CN102603751A - Triazol (4,5-D) pyrimidine derivate and preparation method of triazol (4,5-D) pyrimidine derivate as well as application of triazol (4,5-D) pyrimidine derivate in drug preparation - Google Patents

Triazol (4,5-D) pyrimidine derivate and preparation method of triazol (4,5-D) pyrimidine derivate as well as application of triazol (4,5-D) pyrimidine derivate in drug preparation Download PDF

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CN102603751A
CN102603751A CN2012100434321A CN201210043432A CN102603751A CN 102603751 A CN102603751 A CN 102603751A CN 2012100434321 A CN2012100434321 A CN 2012100434321A CN 201210043432 A CN201210043432 A CN 201210043432A CN 102603751 A CN102603751 A CN 102603751A
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triazolo
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孙宏斌
张�浩
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China Pharmaceutical University
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Abstract

The invention discloses a triazol (4,5-D) pyrimidine derivate and a preparation method of the triazol (4,5-D) pyrimidine derivate as well as application of the triazol (4,5-D) pyrimidine derivate in drug preparation. The derivate is a compound as shown in a formula I. A pharmacodynamic test result shows that the compound shown in the formula I has the remarkable effect of inhibiting platelet aggregation. Therefore, the compound of the formula I can be used for preparing drugs for preventing or treating thrombus and embolism related diseases. The invention also provides the preparation method of the compound of the formula I.

Description

Triazolo (4,5-D) pyrimidine derivatives and preparation method thereof and purposes in pharmacy
Technical field
The present invention relates to the pharmaceutical chemistry field, (4,5-D) pyrimidine derivatives the invention also discloses the preparation method of above-claimed cpd and the purposes in pharmacy to be specifically related to a series of triazolos.
Background technology
After the blood vessel scleratheroma plaque rupture caused endothelial injury, subcutaneous matrix and each other assembling in thrombocyte can adhere to formed the further formation thrombus of back, thrombotic surface that becomes, cause blood vessel obstruction (Nature Reviews, 2010,9,154-169).Myocardial infarction that arterial thrombus causes and cerebral infarction are respectively world today's lethality rate and the highest disease of disability rate.Nowadays the tempo in antiplatelet drug market is very fast, has become one of popular domain of global drug development.Frosst) and clopidogrel drug combination are considered to treat clinically " the standard care method " of acute coronary syndrome; But all there be " opposing phenomenon " in this two kind of line medicine; Cause 15%～40% patient to the no response of this kind treat-ment; And still can comprise thrombosis in the support cardiovascular event (Circulation, 2004,109:166).For card Gray (Ticagrelor) be a kind of novel, have an optionally antiplatelet drug; It is first reversible mating type P2Y12 adp (ADP) receptor antagonist; The platelet aggregation that ADP is caused has the obvious suppression effect, can effectively improve acute coronary patient's symptom (The Lancet, 2010; 375,263-265.).Clinical trial PLATO shows; For card Gray than the effect of irreversible P2Y12 receptor antagonist clopidogrel more by force, sooner and more lasting; Be more suitable for the coronary artery bypass surgery medication, or have multivessel disease and may accept by-pass operation patient (The Lancet, 2010; 375,283-293).And need not metabolism and can bring into play pharmacological action for card Gray, and its oxygen go the alkyl metabolite also have in the body anti-platelet aggregation active (Drug Metab Dispos, 2010,38,1514-1521).
Owing to more approach the natural agonist ADP of P2Y12 acceptor for card Gray's cyclopentyl triazolo pyrimidine structure; So transformation period short (about 12 hours) in the body; Need twice of medication every day; Compliance to the patient is a kind of challenge, as a medicine that reverses fast, miss or directly drug withdrawal make the patient recur myocardial infarction and apoplexy probably.
Therefore, the clinical anti-platelet aggregation new drug that needs exploitation stable in properties, drug effect risk ratio height and can avoid hemorrhage side effect again.
Summary of the invention
Technical problem to be solved by this invention is to overcome above-mentioned shortcoming for card Gray and clopidogrel; Based on deficiency for card Gray and active metabolite thereof; Design, synthesizing new triazolo (4; 5-D) the various ester derivatives of pyrimidine, with the exploitation good effect, spinoff is little and the medicament for resisting platelet aggregation of stable in properties.
The invention discloses a series of like compound of Formula I and pharmacy acceptable salt thereof, solvolyte, shown in compound have good anticoagulant effect.
Figure BSA00000674585300021
Wherein, R represents XCOR 1, X is CH 2CH 2O or key;
R 1Be the substituted straight or branched alkyl of non-substituted or Y, the OR of 1～10 carbon 2, NR 3R 4, phenyl, the substituted phenyl of Z, styryl, 4-hydroxystyrene based, 4-hydroxyl-3-methoxyl-styrene, 3-pyridyl, alkenyl or alkynyl; Wherein Y is fluorine, chlorine, bromine, iodine, itrile group, nitro, amino, amido, sulfonamido, trifluoromethyl, sulfydryl, hydroxyl, acetoxyl group, methoxyl group, oxyethyl group, carboxyl, methoxy acyl group, ethoxy acyl group, aryloxy, phenyl or the substituted phenyl of Z; Z is fluorine, chlorine, bromine, iodine, itrile group, nitro, amino, amido, sulfonamido, trifluoromethyl, sulfydryl, hydroxyl, acetoxyl group, methoxyl group, oxyethyl group, carboxyl, methoxy acyl group or ethoxy acyl group, and the Z group is in 2,3 or 4 of phenyl ring;
R 2Be the straight or branched alkyl or the benzyl of 1～10 carbon;
R 3, R 4Be the straight or branched alkyl of 1～6 carbon, or NR 3R 4For
Figure BSA00000674585300022
Preferred R in the formula I compound of the present invention 1Be the substituted straight or branched alkyl of non-substituted or Y, the OR of 1～6 carbon 4, NR 5R 6, phenyl, the substituted phenyl of Z, styryl, 4-hydroxystyrene based, 4-hydroxyl-3-methoxyl-styrene or 3-pyridyl, wherein Y is amino, amido, sulfonamido, hydroxyl, acetoxyl group, methoxyl group, oxyethyl group, carboxyl, methoxy acyl group, ethoxy acyl group, aryloxy, phenyl or the substituted phenyl of Z; Z is fluorine, chlorine, bromine, iodine, itrile group, nitro, amino, amido, sulfonamido, hydroxyl, acetoxyl group, methoxyl group, oxyethyl group, carboxyl, methoxy acyl group or ethoxy acyl group, and the Z group is in 2,3 or 4 of phenyl ring; R 2Be the straight or branched alkyl or the benzyl of 1～6 carbon; R 3, R 4Be the straight or branched alkyl of 1～6 carbon, or NR 3R 4For
Figure BSA00000674585300023
More preferably R in the formula I compound of the present invention 1For methyl, ethyl, propyl group, the tertiary butyl, tertiary amyl, Phenoxymethyl, methoxyl group, oxyethyl group, isopropoxy, isobutoxy, benzyloxy ,-N (CH 3) 2,-N (CH 2CH 3) 2,-N (CH 3) (CH 2CH 3),
Figure BSA00000674585300024
Figure BSA00000674585300025
Phenyl, 2-hydroxy phenyl, 2-acetoxyl group phenyl, 4-p-methoxy-phenyl, 4-nitrophenyl, styryl, 4-hydroxystyrene based, 4-hydroxyl-3-methoxyl-styrene or 3-pyridyl.
The preferred compound of the present invention is following:
(1S-(1 α, 2 α, 3 β (1S*, 2R*), 5 β))-3-(7-(2-(3, the 4-difluorophenyl) cyclopropyl is amino)-5-(rosickyite base)-3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl)-5-propionyloxy pentamethylene-1,2 glycol I-1;
(1S-(1 α, 2 α, 3 β (1S*, 2R*), 5 β))-3-(7-(2-(3, the 4-difluorophenyl) cyclopropyl is amino)-5-(rosickyite base)-3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl)-5-butyryl acyloxy pentamethylene-1,2 glycol I-2;
(1S-(1 α, 2 α, 3 β (1S*, 2R*), 5 β))-3-(7-(2-(3, the 4-difluorophenyl) cyclopropyl is amino)-5-(rosickyite base)-3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl)-5-pivaloyl oxygen basic ring pentane-1,2 glycol I-3;
(1S-(1 α, 2 α, 3 β (1S*, 2R*), 5 β))-3-(7-(2-(3, the 4-difluorophenyl) cyclopropyl is amino)-5-(rosickyite base)-3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl)-5-benzoyloxy pentamethylene-1,2 glycol I-4;
(1S-(1 α, 2 α, 3 β (1S*, 2R*), 5 β))-3-(7-(2-(3, the 4-difluorophenyl) cyclopropyl is amino)-5-(rosickyite base)-3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl)-5-ethoxycarbonyl-oxygen basic ring pentane-1,2 glycol I-5;
(1S-(1 α, 2 α, 3 β (1S*, 2R*), 5 β))-3-(7-(2-(3, the 4-difluorophenyl) cyclopropyl is amino)-5-(rosickyite base)-3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl)-5-isobutyl boc oxygen basic ring pentane-1,2 glycol I-6;
(1S-(1 α, 2 α, 3 β (1S*, 2R*), 5 β))-3-(7-(2-(3, the 4-difluorophenyl) cyclopropyl is amino)-5-(rosickyite base)-3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl)-5-(2-butyryl oxygen oxyethyl group) pentamethylene-1,2 glycol I-7;
(1S-(1 α, 2 α, 3 β (1S*, 2R*), 5 β))-3-(7-(2-(3, the 4-difluorophenyl) cyclopropyl is amino)-5-(rosickyite base)-3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl)-5-(2-pivaloyl oxygen oxyethyl group) pentamethylene-1,2 glycol I-8;
(1S-(1 α, 2 α, 3 β (1S*, 2R*), 5 β))-3-(7-(2-(3, the 4-difluorophenyl) cyclopropyl is amino)-5-(rosickyite base)-3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl)-5-(2-benzoyl oxygen oxyethyl group) pentamethylene-1,2 glycol I-9;
(1S-(1 α, 2 α, 3 β (1S*, 2R*), 5 β))-3-(7-(2-(3, the 4-difluorophenyl) cyclopropyl is amino)-5-(rosickyite base)-3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl)-5-(2-nicotinoyl oxygen oxyethyl group) pentamethylene-1,2 glycol I-10;
(1S-(1 α, 2 α, 3 β (1S*, 2R*), 5 β))-3-(7-(2-(3, the 4-difluorophenyl) cyclopropyl is amino)-5-(rosickyite base)-3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl)-5-(2-ethoxycarbonyl-oxygen oxyethyl group) pentamethylene-1,2 glycol I-11;
Compound of the present invention also comprises the pharmacy acceptable salt of formula I compound, includes but not limited to the acid salt that The compounds of this invention and following acid form: hydrochloric acid, Hydrogen bromide, sulfuric acid, Hydrocerol A, tartrate, phosphoric acid, lactic acid, acetate, toxilic acid, fumaric acid, oxysuccinic acid, tussol, methylsulfonic acid, Phenylsulfonic acid, tosic acid, pamoic acid (palmoxiric acid), oxalic acid or succsinic acid.
Another object of the present invention provided triazolo (4, the 5-D) preparation method of pyrimidine derivatives formula I compound, following reaction formula:
Figure BSA00000674585300041
Specifically comprise the following steps:
(1) formula II compound or its salt and formula IV compound (acid anhydrides) or formula V compound (R 1The base formyl chloride) (their mol ratio is 1: 1～1: 10) reacts in the presence of alkali (consumption is 1～10 equivalent of formula II compound); Obtain formula I compound; The reaction solvent that is adopted is selected from benzene, toluene, chloroform, normal hexane, hexanaphthene, methylene dichloride, 1; 2-ethylene dichloride, MTBE, tetracol phenixin, ETHYLE ACETATE, propyl acetate, butylacetate, methyl alcohol, ethanol, acetone, THF, ether, acetonitrile, N; The mixed solvent of one or more in dinethylformamide or the methyl-sulphoxide, preferred THF, acetonitrile or N, dinethylformamide; The alkali that is adopted is selected from triethylamine, sodium hydride, potassium hydride KH, 1,8-diazacyclo [5,4,0] hendecene-7, pyridine, diisopropylethylamine, diisopropylamine lithium, salt of wormwood, yellow soda ash, saleratus, sodium hydrogencarbonate, potassium tert.-butoxide or sodium tert-butoxide; Temperature of reaction is subzero 20 ℃ to 100 ℃, and preferred temperature is 0 ℃ to 50 ℃;
(2) formula III compound reaction in the presence of protection of inert gas and acid; Obtain the formula III compound; Used reaction solvent is selected from methyl alcohol, ethanol, propyl alcohol, butanols, acetone, THF, dioxane, N; The mixed solvent of one or more in dinethylformamide, methyl-sulphoxide, pyridine or the acetonitrile, preferred THF; The acid of being adopted is selected from hydrochloric acid, sulfuric acid, phosphoric acid, perchloric acid, hypochlorous acid, trifluoroacetic acid, difluoroacetic acid, a gifblaar poison, trichoroacetic acid(TCA), dichloro acetic acid, Monochloro Acetic Acid, Hydrocerol A, oxysuccinic acid, oxalic acid, Glacial acetic acid min. 99.5, propionic acid, butyric acid; Concentration range is 0.01～10mol/L, preferred 0.1～0.1mol/L; Protecting property gas is selected from nitrogen, carbonic acid gas, helium, argon gas, neon; Temperature of reaction is subzero 20 ℃ to 100 ℃, and preferred temperature is 25 ℃ to 50 ℃;
(3) the formula III compound also can react in the presence of protection of inert gas and iodine; Obtain the formula III compound; Used reaction solvent is selected from methyl alcohol, ethanol, propyl alcohol, butanols, acetone, THF, dioxane, N, the mixed solvent of one or more in dinethylformamide, methyl-sulphoxide, pyridine or the acetonitrile, particular methanol and acetone; Concentration range is 0.1～10% (w/w), and preferred concentration is 0.5%; Protecting property gas is selected from nitrogen, carbonic acid gas, helium, argon gas, neon; Temperature of reaction is subzero 20 ℃ to 100 ℃, and preferred temperature is 30 ℃ to 80 ℃.
In above-mentioned reaction formula, X, R 1Such as in the above-mentioned formula I compound definition.
The preparation of formula II compound or its salt can be carried out with reference to the method for patent WO0192263A1.
Another purpose of the present invention provided triazolo (4, the 5-D) purposes of pyrimidine derivatives formula I compound in pharmacy.
Pharmacodynamic experiment is the result show, compound of Formula I of the present invention has significant anticoagulant effect.The pharmacokinetics experimental result shows that formula I compound of the present invention can be converted into the pharmacologically active metabolite effectively in vivo and bring into play its anticoagulant effect.Above-mentioned experimental result prompting; The compounds of this invention or its pharmacy acceptable salt can be used to prepare the medicine of prevention or treatment thrombus and embolism relative disease, in particular for the thrombotic medicine behind preparation prevention or treatment atheromatosis, myocardial infarction, apoplexy, ischemia cerebral thrombosis, peripheral arterial disease, acute coronary syndrome or the coronary artery interventional procedure.
Description of drawings
Fig. 1 is the proton nmr spectra of compound I-1;
Fig. 2 is the proton nmr spectra of compound I-2;
Fig. 3 is the proton nmr spectra of compound I-3;
Fig. 4 is the proton nmr spectra of compound I-4;
Fig. 5 is the proton nmr spectra of compound I-6;
Fig. 6 is the proton nmr spectra of compound I-7;
Fig. 7 is the proton nmr spectra of compound I-8;
Fig. 8 is the proton nmr spectra of compound I-8;
Fig. 9 is the proton nmr spectra of compound I-9;
Figure 10 is the proton nmr spectra of compound I-10;
Figure 11 is the proton nmr spectra of compound I-11;
Embodiment
Specify content of the present invention through embodiment below.In the present invention, the embodiment of the following stated is in order better to set forth the present invention, is not to be used for limiting scope of the present invention.
Embodiment 1
(1S-(1 α, 2 α, 3 β (1S*, 2R*), 5 β))-3-(7-(2-(3, the 4-difluorophenyl) cyclopropyl is amino)-5-(rosickyite base)-3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl)-5-propionyloxy pentamethylene-1,2 glycol (I-1)
Figure BSA00000674585300051
Steps A
Will (3 α R-(3a α, 4 α, 6 α (1R*, 2S*), 6a α))-((((2-(3 for 7-for 6-for 2-; The 4-difluorophenyl) tetrahydrochysene-2 cyclopropyl) amino-5-(rosickyite base)-3H-[1,2,3] triazolo [4,5-d] pyrimidin-3-yl), 2-dimethyl--4H-cyclopenta--1; 3-dioxane penta-4-alcohol (II-1) (200mg) is dissolved in the acetonitrile (5ml), adds the 0.10ml triethylamine, drips the 151mg propionic anhydride down at 0 ℃, after dropping finishes; Be warming up to room temperature reaction 2 hours, reaction solution is poured in the water (20ml), ETHYLE ACETATE (30ml * 3) aqueous phase extracted, organic phase is with saturated sodium bicarbonate aqueous solution and saturated common salt water washing; Anhydrous sodium sulfate drying, evaporate to dryness organic phase get bullion propionic acid (3 α R-(3a α, 4 α, 6 α (1R*; 2S*), 6a α))-2-(6-((7-(2-(3, the 4-difluorophenyl) cyclopropyl) amino-5-(rosickyite base)-3H-[1,2; 3] tetrahydrochysene-2 triazolo [4,5-d] pyrimidin-3-yl), 2-dimethyl--4H-cyclopenta--1,3-dioxane penta-4-ester (III-1) is (238mg).
Step B
To ((3a α, 4 α, 6 α (1R*, 2S*), 6a α))-((((2-(3 for 7-for 6-for 2-for 3 α R-with step 1 product propionic acid; The 4-difluorophenyl) tetrahydrochysene-2 cyclopropyl) amino-5-(rosickyite base)-3H-[1,2,3] triazolo [4,5-d] pyrimidin-3-yl), 2-dimethyl--4H-cyclopenta--1; The methanol solution (mass ratio is 1%) that adds 10ml iodine in 3-dioxane penta-4-ester (III-1), backflow 3h, it is complete that TLC detects primitive reaction, and reaction solution is poured in the water (20ml); ETHYLE ACETATE (30ml * 3) aqueous phase extracted, organic phase be with 10% hypo solution and saturated common salt water washing, anhydrous sodium sulfate drying, and the evaporate to dryness organic phase gets bullion; Through rapid column chromatography (sherwood oil: ETHYLE ACETATE=1: 5) (1S-(and 1 α, 2 α, 3 β (1S*, 2R*); 5 β))-3-(7-(2-(3, the 4-difluorophenyl) cyclopropyl is amino)-5-(rosickyite base)-3H-1,2,3-triazolo [4; 5-d] pyrimidin-3-yl)-5-propionyloxy pentamethylene-1,2 glycol (I-1) (77mg), yield 48% 1HNMR (300MHz, CD 3OD) δ 0.89～0.95 (3H, t), 1.15 (3H, t), 1.35～1.38 (1H, m), 1.46 (1H, s); 1.60～1.62 (2H, m), 2.12 (1H, s), 2.19～2.24 (1H, m), 2.38～2.42 (2H, q); 2.89～2.95 (2H, m), 3.03～3.11 (2H, m), 4.18 (1H, s), 4.74～4.82 (1H; M), 5.03～5.06 (1H, m), 5.16～5.21 (1H, q), 7.04～7.19 (3H, m) .ESI-MS m/z:535.2 [M+H] +.HRMS for C 24H 29F 2N 6O 4S, calcd 535.1939, found 535.1941.
Embodiment 2
(1S-(1 α, 2 α, 3 β (1S*, 2R*), 5 β))-3-(7-(2-(3, the 4-difluorophenyl) cyclopropyl is amino)-5-(rosickyite base)-3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl)-5-butyryl acyloxy pentamethylene-1,2 glycol (I-2)
Figure BSA00000674585300061
The preparation method replaces with butyryl oxide with reference to embodiment 1 with propionic anhydride, makes compound I-2, 1H NMR (300MHz, CDCl 3) δ 0.92～0.97 (6H, m), 1.43 (2H, m), 1.61～1.69 (4H, m); 2.15 (1H, s), 2.28～2.33 (2H, t), 2.45～2.55 (1H, m); 2.95～3.12 (4H, m), 4.32 (1H, s), 4.67～4.71 (1H; T), 5.07～5.15 (2H, m), 7.00～7.26 (3H, m) .ESI-MS m/z:549.2 [M+H] +.HRMS for C 25H 31F 2N 6O 4S, calcd 549.2096, found 549.2102.
Embodiment 3
(1S-(1 α, 2 α, 3 β (1S*, 2R*), 5 β))-3-(7-(2-(3, the 4-difluorophenyl) cyclopropyl is amino)-5-(rosickyite base)-3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl)-5-pivaloyl oxygen basic ring pentane-1,2 glycol (I-3)
Figure BSA00000674585300071
The preparation method replaces with pivaloyl chloride with reference to embodiment 1 with propionic anhydride, makes compound I-3, 1H NMR (300MHz, CDCl 3) δ 0.96 (3H, s), 1.19 (9H, s), 1.39 (2H, s), 1.67 (3H, s); 2.16 (1H, s), 2.50～2.54 (1H, m), 2.97 (1H, s), 3.04～3.12 (3H, m); 3.34 (1H, s), 4.27～4.28 (1H, d), 4.65～4.68 (1H, t), 5.04～5.08 (1H; Q), 5.11～5.13 (1H, s), 6.72 (1H, s), 7.00～7.10 (2H, m) .ESI-MS m/z:563.2 [M+H] +.HRMS for C 26H 33F 2N 6O 4S, calcd 563.2252, found 563.2254.
Embodiment 4
(1S-(1 α, 2 α, 3 β (1S*, 2R*), 5 β))-3-(7-(2-(3, the 4-difluorophenyl) cyclopropyl is amino)-5-(rosickyite base)-3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl)-5-benzoyloxy pentamethylene-1,2 glycol (I-4)
The preparation method replaces with Benzoyl chloride 99min. with reference to embodiment 1 with propionic anhydride, makes compound I-4, 1H NMR (300MHz, CD 3OD) δ 0.86～0.89 (3H, t), 1.28 (1H, m), 1.57～1.58 (1H, m), 1.70～1.74 (2H, m), 2.12 (1H; S), 2.37～2.42 (1H, m), 3.02～3.08 (2H, m), 3.12 (1H, m), 4.33 (1H, s); 4.79 (1H, m), 4.93 (1H, m), 5.29 (2H, m), 7.05 (1H, s); 7.15～7.20 (2H, m), 7.47～7.50 (2H, m), 7.60～7.63 (1H, m), 8.06～8.09 (2H, m) .ESI-MS m/z:605.2 [M+Na] +.HRMS for C 28H 28F 2N 6O 4SNa, calcd 605.1759, found 605.1765.
Embodiment 5
(1S-(1 α, 2 α, 3 β (1S*, 2R*), 5 β))-3-(7-(2-(3, the 4-difluorophenyl) cyclopropyl is amino)-5-(rosickyite base)-3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl)-5-ethoxycarbonyl-oxygen basic ring pentane-1,2 glycol (I-5)
Figure BSA00000674585300081
The preparation method replaces with Vinyl chloroformate with reference to embodiment 1 with propionic anhydride, makes compound I-5, 1H NMR (300MHz, CD 3OD) δ 0.90～0.94 (3H, m), 1.26～1.31 (3H, t), 1.34～1.36 (2H, m), 1.58～1.63 (2H; M), 2.11 (1H, s), 2.27～2.36 (1H, m), 2.89～3.00 (2H, m); 3.07～3.09 (2H, m), 4.15～4.22 (2H, m), 4.55 (1H, s), 4.78～4.83 (1H; M), 4.91～4.96 (1H, m), 5.15～5.23 (1H, q), 7.05～7.19 (3H, m) .ESI-MS m/z:551.2 [M+H] +.HRMS for C 24H 29F 2N 6O 5S, calcd 551.1888, found 551.1896.
Embodiment 6
(1S-(1 α, 2 α, 3 β (1S*, 2R*), 5 β))-3-(7-(2-(3, the 4-difluorophenyl) cyclopropyl is amino)-5-(rosickyite base)-3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl)-5-isobutyl boc oxygen basic ring pentane-1,2 glycol (I-6)
Figure BSA00000674585300082
The preparation method replaces with isobutyl chlorocarbonate with reference to embodiment 1 with propionic anhydride, makes compound I-6, 1H NMR (300MHz, CD 3OD) δ 0.89～0.99 (9H, d), 0.97～1.09 (1H, m), 1.21～1.24 (1H, t), 1.34～1.36 (1H, m); 1.45 (1H, m), 1.62～1.63 (2H, m), 1.92～2.00 (1H, m), 2.11 (1H; S), 2.29～2.35 (1H, m), 2.91～2.97 (2H, m), 3.06～3.09 (2H, m); 3.92～3.93 (2H, d), 4.08～4.09 (1H, q), 4.21～4.22 (1H, m), 4.77 (1H; M), 4.92～4.95 (1H, m), 5.16～5.21 (1H, q), 7.05～7.22 (3H, m) .ESI-MS m/z:579.2 [M+H] +.HRMSfor C 26H 33F 2N 6O 5S, calcd 579.2201, found 579.2209.
Embodiment 7
(1S-(1 α, 2 α, 3 β (1S*, 2R*), 5 β))-3-(7-(2-(3, the 4-difluorophenyl) cyclopropyl is amino)-5-(rosickyite base)-3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl)-5-(2-butyryl oxygen oxyethyl group) pentamethylene-1,2 glycol (I-7)
Figure BSA00000674585300083
The preparation method replaces with II-1 (3 α R-(3a α, 4 α, 6 α (1R* with reference to embodiment 1; 2S*), 6a α))-2-(6-((7-(2-(3, the 4-difluorophenyl) cyclopropyl) amino-5-(rosickyite base)-3H-[1,2; 3] tetrahydrochysene-2 triazolo [4,5-d] pyrimidin-3-yl), 2-dimethyl--4H-cyclopenta--1,3-dioxane penta-4-yl) the oxygen base)-1-ethanol (II-2); Propionic anhydride replaces with butyryl oxide, makes compound I-7 1H NMR (300MHz, CD 3OD) δ 0.90～0.95 (6H, t), 1.18～1.25 (2H, p), 1.36～1.52 (2H, m), 1.58～1.65 (2H, q), 2.11 (1H; M), 2.22 (1H, p), 2.28～2.33 (2H, t), 2.73～2.77 (1H, m), 2.92 (1H, m); 3.09 (2H, m), 3.73～3.78 (2H, m), 3.91 (1H, m), 4.08～4.13 (1H, m); 4.20～4.23 (2H, t), 4.76～4.83 (1H, m), 5.09～5.12 (1H, q), 7.05～7.16 (3H, m) .ESI-MS m/z:593.2 [M+H] +.HRMS for C 27H 35F 2N 6O 5S calcd 593.2358, found 593.2357.
Embodiment 8
(1S-(1 α, 2 α, 3 β (1S*, 2R*), 5 β))-3-(7-(2-(3, the 4-difluorophenyl) cyclopropyl is amino)-5-(rosickyite base)-3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl)-5-(2-pivaloyl oxygen oxyethyl group) pentamethylene-1,2 glycol (I-8)
Figure BSA00000674585300091
The preparation method replaces with pivaloyl chloride with reference to embodiment 7 with butyryl oxide, makes compound I-8, 1H NMR (300MHz, CD 3OD) δ 0.88～0.96 (3H, m), 1.15～1.18 (9H, s), 1.32～1.44 (2H, m), 1.56～1.61 (2H, q); 2.10 (1H, s), 2.18～2.27 (1H, m), 2.70～2.80 (1H, m), 2.89～3.00 (1H, m); 3.03～3.07 (2H, m), 3.73～3.80 (2H, m), 3.89～3.91 (1H, m), 4.12～4.14 (1H, m); 4.19～4.22 (2H, m), 4.74～4.82 (1H, m), 5.06～5.15 (1H, q), 7.03～7.18 (3H, m) .ESI-MS m/z:607.3 [M+H] +.HRMS for C 28H 36F 2N 6O 5S calcd 607.2514, found 607.2512.
Embodiment 9
(1S-(1 α, 2 α, 3 β (1S*, 2R*), 5 β))-3-(7-(2-(3, the 4-difluorophenyl) cyclopropyl is amino)-5-(rosickyite base)-3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl)-5-(2-benzoyl oxygen oxyethyl group) pentamethylene-1,2 glycol (I-9)
Figure BSA00000674585300092
The preparation method replaces with Benzoyl chloride 99min. with reference to embodiment 7 with butyryl oxide, makes compound I-9, 1H NMR (300MHz, CD 3OD) δ 0.83～0.98 (3H, m), 1.29～1.42 (2H, m), 1.51～1.68 (2H, m), 2.06 (1H, s), 2.23～2.32 (1H; M), 2.72～2.86 (2H, m), 2.95～3.03 (2H, m), 3.83～3.92 (2H, m), 3.97 (1H, m); 4.17～4.19 (1H, m), 4.42～4.45 (2H, t), 4.55 (1H, m), 5.06～5.15 (1H, q); 7.00～7.17 (3H, m), 7.37～7.42 (2H, m), 7.49～7.54 (1H, t), 7.95～7.98 (2H, d) .ESI-MS m/z:627.2 [M+H] +.HRMS for C 30H 32F 2N 6O 5Scalcd 627.2201, found 627.2203.
Embodiment 10
(1S-(1 α, 2 α, 3 β (1S*, 2R*), 5 β))-3-(7-(2-(3, the 4-difluorophenyl) cyclopropyl is amino)-5-(rosickyite base)-3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl)-5-(2-nicotinoyl oxygen oxyethyl group) pentamethylene-1,2 glycol (I-10)
Figure BSA00000674585300101
The preparation method replaces with nicotinoyl chlorine with reference to embodiment 7 with butyryl oxide, makes compound I-10, 1H NMR (300MHz, CD 3OD) δ 0.86～0.19 (3H, t), 1.29～1.37 (2H, m), 1.46～1.60 (2H, m), 2.11～2.27 (2H, m); 2.73～2.90 (2H, m), 3.00～3.09 (2H, m), 3.92～3.98 (3H, d), 4.17 (1H, s); 4.51 (2H, s), 4.79 (1H, s), 5.08～5.16 (1H, q), 7.04～7.20 (3H, m); 7.54 (1H, m), 8.38～8.41 (1H, d), 8.68～8.72 (1H, dd), 9.13 (1H, s).
Embodiment 11
(1S-(1 α, 2 α, 3 β (1S*, 2R*), 5 β))-3-(7-(2-(3, the 4-difluorophenyl) cyclopropyl is amino)-5-(rosickyite base)-3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl)-5-(2-ethoxycarbonyl-oxygen oxyethyl group) pentamethylene-1,2 glycol (I-11)
Figure BSA00000674585300102
The preparation method replaces with Vinyl chloroformate with reference to embodiment 7 with butyryl oxide, makes compound I-11, 1H NMR (300MHz, CD 3OD) δ 0.90～1.03 (3H, m), 1.24～1.27 (3H, t), 1.34～1.35 (1H, m), 1.45 (1H, m), 1.60～1.62 (2H; M), 2.11 (1H, m), 2.21～2.27 (1H, m), 2.72～2.78 (1H, m), 2.91～2.92 (1H, m); 3.03～3.09 (2H, m), 3.74～3.80 (2H, m), 3.90～3.93 (1H, m), 4.13～4.17 (3H, m); 4.25～4.27 (2H, t), 4.78 (1H, m), 5.09～5.11 (1H, q), 7.04～7.19 (3H, m) .ESI-MS m/z:595.2 [M+H] +.HRMS for C 26H 32F 2N 6O 5S, calcd 595.2150, found 595.2153.
Embodiment 12
The platelet aggregation inhibitory activity test
Medicine and preparation: positive drug is prasugrel and replaces card Gray.Positive drug and test-compound are made into suspension with 0.5%CMC-Na (Xylo-Mucine) and supply animals administer to use.
0.5% CMC 99.5, China Medicine (Group) Shanghai Chemical Reagent Co..
ADP, Sigma, the U.S..
Animal: the Wistar rat, 200～250g, male, provide by Zhejiang Province's Experimental Animal Center.Ticket number: SCXK (Shanghai) 2008-0033
Instrument: platelet aggregation instrument (560Ca), CHRONO-LOG, the U.S.
Method: with reference to the BORN turbidimetry (Nature, 1962,194 (4832): 927), to The compounds of this invention (the foregoing description preparation) carry out the pharmacological activity test of platelet aggregation-against.In being rich in hematoblastic blood plasma (PRP), add short condensation prod ADP (ADP) and stir, make platelet aggregation.Hematoblastic gathering causes the variation of optical density(OD), can detect through spectrophotometer.This experiment can be estimated test-compound in vivo or the platelet aggregation effect that causes of treated in vitro.
The platelet aggregation inhibitory activity test: with the rat random packet, gastric infusion test-compound (using preceding 0.5% CMC 99.5 suspendible), dosage is 5mg/kg, blank group per os is irritated stomach and is given the 0.5%CMC-Na with volume.0.5h after, eye socket is got blood, 3.8% Sodium Citrate anti-freezing, and whole blood is 9: 1 with the ratio of antithrombotics, the centrifugal 7min of 1000rpm, preparation platelet rich plasma (PRP).Transfer PRP with platelet poor plasma (PPP), make platelet count remain on 2 * 10 6Individual/ml.Get PRP and add in the test cup, hatch 10min for 37 ℃, with the PRP zeroing, PPP transfers 100%, is inductor with ADP (final concentration is 5 μ M), measures platelet aggregation percentage ratio by turbidimetry with platelet aggregation instrument, carries out statistical comparisons with the t-check.The anticoagulant rate is calculated as follows: anticoagulant rate (%)=[1-(delivery tube is assembled percentage/control tube and assembled percentage)] * 100%.
Result's (seeing Table 1) shows that most of test-compound demonstrates stronger platelet aggregation inhibitory activity.Show that novel anti thrombocyte compound provided by the invention has good DEVELOPMENT PROSPECT.
Anticoagulant effect behind the table 1. rat oral test compound

Claims (10)

  1. Triazolo shown in the formula I (4,5-D) pyrimidine derivatives and pharmacy acceptable salt thereof:
    Figure FSA00000674585200011
    Wherein, R represents XCOR 1, X is CH 2CH 2O or key;
    R 1Be the substituted straight or branched alkyl of non-substituted or Y, the OR of 1～10 carbon 2, NR 3R 4, phenyl, the substituted phenyl of Z, styryl, 4-hydroxystyrene based, 4-hydroxyl-3-methoxyl-styrene, 3-pyridyl, alkenyl or alkynyl; Wherein Y is fluorine, chlorine, bromine, iodine, itrile group, nitro, amino, amido, sulfonamido, trifluoromethyl, sulfydryl, hydroxyl, acetoxyl group, methoxyl group, oxyethyl group, carboxyl, methoxy acyl group, ethoxy acyl group, aryloxy, phenyl or the substituted phenyl of Z; Z is fluorine, chlorine, bromine, iodine, itrile group, nitro, amino, amido, sulfonamido, trifluoromethyl, sulfydryl, hydroxyl, acetoxyl group, methoxyl group, oxyethyl group, carboxyl, methoxy acyl group or ethoxy acyl group, and the Z group is in 2,3 or 4 of phenyl ring;
    R 2Be the straight or branched alkyl or the benzyl of 1～10 carbon;
    R 3, R 4Be the straight or branched alkyl of 1～6 carbon, or NR 3R 4For
    Figure FSA00000674585200012
  2. 2. (4,5-D) pyrimidine derivatives is characterized in that, R in the said formula I compound according to the triazolo of claim 1 1Be the substituted straight or branched alkyl of non-substituted or Y, the OR of 1～6 carbon 2, NR 3R 4, phenyl, the substituted phenyl of Z, styryl, 4-hydroxystyrene based, 4-hydroxyl-3-methoxyl-styrene or 3-pyridyl, wherein Y is amino, amido, sulfonamido, hydroxyl, acetoxyl group, methoxyl group, oxyethyl group, carboxyl, methoxy acyl group, ethoxy acyl group, aryloxy, phenyl or the substituted phenyl of Z; Z is fluorine, chlorine, bromine, iodine, itrile group, nitro, amino, amido, sulfonamido, hydroxyl, acetoxyl group, methoxyl group, oxyethyl group, carboxyl, methoxy acyl group or ethoxy acyl group, and the Z group is in 2,3 or 4 of phenyl ring; R 2Be the straight or branched alkyl or the benzyl of 1～6 carbon; R 3, R 4Be the straight or branched alkyl of 1～6 carbon, or NR 3R 4For
    Figure FSA00000674585200013
    Figure FSA00000674585200014
  3. 3. (4,5-D) pyrimidine derivatives is characterized in that, R in the said formula I compound according to the triazolo of claim 1 1For methyl, ethyl, propyl group, the tertiary butyl, tertiary amyl, Phenoxymethyl, methoxyl group, oxyethyl group, isopropoxy, isobutoxy, benzyloxy ,-N (CH 3) 2,-N (CH 2CH 3) 2,-N (CH 3) (CH 2CH 3),
    Figure FSA00000674585200015
    Phenyl, 2-hydroxy phenyl, 2-acetoxyl group phenyl, 4-p-methoxy-phenyl, 4-nitrophenyl, styryl, 4-hydroxystyrene based, 4-hydroxyl-3-methoxyl-styrene or 3-pyridyl.
  4. 4. (4,5-D) pyrimidine derivatives is characterized in that, said verivate comprises the pharmacy acceptable salt of formula I compound according to each triazolo among the claim 1-3; Comprise the acid salt that compound and following acid form: hydrochloric acid, Hydrogen bromide, sulfuric acid, Hydrocerol A, tartrate, phosphoric acid, lactic acid, acetate, toxilic acid, fumaric acid, oxysuccinic acid, tussol, methylsulfonic acid, Phenylsulfonic acid, tosic acid, pamoic acid (palmoxiric acid), oxalic acid or succsinic acid.
  5. According to the triazolo of claim 1 (4,5-D) pyrimidine derivatives is characterized in that said verivate comprises following compounds:
    (1S-(1 α, 2 α, 3 β (1S*, 2R*), 5 β))-3-(7-(2-(3, the 4-difluorophenyl) cyclopropyl is amino)-5-(rosickyite base)-3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl)-5-propionyloxy pentamethylene-1,2 glycol I-1;
    (1S-(1 α, 2 α, 3 β (1S*, 2R*), 5 β))-3-(7-(2-(3, the 4-difluorophenyl) cyclopropyl is amino)-5-(rosickyite base)-3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl)-5-butyryl acyloxy pentamethylene-1,2 glycol I-2;
    (1S-(1 α, 2 α, 3 β (1S*, 2R*), 5 β))-3-(7-(2-(3, the 4-difluorophenyl) cyclopropyl is amino)-5-(rosickyite base)-3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl)-5-pivaloyl oxygen basic ring pentane-1,2 glycol I-3;
    (1S-(1 α, 2 α, 3 β (1S*, 2R*), 5 β))-3-(7-(2-(3, the 4-difluorophenyl) cyclopropyl is amino)-5-(rosickyite base)-3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl)-5-benzoyloxy pentamethylene-1,2 glycol I-4;
    (1S-(1 α, 2 α, 3 β (1S*, 2R*), 5 β))-3-(7-(2-(3, the 4-difluorophenyl) cyclopropyl is amino)-5-(rosickyite base)-3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl)-5-ethoxycarbonyl-oxygen basic ring pentane-1,2 glycol I-5;
    (1S-(1 α, 2 α, 3 β (1S*, 2R*), 5 β))-3-(7-(2-(3, the 4-difluorophenyl) cyclopropyl is amino)-5-(rosickyite base)-3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl)-5-isobutyl boc oxygen basic ring pentane-1,2 glycol I-6;
    (1S-(1 α, 2 α, 3 β (1S*, 2R*), 5 β))-3-(7-(2-(3, the 4-difluorophenyl) cyclopropyl is amino)-5-(rosickyite base)-3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl)-5-(2-butyryl oxygen oxyethyl group) pentamethylene-1,2 glycol I-7;
    (1S-(1 α, 2 α, 3 β (1S*, 2R*), 5 β))-3-(7-(2-(3, the 4-difluorophenyl) cyclopropyl is amino)-5-(rosickyite base)-3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl)-5-(2-pivaloyl oxygen oxyethyl group) pentamethylene-1,2 glycol I-8;
    (1S-(1 α, 2 α, 3 β (1S*, 2R*), 5 β))-3-(7-(2-(3, the 4-difluorophenyl) cyclopropyl is amino)-5-(rosickyite base)-3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl)-5-(2-benzoyl oxygen oxyethyl group) pentamethylene-1,2 glycol I-9;
    (1S-(1 α, 2 α, 3 β (1S*, 2R*), 5 β))-3-(7-(2-(3, the 4-difluorophenyl) cyclopropyl is amino)-5-(rosickyite base)-3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl)-5-(2-nicotinoyl oxygen oxyethyl group) pentamethylene-1,2 glycol I-10;
    (1S-(1 α, 2 α, 3 β (1S*, 2R*), 5 β))-3-(7-(2-(3, the 4-difluorophenyl) cyclopropyl is amino)-5-(rosickyite base)-3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl)-5-(2-ethoxycarbonyl-oxygen oxyethyl group) pentamethylene-1,2 glycol I-11.
  6. According to claim 1 triazolo (4, the 5-D) preparation method of pyrimidine derivatives, following reaction formula:
    Figure FSA00000674585200021
    Comprise the following steps:
    (1) formula II compound or its salt and formula IV compound or formula V compound react in the presence of alkali; Obtain the formula III compound; Used reaction solvent is selected from benzene, toluene, chloroform, normal hexane, hexanaphthene, methylene dichloride, 1; 2-ethylene dichloride, MTBE, tetracol phenixin, ETHYLE ACETATE, propyl acetate, butylacetate, methyl alcohol, ethanol, acetone, THF, ether, acetonitrile, N; The mixed solvent of one or more in dinethylformamide or the methyl-sulphoxide, preferred THF, acetonitrile or N, dinethylformamide; The alkali that is adopted is selected from triethylamine, sodium hydride, potassium hydride KH, 1,8-diazacyclo [5,4,0] hendecene-7, pyridine, diisopropylethylamine, diisopropylamine lithium, salt of wormwood, yellow soda ash, saleratus, sodium hydrogencarbonate, potassium tert.-butoxide or sodium tert-butoxide; Temperature of reaction is subzero 20 ℃ to 100 ℃, and preferred temperature is 0 ℃ to 50 ℃;
    (2) formula III compound reaction in the presence of protection of inert gas and acid; Obtain the formula III compound; Used reaction solvent is selected from methyl alcohol, ethanol, propyl alcohol, butanols, acetone, THF, dioxane, N; The mixed solvent of one or more in dinethylformamide, methyl-sulphoxide, pyridine or the acetonitrile, preferred THF; The acid of being adopted is selected from hydrochloric acid, sulfuric acid, phosphoric acid, perchloric acid, hypochlorous acid, trifluoroacetic acid, difluoroacetic acid, a gifblaar poison, trichoroacetic acid(TCA), dichloro acetic acid, Monochloro Acetic Acid, Hydrocerol A, oxysuccinic acid, oxalic acid, Glacial acetic acid min. 99.5, propionic acid, butyric acid; Protecting property gas is selected from nitrogen, carbonic acid gas, helium, argon gas, neon; Temperature of reaction is subzero 20 ℃ to 100 ℃, and preferred temperature is 25 ℃ to 50 ℃;
    (3) the formula III compound also can react in the presence of protection of inert gas and iodine; Obtain the formula III compound; Used reaction solvent is selected from methyl alcohol, ethanol, propyl alcohol, butanols, acetone, THF, dioxane, N, the mixed solvent of one or more in dinethylformamide, methyl-sulphoxide, pyridine or the acetonitrile, particular methanol and acetone; Concentration range is 0.1～10% (w/w), and preferred concentration is 0.5%; Protecting property gas is selected from nitrogen, carbonic acid gas, helium, argon gas, neon; Temperature of reaction is subzero 20 ℃ to 100 ℃, and preferred temperature is 30 ℃ to 80 ℃.
    In above-mentioned reaction formula, X, R 1Such as in the above-mentioned formula I compound definition.
  7. As each said triazolo among the claim 1-3 (4, the 5-D) purposes of pyrimidine derivatives in the medicine of preparation prevention or treatment thrombus and embolism relative disease.
  8. 8. purposes as claimed in claim 7 is characterized in that, the thrombotic medicine after being used to prepare prevention or treating atheromatosis, myocardial infarction, apoplexy, ischemia cerebral thrombosis, peripheral arterial disease, acute coronary syndrome or coronary artery interventional procedure.
  9. 9. a pharmaceutical composition that prevents or treat thrombus and embolism relative disease is characterized in that, contains formula I compound or its pharmacy acceptable salt and pharmaceutically acceptable carrier in the said pharmaceutical composition.
  10. 10. pharmaceutical composition as claimed in claim 9 is characterized in that, said pharmaceutical composition is tablet, capsule, slow releasing tablet, granule, powder, syrup, oral liquid or injection.
CN2012100434321A 2012-02-24 2012-02-24 Triazol (4,5-D) pyrimidine derivate and preparation method of triazol (4,5-D) pyrimidine derivate as well as application of triazol (4,5-D) pyrimidine derivate in drug preparation Pending CN102603751A (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103183679A (en) * 2013-03-20 2013-07-03 西藏海思科药业集团股份有限公司 Anticoagulant compound and application thereof
WO2014155389A2 (en) * 2013-03-25 2014-10-02 Glenmark Pharmaceuticals Limited; Glenmark Generics Limited Process for preparation of ticagrelor
CN105481861A (en) * 2014-09-19 2016-04-13 北京普禄德医药科技有限公司 Platelet aggregation inhibitor, and preparation method and application thereof
CN105859720A (en) * 2015-01-20 2016-08-17 上海方楠生物科技有限公司 Method for preparing ticagrelor solution

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001036421A1 (en) * 1999-11-15 2001-05-25 Astrazeneca Ab Novel [1,2,3]-triazolo[4,5-d]pyrimidine compounds
CN102311437A (en) * 2010-07-01 2012-01-11 北京迈劲医药科技有限公司 Preparation method of platelet-aggregation-resisting medicament Ticagrelor

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001036421A1 (en) * 1999-11-15 2001-05-25 Astrazeneca Ab Novel [1,2,3]-triazolo[4,5-d]pyrimidine compounds
CN102311437A (en) * 2010-07-01 2012-01-11 北京迈劲医药科技有限公司 Preparation method of platelet-aggregation-resisting medicament Ticagrelor

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
《安徽化工》 20061230 朱仁发，等 抗恶性肿瘤新药N4- 戊氧碳酰- 5'- 脱氧- 5- 氟胞嘧啶的合成 第22-23页 1-10 , 第6期 *
DIANSONG ZHOU，等: "In Vitro Evaluation of Potential Drug-Drug Interactions with Ticagrelor: Cytochrome P450 Reaction Phenotyping, Inhibition, Induction, and Differential Kinetics", 《DRUG METABOLISM AND DISPOSITION》 *
朱仁发，等: "抗恶性肿瘤新药N4- 戊氧碳酰- 5’- 脱氧- 5- 氟胞嘧啶的合成", 《安徽化工》 *
杨臻峥，等: "抗凝血药替卡格雷", 《药学进展》 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103183679A (en) * 2013-03-20 2013-07-03 西藏海思科药业集团股份有限公司 Anticoagulant compound and application thereof
WO2014155389A2 (en) * 2013-03-25 2014-10-02 Glenmark Pharmaceuticals Limited; Glenmark Generics Limited Process for preparation of ticagrelor
WO2014155389A3 (en) * 2013-03-25 2015-01-15 Glenmark Pharmaceuticals Limited; Glenmark Generics Limited Process for preparation of ticagrelor
CN105481861A (en) * 2014-09-19 2016-04-13 北京普禄德医药科技有限公司 Platelet aggregation inhibitor, and preparation method and application thereof
CN105859720A (en) * 2015-01-20 2016-08-17 上海方楠生物科技有限公司 Method for preparing ticagrelor solution

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Application publication date: 20120725