CN105924382B - S- Manidipine hydrochloride I crystals and preparation method thereof - Google Patents
S- Manidipine hydrochloride I crystals and preparation method thereof Download PDFInfo
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- CN105924382B CN105924382B CN201610444090.2A CN201610444090A CN105924382B CN 105924382 B CN105924382 B CN 105924382B CN 201610444090 A CN201610444090 A CN 201610444090A CN 105924382 B CN105924382 B CN 105924382B
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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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The present invention relates to a kind of S Manidipines hydrochloride I crystals and preparation method thereof.The present invention by after S Manidipines free alkali is dissolved in alcohols or alcohols/water with HCl at salt, then crystallization, obtains a kind of crystallization of S Manidipines hydrochloride, is detected through X-ray powder diffraction, it is determined as crystal form I.There is the product good temperature and humidity stability, residual solvent and moisture to reach quality requirement, be suitble to preparation technical process and long term storage.It can be used for treating the diseases such as hypertension using the compound of the crystal form as the pharmaceutical composition of active constituent.
Description
Technical field
The present invention relates to the I crystals and preparation method thereof of S- Manidipine hydrochlorides, and the pharmaceutical composition containing it
And its medical usage.
Background technology
Entitled (the 4S) -1,4- dihydros -2,6- dimethyl -4- m-nitros base -3,5- pyrroles of S- Manidipine hydrochloride chemistry
Diphosphoglyceric acid's methyl esters 2- (4- benzhydryl -1- piperazinyls) carbethoxy hydrochloride, shown in structure such as following formula (I),
Manidipine hydrochloride is a kind of lipophilic third generation calcium-channel antagonists, is Japanese military field pharmaceutical industries strain formula meeting
Society develops, the dihydropyridine blood-pressure reducing medicine of nineteen ninety listing.This product to blood vessel have it is highly selective, make peripheral vasodilation and drop
Pressure, but to heart almost without inhibiting effect, in addition, being had no significant effect to noradrenaline levels, this product is prompted not activate friendship
Feel nervous system.This product acts on low, length of holding time, and is long-acting depressor, and can diastole goal and efferent glomerular arteriole, it is right
Renal function is beneficial.
A large amount of clinical applications show that an oral Manidipine has fine anti-high blood to mild to moderate hypertensive patient daily
Pressure acts on and good tolerability, and the side reactions such as ankle-joint oedema incidence are significantly lower than Amlodipine, while simultaneously to hypertension
It is also effective to send out diabetes B/nephrosis.
Manidipine hydrochloride contains there are one chiral centre, S- and R- isomers, which can pass through to split, to be prepared, method for splitting warp
It crosses research and has applied for Chinese patent (application number 201510870914.8).The pharmacology of document report Manidipine enantiomter
It learns effect to be different, Kajino et al. [1,2] has studied Manidipine enantiomer and makees the decompression of spontaneous hypertensive rat
With the pressure reduction effect of discovery (S)-enantiomer is 30 times of (R)-enantiomer, is 2 times of racemic modification.
Currently without patent and the crystal form of document report S- Manidipines, because dissolubility is low in vivo for S- Manidipines, belong to
In low molten hypertonic class drug, dissolved corrosion has main influence to the effect of drug in vivo, therefore the stability of its crystal form is very
It is crucial.The present invention is capable of providing a kind of S- Manidipine hydrochloride novel crystal forms and preparation method thereof that stability is high.
Invention content
The present invention provides the I types crystallization of S- Manidipine hydrochlorides shown in formula (I),
It is characterized in that, being radiated using Cu-Ka, the X-ray powder diffraction figure indicated with 2 θ angles and interplanar distance is obtained
Spectrum, the crystallization have X-ray powder diffraction collection as shown in Figure 1, wherein in about 5.54 (15.97), 6.23 (14.18),
9.56 (9.26), 11.05 (8.00), 11.92 (7.42), 15.16 (5.84), 15.78 (5.62), 18.51 (4.79), 19.54
(4.54), 20.78 (4.27), 21.08 (4.22), 21.75 (4.09), 22.20 (4.00), 23.89 (3.73), 24.67
(3.61), there are characteristic peak in 24.94 (3.57), 26.96 (3.31), 27.38 (3.26), 29.51 (3.03) at 30.57 (2.92).
The method for the I types crystallization that S- Manidipines hydrochloride as described above is prepared the present invention further provides a kind of,
Include the following steps：
1) S- Manidipines free alkali is dissolved with solvent, the solvent is selected from C1~C4 alcohols solvents or C1~C4 alcohol
Class/water mixed solvent, the preferred methanol of C1~C4 alcohols, ethyl alcohol, isopropanol, n-butanol, more preferable ethyl alcohol；
2) hydrochloric acid alcoholic solution is added in the solution obtained to step 1) into salt；
3) crystallization, filtering obtain the I types crystallization of S- Manidipine hydrochlorides.
In a preferred embodiment in accordance with this invention, the I types crystallization of S- Manidipines hydrochloride according to the present invention
Preparation method, wherein in step 1) ratio of S- Manidipines free alkali and solvent for use be 1:10~1:100(g/ml).
In another preferred embodiment of the present invention, the I type knots of S- Manidipines hydrochloride according to the present invention
Brilliant preparation method, wherein solvent used in step 1) is C1~C4 alcohols/water mixed solvent, and C1~C4 alcohols is excellent
Select methanol, ethyl alcohol, isopropanol, n-butanol, more preferable ethyl alcohol.
In another preferred embodiment of the present invention, the I type knots of S- Manidipines hydrochloride according to the present invention
Brilliant preparation method, wherein solvent used in step 1) is C1~C4 alcohols/water mixed solvent, and C1~C4 alcohols and water
Volume ratio be 90:10~50:50.
In another preferred embodiment of the present invention, the I type knots of S- Manidipines hydrochloride according to the present invention
Brilliant preparation method, wherein in the hydrochloric acid alcoholic solution being added in step 2), the alcohol is selected from C1~C4 alcohols, preferably methanol, second
Alcohol, isopropanol, butanol, hydrochloric acid a concentration of 20-40% (g/ml) in the solution, preferably 30% (g/ml).
In another preferred embodiment of the present invention, the I type knots of S- Manidipines hydrochloride according to the present invention
Brilliant preparation method, wherein the solvent in step 3) used in crystallization is selected from C1~C4 alcohols solvents or C1~C4 alcohols/water mixing
Solvent, or mixtures thereof the preferred methanol of C1~C4 alcohols, ethyl alcohol, isopropanol, n-butanol, more preferable ethyl alcohol；The crystallization
Temperature be 0~70 DEG C, preferably 10~40 DEG C, more preferable room temperature (20~30 DEG C).
In another preferred embodiment of the present invention, the I type knots of S- Manidipines hydrochloride according to the present invention
Brilliant preparation method, wherein the amount of crystallization solvent used in step 3) is 1-100ml/ relative to S- Manidipine free alkalis
G, preferably 10-50ml/g, more preferable 20-30ml/g.
In another preferred embodiment of the present invention, the I type knots of S- Manidipines hydrochloride according to the present invention
Brilliant preparation method, wherein crystallization solvent used in step 3) is C1~C4 alcohols/water mixed solvent, wherein C1~C4 alcohol
Class and the volume ratio of water are 10:90~99:1.
In another preferred embodiment of the present invention, the I type knots of S- Manidipines hydrochloride according to the present invention
Brilliant preparation method comprising following steps：S- Manidipines are dissolved in absolute ethyl alcohol or ethanol/water solution, then
Previously prepared HCl/ alcoholic solutions are added into the solution of S- Manidipines into salt, S- Manidipine salt is obtained by filtration in crystallization
The I types of hydrochlorate crystallize.
The present invention also provides a kind of pharmaceutical compositions, the I type knots containing S- Manidipines hydrochloride according to the present invention
Brilliant and one or more pharmaceutically acceptable carriers.
It is as described herein it is " pharmaceutically acceptable " be that it is useful for preparing be typically safety, the both toxicity on abiology
Again without other unwanted toxicity, and animal doctor is used and is acceptable pharmaceutical composition with human medicine use.
" carrier " as described herein refers to the diluent, adjuvant or excipient applied together with compound.It can pharmaceutically connect
The carrier received can be liquid, such as water and oil, including oil, animal, plant or synthesis source oil, such as it is peanut oil, big
Soya-bean oil, mineral oil, rapeseed oil etc..Pharmaceutically acceptable carrier can also be physiological saline, gum arabic, gelatin, starch
Paste, talcum powder, keratin, silica gel, urea etc..Furthermore it is also possible to use adjuvant, stabilizer, thickener, lubricant and coloring
Agent etc..
It will be appreciated by those skilled in the art that the pharmaceutical composition of the present invention can be formulated according to specific method of application
At various dosage forms well known in the art, for example, peroral dosage form (pulvis, tablet, capsule, soft capsule, liquid medicine, syrup,
Wine made of broomcorn millet ball, powder, wafer, granula) or topical formulation (emulsifiable paste, ointment, lotion, gel, face cream, plaster, paste, spraying
Agent, aerosol etc.) or ejection preparation (solution, suspending agent, emulsion).In the pharmaceutical composition of the present invention, it is particularly possible to carry
And be suitable for take orally, those of parenteral (intravenously or subcutaneously) or nasal administration, for example, tablet or dragee, sublingual
Piece, gelatine capsule, pastille, suppository, creme, ointment, skin gel, injectable formulation, drinkable suspension etc..
Pharmaceutical composition according to the present invention can include pharmaceutically acceptable carrier, adjuvant or diluent, such as：It fills out
Fill agent, disintegrant, lubricant, suspending agent, adhesive, sweetener, corrigent, preservative, matrix etc..Filler is for example：Starch,
Pregelatinized starch, lactose, mannitol, chitin, microcrystalline cellulose, sucrose etc.；Disintegrant is for example：It is starch, pregelatinized starch, micro-
Crystalline cellulose, sodium carboxymethyl starch, crosslinked polyethylene pyrroles, low-substituted hydroxypropyl cellulose, croscarmellose sodium etc.；Profit
Lubrication prescription is for example：Magnesium stearate, lauryl sodium sulfate, talcum powder, silica etc.；Suspending agent is for example：Polyvinylpyrrolidone,
Microcrystalline cellulose, sucrose, agar, hydroxypropyl methyl cellulose etc.；Adhesive is for example, starch slurry, polyvinylpyrrolidone, hydroxypropyl
Ylmethyl cellulose etc..The composition of the present invention can be made by using any known method in this field, so that patient's medication
Quick, lasting or slow release active constituent can be provided afterwards.
The pharmaceutical composition of the present invention is administered to individual animals such as mammal (rat, mouse, domestication by all means
Animals or humans), all administering modes be it is contemplated that for example, administration can be take orally, part, rectally or through quiet
Arteries and veins, intramuscular, in percutaneous, sheath, Epidural cavity or intraventricular injection.
The dosage of inventive compound can be according to individual situation and weight, the property of the state of an illness and serious journey
Degree, medicament forms, the difference of administration route and dosage period and it is different, can also be selected by those skilled in the art
It selects.Dosage can change between 1-100mg/ days, single-dose or can be administered multiple times daily daily.
The present invention further provides the crystallization of the I types of S- Manidipines hydrochloride according to the present invention or contain its medicine group
Close purposes of the object in the drug for preparing treatment hypertension.
The present invention also provides the crystallization of the I types of S- Manidipines hydrochloride according to the present invention or contain its pharmaceutical composition
Purposes in medicine preparation, the drug are used to prevent or treat various the clinical settings such as coronary heart disease, the cerebrovascular of hypertension
Disease, hypertensive heart disease, hypertensive encephalopathy, chronic renal failure and hypertensive crisis etc..
The stability of crystal form of the I types crystallization of S- Manidipines hydrochloride prepared in accordance with the present invention is good, disclosure satisfy that life
The medicinal requirements of shipping storage are produced, stable processing technique is repeatable controllable, can adapt in industrialized production.
Below with reference to the drawings and specific embodiments, the present invention is furture elucidated, it should be understood that its work for being merely illustrative of
With not limiting the scope of the invention in any way.
Description of the drawings
Fig. 1 is the X-ray powder diffraction collection that the I types of S- Manidipines hydrochloride of the present invention crystallize.
Fig. 2 is the DSC collection of illustrative plates that the I types of S- Manidipines hydrochloride of the present invention crystallize.
Specific implementation mode
The present invention is explained in greater detail below with reference to embodiment, the embodiment of the present invention is merely to illustrate the skill of the present invention
Art scheme, and non-limiting the spirit and scope of the invention.
Experiment test equipment used
1, DSC is composed
Instrument model：DSC figures acquire on TA Q200/2000 differential scanning calorimeters
Method：Linear temperature increase
Sample disc：Aluminium dish, gland
Temperature range：25 DEG C -- setting outlet temperature
Sweep speed (DEG C/min)：10
Protective gas：Nitrogen
2, x-ray diffraction pattern
Instrument model：CPE-135X ray powder diffraction analysis instrument
X-ray：Cu, k α,1.540598；1.544426；1 intensities of K α 2/K α：0.50
X-ray light pipe is set：45kV, 40mA
Divergent slit：Automatically
Monochromator：Nothing
Scan mode：Continuously,
Scanning range (° 2 θ)：2-40°
Scanning step (° 2 θ)：0.013
Embodiment 1
By 1 gram of S- Manidipines free alkali (being prepared according to Chinese patent application 201510870914.8) and the anhydrous second of 20ml
Alcohol mixes.Then, under stiring, 30% HCl/ ethanol solution 5ml are added, continue stirring until dissolving is complete.Gained is clear
Clear solution is being stored at room temperature crystallization 8 hours, and S- Manidipine hydrochlorides 0.82g is then obtained by filtration.It is detected through XRD, the crystallization
In about 5.54 (15.97), 6.23 (14.18), 9.56 (9.26), 11.05 (8.00), 11.92 (7.42), 15.16 (5.84),
15.78 (5.62), 18.51 (4.79), 19.54 (4.54), 20.78 (4.27), 21.08 (4.22), 21.75 (4.09), 22.20
(4.00), 23.89 (3.73), 24.67 (3.61), 24.94 (3.57), 26.96 (3.31), 27.38 (3.26), 29.51
(3.03), there is characteristic peak at 30.57 (2.92).Its X ray diffracting spectrum is shown in that Fig. 1, X ray diffracting data see the table below 1.Its DSC
Spectrogram is shown in Fig. 2, there is 233.5 DEG C of endothermic peak of melting.This crystal form is defined as I crystal.
1 powder x-ray diffraction data of table
Embodiment 2
1 gram of S- Manidipines free alkali and 10ml absolute ethyl alcohols are mixed.Then, under stiring, 30% HCl/ is added
Ethanol solution 5ml continues stirring until dissolving is complete.Gained clear solution is being stored at room temperature crystallization 8 hours, is then being filtered
To S- Manidipine hydrochlorides 0.84g.Itself XRD and DSC collection of illustrative plates is compared through research, determines that product is I crystal.
Embodiment 3
1 gram of S- Manidipines free alkali and 100ml absolute ethyl alcohols are mixed.Then, under stiring, 30% HCl/ is added
Ethanol solution 5ml continues stirring until dissolving is complete.Gained clear solution is being stored at room temperature crystallization 8 hours, is then being filtered
To S- Manidipine hydrochlorides 0.65g.Itself XRD and DSC collection of illustrative plates is compared through research, determines that product is I crystal.
Embodiment 4
1 gram of S- Manidipines free alkali and 90% ethanol/waters of 20ml (volume ratio) are mixed.Then, under stiring, add
The HCl/ methanol solution 5ml for entering 30% continue stirring until dissolving is complete.By gained clear solution to be stored at room temperature crystallization 8 small
When, S- Manidipine hydrochlorides 0.75g is then obtained by filtration.Itself XRD and DSC collection of illustrative plates is compared through research, determines that product is I brilliant
Type.
Embodiment 5
1 gram of S- Manidipines free alkali and 60% ethanol/waters of 50ml (volume ratio) are mixed.Then, under stiring, add
The HCl/ ethanol solution 5ml for entering 30% continue stirring until dissolving is complete.By gained clear solution to be stored at room temperature crystallization 8 small
When, S- Manidipine hydrochlorides 0.81g is then obtained by filtration.Itself XRD and DSC collection of illustrative plates is compared through research, determines that product is I brilliant
Type.
Embodiment 6
1 gram of S- Manidipines free alkali and 50% ethanol/waters of 50ml (volume ratio) are mixed.Then, under stiring, add
The HCl/ ethanol solution 5ml for entering 30% continue stirring until dissolving is complete.By gained clear solution to be stored at room temperature crystallization 8 small
When, S- Manidipine hydrochlorides 0.82g is then obtained by filtration.Itself XRD and DSC collection of illustrative plates is compared through research, determines that product is I brilliant
Type.
Embodiment 7
1 gram of S- Manidipines free alkali and 90% methanol/waters of 50ml (volume ratio) are mixed.Then, under stiring, add
The HCl/ methanol solution 5ml for entering 30% continue stirring until dissolving is complete.By gained clear solution to be stored at room temperature crystallization 8 small
When, S- Manidipine hydrochlorides 0.75g is then obtained by filtration.Itself XRD and DSC collection of illustrative plates is compared through research, determines that product is I brilliant
Type.
Embodiment 8
1 gram of S- Manidipines free alkali and 80% isopropanol/waters of 50ml (volume ratio) are mixed.Then, under stiring,
30% HCl/ aqueous isopropanol 5ml are added, continue stirring until dissolving is complete.Gained clear solution is being stored at room temperature crystallization
8 hours, S- Manidipine hydrochlorides 0.77g is then obtained by filtration.Itself XRD and DSC collection of illustrative plates is compared through research, determines that product is I
Crystal form.
Embodiment 9S- Manidipine hydrochloride I crystal stability experiments
The S- Manidipine hydrochloride Form I samples prepared according to embodiment 1 are stablized according to Chinese Pharmacopoeia requirement
Property experiment, including 60 DEG C of high temperature, high humidity RH92.5%, light durability experiment, result is as shown in table 2 below：
2 S- Manidipine hydrochloride I crystal stability experiment results of table
From upper table 2 it is found that S- Manidipine hydrochloride I crystals prepared by the present invention show it is good
Good stability.
Bibliography
[1]Kajino M,Wada Y,Nagai Y,Nagaoka A,Meguro K.Synthesis and
biological activities of optical isomers of 2-(4-diphenylmethyl-1-
piperazinyl)ethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-
pyridinedicarboxylate(manidipine)dihydrochloride.Chem Pharm Bull 1989；37:
2225–8.
[2]Yoji Tokuma,Hideyo Noguchi Stereoselective pharmacokinetics of
dihydropyridine calcium antagonists。Journal of Chromatography A,1995:694:181-
193.
Claims (23)
1. the I types of S- Manidipine hydrochlorides shown in formula (I) crystallize,
It is characterized in that, being radiated using Cu-Ka, the X-ray powder diffraction collection indicated with 2 θ angles, the crystallization tool are obtained
Just like X-ray powder diffraction collection shown in FIG. 1, wherein about 5.54,6.23,9.56,11.05,11.92,15.16,
15.78,18.51,19.54,20.78,21.08,21.75,22.20,23.89,24.67,24.94,26.96,27.38,
There is characteristic peak at 29.51,30.57.
2. a kind of method for the I types crystallization preparing S- Manidipines hydrochloride according to claim 1 comprising following step
Suddenly：
1) S- Manidipines free alkali is dissolved with solvent, the solvent is selected from C1~C4 alcohols solvents or C1~C4 alcohols/water
Mixed solvent；
2) hydrochloric acid alcoholic solution is added in the solution obtained to step 1) into salt；
3) crystallization, filtering obtain the I types crystallization of S- Manidipine hydrochlorides.
3. according to the method described in claim 2, wherein, C1~C4 alcohols is selected from methanol, ethyl alcohol, isopropanol, n-butanol.
4. according to the method described in claim 3, wherein, C1~C4 alcohols is selected from ethyl alcohol.
5. according to the method described in claim 2, the ratio of S- Manidipines free alkali and solvent for use is wherein in step 1)
1:10~1:100g/ml.
6. according to the method described in claim 2, wherein solvent used in step 1) is C1~C4 alcohols/water mixed solvent.
7. according to the method described in claim 6, wherein, C1~C4 alcohols is selected from methanol, ethyl alcohol, isopropanol, n-butanol.
8. according to the method described in claim 7, wherein, C1~C4 alcohols is selected from ethyl alcohol.
9. according to the method described in claim 6, wherein the volume ratio of C1~C4 alcohols and water is 90:10~50:50.
10. according to the method described in claim 2, in the hydrochloric acid alcoholic solution being added wherein in step 2), the alcohol be selected from C1~
C4 alcohols.
11. according to the method described in claim 10, the wherein described alcohol is selected from methanol, ethyl alcohol, isopropanol, butanol.
12. according to the method described in claim 2, solvent wherein in step 3) used in crystallization be selected from C1~C4 alcohols solvents or
C1~C4 alcohols/water mixed solvent；The temperature of the crystallization is 0~70 DEG C.
13. according to the method for claim 12, wherein C1~C4 alcohols is selected from methanol, ethyl alcohol, isopropanol, positive fourth
Or mixtures thereof alcohol.
14. according to the method for claim 13, wherein C1~C4 alcohols is selected from ethyl alcohol.
15. according to the method for claim 12, wherein the temperature of the crystallization is 10~40 DEG C.
16. according to the method for claim 12, wherein the temperature of the crystallization is 20~30 DEG C.
17. amount of the crystallization solvent relative to S- Manidipine free alkalis used according to the method for claim 12,
For 1-100ml/g.
18. amount of the crystallization solvent relative to S- Manidipine free alkalis used according to the method for claim 17,
For 10-50ml/g.
19. amount of the crystallization solvent relative to S- Manidipine free alkalis used according to the method for claim 18,
For 20-30ml/g.
20. according to the method described in claim 7, crystallization solvent used in it be C1~C4 alcohols/water mixed solvent, wherein
The volume ratio of C1~C4 alcohols and water is 10:90~99:1.
21. a kind of pharmaceutical composition, the I types crystallization containing S- Manidipines hydrochloride according to claim 1 and
One or more pharmaceutically acceptable carriers.
22. the I types of S- Manidipines hydrochloride according to claim 1 crystallize or drug according to claim 21
Purposes of the composition in the drug for preparing treatment hypertension.
23. the I types of S- Manidipines hydrochloride according to claim 1 crystallize or drug according to claim 10
The purposes of composition in medicine preparation, the drug for prevent or treat coronary heart disease, cerebrovascular disease, hypertensive heart disease,
Hypertensive encephalopathy, chronic renal failure and hypertensive crisis.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4994461A (en) * | 1987-03-27 | 1991-02-19 | Byk Gulden Lomberg Chemische Fabrik Gmbh | 1,4-dihydropyridine enantiomers |
| CN104860873A (en) * | 2015-05-28 | 2015-08-26 | 石家庄学院 | Preparation method for (S)-1,4-dihydropyridine calcium ion antagonist |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH02275854A (en) * | 1989-01-06 | 1990-11-09 | Takeda Chem Ind Ltd | Optically active dihydropyridine derivative, production and its use |
-
2016
- 2016-06-20 CN CN201610444090.2A patent/CN105924382B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4994461A (en) * | 1987-03-27 | 1991-02-19 | Byk Gulden Lomberg Chemische Fabrik Gmbh | 1,4-dihydropyridine enantiomers |
| CN104860873A (en) * | 2015-05-28 | 2015-08-26 | 石家庄学院 | Preparation method for (S)-1,4-dihydropyridine calcium ion antagonist |
Non-Patent Citations (1)
| Title |
|---|
| Synthesis and biological activities of optical isomers of 2-(4-diphenylmethyl-1-piperazinyl)ethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate (manidipine) dihydrochloride;Kajimo, Masahiro，等;《Chemical & Pharmaceutical Bulletin》;19890831;第37卷(第8期);第2225-2228页 * |
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