CN102260268A - Benzylthio acetamido acetylpyrazine triazole derivative as well as preparation thereof and application thereof - Google Patents
Benzylthio acetamido acetylpyrazine triazole derivative as well as preparation thereof and application thereof Download PDFInfo
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Abstract
The invention provides a benzylthio acetamido acetylpyrazine triazole derivative. A target compound (I) is obtained by condensing a sulfydryl acetamido acetic acid derivative and a benzyl chloride derivative, condensing the condensed derivatives and 2-piperazinone, reacting the obtained condensed product and trimethyloxonium tetrafluoroborate so as to obtain a methoxy imide compound, and carrying out cyclization on the methoxy imide compound and hydrazine, trifluoroaceticanhydride, acetic anhydride, propionic anhydride, trifluoroacetyl chloride, acetyl chloride or acrylyl chloride. The preparation method provided by the invention has the advantages of reasonable design, stable process, easily obtained raw materials for production, no use of high pressure hydrogenation and good production feasibility. By using the benzylthio acetamido acetylpyrazine triazole derivative provided by the invention, dipeptidyl peptidase-IV (DPP-4) can be selectively inhibited; an effect of reducing blood sugar is obtained; and the derivative can be applied to the preparation of drugs for reducing the blood sugar and has the following structural formula (I).
Description
Technical field
The invention belongs to technical field of pharmaceuticals, relate to benzylthio-acetamido acetylpyrazine triazole derivative and preparation method thereof and application.Benzylthio-acetamido acetylpyrazine triazole derivative of the present invention has the effect of lowering blood glucose.
Technical background
Sitagliptin (Sitagliptin) is first DPP IV (DPP-4) inhibitor of FDA approval listing, can increase secretion of insulin in blood sugar dependency ground, effect with obvious lowering blood glucose is applicable to the diabetes B patient that can not tolerate other ofhypoglycemic medicine.
The chemical name of sitagliptin is (3R)-3-amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-1,2,4-triazolo [4,3-a] pyrazine-7-yl]-4-(2,4, the 5-trifluorophenyl) fourth-1-ketone, structural formula is as follows:
At present, the synthetic route about sitagliptin and intermediate thereof exists shortcoming with high costs.
For example, in document WO 2004085378A1, WO2005020920A2 and WO2005097733A1, final step need be used chiral catalysis reagent: 1,5-cyclopentadiene rhodium chloride dimer and iridium and Ferrocenediphosphines (being called Josiphos now) ligand complex, these two reagent all are and expensive metal catalyst; In document WO 2004085661A2, change into utilize chiral auxiliary(reagent) ((S)-phenylglycinamide) to introduce amino after, hydrogenation under the catalysis of oxidation alms bowl is sloughed phenylglycocoll at last again and is obtained final product, than the said synthesis route cost reduction is arranged slightly; And in document WO 2004087650A2,, have to use low temperature (20 ℃) reaction simultaneously though abandoned chiral catalyst, and final step needs high-pressure hydrogenation again, and working condition is comparatively harsh.
Summary of the invention
The object of the invention is to provide a kind of benzylthio-acetamido acetylpyrazine triazole derivative, has following general structure (I):
Wherein:
R is CH
3(L configuration, D configuration or racemize), C
2H
5(L configuration, D configuration or racemize), C
6H
5Among (L configuration, D configuration or racemize) or the H one;
R ' is CH
3, C
2H
5, C
6H
5Or among the H one;
R ' ' is CH
3O, C
2H
5O, CH
3, C
2H
5, among Cl or the F one;
X is CF
3, CH
3Or C
2H
5In one;
N is in 0,1 or 2.
When n=0, described a kind of benzylthio-acetamido acetylpyrazine triazole derivative has following general structure (II):
When n=1, described a kind of benzylthio-acetamido acetylpyrazine triazole derivative has following general structure (III):
When n=2, described a kind of benzylthio-acetamido acetylpyrazine triazole derivative has following general structure (IV):
。
Another object of the present invention provides a kind of preparation method of benzylthio-acetamido acetylpyrazine triazole derivative: realize by following steps:
Mercaptoacetylamide guanidine-acetic acid derivative (a) is dissolved in the organic solvent, add basic cpd, room temperature drips the benzyl chloride derivative, condensation reaction obtains compound (b, (b) is dissolved in the organic solvent with compound, add basic cpd, add 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (EDC) under the room temperature again, 1-hydroxyl-benzo-triazole (HOBT) and 2-piperazine ketone, condensation reaction obtains compound (c), compound (c) is dissolved in the organic solvent, add the reaction of trimethylammonium oxygen Tetrafluoroboric acid and obtain methoxyl group group with imine moiety (d), generate compound (e) with hydrazine reaction again, again with trifluoroacetic anhydride, diacetyl oxide, propionic anhydride, trifluoroacetyl chloride, Acetyl Chloride 98Min. or propionyl chloride ring-closure reaction obtain compound (II), compound (II) is at methyl alcohol, in ethanol or the acetate, obtain compound (III) and compound (IV) respectively by oxidizing reaction with hydrogen peroxide.
Reaction formula is:
R wherein, R ', R ' ', X are as mentioned above.
Described organic solvent is N, dinethylformamide, a kind of in N,N-dimethylacetamide, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile, methylene dichloride or the chloroform.
Described basic cpd is a kind of in triethylamine, tripropyl amine, yellow soda ash, salt of wormwood, sodium hydroxide or the potassium hydroxide.
Described benzyl chloride derivative is to the methoxyl group benzyl chloride, to oxyethyl group benzyl chloride, p-chlorobenzyl chlorine, to fluorobenzyl chloride, to methyl-benzyl chlorine, to ethylbenzyl chloride, to trifluoromethyl benzyl chloride or a kind of in the nitrobenzyl chloride.
Described compound (b) is 1:1.5-2.0:0.5-0.7:1 with the mol ratio of EDC, HOBT and 2-piperazine ketone, is preferably 1:1.5:0.5:1.
A further object of the present invention provides the application of a kind of benzylthio-acetamido acetylpyrazine triazole derivative in preparation lowering blood glucose medicine.
The present invention is reasonable in design, and the synthesis technique of the existing sitagliptin of step is brief, easy to operate, yield height, good production feasibility.Benzylthio-acetamido acetylpyrazine triazole derivative of the present invention can optionally suppress DPP IV (DPP-4), and hypoglycemic activity more is better than sitagliptin, can reduce the treatment cost.Be more suitable for taking medicine for a long time the patient.
Embodiment
The present invention is further described in conjunction with the embodiments.Present invention is described for following examples, and these examples only are can not be interpreted as limitation of the scope of the invention for explanation.
Embodiment 1
Take by weighing N-(2-mercapto radical propionyl group)-glycine (tiopronin) (3.92g 0.024mol) is dissolved into N, among dinethylformamide (DMF) 20ml, take by weighing again salt of wormwood (8.28g, 0.06mol), stirring at room 15min; Dropping to the methoxy benzyl chloride (3.76g, 0.024mol) in the single port bottle, stirring at room 3h, TLC detect to reacting completely; React completely the back with saturated aqueous sodium hydroxide solution adjusting pH value to 13, with ethyl acetate extraction 3 times (20ml/ time), mainly is the collection decon; Regulate down about pH value to 2 in low temperature, with ethyl acetate extraction 3 times (40ml/ time), merge organic layer and drying, filter, evaporated under reduced pressure gets compound (b-1), and yield is 82%.
The 1H nuclear magnetic resonance spectrum of this compound in deuterochloroform: δ 1.48 (CH3, d, 3H), 3.65 (CH, m, H), 3.70 (CH2, m, 2H), 3.72 (CH3, m, 3H), 4.14 (CH2, s, 2H), 6.65 (2CH, d, 2H), 6.95 (2CH, d, 2H) ppm.
MS:m/z:?284.09(M+1)。
Embodiment 2
(0.85g 0.003mol) is dissolved among the DMF 10ml, adds triethylamine 1ml again, stirring at room 10min to take by weighing compound (b-1); Add EDC(0.86g again, 0.0045mol), HOBT(0.2g, 0.0015mol) and 2-piperazine ketone (0.3g, 0.003mol), stirring at room 5h, TLC detect to complete reaction; Decompression steams DMF, adds saturated sodium bicarbonate aqueous solution, and ethyl acetate extraction merges organic layer, dry filter, and evaporated under reduced pressure gets compound (c-1), and yield is 85%.
The 1H nuclear magnetic resonance spectrum of this compound in deuterochloroform: δ 1.48 (CH3, d, 3H), 3.46 (2CH2, s, 4H), 3.65 (CH, m, H), 3.70 (CH2, m, 2H), 3.72 (CH3, m, 3H), 4.09 (2CH2, s, 4H), 6.65 (2CH, d, 2H), 6.95 (2CH, d, 2H) ppm.
MS:m/z:?366.14(M+1)。
Embodiment 3
To compound (c-1) (438.54mg, 1.2mmol) methylene dichloride (6ml) solution in add trimethylammonium oxygen Tetrafluoroboric acid (207mg, 1.4mmol), the stirring at room reaction is spent the night, and reaction solution is mixed with sodium bicarbonate aqueous solution, uses ethyl acetate extraction 2 times, organic phase salt water washing, anhydrous sodium sulfate drying is concentrated into the dried compound (d-1) that obtains, and yield is 86%.
The 1H nuclear magnetic resonance spectrum of this compound in deuterochloroform: δ 1.48 (CH3, d, 3H), 1.6 (CH2, t, 2H), 3.2 (2CH2, t, 4H), 3.39 (CH3, s, 3H), 3.65 (CH, m, H), 3.70 (CH2, m, 2H), 3.72 (CH3, m, 3H), 4.09 (CH2, s, 2H), 6.65 (2CH, d, 2H), 6.95 (2CH, d, 2H) ppm.
MS:m/z:?380.16(M+1)。
Embodiment 4
To hydrazine (0.09ml, 3.0mmol) methylene dichloride (3ml) solution in add compound (d-1) (0.47g, 1.23mmol), mixture stirring at room 3 hours, the reaction solution concentrating under reduced pressure adds twice toluene again and mixes with residue, concentrate and remove excessive hydrazine, residuum vacuum-drying is spent the night, and obtains compound (e-1), and yield is 84%.
The 1H nuclear magnetic resonance spectrum of this compound in deuterochloroform: δ 1.48 (CH3, d, 3H), 1.6 (CH2, t, 2H), 3.2 (2CH2, t, 4H), 3.65 (CH, m, H), 3.70 (CH2, m, 2H), 3.72 (CH3, m, 3H), 4.09 (CH2, s, 2H), 6.65 (2CH, d, 2H), 6.95 (2CH, d, 2H) ppm.
MS:m/z:?380.17(M+1)。
Embodiment 5
The compound (e-1) of gained of last step is dissolved in contains triethylamine (0.42ml, 3.0mmol) in methylene dichloride (10ml) solution, add trifluoroacetic anhydride (0.63g, 3.0mmol), mixed solution is heated to 35 ℃ of reactions 2 hours, remove and desolvate, add twice toluene in the residue, be concentrated into dried after the mixing, the oily residue that obtains is dissolved in the propyl carbinol, is heated to 120 ℃ of reactions and spends the night, and concentrates to remove to desolvate, residue is crossed post (eluent: 3%-10% ammonium hydroxide methanol solution is in methylene dichloride) and is obtained compound (II-1), and yield is 75%.
The 1H nuclear magnetic resonance spectrum of this compound in deuterochloroform: δ 1.48 (CH3, d, 3H), 3.65 (CH, m, H), 3.68 (CH2, m, 2H), 3.70 (CH2, m, 2H), 3.72 (CH3, m, 3H), 3.99 (CH2, m, 2H), 4.09 (CH2, s, 2H), 4.46 (CH2, s, 2H), 6.65 (2CH, d, 2H), 6.95 (2CH, d, 2H) ppm.
MS:m/z:?458.14(M+1)。
Embodiment 6
With compound (II-1) 500mg(1.1mmol) be dissolved in the methyl alcohol 10ml solution, stir; Add peroxide water 3ml again, reaction about 10 ℃; TLC detects to reacting completely, and after reacting completely reaction solution is reduced pressure at low temperatures and removes, and cooling is left standstill; Wait to separate out the solid after-filtration, filtration cakes torrefaction obtains compound (III-1), and yield is 90%.
The 1H nuclear magnetic resonance spectrum of this compound in deuterochloroform: δ 1.50 (CH3, d, 3H), 3.66 (CH, m, H), 3.68 (CH2, s, 2H), 3.72 (CH3, m, 3H), 3.83 (CH2, m, 2H), 3.99 (CH2, m, 2H), 4.09 (CH2, s, 2H), 4.46 (CH2, s, 2H), 6.65 (2CH, d, 2H), 6.95 (2CH, d, 2H) ppm.
MS:m/z:?473.13(M+1)。
Embodiment 7
With compound (II-1) 500mg(1.1mmol) be dissolved in the acetate 10ml solution, stir; Add peroxide water 3ml again, reaction about 70 ℃; TLC detects to reacting completely, and after reacting completely major part is removed in the reaction solution decompression, adds a spot of water again, and product is separated out; Wait to separate out the solid after-filtration, filtration cakes torrefaction obtains compound (IV-1), and yield is 87%.
The 1H nuclear magnetic resonance spectrum of this compound in deuterochloroform: δ 1.56 (CH3, d, 3H), 3.68 (CH2, m, 2H), 3.72 (CH3, m, 3H), 3.99 (CH2, m, 2H), 4.09 (CH2, s, 2H), 4.11 (CH, m, H), 4.46 (CH2, s, 2H), 4.67 (CH2, s, 2H), 6.65 (2CH, d, 2H), 6.95 (2CH, d, 2H) ppm.
MS:m/z:?490.13(M+1)。
Embodiment 8
Take by weighing N-(2-sulfydryl ethanoyl)-glycine (removing the first tiopronin) (3.58g 0.024mol) is dissolved among the DMF 20ml, take by weighing again salt of wormwood (8.28g, 0.06mol), stirring at room 15min; Dropping to the methoxy benzyl chloride (3.76g, 0.024mol) in the single port bottle, stirring at room 3h, TLC detect to reacting completely; React completely the back with saturated aqueous sodium hydroxide solution adjusting pH value to 13, with ethyl acetate extraction 3 times (20ml/ time), mainly is the collection decon; Regulate down about pH value to 2 in low temperature, with ethyl acetate extraction 3 times (40ml/ time), merge organic layer and drying, filter, evaporated under reduced pressure gets compound (b-2), and yield is 83%.
The 1H nuclear magnetic resonance spectrum of this compound in deuterochloroform: δ 3.33 (CH2, s, 2H), 3.70 (CH2, d, 2H), 3.72 (CH3, d, 3H), 4.14 (CH2, s, 2H), 6.65 (2CH, d, 2H), 6.95 (2CH, d, 2H) ppm.
MS:m/z:270.07(M+1)。
Embodiment 9
(0.62g 0.0023mol) is dissolved among the DMF10ml, adds triethylamine 1ml again, stirring at room 10min to take by weighing compound (b-2); Add again EDC (0.66g, 0.00345mol), HOBT (0.16mg, 0.00115mol) (0.23,0.0023mol), stirring at room 5h, TLC detect to complete reaction with 2-piperazine ketone; Decompression steams DMF, adds saturated sodium bicarbonate aqueous solution, and ethyl acetate extraction merges organic layer, dry filter, and evaporated under reduced pressure gets (c-2), and yield is 84%.
The 1H nuclear magnetic resonance spectrum of this compound in deuterochloroform: δ 1.48 (CH3, d, 3H), 3.46 (2CH2, s, 4H), 3.33 (CH2, m, 2H), 3.70 (CH2, m, 2H), 3.72 (CH3, m, 3H), 4.09 (2CH2, s, 4H), 6.65 (2CH, d, 2H), 6.95 (2CH, d, 2H) ppm.
MS:m/z:352.13(M+1)。
Embodiment 10
To compound (c-2) (421.7mg, 1.2mmol) methylene dichloride (6ml) solution in add trimethylammonium oxygen Tetrafluoroboric acid (207mg, 1.4mmol), the stirring at room reaction is spent the night, and reaction solution is mixed with sodium bicarbonate aqueous solution, uses ethyl acetate extraction 2 times, organic phase salt water washing, anhydrous sodium sulfate drying is concentrated into the dried compound (d-2) that obtains, and yield is 86%.
The 1H nuclear magnetic resonance spectrum of this compound in deuterochloroform: δ 1.6 (CH2, t, 2H), 3.2 (2CH2, t, 4H), 3.33 (CH2, s, 2H), 3.39 (CH3, s, 3H), 3.70 (CH2, d, 2H), 3.72 (CH3, d, 3H), 4.09 (CH2, s, 2H), 6.65 (2CH, d, 2H), 6.95 (2CH, d, 2H) ppm.
MS:m/z:?366.14(M+1)。
Embodiment 11
To hydrazine (0.09ml, 3.0mmol) methylene dichloride (3ml) solution in add compound (d-2) (0.45g, 1.23mmol), mixture stirring at room 3 hours, the reaction solution concentrating under reduced pressure adds twice toluene again and mixes with residue, concentrate and remove excessive hydrazine, residuum vacuum-drying is spent the night, and obtains compound (e-2), and yield is 83%.
The 1H nuclear magnetic resonance spectrum of this compound in deuterochloroform: δ 1.6 (CH2, t, 2H), 3.2 (2CH2, t, 4H), 3.33 (CH2, s, 2H), 3.70 (CH2, d, 2H), 3.72 (CH3, d, 3H), 4.09 (CH2, s, 2H), 6.65 (2CH, d, 2H), 6.95 (2CH, d, 2H) ppm.
MS:m/z:?366.15(M+1)。
Embodiment 12
The compound (e-2) of gained of last step is dissolved in contains triethylamine (0.42ml, 3.0mmol) in methylene dichloride (10ml) solution, add trifluoroacetic anhydride (0.63g, 3.0mmol), mixed solution is heated to 35 ℃ of reactions 2 hours, remove and desolvate, add twice toluene in the residue, be concentrated into dried after the mixing, the oily residue that obtains is dissolved in the propyl carbinol, is heated to 120 ℃ of reactions and spends the night, and concentrates to remove to desolvate, residue is crossed post (eluent: 3%-10% ammonium hydroxide methanol solution is in methylene dichloride) and is obtained compound (II-2), and yield is 78%.
The 1H nuclear magnetic resonance spectrum of this compound in deuterochloroform: δ 3.33 (CH2, s, 2H), 3.68 (CH2, m, 2H), 3.70 (CH2, m, 2H), 3.72 (CH3, m, 3H), 3.99 (CH2, m, 2H), 4.09 (CH2, s, 2H), 4.46 (CH2, s, 2H), 6.65 (2CH, d, 2H), 6.95 (2CH, d, 2H) ppm.
MS:m/z:?444.12(M+1)。
Embodiment 13
Compound (II-2) 488mg (1.1mmol) is dissolved in the methyl alcohol 10ml solution, stirs; Add peroxide water 3ml again, reaction about 10 ℃; TLC detects to reacting completely, and after reacting completely reaction solution is reduced pressure at low temperatures and removes, and cooling is left standstill; Wait to separate out the solid after-filtration, filtration cakes torrefaction obtains compound (III-2), and yield is 89%.
The 1H nuclear magnetic resonance spectrum of this compound in deuterochloroform: δ 3.46 (CH2, s, 2H), 3.68 (CH2, m, 2H), 3.72 (CH3, m, 3H), 3.83 (CH2, m, 2H), 3.99 (CH2, t, 2H), 4.09 (CH2, s, 2H), 4.46 (CH2, s, 2H), 6.65 (2CH, d, 2H), 6.95 (2CH, d, 2H) ppm.
MS:m/z:?460.12(M+1)。
Embodiment 14
Compound (II-2) 488mg (1.1mmol) is dissolved in the acetate 10ml solution, stirs; Add peroxide water 3ml again, reaction about 70 ℃; TLC detects to reacting completely, and after reacting completely major part is removed in the reaction solution decompression, adds a spot of water again, and product is separated out; Wait to separate out the solid after-filtration, filtration cakes torrefaction obtains compound (IV-2), and yield is 85%.
The 1H nuclear magnetic resonance spectrum of this compound in deuterochloroform: δ 3.68 (CH2, m, 2H), 3.72 (CH3, m, 3H), 3.99 (CH2, t, 2H), 4.09 (CH2, s, 2H), 4.3 (CH2, s, 2H), 4.37 (CH2, m, 2H), 4.46 (CH2, s, 2H), 6.65 (2CH, d, 2H), 6.95 (2CH, d, 2H) ppm.
MS:m/z:?476.11(M+1)。
Embodiment 15
Take by weighing N-(2-sulfydryl ethanoyl)-D-L-Ala (3.92g 0.024mol) is dissolved among the DMF 20ml, take by weighing again salt of wormwood (8.28g, 0.06mol), stirring at room 15min; Dropping to the methyl benzyl chloride (3.37g, 0.024mol) in the single port bottle, stirring at room 3h, TLC detect to reacting completely; React completely the back with saturated aqueous sodium hydroxide solution adjusting pH value to 13, with ethyl acetate extraction 3 times (20ml/ time), mainly is the collection decon; Regulate down about pH value to 2 in low temperature, with ethyl acetate extraction 3 times (40ml/ time), merge organic layer and drying, filter, evaporated under reduced pressure gets compound (b-3), and yield is 78%.
The 1H nuclear magnetic resonance spectrum of this compound in deuterochloroform: δ 1.43 (CH3, d, 3H), 2.19 (CH3, s, 3H), 3.33 (CH2, s, 2H), 3.70 (CH2, s, 2H), 4.64 (CH, m, H), 7.09 (2CH, d, 2H), 7.19 (2CH, d, 2H) ppm.
MS:m/z:?268.09(M+1)。
Embodiment 16
(0.61g 0.0023mol) is dissolved among the DMF10ml, adds triethylamine 1ml again, stirring at room 10min to take by weighing compound (b-3); Add again EDC (0.66g, 0.00345mol), HOBT (0.16mg, 0.00115mol) (0.23,0.0023mol), stirring at room 5h, TLC detect to complete reaction with 2-piperazine ketone; Decompression steams DMF, adds saturated sodium bicarbonate aqueous solution, and ethyl acetate extraction merges organic layer, dry filter, and evaporated under reduced pressure gets (c-3), and yield is 83%.
The 1H nuclear magnetic resonance spectrum of this compound in deuterochloroform: δ 1.48 (CH3, d, 3H), 2.19 (CH3, s, 3H), 3.46 (2CH2, s, 4H), 3.33 (CH2, s, 2H), 3.70 (CH2, s, 2H), 4.09 (CH2, s, 2H), 4.71 (CH, q, H), 7.09 (2CH, d, 2H), 7.19 (2CH, d, 2H) ppm.
MS:m/z:350.15(M+1)。
Embodiment 17
To compound (c-3) (419.34mg, 1.2mmol) methylene dichloride (6ml) solution in add trimethylammonium oxygen Tetrafluoroboric acid (207mg, 1.4mmol), the stirring at room reaction is spent the night, and reaction solution is mixed with sodium bicarbonate aqueous solution, uses ethyl acetate extraction 2 times, organic phase salt water washing, anhydrous sodium sulfate drying is concentrated into the dried compound (d-3) that obtains, and yield is 81%.
The 1H nuclear magnetic resonance spectrum of this compound in deuterochloroform: δ 1.48 (CH3, d, 3H), 1.6 (CH2, t, 2H), 2.19 (CH3, s, 3H), 3.2 (2CH2, t, 4H), 3.33 (CH2, t, 2H), 3.39 (CH3, t, 3H), 3.70 (CH2, s, 2H), 4.71 (CH, s, H), 7.09 (2CH, d, 2H), 7.19 (2CH, d, 2H) ppm.
MS:m/z:?364.16(M+1)。
Embodiment 18
To hydrazine (0.09ml, 3.0mmol) methylene dichloride (3ml) solution in add compound (d-3) (0.447g, 1.23mmol), mixture stirring at room 3 hours, the reaction solution concentrating under reduced pressure adds twice toluene again and mixes with residue, concentrate and remove excessive hydrazine, residuum vacuum-drying is spent the night, and obtains compound (e-3), and yield is 80%.
The 1H nuclear magnetic resonance spectrum of this compound in deuterochloroform: δ 1.48 (CH3, d, 3H), 1.6 (CH2, t, 2H), 2.19 (CH3, s, 3H), 3.2 (2CH2, t, 4H), 3.33 (CH2, t, 2H), 3.70 (CH2, s, 2H), 4.71 (CH, s, H), 7.09 (2CH, d, 2H), 7.19 (2CH, d, 2H) ppm.
MS:m/z:?364.17(M+1)。
Embodiment 19
The compound (e-3) of gained of last step is dissolved in contains triethylamine (0.42ml, 3.0mmol) in methylene dichloride (10ml) solution, add trifluoroacetic anhydride (0.63g, 3.0mmol), mixed solution is heated to 35 ℃ of reactions 2 hours, remove and desolvate, add twice toluene in the residue, be concentrated into dried after the mixing, the oily residue that obtains is dissolved in the propyl carbinol, is heated to 120 ℃ of reactions and spends the night, and concentrates to remove to desolvate, residue is crossed post (eluent: 3%-10% ammonium hydroxide methanol solution is in methylene dichloride) and is obtained compound (II-3), and yield is 74%.
The 1H nuclear magnetic resonance spectrum of this compound in deuterochloroform: δ 1.48 (CH3, d, 3H), 2.19 (CH3, s, 3H), 3.33 (CH2, s, 2H), 3.68 (CH2, t, 2H), 3.70 (CH2, t, 2H), 3.99 (CH2, t, 2H), 4.46 (CH2, s, 2H), 4.71 (CH, q, H), 7.09 (2CH, d, 2H), 7.19 (2CH, d, 2H) ppm.
MS:m/z:?442.14(M+1)。
Embodiment 20
Compound (II-3) 486mg (1.1mmol) is dissolved in the methyl alcohol 10ml solution, stirs; Add peroxide water 3ml again, reaction about 10 ℃; TLC detects to reacting completely, and after reacting completely reaction solution is reduced pressure at low temperatures and removes, and cooling is left standstill; Wait to separate out the solid after-filtration, filtration cakes torrefaction obtains compound (III-3), and yield is 85%.
The 1H nuclear magnetic resonance spectrum of this compound in deuterochloroform: δ 1.48 (CH3, d, 3H), 2.19 (CH3, s, 3H), 3.46 (CH2, s, 2H), 3.68 (CH2, t, 2H), 3.83 (CH2, s, 2H), 3.99 (CH2, t, 2H), 4.46 (CH2, s, 2H), 4.71 (CH, q, H), 6.94 (4CH, s, 4H) ppm.
MS:m/z:?458.14(M+1)。
Embodiment 21
Compound (II-3) 486mg (1.1mmol) is dissolved in the acetate 10ml solution, stirs; Add peroxide water 3ml again, reaction about 70 ℃; TLC detects to reacting completely, and after reacting completely major part is removed in the reaction solution decompression, adds a spot of water again, and product is separated out; Wait to separate out the solid after-filtration, filtration cakes torrefaction obtains compound (IV-3), and yield is 80%.
The 1H nuclear magnetic resonance spectrum of this compound in deuterochloroform: δ 1.48 (CH3, d, 3H), 2.19 (CH3, s, 3H), 3.68 (CH2, t, 2H), 3.99 (CH2, t, 2H), 4.30 (CH2, s, 2H), 4.37 (CH2, s, 2H), 4.46 (CH2, s, 2H), 4.71 (CH, q, H), 6.94 (4CH, s, 4H) ppm.
MS:m/z:?474.13(M+1)。
Embodiment 22
Take by weighing N-(2-mercapto radical propionyl group)-L-L-Ala (4.25g 0.024mol) is dissolved among the DMF 20ml, take by weighing again salt of wormwood (8.28g, 0.06mol), stirring at room 15min; Dropping to fluorobenzyl chloride (3.47g, 0.024mol) in the single port bottle, stirring at room 3h, TLC detect to reacting completely; React completely the back with saturated aqueous sodium hydroxide solution adjusting pH value to 13, with ethyl acetate extraction 3 times (20ml/ time), mainly is the collection decon; Regulate down about pH value to 2 in low temperature, with ethyl acetate extraction 3 times (40ml/ time), merge organic layer and drying, filter, evaporated under reduced pressure gets compound (b-4), and yield is 80%.
The 1H nuclear magnetic resonance spectrum of this compound in deuterochloroform: δ 1.43 (CH3, d, 3H), 1.58 (CH3, d, 3H), 3.33 (CH2, s, 2H), 3.99 (CH, q, H), 4.64 (CH, q, H), 6.92 (2CH, t, 2H), 7.10 (2CH, t, 2H) ppm.
MS:m/z:?286.08(M+1)。
Embodiment 23
(0.66g 0.0023mol) is dissolved among the DMF10ml, adds triethylamine 1ml again, stirring at room 10min to take by weighing compound (b-4); Add again EDC (0.66g, 0.00345mol), HOBT (0.16mg, 0.00115mol) (0.23,0.0023mol), stirring at room 5h, TLC detect to complete reaction with 2-piperazine ketone; Decompression steams DMF, adds saturated sodium bicarbonate aqueous solution, and ethyl acetate extraction merges organic layer, dry filter, and evaporated under reduced pressure gets (c-4), and yield is 82%.
The 1H nuclear magnetic resonance spectrum of this compound in deuterochloroform: δ 1.48 (2CH3, d, 6H), 3.46 (2CH2, s, 4H), 3.65 (CH, m, H), 3.70 (CH2, m, 2H), 4.09 (CH2, s, 2H), 4.71 (CH, q, H), 7.049 (2CH, m, 2H), 7.11 (2CH, m, 2H) ppm.
MS:m/z:?368.14(M+1)。
Embodiment 24
To compound (c-4) (440.93mg, 1.2mmol) methylene dichloride (6ml) solution in add trimethylammonium oxygen Tetrafluoroboric acid (207mg, 1.4mmol), the stirring at room reaction is spent the night, and reaction solution is mixed with sodium bicarbonate aqueous solution, uses ethyl acetate extraction 2 times, organic phase salt water washing, anhydrous sodium sulfate drying is concentrated into the dried compound (d-4) that obtains, and yield is 85%.
The 1H nuclear magnetic resonance spectrum of this compound in deuterochloroform: δ 1.48 (2CH3, d, 6H), 1.6 (CH3, t, 3H), 3.2 (2CH2, t, 4H), 3.39 (CH3, s, 3H), 3.65 (CH, m, H), 3.70 (CH2, m, 2H), 4.71 (CH, q, H), 7.04 (2CH, m, 2H), 7.11 (2CH, m, 2H) ppm.
MS:m/z:382.15(M+1)。
Embodiment 25
To hydrazine (0.09ml, 3.0mmol) methylene dichloride (3ml) solution in add compound (d-4) (0.47g, 1.23mmol), mixture stirring at room 3 hours, the reaction solution concentrating under reduced pressure adds twice toluene again and mixes with residue, concentrate and remove excessive hydrazine, residuum vacuum-drying is spent the night, and obtains compound (e-4), and yield is 83%.
The 1H nuclear magnetic resonance spectrum of this compound in deuterochloroform: δ 1.48 (2CH3, d, 6H), 1.6 (CH3, t, 3H), 3.2 (2CH2, t, 4H), 3.65 (CH, m, H), 3.70 (CH2, m, 2H), 4.71 (CH, q, H), 7.04 (2CH, m, 2H), 7.11 (2CH, m, 2H) ppm.
MS:m/z:382.16(M+1)。
Embodiment 26
The compound (e-4) of gained of last step is dissolved in contains triethylamine (0.42ml, 3.0mmol) in methylene dichloride (10ml) solution, add trifluoroacetic anhydride (0.63g, 3.0mmol), mixed solution is heated to 35 ℃ of reactions 2 hours, remove and desolvate, add twice toluene in the residue, be concentrated into dried after the mixing, the oily residue that obtains is dissolved in the propyl carbinol, is heated to 120 ℃ of reactions and spends the night, and concentrates to remove to desolvate, residue is crossed post (eluent: 3%-10% ammonium hydroxide methanol solution is in methylene dichloride) and is obtained compound (II-4), and yield is 73%.
The 1H nuclear magnetic resonance spectrum of this compound in deuterochloroform: δ 1.48 (2CH3, d, 6H), 3.65 (CH, d, H), 3.68 (CH2, s, 2H), 3.70 (CH2, s, 2H), 3.99 (CH2, q, 2H), 4.46 (CH, q, H), 4.71 (CH, t, H), 7.04 (2CH, t, 2H), 7.11 (2CH, t, 2H) ppm.
MS:m/z:?460.14(M+1)。
Embodiment 27
Compound (II-4) 505mg (1.1mmol) is dissolved in the methyl alcohol 10ml solution, stirs; Add peroxide water 3ml again, reaction about 10 ℃; TLC detects to reacting completely, and after reacting completely reaction solution is reduced pressure at low temperatures and removes, and cooling is left standstill; Wait to separate out the solid after-filtration, filtration cakes torrefaction obtains compound (III-4), and yield is 86%.
The 1H nuclear magnetic resonance spectrum of this compound in deuterochloroform: δ 1.48 (CH3, t, 3H), 1.50 (CH3, t, 3H), 3.66 (CH, m, H), 3.68 (CH2, s, 2H), 3.83 (CH2, t, 2H), 3.99 (CH2, t, 2H), 4.46 (CH, s, H), 4.71 (CH, q, H), 6.85 (2CH, t, 2H), 7.04 (2CH, t, 2H) ppm.
MS:m/z:?476.13(M+1)。
Embodiment 28
Compound (II-4) 505mg (1.1mmol) is dissolved in the acetate 10ml solution, stirs; Add peroxide water 3ml again, reaction about 70 ℃; TLC detects to reacting completely, and after reacting completely major part is removed in the reaction solution decompression, adds a spot of water again, and product is separated out; Wait to separate out the solid after-filtration, filtration cakes torrefaction obtains compound (IV-4), and yield is 82%.
The 1H nuclear magnetic resonance spectrum of this compound in deuterochloroform: δ 1.48 (CH3, d, 3H), 1.56 (CH3, d, 3H), 3.68 (CH2, m, 2H), 3.99 (CH2, m, 2H), 4.11 (CH2, q, 2H), 4.46 (CH2, s, 2H), 4.67 (CH, s, H), 4.71 (CH, q, H), 6.85 (2CH, t, 2H), 7.04 (2CH, t, 2H) ppm.
MS:m/z:492.13(M+1)。
Embodiment 29
Take by weighing N-(2-sulfydryl ethanoyl)-L-phenylglycine (5.4g 0.024mol) is dissolved among the DMF 20ml, take by weighing again salt of wormwood (8.28g, 0.06mol), stirring at room 15min; Dropping to fluorobenzyl chloride (3.47g, 0.024mol) in the single port bottle, stirring at room 3h, TLC detect to reacting completely; React completely the back with saturated aqueous sodium hydroxide solution adjusting pH value to 13, with ethyl acetate extraction 3 times (20ml/ time), mainly is the collection decon; Regulate down about pH value to 2 in low temperature, with ethyl acetate extraction 3 times (40ml/ time), merge organic layer and drying, filter, evaporated under reduced pressure gets compound (b-5), and yield is 74%.
The 1H nuclear magnetic resonance spectrum of this compound in deuterochloroform: δ 3.33 (CH2, s, 2H), 3.70 (CH2, d, 2H), 3.72 (CH3, d, 3H), 5.75 (CH, s, H), 6.65 (2CH, d, 2H), 6.95 (2CH, m, 2H), 7.06 (2CH, m, 2H), 7.25 (CH, m, H), 7.31 (2CH, m, 2H) ppm.
MS:m/z:346.1(M+1)。
Embodiment 30
(0.79g 0.0023mol) is dissolved among the DMF10ml, adds triethylamine 1ml again, stirring at room 10min to take by weighing compound (b-5); Add again EDC (0.66g, 0.00345mol), HOBT (0.16mg, 0.00115mol) (0.23,0.0023mol), stirring at room 5h, TLC detect to complete reaction with 2-piperazine ketone; Decompression steams DMF, adds saturated sodium bicarbonate aqueous solution, and ethyl acetate extraction merges organic layer, dry filter, and evaporated under reduced pressure gets (c-5), and yield is 77%.
The 1H nuclear magnetic resonance spectrum of this compound in deuterochloroform: δ 3.33 (CH2, s, 2H), 3.46 (2CH2, s, 4H), 3.70 (CH2, d, 2H), 3.72 (CH3, d, 3H), 4.09 (CH2, s, 2H), 5.82 (CH, s, H), 6.65 (2CH, d, 2H), 6.95 (2CH, d, 2H), 7.06 (2CH, d, 2H), 7.25 (CH, d, H), 7.31 (2CH, m, 2H) ppm.
MS:m/z:428.16(M+1)。
Embodiment 31
To compound (c-5) (513mg, 1.2mmol) methylene dichloride (6ml) solution in add trimethylammonium oxygen Tetrafluoroboric acid (207mg, 1.4mmol), the stirring at room reaction is spent the night, and reaction solution is mixed with sodium bicarbonate aqueous solution, uses ethyl acetate extraction 2 times, organic phase salt water washing, anhydrous sodium sulfate drying is concentrated into the dried compound (d-5) that obtains, and yield is 80%.
The 1H nuclear magnetic resonance spectrum of this compound in deuterochloroform: δ 1.6 (CH2, t, 2H), 3.2 (2CH2, t, 4H), 3.33 (CH2, s, 2H), 3.39 (CH3, s, 3H), 3.70 (CH2, d, 2H), 3.72 (CH3, d, 3H), 5.82 (CH, s, H), 6.65 (2CH, d, 2H), 6.95 (2CH, d, 2H), 7.06 (2CH, d, 2H), 7.25 (CH, m, H), 7.31 (2CH, m, 2H) ppm.
MS:m/z:442.17(M+1)。
Embodiment 32
To hydrazine (0.09ml, 3.0mmol) methylene dichloride (3ml) solution in add compound (d-5) (0.54g, 1.23mmol), mixture stirring at room 3 hours, the reaction solution concentrating under reduced pressure adds twice toluene again and mixes with residue, concentrate and remove excessive hydrazine, residuum vacuum-drying is spent the night, and obtains compound (e-5), and yield is 78%.
The 1H nuclear magnetic resonance spectrum of this compound in deuterochloroform: δ 1.6 (CH2, t, 2H), 3.2 (2CH2, t, 4H), 3.33 (CH2, s, 2H), 3.70 (CH2, d, 2H), 3.72 (CH3, d, 3H), 5.82 (CH, s, H), 6.65 (2CH, d, 2H), 6.95 (2CH, d, 2H), 7.06 (2CH, d, 2H), 7.25 (CH, m, H), 7.31 (2CH, m, 2H) ppm.
MS:m/z:442.18(M+1)。
Embodiment 33
The compound (e-5) of gained of last step is dissolved in contains triethylamine (0.42ml, 3.0mmol) in methylene dichloride (10ml) solution, add trifluoroacetyl chloride (0.4g, 3.0mmol), mixed solution is heated to 35 ℃ of reactions 2 hours, remove and desolvate, add twice toluene in the residue, be concentrated into dried after the mixing, the oily residue that obtains is dissolved in the propyl carbinol, is heated to 120 ℃ of reactions and spends the night, and concentrates to remove to desolvate, residue is crossed post (eluent: 3%-10% ammonium hydroxide methanol solution is in methylene dichloride) and is obtained compound (II-5), and yield is 72%.
The 1H nuclear magnetic resonance spectrum of this compound in deuterochloroform: δ 3.33 (CH2, s, 2H), 3.68 (CH2, d, 2H), 3.70 (CH2, d, 2H), 3.72 (CH3, d, 3H), 3.99 (CH2, d, 2H), 4.46 (CH2, d, 2H), 5.82 (CH, s, H), 6.65 (2CH, d, 2H), 6.95 (2CH, m, 2H), 7.06 (2CH, m, 2H), 7.25 (CH, m, H), 7.31 (2CH, m, 2H) ppm.
MS:m/z:520.16(M+1)。
Embodiment 34
Compound (II-5) 571mg (1.1mmol) is dissolved in the methyl alcohol 10ml solution, stirs; Add peroxide water 3ml again, reaction about 10 ℃; TLC detects to reacting completely, and after reacting completely reaction solution is reduced pressure at low temperatures and removes, and cooling is left standstill; Wait to separate out the solid after-filtration, filtration cakes torrefaction obtains compound (III-5), and yield is 83%.
The 1H nuclear magnetic resonance spectrum of this compound in deuterochloroform: δ 3.46 (CH2, s, 2H), 3.68 (CH2, d, 2H), 3.72 (CH3, d, 3H), 3.83 (CH2, d, 2H), 3.99 (CH2, d, 2H), 4.46 (CH2, d, 2H), 5.82 (CH, s, H), 6.65 (2CH, d, 2H), 6.95 (2CH, m, 2H), 7.06 (2CH, m, 2H), 7.25 (CH, m, H), 7.31 (2CH, m, 2H) ppm.
MS:m/z:536.15(M+1)。
Embodiment 35
Compound (II-5) 571mg (1.1mmol) is dissolved in the acetate 10ml solution, stirs; Add peroxide water 3ml again, reaction about 70 ℃; TLC detects to reacting completely, and after reacting completely major part is removed in the reaction solution decompression, adds a spot of water again, and product is separated out; Wait to separate out the solid after-filtration, filtration cakes torrefaction obtains compound (IV-5), and yield is 77%.
The 1H nuclear magnetic resonance spectrum of this compound in deuterochloroform:
δ?3.68(CH2,d,2H),3.72(CH3,d,3H),3.99(CH2,d,2H),4.30(CH2,s,2H),4.37(CH2,d,2H),4.46(CH2,d,2H),5.82(CH,s,H),6.65(2CH,d,2H),6.95(2CH,m,2H),7.06(2CH,m,2H),7.25(CH,m,H),7.31(2CH,m,2H)ppm。
MS:m/z:552.15(M+1)。
Embodiment 36
The pharmacodynamic action of benzylthio-acetamido acetylpyrazine triazole derivative of the present invention is realized by its hypoglycemic activity to the mouse diabetes model due to the tetraoxypyrimidine.
Test medication: sitagliptin, compound (II-1), compound (II-2), compound (II-3), compound (II-4), compound (II-5), compound (III-1), compound (IV-1), make suspension with 0.5% CMC-Na solution before the test, standby.
Instrument: three promise blood glucose meter, blood sugar test paper, 1ml disposable syringe, mouse stomach device.
Animal: female ICR mouse.
Modeling method: water 12h is can't help in the mouse fasting, disposable tail vein injection 80mg/kg (0.2mL/10g) tetraoxypyrimidine.Surveying (12h) blood sugar FBG on an empty stomach after 6 days, is 13.1 to 16.1 to be required animal model with FBG.Be chosen to the divide into groups hypoglycemic test of mould mouse.Be divided into 9 groups at random, 6 every group.7 groups is test group, gives different The compounds of this invention, and 1 group of control group gives sitagliptin, and 1 group of model control group waits capacity physiological saline.
Medication: press reagent compound method compounding pharmaceutical, with the administration of 0.2ml/10g capacity, dosage is: 300 mg/kg, once a day, administration 7 days after half an hour, is surveyed 12h blood sugar on an empty stomach, relatively hypoglycemic effect after the last administration.
Detect index: FBG.Blood sugar detection is all got blood with docking, measures blood glucose value (mmol/L) with blood glucose meter.The result represents with mean+SD.
Experimental result is referring to table 1:
The different compounds of table 1 are to influence (n=6, the unit: mmol/L) of diabetic mice fasting plasma glucose
Adopt one-way analysis of variance, relatively the difference of each compound group and model control group shows that The compounds of this invention and sitagliptin all can reduce the fasting plasma glucose (P＜0.01) of diabetic mice significantly; Each compound group and sitagliptin group compare, and Compound I I-1, II-3, II-4, II-5, III-1 and IV-1 fasting plasma glucose are starkly lower than the sitagliptin group, and the hypoglycemic effect of prompting aforesaid compound may be better than sitagliptin.
Embodiment 37
Measure absorbancy by microplate reader, sitagliptin, compound (II-1), compound (II-2), compound (II-3) have been compared, compound (II-4), compound (II-5), compound (III-1), compound (IV-1), compound (III-2), compound (IV-2), compound (III-3), compound (IV-3), compound (III-4), compound (IV-4), compound (III-5) and compound (IV-5) suppress the IC50 value of rat blood serum dipeptidyl peptidase-IV (DPP-4), and the result is referring to table 2.
Compound of the present invention has superiority than sitagliptin to the restraining effect IC50 value of rat blood serum dipeptidyl peptidase-IV (DPP-4).
Claims (8)
1. benzylthio-acetamido acetylpyrazine triazole derivative is characterized in that having following general structure (I):
Wherein:
R is CH
3, C
2H
5, C
6H
5Or among the H one, described CH
3, C
2H
5, C
6H
5Comprise L configuration, D configuration or racemize;
R ' is CH
3, C
2H
5, C
6H
5Or among the H one;
R ' ' is CH
3O, C
2H
5O, CH
3, C
2H
5, among Cl or the F one;
X is CF
3, CH
3Or C
2H
5In one;
N is in 0,1 or 2.
2. a kind of benzylthio-acetamido acetylpyrazine triazole derivative according to claim 1 is characterized in that,
(1) when n=0, described a kind of benzylthio-acetamido acetylpyrazine triazole derivative has following general structure (II):
(2) when n=1, described a kind of benzylthio-acetamido acetylpyrazine triazole derivative has following general structure (III):
(3) when n=2, described a kind of benzylthio-acetamido acetylpyrazine triazole derivative has following general structure (IV):
3. the preparation method of a kind of benzylthio-acetamido acetylpyrazine triazole derivative according to claim 2, it is characterized in that, realize by following steps: mercaptoacetylamide guanidine-acetic acid derivative (a) is dissolved in the organic solvent, add basic cpd, room temperature drips the benzyl chloride derivative, condensation reaction obtains compound (b) compound (b) is dissolved in the organic solvent, add basic cpd, add 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride under the room temperature again, 1-hydroxyl-benzo-triazole and 2-piperazine ketone, condensation reaction obtains compound (c), compound (c) is dissolved in the organic solvent, add the reaction of trimethylammonium oxygen Tetrafluoroboric acid and obtain methoxyl group group with imine moiety (d), generate compound (e) with hydrazine reaction again, again with trifluoroacetic anhydride, diacetyl oxide, propionic anhydride, trifluoroacetyl chloride, Acetyl Chloride 98Min. or propionyl chloride ring-closure reaction obtain compound (II), compound (II) is at methyl alcohol, in ethanol or the acetate, obtain compound (III) and compound (IV) with hydrogen peroxide respectively by oxidizing reaction
Reaction formula is:
R wherein, R ', R ' ', X are according to claim 1.
4. preparation method according to claim 2 is characterized in that, used organic solvent is N, a kind of in dinethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile, methylene dichloride or the chloroform.
5. preparation method according to claim 2 is characterized in that, used basic cpd is a kind of in triethylamine, tripropyl amine, yellow soda ash, salt of wormwood, sodium hydroxide or the potassium hydroxide.
6. preparation method according to claim 2, it is characterized in that used benzyl chloride derivative is to the methoxyl group benzyl chloride, to oxyethyl group benzyl chloride, p-chlorobenzyl chlorine, to fluorobenzyl chloride, to methyl-benzyl chlorine, to ethylbenzyl chloride, to trifluoromethyl benzyl chloride or a kind of in the nitrobenzyl chloride.
7. preparation method according to claim 2, it is characterized in that described compound (b) is 1:1.5-2.0:0.5-0.7:1 with the mol ratio of 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride, 1-hydroxyl-benzo-triazole and 2-piperazine ketone.
8. the application of a kind of benzylthio-acetamido acetylpyrazine triazole derivative according to claim 1 in the preparation hypoglycemic drug, described hypoglycemic by the realization of selectivity inhibition dipeptidyl peptidase-IV.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060194977A1 (en) * | 2003-03-19 | 2006-08-31 | Yi Xiao | Process for the preparation of chiral beta amino acid derivatives by asymmetric hydrogenation |
| US20070037785A1 (en) * | 2003-10-15 | 2007-02-15 | Siegfried Ansorge | Novel dipeptidyl peptidase IV inhibitors used for functionally influencing different cells and treating immunological, infammatory, neuronal, and other diseases |
| CN1942186A (en) * | 2004-03-09 | 2007-04-04 | 国家卫生研究院 | Pyrrolidine compounds |
| CN101945858A (en) * | 2008-03-05 | 2011-01-12 | 默克专利有限公司 | As the pyrazinones derivative of insulin secretion stimulant, the method that obtains them and the purposes in the treatment diabetes thereof |
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|---|---|---|---|---|
| US20060194977A1 (en) * | 2003-03-19 | 2006-08-31 | Yi Xiao | Process for the preparation of chiral beta amino acid derivatives by asymmetric hydrogenation |
| US20070037785A1 (en) * | 2003-10-15 | 2007-02-15 | Siegfried Ansorge | Novel dipeptidyl peptidase IV inhibitors used for functionally influencing different cells and treating immunological, infammatory, neuronal, and other diseases |
| CN1942186A (en) * | 2004-03-09 | 2007-04-04 | 国家卫生研究院 | Pyrrolidine compounds |
| CN101945858A (en) * | 2008-03-05 | 2011-01-12 | 默克专利有限公司 | As the pyrazinones derivative of insulin secretion stimulant, the method that obtains them and the purposes in the treatment diabetes thereof |
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| 张亚安等: "二肽基肽酶-Ⅳ抑制剂及其构效关系的研究进展", 《国际药学研究杂志》, vol. 36, no. 1, 28 February 2009 (2009-02-28), pages 37 - 38 * |
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| CP03 | Change of name, title or address |
Address after: 5, building 7, building 39, 310011 Cheung Road, Hangzhou, Zhejiang, Gongshu District Patentee after: HANGZHOU ADAMERCK PHARMLABS INC. Address before: 7, No. 310011, 39 Cheung Road, Hangzhou, Zhejiang, Gongshu District Patentee before: Hangzhou Aomo Medical Technology Co., Ltd. |