CN106432189A - Cinnamamide derivatives as well as preparation method and medical application thereof - Google Patents

Cinnamamide derivatives as well as preparation method and medical application thereof Download PDF

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Publication number
CN106432189A
CN106432189A CN201610837783.8A CN201610837783A CN106432189A CN 106432189 A CN106432189 A CN 106432189A CN 201610837783 A CN201610837783 A CN 201610837783A CN 106432189 A CN106432189 A CN 106432189A
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China
Prior art keywords
amine derivative
preparation
thromboxane
acryloyl amine
pharmaceutically acceptable
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CN201610837783.8A
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Chinese (zh)
Inventor
徐奎
王陈
刘丽
王亚丽
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Anhui Province Yi Xinming Pharmaceutical Technology Co Ltd
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Anhui Province Yi Xinming Pharmaceutical Technology Co Ltd
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Priority to CN201610837783.8A priority Critical patent/CN106432189A/en
Publication of CN106432189A publication Critical patent/CN106432189A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms

Abstract

The invention belongs to the technical field of medicinal chemistry and medicines and discloses cinnamamide derivatives (I) and (II) as well as a preparation method and a medical application thereof. The novel compound has remarkable anti-platelet aggregation activity, and a new candidate medicine is provided for patients suffering from thromboembolic diseases.

Description

Benzene acryloyl amine derivative and preparation method thereof and medical usage
Technical field
The present invention relates to pharmaceutical chemistry and pharmaceutical technology field are and in particular to formula（Ⅰ）Or formula（Ⅱ）Shown benzene acryloyl Amine derivative or its pharmaceutically acceptable salt and preparation method thereof and the purposes in pharmacy.
Background technology
Thromboxane synthetase inhibitor induces one concern as Novel anti-platelet agent.Thromboxane A2It is peanut with prostacyclin The activated product of tetraene acid metabolic, both of which is by intermediate product prostaglandin endoperoxides PGH2It is transformed, but biological alive Property is but completely contrary.In blood platelet, PGH2Main generation thromboxane A in the presence of thromboxane synthetase2.Blood vessel endothelium is thin Prostacyclin synthase in born of the same parents is then by PGH2It is converted into PGI2.Thromboxane A2It is very strong blood platelet induced polymerization inhibitor and vessel retraction Agent, and PGI2But it is RA233 and vasodilator.Aspirin etc. is non-to stay body AID because acting on ring Oxidizing ferment and block arachidonic acid and be converted into PGH2, suppress thromboxane A simultaneously2And PGI2Formation.Thromboxane Synthetase system Then high degree of specificity blocks thromboxane A for agent2Generate, and do not suppress PGI2Generation.
Moncada in 1976 etc. finds, anti-inflammatory agent benzydamine suppresses PGH2It is converted into thromboxane A2, but it is selectively Very poor, also can suppress Cycloxygenase.Scholar is separately had to report, phosphoric acid phloretin derivative N-0164 suppresses thromboxane synthetase, but It is the antagonist of smooth muscle prostaglandin receptor simultaneously.The report such as Needleman in 1977, laboratory conventional buffers miaow Azoles has the effect of specificity suppression thromboxane synthetase.In the same year, Miyamota and Gorman etc. finds pyridines chemical combination in succession Thing and thromboxane A2/PGH2Analog is thromboxane synthetase inhibitor.Based on structure-activity relationship, chemist is to above-mentioned chemical combination Thing has carried out structure of modification, develops a series of reactive derivatives.
The research of domestic antiplatelet drug is begun the beginning of the seventies, mostly sets about it is intended to therefrom find from Chinese herbal medicine promoting blood circulation and removing blood stasis There is the antiplatelet new drug of clinical value.So far, the antiplatelet Chinese herbal medicine being reported in media or effective ingredient, there is no and be clearly Selective thromboxane synthetase inhibitor person.Li Chengzhu etc. once suppressed platelet thrombus element A according to danshensu2Sample material generate and Speculate that it is thromboxane A2Synthetase inhibitors.The report rhizome of chuanxiong piperazine such as Wu Yusheng may be thromboxane synthetase inhibitor, but after No to report further.
Find thromboxane A from 1977 first2Synthetase inhibitors glyoxaline compound, thus result in a series of new The synthesis of imidazole derivative, this is the wide class synthetase inhibitors of current research.
At present to treatment thromboxane A2There is the drug research of related disorders, have focused largely on thromboxane A2The suppression and front of synthesis Row parathyrine（PGH2）, thromboxane A2On receptor antagonist, many potent and high selectivity thromboxane synthetase inhibitor is used for clinic Test, but result is disappointing, it is believed that being due to PGH2Accumulate and thromboxane A can be acted on2Acceptor causes blood platelet Assemble and vessel retraction.Great mass of data proves, use in conjunction thromboxane synthetase inhibitor and thromboxane receptor antagonist ( TxRA) a kind of more effective than alone, thromboxane synthetase inhibitor can suppress thromboxane A2Synthesis, and make the PGH of rising2Turn It is changed into prostacyclin (PGI2), PGE2( PGE2), PGD2( PGD2) etc. beneficial prostaglandin, Thromboxane receptor antagonist then stops PGH2And thromboxane A2With its receptor binding.Based on this theory, in succession study in recent years Many has TxRA and a compound of thromboxane synthetase inhibitor double activity.
Content of the invention
The overall purpose of the present invention is to be to prepare a kind of imidazoles benzene acryloyl amine derivative, has thromboxane to develop A2Material with the new drug biologically active of selective thromboxane synthetase inhibitor double activity.
To thromboxane A2Space structure Structure-activity analysis research in it is found that design noval chemical compound, carbonyl and alkali 7 atoms of atomic separation of property group, are best suitable for and thromboxane A2Synzyme combines, because this molecular length is suitably inserted into just To in thromboxane synthetase.According to this feature, we pass through CAD, establish the isopotential map of target compound, By analyzing isopotential map, obtain the information of some such compound structure designs, thus complete the present invention.
It is an object of the present invention to provide a kind of formula（Ⅰ）Or formula（Ⅱ）Shown benzene acryloyl amine derivative or its pharmacy Upper acceptable salt：
It is a further object to provide preparation has formula（Ⅰ）Or formula（Ⅱ）Compound or its pharmaceutically acceptable salt Method；
It is also another object of the present invention to provide containing formula（Ⅰ）Or formula（Ⅱ）Compound or its pharmaceutically acceptable salt conduct Active ingredient, and the Pharmaceutical composition of one or more pharmaceutically acceptable carrier, excipient or diluent, and its controlling Treat the application of platelet aggregation or thrombotic disease aspect.In conjunction with the purpose of the present invention, present invention is carried out specifically Description.
The purpose of the present invention is realized by following measures：
It is an object of the invention to provide formula（Ⅰ）Or formula（Ⅱ）Shown benzene acryloyl amine derivative or it is pharmaceutically acceptable Salt：
Formula（Ⅰ）Technology path specific as follows：
Formula（Ⅱ）Technology path specific as follows：
It is yet another object of the invention to provide the officinal salt implementing the compound of the present invention is selected from hydrochloride, hydrobromic acid Salt, phosphate, formates, acetate, propionate, oxalate, malonate, butyrate, lactate, mesylate, second sulphur Hydrochlorate, tosilate, maleate, benzoate, succinate, picrate, tartaric acid, citrate, fumaric acid Salt.
The present invention a kind of benzene acryloyl amine derivative of above-mentioned formula I or formula II expression or its pharmaceutically acceptable salt, can By presented in hydrate or solvent thing, no matter any it is included within the scope of the invention.As the solvent obtaining The solvent of thing, has methyl alcohol, ethanol, isopropanol, acetone, ethyl acetate, isopropyl ether etc..
Above-mentioned manufacture method, only represents one of the method for type I compound of manufacture present invention example.The compounds of this invention Manufacture method is not limited in these methods, in the embodiment of this specification, due to more specifically understanding chemical combination of the present invention The manufacture method of thing, so, those skilled in the art, the explanation with specific embodiment according to the above description, as needed, to this plus With suitable modification, just can produce including in the compound of above-mentioned formula I or their salt.
Formula of the present invention（Ⅰ）Or formula（Ⅱ）Compound, can as active ingredient be used for preparation treatment platelet aggregation or The purposes of the medicine of thrombotic disease.
The present invention, through the large database concept literature search such as scifinder, reaxys, does not still have discovery to have document report mistake at present Such compound and preparation method and utilization.
Compared with prior art, beneficial effects of the present invention are embodied in：
1）Pharmacological testing shows, the compounds of this invention specifically significant platelet aggregation inhibitory activity, is that thrombotic disease is suffered from Person provides new drug candidate；
2）Noval chemical compound of the present invention, mild condition needed for synthesis, yield is also high, and structure is novel, has no report.
Specific embodiment
The following examples can conduct further description to the present invention, however, these embodiments should not be used as to this The restriction of invention scope.
Embodiment 1：The preparation of chemical compounds I
The there-necked flask that 1000ml is dried, installs agitator, thermometer, is added thereto to 3- butene-1-amine（28.5g,
0.4mol）, anhydrous K2CO3（58g, 0.42mol）And the dichloromethane 310ml being dried, it is cooled to -5 DEG C～0 DEG C, stirring Under, it is slowly added to acryloyl chloride（36.5g, 0.4mol）Dichloromethane solution 100ml, addition finishes, and insulated and stirred reacts 1h, It is warming up to and reaction 7h, TLC identification terminal are stirred at room temperature again【Thin-layer developing condition（Petroleum ether-ethyl acetate=10：1）】, instead Should finish, filter, filtrate water（3×50ml）Washing, anhydrous Na2SO4It is dried, be filtered to remove drier, filtrate<40 DEG C of decompressions It is concentrated to dryness, obtain pale yellowish oil liquid 41.6g（Intermediate 1）, yield 83%, it is directly used in next step.
Intermediate 1（41.6g, 0.33mol）, the toluene 416ml that is dried, stirring is lower to add second generation Ge Labu catalyst 0.7g, is warming up to 85 DEG C～90 DEG C, stirring reaction 7h, GC identification terminal, and reaction finishes, and is cooled to room temperature, adds ammoniacal liquor 8.5ml, stirs 1h, filters, filtrate water（3×30ml）Washing, anhydrous Na2SO4It is dried, be filtered to remove drier, reduced pressure concentration To dry, filtrate addition isopropyl ether 300ml, flow back 20min, is cooled to -5 DEG C～0 DEG C standing 6h, filters, the appropriate isopropyl of solid Ether washs, and obtains white powdery solids 24g（Intermediate 2）, yield 75%, mp：148～151 DEG C.
Ozagrel（79g, 0.35mol）, dichloromethane 500ml, DMF 5ml, be stirred at room temperature down, add oxalyl chloride （220g, 1.75mol）, first 0.5h is stirred at room temperature, then is warming up to 45 DEG C～50 DEG C stirring reactions 2.5h, TLC identification terminal 【Thin-layer developing condition（Petroleum ether-ethyl acetate=10：2）】, reaction finishes, and is evaporated to dry, residue adds dichloromethane Reducing pressure after alkane 100ml, it is dry to be evaporated to again, and so repeatedly 3 times, obtains faint yellow solid 78.6g（Intermediate 3）, yield 91%.
Intermediate 2（21g, 0.216mol）, anhydrous tetrahydro furan 250ml, be cooled to -5 DEG C～0 DEG C, add NaH（60%, 12g, 0.3mol）, insulated and stirred reaction 2h, then it is slow added into intermediate 3（54g, 0.2mol）, insulation reaction 21h, TLC Identification terminal【Thin-layer developing condition（Acetate-methanol=2：1）】, reaction finishes, and adds saturated ammonium chloride solution 20ml, stirs 10min, stratification, organic layer saturated sodium bicarbonate solution（2×30ml）And water（2×50ml）Washing, no Water Na2SO4It is dried, be filtered to remove drier, be evaporated to dry, acetone recrystallization, obtain white crystalline powder chemical compounds I 50g, yield 82%.mp：165～168 DEG C, HPLC content 99.1%.EIS-MS, m/z：308[M+H]+；1H NMR（400MHz, CH3OH-d3/TMS）：δH（ppm）： 7.84（T, J=15.8Hz, 1H）, 7.76 (d, J=6.4Hz, 1H), 7.39 (d, J= 6.5Hz, 1H), 7.11～7.32 (m, 4H), 7.01～7.09 (m, 2H), 6.83～7.02 (m, 2H), 3.54（T, J= 15.8Hz, 2H）, 5.63（S, 2H）, 2.34～2.40 (m, 2H).
Embodiment 2：The preparation of chemical compounds I tartrate
Chemical compounds I（10g, 0.0325mol）With ethanol 50ml, under room temperature, add tartaric acid（5.3g, 0.035mol）,
It is heated to 45 DEG C～50 DEG C, stirs 20min, be cooled to 0 DEG C～5 DEG C, stand overnight, filter, solid is washed with cold ethanol Wash, 45 DEG C～50 DEG C dryings of vacuum, obtain white powdery solids 11.6g, HPLC content 99.4%.
Embodiment 3：The preparation of compound ii
Intermediate 3（20g, 0.081mol）, anhydrous tetrahydro furan 120ml, it is heated to flowing back, now, add hmds Alkane（14.5g, 0.09mol）And triethylamine 11ml, it is stirred at reflux overnight, be evaporated to dry, residue from dichloromethane（3× 200ml）Extraction, merges organic layer, uses water（3×50ml）And saturated aqueous common salt（2×50ml）Washing, anhydrous Na2SO4It is dried, mistake Filter drier, be evaporated to dry, recrystallisation from isopropanol, obtain yellow powdery solid compound ii 9.7g, yield 53%, mp：236～241 DEG C, HPLC content 98.2%.EIS-MS, m/z：452[M+H]+；1H NMR（400MHz, CH3OH-d3/TMS）：δH （ppm）： 7.65（T, J=15.8Hz, 2H）, 7.19～7.38 (m, 8H), 7.11～7.17 (m, 4H), 7.02～7.10 (m, 2H), 6.83 (d, J=6.5Hz, 2H), 5.57（S, 4H）, 3.39 (d, J=5.9Hz, 4H).
Embodiment 4：The preparation of compound ii tartrate
With reference to embodiment 2, that is, compound ii tartrate, HPLC content 98.9% are obtained.
Embodiment 5：External platelet aggregation inhibitory activity testing experiment
1st, test method
Respectively the compounds of this invention being configured to concentration first before test is 1.0 × 10-6M DMSO solution, in this concentration It is 0. 5 × 10 that lower activity preferably compound is further continued for configuration concentration-6M and 0.25 × 10-6Tri- kinds of strength solution of M, administration Measure as 5 μ l；Method of administration is external；Positive control drug is aspirin, and with DMSO dissolving before test, dosage is also 5 μ l. By the blood taking from rabbit auricular vein blood vessel with 3.8% sodium citrate anti-freezing (whole blood and anti-coagulants volume ratio 9:1), under room temperature Centrifugation (500-800rpm/min, 10min) preparation enrichment thrombocyte plasma (PRP).After isolating PRP, then it is centrifuged (3000rpm/min, 10min) prepares platelet poor plasma (PPP), adjusts 0 with PPP.Take PRP 200 μ L to be separately added into etc. to rub The DMSO 5 μ L of the compounds of this invention of your concentration, solvent control group adds isometric DMSO solvent, after incubating 5min, with 20 μ l 5mmol/lADP, 1mg/ml collagen, 20umol/l arachidonic acid is derivant, measures platelet aggregation reaction.
2nd, the PAgT result of ADP induction
Using Bron turbidimetry, first with ADP as derivant, external platelet aggregation-against is carried out to the compounds of this invention Determination of activity result see table：
Result shows：The compounds of this invention shows preferable platelet aggregation inhibitory activity.
3rd, collagen-induced PAgT result
By data in table, during with collagen for derivant, the compounds of this invention shows certain antiplatelet
Aggregation activity, has significant difference compared with blank group.
4th, the PAgT result of AA induction
By data in table, during with arachidonic acid for derivant, the compounds of this invention platelet aggregation inhibitory activity is all relatively Weak, and it is below positive control drug aspirin.

Claims (6)

1. formula（Ⅰ）Or formula（Ⅱ）Shown benzene acryloyl amine derivative or its pharmaceutically acceptable salt：
.
2. the benzene acryloyl amine derivative described in claim 1 or its pharmaceutically acceptable salt it is characterised in that：Described medicine On, acceptable salt is hydrochloride, hydrobromate, phosphate, formates, acetate, propionate, oxalate, malonic acid Salt, butyrate, lactate, mesylate, esilate, tosilate, maleate, benzoate, succinate, hardship Taste hydrochlorate, tartaric acid, citrate, fumarate.
3. claim 1 Chinese style（Ⅰ）Benzene acryloyl amine derivative preparation method, including：
.
4. claim 1 Chinese style（Ⅱ）Benzene acryloyl amine derivative preparation method, including：
.
5. pharmaceutical composition, including the benzene acryloyl amine derivative any one of Claims 1 to 4 or its pharmaceutically can connect The salt being subject to, and pharmaceutically acceptable excipient or carrier.
6. the benzene acryloyl amine derivative described in claim 1 or its pharmaceutically acceptable salt are used for preparation treatment platelet aggregation The purposes of the medicine of collection or thrombotic disease.
CN201610837783.8A 2016-09-21 2016-09-21 Cinnamamide derivatives as well as preparation method and medical application thereof Pending CN106432189A (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4226878A (en) * 1978-06-13 1980-10-07 Kissei Pharmaceutical Co., Ltd. Imidazole derivative
US4562199A (en) * 1983-08-11 1985-12-31 Thorogood Peter B Imidazole derivatives, compositions and use
US4665080A (en) * 1984-07-06 1987-05-12 Hoechst Aktiengesellschaft Imidazolyl compounds and their use as medicaments
CN101219994A (en) * 2007-01-10 2008-07-16 王立峰 Ozagrel ester, composition and production method thereof
CN104628649A (en) * 2015-01-23 2015-05-20 云南昊邦制药有限公司 2-(alpha-hydroxy amyl) benzamide derivate as well as preparation method, preparation and application thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4226878A (en) * 1978-06-13 1980-10-07 Kissei Pharmaceutical Co., Ltd. Imidazole derivative
US4562199A (en) * 1983-08-11 1985-12-31 Thorogood Peter B Imidazole derivatives, compositions and use
US4665080A (en) * 1984-07-06 1987-05-12 Hoechst Aktiengesellschaft Imidazolyl compounds and their use as medicaments
CN101219994A (en) * 2007-01-10 2008-07-16 王立峰 Ozagrel ester, composition and production method thereof
CN104628649A (en) * 2015-01-23 2015-05-20 云南昊邦制药有限公司 2-(alpha-hydroxy amyl) benzamide derivate as well as preparation method, preparation and application thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
SUNG-EUN LEE 等: "Antiplatelet Activities of Newly Synthesized Derivatives of Piperlongumine", 《PHYTOTHER. RES.》 *
VIDADALA RAMASUBBA RAO 等: "Synthesis and biological evaluation of new piplartine analogues as potent aldose reductase inhibitors (ARIs)", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 *

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