CN106008507B - Xanthine derivative - Google Patents
Xanthine derivative Download PDFInfo
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- CN106008507B CN106008507B CN201610365388.4A CN201610365388A CN106008507B CN 106008507 B CN106008507 B CN 106008507B CN 201610365388 A CN201610365388 A CN 201610365388A CN 106008507 B CN106008507 B CN 106008507B
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- hydrogen atom
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- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical class O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 title abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 36
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 abstract description 28
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 abstract description 24
- 238000012360 testing method Methods 0.000 abstract description 20
- 239000003814 drug Substances 0.000 abstract description 13
- 241000282472 Canis lupus familiaris Species 0.000 abstract description 7
- 230000001629 suppression Effects 0.000 abstract description 5
- 230000002401 inhibitory effect Effects 0.000 abstract description 4
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 abstract description 3
- 201000010099 disease Diseases 0.000 abstract description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 3
- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- 238000006243 chemical reaction Methods 0.000 description 21
- 239000007787 solid Substances 0.000 description 20
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 19
- 125000000217 alkyl group Chemical group 0.000 description 18
- 108010088406 Glucagon-Like Peptides Proteins 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 14
- 230000000694 effects Effects 0.000 description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 238000001819 mass spectrum Methods 0.000 description 12
- 238000004809 thin layer chromatography Methods 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
- 210000004369 blood Anatomy 0.000 description 10
- 239000008280 blood Substances 0.000 description 10
- 239000008103 glucose Substances 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 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 6
- LTXREWYXXSTFRX-QGZVFWFLSA-N Linagliptin Chemical compound 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 5
- 241001465754 Metazoa Species 0.000 description 5
- 229940125904 compound 1 Drugs 0.000 description 5
- 206010012601 diabetes mellitus Diseases 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 229960002397 linagliptin Drugs 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- MJBPUQUGJNAPAZ-UHFFFAOYSA-N Butine Natural products O1C2=CC(O)=CC=C2C(=O)CC1C1=CC=C(O)C(O)=C1 MJBPUQUGJNAPAZ-UHFFFAOYSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 125000001309 chloro group Chemical group Cl* 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 125000001153 fluoro group Chemical group F* 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- QOLHWXNSCZGWHK-BWBORTOCSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecylcarbamoyloxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OC(=O)NCCCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 QOLHWXNSCZGWHK-BWBORTOCSA-N 0.000 description 3
- 229940126559 Compound 4e Drugs 0.000 description 3
- 102000004877 Insulin Human genes 0.000 description 3
- 108090001061 Insulin Proteins 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 238000003304 gavage Methods 0.000 description 3
- 238000007689 inspection Methods 0.000 description 3
- 229940125396 insulin Drugs 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 2
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- QTEQVEJOXGBDGI-UHFFFAOYSA-N 8-bromo-3-methyl-7h-purine-2,6-dione Chemical class O=C1NC(=O)N(C)C2=C1NC(Br)=N2 QTEQVEJOXGBDGI-UHFFFAOYSA-N 0.000 description 2
- 102000004860 Dipeptidases Human genes 0.000 description 2
- 108090001081 Dipeptidases Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 101000684208 Homo sapiens Prolyl endopeptidase FAP Proteins 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 229910001413 alkali metal ion Inorganic materials 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000002146 bilateral effect Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 229910021645 metal ion Inorganic materials 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000007619 statistical method Methods 0.000 description 2
- 238000010025 steaming Methods 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 229940075420 xanthine Drugs 0.000 description 2
- QVHJQCGUWFKTSE-YFKPBYRVSA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound OC(=O)[C@H](C)NC(=O)OC(C)(C)C QVHJQCGUWFKTSE-YFKPBYRVSA-N 0.000 description 1
- 150000000183 1,3-benzoxazoles Chemical class 0.000 description 1
- UTDVHCQTKWTQEA-UHFFFAOYSA-N 1-(2-aminoacetyl)-n-(4-methyl-2-oxochromen-7-yl)pyrrolidine-2-carboxamide Chemical compound C1=CC=2C(C)=CC(=O)OC=2C=C1NC(=O)C1CCCN1C(=O)CN UTDVHCQTKWTQEA-UHFFFAOYSA-N 0.000 description 1
- VVKQNCHUKOHTDO-UHFFFAOYSA-N 2-(bromomethyl)-1,3-benzoxazole Chemical class C1=CC=C2OC(CBr)=NC2=C1 VVKQNCHUKOHTDO-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000012449 Kunming mouse Methods 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical class OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 208000004880 Polyuria Diseases 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 102000012479 Serine Proteases Human genes 0.000 description 1
- 108010022999 Serine Proteases Proteins 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910001420 alkaline earth metal ion Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000002508 compound effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- LGTLXDJOAJDFLR-UHFFFAOYSA-N diethyl chlorophosphate Chemical compound CCOP(Cl)(=O)OCC LGTLXDJOAJDFLR-UHFFFAOYSA-N 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000035619 diuresis Effects 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 230000002262 irrigation Effects 0.000 description 1
- 238000003973 irrigation Methods 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L magnesium chloride Substances [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000022558 protein metabolic process Effects 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- -1 sulfydryl Chemical group 0.000 description 1
- AKQXKEBCONUWCL-MRVPVSSYSA-N tert-butyl (3r)-3-aminopiperidine-1-carboxylate Chemical class CC(C)(C)OC(=O)N1CCC[C@@H](N)C1 AKQXKEBCONUWCL-MRVPVSSYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 description 1
- 229960001254 vildagliptin 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
Abstract
The invention discloses a kind of xanthine derivative and isomers, by the influence experiment of normal mouse sugar tolerance and to DPP IV active suppression tests in beagle dog bodies, the compounds of this invention and excellent DPP IV inhibitory activity is shown, can be used in preparing the purposes treated in the disease medicament related to dipeptidyl peptidase IV.
Description
Technical field
The present invention relates to medicinal chemistry art, and in particular to a kind of xanthine derivative, its preparation method and its derivative
Purposes as one week medicine being administered once especially as dipeptidyl peptidase IV (DPP-IV) inhibitor.
Background technology
Diabetes are a kind of metabolic diseases of multi-pathogenesis, are characterized in chronic hyperglycemia, with because of insulin secretion and/or
It is disorderly to act on sugar caused by defect, fat and protein metabolism.Diabetes are also a kind of very ancient disease, are due to human body
Interior insulin is relative or concentration of glucose raises definitely in blood caused by shortage, causes sugar largely to be discharged from urine, and adjoint
More drink, diuresis, the symptom such as eat more, become thin, be dizzy, be weak.
In treating diabetes, kinesiatrics and dietetic treatment are two kinds of essential diabetes remedies.When this
When two kinds of therapies are not enough to symptom management, insulin or OHA can be used.But because these hypoglycemic medicines are present
Many side effects, develop a kind of new, low side effect and can effectively treat diabetes medicine it is particularly important.
Dipeptidyl peptidase IV (DPP-IV) is a kind of serine protease, and it is residual that it can contain a proline in secondary end
N- ends dipeptidase is cracked in the peptide chain of base, although (DPP-IV) is not demonstrate,proved completely also the physiological action of mammal
It is real, but it is metabolized in neural enzyme, T- cell-stimulatings, and cancer metastasis enters endothelium and inhibition of HIV enters lymphoid cell process
In all play it is very important effect (WO98/19998).
There are some researches show (DPP-IV) can prevent the secretion of glucagon like peptide (GLP) -1, N- ends in (GLP) -1 are cracked
The dipeptidase of group-the third at end, it is degraded to inactive (GLP) -1 (7-36) acid amides from (GLP) -1 of activity form and be degraded to
Inactive (GLP) -1 (9-36) acid amides Endocrinology, 1999,140：5356-5363).Under physiological conditions, circulation
Complete (GLP) -1 half-life period is very short in blood, DPP-IV be degraded to the inactive metabolin after (GLP) -1 can with (GLP) -1 by
Body combination antagonistic activity (GLP) -1 is so as to shorten the physiological reaction to (GLP) -1, and (DPP-IV) inhibitor can be protected completely
Even exogenous (GLP) -1 of endogenous is not inactivated by (DPP-IV), greatly improves (GLP) -1 physiologically active (5-10
Times), because the secretion of (GLP) -1 pair of pancreatic insulin is an important stimulator and can directly affect the distribution of glucose,
Therefore effect (US6110949) well is played in treatment of the DPP-IV inhibitor to Non-Insulin Dependent Diabetes Mellitus example.
Although several DPP-IV inhibitors are had listed at present, such as phosphoric acid Xi Gelieting, vildagliptin, benzoic acid Ah lattice
Spit of fland etc. is arranged, but is to be administered once for one day, in order to increase the compliance of patient, it is necessary to which the DPP-IV being administered once for one week suppresses
Agent, therefore the demand to new long-acting DPP-IV inhibitor clinically still be present.
The content of the invention
Application the present invention relates to xanthine substitutive derivative and preparation method thereof and in medicine, particularly logical formula (I)
Shown xanthine substitutive derivative and its all stereoisomers, and its be particularly as one week therapeutic agent being administered once
For the activity inhibition of dipeptidyl peptidase IV (DPP-IV).
Present invention relates particularly to the compound shown in following logical formula (I) structure：
Wherein：R1It is independently selected from hydrogen atom, fluorine atom, chlorine atom, bromine atoms, iodine atom, amino or cyano group；
R2It is independently selected from hydrogen atom ,-SO2R3、-PO(OR3)2、-COCHR4R5、-COOR6Or-CONHR6；
R3For hydrogen atom, metal ion or C1-C5Straight or branched alkyl, wherein C1_C5It is any in straight or branched alkyl
Hydrogen atom further can be substituted by hydroxyl, sulfydryl or amino；Wherein metal ion is alkali metal ion or alkaline-earth metal ions；
R4For hydrogen atom or C1-C5Straight or branched alkyl, wherein C1_C5Any hydrogen atom can enter in straight or branched alkyl
One step is substituted by hydroxyl, sulfydryl or amino；
R5For hydroxyl, sulfydryl, amino or C1-C5Straight or branched alkyl, wherein C1_C5Any hydrogen in straight or branched alkyl
Atom further can be substituted by hydroxyl, sulfydryl or amino；
R6For C1-C5Straight or branched alkyl, wherein C1_C5Any hydrogen atom can be further by hydroxyl in straight or branched alkyl
Base, sulfydryl or amino substitution.
Further, in general formula compound：
R1It is independently selected from hydrogen atom, fluorine atom or chlorine atom；
R2It is independently selected from hydrogen atom ,-SO2R3、-PO(OR3)2、-COCHR4R5、-COOR6Or-CONHR6；
R3For alkali metal ion, C1_C3Straight or branched alkyl；
R4For hydrogen atom or C1_C5Straight or branched alkyl, wherein C1_C5Any hydrogen atom can enter in straight or branched alkyl
One step is substituted by hydroxyl or amino；
R5For hydroxyl, amino or C1_C3Straight or branched alkyl, wherein C1_C3Any hydrogen atom in straight or branched alkyl
Further it can be substituted by hydroxyl or amino；
R6For C1_C3Straight or branched alkyl, wherein C1_C3Any hydrogen atom can be further by hydroxyl in straight or branched alkyl
Base or amino substitution.
Further, in general formula compound：
R1It is independently selected from hydrogen atom, fluorine atom or the chlorine atom in 5 substitutions of (1,3- benzoxazoles -2- bases) methyl；
R2It is independently selected from hydrogen atom ,-SO2R3、-PO(OR3)2Or-COCHR4R5；
R3For C1_C3Straight chained alkyl；
R4For hydrogen atom or C1_C4Straight or branched alkyl, wherein C1_C4Any hydrogen atom can enter in straight or branched alkyl
One step is substituted by hydroxyl or amino；
R5For hydroxyl or amino.
In addition, the compound shown in the logical formula (I) structure of the present invention also includes：
Wherein R1It is independently selected from hydrogen atom, fluorine atom, chlorine atom, bromine atoms, iodine atom, amino or cyano group；R2It is independently selected from
COCHR4R5；R4、R5For different substituents；And R4For C1_C4Straight or branched alkyl, wherein C1_C4In straight or branched alkyl
When any hydrogen atom further can be substituted by hydroxyl or amino, with R4、R5The asymmetric carbon atom of connection is R, S or R and S mixing
Configuration.
The preferred compound of compound shown in the logical formula (I) of the present invention includes, but are not limited to：
The preparation method of compound and its stereoisomer described in formula of the present invention, comprises the following steps：
Under the conditions of room temperature (10~25 DEG C), the bromo- 3- methyl xanthines of initiation material 8- and the bromo- 2- butine of 1- are reacted,
The product a of generation be further substituted with the derivative of 2- bromomethyl -1,3- benzoxazoles reaction generation product b, intermediate b with
(R) after -3- t-butoxycarbonyl aminos piperidines reaction generation c, intermediate c and TFA reaction completely, dissociate into alkali and obtain compound d,
By d and R2-X(R2For SO2R3、PO(OR3)2、OCCHR4R5、COOR6Or CONHR6, X is halogen or hydroxyl) and reaction generation product e.
If raw material R2R in-X2For SO2R3Or PO (OR3)2, R is just obtained after the product hydrolysis of generation3For the corresponding product of hydrogen atom.It is if former
Expect R2R in-X2Containing blocking group, the product of generation further sloughs protection, you can obtains target compound.
Embodiment
The present invention is described in further detail with reference to embodiments, but not limitation of the present invention, it is all according to
The equivalent substitution of any this area that the disclosure of invention is made, belongs to protection scope of the present invention.
The structure of compound be by mass spectrum (MS) or nuclear magnetic resonance (1HNMR) determine；
Nuclear magnetic resonance (1HNMR) displacement (δ) is provided with the unit of hundred a ten thousandths (ppm)；
Nuclear magnetic resonance (1HNMR measure) is to use BrukerAVANCE-300 nuclear magnetic resonance spectrometers, and measure solvent is six deuterated diformazans
Base sulfoxide (DMSO-d6), tetramethylsilane (TMS) is inside designated as, chemical shift is with 10-6(ppm) provided as unit；
The measure of mass spectrum (MS) is with FINNIGAN LCQAd (ESI) mass spectrograph (manufacturer：Therm, model：Finnigan
LCQ advantage MAX)；
Thin layer silica gel uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plates；
Column chromatography is carrier typically using Yantai Huanghai Sea silica gel 200-300 mesh silica gel；
Carried out under nitrogen atmosphere without specified otherwise, reaction in embodiment；
Blanket of nitrogen refers to that reaction bulb connects the nitrogen balloon of a 1L volume；
Without specified otherwise in embodiment, the solution in reaction refers to the aqueous solution；
Room temperature refers to 10 to 25 degrees Celsius of environment temperature in embodiment.
Embodiment 1
First step compound 1a synthesis
Using known method, bromo- 3 methyl-xanthines (5g, 20.4mmol) of 8- are dissolved in DMF
In (35ml), DIPEA (2.633g, 49.4mmol), the bromo- 2- butine (2.714g, 36.2mmol) of 1- are added,
Overnight, thin-layer chromatography tracking reaction is complete, and reaction solution is poured into 400ml water, there is solid precipitation, filters, washing for room temperature reaction
Solid, the bromo- 7- of 8- (2- butine -1- bases) -3 methyl-xanthine 1a (5.2g, yellow solid), yield are obtained after drying：85.8%.
MS m/z(ES):297,299 [M+1]
Second step compound 1b synthesis
Using known method, 2- bromomethyl -5- fluorine benzoxazoles (2.4g, 10.4mmol) is dissolved in N, N- dimethyl methyls
In acid amides (70ml), 8- bromo- 7- (2- butine -1- bases) -3 methyl-xanthine 1a (3g, 10.4mmol), potassium carbonate are added
(2.2g, 15.6mmol), overnight, thin-layer chromatography tracking reaction is complete, and reaction solution is poured into 800ml water, separates out for room temperature reaction
Solid, filter, wash solid, product compound 1b (4.1g, yellow solid), yield are obtained after drying：88.2%.
MS m/z(ES):446,448 [M+1]
3rd step compound 1c synthesis
1b (4.1g, 9.19mmol) is dissolved in DMF (50ml), adds (R)-N-Boc-3- amino
Piperidines (1.84g, 9.19mmol), potassium carbonate (1.9g, 13.8mmol) are heated to 75 DEG C and reacted 2 hours, and thin-layer chromatography tracking is anti-
Should be complete, after question response system is cooled to room temperature, it is added in 1000ml water, separates out solid, filters, washing solid, dry
Product compound 1c (5g, yellow solid), yield：96.1%.
MS m/z(ES):566[M+1]
The synthesis of 4th step compound 1
1c (5g, 8.85mmol) is dissolved in dichloromethane (30ml), instills trifluoroacetic acid (5ml) at room temperature, 30 degree anti-
It should stay overnight, thin-layer chromatography tracking reaction is complete.After being concentrated under reduced pressure, dichloromethane (50ml) dissolving is added, aqueous sodium carbonate is adjusted
PH is extracted once to alkalescence, liquid separation, dichloromethane, is merged organic phase, is dried, column chromatography for separation obtains product compound 1 after concentration
(3.75g, yellow solid), yield：91.2%.
MS m/z(ES):466[M+1]
1H NMR(300MHz,DMSO)δ1.69-1.72(m,2H),1.80(s,3H),1.94-2.03(m,2H),3.00–
3.08 (m, 1H), 3.20-3.26 (m, 2H), 3.42-3.52 (m, 6H, NH2), 3.71-3.75 (m, 1H), 4.97 (q, J=
16.5Hz, 2H), 5.35 (s, 2H), 7.26 (td, J=9.3,2.4Hz, 1H), 7.58 (dd, J=9.0,2.4Hz, 1H), 7.76
(dd, J=9.0,4.5Hz, 1H).
Embodiment 2
The first step is the same as the first step of embodiment 1；
Second step is the same as the second step of embodiment 1；
3rd step is the same as the step of embodiment 1 the 3rd；
4th step is the same as the step of embodiment 1 the 4th；
The synthesis of 5th step compound 2
Using known method, compound 1 (100mg, 0.21mmol) is dissolved in dichloromethane (5ml), adds three second
Amine (43mg, 0.43mmol), then methane sulfonyl chloride (27mg, 0.24mmol) is instilled, room temperature reaction is overnight.Thin-layer chromatography tracking is anti-
Should, display consumption of raw materials is complete, is washed with saturated aqueous common salt (5ml*2), liquid separation, dries, through preparing thin-layer chromatography (dichloro after concentration
Methane:Methanol=10:1) product compound 2 (92mg, light yellow solid), yield are purified to obtain：79.3%.
MS m/z(ES):544[M+1]
1H NMR(300MHz,DMSO)δ1.46-1.53(m,1H),1.67-1.71(m,1H),1.79-1.85(m,4H),
1.95-1.99(m,1H),2.92-3.09(m,5H),3.41-3.60(m,5H),3.72-3.77(m,1H),4.89(s,2H),
5.34 (s, 2H), 7.25 (td, J=9.3,2.7Hz, 1H), 7.34 (d, J=7.5Hz, 1H), 7.57 (dd, J=8.7,2.4Hz,
1H), 7.76 (dd, J=9.0,4.2Hz, 1H).
Embodiment 3
The first step is the same as the first step of embodiment 1；
Second step is the same as the second step of embodiment 1；
3rd step is the same as the step of embodiment 1 the 3rd；
4th step is the same as the step of embodiment 1 the 4th；
The synthesis of 5th step compound 3
Using known method, compound 1 (100mg, 0.21mmol) is dissolved in dichloromethane (5ml), adds three second
Amine (43mg, 0.43mmol), then diethyl chloro-phosphate (41mg, 0.24mmol) is instilled, room temperature reaction is overnight.Thin-layer chromatography tracks
Reaction, display consumption of raw materials are complete.Saturated aqueous common salt (5ml*2) is washed, and is dried, through preparing thin-layer chromatography (dichloromethane after concentration:
Methanol=10:1) product compound 3 (111mg, light yellow solid), yield are purified to obtain：84.1%.
MS m/z(ES):602[M+1]
1H NMR (300MHz, DMSO) δ 1.23 (t, J=6.7Hz, 6H), 1.40-1.43 (m, 1H), 1.63-1.66 (m,
1H),1.79-1.93(m,5H),2.84-3.03(m,2H),3.17-3.18(m,1H),3.40(s,3H),3.59-3.72(m,
2H), 3.90-3.95 (m, 4H), 4.89 (s, 2H), 5.12 (t, J=10.4Hz, 1H), 5.34 (s, 2H), 7.22-7.28 (m,
1H), 7.55-7.59 (m, 1H), 7.75 (dd, J=9.0,4.5Hz, 1H).
Embodiment 4
The first step is the same as the first step of embodiment 1；
Second step is the same as the second step of embodiment 1；
3rd step is the same as the step of embodiment 1 the 3rd；
4th step is the same as the step of embodiment 1 the 4th；
5th step compound 4e synthesis
Using known method, compound 1 (200mg, 0.43mmol) is dissolved in dichloromethane (5ml), at room temperature according to
Secondary addition N-Boc-L- alanine (85mg, 0.45mmol), dicyclohexylcarbodiimide (106mg, 0.51mmol), 1- hydroxy benzenes
And triazole (65mg, 0.48mmol), sodium carbonate (100mg, 0.94mmol).Room temperature reaction overnight, thin-layer chromatography tracking reaction, shows
Show that consumption of raw materials is complete, filter, dichloromethane (5ml*3) filter wash cake, filtrate is concentrated to give product compound 4e, and (240mg, yellow are solid
Body), yield：87.7%.
MS m/z(ES):637[M+1]
The synthesis of 6th step compound 4
Using known method, compound 4e (240mg, 0.38mmol) is dissolved in dichloromethane (5ml), dripped at room temperature
Enter trifluoroacetic acid (0.5ml), 30 degree are reacted 3 hours, thin-layer chromatography tracking reaction, and display consumption of raw materials is complete.After being concentrated under reduced pressure,
Residue is dissolved in dichloromethane (5ml), and sodium bicarbonate solution is adjusted to alkalescence, liquid separation, and aqueous phase extracts one with dichloromethane (5ml)
It is secondary, merge organic phase, dry, through preparing thin-layer chromatography (dichloromethane after concentration:Methanol=10:1) product compound 4 is purified to obtain
(170mg, faint yellow solid), yield：84.2%.
MS m/z(ES):537[M+1]
1H NMR (300MHz, DMSO) δ 1.14 (d, J=6.6Hz, 3H), 1.52-1.57 (m, 1H), 1.79-1.83 (m,
6H),2.97-3.04(m,1H),3.09-3.17(m,2H),3.29-3.31(m,1H),3.41(s,3H),3.57-3.68(m,
2H),3.86(s,br,2H,NH2), 4.88 (s, 2H), 5.34 (s, 2H), 7.26 (td, J=9.3,2.4Hz, 1H), 7.58 (dd,
J=8.7,2.4Hz, 1H), 7.76 (dd, J=8.7,4.2Hz, 1H), 7.97 (d, J=7.8Hz, 1H).
Test example I：Influence to normal glucose tolerance in mice
Test objective：Study the embodiment compound effect being administered once to glucose tolerance in mice in one week, and with structure homologue
BI 1356 is compared.
1.1.1, test material
(1) medicine
Instrument medicine：Glucose, GC≤99.5%, provided by sigma companies, lot number 101021941, specification 100g/ bottles；
Positive control drug：BI 1356 (linagliptin), auspicious chemical Science and Technology Ltd. is won by Shanghai and provided, specification
2g,
CAT：YRY0687, LCT#：YR120503；
The compound of embodiment 1, provided by Chengdu Yuan Dong Pharma Inc.s study on the synthesis room, pale solid, lot number：
20120925；
The compound of embodiment 2, provided by Chengdu Yuan Dong Pharma Inc.s study on the synthesis room, faint yellow solid, lot number：
20120924；
The compound of embodiment 3, provided by Chengdu Yuan Dong Pharma Inc.s study on the synthesis room, yellow solid, lot number：
20121011；
The compound of embodiment 4, provided by Chengdu Yuan Dong Pharma Inc.s study on the synthesis room, faint yellow solid, lot number：
20121015；
The dosage regimen of effect of the embodiment compound of table 1 to glucose tolerance in mice
(2) test equipment：
FA2204B electronic balances, provided by Shanghai precision instrument scientific instrument Co., Ltd；
METTLER-toledo assay balances, XS-105 types, produced by Mettler Toledo Inc. of Switzerland；
Blood sugar test paper：The full vigor type blood sugar test papers of Luo Kang, specification：50 dresses, lot number 23435532, by Roche Diagnistics' product
(Shanghai) Co., Ltd. provides；
Operating scissors, syringe etc.；
(3) experimental animal：KM mouse, 18~22g of body weight, male and female half and half, carried by Chengdu up to large bio tech ltd
For production facility licensing:SCXK (river) 2008-24.Animal is raised after buying back in Animal House, adaptability observation at least 3 days, inspection
It is used to test after epidemic disease is qualified.
1.1.2, test method：
(1) fasting at least 12 hours before on-test；
(2) it is grouped：To its fasting blood sugar of the mouse assay after fasting, divided according to its result according to table 1 for 6 groups, every group
10, male and female half and half, no difference of science of statistics between group；
(3) it is administered：After being grouped according to table 1, every group of gavage gives corresponding by reagent, and blank group fills the steaming of respective volume
Distilled water；
(4) 168 hours blood-sugar level measurings after being administered：167.5 hours after administration, gavage gives glucose (8g/kg), respectively
Measure gives the blood glucose value of 30min, 60min after glucose；
(5) statistical method：Counted using Excel, test data is represented using (x ± SD), is compared between multigroup
Statistics comparison is carried out using the bilateral T methods of inspection.
1.1.3, result of the test
Effect (5mg/kg, be administered 168 hour, (x ± SD)) of the embodiment compound of table 2 to glucose tolerance in mice
Note：Compared with blank group,*P ＜ 0.05,*P ＜ 0.01；
Compared with positive group,▲P ＜ 0.05,▲▲P ＜ 0.01.
1.1.4, conclusion
As a result show, 168 hours after being administered under 5mg/kg dosage, the compound of embodiment 1, the compound of embodiment 2, implement
The compound of example 3, the compound of embodiment 4 are shown better than positive blood sugar reducing function (P ＜ 0.05), illustrate that the compounds of this invention has
There is long-acting blood sugar reducing function.
Test example II：To DPP-IV active suppression tests in beagle dog bodies
1st, test objective：
Activity suppression of the embodiment compound to DPP IV (DPP-IV) enzyme of normal beagle dogs is observed, and it is right
Its action time carries out pre-test.
2nd, test material
(1) medicine
Positive control drug：BI 1356 (linagliptin), auspicious chemical Science and Technology Ltd. is won by Shanghai and provided, specification
2g, CAT：YRY0687, LCT#：YR120503；
The compound of embodiment 3, provided by Chengdu Yuan Dong Pharma Inc.s study on the synthesis room, yellow solid, lot number：
20121011；
The compound of embodiment 4, provided by Chengdu Yuan Dong Pharma Inc.s study on the synthesis room, faint yellow solid, lot number：
20121015；
Dosage regimen of the embodiment compound of table 3 to beagle dog DPP-IV activity suppressions
(2) test equipment：
Operating scissors, irrigation stomach device, dog fixed mount etc.；
(3) experimental animal：Normal beagle dogs, body weight 10kg, male, weight differences are less than 1kg, reach large biology by Chengdu
Science and Technology Ltd. provides, animal quality certification number：SCXK (river) 2008-24.Animal is raised after buying back to be seen in Animal House, adaptability
Examine at least 3 days, quarantine qualified rear for testing.
3rd, test method：
Fasting at least 12 hours before administration in (1) first day；
(2) it is grouped：Divide according to table 1 for 4 groups, every group 5, no difference of science of statistics between group；
(3) it is administered：After being grouped according to table 1, every group of gavage gives corresponding by reagent, and blank group fills the steaming of respective volume
Distilled water, 0h, 1h, 4h, 7h, 12h, 24h, 48h, 72h, 96h, 120h, 144h, 168h take serum measure DPP-IV work before administration
Property.
4th, assay method
5uL blood serum samples are taken, add 80mM MgCl2Buffer solution 50uL, mix, incubate bath 5 minutes in room temperature in advance, add
10uL0.1mM reaction substrate Gly-Pro-AMC and 40uL buffer solutions, lucifuge, determined after mixing at interval of 3 minutes row first order fluorescences
(excitation wave 380nm/ transmitted wave 460nm), until 18 minutes, survey 6 times altogether ,-fluorescent value curve done the time according to measurement result,
It is energy value to obtain slope, and using serum DPPIV energy values before administration as 100%, each time point blood after being administered is calculated by following equation
Clear DPPIV Rate activity value.
Energy value × 100% before energy value/administration after Rate activity value (%)=administration
5th, statistical method：Counted using Excel, test data is represented using (x ± SD), is compared between multigroup and is adopted
Statistics comparison is carried out with the bilateral T methods of inspection.
6th, result of the test
Inhibitory action (x ± SD) of the embodiment compound of table 4 to beagle dogs DPP-IV activity
| Time (h) after administration | Blank group | Positive group | The compound group of embodiment 3 | The compound group of embodiment 4 |
| 0 | 100.0 | 100.0 | 100.0 | 100.0 |
| 1 | 91.0±2.1 | 9.7±0.5* | 10.3±2.6* | 9.3±1.5* |
| 4 | 92.1±1.8 | 12.4±1.9** | 14.5±2.4* | 11.9±1.8* |
| 7 | 93.9±3.6 | 14.5±1.7** | 15.9±2.1* | 13.7±2.2* |
| 12 | 95.5±4.1 | 17.5±3.4** | 19.1±6.1* | 16.8±5.2* |
| 24 | 98.2±3.8 | 98.2±3.8 | 23.5±7.3* | 19.5±4.5* |
| 48 | 101.2±3.9 | 21.3±10.9* | 25.3±10.6* | 20.3±9.5* |
| 72 | 103.5±4.6 | 40.5±9.5* | 39.5±9.7* | 24.5±9.3* ▲ |
| 96 | 102.7±5.4 | 45.1±15.6** | 45.8±15.4* | 29.7±10.4* ▲ |
| 120 | 103.3±4.9 | 56.1±15.9* | 47.1±15.5* | 30.1±14.5* ▲ ▲ |
| 144 | 105.4±4.2 | 68.9±19.8* | 49.5±16.5* ▲ | 34.5±12.8* ▲ ▲ |
| 168 | 107.0±5.1 | 107.0±5.1 | 52.5±18.8* ▲ | 39.5±13.8* ▲ ▲ |
Note：Compared with blank group,*P ＜ 0.05 '*P ＜ 0.01；
Compared with positive group,▲P ＜ 0.05,▲▲P ＜ 0.01.
The above results show that compound of the embodiment of the present invention shows good DPP-IV inhibitory activity, the chemical combination of embodiment 4
Thing 144h after 96h and the administration of the compound of embodiment 3 upon administration, and positive group compared and have significant difference (P ＜ 0.05), to
The suppression of DPP-IV activity still reaches 50%, DPP-IV inhibiting rates after medicine 168h>It is longer than positive drug on 50% time, can expires
Foot is administered once for one week.
Show that compound of the embodiment of the present invention shows long-acting blood sugar reducing function according to the above results, for the general of this area
For logical technical staff it is apparent that in the spirit or scope without departing from the present invention, can to the compounds of this invention, composition with
And a variety of modification and transformations that method is carried out, therefore, the present invention includes the modification and transformation to the present invention, as long as in claim
With its in equivalent scope.
Claims (1)
1. compound as follows：
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| CN1675212A (en) * | 2002-08-21 | 2005-09-28 | 贝林格尔英格海姆法玛两合公司 | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
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| CN1675212A (en) * | 2002-08-21 | 2005-09-28 | 贝林格尔英格海姆法玛两合公司 | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
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| CN106008507A (en) | 2016-10-12 |
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