WO2009092301A1 - 二氢吡啶类钙拮抗剂化合物及其制备方法与医药用途 - Google Patents
二氢吡啶类钙拮抗剂化合物及其制备方法与医药用途 Download PDFInfo
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- WO2009092301A1 WO2009092301A1 PCT/CN2009/070031 CN2009070031W WO2009092301A1 WO 2009092301 A1 WO2009092301 A1 WO 2009092301A1 CN 2009070031 W CN2009070031 W CN 2009070031W WO 2009092301 A1 WO2009092301 A1 WO 2009092301A1
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- nitrophenyl
- dihydro
- piperazinyl
- dimethyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Definitions
- This invention relates to dihydropyridine calcium antagonist compounds and to methods for their preparation and their use in the treatment of cardiovascular diseases. Background technique
- Calcium antagonists also known as calcium channel blockers, can inhibit transmembrane calcium influx and intracellular calcium release, reduce intracellular free calcium concentration and its utilization, inhibit ATPase activity, reduce myocardial contractility; Cell relaxation, vasodilation, and reduction of peripheral vascular resistance.
- calcium antagonists are mainly used for the treatment of hypertension, angina pectoris, arrhythmia, congestive cardiomyopathy and ischemic heart disease. They are a wide range of cardiovascular drugs. With more and more new drugs on the market, especially dihydropyridines are attracting attention, not only the antihypertensive effect is exact, but also the side effects are small and the price is cheap, which has become a clinical first-line drug.
- nifedipine (1) its side chain ester structure is electrically neutral, so its water solubility is poor and absorption is poor; nicardipine (2) ester group is introduced
- the water-soluble amino side chain has a good absorption effect, but it does not have long-acting calcium antagonism because of the first-pass effect of the liver or the metabolism in the body too fast.
- the technical problem to be solved by the present invention is: how to apply the basic theory of drug design, combined with computer-aided drug design means, design and synthesize a series of novel dihydropyridine compounds with good calcium antagonistic activity, and resist high Blood pressure activity screening, in order to obtain new antihypertensive drugs with higher antihypertensive activity than existing drugs, for hypertension Treatment of the disease.
- Another object of the invention is to provide a process for the preparation of these compounds.
- a further object of the invention is to provide the use of these compounds in the treatment of cardiovascular diseases.
- the present invention provides the following technical solutions:
- the substituent may be: dc 4 alkyl, dc 4 alkoxy, halogen, cyano, trifluoromethyl, trifluoromethoxy , methylthio, nitro, amino, hydroxy.
- R 2 represents a dC 8 alkyl group which optionally carries a hydroxyl group or a dC 6 alkoxy substituent.
- X stands for 0, S or a single bond.
- R 2 , R 3 , R 4 , R 5 , R 6 , X, n are as defined above.
- Preferred according to the invention are 2-methoxyphenyl, 2,3-dichlorophenyl, p-nitrophenyl, p-methylphenyl, benzhydryl; preferably methyl, ethyl; preferably hydrogen; 4 is preferably 3-nitro; R 5 and R 6 are each preferably methyl, X is preferably 0 or a single bond; m is preferably 0, 1, 2, 3; n is preferably 2, 3, 4.
- pharmaceutically acceptable salts thereof include the addition salts of the compound of the formula (I), the compound of the formula ( ⁇ ) with the following acids: sulfuric acid, nitric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, formic acid, acetic acid, maleic acid. , citric acid, tartaric acid, lactic acid, benzenesulfonic acid, p-toluenesulfonic acid, pyruvic acid, fumaric acid.
- preferred pharmaceutically acceptable salts are the monohydrochloride salts of the compounds of formula (I) and formula ( ⁇ ) Or dihydrochloride.
- Preferred compounds of formula (I), compounds of formula (II) or pharmaceutically acceptable salts thereof include:
- the formula I b is substituted with the formula Ic under NaOH catalysis; or the formula lb is substituted with the formula Ic under the catalysis of triethylamine; or the formula I b is directly related to the formula I c A substitution reaction occurs.
- the general formula I a is substituted with the formula I d under the catalysis of NaOH; or the formula I a is in the triethylamine
- substitution reaction with the formula I d occurs under catalysis; or the formula I a directly undergoes a substitution reaction with the formula I d .
- R 2 , R 3 , R 4 , R 5 , R 6 , X, m are as defined above, and Y is a halogen atom.
- R 2 , R 3 , R 4 , R 6 , X, n are as defined above.
- the preparation method of the compound I b of the general formula is as follows:
- the substitution reaction of the formula I a with piperazine is carried out.
- the structural formula of some compounds involved in the present invention is as follows:
- a compound of the formula (I) or a compound of the formula ( ⁇ ) can be reacted with an acid to form an addition salt.
- the present invention also provides an anti-cardiovascular pharmaceutical composition containing the compound of the formula (I) or the compound of the formula ( ⁇ ) or a pharmaceutically acceptable salt thereof as an active ingredient.
- the pharmaceutical composition contains a pharmaceutically active ingredient and a pharmaceutically acceptable carrier, wherein the active ingredient is in the group 01 ⁇ 99. 99% ⁇ The weight ratio of the composition is 0. 01-99. 99%.
- the pharmaceutical compositions are in the form of a pharmaceutically acceptable preparation.
- the medicinal preparation is selected from the group consisting of tablets, capsules, oral liquids, mixtures, buccal preparations, granules, granules, pills, powders, ointments, dandruffs, suspensions, solutions, injections, powder injections, lyophilized powders Preparations such as injections, suppositories, ointments, plasters, creams, sprays, aerosols, drops, patches, and the like.
- each dose is 0.1 mg-100 mg, and each dose refers to each preparation unit, such as a tablet.
- Each tablet, each capsule, can also be taken at a dose of 100 mg per dose.
- the pharmaceutical composition of the present invention can be used as a solid or semisolid pharmaceutical preparation in the form of a powder, a tablet, a capsule, a suppository or an ointment.
- the solid carrier which can be used is one or more selected from the group consisting of a diluent, a disintegrating agent, a flavoring agent, a solubilizing agent, a lubricant, a suspending agent, a binder, a swelling agent and the like, or may be an encapsulating substance.
- Suitable solid carriers include magnesium carbonate, magnesium stearate, talc, sucrose, lactose, pectin, dextrin, starch, gelatin, methylcellulose, sodium carboxymethylcellulose, low boiling waxes, cocoa butter, and the like. Because of their ease of administration, tablets, powders, and capsules are among the best oral solid preparations.
- Liquid preparations of the invention include solutions, suspensions and emulsions.
- an injection preparation for parenteral administration may be in the form of water or a water-propylene glycol solution, adjusting its isotonicity, pH, etc. to suit physiological conditions of a living body.
- the liquid preparation can also be prepared in the form of a solution in polyethylene glycol, an aqueous solution.
- An oral aqueous solution can be prepared by dissolving the active ingredient in water, followed by adding an appropriate amount of a coloring agent, a flavoring agent, a stabilizer, and a thickening agent.
- the micronized active ingredient can be dispersed in viscous materials such as natural and synthetic gums, methylcellulose, sodium carboxymethylcellulose, and other known suspending agents to prepare aqueous suspensions suitable for oral administration.
- Dosage unit form of the formulation refers to a physically discrete unit suitable as a single dose, each unit containing a calculated predetermined amount of active ingredient which produces the desired therapeutic effect.
- dosage unit forms can be in the form of a package such as a tablet, a capsule or a powder in a vial or vial, or an ointment, gel or cream in a tube or vial.
- the amount of the active ingredient contained in the dosage unit form may vary, it is generally adjusted in the range of from 1 to 800 mg, depending on the potency of the selected active ingredient.
- the dosage administered according to the invention may vary with the needs of the patient, the severity of the treatment, the compound selected, and the like.
- the preferred dosage for a particular situation can be determined in a conventional manner.
- the amount of treatment initiated is lower than the optimal dose of the active ingredient, and then the dosage is gradually increased until the optimal therapeutic effect is achieved.
- the total daily dose can be divided into several parts, divided into several doses, such as 1-4 times a day, 1-10 doses per dose.
- the reference substance levamlodipine besylate, the compounds ⁇ 4 , ⁇ 5 , ⁇ 6 , ⁇ 14 , ⁇ 2 were all provided by the Department of Medicinal Chemistry, China Pharmaceutical University.
- the BL-410 biological function experiment system and the HW-400S constant temperature smooth muscle groove are produced by Chengdu Taimeng Technology Co., Ltd.
- the male rats were stunned by headshots, and the thoracic aorta was quickly taken and placed in a KH solution with a mixture of 95% 0 2 + 5% CO 2 . Carefully remove the surrounding connective tissue and cut the blood vessels into a vascular ring about 3 mm wide. Avoid excessive pulling to prevent damage to the endothelium.
- the vascular ring was suspended in a bath containing 30 ml of K-H solution, and a mixture of 95% 0 2 + 5% C0 2 was continuously passed, and the temperature was maintained (37 ⁇ 0.5 ° C), and the resting tension was adjusted to 2. 0g. Balance for 2h, change the liquid every 15 minutes.
- the concentration of the drug was determined to be 0. 05 mol/L, 0. 1 ⁇ mol/L, respectively. 0. 5 mol/L, 1 ⁇ mol/L, 2 mol/L, 4 ⁇ mol/L, 10 ⁇ mol/L, and the change in tension was recorded.
- the degree of vasodilation is expressed as the inhibition rate, that is, the difference between the maximum tension of KC1 induced contraction and the vascular tension after the addition of different concentrations of the drug, and the ratio of the difference to the maximum contraction amplitude induced by KC1 reflects the degree of vasodilation.
- the number of arterial ring specimens in each drug group was 6 cases, that is, the experiment was repeated 6 times.
- the compounds ⁇ 4 , ⁇ 5 , ⁇ 6 , ⁇ 14 , ⁇ 2 have an inhibitory effect on the complete endothelial vascular ring contraction induced by KC1. Its IC 5 . They were 2.0, 0.5, 1. 9, 0.2, 0. 8 mol/L, respectively, which were smaller than the IC 5 of the reference substance levamlodipine besylate. The value of 4.
- the compound of the present invention or a pharmaceutically acceptable salt thereof exhibits excellent receptor binding ability in the treatment of cardiovascular diseases, prolongs metabolism, increases bioavailability, and reduces side effects, and has wide application value.
- Example 1 1, 4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl ester 2-(N_l-piperazinyl) B Base ester ( ⁇ )
- IR (cm_: 3550, 3340, 3085, 2961, 2924, 2852, 2816, 1700, 1528, 1503, 1457, 1348, 1260, 1212, 1095, 1020, 802, 704, 702, 678
- Example 3 1, 4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl ester 3_ (N_4_(3_(2-methoxy) phenoxy) propyl) piperazinyl) propyl ester (12) with reference to synthesis I i, and I b 2 obtained by the I c 2 system, a yield of 65.5%.
- Example 5 1, 4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl ester 3_ (N_4_ (2- (2-) Oxyphenoxy)ethyl)piperazinyl)propyl ester hydrochloride (1 4 )
- Compound I b 2 1. 37 g (0. 003 mol), I Cl 0. 693 g (0. 003 mol), sodium hydroxide 0. 12g (0. 003mol), 10ml of toluene, stirred, and stirred at 60 ° C for 1h, concentrated under reduced pressure.
- Example 6 1, 4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl ester 4- (N-4-(2- (2-Methoxyphenoxy)ethyl)piperazinyl)butyl ester hydrochloride (I 5 ) According to the I 4 synthesis method, prepared from I b 3 and I Cl , yield 73%, mpl63 ⁇ 166 ° C.
- Example 7 1, 4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl ester 2-(N_4_(diphenylmethyloxy) Ethyl)piperazinyl)ethyl ester hydrochloride (I 6 )
- Example 8 1, 4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl ester 3_ (N-4-(diphenylene) Oxyethylethyl piperazinyl) propyl ester hydrochloride (I 7 )
- the yield is 32. 2%, mpl 59 to 162 ° C, according to the I 6 synthesis method, which is obtained from I b 2 and I c 3 .
- Example 10 1, 4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl ester 3_ (N_4_(4-nitrobenzyl) Piperazinyl)propyl ester hydrochloride (1 9 ) was prepared according to the I 8 synthesis method from I b 2 and I c 4 in a yield of 42.3%, mp 70 to m ° C.
- Example 11 1, 4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl ester 3_ (N_4_(4-methylbenzyl) Piperazinyl)propyl ester hydrochloride (I 10 ) According to the 18 synthesis method, it was obtained from I b 2 and I c 5 in a yield of 32.7%, mpl 63 to 165 °C.
- Example 12 1, 4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl ester 2-(N-4-(2, 3-dichlorophenyl) piperazinyl)ethyl ester (I u)
- Example 14 1, 4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl ester 4-(N_4_(2,3-dichloro Phenyl) piperazinyl)butyl ester hydrochloride (I 13 )
- the yield is 66.0%, mpl 70 to 173 ° C, according to the synthesis method of 1 12 , which is obtained from I a 3 and 1 4 hydrochloride.
- Example 16 1, 4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid ethyl ester 2- (N-4-(2- (2-methoxyphenoxy)ethyl)piperazinyl)ethyl ester (I 15 )
- Example 17 1, 4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid ethyl ester 3_ (N_4_ (2- (2-) oxy-phenoxy) ethyl) piperazinyl) I 15 synthesis method propyl ester (I 16) with reference to the I d 2 and I 3 ⁇ 4 obtained, yield 32.1%.
- Example 18 1, 4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid ethyl ester 2- (N-4-(3- (2-methoxyphenoxy) propyl) piperazinyl) ethyl ester (I 17) with reference to I 15 synthesis method, and the I 3 ⁇ 4 I d 3 was prepared in a yield of 38.2%.
- Example 19 1, 4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid ethyl ester 3_ (N-4-(3-( 2-methoxyphenoxy) propyl) piperazinyl) propyl ester (I 18 is) Referring I 15 synthesis method, the 3 ⁇ 4 I and I d 3 was prepared in a yield of 32.7%.
- Example 21 1, 4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl ester 3_ (N_4_(3_(2-methoxy) Benzyloxy) -2-hydroxypropyl) piperazinyl) propyl ester hydrochloride (II 2 ) Manufactured from I b 2 and Il, with a yield of 52.1%, mpl68 ⁇ 171 °C.
- Example 22 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl ester 4- (N_4_ (3_ (2-) oxy-phenoxy) -2-hydroxypropyl) piperazinyl) butyl ester hydrochloride (II 3)
- N_4_ (3_ (2-) oxy-phenoxy) -2-hydroxypropyl
- piperazinyl butyl ester hydrochloride
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Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12/863,593 US8163907B2 (en) | 2008-01-21 | 2009-01-05 | Dihydropyridine calcium antagonist compounds, preparation methods, and medical uses thereof |
EP09703392.2A EP2251337B1 (en) | 2008-01-21 | 2009-01-05 | Dihydropyridine calcium antagonist compounds, preparation methods and medical uses thereof |
JP2010542502A JP2011509948A (ja) | 2008-01-21 | 2009-01-05 | ジヒドロピリジン類カルシウム拮抗剤化合物及びその調製方法と医薬用途 |
CA2712619A CA2712619C (en) | 2008-01-21 | 2009-01-05 | Dihydropyridine calcium antagonist compounds, preparation methods and medical uses thereof |
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CN200810018711.6 | 2008-01-21 | ||
CNA2008100187116A CN101215258A (zh) | 2008-01-21 | 2008-01-21 | 二氢吡啶类钙拮抗剂化合物及其制备方法与医药用途 |
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WO2009092301A1 true WO2009092301A1 (zh) | 2009-07-30 |
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PCT/CN2009/070031 WO2009092301A1 (zh) | 2008-01-21 | 2009-01-05 | 二氢吡啶类钙拮抗剂化合物及其制备方法与医药用途 |
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US (1) | US8163907B2 (zh) |
EP (1) | EP2251337B1 (zh) |
JP (1) | JP2011509948A (zh) |
KR (1) | KR101215785B1 (zh) |
CN (2) | CN101215258A (zh) |
CA (1) | CA2712619C (zh) |
WO (1) | WO2009092301A1 (zh) |
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CN101215258A (zh) * | 2008-01-21 | 2008-07-09 | 中国药科大学 | 二氢吡啶类钙拮抗剂化合物及其制备方法与医药用途 |
CN102372692B (zh) * | 2010-08-19 | 2014-02-26 | 山东轩竹医药科技有限公司 | 二氢吡啶衍生物 |
US8718389B2 (en) | 2011-04-13 | 2014-05-06 | Huawei Technologies Co., Ltd. | Image encoding and decoding methods and related devices |
EP2964611B1 (en) * | 2013-03-08 | 2022-10-19 | The United States of America, as represented by The Secretary, Department of Health and Human Services | Potent and selective inhibitors of monoamine transporters; method of making; and use thereof |
US11365195B2 (en) | 2017-11-13 | 2022-06-21 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Atypical inhibitors of monoamine transporters; method of making; and use thereof |
Citations (8)
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EP0094159A1 (en) * | 1982-05-10 | 1983-11-16 | Takeda Chemical Industries, Ltd. | Dihydropyridine derivatives, their production and use |
WO1986004581A1 (en) * | 1985-02-11 | 1986-08-14 | Imperial Chemical Industries Plc | Dihydropyridine alkanolamines |
JPS61194069A (ja) * | 1985-02-25 | 1986-08-28 | Kyoto Yakuhin Kogyo Kk | 1,4−ジヒドロピリジン誘導体 |
JPS6391366A (ja) * | 1986-10-03 | 1988-04-22 | Kyoto Yakuhin Kogyo Kk | 1,4−ジヒドロピリジン誘導体 |
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CN1720243A (zh) * | 2002-10-07 | 2006-01-11 | 瓦卡尔治疗公司 | 具有同时阻滞l-型钙通道和抑制3型磷酸二酯酶活性能力的二氢吡啶化合物 |
CN101215258A (zh) * | 2008-01-21 | 2008-07-09 | 中国药科大学 | 二氢吡啶类钙拮抗剂化合物及其制备方法与医药用途 |
Family Cites Families (6)
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EP0097821B1 (en) * | 1982-06-03 | 1988-07-13 | Pierrel S.p.A. | Dihydropyridines with an antagonistic activity to calcium, process for their preparation, and pharmaceutical compositions containing them |
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2008
- 2008-01-21 CN CNA2008100187116A patent/CN101215258A/zh active Pending
-
2009
- 2009-01-05 KR KR1020107018562A patent/KR101215785B1/ko active IP Right Grant
- 2009-01-05 EP EP09703392.2A patent/EP2251337B1/en active Active
- 2009-01-05 CA CA2712619A patent/CA2712619C/en active Active
- 2009-01-05 US US12/863,593 patent/US8163907B2/en active Active
- 2009-01-05 WO PCT/CN2009/070031 patent/WO2009092301A1/zh active Application Filing
- 2009-01-05 JP JP2010542502A patent/JP2011509948A/ja active Pending
- 2009-01-07 CN CN2009100000890A patent/CN101525314B/zh active Active
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CN101215258A (zh) * | 2008-01-21 | 2008-07-09 | 中国药科大学 | 二氢吡啶类钙拮抗剂化合物及其制备方法与医药用途 |
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KANJI M. ET AL.: "New 1,4-dihydropyridine derivatives with potent and long-lasting hypotensive effect", CHEM. PHARM. BULL., vol. 33, no. 9, 1985, pages 3787 - 3797 * |
See also references of EP2251337A4 * |
ZHOU XIN-MEI; YAO HUI; XIA MAN-LI ET AL., JOURNAL OF ZHEJIANG UNIVERSITY: MEDICAL SCIENCES, vol. 35, no. 1, 2006, pages 29 - 33 |
Also Published As
Publication number | Publication date |
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JP2011509948A (ja) | 2011-03-31 |
CN101215258A (zh) | 2008-07-09 |
CN101525314A (zh) | 2009-09-09 |
US20110201811A1 (en) | 2011-08-18 |
EP2251337A1 (en) | 2010-11-17 |
KR20100105781A (ko) | 2010-09-29 |
CA2712619C (en) | 2013-03-26 |
KR101215785B1 (ko) | 2012-12-26 |
CN101525314B (zh) | 2012-01-04 |
EP2251337B1 (en) | 2013-11-20 |
EP2251337A4 (en) | 2011-03-30 |
CA2712619A1 (en) | 2009-07-30 |
US8163907B2 (en) | 2012-04-24 |
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