)CC1C=I)C=* Chemical compound C*(C(CCC1)CC1C=I)C=* 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 2
- 239000001828 Gelatine Substances 0.000 description 2
- 102400000326 Glucagon-like peptide 2 Human genes 0.000 description 2
- 101800000221 Glucagon-like peptide 2 Proteins 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- LTXREWYXXSTFRX-QGZVFWFLSA-N Linagliptin Chemical group N=1C=2N(C)C(=O)N(CC=3N=C4C=CC=CC4=C(C)N=3)C(=O)C=2N(CC#CC)C=1N1CCC[C@@H](N)C1 LTXREWYXXSTFRX-QGZVFWFLSA-N 0.000 description 2
- 206010049287 Lipodystrophy acquired Diseases 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 102100023832 Prolyl endopeptidase FAP Human genes 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- AQNQQHJNRPDOQV-UHFFFAOYSA-N bromocyclohexane Chemical compound BrC1CCCCC1 AQNQQHJNRPDOQV-UHFFFAOYSA-N 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 239000012069 chiral reagent Substances 0.000 description 2
- 238000013375 chromatographic separation Methods 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000003925 fat Substances 0.000 description 2
- 108010072257 fibroblast activation protein alpha Proteins 0.000 description 2
- 238000001640 fractional crystallisation Methods 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(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](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)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(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 2
- 229960004666 glucagon Drugs 0.000 description 2
- TWSALRJGPBVBQU-PKQQPRCHSA-N glucagon-like peptide 2 Chemical compound C([C@@H](C(=O)N[C@H](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]([C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O)[C@@H](C)CC)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=CC=C1 TWSALRJGPBVBQU-PKQQPRCHSA-N 0.000 description 2
- 125000005456 glyceride group Chemical group 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 208000000509 infertility Diseases 0.000 description 2
- 230000036512 infertility Effects 0.000 description 2
- 231100000535 infertility Toxicity 0.000 description 2
- 239000003978 infusion fluid Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 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 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 208000002551 irritable bowel syndrome Diseases 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 208000006132 lipodystrophy Diseases 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- GRJHONXDTNBDTC-UHFFFAOYSA-N phenyl trifluoromethanesulfonate Chemical compound FC(F)(F)S(=O)(=O)OC1=CC=CC=C1 GRJHONXDTNBDTC-UHFFFAOYSA-N 0.000 description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- YCUDHDNCZHPAJK-UHFFFAOYSA-N tert-butyl 3-bromopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC(Br)C1 YCUDHDNCZHPAJK-UHFFFAOYSA-N 0.000 description 2
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- 229940075966 (+)- menthol Drugs 0.000 description 1
- NOOLISFMXDJSKH-AEJSXWLSSA-N (+)-menthol Chemical compound CC(C)[C@H]1CC[C@H](C)C[C@@H]1O NOOLISFMXDJSKH-AEJSXWLSSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- AAWZDTNXLSGCEK-LNVDRNJUSA-N (3r,5r)-1,3,4,5-tetrahydroxycyclohexane-1-carboxylic acid Chemical compound O[C@@H]1CC(O)(C(O)=O)C[C@@H](O)C1O AAWZDTNXLSGCEK-LNVDRNJUSA-N 0.000 description 1
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- WGMSTZBEMVJMCR-UHFFFAOYSA-N 1-(bromomethyl)isoquinoline Chemical compound C1=CC=C2C(CBr)=NC=CC2=C1 WGMSTZBEMVJMCR-UHFFFAOYSA-N 0.000 description 1
- 235000020927 12-h fasting Nutrition 0.000 description 1
- LNSCNEJNLACZPA-UHFFFAOYSA-N 2,3-dihydroxy-2,3-bis(2-methylphenyl)butanedioic acid Chemical compound CC1=CC=CC=C1C(O)(C(O)=O)C(O)(C(O)=O)C1=CC=CC=C1C LNSCNEJNLACZPA-UHFFFAOYSA-N 0.000 description 1
- BHNQPLPANNDEGL-UHFFFAOYSA-N 2-(4-octylphenoxy)ethanol Chemical compound CCCCCCCCC1=CC=C(OCCO)C=C1 BHNQPLPANNDEGL-UHFFFAOYSA-N 0.000 description 1
- QGXNHCXKWFNKCG-UHFFFAOYSA-N 2-(bromomethyl)benzonitrile Chemical compound BrCC1=CC=CC=C1C#N QGXNHCXKWFNKCG-UHFFFAOYSA-N 0.000 description 1
- HBJXHKUKLGSSQU-UHFFFAOYSA-N 2-[(8-bromo-3-methyl-2,6-dioxopurin-7-yl)methyl]benzonitrile Chemical compound C1=2C(=O)NC(=O)N(C)C=2N=C(Br)N1CC1=CC=CC=C1C#N HBJXHKUKLGSSQU-UHFFFAOYSA-N 0.000 description 1
- JKRRYWAGVMFXPG-UHFFFAOYSA-N 2-[(8-chloro-3-methyl-2,6-dioxopurin-7-yl)methyl]benzonitrile Chemical compound C1=2C(=O)NC(=O)N(C)C=2N=C(Cl)N1CC1=CC=CC=C1C#N JKRRYWAGVMFXPG-UHFFFAOYSA-N 0.000 description 1
- KMGUEILFFWDGFV-UHFFFAOYSA-N 2-benzoyl-2-benzoyloxy-3-hydroxybutanedioic acid Chemical compound C=1C=CC=CC=1C(=O)C(C(C(O)=O)O)(C(O)=O)OC(=O)C1=CC=CC=C1 KMGUEILFFWDGFV-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTEQVEJOXGBDGI-UHFFFAOYSA-N 8-bromo-3-methyl-7h-purine-2,6-dione Chemical compound O=C1NC(=O)N(C)C2=C1NC(Br)=N2 QTEQVEJOXGBDGI-UHFFFAOYSA-N 0.000 description 1
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical class O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 1
- 208000010444 Acidosis Diseases 0.000 description 1
- 208000009304 Acute Kidney Injury Diseases 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 108010039627 Aprotinin Proteins 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 102400000113 Calcitonin Human genes 0.000 description 1
- 108060001064 Calcitonin Proteins 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 206010007733 Catabolic state Diseases 0.000 description 1
- CZJCZCBRZQMSBB-UHFFFAOYSA-N Cc1nc(CBr)nc2ccccc12 Chemical compound Cc1nc(CBr)nc2ccccc12 CZJCZCBRZQMSBB-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- AAWZDTNXLSGCEK-UHFFFAOYSA-N Cordycepinsaeure Natural products OC1CC(O)(C(O)=O)CC(O)C1O AAWZDTNXLSGCEK-UHFFFAOYSA-N 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 206010013883 Dwarfism Diseases 0.000 description 1
- 208000004232 Enteritis Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 239000004386 Erythritol Substances 0.000 description 1
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 206010016936 Folliculitis Diseases 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 102000018997 Growth Hormone Human genes 0.000 description 1
- 108010051696 Growth Hormone Proteins 0.000 description 1
- 206010056438 Growth hormone deficiency Diseases 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010020649 Hyperkeratosis Diseases 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 208000031773 Insulin resistance syndrome Diseases 0.000 description 1
- 208000007976 Ketosis Diseases 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- 206010052178 Lymphocytic lymphoma Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 206010027417 Metabolic acidosis Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 206010028851 Necrosis Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- AAWZDTNXLSGCEK-ZHQZDSKASA-N Quinic acid Natural products O[C@H]1CC(O)(C(O)=O)C[C@H](O)C1O AAWZDTNXLSGCEK-ZHQZDSKASA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 208000033626 Renal failure acute Diseases 0.000 description 1
- 102000012479 Serine Proteases Human genes 0.000 description 1
- 108010022999 Serine Proteases Proteins 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 240000006394 Sorghum bicolor Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229930182558 Sterol Chemical class 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 206010042971 T-cell lymphoma Diseases 0.000 description 1
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 206010064390 Tumour invasion Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 201000011040 acute kidney failure Diseases 0.000 description 1
- 208000012998 acute renal failure Diseases 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 229960004405 aprotinin Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 1
- 229960004015 calcitonin Drugs 0.000 description 1
- XAAHAAMILDNBPS-UHFFFAOYSA-L calcium hydrogenphosphate dihydrate Chemical compound O.O.[Ca+2].OP([O-])([O-])=O XAAHAAMILDNBPS-UHFFFAOYSA-L 0.000 description 1
- 230000009400 cancer invasion Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000001913 cellulose Chemical class 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Chemical class 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 229940081733 cetearyl alcohol Drugs 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 206010009887 colitis Diseases 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000003001 depressive effect Effects 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 229940095079 dicalcium phosphate anhydrous Drugs 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
- 235000019414 erythritol Nutrition 0.000 description 1
- 229940009714 erythritol Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 230000035558 fertility Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000030136 gastric emptying Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 208000007565 gingivitis Diseases 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 239000000122 growth hormone Substances 0.000 description 1
- 229940116364 hard fat Drugs 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 1
- UBHWBODXJBSFLH-UHFFFAOYSA-N hexadecan-1-ol;octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO.CCCCCCCCCCCCCCCCCCO UBHWBODXJBSFLH-UHFFFAOYSA-N 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 210000003405 ileum Anatomy 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000002473 insulinotropic effect Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 229960004903 invert sugar Drugs 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 210000005159 islet delta cell Anatomy 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 210000002510 keratinocyte Anatomy 0.000 description 1
- 230000004140 ketosis Effects 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 229960004873 levomenthol Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000002583 male contraceptive agent Substances 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 229960003105 metformin Drugs 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- NIHNNTQXNPWCJQ-UHFFFAOYSA-N o-biphenylenemethane Natural products C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- PEUGKEHLRUVPAN-UHFFFAOYSA-N piperidin-3-amine Chemical compound NC1CCCNC1 PEUGKEHLRUVPAN-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 230000000291 postprandial effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical class [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 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
- 239000003755 preservative agent Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000003938 response to stress Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WUOQXNWMYLFAHT-MRVPVSSYSA-N tert-butyl n-[(3r)-piperidin-3-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H]1CCCNC1 WUOQXNWMYLFAHT-MRVPVSSYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种作为二肽基肽酶-4(DPP-IV)抑制剂的化合物,可用于治疗可因抑制DPP-IV活性而受益的所有症状或病症,例如I型和II型糖尿病、糖尿病并发症及其它相关疾病。
Description
技术领域
本发明涉及一种作为DPP-IV抑制剂的双胍衍生物,其用于可治疗可因抑制DPP-IV活性而受益的所有症状或病症,例如I型和II型糖尿病、糖尿病并发症及其它相关疾病。
背景技术
二肽基肽酶-4(DPP-4)是一种高特异性丝氨酸蛋白酶,它的天然底物是胰高血糖素样肽1(GLP-1)和葡萄糖促胰岛素多肽(GIP)。GLP-1具有多种生理功能,在胰腺可增加葡萄糖依赖的胰岛素分泌、抑制高血糖素的分泌,使胰岛D细胞增生;在胃肠道可延缓餐后胃排空,从而延缓肠道葡萄糖吸收。GIP具有促胰岛素分泌功能。DPP-4能快速降解体内的GLP-l和GIP,使之失活。健康人体内的GLP-1主要由回肠和结肠的L细胞分泌,在人体内的基础浓度大约为5~10pmol/L,餐后浓度可升高2~3倍。其生物活性半衰期仅有大约2分钟。DPP-4抑制剂通过竞争性结合DPP-4活化部位,降低酶的催化活性,从而抑制GLP-1和GIP的降解。
DPP-4广泛存在于血浆、胃肠道、肾脏、淋巴结和结缔组织等体内组织中,其中肾脏最多。其家族成员包括DPP-1、DPP-2、DPP-3、DPP-4、DPP-8、DPP-9和成纤维细胞活化蛋白-α(FAP)。DPP-4的分子量为220kD,活性体为二聚体形式,每个亚单位包含两个结构域,控制底物的出入口位于两个结构域之间的一个大小为30~45A的大型洞穴,其内的袋状结构便是DPP-4的活性部位,凡是结构的N端第二位上是脯氨酸(Pro)或丙氨酸(Ala)的多肽都是DPP-4发挥活性的主要底物。
由于体内DPP-4的迅速降解作用,GLP-1在体内半衰期很短(<2min),研究发现当DPP-4活性被抑制后GLP-1的作用时间便有效延长,从而发挥降低血糖水平作用。DPP-4抑制剂作用机理便是基于其结构与天然底物相似,含有Xaa-Pro类似结构,能够竞争性结合DPP-4活性部位,而且亲和力远大于天然底物,因而改变了DPP-4的构象,降低催化活性。实验证明DPP-4抑制剂可在24h内可逆性地抑制大约90%的DPP-4酶活性。因而DPP-4抑制剂能够通过提高体内GLP-1浓度,延长其降糖作用时间,并且抑制胰高血糖素分泌,延长GLP-1对胰岛素分泌的刺激持续时间。因为GLP-1对胰岛素分泌的调节作用呈现严格的血糖浓度依赖性,只有在血糖升高时,GLP-1才会增加胰岛素分泌,所以DPP-4抑制剂不会引起低血糖发生风险。DPP-4抑制剂独特作用机理和良好的安全性特点,成为了糖尿病新药研究的热点领域。研究发现,一些DPP-4抑制剂和二甲双胍联合治疗糖尿病可显著改善血糖水平,并且低血糖、体重增加和其他不良事件风险较低。但仍然缺乏低血糖、体重增加和其他不良事件风险低的单一化合物。
发明内容
本发明提供一类作为DPP-IV抑制剂的双胍衍生物,可用于预防或者治疗与在DPP-IV抑制作用中受益的相关疾病,具有低血糖、体重增加和其他不良事件风险低发生率。具体地,本发明提供如下式(I)所示的化合物、其立体异构体,或者其药学上可接受的盐:
其中,
R1代表C1-6烷基,所述C1-6烷基可被R11或R12-CO-取代,并且R11代表C6-10芳基、喹啉基、异喹啉基、喹唑啉基、噌啉基或吲哚基,R12代表二(C1-6烷基)氨基、吡咯烷-1-基、哌啶-1-基或C6-10芳基;
R2代表C1-6烷基或C6-10芳基;
R3代表氢、1个或多个卤素原子、或者1个或多个氰基;
R4代表氢、C1-8烷基、C3-8环烷基、C3-8元杂环烷基、C6-10芳基或C5-10元杂芳基。
在一个优选实施方案中,R1代表二甲氨基羰基甲基、吡咯烷-1-基羰基甲基、苯基羰基甲基、苄基、喹啉基甲基、异喹啉基甲基、喹唑啉基甲基或噌啉基甲基。
在另一个优选实施方案中,R2代表甲基、异丙基或苯基。
在另一个优选实施方案中,R3代表氢、氟、氯、溴、碘或氰基。
在另一个优选实施方案中,R4代表氢、甲基、乙基、异丙基、正丁基、环己基、哌啶基、吡咯烷基、吡啶基或苯基。
本发明化合物的盐包括所有的酸加成盐和所有与碱形成的盐,尤其是所有的药学上可接受的酸加成盐和与碱形成的盐。特别地,可使用药学中常用的无机酸/碱或有机酸/碱制得生理学可耐受的盐,该盐包括水不溶性盐以及水溶性盐。适于形成药学或生理学可接受的酸加成盐的无机酸包括但不限于盐酸、氢溴酸、磷酸、硫酸等。适于形成药学或生理学可接受的酸加成盐的有机酸包括,例如且不限于,柠檬酸、马来酸、富马酸、琥珀酸、乳酸、酒石酸、甲磺酸等。因此,与无机酸或有机酸形成的药学或生理学可接受的酸加成盐可包括但不限于盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、柠檬酸盐、马来酸盐、富马酸盐、琥珀酸盐、乳酸盐、酒石酸盐、甲基磺酸盐等。
本发明的化合物的盐还可包括不适于药物用途但可用于例如式(I)的游离化合物或其药学可接受的盐的分离或纯化的盐。
除非特别地指出具体的异构体形式,式(I)化合物的所有异构体形式均预期在本发明内,包括所有区域异构体形式和立体异构体形式,例如所有手性形式、对映异构体形式、非对映异构体形式、外消旋形式、互变异构体形式和所有几何异构体形式。很显然,优选药学上最有效且最无副作用的异构体。
应当理解本发明的化合物含有至少一个、两个或多个经不对称取代的碳原子,且可作为纯非对映异构体或非对映异构体混合物以光学活性形式或外消旋形式被分离。
本发明涵盖所有可能的立体异构体,尤其是本文提及的非对映异构体和对映异构体,例如以基本上纯形式,以富集形式和/或以任何混合比例的形式,包括外消旋形式,以及其盐。
一般来说,基本上纯的立体异构体可根据本领域技术人员熟知的合成原理获得,例如通过相应混合物的分离,通过使用立体化学上纯的起始物料和/或通过立体选择性合成获得。本领域已知如何制备光学活性形式,如通过外消旋形式的拆分或通过例如从光学活性起始物料合成和/或通过使用手性试剂来制备。
本发明的对映异构体纯的化合物可通过不对称合成例如通过制备和分离适当的非对映异构体的化合物/中间体,和/或通过使用手性反应组分(例如手性试剂、手性催化剂、手性配体、手性合成子、手性砌块等)制备,其中所述非对映异构体的化合物/中间体可通过已知的例如手性色谱分离或从适宜溶剂中分级结晶而分离得到。
此外,本领域的技术人员知晓如何从相应的外消旋混合物制备对映异构体纯的化合物,例如通过在手性分离柱上色谱分离相应的外消旋化合物;或通过使用适当的拆分试剂拆分外消旋化合物;例如通过外消旋化合物与光学活性的酸或碱形成非对映异构体的盐,随后拆分该盐并从该盐中释放所需的化合物;或通过使用手性助剂衍生该相应的外消旋化合物,随后分离非对映异构体并除去该手性辅助基团;通过外消旋物的动力学拆分(例如通过酶法拆分);通过在适宜条件下从镜像晶体的聚集物对映选择性结晶;或通过在手性助剂存在下从适宜溶剂中分级结晶制备。
所得到的式(I)的化合物可分离成其对映异构体和/或非对映异构体。例如,顺式/反式混合物可分离成它们的顺式或反式异构体,且具有至少一个光学活性碳原子的化合物可拆分成它们的对映异构体。
对映异构体优选通过以下方法分离:手性相上的柱分离,或从光学活性溶剂中重结晶,或与光学活性物质尤其是酸和其活化的衍生物或醇反应形成盐或衍生物如酯或酰胺,并分离由此得到的盐或衍生物的非对映异构体混合物,例如基于它们溶解性的差异;同时通过适宜试剂的作用,游离对映体可从纯非对映异构体盐或衍生物中释放。常用的光学活性酸为例如D和L型酒石酸或二苯甲酰酒石酸、二-邻甲苯基酒石酸、苹果酸、扁桃酸、樟脑磺酸、谷氨酸、天冬氨酸或奎尼酸。光学活性醇可为,例如,(+)或(-)薄荷醇和酰胺中的光学活性酰基,例如,可为(+)或(-)薄荷基氧基羰基。
本领域的技术人员应当理解有机化合物或它们的盐可与溶剂分子一同分离或可与它们接触的溶剂、它们反应所在的溶剂、它们从中分离的溶剂(例如,沉淀、结晶、冻干等)等形成络合物。根据本领域技术人员的认识,例如当以固体形式获得或分离时,本发明的一些化合物可含有可变量或固定量的溶剂(包括水性和/或非水性溶剂)。因此,本发明的化合物的溶剂合物(包括水合物、有机溶剂合物和混合的水合物/有机溶剂合物)包括在本发明的范围内。本发明化合物的溶剂合物可包括化学计量的溶剂合物或非化学计量的溶剂合物、紧密结合的溶剂合物或弱结合的溶剂合物,以及同种溶剂合物或异种溶剂合物。优选地,所用的溶剂为药学可接受的溶剂,例如水和/或低分子量脂肪醇如乙醇等。在一项实施方案中,本发明化合物的溶剂合物可包括,例如,水合物或醇合物,或混合的水合物/醇合物。本发明包括未溶剂化形式和所有的溶剂化形式。同样地,本发明包括任何溶剂合物、非溶剂合物、水合物、无水物、吸湿性和/或非吸湿性的形式。
由于本发明的化合物及其相应的药学上可接受的盐具有抑制DPP-IV活性和调节血糖水平的能力,其适于治疗可因抑制DPP-IV活性而受益的所有症状或病症。因此,预期根据本发明的化合物将适于预防或治疗的疾病或症状,如I型与II型糖尿病、糖尿病并发症(譬如视网膜病、肾病或神经病)、新陈代谢酸中毒或酮症、反应性低血糖、胰岛素抗药性、代谢综合症、不同来源的脂肪代谢障碍、关节炎、动脉粥样硬化及相关疾病、肥胖、同种移植物移植及降血钙素所引起的骨质疏松症。此外,这些物质也适于预防β-细胞变性,譬如胰β-细胞的细胞凋零或坏死。该物质也适于改善或恢复胰细胞的功能,以及增加肢β-细胞的数目与大小。此外,且基于因胰高血糖素肽如GLP-1与GLP-2的作用及其与DPP-IV抑制的连结,同样地,根据本发明的化合物适用于达到另外的镇静或焦虑舒解作用,且亦有利地影响手术或激素应力回应后的降解代谢状态,或降低心肌梗塞后的死亡率或发病率。它也适合于治疗与上文所提及的作用有关,且通过GLP-1或GLP-2所引入的全部症状。根据本发明的化合物亦可作为利尿剂或抗高血压剂使用,且适用于预防与治疗急性肾衰竭。此外,根据本发明的化合物可用于治疗呼吸道炎性疾病。同样它也适于预防与治疗慢性炎性肠疾病,如刺激性肠综合症(IBS)、克隆氏病或溃疡性结肠炎以及胰腺炎。同样地,其可用于胃肠道的所有伤害种类或损害,如结肠炎与肠炎。亦预期DPP-IV抑制剂且因此根据本发明的化合物,也可在人类或哺乳动物中用于治疗不孕症或改善生育能力,特別是当不孕症是与胰岛素抗药性或多囊卵巢综合症有关时。另一方面,这些物质是适用于影响精子的能动性,且因此可作为男性避孕药使用。另外该物质也适合治疗与矮小有关的生长激素缺乏,且也有利地使用于其中可使用生长激素的任何症状。根据本发明的化合物,基于其对DPP-IV的抑制作用,亦适合治疗各种自身免疫疾病,譬如风湿性关节炎、多发性硬化、甲状腺症及巴塞杜氏病等。其亦可用于治疗病毒疾病,以及例如在HIV感染中,刺激血液制造,在良性前列腺增生、牙龈炎中,以及治疗神经元缺陷,与神经变性疾病,譬如阿尔茨海默氏疾病。所述化合物亦可用于治疗胖瘤,特别是改变肿瘤侵入以及转移;这里的实例为其在治疗T-细胞淋巴瘤、急性淋巴细胞淋巴瘤白血病、以细胞基的甲状腺癌、基底细胞癌或乳腺癌中的用途。其他适应症为中风、各种起源的心肌缺血、帕金森氏病及偏头痛。此外,其他适应症包括毛囊炎与表皮角化过度、增加的角质细胞增生、牛皮癣、脑脊髄炎、肾小球肾炎、脂肪代谢障碍以及所有不同成因的身心学、抑郁及神经性精神病学疾病。
本发明的化合物或其药学上可接受的盐可用作药物,例如以用于肠内、胃肠外或局部给药的药物组合物的形式。它们可以本领域可用的任何普遍接受的给药方式给药,例如口服给药,例如以片剂、包衣片剂、糖衣片剂、硬明胶胶囊和软明胶胶囊、溶液、乳剂或混悬液的形式,经直肠给药,例如以栓剂的形式,经胃肠外(包括经静脉)给药,例如以注射溶液或输注溶液的形式,或局部给药,例如以软膏剂、乳膏剂或油的形式。在可能的给药方式中,优选口服和静脉递送。
本发明的药物组合物通常可含有总量为从约0.05至80重量%或从约0.1至50重量%的至少一种本发明的化合物,任选地和药学上可接受的载体和/或赋形剂。
除一种或多种赋形剂外,包含于本发明的剂型或药物组合物中的本发明式(I)化合物或其互变异构体或盐的量,可以为至少0.1%至0.5%,或至少0.5%至1.5%,或至少1%至3%。
本领域的技术人员基于他/她的专业知识熟悉药学可接受的赋形剂,如稀释剂、载体、粘合剂、崩解剂、表面活性剂、润滑剂、载体、助剂、佐剂和/或,其它已知适于制备药物组合物的添加剂。
作为药学可接受的赋形剂,通常已知适于药物组合物的任何赋形剂在考虑之中。其实例包括但不限于,稀释剂、填充剂、粘合剂、崩解剂、润滑剂、助流剂、溶剂、分散剂、乳化剂、增溶剂、凝胶形成剂、软膏剂基质、抗氧化剂、防腐剂、稳定剂、载体、增稠剂、络合剂、缓冲剂、pH调节剂(例如,以得到中性、碱性或酸性制剂)、渗透促进剂、聚合物、包衣剂、推进剂、张力调节剂、表面活性剂、着色剂、调味剂、甜味剂和染料。
通常,适宜的载体材料不仅为无机载体材料,还为有机载体材料。因此,例如乳糖、淀粉(如玉米淀粉)或其衍生物、滑石、二氧化硅、聚乙烯吡咯烷酮、硬脂酸或其盐可用作片剂、包衣片剂、糖衣片剂和硬明胶胶囊的载体材料。用于软明胶胶囊的适宜的载体材料为,例如植物油、蜡、脂肪以及半固体和液体多元醇。用于溶液和糖浆剂生产的适宜的载体材料为,例如水、多元醇、蔗糖、转化糖等。用于注射或输注溶液的适宜的载体材料为,例如水、醇、多元醇、甘油和植物油。用于栓剂的适宜的载体材料为,例如中性油或硬化油、蜡、脂肪以及半液体或液体多元醇或聚乙二醇。用于局部制剂的适宜的载体材料为甘油酯、半合成和合成的甘油酯、氢化油、液体蜡、液体石蜡、液体脂肪醇、甾醇、聚乙二醇和纤维素衍生物。
使用适合所需药物组合物、配方或制剂以及所需给药方式的类型的赋形剂、载体和/或稀释剂。
本发明的药物组合物可通过将一种或多种式(I)的化合物或其药学可接受的盐与适宜的赋形剂例如已知的惰性稀释剂、载体、崩解剂、佐剂、表面活性剂、粘合剂和/或润滑剂混合而得到。所述片剂还可由数层构成。本发明的组合物还可含有其它活性物质。
因此,本发明的组合物可通过本身已知的和本领域技术人员熟悉的方法制备,例如通过将所述的式(I)的化合物或其药学可接受的盐任选地和一种或多种常规的固体或液体载体和/或稀释剂,掺入至常规制剂例如普通片剂或包衣片剂、胶囊、粉末剂、混悬剂或栓剂中制备。所述载体的实例包括但不限于玉米淀粉、乳糖、葡萄糖、微晶纤维素、硬脂酸镁、聚乙烯吡咯烷酮、柠檬酸、酒石酸、水、水/乙醇、水/甘油、水/山梨醇、水/聚乙二醇、聚乙二醇、鲸蜡硬脂醇、羧甲基纤维素或脂肪物质如硬脂或其适宜的混合物。
本发明化合物的适宜的稀释剂的实例可包括纤维素粉、磷酸氢钙、赤藓糖醇、低取代的羟基丙基纤维素、甘露糖醇、预胶化淀粉或木糖醇。
取决于所给予的化合物、所治疗或预防的疾病的性质和严重性、患者的年龄和个体状况和给药方式和频率,本发明化合物的剂量可在宽范围内变化,并且当然符合各具体病例中个体的需求。通常,本发明化合物的量考虑DPP-IV抑制剂常用的数量级。当以静脉途径给药时,本发明化合物通常所需的剂量可为0.001mg至10mg,或0.01mg至10mg,或0.1mg至10mg,如0.25mg至5mg,而当以口服途径给药时,可为0.005mg至100mg,或0.05mg至100mg,或0.5mg至100mg,如2.5mg至50mg或0.5mg至10mg,优选2.5mg至10mg或1mg至5mg,各种情况中一天1至4次给药。取决于所述剂量,以若干剂量单位给予日剂量可能是便利的。
通用制备方法
本发明的化合物可采用以下通用制备方法获得,所述方法包括:
使式(II)化合物与双氰胺接触以获得式(I):
其中,R1-R4的定义如上文所示;
R5代表氢或者氨基保护基。
其中,所述的氨基保护基是本领域公知的,包括但不限于甲氧羰基、乙氧羰基、叔丁氧基羰基、苄氧羰基、2-联苯基-2-丙氧羰基(BPoc)、对甲苯磺酰基(Tosyl)、三氟乙酰基、笏甲氧羰基(Fmoc)、烯丙氧羰基(Alloc)、三甲基硅乙氧羰基(Teoc)、邻苯二甲酰基(Pht)、对甲苯磺酰基(Tos)、三氟乙酰基(Tfa)、邻或对硝基苯磺酰基(Ns)、特戊酰基、苯甲酰基、三苯甲基(Trt)、2,4-二甲氧基苄基(Dmb)、对甲氧基苄基(PMB)、苄基等。
当式(II)中R5代表氨基保护基时,在与双氰胺接触前需要事先将所述的氨基保护基脱除。
在一个实施方案中,包括使式(III)化合物与式(IV)化合物接触的步骤,以获得R5代表氨基保护基的式(II)化合物:
其中当需要时为了获得R5代表氢的式(II)化合物,可选地将氨基保护基Pr1脱除。
其中式(IV)化合物可由3-氨基哌啶(式(V)化合物)依次经不同的氨基保护基Pr1、Pr2保护,然后引入R4基团,再选择性脱除Pr2保护基而制得:
其中Pr1和Pr2代表氨基保护基。本文所述的氨基保护基是本领域公知的那些,包括但不限于甲氧羰基、乙氧羰基、叔丁氧基羰基、苄氧羰基、2-联苯基-2-丙氧羰基(BPoc)、对甲苯磺酰基(Tosyl)、三氟乙酰基、笏甲氧羰基(Fmoc)、烯丙氧羰基(Alloc)、三甲基硅乙氧羰基(Teoc)、邻苯二甲酰基(Pht)、对甲苯磺酰基(Tos)、三氟乙酰基(Tfa)、邻或对硝基苯磺酰基(Ns)、特戊酰基、苯甲酰基、三苯甲基(Trt)、2,4-二甲氧基苄基(Dmb)、对甲氧基苄基(PMB)、苄基等。
式(III)化合物可由8-卤代黄嘌呤衍生物依次被含R1基团的卤代物和R3基团的卤代物取代而制得:
式中各X相同或不同,且代表卤素原子。
具体实施方式
式(III)化合物的制备
1.8-溴-7-(2-丁炔-1-基)-3-甲基-1-(喹啉-2-基甲基)-3,7-黄嘌呤(化合物III-1)的制备
(1)8-溴-7-(2-氰基苄基)-1,3-二甲基-3,7-黄嘌呤的制备
将3-甲基-8-溴-黄嘌呤与N-乙基二异丙基胺(DIPEA)的N,N-二甲基甲酰胺溶液混合,加入2-氰基苄基溴,并于室温下搅拌过夜。为进行处理,将反应混合物倒入水中。将所析出的沉淀物抽滤,以水洗涤,并干燥,得3-甲基-7-(2-氰基苄基)-8-溴-黄嘌呤(分子式:C14H10BrN5O2)。
质谱(ESI+):m/z=36[1M+H]+;
元素分析:C,46.69;H,2.80;Br,22.19;N,19.44;O,8.88。
(2)8-溴-7-(2-氰基苄基)-3-甲基-1-(喹啉-2-基甲基)-3,7-黄嘌呤的制备
将2-溴甲基喹啉添加至3-甲基-7-(2-氰基苄基)-8-氯-黄嘌呤与碳酸钾的N,N-二甲基甲酰胺混合溶液中。将反应混合物于室温下搅拌8小时。水溶液处理后,使粗产物经过硅股柱层析纯化,以二氯甲烷/甲醇洗脱,得1-(喹啉-2-基甲基)-3-甲基-7-(2-氰基苄基)-8-溴-3,7-黄嘌呤(分子式:C24H17BrN6O2)。
质谱(ESI+):m/z=502[M+H]+;
元素分析:C,57.50;H,3.42;Br,15.94;N,16.76;O,6.38。
1H-NMR(d6-DMSO):8.07(1H),8.01(1H),7.79(1H),7.64(1H),7.48-7.55(4H),7.32(2H),5.47(2H),4.76(2H),3.40(3H)
类似地,分别用苄基溴、2-溴甲基-4-甲基喹唑啉、1-溴甲基异喹啉、N,N-二甲基-2-溴-乙酰胺、1-溴代乙酰基吡咯烷或苯基羰基甲基代替2-溴甲基喹啉,以制备以下化合物:
式(IV)化合物的制备
1.N-正丁基-N-((R)-哌啶-3-基)氨基甲酸叔丁酯(化合物IV-1)的制备
(1)(R)-3-(叔丁氧羰基氨基)哌啶-1-羧酸苄酯的制备
在0-5℃下先后用三乙胺和氯甲酸苄酯处理(R)-3-(叔丁氧羰基氨基)哌啶的THF溶液,并在该温度下搅拌24小时。然后将反应混合物真空蒸发至大约1/4体积,并在乙酸乙酯和1M盐酸溶液之间分配。分出有机相,按顺序用另外部分的1M盐酸溶液、饱和NaHCO3水溶液和盐水溶液洗涤。然后将有机相部分用无水硫酸镁干燥,过滤,并真空蒸发得到(R)-3-(叔丁氧羰基氨基)哌啶-1-羧酸苄酯(分子式:C18H26N2O4)。
质谱(ESI+):m/z=335[M+H]+;
元素分析:C,64.65;H,7.84;N,8.38;O,19.14。
(2)(R)-3-(叔丁氧羰基(正丁基)氨基)哌啶-1-羧酸苄酯的制备
将(R)-3-(叔丁氧羰基氨基)哌啶-1-羧酸苄酯在0-5℃下溶于DMF,并用氢化钠的60%悬浮液处理。将反应混合物升温至室温10min,然后再次冷却,并加入溴丁烷。2小时后,升温至室温,加入额外量的溴丁烷,并将反应混合物搅拌16小时。然后将反应混合物真空蒸发至~1/4体积,并在乙酸乙酯和水之间分配。然后将有机相部分用盐水溶液洗涤,用无水硫酸镁干燥,过滤,并真空蒸发得到残余物,将其用乙酸乙酯/己烷进行硅胶层析以获得N-正丁基化产物(分子式:C22H34N2O4)。
质谱(ESI+):m/z=391[M+H]+;
元素分析:C,67.66;H,8.78;N,7.17;O,16.39。
(3)N-正丁基-N-((R)-哌啶-3-基)氨基甲酸叔丁酯的制备
将N-正丁基化产物溶于乙醇中,用10%钯碳处理,并在60-70psi氢气下氢化6小时。然后将粗反应混合物用硅藻土过滤,真空蒸发,并再次溶于乙醇,将其通过尼龙注射器式过滤器过滤以除去残留催化剂。将混合物蒸发以获得标题化合物(分子式:C14H28N2O2)。
质谱(ESI+):m/z=257[M+H]+;
元素分析:C,65.59;H,11.01;N,10.93;O,12.48。
1H-NMR(d6-DMSO):3.61(1H),3.09(1H),2.95(2H),2.85(1H),2.75(2H),2.0(1H),1.86(1H),1.61(1H),1.51(3H),1.45(1H),1.42(9H),1.30(2H),0.89(3H)。
2.(R)-N-环己基-N-(哌啶-3-基)氨基甲酸叔丁酯(化合物IV-2)的制备
将(R)-3-(叔丁氧羰基氨基)哌啶-1-羧酸苄酯溶于DMF中,并用氢化钠的60%悬浮液处理。将反应混合物升温至室温15分钟,然后再次冷却,并加入溴代环己烷。2小时后,升温至室温,加入额外量的溴代环己烷,并将反应混合物搅拌16小时。然后将反应混合物真空蒸发至~1/4体积,并在乙酸乙酯和水之间分配。然后将有机相部分用盐水溶液洗涤,用无水硫酸镁干燥,过滤,并真空蒸发得到残余物,将其用乙酸乙酯/己烷进行硅胶层析以获得N-环己烷基化的中间体。将N-环己烷基化的中间体溶于乙醇中,用10%钯碳处理,并在60-70psi氢气下氢化6小时。然后将粗反应混合物用硅藻土过滤,真空蒸发,并再次溶于乙醇,过滤以除去残留催化剂。将混合物蒸发以获得标题化合物(分子式:C16H30N2O2)。
质谱(ESI+):m/z=283[M+H]+;
元素分析:C,68.04;H,10.71;N,9.92;O,11.33。
1H-NMR(d6-DMSO):3.61(1H),3.55(1H),3.09(1H),2.85(1H),2.74(2H),2.0(1H),1.86(1H),1.72(2H),1.61(1H),1.51(2H),1.48(2H),1.45(2H),1.43(9H),1.16(4H)。
3.(R)-N-苯基-N-(哌啶-3-基)氨基甲酸叔丁酯(化合物IV-3)的制备
将(R)-3-(叔丁氧羰基氨基)哌啶-1-羧酸苄酯在0-5℃下溶于DMF,用氢化钠的60%悬浮液处理。将反应混合物升温至室温30分钟,然后再次冷却,并加入三氟甲磺酸苯酯。3小时后,升温至室温,加入额外量的三氟甲磺酸苯酯,并将反应混合物搅拌18小时。然后将反应混合物真空蒸发至~1/4体积,并在乙酸乙酯和水之间分配。然后将有机相部分用盐水溶液洗涤,用无水硫酸镁干燥,过滤,并真空蒸发得到残余物,将其用乙酸乙酯/己烷进行硅胶层析以获得N-苯基化的中间体。将N-苯基化的中间体溶于乙醇中,用10%钯碳处理,并在60-70psi氢气下氢化6小时。然后将粗反应混合物用硅藻土过滤,真空蒸发,并再次溶于乙醇,过滤以除去残留催化剂。将混合物蒸发以获得标题化合物(分子式:C16H24N2O2)。
质谱(ESI+):m/z=277[M+H]+;
元素分析:C,69.53;H,8.75;N,10.14;O,11.58。
1H-NMR(d6-DMSO):7.72(2H),7.32(2H),6.99(1H),3.60(1H),3.28(1H),3.03(1H),2.75(2H),2.03(1H),2.01(1H),1.77(1H),1.46-1.50(2H),1.42(9H)。
4.3-(叔丁氧羰基((3R)-哌啶-3-基)氨基)哌啶-1-羧酸叔丁酯(化合物IV-4)的制备
将(R)-3-(叔丁氧羰基氨基)哌啶-1-羧酸苄酯在0-5℃下溶于DMF,用氢化钠的60%悬浮液处理。将反应混合物升温至室温10min,然后再次冷却,并加入3-溴哌啶-1-羧酸叔丁酯。2小时后,升温至室温,加入额外量的3-溴哌啶-1-羧酸叔丁酯,并将反应混合物搅拌16小时。然后将反应混合物真空蒸发至~1/4体积,并在乙酸乙酯和水之间分配。然后将有机相部分用盐水溶液洗涤,用无水硫酸镁干燥,过滤,并真空蒸发得到残余物。
将残余物溶于乙醇中,用10%钯碳处理,并在60-70psi氢气下氢化6.5小时。然后将粗反应混合物用硅藻土过滤,真空蒸发,并再次溶于乙醇,过滤以除去残留催化剂。将混合物蒸发,用乙酸乙酯/己烷进行硅胶层析以获得标题化合物(分子式:C20H37N3O4)。
质谱(ESI+):m/z=384[M+H]+;
元素分析:C,62.63;H,9.72;N,10.96;O,16.69。
1H-NMR(d6-DMSO):3.75(2H),3.61(1H),3.54(2H),3.49(1H),3.08(1H),2.86(1H),2.74(2H),2.12(1H),1.87(2H),1.70(2H),1.61(2H),1.49(2H),1.42(18H)。
式(II)化合物的制备
1.l-(喹啉-2-基甲基)-3-甲基-7-(2-氰基苄基)-8-((R)-3-正丁基氨基-哌啶-1-基)-黄嘌呤(化合物II-1)的制备
将(R)-3-叔丁氧羰基(正丁基)氨基哌啶(化合物IV-1)添加至1-((喹啉-2-基)甲基)-3-甲基-7-(2-氰基苄基)-8-氯-黄嘌呤(化合物III-2)与碳酸钠的二甲亚砜混合溶液中。将反应混合物于60℃下搅拌18小时。为进行处理,将其与水混合,并抽滤所形成的沉淀物。使固体沉淀物溶于二氯甲烷中,与三氟醋酸混合,并于室温下搅拌半小时。为进行处理,将反应混合物以二氯甲烷稀释,并以饱和碳酸钾溶液洗涤,有机相用无水硫酸钠干燥,蒸干,并经过硅胶柱层析,以二氯甲烷/甲醇(1:0至4:1)洗脱,得(R)-8-(3-正丁基氨基哌啶-1-基)-7-(2-氰基苄基)-3-甲基-1-((喹啉-2-基)甲基)-3,7-黄嘌呤(分子式:C33H36N8O2;)。
质谱(ESI+):m/z=577[M+H]+;
元素分析:C,68.73;H,6.29;N,19.43;O,5.55;
1H-NMR(d6-DMSO):8.07(1H),8.02(1H),7.76(1H),7.61(1H),7.48-7.59(4H),7.32(2H),5.46(2H),4.75(2H),3.38(1H),3.35(3H),3.32(1H),3.27(3H),2.63(1H),2.53(2H),1.70(1H),1.50(1H),1.42(2H),1.35(4H),0.89(3H)。
以类似方法还可制备得到以下化合物:
表1
式(I)化合物的制备
实施例1:l-(喹啉-2-基甲基)-3-甲基-7-(2-氰基苄基)-8-((R)-3-(N1-正丁基双胍基)-哌啶-1-基)-黄嘌呤(化合物I-1)的制备
将双氰胺溶于异丙醇中,加入(R)-8-(3-正丁基氨基哌啶-1-基)-7-(2-氰基苄基)-3-甲基-1-(喹啉-2-基甲基)-3,7-黄嘌呤(化合物II-1),用36%HCl调节pH5~6,控制温度在80~100℃反应6小时,反应完成后静置冷却,析出大量白色晶体,抽滤,洗涤,干燥后用无水乙醇重结晶,得标题化合物(分子式:C35H40N12O2)。
质谱(ESI+):m/z=661[M+H]+
元素分析:C,63.62;H,6.10;N,25.44;O,4.84。
1H-NMR(d6-DMSO):8.06(1H),8.01(1H),7.83(2H),7.75(1H),7.63(1H),7.52(3H),7.46(1H),7.30(2H),6.62(2H),5.47(2H),4.76(2H),3.61(1H),3.39(3H),3.34(1H),3.30(2H),3.25(2H),2.63(1H),2.15(1H),1.83(1H),1.48-1.58(5H),1.30(2H),0.89(3H)。
实施例2:l-苄基-3-甲基-7-(2-氰基苄基)-8-((R)-3-(N1-正丁基双胍基)-哌啶-1-基)-黄嘌呤(化合物I-2)的制备
将双氰胺溶于异丙醇中,加入(R)-8-(3-正丁基氨基哌啶-1-基)-7-(2-氰基苄基)-3-甲基-1-苄基-3,7-黄嘌呤(化合物II-2),用36%HCl调节pH5~6,控制温度在80~100℃反应6.5小时,反应完成后静置冷却,析出大量白色晶体,抽滤,洗涤,干燥后用无水乙醇重结晶,得标题化合物(分子式:C32H39N11O2)。
质谱(ESI+):m/z=610[M+H]+
元素分析:C,63.04;H,6.45;N,25.27;O,5.25。
1H-NMR(d6-DMSO):7.84(2H),7.55(3H),7.20-7.53(6H),6.63(2H),5.46(2H),5.01(2H),3.60(1H),3.35(1H),3.38(3H),3.34(2H),3.27(2H),2.63(1H),2.15(1H),1.83(1H),1.48-1.58(5H),1.30(2H),0.89(3H)。
实施例3:l-(4-甲基喹唑啉-2-基甲基)-3-甲基-7-(2-氰基苄基)-8-((R)-3-(N1-环己基双胍基)-哌啶-1-基)-黄嘌呤(化合物I-3)的制备
将双氰胺溶于异丙醇中,加入(R)-8-(3-环己基氨基哌啶-1-基)-7-(2-氰基苄基)-3-甲基-1-(4-甲基喹唑啉-2-基甲基)-3,7-黄嘌呤(化合物II-3),用36%HCl调节pH5~6,控制温度在80~100℃反应5.5小时,反应完成后静置冷却,析出大量白色晶体,抽滤,洗涤,干燥后用无水乙醇重结晶,得标题化合物(分子式:C37H43N13O2)。
质谱(ESI+):m/z=702[M+H]+
元素分析:C,63.32;H,6.18;N,25.94;O,4.56。
1H-NMR(d6-DMSO):8.13(1H),7.84(2H,br),7.81(2H),7.59(1H),7.53(3H),7.34(1H),6.63(2H,br),5.46(2H),4.42(2H),3.61(1H),3.38(3H),3.34(1H),3.26(2H),2.94(3H),2.63(1H),2.57(1H),2.10(1H,br),1.82(1H),1.72(2H),1.59(2H),1.45-1.48(5H,m),1.16(4H)。
实施例4:l-(异喹啉-1-基甲基)-3-甲基-7-(2,3-二氰基苄基)-8-((R)-3-(N1-环己基双胍基)-哌啶-1-基)-黄嘌呤(化合物I-4)的制备
将双氰胺溶于异丙醇中,加入(R)-8-(3-环己基氨基哌啶-1-基)-7-(2,3-二氰基苄基)-3-甲基-1-(喹啉-2-基甲基)-3,7-黄嘌呤(化合物II-4),用36%HCl调节pH5~6,控制温度在80~100℃反应6小时,反应完成后静置冷却,析出大量白色晶体,抽滤,洗涤,干燥后用无水乙醇重结晶,得标题化合物(分子式:C38H41N13O2)。
质谱(ESI+):m/z=712[M+H]+
元素分析:C,64.12;H,5.81;N,25.58;O,4.50。
实施例5:l-(二甲氨基羰基甲基)-3-甲基-7-(2-氰基苄基)-8-((R)-3-(N1-苯基双胍基)-哌啶-1-基)-黄嘌呤(化合物I-5)的制备
将双氰胺溶于异丙醇中,加入(R)-8-(3-苯基氨基哌啶-1-基)-7-(2-氰基苄基)-3-甲基-1-(二甲氨基羰基甲基)-3,7-黄嘌呤(化合物II-1),用36%HCl调节pH5~6,控制温度在80~100℃反应6小时,反应完成后静置冷却,析出大量白色晶体,抽滤,洗涤,干燥后用无水乙醇重结晶,得标题化合物(分子式:C31H36N12O3)。
质谱(ESI+):m/z=625[M+H]+
元素分析:C,59.60;H,5.81;N,26.91;O,7.68。
实施例6:l-(吡咯烷-1-基羰基甲基)-3-异丙基-7-(2,3-二氰基苄基)-8-((R)-3-(N1-苯基双胍基)-哌啶-1-基)-黄嘌呤(化合物I-6)的制备
将双氰胺溶于异丙醇中,加入(R)-8-(3-苯基氨基哌啶-1-基)-7-(2,3-二氰基苄基)-3-异丙基-1-(吡咯烷-1-基羰基甲基)-3,7-黄嘌呤(化合物II-1),用36%HCl调节pH5~6,控制温度在80~100℃反应6小时,反应完成后静置冷却,析出大量白色晶体,抽滤,洗涤,干燥后用无水乙醇重结晶,得标题化合物(分子式:C36H41N13O3)。
质谱(ESI+):m/z=704[M+H]+
元素分析:C,61.44;H,5.87;N,25.87;O,6.82。
实施例7:l-(苯基羰基甲基)-3-苯基-7-(2,3-二氰基苄基)-8-((R)-3-(N1-哌啶-3-基双胍基)-哌啶-1-基)-黄嘌呤(化合物I-7)的制备
将双氰胺溶于异丙醇中,加入(R)-8-(3-(哌啶-3-基)氨基哌啶-1-基)-7-(2,3-二氰基苄基)-3-苯基-1-(苯基羰基甲基)-3,7-黄嘌呤(化合物II-1),用36%HCl调节pH5~6,控制温度在80~100℃反应6小时,反应完成后静置冷却,析出大量白色晶体,抽滤,洗涤,干燥后用无水乙醇重结晶,得标题化合物(分子式:C40H41N13O3)。
质谱(ESI+):m/z=7[2+H]+
元素分析:C,63.90;H,5.50;N,24.22;O,6.38。
应用实施例
1.DPP-IV检测
使用人类结肠癌细胞系Caco-2的萃取物作为DPP-IV来源。为诱发DPP-IV表达,细胞的分化按文献(Reiher等,“肠细胞系Caco-2的增加表达”,在Proc.Natl.Acad.Sci.第90卷,第5757-5761页(1993))中所述进行。细胞萃取物是于4℃下,通过在35,000g下离心30分钟(以去除细胞碎屑),将其溶解于缓冲剂(10μmTnsHC1,0.15MNaCl,0.04t.i.u.抑酶肽,0.5%Nonidet-P40,pH8.0)中而得到。
将50微升最后浓度为100μm的酰氨基-4-三氟甲基香豆素(AFC)基质溶液放置在黑色微滴定板中。将20微升检测缓冲液(最后浓度为50μmTns-HCl,pH7.8,50μmNaCl,1%DMSO)以吸移管吸取。反应是通过添加30微升已溶解的Caco-2蛋白质(每孔最后浓度为0.14微克蛋白质)开始。通常将要被研究的待测物质,预先稀释在20微升检测缓冲液而再添加,其中检测缓冲液的体积相应减少。反应是在环境温度下进行,培养60分钟。然后,在Victor14Multilabel计数器中测量萤光,激发波长为405毫微米,而发射波长为535毫微米。空白试验读数(相当于0%活性)是在没有任何Caco-2蛋白质(体积由检测缓冲液置換)的混合物中获得,对照值(相当于100%活性)是在未添加物质的混合物中获得。于讨论中的待测物质的药效,以IC50值代表,是由剂量/活性曲线计算,其在各情况中包含11个测量点。
本发明的实施例I-1~7的化合物(双胍衍生物)的IC50值≤10nM,并且其IC50值显著低于相应的氨基衍生物,例如低于大约1/5~1/10。详细结果见下表2。
表2、本发明化合物对DPP-IV的抑制作用
化合物编号 | IC50(nM) |
化合物I-1 | 0.3 |
化合物I-2 | 0.5 |
化合物I-3 | 0.06 |
化合物I-4 | 0.2 |
化合物I-5 | 0.05 |
化合物I-6 | 0.01 |
化合物I-7 | 0.08 |
2.本发明化合物对四氧嘧啶糖尿病小鼠血糖的影响
选健康小鼠60只,随机分出10只作为正常对照组(生理盐水0.5ml/只),其余50只小鼠禁食不禁水24小时,各鼠均腹腔注射四氧嘧啶180mg/kg,其后72小时眼眶采血测定血糖,血糖浓度高于11.1mmol/L者为糖尿病模型小鼠。将50只糖尿病模型小鼠随机分为5组:实验性糖尿病空白组(生理盐水0.5ml/只),利格列汀组(5mg/kg),本发明化合物的高剂量组(5mg/kg)、中剂量组(1mg/kg)、低剂量组(0.2mg/kg)。每天上午8:00~9:00灌胃给药,连续30d。禁食12h从后小鼠眼眶后静脉丛取血测血糖值。
结果显示,本发明的实施例I-1~7化合物(双胍衍生物)均不同程度表现出比相应的氨基衍生物更强烈的降血糖作用和显著延长的作用时间,而且不易出现低血糖。例如,实施例I-1~7的化合物的低剂量组均表现出具有比利格列汀组更强且更持久的降血糖能力,具有显著性差异(p<0.05)。
Claims (4)
1.选自以下所示结构的化合物、其立体异构体,或者其药学上可接受的盐:
2.一种药物组合物,其包括根据权利要求1所述的化合物。
3.根据权利要求1所述的化合物在制备药物中的应用,所述的药物用于预防或治疗与DPP-IV相关的疾病。
4.根据权利要求3所述的应用,所述的疾病选自I型糖尿病、II型糖尿病、成人隐匿性自身免疫性糖尿病,葡萄糖耐量降低、空腹血糖受损、餐后高血糖症、吸收后高血糖症、超重、肥胖症、高胆固醇血症、高甘油三酯血症、高血压、动脉粥样硬化、内皮功能障碍、骨质疏松、慢性全身性炎症、非酒精性脂肪肝病、视网膜病变、神经病变、肾病、多囊卵巢综合症和/或代谢综合症。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410831183.1A CN104478880B (zh) | 2014-12-26 | 2014-12-26 | 作为dpp-iv抑制剂的双胍衍生物 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410831183.1A CN104478880B (zh) | 2014-12-26 | 2014-12-26 | 作为dpp-iv抑制剂的双胍衍生物 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN104478880A CN104478880A (zh) | 2015-04-01 |
CN104478880B true CN104478880B (zh) | 2016-03-02 |
Family
ID=52753504
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201410831183.1A Active CN104478880B (zh) | 2014-12-26 | 2014-12-26 | 作为dpp-iv抑制剂的双胍衍生物 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN104478880B (zh) |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE10238243A1 (de) * | 2002-08-21 | 2004-03-04 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 8-[3-Amino-piperidin-1-yl]-xanthine, deren Herstellung und deren Verwendung als Arzneimittel |
DE102004054054A1 (de) * | 2004-11-05 | 2006-05-11 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verfahren zur Herstellung chiraler 8-(3-Amino-piperidin-1-yl)-xanthine |
-
2014
- 2014-12-26 CN CN201410831183.1A patent/CN104478880B/zh active Active
Also Published As
Publication number | Publication date |
---|---|
CN104478880A (zh) | 2015-04-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11932618B2 (en) | GLP-1 receptor agonist and use thereof | |
JP4980069B2 (ja) | 二環式イミダゾール誘導体、その製法及びその医薬組成物としての使用 | |
JP2007513989A (ja) | 新規なピペリジン−1−イル及び2−([1,4]ジアゼピン−1−イル)−イミダゾ[4,d]ピペラジン−4−オン、その製法及び医薬組成物としての使用 | |
CA2498423A1 (en) | Combination drug | |
EP2906562A1 (en) | Pde9i with imidazo pyrazinone backbone | |
EP1569936A1 (de) | Neue substituierte imidazo-pyridinone und imidazo-pyridazinone, ihre herstellung und ihre verwendung als arzneimittel | |
EP3842431B1 (en) | [1,2,4]triazolo[1,5-a]pyridine compound as jak inhibitor and application thereof | |
JP2010507581A (ja) | PKC−θ阻害薬としてのプリン類 | |
TW202128659A (zh) | Glp-1受體激動劑及其用途 | |
JP2004244412A (ja) | 4位に置換基を有する2−シアノピロリジン誘導体及びその製造方法並びにそれを含有する薬剤 | |
CA2290252C (en) | Process and intermediates for growth hormone secretagogues | |
KR100286786B1 (ko) | 2,7-치환된옥타하이드로-피롤로[1,2-에이]피라진유도체 | |
CN104592235B (zh) | 一种制备作为二肽基肽酶-4抑制剂的化合物的中间体 | |
EP0328700A1 (en) | 4,7-Dihydropyrazolo(1,5-a)pyrimidine compound and pharmaceutical use thereof | |
CN104478880B (zh) | 作为dpp-iv抑制剂的双胍衍生物 | |
CN104478879B (zh) | 一种作为二肽基肽酶-4抑制剂的化合物 | |
WO2010123018A1 (ja) | ジアザスピロアルカン誘導体 | |
CN105503873B (zh) | 一种作为二肽基肽酶‑4抑制剂的化合物的制备方法 | |
KR102174395B1 (ko) | 쿠마린-3-카복시아마이드 유도체, 이의 제조방법 및 이를 유효성분으로 포함하는 유로텐신-ⅱ 수용체 활성 관련 질환의 예방 또는 치료용 약학적 조성물 | |
WO2010146597A1 (en) | 2-amino-2- [8-(dimethyl carbamoyl)- 8-aza- bicyclo [3.2.1] oct-3-yl]-exo- ethanoyl derivatives as potent dpp-iv inhibitors | |
KR100848490B1 (ko) | 베타아미노기를 갖는 1,2,5-트리아제판 유도체, 이의약학적으로 허용 가능한 염 및 이의 제조 방법 | |
WO2024101763A1 (ko) | 아릴시클로알킬아마이드 구조를 갖는 이소인돌리논 유도체 및 이의 용도 | |
KR100913495B1 (ko) | 베타아미노기를 갖는 1,4-디아제펜 유도체, 이의약학적으로 허용 가능한 염 및 이의 제조 방법 | |
KR100792275B1 (ko) | 베타아미노기를 갖는 고리화된 히드라자이드 유도체, 이의 약학적으로 허용 가능한 염 및 이의 제조 방법 | |
KR100531189B1 (ko) | 아실기를 포함하는 피라졸리딘 유도체와 이의 약학적으로허용가능한 염 및 이의 제조 방법 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant |