CN103936737B - Xanthine derivative - Google Patents
Xanthine derivative Download PDFInfo
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- CN103936737B CN103936737B CN201310024815.9A CN201310024815A CN103936737B CN 103936737 B CN103936737 B CN 103936737B CN 201310024815 A CN201310024815 A CN 201310024815A CN 103936737 B CN103936737 B CN 103936737B
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- Prior art keywords
- hydrogen atom
- independently selected
- straight
- branched alkyl
- compound
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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 43
- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 claims abstract description 25
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 claims abstract description 25
- 239000003814 drug Substances 0.000 claims abstract description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 8
- 201000010099 disease Diseases 0.000 claims abstract description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 40
- 125000000217 alkyl group Chemical group 0.000 claims description 34
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 20
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 125000001153 fluoro group Chemical group F* 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 5
- 125000001246 bromo group Chemical group Br* 0.000 claims description 4
- 208000002705 Glucose Intolerance Diseases 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 201000009104 prediabetes syndrome Diseases 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims 2
- 229910052740 iodine Inorganic materials 0.000 claims 2
- 239000011630 iodine Substances 0.000 claims 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 238000012360 testing method Methods 0.000 abstract description 20
- 230000001629 suppression Effects 0.000 abstract description 8
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 abstract description 4
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 abstract description 4
- 230000002401 inhibitory effect Effects 0.000 abstract description 2
- 150000001720 carbohydrates Chemical class 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 43
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 239000000047 product Substances 0.000 description 24
- 239000007787 solid Substances 0.000 description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
- 238000004809 thin layer chromatography Methods 0.000 description 20
- 230000015572 biosynthetic process Effects 0.000 description 19
- 238000001819 mass spectrum Methods 0.000 description 19
- 238000003786 synthesis reaction Methods 0.000 description 19
- 238000000034 method Methods 0.000 description 18
- 108010088406 Glucagon-Like Peptides Proteins 0.000 description 14
- 230000000694 effects Effects 0.000 description 13
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 11
- 239000008103 glucose Substances 0.000 description 11
- 239000000376 reactant Substances 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 210000004369 blood Anatomy 0.000 description 10
- 239000008280 blood Substances 0.000 description 10
- 239000002994 raw material Substances 0.000 description 10
- 229920006395 saturated elastomer Polymers 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 238000000746 purification Methods 0.000 description 8
- 235000002639 sodium chloride Nutrition 0.000 description 8
- 239000011780 sodium chloride Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 208000035126 Facies Diseases 0.000 description 7
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 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
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- 239000000243 solution Substances 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
- 206010012601 diabetes mellitus Diseases 0.000 description 5
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- 238000003756 stirring Methods 0.000 description 5
- -1 sulfydryl Chemical group 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
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- 229940079593 drug Drugs 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 102000004877 Insulin Human genes 0.000 description 3
- 108090001061 Insulin Proteins 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 229940125396 insulin Drugs 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
- 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 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
- FOLCUFKJHSQMEL-BIXPGCQOSA-N (4-butylcyclohexyl) N-[(2S)-4-methyl-1-oxo-1-[[(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]pentan-2-yl]carbamate Chemical compound CCCCC1CCC(CC1)OC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C[C@@H]2CCNC2=O)C=O FOLCUFKJHSQMEL-BIXPGCQOSA-N 0.000 description 2
- UXKLQDCALAWFIU-VKNDCNMPSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-tetradecoxy-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](O)[C@H](C(O2)(C(O)=O)C(O)(C(O1)C(O)=O)C(O)=O)OCCCCCCCCCCCCCC)C1=CC=CC=C1 UXKLQDCALAWFIU-VKNDCNMPSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- QLVGHFBUSGYCCG-UHFFFAOYSA-N 2-amino-n-(1-cyano-2-phenylethyl)acetamide Chemical compound NCC(=O)NC(C#N)CC1=CC=CC=C1 QLVGHFBUSGYCCG-UHFFFAOYSA-N 0.000 description 2
- XNMQEEKYCVKGBD-UHFFFAOYSA-N 2-butyne Chemical compound CC#CC XNMQEEKYCVKGBD-UHFFFAOYSA-N 0.000 description 2
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
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- 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
- 238000007865 diluting Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000009826 distribution Methods 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
- 238000009207 exercise therapy Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 108010043293 glycyl-prolyl-glycyl-glycine Proteins 0.000 description 1
- 229910052739 hydrogen Inorganic materials 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
- 238000000338 in vitro Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002207 metabolite Substances 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
- 239000013642 negative control Substances 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 229940127017 oral antidiabetic Drugs 0.000 description 1
- 239000003538 oral antidiabetic agent Substances 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 206010036067 polydipsia Diseases 0.000 description 1
- 208000022530 polyphagia Diseases 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 description 1
- 229960004034 sitagliptin Drugs 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- BXHWWPNRUOHACS-MRVPVSSYSA-N tert-butyl (3r)-1-aminopiperidine-3-carboxylate Chemical class CC(C)(C)OC(=O)[C@@H]1CCCN(N)C1 BXHWWPNRUOHACS-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
- 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
- 239000012224 working solution Substances 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 Table
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses class xanthine derivative and an isomer, tested and external DPP IV active suppression test by the impact of normal mouse carbohydrate tolerance, the compounds of this invention demonstrates the DPP IV inhibitory activity of excellence, it is possible to for preparing the purposes in the disease medicament that treatment is relevant to dipeptidyl peptidase IV.
Description
Technical field
The present invention relates to medicinal chemistry art, be specifically related to a class xanthine derivative, its preparation method and derivant thereof
As the medicine being administered once for a week especially as the purposes of DPP IV (DPP-IV) inhibitor.
Background technology
Diabetes are the metabolic diseases of a kind of multi-pathogenesis, are characterized in chronic hyperglycemia, with because of insulin secretion and/or
Sugar, fat and the protein metabolism disorder that effect defect causes.Diabetes are also the most ancient a kind of diseases, are due to human body
In the blood that interior insulin relatively or definitely lacks and causes, concentration of glucose raises, and causes sugar to be discharged from urine in a large number, and adjoint
Polydipsia, polyuria, polyphagia, become thin, the symptom such as dizzy, weak.
In treating diabetes, exercise therapy and dietetic therapy are two kinds of requisite diabetes remedies.When this
When two kinds of therapies are not enough to symptom management, it is possible to use insulin or oral antidiabetic drug.But owing to these hypoglycemic medicines exist
A lot of side effect, develop a kind of novel, low side effect and can effectively to treat the medicine of diabetes particularly important.
DPP IV (DPP-IV) is a kind of serine protease, and it is residual that it can contain a proline at secondary end
N-end dipeptidase is cracked, although the physiological action of mammal is demonstrate,proved by (DPP-IV) the most completely in the peptide chain of base
Real, but it is at neural enzymes metabolism, T-cell-stimulating, and cancer cell metastasis enters endothelium and inhibition of HIV enters lymphoid cell process
In all play very important effect (WO98/19998).
There are some researches show that (DPP-IV) can stop the secretion of glucagon like peptide (GLP)-1, N-end in cracking (GLP)-1
Group-the third dipeptidase of end so that it is be degraded to inactive (GLP)-1 (7-36) amide from (GLP)-1 of activity form and be degraded to
Inactive (GLP)-1 (9-36) amide Endocrinology, 1999,140:5356-5363).Under physiological conditions, circulation
In blood, the half-life of complete (GLP)-1 is the shortest, and the inactive metabolite after DPP-IV is degraded to (GLP)-1 can be subject to (GLP)-1
Body combines antagonistic activity (GLP)-1 thus shortens the physiological reaction to (GLP)-1, and (DPP-IV) inhibitor can be protected completely
The most ectogenic (GLP)-1 of endogenous is not inactivated by (DPP-IV), improves the physiologically active (5-10 of (GLP)-1 greatly
Times), owing to the secretion of (GLP)-1 pair of pancreatic insulin is an important stimulator the distribution that can directly affect glucose,
Therefore well effect (US6110949) is played in the treatment of non-insulin-dependent diabetes mellitus example by DPP-IV inhibitor.
Although having had listed several DPP-IV inhibitor at present, such as phosphoric acid sitagliptin, vildagliptin, benzoic acid Ah lattice
Row spit of fland etc., but be one day and be administered once, in order to increase the compliance of patient, the DPP-IV suppression needing be administered once for a week
, the most still there is the demand to new long-acting DPP-IV inhibitor in agent.
Summary of the invention
The present invention relates to xanthine substitutive derivative and preparation method thereof and in application pharmaceutically, particularly lead to formula (I)
Shown xanthine substitutive derivative or its all of stereoisomer, and special as the therapeutic agent being administered once for a week
It it is the activity inhibition for 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, atomic iodine, amino or cyano group；
R2It is independently selected from hydrogen atom ,-SO2R4、-PO(OR4)2、-COCHR5R6、-COOR7Or-CONHR7；
R4For hydrogen atom, metal ion or C1-C5On straight or branched alkyl, and this alkyl, any hydrogen atom is permissible
Replaced by hydroxyl, sulfydryl, amino；Wherein metal ion is alkali metal ion or alkaline-earth metal ions；
R5For hydrogen atom or C1-C5On straight or branched alkyl, and this alkyl, any hydrogen atom can be by hydroxyl, sulfydryl, ammonia
Base replaces；
R6For hydroxyl, sulfydryl, amino or C1-C5On straight or branched alkyl, and this alkyl, any hydrogen atom can be by hydroxyl
Base, sulfydryl, amino replace；
R7For C1-C5Straight or branched alkyl, wherein, C1-C5On straight or branched alkyl any hydrogen atom can by hydroxyl,
Sulfydryl, amino replace；
R3It is independently selected from hydrogen atom, methyl, ethyl or acetyl group；
A is independently selected from N or CH.
Further, the present invention leads to formula (I) compound, wherein:
R1It is independently selected from hydrogen atom, fluorine atom or chlorine atom；
R2It is independently selected from hydrogen atom ,-SO2R4、-PO(OR4)2Or-COCHR5R6；
R4For hydrogen atom, C1-C3Straight or branched alkyl；
R5For hydrogen atom or C1-C5Straight or branched alkyl, wherein C1-C5On straight or branched alkyl, any hydrogen atom can enter
One step is replaced by hydroxyl or amino；
R6For hydroxyl, amino or C1-C3Straight or branched alkyl, wherein C1-C3Any hydrogen atom on straight or branched alkyl
Can be replaced by hydroxyl or amino further；
R3It is independently selected from hydrogen atom, methyl or ethyl；
A is independently selected from N or CH.
Further, the present invention leads to formula (I) compound, wherein:
R1It is independently selected from fluorine atom or chlorine atom；
R4For hydrogen atom or C1-C3Straight chained alkyl；
R5For hydrogen atom or C1-C4Straight or branched alkyl, wherein C1-C4On straight or branched alkyl, any hydrogen atom can enter
One step is replaced by hydroxyl or amino；
R6For hydroxyl or amino；
R3It is independently selected from hydrogen atom or methyl；
A is independently selected from N or CH.
Also include additionally, the present invention leads to the compound shown in formula (I) structure:
R1It is independently selected from hydrogen atom, fluorine atom, chlorine atom, bromine atoms, atomic iodine, amino or cyano group；
R2It is independently selected from-COCHR5R6；R5、R6For different substituents；And R5For C1-C4Straight or branched alkyl, wherein
C1-C4When on straight or branched alkyl, any hydrogen atom can be replaced by hydroxyl or amino further, with R5、R6The chiral carbon connected
Atom can be the mix-configuration of R, S or R and S；
R3It is independently selected from hydrogen atom, methyl, ethyl or acetyl group；
A is independently selected from N or CH.
Preferably the compounds of this invention, but be not limited to:
Compound described in formula of the present invention and the preparation method of stereoisomer thereof, comprise the following steps:
Under the conditions of room temperature (10 ~ 25 DEG C), bromo-with 1-for bromo-for initiation material 8-3-methylxanthine 2-butyne is reacted, raw
It is anti-with (R)-3-t-butoxycarbonyl amino piperidines that the product a become is substituted reaction generation product c, intermediate c further with raw material b
D, intermediate d should be generated and obtain compound e after sloughing Boc protection group in acid condition, by e and R2-X(wherein R2For SO2R4、
PO(OR4)2、COCHR5R6、COOR7Or CONHR7, X is halogen or hydroxyl) and generate compound f, f and R after substitution reaction3-X(its
In, R3For methyl, ethyl or acetyl group, X is halogen or hydroxyl) reaction generation product g.If raw material R2R in-X2For SO2R4Or PO
(OR4)2, after the product hydrolysis of generation, just obtain R4Corresponding product for hydrogen atom.If raw material R2R in-X2Containing blocking group, raw
The product become sloughs protection further, i.e. can get target compound.
The invention discloses the compound described in formula 1 compound and stereoisomer at preparation treatment and dipeptidyl peptidase
Purposes in IV relevant disease, be further treatment type Ⅱdiabetes mellitus or impaired glucose tolerance disease medicament in purposes and
Purposes in preparation treatment diabetic complication relevant disease.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described in further detail, but not limitation of the present invention, all according to
The equivalent 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, NMR (1HNMR) determine；
Nuclear magnetic resonance, NMR (1HNMR) displacement (δ) is given with the unit of 1/1000000th (ppm)；
Nuclear magnetic resonance, NMR (1HNMR) mensuration is to use BrukerAVANCE-300 nuclear magnetic resonance spectrometer, and measuring solvent is six deuterated diformazans
Base sulfoxide (DMSO-d6), inside it being designated as tetramethylsilane (TMS), chemical shift is with 10-6(ppm) be given as unit；
The mensuration FINNIGAN LCQAd(ESI of mass spectrum (MS)) mass spectrograph (manufacturer: Therm, model: Finnigan
LCQ advantage MAX)；
Thin layer silica gel uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plate；
IC50The mensuration envision(PerkinElmer company of value)；
It is carrier that column chromatography generally uses Yantai Huanghai Sea silica gel 200-300 mesh silica gel；
Without specified otherwise in embodiment, reaction is carried out the most under nitrogen atmosphere；
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 aqueous solution；
In embodiment, room temperature refers to the ambient temperature of 10 to 25 degrees Celsius.
Embodiment 1
The synthesis of first step compound 1a
Use known method, bromo-for 8-3-methylxanthine (20g, 81.6mmol) be dissolved in DMF(120ml) in, add
DIPEA (15.8g, 122.4mmol), the bromo-2-butyne of 1-(10.9g, 81.6mmol), room temperature reaction is overnight, thin
Layer chromatography follows the tracks of reaction process, after reaction completely, is poured into water by reactant liquor, sucking filtration, and solid is washed 3 times, is dried to obtain commercialization
Compound 1a(20.8g, faint yellow solid), yield: 85.5%.
MS m/z (ES): 297,299 [M+1]
The synthesis of second step compound 1b
Use known method, by 1a(5g, 16.8mmol) it is dissolved in DMF(30ml) in, add DBU(3.8g,
25.2mmol), compound b(5.8g, 17.6mmol), room temperature reaction is overnight.Thin layer chromatography follows the tracks of reaction process, and reaction is completely
After, reactant liquor is poured into water, sucking filtration, solid is washed 3 times, is dried to obtain product compound 1b(8.3g, yellow solid), yield:
90.5%。
MS m/z (ES): 545,547 [M+1]
The synthesis of the 3rd step compound 1c
Use known method, by 1b(8.3g, 15.2mmol) it is dissolved in DMF(50ml) in, add (R)-3-tertiary butyloxycarbonyl
Base amino piperidine (3.3g, 16.7mmol), potassium carbonate (4.2g, 30.4mmol), be warming up to 75 DEG C and react 2 hours.Thin layer chromatography
Following the tracks of reaction process, after reaction completely, be poured into water by reactant liquor, sucking filtration, solid is washed 3 times, is dried to obtain product compound 1c
(8.1g, yellow solid), yield: 80.3%.
MS m/z(ES):665[M+1]
The synthesis of the 4th step compound 1
Use known method, by 1c(8.1g, 12.2mmol) it is dissolved in DCM(100ml) in, instill TFA(15ml), drip
Complete room temperature reaction is overnight.Thin layer chromatography follows the tracks of reaction process, after reaction completely, is concentrated to dryness by reactant liquor, adds DCM
(50ml), stirring is cooled to about 0 DEG C, instills saturated NaHCO3Solution, regulates pH ≈ 8, and separatory, aqueous phase extracts with appropriate DCM
Twice, organic facies merges, and crosses post (DCM:MeOH=10:1) purification, obtain product compound 1(4.7g after being concentrated to dryness, and yellow is solid
Body), yield: 82.8%.
MS m/z(ES):465[M+1]
1H NMR(300MHz,DMSO)δ1.69-1.72(m,2H),1.80(s,3H),1.94-2.03(m,2H),2.93–
3.00(m,1H),3.10–3.13(m,2H),3.40(s,3H),3.53–3.73(m,2H),4.92(s,2H),5.43(s,2H),
7.01-7.09(m,1H),7.30(dd,J=2.6,9.2Hz,1H),7.51-7.55(m,1H),8.21(s,br,1H)。
Embodiment 2
The first step is with embodiment 1 first step；
Second step is with embodiment 1 second step；
3rd step is with embodiment 1 the 3rd step；
4th step is with embodiment 1 the 4th step；
The synthesis of the 5th step compound 2
Use known method, by 1(500mg, 1.08mmol) it is dissolved in DCM(10ml) in, addition triethylamine (217mg,
2.15mmol), under stirring, instill methane sulfonyl chloride (135mg, 1.18mmol), drip complete room temperature reaction overnight.Thin layer chromatography is followed the tracks of
Reaction, consumption of raw materials completely after, reactant liquor saturated aqueous common salt washes twice, and organic facies concentrates, prepare thin layer chromatography (DCM:
MeOH=10:1) purification, obtains product compound 2(261mg, yellow solid), yield: 44.4%.
MS m/z(ES):543[M+1]
1H NMR(300MHz,DMSO)1.46-1.52(m,1H),1.67-1.73(m,1H),1.80(s,3H),1.90-
1.98(m,2H),2.89(s,3H),3.05-3.10(m,3H),3.41(s,3H),3.56-3.61(m,1H),3.73-3.77(m,
1H),4.90(s,2H),5.42(s,2H),7.02-7.10(m,1H),7.28-7.36(m,2H),7.51-7.55(m,1H),
8.10(s,br,H,)。
Embodiment 3
The first step is with embodiment 1 first step；
Second step is with embodiment 1 second step；
3rd step is with embodiment 1 the 3rd step；
4th step is with embodiment 1 the 4th step；
The synthesis of the 5th step compound 3d
Use known method, by 1(500mg, 1.08mmol) it is dissolved in DCM(10ml) in, add DCC(268mg,
1.3mmol), HOBT(146mg, 1.08mmol), K2CO3(224mg, 1.62mmol), N-Boc-L-alanine (204mg,
1.08mmol), room temperature reaction is overnight.Thin layer chromatography follows the tracks of reaction, and display consumption of raw materials is complete.Sucking filtration, with appropriate DCM washing filter
Cake, filtrate is concentrated to dryness and obtains product compound 3d(412mg, yellow solid), yield: 60.2%.
MS m/z(ES):636[M+1]
The synthesis of the 6th step compound 3
Use known method, by 3d(412mg, 0.65mmol) it is dissolved in DCM(10ml) in, instill TFA(1ml), drip and finish
Overnight, thin layer chromatography follows the tracks of reaction to room temperature reaction, and display consumption of raw materials is complete.Reactant liquor is concentrated to dryness, and adds 10mlDCM, stirs
Mix and be cooled to about 0 DEG C, instill saturated NaHCO3Solution, regulates pH ≈ 8, separatory, and aqueous phase is extracted twice with appropriate DCM, merges
Organic facies, is concentrated to dryness, and residue, with preparing thin layer chromatography (DCM:MeOH=10:1) purification, obtains product compound 3
(294mg, yellow solid), yield: 84.6%.
MS m/z(ES):536[M+1]
1H NMR (300MHz, DMSO) δ 1.13 (d, J=6.8Hz, 3H), 1.53-1.59 (m, 1H), 1.78-1.95 (m,
6H),2.98-3.17(m,2H),3.22-3.30(m,1H),3.42(s,3H),3.56-3.68(m,3H),3.88(s,br,2H),
4.91(s,2H),5.44(s,2H),7.07-7.13(m,1H),7.01-7.09(m,1H),7.29(dd,J=2.7,9.3Hz,
1H),7.51-7.56(m,1H),7.92(d,J=7.3Hz,1H),8.52(s,br,1H)。
Embodiment 4
The first step is with embodiment 1 first step；
The synthesis of second step compound 4b
Use known method, by 1a(5g, 16.8mmol) it is dissolved in DMF(30ml) in, add DBU(3.8g,
25.2mmol), compound c(5.8g, 17.6mmol), room temperature reaction is overnight.Thin layer chromatography follows the tracks of reaction process, and reaction is completely
After, reactant liquor is poured into water, sucking filtration, solid is washed 3 times, is dried to obtain product compound 4b(8.1g, yellow solid), yield:
89%。
MS m/z (ES): 544,546 [M+1]
The synthesis of the 3rd step compound 4c
Use known method, by 4b(8.1g, 14.9mmol) it is dissolved in DMF(50ml) in, add (R)-3-tertiary butyloxycarbonyl
Base amino piperidine (3.3g, 16.4mmol), potassium carbonate (4.1g, 29.8mmol), be warming up to 75 DEG C and react 2 hours.Thin layer chromatography
Following the tracks of reaction process, after reaction completely, be poured into water by reactant liquor, sucking filtration, solid is washed 3 times, is dried to obtain product compound 4c
(9.1g, yellow solid), yield: 91.9%.
MS m/z(ES):664[M+1]
The synthesis of the 4th step compound 4
Use known method, by 4c(9.1g, 13.7mmol) it is dissolved in DCM(100ml) in, instill TFA(15ml), drip and finish
Room temperature reaction is overnight.Thin layer chromatography follows the tracks of reaction process, after reaction completely, is concentrated to dryness by reactant liquor, adds DCM(50ml),
Stirring is cooled to about 0 DEG C, instills saturated NaHCO3Solution, regulates pH ≈ 8, and separatory, aqueous phase is extracted twice with appropriate DCM, has
Machine merges mutually, crosses post (DCM:MeOH=10:1) purification, obtain product chemical combination after being concentrated to dryness
Thing 4(5.5g, yellow solid), yield: 86.9%.
MS m/z(ES):464[M+1]
1H NMR(300MHz,DMSO)δ1.68-1.72(m,2H),1.81(s,3H),1.93-2.02(m,2H),2.85–
2.90(m,1H),2.95–3.16(m,2H),3.42(s,3H),3.52–3.73(m,2H),4.94(s,2H),5.44(s,2H),
6.24 (s, 1H), 6.76-6.84 (m, H), 7.04 (m, 1H), 7.41-7.47 (m, 1H), 8.53 (s, b r, 1H).
Embodiment 5
The first step is with embodiment 1 first step；
Second step is with embodiment 4 second step；
3rd step is with embodiment 4 the 3rd step；
4th step is with embodiment 4 the 4th step；
The synthesis of the 5th step compound 5d
Use known method, by 4(500mg, 1.08mmol) it is dissolved in DCM(10ml) in, addition triethylamine (218mg,
2.16mmol), it is cooled to about 0 DEG C, instills diethyl chloro-phosphate (205mg, 1.12mmol), drip and finish that to warm naturally to room temperature anti-
Should be overnight.Thin layer chromatography follows the tracks of reaction, and after consumption of raw materials is complete, reactant liquor saturated aqueous common salt washes twice, organic facies nothing
Water magnesium sulfate is dried, sucking filtration, with preparing thin layer chromatography (DCM:MeOH=10:1) purification after filtrate concentration, obtains product compound 5d
(334mg, yellow solid), yield: 51.7%.
MS m/z(ES):600[M+1]
The synthesis of the 6th step compound 5
Use known method, by 5d(334mg, 0.56mmol) it is dissolved in DMF(5ml) in, addition potassium carbonate (155mg,
1.12mmol), iodomethane (88mg, 0.62mmol), room temperature reaction is overnight.Thin layer chromatography follows the tracks of reaction, after consumption of raw materials is complete,
Adding 50ml saturated aqueous common salt, be extracted twice with appropriate EA, separatory, organic facies is dried after washing with appropriate saturated aqueous common salt, mistake
Filter, with preparing thin layer chromatography (DCM:MeOH=10:1) purification after filtrate concentration, obtains product compound 5(303.6mg, and yellow is solid
Body), yield: 89.3%.
MS m/z(ES):614[M+1]
1H NMR(300MHz,DMSO)δ1.22-1.26(m,6H),1.40-1.45(m,1H),1.63-1.66(m,1H),
1.77(s,3H),1.88-1.94(m,2H),2.95-3.03(m,2H),3.14-3.20(m,1H),3.40(s,3H),3.58-
3.63(m,1H),3.67(s,3H),3.70-3.74(m,1H),3.91-3.96(m,4H),4.90(s,2H),5.08-5.14(m,
1H), 5.32 (s, 2H), 6.24 (s, 1H), 6.76-6.84 (m, H), 7.04 (m, 1H), 7.41-7.47 (m, 1H).
Embodiment 6
The first step is with embodiment 1 first step；
Second step is with embodiment 4 second step；
3rd step is with embodiment 4 the 3rd step；
4th step is with embodiment 4 the 4th step；
The synthesis of the 5th step compound 6d
Use known method, by 4(500mg, 1.08mmol) it is dissolved in DCM(10ml) in, add DCC(268mg,
1.3mmol), HOBT(146mg, 1.08mmol), K2CO3(224mg, 1.62mmol), N-Boc-L-alanine (204mg,
1.08mmol), room temperature reaction is overnight.Thin layer chromatography follows the tracks of reaction, and display consumption of raw materials is complete.Sucking filtration, with appropriate DCM washing filter
Cake, filtrate is concentrated to dryness and obtains product compound 6d(402mg, yellow solid), yield: 58.3%.
MS m/z(ES):635[M+1]
The synthesis of the 6th step compound 6e
Use known method, by 6d(402mg, 0.63mmol) it is dissolved in DMF(5ml) in, addition potassium carbonate (174mg,
1.26mmol), iodomethane (98mg, 0.69mmol), room temperature reaction is overnight.Thin layer chromatography follows the tracks of reaction, and consumption of raw materials is complete
After, adding 50ml saturated aqueous common salt, be extracted twice with appropriate EA, separatory, organic facies is dried after washing with appropriate saturated aqueous common salt,
Filtering, with preparing thin layer chromatography (DCM:MeOH=10:1) purification after filtrate concentration, obtain product compound 6e(353mg, yellow is solid
Body), yield: 85.7%.
MS m/z(ES):649[M+1]
The synthesis of the 7th step compound 6
Use known method, by 6e(353mg, 0.54mmol) it is dissolved in DCM(5ml) in, instill TFA(1ml), drip complete room
Temperature reaction is overnight.Thin layer chromatography follows the tracks of reaction process, after reaction completely, is concentrated to dryness by reactant liquor, adds DCM(5ml), stirring
It is cooled to about 0 DEG C, instills saturated NaHCO3Solution, regulates pH ≈ 8, and separatory, aqueous phase is extracted twice with appropriate DCM, organic facies
Merge, cross post (DCM:MeOH=10:1) purification after being concentrated to dryness, obtain product compound 6(235mg, yellow solid), yield:
79.6%。
MS m/z(ES):549[M+1]
1H NMR (300MHz, DMSO) δ 1.12 (d, J=6.8Hz, 3H), 1.52-1.58 (m, 1H), 1.78-1.95 (m,
6H),2.97-3.16(m,2H),3.22-3.29(m,1H),3.41(s,3H),3.56-3.64(m,3H),3.68(s,3H),
3.86 (s, br, 2H), 4.89 (s, 2H), 5.45 (s, 2H), 6.25 (s, 1H), 6.75-6.84 (m, H), 7.04 (m, 1H),
7.40-7.47(m,1H),7.92(d,J=7.9Hz,1H)。
Test example 1: external DPP-IV active suppression test
1, test objective:
Observe the sample activity suppression to DPP IV (DPP-IV) enzyme, to evaluate the inhibition of sample.
2, test material:
2.1, DPP IV (DPP-IV): SIGMA product, article No. D4943-1VL.
2.2, substrate: Gly-Pro-7-amido-4-methylcoumarin solution: SIGMA product, article No. G2761-
25mg,FW=41.03。
2.3, DPP-IV Buffer: containing 25mM Hepes, 140mM NaCl, 1%BSA, 80mM MgCl2, adjusting pH is 8.0.
2.4, positive control drug: BI 1356 (linagliptin), Shanghai winning auspicious chemistry Science and Technology Ltd. provides,
Specification 2g, CAT:YRY0687, LCT#:YR120503；DMSO is dissolved as 10mM liquid storage, and working solution distilled water diluting is 10uM,
Final concentration of 1uM.
2.5, detecting instrument: envision(PerkinElmer company)
3, test principle:
Dipeptidyl peptidase IV (DPP-IV) at room temperature hydrolyzable Gly-Pro-7-amido-4-methylcoumarin
Hydrobromide, generates 7-amido-4-methyl coumarin(7-amino-4-methylcoumarin), this material is at 355nm
Under excitation wavelength, the fluorescence of 460nm wavelength can be launched, by the activity of detection product amount change reflection enzyme.
4, test method:
Containing DPP-IV(Sigma in 200 μ L reaction systems), 25mM HEPES buffer (containing 140mM NaCl, 1%BSA,
80mM MgCl2) and testing sample, set up blank (without enzyme and sample) and negative control (without sample), room temperature simultaneously
Reaction 10min, adds dipeptidyl peptidase IV substrate GLY-PRO-GLY-GLY, room temperature reaction 30min, measures fluorescence intensity F, swashs
Send out wavelength 355nm, launch wavelength 460nm.Suppression ratio is calculated according to fluorescence intensity F value, suppression ratio=[1-(F sample-F is blank)/
(F feminine gender-F is blank)] × 100.During primary dcreening operation, each sample list concentration sets duplicate hole, and the suppression ratio sample more than 70% carries out false sun
Property get rid of test, confirm as positive mensuration IC50Value, six concentration of each sample gradient dilution during mensuration, each concentration sets double
Multiple hole.According to suppression ratio, the 4Parameter Logistic Model in application Xlfit software calculates IC50。
5, result of the test: the compounds of this invention IC50Determination data is as follows:
According to above-described embodiment compound in vitro tests data to DPP-IV enzyme inhibition activity, and positive drug ratio
Relatively, embodiment of the present invention compound has significant DPP-IV inhibitory activity.
Test example II: the impact on normal glucose tolerance in mice
Test objective: research embodiment compound is administered once the effect to glucose tolerance in mice, and and analog for one week
BI 1356 compares.
1.1.1, test material
(1) medicine
Instrument medicine: glucose, GC 99.5%, sigma company provide, lot number 101021941, specification 100g/ bottle；
Positive control drug: BI 1356 (linagliptin), Shanghai winning auspicious chemistry Science and Technology Ltd. provides, specification
2g, CAT:YRY0687, LCT#:YR120503；
Embodiment 1 compound, is provided by Yuan Dong Pharma Inc. study on the synthesis room, Chengdu, pale solid, lot number:
20120929；
Embodiment 3 compound, is provided by Yuan Dong Pharma Inc. study on the synthesis room, Chengdu, faint yellow solid, lot number:
20120827；
Embodiment 5 compound, is provided by Yuan Dong Pharma Inc. study on the synthesis room, Chengdu, yellow solid, lot number:
20121015；
Embodiment 6 compound, is provided by Yuan Dong Pharma Inc. study on the synthesis room, Chengdu, faint yellow solid, lot number:
20121015；
The table 1 embodiment compound dosage regimen to the effect of glucose tolerance in mice
(2) test equipment:
FA2204B electronic balance, is provided by Shanghai precision instrument scientific instrument company limited；
METTLER-toledo analytical balance, XS-105 type, Mettler Toledo Inc. of Switzerland produce；
Blood sugar test paper: Luo Kang full vigor type blood sugar test paper, specification: 50 dresses, lot number 23435532, by Roche Diagnistics's product
(Shanghai) Co., Ltd. provides；
Operating scissors, syringe etc.；
(3) experimental animal: KM mice, body weight 18～22g, male and female half and half, Da Shuo bio tech ltd, Chengdu carry
Confession, production facility licence: SCXK (river) 2008-24.Animal is raised after buying back in Animal House, adaptability observation at least 3 days, inspection
It is used for testing after epidemic disease is qualified.
1.1.2, test method:
(1) fasting at least 12 hours before on-test；
(2) packet: to its fasting blood sugar of the mouse assay after fasting, be divided into 6 groups according to its result according to table 1, often group
10, male and female half and half, no difference of science of statistics between group；
(3) being administered: after being grouped according to table 1, often group gavage gives accordingly by reagent, and blank group fills the steaming of respective volume
Distilled water；
(4) 168 hours blood glucose pH-value determination pHs after being administered: being administered latter 167.5 hours, gavage gives glucose (8g/kg), respectively
Measure and give the blood glucose value of 30min, 60min after glucose；
(5) statistical method: use Excel to add up, test data uses (x ± SD) to represent, compares between many groups
Use the bilateral T method of inspection to carry out statistics to compare.
1.1.3, result of the test
The effect statistical result (5mg/kg is administered 168 hours, (x ± SD)) to glucose tolerance in mice of the table 2 embodiment compound
Note: compared with blank group,*P ＜ 0.05,*P ＜ 0.01；
Compared with positive group,▲P ＜ 0.05.
1.1.4, conclusion
Result shows, is administered latter 168 hours under 5mg/kg dosage, embodiment 1 compound, embodiment 3 compound, enforcement
Example 5 compound, embodiment 6 compound all show the blood sugar reducing function (P ＜ 0.05) being better than the positive, wherein embodiment 3 compound
Effect best, illustrate that the compounds of this invention has long-acting blood sugar reducing function.
Show that embodiment of the present invention compound demonstrates long-acting blood sugar reducing function according to the above results, general for this area
Be apparent that in the spirit or scope without departing from the present invention for logical technical staff, can to the compounds of this invention, compositions with
And the multiple modification and transformation that method is carried out, therefore, the present invention comprises the modification and transformation to the present invention, as long as in claim
In the range of its equivalent.
Claims (7)
1. the compound shown in formula I:
Wherein: R1It is independently selected from fluorine atom, chlorine atom, bromine atoms, atomic iodine；
R2It is independently selected from hydrogen atom ,-SO2R4、-PO(OR4)2、-COCHR5R6；
R4For C1_C5Straight or branched alkyl, wherein C1_C5On straight or branched alkyl any hydrogen atom can further by hydroxyl,
Sulfydryl or amino replace；
R5For C1_C5Straight or branched alkyl, wherein C1_C5On straight or branched alkyl any hydrogen atom can further by hydroxyl,
Sulfydryl or amino replace；
R6For amino or C1_C5Straight or branched alkyl, wherein C1_C5On straight or branched alkyl any hydrogen atom can further by
Hydroxyl, sulfydryl or amino replace；
R3It is independently selected from hydrogen atom, methyl, ethyl or acetyl group；
A is independently selected from N or CH.
Compound the most according to claim 1, wherein:
R1It is independently selected from fluorine atom or chlorine atom；
R2It is independently selected from hydrogen atom ,-SO2R4、-PO(OR4)2、-COCHR5R6；
R4For hydrogen atom, C1_C3Straight or branched alkyl；
R5For C1_C5Straight or branched alkyl, wherein C1_C5On straight or branched alkyl any hydrogen atom can further by hydroxyl or
Amino replaces；
R6For amino or C1-C3Straight or branched alkyl, wherein C1_C3On straight or branched alkyl, any hydrogen atom can be further
Replaced by hydroxyl or amino；
R3It is independently selected from hydrogen atom, methyl or ethyl；
A is independently selected from N or CH.
Compound the most according to claim 2,
R1It is independently selected from fluorine atom or chlorine atom；
R2It is independently selected from hydrogen atom ,-SO2R4、-PO(OR4)2Or-COCHR5R6；
R4For hydrogen atom or C1_C3Straight chained alkyl；
R5For C1_C4Straight or branched alkyl, wherein C1_C4On straight or branched alkyl any hydrogen atom can further by hydroxyl or
Amino replaces；
R6For amino；
R3It is independently selected from hydrogen atom or methyl；
A is independently selected from N or CH.
Compound the most according to claim 1,
R1It is independently selected from fluorine atom, chlorine atom, bromine atoms, atomic iodine；
R2It is independently selected from-COCHR5R6；R5、R6For different substituents；And R5For C1_C4Straight or branched alkyl, wherein C1_C4Directly
When on chain or branched alkyl, any hydrogen atom can be replaced by hydroxyl or amino further, with R5、R6The chiral carbon atom connected is permissible
For R, S or R and the mix-configuration of S；
R3It is independently selected from hydrogen atom, methyl, ethyl or acetyl group；
A is independently selected from N or CH.
Compound the most according to claim 1, it is characterised in that described compound is selected from:
6. according to the compound described in any one of Claims 1 to 5 at preparation treatment and the medicine of dipeptidyl peptidase IV relevant disease
Purposes in thing.
7. according to the compound described in any one of Claims 1 to 5 in preparation treatment type Ⅱdiabetes mellitus or impaired glucose tolerance
Purposes in disease medicament.
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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 |
Non-Patent Citations (1)
| Title |
|---|
| 基于药物设计的二肽基酶-IV抑制剂研究;张微微等;《亚太传统医药》;20120630;第8卷(第6期);第202-205页 * |
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