CN101665465B - Thrombase inhibitor containing guanidyl heterocyclic compound and preparation method thereof - Google Patents
Thrombase inhibitor containing guanidyl heterocyclic compound and preparation method thereof Download PDFInfo
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- CN101665465B CN101665465B CN2007100462231A CN200710046223A CN101665465B CN 101665465 B CN101665465 B CN 101665465B CN 2007100462231 A CN2007100462231 A CN 2007100462231A CN 200710046223 A CN200710046223 A CN 200710046223A CN 101665465 B CN101665465 B CN 101665465B
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Abstract
The invention belongs to the field of chemosynthesis and relates to a thrombase inhibitor containing guanidyl heterocyclic compound and a preparation method thereof. In the invention, an alkaline group which has high affinity with a thrombase active site is constructed and a compound which has anticoagulation effect and the structural formula is synthesized, and the thrombase inhibitor can be directly prepared. The target compound obtained from the invention undergoes activity tests, and results show that the target compound can obviously inhibit the generation of thrombases. The synthesizing method realizes simple step operation separation, utilizes common reagents, has short course and achieves high yield in each step.
Description
Technical field
The invention belongs to the field of chemical synthesis, relate to and contain the Guanidinyl heterocycle compounds inhibitor, be specifically related to a kind of thrombin inhibitors that contains Guanidinyl heterocycle compounds and preparation method thereof.
Background technology
Thromboembolism and complication thereof are to cause the current social people's morbidity and one of the most important reason that causes death.Studies show that zymoplasm advances in blood coagulation and plays important effect aspect the rank, therefore becomes the first-selected target of development anticoagulant.The research of past many decades anti-freezing formulation art is very active, and has obtained sizable progress.And for research and development have efficiently, safety and to be easy to the moving and medicine of oral and gratifying medicine be the emphasis and the direction in this field in recent years for the anticoagulant of character.
Be used for employed medicine of anticoagulation therapy such as Warfarin in early days clinically, heparin or low molecular weight heparin and natural thrombin inhibitors r-hirudin etc., because their therapeutic domain is narrow, do not have specificity, perhaps in use need to drop into a large amount of monitoring, and be easy to cause shortcomings such as other complication, cause its range of application to be subjected to bigger restriction.
In order to improve anticoagulating active and the better generation of control zymoplasm, many anti-freezing strategies are applied among the research.Through unremitting effort for many years, the thrombin inhibitors of synthetic has been obtained many great progress as anticoagulant active research, and research and development have oral bioactive direct thrombin inhibitors and become one of the research focus in this field already.At present the thrombin inhibitors compounds of being developed has in this respect been developed into the s-generation from the first-generation, but have only minority to have pharmacokinetics and pharmacodynamic properties in the suitable body in them, and this judge that just can they further carry out the important evidence of clinical study.
Argatroban (Argatroban) is that (nineteen ninety is in Japan) can be applied to clinical first-generation thrombin inhibitors first, be used for treating arterial thrombosis and cause by acute apoplexy hemorrhage.2000, argatroban passed through the U.S. FDA authentication, was used for the special for treating thrombocytopenia.But clinical practice shows that the oral administration biaavailability of argatroban is lower, can only pass through intravenously administrable, and only there is 30min the transformation period in human body.Even so, argatroban remains the first-selected medication of clinical treatment embolism.
Melagatran (Melagatran) with highly selective has good selectivity to molten fine proteolytic enzyme and Quimotrase, but oral administration biaavailability is not high.Therefore, it is made two prodrug---Xi Meijia groups (Ximelagatran), thereby improved oral administration biaavailability.Through long-term clinical study, Xi Meijia group can twice administration in a day, and do not need monitoring.It can be used for the venous thromboembolism that the tender shape operation of prevention of surgical causes, also can be used as the long-term auxiliary medicaments of treatment venous thrombosis, therefore can also prevent heart valve anterior chamber's fibriilar formation, become (in December, 2003) first synthetic anti-freezing preparation in a large number of France's approval.From the document of having reported, Melagatran and Xi Meijia group are gratifying as the clinical efficacy of thrombin inhibitors.
Norbert H.Hauel (the J.Med.Chem.2002 of Germany in 2002,45,1757-1766) seminar has reported the s-generation thrombin inhibitors BIBR-953 of Boehringer Ingelheim Pharma KG company exploitation and synthesizing of two prodrug BIBR-1048 thereof:
BIBR-953 and prodrug BIBR-1048 thereof are as a kind of thrombin inhibitors of efficient, highly selective, and internal and external test shows that it and zymoplasm have high avidity, and has good activity in vivo prospect.But in this route be that synthetic key intermediate compound (i) productive rate of condensing agent is lower with CDI, Chinese patent application (publication number: CN1861596) use HOBt/EDCI replaced C DI, simultaneously part steps is optimized, obtained result preferably.
Summary of the invention
Purpose of the present invention aims to provide a kind of thrombin inhibitors that contains Guanidinyl heterocycle compounds.
Further purpose of the present invention aims to provide the preparation method of above-mentioned thrombin inhibitors.
In view of BIBR-953 combines with the thrombin activity site by its aminoterminal, the present invention is optimized transformation to its aminoterminal, strengthening itself and the avidity in thrombin activity site, thus better Trombin inhibiting generation.
Present method is with 1,2, and 5-trisubstituted benzene and imidazoles are center framework, makes up the basic group with thrombin activity site high-affinity, sets up achirality novel, efficient, high yield, non-peptide class contain Guanidinyl heterocycle compounds.
Further purpose of the present invention aims to provide the purposes of the antithrombin generation of this compounds.
Thrombase inhibitor containing guanidyl heterocyclic compound of the present invention is replacing 1,2, and 5-trisubstituted benzene and imidazoles are center framework, have following structural formula:
Wherein, R
1Be phenyl or substituted-phenyl :-C
6H
5, 4-X-C
6H
4, perhaps be heterocyclic such as pyridine or substituted pyridines :-C
5H
4N, 4-CH
3-C
5H
3N, 6-CH
3-C
5H
3N, 6-X-C
6H
4N; R
2For guanidine radicals or replace guanidine radicals :-NHC (=NH)-NH
2,-NHC (=NR ')-NHR " ,-CH
2-NHC (=NH)-NH
2,-CH
2-NHC (=NR ')-NHR ", R ' wherein, R " for containing C
1～C
10Substituting group; X is a halogen.
The above-mentioned guanidine compound that contains has been optimized and has been had with 1,2, and 5-trisubstituted benzene and imidazoles are the structure of the compound group of center framework, thereby have strengthened the avtive spot of zymoplasm and combining of this mediation substrate.Described compound has the obvious suppression effect to the generation of zymoplasm.
Purpose of the present invention is achieved through the following technical solutions:
The present invention preferably has following structure I, II, and III, IV, the compound of V and VI:
Compound of the present invention prepares by following synthetic method,
Wherein, specific synthetic product is represented with Arabic numerals according to the numbering in the structural formula.
1. prepare starting compound 1 (its synthetic method is seen national inventing patent CN1861596):
R wherein
1Be phenyl or substituted-phenyl :-C
6H
5, 4-X-C
6H
4, perhaps be heterocyclic such as pyridine or substituted pyridines :-C
5H
4N, 4-CH
3-C
5H
3N, 6-CH
3-C
5H
3N, 6-X-C
6H
4N; X is a halogen;
(its synthetic method is with reference to Synthesis 2004,1,37-42) to prepare the compound 6 that contains guanidine radicals
Wherein R ' is C
1～C
10Substituting group, be recommended as carbobenzoxy-(Cbz) C
8H
7O
2, carbobenzoxy C
7H
5O
2, tertbutyloxycarbonyl C
5H
9O
2, just own oxygen carbonyl C
8H
16O
2Or other.
2. by following synthetic route synthesising target compound:
Synthesising target compound comprises the steps:
(1) compound 1 is dissolved in a kind of alcoholic solution, behind the adding palladium carbon, feeds hydrogen, and continuously stirring 10～30h filters, and concentrates and promptly gets compound 2; Perhaps compound 1 is dissolved in a kind of solvent, adds reductive agent, and continuously stirring is until reacting completely the treated compound 2 that obtains; Perhaps compound 1 is dissolved in a kind of alcoholic solution, adds catalyzer, and feeding gas is saturated until so-called alcoholic solution, feeds hydrogen again, and reaction is filtered until fully under this atmosphere, concentrates and promptly gets compound 2.
Said alcoholic solution is meant methyl alcohol, ethanol, the trimethyl carbinol, propyl carbinol, the pure and mild ethanol of n-hexyl alcohol etc., particularly nail.
Said a kind of solvent refers to ether solvent, comprises ether, methyl tertiary butyl ether, and tetrahydrofuran (THF)s etc. are meant tetrahydrofuran (THF) especially.
Said gas refers in particular to ammonia.
Said reductive agent comprises lithium aluminium hydride, sodium borohydride, and lithium borohydride, the borine tetrahydrofuran (THF), borine dimethyl sulphides etc. refer in particular to lithium aluminium hydride and borine tetrahydrofuran (THF).
Said catalyzer refers to reduced iron powder, Raney nickel, and red aluminium (Red-Al), reduction zinc powders etc. refer in particular to Raney nickel.
(2) compound 2 is dissolved in a kind of organic solvent, adds a kind of organic bases, adds compound 6 again, adds a kind of inorganic salt subsequently.Continuously stirring 1～10h, after filtration, extraction obtains compound 3 behind the si-enriched plastic column chromatography.
Said a kind of organic solvent nail alcohol, ethanol, methyl-sulphoxide, N, dinethylformamide, tetramethylene sulfone, methylene dichloride, trichloromethane, tetracol phenixin etc., particularly N, dinethylformamide or methyl-sulphoxide.
Said organic bases refers to dimethylamine, triethylamine, Isopropylamine, N, N-diisopropylethylamine, TERTIARY BUTYL AMINE, n-Butyl Amine 99 etc., particularly N, N-diisopropylethylamine or triethylamine.
Said a kind of inorganic salt refer to the high-valency metal muriate, comprise iron(ic) chloride, mercury chloride, calcium chloride, cupric chloride etc., particularly mercury chloride.
(3) in a kind of organic solution of compound 3, add a kind of acid, reaction 2～8h concentrates, and alkalization promptly gets compound 4; Perhaps compound 3 is dissolved in a kind of alcoholic solution, adds catalyzer, feeds hydrogen, and successive reaction 3～10h after filtration, concentrates and promptly obtains compound 4.
Said organic solution is meant C
1～C
4Hydrochloric ether, or methyl alcohol, ethanol, dioxane, N, dinethylformamide, methyl-sulphoxide etc., particularly methylene dichloride or dioxane;
Said acid is organic acid, and particularly trifluoroacetic acid perhaps is meant sour gas, particularly hydrogenchloride.
Said alcoholic solution is a methyl alcohol, ethanol, the trimethyl carbinol, n-hexyl alcohol etc., particularly methyl alcohol or ethanol.
Said catalyzer refers to metal catalyst, comprises palladium, cobalt, and iron, zinc etc. perhaps refer to the immobilized thing or the alloy of described metal catalyst comprise palladium hydroxide carbon, palladium carbon, Raney nickel, iron-nickel alloy, iron-zinc alloy etc., particularly palladium carbon or palladium hydroxide carbon.
(4) compound 4 is dissolved in the mixed solution of a kind of alcohol and water, adds mineral alkali, stirs 2～10h, thin up, and acidifying promptly has precipitation to separate out, and filters and promptly gets compound 5.
Said alcohol is nail alcohol or ethanol particularly.Said mineral alkali refers in particular to potassium hydroxide, sodium hydroxide or lithium hydroxide.
Simultaneously, the present invention according to the method for synthetic compound 1, has synthesized compound 7 in order to make up and the direct-connected guanidino group of phenyl ring:
The synthetic route of target compound 11 is consistent with above-mentioned route:
(5) compound 7 is dissolved in a kind of alcoholic solution, adds palladium carbon, feeds hydrogen, and successive reaction 3～10h after filtration, concentrates and promptly obtains compound 8.
Said alcoholic solution is a methyl alcohol, ethanol, the trimethyl carbinol, n-hexyl alcohol etc., particularly methyl alcohol or ethanol.
(6) by compound 8 synthetic compounds 9, itself and above-mentioned condition (2) are in full accord.
(7) by compound 9 synthetic compounds 10, itself and above-mentioned condition (3) are in full accord.
(8) by compound 10 synthetic compounds 11, itself and above-mentioned condition (4) are in full accord.
The present invention has made up a kind of and basic group thrombin activity site high-affinity, has synthesized the compound with anti-freezing effect, can prepare direct thrombin inhibitors.It is simple that its outstanding advantage is that the operation of synthetic method step separates, and used reagent is common agents, and route is shorter, and each step productive rate is higher.
Compound of the present invention has the obvious suppression effect to the generation of zymoplasm.
Method of the present invention is simple, and productive rate is higher.The guanidine radicals structure that compound had that makes can more efficientlyly combine with the avtive spot of zymoplasm.The gained target compound has the effect that Trombin inhibiting produces through active testing, is a kind of direct thrombin inhibitors compounds.
Embodiment
Further specify the present invention with embodiment below.
Embodiment 1
Work as R
1During for the 2-pyridine,
Synthetic 3-(2-[(4-cyano group-benzene imines)-methylene radical]-1-methylene radical-1 hydrogen-benzoglyoxaline-5-carbonyl }-pyridine-2-imines)-ethyl propionate (1)
With compound 2-(4-cyano group-phenylamino)-acetate (2.32g; 13.2mmol) be dissolved among the 80ml DMF; add HOBT (1.96g; 14.5mmol), (2.77g 14.5mmol) stirs 10～60min in adding EDCI below 0 ℃; slowly rise to room temperature; adding diamine compound 3-(N, and N-(2-pyridine)-[3-amino-4-methylamino-benzoyl]-ethyl propionate (5.0g, 14.5mmol).Reaction 2～6h concentrates, and with a large amount of ethyl acetate dilutions, saturated aqueous common salt is given a baby a bath on the third day after its birth inferior, through Na
2SO
4After the drying, concentrate, the thick product 1.5h that refluxes in 60ml acetate after concentrating, adds alkalization, with ethyl acetate extraction (60mL * 3) three times, organic phase with the saturated common salt washing once, through Na
2SO
4After the drying, concentrate, thick product purification by silica gel column chromatography obtains white solid 1 (5.8g, 89.6%).
Synthetic 3-(2-[(4-aminomethyl-benzene imines)-methylene radical]-1-methylene radical-1 hydrogen-benzoglyoxaline-5-carbonyl }-pyridine-2-imines)-ethyl propionate (2)
With compound 1 (5.5g 11.40mmol) is dissolved in the 100ml anhydrous methanol, adds the catalyzer Raney nickel, then with to feed ammonia saturated to solution in the encloses container, successive reaction 2～18h under logical atmosphere of hydrogen again.Reaction finishes, and the elimination solid matter after filtrate concentrates, gets white solid 2 (5.30g, 93%).
Synthetic 3-(2-[(4-methyl guanidine radicals-benzene imines)-methylene radical]-1-methylene radical-1 hydrogen-benzoglyoxaline-5-carbonyl }-pyridine-2-imines)-ethyl propionate (4)
Recommend following two kinds of methods:
1) (1.0g 7.19mmol) is dissolved in the 15ml water, adds the sodium hydroxide solution 10ml of isopyknic dioxane and 1N subsequently, after the stirred for several minute, adds (Boc) with methylthio group miaow base vitriol
2O (7.85g, 35.97mmol).Reaction 2～10h is until reacting completely.The concentration response system to there being a large amount of solids to separate out, leaches solid, adds acetic acid ethyl dissolution, and it is inferior to give a baby a bath on the third day after its birth with 0 ℃～70 ℃ saturated aqueous common salt, and organic phase merges the back with Na
2SO
4Drying concentrates, and thick product recrystallization gets white solid 6 (1.77g, 88%).
With compound 2 (3.0g 6.17mmol) is dissolved among the 25ml DMF, adds the 0.9ml triethylamine, stirred for several minute, add subsequently compound 6 (3.68g, 10.30mmol), in system, add again mercury chloride (1.78g, 6.17mmol).Reaction 2～6h adds water 30ml, and with ethyl acetate extraction, organic phase is given a baby a bath on the third day after its birth inferior with saturated aqueous common salt, with Na
2SO
4Drying concentrates, and thick product purification by silica gel column chromatography obtains white solid 3 (3.64g, 81.1%).
With compound 2 (2.0g 2.74mmol) is dissolved in the 8ml methylene dichloride, adds the 16ml trifluoroacetic acid, stirs 2～5h, after reaction finishes, revolves and boils off reaction solution, and remnants add the alkalization of 1.5N ammoniacal liquor, evaporate to dryness, crude product 4, this compound is without being further purified.
2) with methylthio group miaow base vitriol (1.0g 7.19mmol) is dissolved in the 15ml water, adds sodium hydroxide solution 30ml and the excess bicarbonate of 1N, after the stirred for several minute, add Cbz-Cl (3.68g, 21.59mmol).Reaction 2～5h.Add the 30ml saturated solution of sodium bicarbonate, ethyl acetate extraction, organic phase is given a baby a bath on the third day after its birth inferior with saturated aqueous common salt, Na
2SO
4Drying concentrates, and thick product purification by silica gel column chromatography obtains white solid 6 (2.50g, 97%).
With compound 2 (5.0g 10.30mmol) is dissolved among the 40ml DMF, adds the 1.5ml triethylamine, stirred for several minute, add subsequently compound 6 (3.68g, 10.30mmol), in system, add again mercury chloride (2.79g, 10.30mmol).Reaction 2～6h adds water 50ml, and with ethyl acetate extraction, organic phase is given a baby a bath on the third day after its birth inferior with saturated aqueous common salt, with Na
2SO
4Drying concentrates, and thick product purification by silica gel column chromatography obtains white solid 3 (6.35g, 82.0%).
With compound 3 (4.00g 5.03mmol) is dissolved in the 80ml anhydrous methanol, adds 10%Pd/C 1.0g, 20 ℃～60 ℃ down logical hydrogen reaction until fully.Leach solid, filtrate concentrates, and gets white solid 4 (2.42g, 91.0%).
Synthetic 3-(2-[(4-methyl guanidine radicals-benzene imines)-methylene radical]-1-methylene radical-1 hydrogen-benzoglyoxaline-5-carbonyl }-pyridine-2-imines)-propionic acid (5)
(0.83g 1.57mmol) is dissolved in 15ml dehydrated alcohol 30ml H with compound 4
2Among the O, (180g 4.71mmol), stirs 3h under the room temperature to add sodium hydroxide.Thin up, with in an amount of acetate and after, leave standstill, have the precipitation separate out, elimination solution, the solid water, dehydrated alcohol, anhydrous diethyl ether drip washing promptly obtains white solid 5 (0.62g, 78.8%).
1H?NMRδ(300MHz，DMSO-d
6)：9.21(br，1H)，8.33(m，1H)，7.56-7.54(m，2H)，7.49(s，1H)，7.39-7.36(d，2H)，7.19-6.97(m，5H)，6.70-6.68(d，2H)，6.33(m，1H)，4.52-4.51(d，2H)，4.08-4.02(m，4H)，3.76(s，3H)，2.25-2.23(t，2H)；
ESI-MS(M/z)：501.3(M
++1)
Embodiment 2
Work as R
1During for the 2-pyridine:
Synthetic 3-(2-[(4-nitro-benzene imines)-methylene radical]-1-methylene radical-1 hydrogen-benzoglyoxaline-5-carbonyl }-pyridine-2-imines)-ethyl propionate (7)
With compound 2-(4-nitro-phenylamino)-acetate (3.14g; 15.95mmol) be dissolved among the 20ml DMF; add HOBT (2.40g; 17.54mmol), (3.35g 17.54mmol) stirs 5～60min in adding EDCI below 0 ℃; slowly rise to room temperature; adding diamine compound 3-(N, and N-(2-pyridine)-[3-amino-4-methylamino-benzoyl]-ethyl propionate (6.0g, 17.54mmol).Reaction 2～6h concentrates, and with a large amount of ethyl acetate dilutions, saturated aqueous common salt is given a baby a bath on the third day after its birth inferior, through Na
2SO
4After the drying, concentrate, the thick product 1.5h that refluxes in 30ml acetate after concentrating, adds alkalization, with ethyl acetate extraction (30mL * 3) three times, organic phase with the saturated common salt washing once, through Na
2SO
4After the drying, concentrate, thick product purification by silica gel column chromatography obtains white solid 7 (4.32g, 53%).
Synthetic 3-(2-[(4-amino-benzene imines)-methylene radical]-1-methylene radical-1 hydrogen-benzoglyoxaline-5-carbonyl }-pyridine-2-imines)-ethyl propionate (8)
(4.32g 8.61mmol) is dissolved in the 100ml anhydrous methanol, adds 10%Pd/C450mg, successive reaction 2～10h under logical atmosphere of hydrogen with compound 7.Reaction finishes, and the elimination solid matter after filtrate concentrates, gets white solid 8 (3.90g, 95%).
Synthetic 3-(2-[(4-guanidine radicals-benzene imines)-methylene radical]-1-methylene radical-1 hydrogen-benzoglyoxaline-5-carbonyl }-pyridine-2-imines)-ethyl propionate (10)
With methylthio group miaow base vitriol (1.0g 7.19mmol) is dissolved in the 15ml water, adds sodium hydroxide solution 30ml and the excess bicarbonate of 1N, after the stirred for several minute, add Cbz-Cl (3.68g, 21.59mmol).Reaction 2～5h.Add the 30ml saturated solution of sodium bicarbonate, ethyl acetate extraction, organic phase is given a baby a bath on the third day after its birth inferior with saturated aqueous common salt, Na
2SO
4Drying concentrates, and thick product purification by silica gel column chromatography obtains white solid 6 (2.50g, 97%).
With compound 8 (4.00g 8.47mmol) is dissolved among the 40ml DMF, adds the 1.3ml triethylamine, stirred for several minute, add subsequently compound 6 (3.03g, 8.47mmol), in system, add again mercury chloride (2.30g, 8.47mmol).Reaction 2～6h adds water 50ml, and with ethyl acetate extraction, organic phase is given a baby a bath on the third day after its birth inferior with saturated aqueous common salt, with Na
2SO
4Drying concentrates, and thick product purification by silica gel column chromatography obtains white solid 9 (6.11g, 92.6%).
With compound 9 (5.0g 6.41mmol) is dissolved in the 100ml anhydrous methanol, adds 10%Pd/C 1.0g, 20～60 ℃ down logical hydrogen reaction until fully.Leach solid, filtrate concentrates, and gets white solid 10 (2.20g, 73.3%).
Synthetic 3-(2-[(4-guanidine radicals-benzene imines)-methylene radical]-1-methylene radical-1 hydrogen-benzoglyoxaline-5-carbonyl }-pyridine-2-imines)-propionic acid (11)
(1.5g 2.91mmol) is dissolved in 25ml dehydrated alcohol 50ml H with compound 10
2Among the O, (350mg 8.73mmol), stirs 3h under the room temperature to add sodium hydroxide.Thin up, with in an amount of acetate and after, leave standstill, have the precipitation separate out, elimination solution, the solid water, dehydrated alcohol, anhydrous diethyl ether drip washing promptly obtains white solid 5 (1.17g, 83.6%).
1H?NMRδ(300MHz，DMSO-d
6)：9.29(br，1H)，8.39-8.37(m，1H)，7.58-7.41(m，3H)，7.19-7.14(3，6H)，6.99-6.95(m，3H)，6.80-6.77(d，2H)，4.54(s，2H)，4.20-4.15(t，2H)，3.79(s，3H)，2.64-2.90(t，2H)；
ESI-MS(M/z)：486.5(M
++1)
Embodiment 3
Work as R
1During for 4-fluoro-phenyl,
Synthetic 3-(2-[(4-methyl guanidine radicals-benzene imines)-methylene radical]-1-methylene radical-1 hydrogen-benzoglyoxaline-5-carbonyl }-4-fluorophenyl-2-imines)-propionic acid
Synthetic method such as embodiment 1,
1H?NMRδ(300MHz，DMSO-d
6)：7.87(m，1H)，7.54-7.49(m，2H)，7.29-7.24(m，4H)，7.11-7.04(m，5H)，6.73-6.71(d，2H)，4.60(s，2H)，4.17-4.15(d，2H)，4.06-4.01(t，2H)，3.81(s，3H)，2.58-2.53(t，2H)；
ESI-MS(M/z)：517.6(M
++1)
Embodiment 4
Work as R
1During for 4-methyl-2-pyridine,
Synthetic 3-(2-[(4-methyl guanidine radicals-benzene imines)-methylene radical]-1-methylene radical-1 hydrogen-benzoglyoxaline-5-carbonyl }-4-methyl-pyridine-2-imines)-propionic acid
Synthetic method such as embodiment 1,
1H?NMRδ(300MHz，DMSO-d
6)：8.11-8.09(d，1H)，7.47(s，1H)，7.35-7.33(d，1H)，7.17-7.15(d，1H)，7.03-6.90(m，4H)，6.67-6.65(d，2H)，4.47(s，2H)，4.05(s，2H)，3.97-3.92(t，2H)，3.72(s，3H)，2.22-2.17(t，2H)，2.09(s，3H)；
ESI-MS(M/z)：514.3(M
++1)。
The experiment of embodiment 5 antithrombin activities
Experiment is a pressed powder among the embodiment 4 with compound, and molecular weight is 513.5.
Compare with normal control group PCT (20.6 ± 0.9 seconds), this compound application of sample group has utmost point significant difference, the result be respectively 1*E-5 (178.8 ± 14.4**), 1*E-6 (33.3 ± 2.9**), 1*E-7 (20.3 ± 0.6).Show that this compound has external antithrombin activity, present tangible dose-effect relationship between each dosage group.(1*E-6 relatively compares with the physiological saline control group P＜0.01 with 1*E-7) through preliminary active testing, this compound has stronger antithrombin activity.
Claims (12)
1. thrombin inhibitors that contains Guanidinyl heterocycle compounds is characterized in that wherein said compound has following structural formula:
Wherein, R
1Be following phenyl or substituted-phenyl :-C
6H
5, 4-X-C
6H
4, perhaps be following pyridine or substituted pyridinyl :-C
5H
4N, 4-CH
3-C
5H
3N, 6-CH
3-C
5H
3N;
R
2For :-NHC (=NH)-NH
2,-CH
2-NHC (=NH)-NH
2,
Wherein X is a halogen.
2. by the described thrombin inhibitors that contains Guanidinyl heterocycle compounds of claim 1, it is characterized in that the wherein said Guanidinyl heterocycle compounds that contains is to have following structure I, II, the compound of III and VI:
3. the described preparation method who contains the thrombin inhibitors of Guanidinyl heterocycle compounds of claim 1 is characterized in that, the described Guanidinyl heterocycle compounds that contains synthesizes by following synthetic route,
Wherein, R
1Definition with claim 1, R ' is tertbutyloxycarbonyl or carbobenzoxy-(Cbz); Compound 1 or compound 7 be through catalytic reduction, and the reduzate of gained directly is coupled with guanidine radicals reagent, and deprotection gets corresponding prodrug, gets target compound through hydrolysis.
4. by the described preparation method of claim 3, it is characterized in that, is raw material with compound 1 or 7 wherein, is reduced under the catalysis of metal reagent and obtains corresponding primary amines, and this amino and guanidine radicals reagent are coupled.
5. by the described method of claim 4, wherein said metal reagent is Raney nickel or palladium carbon.
6. by the described preparation method of claim 3, it is characterized in that, wherein by compound 2 or 8 and guanidine radicals reagent be dissolved in N, dinethylformamide; under the effect of alkali, react, through thin up, extraction, drying; concentrate, silica gel column chromatography, the compound 3 or 9 of R ' radical protection.
7. by the described preparation method of claim 3, it is characterized in that wherein said compound 3 adds sour deprotection base R ' in a kind of organic solution, through concentrating, alkalization gets compound 4.
8. by the described method of claim 7, wherein said organic solution is methylene dichloride or dioxane; Wherein said acid is trifluoroacetic acid or sour gas hydrogenchloride; Wherein said protecting group R ' is a tertbutyloxycarbonyl.
9. by the described preparation method of claim 3, it is characterized in that wherein said compound 9 is deprotection base R ' in the presence of metal catalyst, after filtration, concentrated compound 10.
10. by the described method of claim 9, wherein said metal catalyst is palladium carbon or palladium hydroxide carbon; Wherein said protecting group R ' is a carbobenzoxy-(Cbz).
11., it is characterized in that wherein said compound 4 or 10 aqueous ethanolic solution and sodium hydroxide reaction behind the thin up, are separated out solid after the acidifying by the described preparation method of claim 3, after filtration, wash target compound 5 or 11.
12., it is characterized in that described thrombin inhibitors is a kind of direct thrombin inhibitors by the described thrombin inhibitors that contains Guanidinyl heterocycle compounds of claim 1.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007100462231A CN101665465B (en) | 2007-09-19 | 2007-09-19 | Thrombase inhibitor containing guanidyl heterocyclic compound and preparation method thereof |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6414008B1 (en) * | 1997-04-29 | 2002-07-02 | Boehringer Ingelheim Pharma Kg | Disubstituted bicyclic heterocycles, the preparation thereof, and their use as pharmaceutical compositions |
| CN1568307A (en) * | 2000-10-06 | 2005-01-19 | 三维药物公司 | Aminopyridyl-substituted phenyl acetamides as protease inhibitors |
| CN1861596A (en) * | 2005-12-16 | 2006-11-15 | 复旦大学 | Process for synthesizing antithrombin inhibitor of non-asymmetric non-peptide kind |
| CN101440085A (en) * | 2007-11-21 | 2009-05-27 | 复旦大学 | Thrombin inhibitors containing guanidine heterocyclic compound and preparation thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6414008B1 (en) * | 1997-04-29 | 2002-07-02 | Boehringer Ingelheim Pharma Kg | Disubstituted bicyclic heterocycles, the preparation thereof, and their use as pharmaceutical compositions |
| CN1568307A (en) * | 2000-10-06 | 2005-01-19 | 三维药物公司 | Aminopyridyl-substituted phenyl acetamides as protease inhibitors |
| CN1861596A (en) * | 2005-12-16 | 2006-11-15 | 复旦大学 | Process for synthesizing antithrombin inhibitor of non-asymmetric non-peptide kind |
| CN101440085A (en) * | 2007-11-21 | 2009-05-27 | 复旦大学 | Thrombin inhibitors containing guanidine heterocyclic compound and preparation thereof |
Non-Patent Citations (1)
| Title |
|---|
| Norbert H.Hauel,et al.Structure-Based Design of Novel Potent Nonpeptide Thrombin Inhibitors.《J.Med.Chem.》.2002,第45卷(第9期),1757-1766. * |
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