CN103058953B - Tetrahydrobenzothiazole derivate for treating nerve diseases - Google Patents
Tetrahydrobenzothiazole derivate for treating nerve diseases Download PDFInfo
- Publication number
- CN103058953B CN103058953B CN201310001075.7A CN201310001075A CN103058953B CN 103058953 B CN103058953 B CN 103058953B CN 201310001075 A CN201310001075 A CN 201310001075A CN 103058953 B CN103058953 B CN 103058953B
- Authority
- CN
- China
- Prior art keywords
- formula
- amino
- compound
- pharmacy
- acceptable salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- XOBNZYBTOQEBFK-UHFFFAOYSA-N CCCNC(CCC1)CCc2c1cc(N)[s]2 Chemical compound CCCNC(CCC1)CCc2c1cc(N)[s]2 XOBNZYBTOQEBFK-UHFFFAOYSA-N 0.000 description 1
- 0 C[C@](CC1)Cc2c1nc(*)[s]2 Chemical compound C[C@](CC1)Cc2c1nc(*)[s]2 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Abstract
The invention discloses a tetrahydrobenzothiazole derivate for treating nerve diseases. Particularly, the tetrahydrobenzothiazole derivate comprises compounds shown in the following formula I: (S)-(-)-2-amino-6-(propionamide)-4,5,6,7- tetrahydrobenzothiazole, acceptable salt of the compounds in pharmacy or solvates of the compounds. The compounds or compositions of the tetrahydrobenzothiazole derivate can be used for treating nervous system diseases.
Description
Technical field
The present invention relates to a kind of the Tetrahydrobenzothiazderivative derivative such as pramipexole and dihydrochloride monohydrate thereof that are used for the treatment of sacred disease.
Background technology
Pramipexole is used to Parkinson disease that is early stage and late period, for stimulating the dopamine receptor in brain as a kind of dopamine gaonist.In actual applications, preferred pramipexole dihydrochloride monohydrate is as the Parkinsonian compound for the treatment of.The chemical name of pramipexole dihydrochloride monohydrate is (S)-(-)-2-amino-6-(third is amino)-4,5,6,7-tetrahydro benzothiazol dihydrochloride monohydrate, wherein (S) represents that body of Pramipexole dihydrochloride is S configuration, and (-) represents that body of Pramipexole dihydrochloride is left-handed.Known S configuration, left-handed body of Pramipexole dihydrochloride as medical material, can treat Parkinsonian medicine for preparing.Specifically, following levoform S (-) pramipexole (
form with its dihydrochloride monohydrate) be applied to clinical, and be commonly referred to be impurity with bottom right formula R (+) pramipexole and do not wish to appear in the pramipexole preparation gone on the market.
Containing 1 chiral carbon atom in pramipexole molecule, in the process by controlled syntheses target compound body of Pramipexole dihydrochloride, need the content controlling its optical isomer.For the optical isomer impurity of body of Pramipexole dihydrochloride, need to carry out quality control in the middle of pharmaceutical synthesis process.Containing the difficult point that the separation of the optical isomer of chiral carbon atom is quality control in chiral drug synthesis and production process always, the quality control aspect of the synthesis being separated in body of Pramipexole dihydrochloride medicine and production process that realize body of Pramipexole dihydrochloride and optical isomer thereof has realistic meaning.
At present, the synthetic method about pramipexole and dihydrochloride monohydrate thereof has many reports.J.Med.Chem.1987,30,494-498 disclose a kind of preparation method of body of Pramipexole dihydrochloride, and the method for raw material, leads to N with (-) 2-amino-6-propionamido-4,5,6,7-tetrahydro benzothiazol in THF (oxolane)
2under protection, react with the Borane solution of THF and obtain (S)-(-)-2-amino-6-(third amino)-4,5,6,7-tetrahydro benzo thiophenes and stare at, being then converted into dihydrochloride; The particular content of this preparation method is, at room temperature also logical N
2under protection, dropwise add the Borane solution of THF toward containing in the THF of (-) 2-amino-6-propionamido-4,5,6,7-tetrahydro benzothiazol, then stirring reaction 1 hour cooling at 50 DEG C, then add water and concentrated hydrochloric acid; Evaporate THF and add 25% sodium hydroxide solution in aqueous phase, then filter and be precipitated ((S)-(-)-2-amino-6-(third is amino)-4,5,6,7-tetrahydro benzothiazol), the precipitation obtained is washed and it is dissolved in the ethyl acetate of heat; Remove the moisture (Mg in solution
2sO
4) and concentrated, filter and be precipitated, wash the precipitation obtained by ethyl acetate, to convert it into as dihydrochloride and recrystallization obtains (S)-(-)-2-amino-6-(the third amino)-4,5 from methanol, 6,7-tetrahydro benzothiazol dihydrochloride; The shortcoming of the method is that the Borane solution manufacture method of THF is complicated, be not suitable for commercial production, and due to the colourless severe toxicity of borine, inflammable, explosive, facile hydrolysis, poor stability, not easily preserves transport, and therefore reaction safety is low.Chinese patent CN1834092 improves said method, uses NaBH
4and BF
3generate borine in position, but boron trifluoride ether solution meets water decomposition, irritant abnormal smells from the patient, and ether height is inflammable, severe reaction conditions and very high to equipment requirements, also should not carry out suitability for industrialized production.Chinese patent CN101676272 sodium borohydride, lithium aluminium hydride are reduced as reducing agent, condition comparatively relaxes, but need to react at reflux, response time is very long, oxolane boiling point as solvent is lower, severe to the organic component corrosivity except politef, easily causing run, drip, leak, there is the danger of blast in oxolane at reflux, therefore requires very high to equipment, Factory Building; And lithium aluminium hydride is expensive and all very sensitive to water and air, there is the danger of combustion explosion; So equally not easily carry out suitability for industrialized production.Chinese patent CN101585818A discloses a kind of preparation method of the intermediate for the preparation of body of Pramipexole dihydrochloride, and step is: in a solvent, with 2-amino-6-propionamido-4,5,6,7-tetrahydro benzothiazol at Zn (BH
4)
2under existence, carry out reduction reaction, from product, then collect 2-amino-6-Propylamino-4,5,6,7-tetrahydro benzothiazol; The method needs to carry out in high temperature environments, and the oxolane boiling point as solvent is low, inflammable and explosive; Have infringement to consersion unit, to Factory Building and equipment requirements high; And Zn (BH
4)
2preparation difficulty, not easily preserves.In addition, CN101622235A also discloses a kind of new method of synthesizing pramipexole.
In these synthetic methods existing, isomer in product has multiple synthesis mode to avoid, chiral raw material is such as used to be prepared, or such as prepare isomer mixture in advance, then separation is carried out to this pramipexole isomer mixture, L-(+)-tartaric acid is such as used to split, for example, see (the Wang Wenting described in detail in the disclosed document such as Wang Wenting, Deng, the synthesis of body of Pramipexole dihydrochloride, Chinese Journal of Pharmaceuticals, 2012,43 (7): 524).Such as CN101429173A discloses a kind of preparation method of midbody 2,6-diamino-4,5,6, the 7-tetrahydrochysene-benzothiazole for the preparation of pramipexole again.Those skilled in the art are with reference to these known methods and combine and had experience can obtain (S)-(-) pramipexole or obtained (R)-(+) pramipexole and their salt and solvate thereof.
Summary of the invention
The object of this invention is to provide a kind of substantially pure (S)-(-) pramipexole or the acceptable salt of its pharmacy or solvate.
The present invention seeks to be realized by following scheme of the invention:
Scheme of the invention 1, a kind of compound, wherein comprise compound shown in following formula I (S)-(-)-2-amino-6-(third is amino)-4,5,6,7-tetrahydro benzothiazols:
Or the acceptable salt of its pharmacy, or their solvate.
Scheme of the invention 2, compound according to scheme of the invention 1, the acceptable salt of pharmacy of wherein said formula I is its hydrochlorate.
Scheme of the invention 3, compound according to scheme of the invention 1-2, the acceptable salt of pharmacy of wherein said formula I is its dihydrochloride.
Scheme of the invention 4, compound according to scheme of the invention 1-3, the solvate of wherein said formula I or its salt is hydrate.
Scheme of the invention 5, compound according to scheme of the invention 4, wherein said hydrate is monohydrate.
Scheme of the invention 6, compound according to scheme of the invention 1-5, wherein said formula I is dihydrochloride monohydrate, i.e. (S)-(-)-2-amino-6-(third is amino)-4,5,6,7-tetrahydro benzothiazol dihydrochloride monohydrate.
Scheme of the invention 7, compound according to scheme of the invention 1-6, wherein also comprise with the amino of (R)-(+)-2-shown in Formula Il-6-(third is amino)-4,5,6,7-tetrahydro benzothiazols:
Or the acceptable salt of its pharmacy, or their solvate.
Scheme of the invention 8, compound according to scheme of the invention 1-7, the mol ratio of wherein said formula I and formula II compound is greater than 200:1 (such as between 200 ~ 3000:1).
Scheme of the invention 9, compound according to scheme of the invention 1-7, the mol ratio of wherein said formula I and formula II compound is greater than 250:1 (such as between 250 ~ 3000:1).
Scheme of the invention 10, compound according to scheme of the invention 1-7, the mol ratio of wherein said formula I and formula II compound is greater than 300:1 (such as between 300 ~ 3000:1).
Scheme of the invention 11, compound according to scheme of the invention 1-7, the mol ratio of wherein said formula I and formula II compound is greater than 350:1 (such as between 350 ~ 3000:1).
Scheme of the invention 12, compound according to scheme of the invention 1-7, the mol ratio of wherein said formula I and formula II compound is greater than 400:1 (such as between 400 ~ 3000:1).
Scheme of the invention 13, compound according to scheme of the invention 1-7, it is under the HPLC chromatographic condition that the separating degree between formula I and formula II compound can be made to be greater than 3, in this compound gained HPLC collection of illustrative plates, the chromatographic peak area ratio of described formula I and formula II compound is greater than 200:1 (such as between 200 ~ 3000:1).
Scheme of the invention 14, compound according to scheme of the invention 1-7, it is under the HPLC chromatographic condition that the separating degree between formula I and formula II compound can be made to be greater than 3, in this compound gained HPLC collection of illustrative plates, the chromatographic peak area ratio of described formula I and formula II compound is greater than 250:1 (such as between 250 ~ 3000:1).
Scheme of the invention 15, compound according to scheme of the invention 1-7, it is under the HPLC chromatographic condition that the separating degree between formula I and formula II compound can be made to be greater than 3, in this compound gained HPLC collection of illustrative plates, the chromatographic peak area ratio of described formula I and formula II compound is greater than 300:1 (such as between 300 ~ 3000:1).
Scheme of the invention 16, compound according to scheme of the invention 1-7, it is under the HPLC chromatographic condition that the separating degree between formula I and formula II compound can be made to be greater than 3, in this compound gained HPLC collection of illustrative plates, the chromatographic peak area ratio of described formula I and formula II compound is greater than 350:1 (such as between 350 ~ 3000:1).
Scheme of the invention 17, compound according to scheme of the invention 1-7, it is under the HPLC chromatographic condition that the separating degree between formula I and formula II compound can be made to be greater than 3, in this compound gained HPLC collection of illustrative plates, the chromatographic peak area ratio of described formula I and formula II compound is greater than 400:1 (such as between 400 ~ 3000:1).
In the present invention, above-mentioned mol ratio or peak area ratio also can with concrete numeric representations, such as " mol ratio is greater than 350:1 " also can be expressed as " mol ratio is greater than 350 ", " peak area ratio is greater than 350:1 " also can be expressed as " peak area ratio is greater than 350 ", mol ratio " between 350 ~ 3000:1 " also can be expressed as mol ratio " between 350 ~ 3000 ", and " mol ratio is 350:1 " also can be expressed as " mol ratio is 350 ".
Scheme of the invention 18, a kind of pharmaceutical composition, wherein comprise the compound according to scheme of the invention 1-13, and the acceptable adjuvant of pharmacy.
Scheme of the invention 19, pharmaceutical composition according to scheme of the invention 18, it is in tablet or the form of capsule.
Scheme of the invention 20, pharmaceutical composition according to scheme of the invention 19, it is in rapid release or the tablet of slow release or the form of capsule.
Scheme of the invention 21, pharmaceutical composition according to scheme of the invention 18-20, wherein comprise formula I or the acceptable salt of its pharmacy of 0.1 ~ 5mg in each tablet or capsule, or their solvate.
Scheme of the invention 22, pharmaceutical composition according to scheme of the invention 18-21, the acceptable adjuvant of wherein said pharmacy comprises magnesium salt, such as but not limited to magnesium carbonate, magnesium bicarbonate, magnesium silicate, magnesium stearate.
Scheme of the invention 23, pharmaceutical composition according to scheme of the invention 18-22, comprise compound shown in following formula I (S)-(-)-2-amino-6-(third is amino)-4,5,6,7-tetrahydro benzothiazols:
Or the acceptable salt of its pharmacy, or their solvate, and optional with the amino of (R)-(+)-2-shown in Formula Il-6-(third is amino)-4,5,6,7-tetrahydro benzothiazols:
Or the acceptable salt of its pharmacy, or their solvate;
The mol ratio of formula I and formula II compound described in this pharmaceutical composition is greater than 200:1 (such as between 200 ~ 3000:1), is greater than 250:1 (such as between 250 ~ 3000:1), is greater than 300:1 (such as between 300 ~ 3000:1), is greater than 350:1 (such as between 350 ~ 3000:1) or is greater than 400:1 (such as between 400 ~ 3000:1).
Scheme of the invention 24, pharmaceutical composition according to scheme of the invention 18-22, comprise compound shown in following formula I (S)-(-)-2-amino-6-(third is amino)-4,5,6,7-tetrahydro benzothiazols:
Or the acceptable salt of its pharmacy, or their solvate, and optional with the amino of (R)-(+)-2-shown in Formula Il-6-(third is amino)-4,5,6,7-tetrahydro benzothiazols:
Or the acceptable salt of its pharmacy, or their solvate;
Under the HPLC chromatographic condition that the separating degree between formula I and formula II compound can be made to be greater than 3, in this pharmaceutical composition gained HPLC collection of illustrative plates, the chromatographic peak area ratio of described formula I and formula II compound is greater than 200:1 (such as between 200 ~ 3000:1), is greater than 250:1 (such as between 250 ~ 3000:1), is greater than 300:1 (such as between 300 ~ 3000:1), is greater than 350:1 (such as between 350 ~ 3000:1) or is greater than 400:1 (such as between 400 ~ 3000:1).
Scheme of the invention 25, pharmaceutical composition according to scheme of the invention 23-24, the acceptable salt of pharmacy of wherein said formula I is its hydrochlorate.
Scheme of the invention 26, pharmaceutical composition according to scheme of the invention 23-24, the acceptable salt of pharmacy of wherein said formula I is its dihydrochloride.
Scheme of the invention 27, pharmaceutical composition according to scheme of the invention 23-24, the solvate of wherein said formula I or its salt is hydrate.
Scheme of the invention 28, pharmaceutical composition according to scheme of the invention 23-24, wherein said hydrate is monohydrate.
Scheme of the invention 29, pharmaceutical composition according to scheme of the invention 23-24, wherein said formula I dihydrochloride monohydrate, i.e. (S)-(-)-2-amino-6-(third is amino)-4,5,6,7-tetrahydro benzothiazol dihydrochloride monohydrate.
In the compounds of this invention, key component is formula I or the acceptable salt of its pharmacy or their solvate, and formula II compound or the acceptable salt of its pharmacy or their solvate are considered as trace impurity.Therefore from then on meaning is said, although the compounds of this invention can simply be interpreted as the mixture comprising many kinds of substance, but it is formula I or the acceptable salt of its pharmacy or their solvate in essence, wherein containing trace (such as the mole percent of formula I lower than 0.5%, such as lower than 0.4% or lower) as the formula II compound of impurity level or the acceptable salt of its pharmacy or their solvate.
For the compounds of this invention, many known methods can be adopted to measure the amount of formula I and the formula II compound comprised in them, and the relative quantity of the two can be calculated.Such as can with reference to the HPLC method described in CN101769902A, the document is incorporated to herein by reference with its full content.
Especially, in the present invention, if not otherwise indicated, following HPLC method (it is positive HPLC method) is adopted to measure amount and the relative quantity of the two of the compounds of this invention compounds of formula I and formula II compound:
(1) instrument and condition:
High performance liquid chromatograph: Shimadzu: LC-10ATvp, SPD-M10Avp, SCL-10Avp, DGU-12A;
Chromatographic column: AD-H (Daicel, 4.6mm × 250mm, 5 μm);
Mobile phase: normal hexane-dehydrated alcohol-diethylamine=80:20:0.1;
Flow velocity: 1.0ml/min;
Sampling volume: 20 μ l;
Determined wavelength: 262nm;
(2) operating procedure: take (S)-(-) pramipexole dihydrochloride monohydrate and each 5mg of optical isomer (R)-(+) pramipexole thereof respectively, be placed in 25ml volumetric flask, add anhydrous alcohol solution and dilute and put scale, shake up, filter, as biased sample solution.Separately take (S)-(-) pramipexole dihydrochloride monohydrate 5mg, be placed in 25ml volumetric flask, add anhydrous alcohol solution and dilute and put scale, shake up, filter, as (S)-(-) pramipexole quality control solution.Separately take (R)-(+) pramipexole 5mg, be placed in 25ml volumetric flask, add anhydrous alcohol solution and dilute and put scale, shake up, filter, as (R)-(+) pramipexole quality control solution.
Draw each quality control solution and biased sample solution 20 μ l injection liquid chromatography respectively, carry out efficient liquid phase chromatographic analysis by above-mentioned condition, record chromatogram; Use the retention time of each quality control solution to belong to (retention time namely determining two isomers in biased sample solution chromatogram) chromatographic peak each in the chromatogram of biased sample solution, and calculate two peak-to-peak separating degrees of isomer.In the typical color spectrogram (not providing) of above chromatographic condition gained biased sample solution, (R)-(+) pramipexole first goes out peak, (S)-(-) peak (retention time is about 14min) is gone out after pramipexole, and the two separating degree >4, can meet to measure and require (pharmaceutical analysis those skilled in the art understand typically separating degree be greater than 2 namely think have good separating degree and can meet separation requirement).
(3) sample determination: the compounds of this invention anhydrous alcohol solution is made the solution of about 200 μ g/ml, to filter, as need testing solution.Draw 20 μ l need testing solutions, injection liquid chromatography, carries out efficient liquid phase chromatographic analysis by above-mentioned condition, record chromatogram; The retention time of record (S)-(-) pramipexole and both (R)-(+) pramipexoles and peak area.
Above-mentioned HPLC method all can reach 0.01 μ g/ml for the detectability of two kinds of isomers, and visible the method can measure effectively for the isomer of trace.
For (R)-(+) pramipexole of test, also can measure its chromatographic purity, particularly measure the relative quantity of (S)-(-) pramipexole as impurity that wherein may contain.
Those skilled in the art know that, for (S)-(-) pramipexole and (R)-(+) pramipexole, when injecting this two kinds of isomers of material of equal molar quantities in chromatograph of liquid, because having substantially identical extinction coefficient, (two kinds of isomer mobile phases such as to be mixed with at the solution of molar concentration for they, they are identical at ultraviolet 262nm place absorbance), the peak area that the two display is substantially identical in liquid chromatogram.In addition, when (S)-(-) pramipexole exists in different forms, such as it exists with free alkali form, or exist with acceptable salt such as dihydrochloride form, or exist with solvate such as (S)-(-) pramipexole dihydrochloride monohydrate form, when being mixed with solution (such as the dehydrated alcohol of 200 μ g/ml) of a certain absolute concentration, their face, peak kinds in chromatogram are not identical, particularly the less then peak area of mole is larger, the peak area of such as free alkali maximum (because in the solution under equal mass concentration its molar concentration relatively maximum), and the peak area of (S)-(-) pramipexole dihydrochloride monohydrate minimum (because in the solution under equal mass concentration its molar concentration relatively minimum).Therefore, be appreciated that, when the compounds of this invention (mainly (S)-(-) pramipexole of formula I, may (R)-(+) pramipexole of formula II containing trace/impurity level) no matter (such as its pharmaceutical salts such as its dihydrochloride in what manner, such as its solvate such as its dihydrochloride monohydrate) injection liquid phase spectrum spectrometer, (S)-(-) pramipexole shown in chromatogram substantially can be easily with the mol ratio of both (R)-(+) pramipexoles, reflect with the peak area ratio of the two intuitively, namely (S)-(-) pramipexole and the mol ratio of both (R)-(+) pramipexoles are substantially equal to the peak area ratio of the two.The present inventor find in the test of all multiple batches of (more than 20 times) mol ratio when both (S)-(-) pramipexole and (R)-(+) pramipexole calibrated for both during 1:1 under the multiple HPLC chromatographic condition that the separating degree between formula I and formula II compound can be made to be greater than 3, detect at 262nm wavelength place, (S)-(-) pramipexole and the peak area ratio both (R)-(+) pramipexole are all in 1:(1.0007 ~ 1.0009) between, namely only there is the deviation of about 8/10000 between mol ratio and peak area ratio two kinds of arithmetic result.Therefore, under the HPLC chromatographic condition that the separating degree between formula I and formula II compound can be made to be greater than 3, detect at 262nm wavelength place, (S)-(-) pramipexole is substantially equal to mol ratio with the peak area ratio of both (R)-(+) pramipexoles.
In addition, for pharmaceutical composition of the present invention, owing to which are added the compound of the various embodiment of the present invention as active component, thus in these pharmaceutical compositions, also may there is (R)-(+) pramipexole or its pharmaceutical salts or solvate that can be understood as impurity.Those skilled in the art know that, these pharmaceutical compositions are when example HPLC method as described in the present invention measures, the mol ratio of (S)-(-) pramipexole and both (R)-(+) pramipexoles in compositions can be reflected equally exactly, and typically this to join the mol ratio that mol ratio measured in pharmaceutical composition and the crude drug i.e. such as the compounds of this invention preparing said composition be measured to identical or close.
When the present inventor finds to contact together containing magnesium material and (S)-(-) pramipexole, the amount of (R)-(+) pramipexole as impurity wherein comprised there will be change.And by the amount that controls (R)-(+) pramipexole in the compounds of this invention to a certain extent after, this change is controlled.In one embodiment, in the present composition, (S)-(-) pramipexole can rule of thumb be determined with the weight ratio containing magnesium material; In one embodiment, in the present composition, (S)-(-) pramipexole is (with (S)-(-) 2-amino-6-third amino-4,5,6,7-tetrahydro benzothiazol meter, do not consider salify and solvate) and be 1:0.1 ~ 10, such as 1:0.2 ~ 5 containing the weight ratio of magnesium material.
Although be described the assay method of the compounds of this invention compounds of formula I and formula II compound, but it will be apparent to those skilled in the art that in fact this kind of assay method can be easy to change.Even if such as above-described positive HPLC method, mobile phase wherein used can be done to change on a large scale according to different situations, such as make change according to the concrete filler, length, filler granule size, column temperature, flow rate of mobile phase etc. of chromatographic column, make the appearance time of formula I within the scope of 5-100min and make between formula I and formula II compound, to reach effective separating degree (such as separating degree is greater than 3).
The compounds of this invention pramipexole is a kind of non-Ergota class dopamine agonist.In vitro study shows, and the specificity of pramipexole to D2 receptor is higher and have intrinsic activity completely, to the affinity of D3 receptor higher than D2 and D4 receptor.This combination and the parkinsonian dependency of pramipexole and D3 receptor are indefinite.The parkinsonian precise mechanism of pramipexole treatment it be unclear that, and thinks relevant with the striatal dopamine receptor of activation at present.Animal electricity physiological test shows, and pramipexole affects striatal neuron discharge frequency by activating the dopamine receptor of striatum and black substance.Pramipexole oral absorption is complete rapidly.Absolute bioavailability is higher than 90%, and maximal plasma concentration occurs between 1-3 hour after the tablet has been ingested.Take the degree that can not reduce pramipexole absorption together with food, but its absorption rate can be reduced.Pramipexole demonstrates linear kinetics feature, and between patient, blood plasma level difference is very little.Pramipexole sheet of the present invention can be used to treat the S&S of idiopathic parkinsonism, separately (without levodopa) or with levodopa coupling.Such as, when the curative effect of end-stage disease levodopa weakens gradually or occur change and fluctuate (agent end phenomenon or " switch " fluctuation), need to apply this product.
Detailed description of the invention
To describe the present invention in more detail by embodiment below, following explanation is only to explain the present invention, does not limit its content.Reaction raw materials of the present invention all can commercially have been bought, more such as prepare (-) 2-amino-6-propionamido-4 used in the example of chemical combination, 5,6,7-tetrahydro benzothiazol comes can by purchase commercially available prod or according to J.Med.Chem.1987,30,494-498 catches the method preparation of confession.
embodiment 1
(1) preparation of amino-4,5,6, the 7-tetrahydro benzothiazols of (S)-(-) 2-amino-6-third
By (-) 2-amino-6-propionamido-4,5,6,7-tetrahydro benzothiazol (227.33g, 1mol) joins in oxolane (1362ml), stirs and makes it dissolve, then sodium borohydride (94.68g is added fast, 2.5mol) stir, be then cooled to-5 DEG C, then at-5 ~ 0 DEG C, slowly drip I
2(253.8g, 1mol) and oxolane 725ml (I
2mass concentration be 35%) solution, drip and finish, slowly be warming up to 35 DEG C, insulation reaction 8h, then less than 10 DEG C are cooled to, first drip tap water 45ml, avoid reaction too fierce, then drip mass fraction be 37% hydrochloric acid 946.8ml be then slowly warming up to 40 DEG C, keep 30min, then oxolane is reclaimed by the method for distilling under reduced pressure, after recovery, surplus solution 30% sodium hydroxide solution regulates pH=12, separate out a large amount of solid, be cooled to less than 10 DEG C, stir 30min, use buchner funnel sucking filtration, water 600ml washs 2 times, white solid (S)-(-) 2-amino-6-third amino-4 is dried to obtain in 40 DEG C of air blast, 5, 6, 7-tetrahydro benzothiazol (198.6g, molar yield 94%).
the preparation of (2) two hydrochloric acid one hydrated valaciclovirs
By (S)-(-) 2-amino-6-third amino-4 obtained in (1), 5, 6, 7-tetrahydro benzothiazol (198.6g, 0.94mol) be dissolved in 1390ml dehydrated alcohol, add needle-use activated carbon 42g, be warming up to 50 DEG C, stir 30min, filter, filtrate is cooled to less than 10 DEG C, and keep less than 10 DEG C drip mass fractions be 37% concentrated hydrochloric acid 198ml, stir 10h, sucking filtration, filter cake 95% ethanol 200ml washs 2 times, 40 DEG C of vacuum dryings obtain the dihydrochloride monohydrate (256.5g of product (S)-(-) pramipexole, molar yield 90.3%), for white is to off-white powder, melt at 296 ° of C to 301 ° of C and have decomposition.Measure through HPLC, (S)-(-) 2-amino-6-third amino-4 in this product, 5,6,7-tetrahydro benzothiazol and (R)-(+) 2-amino-6-third amino-4,5,6, the peak area ratio of 7-tetrahydro benzothiazol is 142:1 (because peak area ratio only differs 8/10000 with mol ratio, therefore it also can be regarded as mol ratio in the present invention, lower same).
embodiment 1c: test amino-4,5,6, the 7-tetrahydro benzothiazol disalts of (R)-(+) 2-amino-6-third
the preparation of acid monohydrate
(R)-(+) 2-amino-6-third used in the present invention amino-4,5,6,7-tetrahydro benzothiazol, can with reference to J.Med.Chem.1987,30, the method that 494-498 provides prepares (+) 2-amino-6-propionamido-4,5,6,7-tetrahydro benzothiazol, then prepares with reference to said method.The present inventor is in other test, prepare (R)-(+) 2-amino-6-third amino-4,5,6,7-tetrahydro benzothiazol, (R)-(+) 2-amino-6-third obtained amino-4,5,6,7-tetrahydro benzothiazol two hydrochloride monohydrate chromatographic purity is 99.62% (i.e. (R)-(+) 2-amino-6-third amino-4,5,6,7-tetrahydro benzothiazol and (S)-(-) 2-amino-6-third amino-4,5, the mol ratio (peak area ratio) of 6,7-tetrahydro benzothiazol is 262:1).Those skilled in the art know that, no matter but should (R)-(+) 2-amino-6-third amino-4,5,6, how high 7-tetrahydro benzothiazol chromatographic purity is, as long as it accounts for major part (such as purity more than 70%, more than 80%, more than 90% or more than 95%), it determines its retention time in chromatogram and the separating degree in chromatograph for calculating itself and (S)-(-) pramipexole as the present invention is qualitative, is enough to meet the requirement in experimental implementation of the present invention.
embodiment 2: amino-4,5,6, the 7-tetrahydro benzothiazol dihydrochlorides of preparation (S)-(-) 2-amino-6-third
Method with reference to CN1834092A embodiment 1 is carried out, and obtains amino-4,5,6, the 7-tetrahydro benzothiazol dihydrochlorides of (S)-(-) 2-amino-6-third.Measure through HPLC, (S)-(-) 2-amino-6-third amino-4 in this product, 5,6,7-tetrahydro benzothiazol and (R)-(+) 2-amino-6-third amino-4, the peak area ratio (also can be regarded as mol ratio) of 5,6,7-tetrahydro benzothiazol is 117:1.
embodiment 3: amino-4,5,6, the 7-tetrahydro benzothiazol dihydrochlorides of preparation (S)-(-) 2-amino-6-third
With reference to the document (Wang Wenting of Wang Wenting etc., Deng, the synthesis of body of Pramipexole dihydrochloride, Chinese Journal of Pharmaceuticals, 2012,43 (7): 524) method (" experimental section " in literary composition describes in detail) recorded, adopt L-(+)-tartaric acid to carry out chiral separation in preparation process, obtain (S)-(-) 2-amino-6-third amino-4,5,6,7-tetrahydro benzothiazol dihydrochloride.Measure through HPLC, (S)-(-) 2-amino-6-third amino-4 in this product, 5,6,7-tetrahydro benzothiazol and (R)-(+) 2-amino-6-third amino-4, the peak area ratio (also can be regarded as mol ratio) of 5,6,7-tetrahydro benzothiazol is 98.5:1.
embodiment 4: amino-4,5,6, the 7-tetrahydro benzothiazol dihydrochlorides of preparation (S)-(-) 2-amino-6-third
monohydrate
Make the product of embodiment 3 be spread out in plate, thickness is less than 1mm, within 12 hours, makes balance with the air atmosphere featheriness of RH75%, is amino-4,5,6, the 7-tetrahydro benzothiazol dihydrochloride monohydrates of (S)-(-) 2-amino-6-third after measured.Measure through HPLC, (S)-(-) 2-amino-6-third amino-4 in this hydrate, 5,6,7-tetrahydro benzothiazol and (R)-(+) 2-amino-6-third amino-4, the peak area ratio (also can be regarded as mol ratio) of 5,6,7-tetrahydro benzothiazol is 98.5:1.
embodiment 5: amino-4,5,6, the 7-tetrahydro benzothiazol dihydrochlorides of preparation (S)-(-) 2-amino-6-third
With reference to the document (Jinhua of Jinhua etc., Deng, the study on the synthesis of body of Pramipexole dihydrochloride, Chinese pharmaceutical chemistry magazine, 2011,21 (6): 430) method (" experimental section " in literary composition describes in detail) recorded, adopt L-(+)-tartaric acid to carry out chiral separation in preparation process, obtain (S)-(-) 2-amino-6-third amino-4,5,6,7-tetrahydro benzothiazol dihydrochloride.Measure through HPLC, (S)-(-) 2-amino-6-third amino-4 in this product, 5,6,7-tetrahydro benzothiazol and (R)-(+) 2-amino-6-third amino-4, the peak area ratio (also can be regarded as mol ratio) of 5,6,7-tetrahydro benzothiazol is 98.9:1.
embodiment 6: preparation (S)-(-) 2-amino-6-third amino-4,
5,
6,
7-tetrahydro benzothiazol dihydrochloride monohydrate
The pramipexole dihydrochloride monohydrate (mol ratio of S-isomer and R isomer is 142) embodiment 1 obtained carries out recrystallization 1 time with methanol-lactic acid mixed liquor (methanol and Pfansteihl volume ratio 20:1).Obtain white crystalline powder, melt at 296 ° of C to 301 ° of C and have decomposition.Measure through HPLC, (S)-(-) 2-amino-6-third amino-4 in this product, 5,6,7-tetrahydro benzothiazol and (R)-(+) 2-amino-6-third amino-4, the peak area ratio (also can be regarded as mol ratio) of 5,6,7-tetrahydro benzothiazol is 292:1.
embodiment 7: amino-4,5,6, the 7-tetrahydro benzothiazol dihydrochlorides of preparation (S)-(-) 2-amino-6-third
monohydrate
The method of reference example 6, recrystallization process 2 times, the mol ratio of S-isomer and R-isomer in product is 389:1.
embodiment 8: amino-4,5,6, the 7-tetrahydro benzothiazol dihydrochlorides of preparation (S)-(-) 2-amino-6-third
monohydrate
The method of reference example 6, use methanol-lactic acid mixed liquor (methanol and Pfansteihl volume ratio 20:2) recrystallization process 2 times, the mol ratio of S-isomer and R-isomer in product is 875:1.
embodiment 9: amino-4,5,6, the 7-tetrahydro benzothiazol dihydrochlorides of preparation (S)-(-) 2-amino-6-third
monohydrate
The method of reference example 6, use methanol-lactic acid mixed liquor (methanol and Pfansteihl volume ratio 20:2) recrystallization process 3 times, the mol ratio of S-isomer and R-isomer in product is 1535:1.
embodiment 10: amino-4,5,6,7-tetrahydro benzothiazol two hydrochloric acid of preparation (S)-(-) 2-amino-6-third
salt monohydrate
The method of reference example 6, use 95% ethanol-lactic acid mixed liquor (ethanol and Pfansteihl volume ratio 20:1) recrystallization process 2 times, the mol ratio of S-isomer and R-isomer in product is 2175:1.
embodiment 11: amino-4,5,6,7-tetrahydro benzothiazol two hydrochloric acid of preparation (S)-(-) 2-amino-6-third
salt monohydrate
The method of reference example 6, use 95% ethanol-lactic acid mixed liquor (ethanol and Pfansteihl volume ratio 20:2) recrystallization process 4 times, the mol ratio of S-isomer and R-isomer in product is 2986:1, and the total recovery of recrystallization process is 94%; When repeating a recrystallization again, the mol ratio of S-isomer and R-isomer in product is 3100:1, and the total recovery of recrystallization process is 92%; When repeating a recrystallization again, the mol ratio of S-isomer and R-isomer in product is 3800:1, the total recovery of recrystallization process is 81%, and during continuation recrystallization process, total recovery can continue to reduce significantly, lower as its practicality of medical material medicine in commercial production.Therefore, in one embodiment of the invention, the mol ratio of formula I and formula II compound is between 350 ~ 3000:1.
embodiment 12: amino-4,5,6,7-tetrahydro benzothiazol two hydrochloric acid of preparation (S)-(-) 2-amino-6-third
-4,5,6,7-tetrahydro benzothiazol two hydrochloric acid one hydrations amino with (R)-(+) 2-amino-6-third of salt monohydrate
both things have the mixture of different mol ratio
Get a certain amount of embodiment 1c gained (R)-(+) 2-amino-6-third amino-4,5,6,7-tetrahydro benzothiazol two hydrochloride monohydrate and a certain amount of embodiment 11 gained (S)-(-) 2-amino-6-third amino-4,5,6,7-tetrahydro benzothiazol dihydrochloride monohydrate, mix homogeneously, easily can obtain S-isomer and R-ratios of the isomers is the mixture of different mol ratio, the mixture of mol ratio in the scope of 50 ~ 3000:1 of such as S-isomer and R-isomer.Such as get the mixture that 50 grams of S-isomers and 1 gram of R-isomer are mixed to get, the mol ratio of its S-isomer and R-isomer is about 50:1, and namely mol ratio is 50; Such as get the mixture that 500 grams of S-isomers and 1 gram of R-isomer are mixed to get, the mol ratio of its S-isomer and R-isomer is about 500:1.Concrete proportioning can vide infra table 1.
embodiment 13: the compatibility test of the compounds of this invention and magnesium salt
The each S-isomeric compound of Example 1 ~ 12 gained is (all with (S)-(-) 2-amino-6-third amino-4 respectively, 5,6,7-tetrahydro benzothiazol meter, do not consider salify and solvate), mix with weight ratio 1:0.2,1:1 or 1:5 with magnesium stearate, grind well, uniformly mixture.This mixture is carried out high temperature accelerated test, namely places 6 months under 40 ° of C relative humidity 70% conditions.The process of mensuration high temperature accelerated test is the S-isomer of sample and the mol ratio of R-isomer after 6 months, and calculate the mol ratio percent change caused by high-temperature process, namely the mol ratio accelerating process (can be regarded as 0 month) sample without high temperature deducts the difference of the mol ratio gained of sample in June, divided by the percent of the mol ratio of 0 month sample, such as a certain sample, the S-isomer of 0 month and the mol ratio of R-isomer are 500:1 (namely 500), and mol ratio during June is 450:1 (450), then mol ratio percent change is (500-490)/500*100%=2%.
The material with different composition demonstrates different variation tendencies with mol ratio difference after magnesium stearate mix, specifically as with following table 1.
Table 1:
More than test discovery, when the amount of R-isomer in pramipexole is increased to a certain degree, there is the result that R-isomer obviously increases in it with magnesium salt after mixing, this is less desirable for clinical application.In addition, inventor to mixture that is above and magnesium salt use cannot separating isomers conventional H PLC method (see, Qu Lili, HPLC measures body of Pramipexole dihydrochloride content, packet header medical college journal, 28th volume article 4 phase 16-17 pages) measure, the whole sample pramipexole changes of contents in upper table are all very low, each sample its corresponding without June accelerated test sample compare percentage composition difference be no more than 2% (sample percentage composition deducted sample percentage composition in June in 0 month).After the pramipexole isomer of above result display different ratio mixes with magnesium salt, not there is significant change in isomer total amount, but S-isomer and R-isomer relative quantity there occurs and change in various degree, and result is presented at when isomer mol ratio is greater than 350 (namely relative S-enantiomeric purity is greater than 99.72%) and demonstrates good stability.In addition with reference to the method shown in above-mentioned table 1 of use, but magnesium salt wherein being replaced with magnesium silicate, there is the result identical with using magnesium stearate in result.
embodiment 14: the preparation comprising the tablet of body of Pramipexole dihydrochloride
The formula of preparation 1000 tablets of tablets:
Embodiment 8 gained body of Pramipexole dihydrochloride: 1g,
Mannitol-D:121.5g,
Corn starch: 79.85g,
Silica sol: 2.3g,
Polyvidone (K25): 2.35g,
Magnesium stearate: 3g.
Preparation method:
A () each material was crushed to 60 ~ 80 orders in advance.Mannitol-D, corn starch (61.85g) are loaded in fluidised bed granulator,
B pramipexole dihydrochloride and polyvidone are dissolved in the water to form solution by (), and by the granule of this spray solution in this fluidised bed granulator, these mixture are made granule to form particulate mixtures,
C this particulate mixtures is dried to the end point moisture content of about 1.0% to about 2.5% by (),
D this particulate mixtures of step (c) mixes with silica sol, corn starch (18g) and magnesium stearate by (), and blending is to form final blend,
E () uses tablet machine this final blend to be pressed into tablet (get the whole mixed material dress hard gelatin capsule shell of wherein part about 20% before tabletting, make capsule, every is 1mg containing active component).
The same method with reference to embodiment 13 of tablet of preparation measures the mol ratio percent change after accelerated test June, the tablet that result display uses embodiment 8 gained body of Pramipexole dihydrochloride to prepare as crude drug, the mol ratio percent change after its accelerated test June is 1.3%.
With reference to method above, use different material to prepare tablet, measure the mol ratio percent change after accelerated test June, the results are shown in Table 2.After display mix with the pharmaceutical adjunct comprising magnesium salt, mol ratio percent change (%) appearance after tablet June and the similar variation tendency of crude drug; And when not adding magnesium salt, the raw material that R-content of isomer is higher, gained preparation mol ratio percent change is less.
Table 2
Magnesium stearate is not added when * represents and prepares tablet in table.
embodiment 15: the preparation comprising the slow releasing tablet of body of Pramipexole dihydrochloride
Prescription (every sheet amount, mg):
Preparation method:
(1) each component was ground into 60-80 object fine powder in advance.In a mixer, active component and small part (about 15%) hypromellose is made to be pre-mixed.
(2) then in a mixer, the mixture in step (1) is mixed homogeneously with remaining hypromellose, corn starch, carbomer, then adds silica sol and magnesium stearate, make the abundant mix homogeneously of material.
(3) by by final mixture tabletting in suitable tablet machine, the matrix tablet of spacetabs type is prepared.
In the preparation process of slow releasing tablet, use the different body of Pramipexole dihydrochloride raw materials prepared in foregoing embodiments of the present invention, obtain different slow releasing tablets.Measure the mol ratio percent change after these slow releasing tablet accelerated tests June, the results are shown in Table 3.Display mix the variation tendency that mol ratio percent change (%) occurs and crude drug is similar after tablet afterwards June with the pharmaceutical adjunct comprising magnesium salt; And when not adding magnesium salt, the raw material that R-content of isomer is higher, gained preparation mol ratio percent change is less.
Table 3
Magnesium stearate is not added when * represents and prepares slow releasing tablet in table.
Claims (18)
1. a Medicinal crude drug, its active component is compound shown in following formula I (S)-(-)-2-amino-6-(third is amino)-4,5,6,7-tetrahydro benzothiazols:
I
Or the acceptable salt of its pharmacy, or their monohydrate;
Also comprise in this Medicinal crude drug as impurity with compound shown in Formula Il (R)-(+)-2-amino-6-(third amino)-4,5,6,7-tetrahydro benzothiazols:
II
Or the acceptable salt of its pharmacy, or their monohydrate;
Under the HPLC chromatographic condition that the separating degree between formula I and formula II compound can be made to be greater than 3, in this Medicinal crude drug gained HPLC collection of illustrative plates, the chromatographic peak area of described formula I and formula II compound is than between 350 ~ 3000:1.
2. Medicinal crude drug according to claim 1, the acceptable salt of pharmacy of wherein said formula I is its hydrochlorate.
3. Medicinal crude drug according to claim 1, the acceptable salt of pharmacy of wherein said formula I is its dihydrochloride.
4. Medicinal crude drug according to claim 1, wherein said active component is (S)-(-)-2-amino-6-(third is amino)-4,5,6,7-tetrahydro benzothiazol dihydrochloride monohydrates.
5., according to the Medicinal crude drug of any one of claim 1-4, the chromatographic peak area of described formula I and formula II compound is than between 400 ~ 3000:1.
6. a pharmaceutical composition, wherein comprises the Medicinal crude drug of any one of claim 1-5, and the acceptable adjuvant of pharmacy.
7. pharmaceutical composition according to claim 6, it is in tablet or the form of capsule.
8. pharmaceutical composition according to claim 6, it is in rapid release or the tablet of slow release or the form of capsule.
9. pharmaceutical composition according to claim 8, wherein comprises formula I or the acceptable salt of its pharmacy of 0.1 ~ 5mg in each tablet or capsule, or their monohydrate.
10., according to the pharmaceutical composition of any one of claim 6-9, the acceptable adjuvant of wherein said pharmacy comprises magnesium salt.
11. pharmaceutical compositions according to claim 10, wherein said magnesium salt is selected from: magnesium carbonate, magnesium bicarbonate, magnesium silicate, magnesium stearate.
12. pharmaceutical compositions according to claim 10, the weight ratio of wherein said formula I and magnesium salt is 1:0.1 ~ 10.
13. pharmaceutical compositions according to claim 10, the weight ratio of wherein said formula I and magnesium salt is 1:0.2 ~ 5.
14. according to the pharmaceutical composition of any one of claim 6-9, wherein comprises compound shown in the following formula I as active component (S)-(-)-2-amino-6-(third is amino)-4,5,6,7-tetrahydro benzothiazols:
I
Or the acceptable salt of its pharmacy, or their monohydrate, and as impurity with compound shown in Formula Il (R)-(+)-2-amino-6-(third is amino)-4,5,6,7-tetrahydro benzothiazols:
II
Or the acceptable salt of its pharmacy, or their monohydrate;
Under the HPLC chromatographic condition that the separating degree between formula I and formula II compound can be made to be greater than 3, in this pharmaceutical composition gained HPLC collection of illustrative plates, the chromatographic peak area of described formula I and formula II compound is than between 350 ~ 3000:1.
15. pharmaceutical compositions according to claim 14, the chromatographic peak area of wherein said formula I and formula II compound is than between 400 ~ 3000:1.
16. pharmaceutical compositions according to claim 10, wherein comprise compound shown in the following formula I as active component (S)-(-)-2-amino-6-(third is amino)-4,5,6,7-tetrahydro benzothiazols:
I
Or the acceptable salt of its pharmacy, or their monohydrate, and as impurity with compound shown in Formula Il (R)-(+)-2-amino-6-(third is amino)-4,5,6,7-tetrahydro benzothiazols:
II
Or the acceptable salt of its pharmacy, or their monohydrate;
Under the HPLC chromatographic condition that the separating degree between formula I and formula II compound can be made to be greater than 3, in this pharmaceutical composition gained HPLC collection of illustrative plates, the chromatographic peak area of described formula I and formula II compound is than between 350 ~ 3000:1.
17. pharmaceutical compositions according to claim 11, wherein comprise compound shown in the following formula I as active component (S)-(-)-2-amino-6-(third is amino)-4,5,6,7-tetrahydro benzothiazols:
I
Or the acceptable salt of its pharmacy, or their monohydrate, and as impurity with compound shown in Formula Il (R)-(+)-2-amino-6-(third is amino)-4,5,6,7-tetrahydro benzothiazols:
II
Or the acceptable salt of its pharmacy, or their monohydrate;
Under the HPLC chromatographic condition that the separating degree between formula I and formula II compound can be made to be greater than 3, in this pharmaceutical composition gained HPLC collection of illustrative plates, the chromatographic peak area of described formula I and formula II compound is than between 350 ~ 3000:1.
18. pharmaceutical compositions according to claim 12, wherein comprise compound shown in the following formula I as active component (S)-(-)-2-amino-6-(third is amino)-4,5,6,7-tetrahydro benzothiazols:
I
Or the acceptable salt of its pharmacy, or their monohydrate, and as impurity with compound shown in Formula Il (R)-(+)-2-amino-6-(third is amino)-4,5,6,7-tetrahydro benzothiazols:
II
Or the acceptable salt of its pharmacy, or their monohydrate;
Under the HPLC chromatographic condition that the separating degree between formula I and formula II compound can be made to be greater than 3, in this pharmaceutical composition gained HPLC collection of illustrative plates, the chromatographic peak area of described formula I and formula II compound is than between 350 ~ 3000:1.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510077270.7A CN104744400B (en) | 2012-11-22 | 2013-01-01 | Tetrahydrobenzothiazderivative derivative for treating sacred disease |
| CN201310001075.7A CN103058953B (en) | 2012-11-22 | 2013-01-01 | Tetrahydrobenzothiazole derivate for treating nerve diseases |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210483331 | 2012-11-22 | ||
| CN201210483331.6 | 2012-11-22 | ||
| CN201310001075.7A CN103058953B (en) | 2012-11-22 | 2013-01-01 | Tetrahydrobenzothiazole derivate for treating nerve diseases |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510077270.7A Division CN104744400B (en) | 2012-11-22 | 2013-01-01 | Tetrahydrobenzothiazderivative derivative for treating sacred disease |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103058953A CN103058953A (en) | 2013-04-24 |
| CN103058953B true CN103058953B (en) | 2015-03-25 |
Family
ID=48101885
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310000517.6A Active CN103435571B (en) | 2012-11-22 | 2013-01-01 | Tetrahydrobenzothiazderivative derivative and preparation method thereof |
| CN201510077270.7A Expired - Fee Related CN104744400B (en) | 2012-11-22 | 2013-01-01 | Tetrahydrobenzothiazderivative derivative for treating sacred disease |
| CN201310001075.7A Active CN103058953B (en) | 2012-11-22 | 2013-01-01 | Tetrahydrobenzothiazole derivate for treating nerve diseases |
Family Applications Before (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310000517.6A Active CN103435571B (en) | 2012-11-22 | 2013-01-01 | Tetrahydrobenzothiazderivative derivative and preparation method thereof |
| CN201510077270.7A Expired - Fee Related CN104744400B (en) | 2012-11-22 | 2013-01-01 | Tetrahydrobenzothiazderivative derivative for treating sacred disease |
Country Status (1)
| Country | Link |
|---|---|
| CN (3) | CN103435571B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103435571B (en) * | 2012-11-22 | 2015-12-09 | 北京三泉医药技术有限公司 | Tetrahydrobenzothiazderivative derivative and preparation method thereof |
| CN112858527B (en) * | 2021-03-08 | 2022-11-01 | 成都倍特药业股份有限公司 | Detection method of related substances of pramipexole dihydrochloride sustained-release tablets |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1671381A (en) * | 2002-07-25 | 2005-09-21 | 法马西亚公司 | Pramipexole once-daily dosage form |
| CN1834092A (en) * | 2005-03-15 | 2006-09-20 | 姜能桥 | Prepn. of pramipexole |
| WO2006117614A1 (en) * | 2005-05-03 | 2006-11-09 | Ranbaxy Laboratories Limited | Process for the preparation of pramipexole and new anhydrous forms of its dihydrochloride |
| CN101005830A (en) * | 2004-08-13 | 2007-07-25 | 贝林格尔·英格海姆国际有限公司 | Extended release tablet formulation containing pramipexole or a pharmaceutically acceptable salt thereof, method for manufacturing the same and use thereof |
| CN101622235A (en) * | 2007-02-07 | 2010-01-06 | 克尔克制药厂新梅斯托股份公司 | The new synthetic method of pramipexole and pharmaceutically acceptable salt thereof |
| CN102772403A (en) * | 2011-05-10 | 2012-11-14 | 浙江京新药业股份有限公司 | Preparation method for pramipexole preparation |
| CN103435571A (en) * | 2012-11-22 | 2013-12-11 | 刘炜 | Tetrahydrobenzothiazole derivative and preparation method thereof |
-
2013
- 2013-01-01 CN CN201310000517.6A patent/CN103435571B/en active Active
- 2013-01-01 CN CN201510077270.7A patent/CN104744400B/en not_active Expired - Fee Related
- 2013-01-01 CN CN201310001075.7A patent/CN103058953B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1671381A (en) * | 2002-07-25 | 2005-09-21 | 法马西亚公司 | Pramipexole once-daily dosage form |
| CN101005830A (en) * | 2004-08-13 | 2007-07-25 | 贝林格尔·英格海姆国际有限公司 | Extended release tablet formulation containing pramipexole or a pharmaceutically acceptable salt thereof, method for manufacturing the same and use thereof |
| CN1834092A (en) * | 2005-03-15 | 2006-09-20 | 姜能桥 | Prepn. of pramipexole |
| WO2006117614A1 (en) * | 2005-05-03 | 2006-11-09 | Ranbaxy Laboratories Limited | Process for the preparation of pramipexole and new anhydrous forms of its dihydrochloride |
| CN101622235A (en) * | 2007-02-07 | 2010-01-06 | 克尔克制药厂新梅斯托股份公司 | The new synthetic method of pramipexole and pharmaceutically acceptable salt thereof |
| CN102772403A (en) * | 2011-05-10 | 2012-11-14 | 浙江京新药业股份有限公司 | Preparation method for pramipexole preparation |
| CN103435571A (en) * | 2012-11-22 | 2013-12-11 | 刘炜 | Tetrahydrobenzothiazole derivative and preparation method thereof |
Non-Patent Citations (3)
| Title |
|---|
| European Directorate for the Quality of Medicines & HealthCare.Pramipexole Dihydrochloride Monohydrate.《European Pharmacopoeia 7.0》.2010,第2779-2780页. * |
| 盐酸普拉克索的合成;汪文婷等;《中国医药工业杂志》;20120731;第43卷(第7期);第524-526页 * |
| 盐酸普拉克索的合成研究;金华等;《中国药物化学杂志》;20111231;第21卷(第6期);第430-432页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104744400A (en) | 2015-07-01 |
| CN104744400B (en) | 2017-08-11 |
| CN103435571A (en) | 2013-12-11 |
| CN103058953A (en) | 2013-04-24 |
| CN103435571B (en) | 2015-12-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103068384B (en) | Cyclopropyl dicarboxamides and analogs exhibiting anti-cancer and anti-proliferative activities | |
| JP5934202B2 (en) | 5-Chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide, its salts and uses thereof | |
| CN102325778B (en) | Nalmefene hydrochloride dihydrate | |
| EA029060B1 (en) | Process for the preparation of vortioxetine salts | |
| CN103608343A (en) | Crystalline forms and processes for preparation of condensed azacycles (cannabinoid receptor modulators) | |
| CA2597622C (en) | Crystalline base of trans-1-((1r,3s)-6-chloro-3-phenylindan-1-yl)-3,3-dimethylpiperazine | |
| CN104736540B (en) | The preparation method of pemetrexed and its lysine salt | |
| TWI414289B (en) | Use of indole derivatives as nurr-1 activators | |
| CN103058953B (en) | Tetrahydrobenzothiazole derivate for treating nerve diseases | |
| AU2011246707B2 (en) | Process for the production of ralfinamide methanesulfonate salts or their R-enantiomers | |
| CN113651770A (en) | Novel crystal form of epalrestat, preparation method and application thereof | |
| CA2842495C (en) | 5,6,7,8-tetrahydro-6-[n,n-bis[(2-thienyl)ethyl]]amino-1-naphthol, and preparing method and use thereof | |
| AU2011246707A1 (en) | Process for the production of ralfinamide methanesulfonate salts or their R-enantiomers | |
| WO2023193563A1 (en) | Crystal form a of thienopyridine compound, and preparation method therefor and pharmaceutical composition thereof | |
| CA2744458A1 (en) | Novel processes and pure polymorphs | |
| WO2014036865A1 (en) | Method for preparing fingolimod mucate and crystal thereof and application of fingolimod mucate and crystal thereof | |
| CN101146805A (en) | Production method for thiazolidinedione compound and its production intermediate | |
| AU2021106179A4 (en) | New crystalline form of epalrestat as well as preparation method and application thereof | |
| JP2021507927A (en) | Crystal form of barbenazintosilate and its production method and application | |
| CN104447292A (en) | 2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropionic acid polymorph as well as preparation method and pharmaceutical composition thereof | |
| CN103804366B (en) | Lafutidine crystal compound | |
| CN109776543A (en) | Buddhist nun's salt, its crystal, preparation method, pharmaceutical composition and application are replaced according to Shandong | |
| CN101787029A (en) | Long-chain alkyl coptisine halate derivative, synthesis method and application | |
| US8754129B2 (en) | Crystalline vorinostat form VI | |
| JP2020200300A (en) | Novel crystal form of eldecalcitol, and preparation method and use thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C41 | Transfer of patent application or patent right or utility model | ||
| CB03 | Change of inventor or designer information |
Inventor after: Hou Qiwei Inventor after: Xie Liang Inventor after: Li Xiaoyun Inventor after: Wang Bo Inventor before: Liu Wei |
|
| COR | Change of bibliographic data | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20160715 Address after: 375 No. 415001 Changde province Hunan City Deshan Changde economic and Technological Development Zone Avenue Patentee after: Hunan Dongting Pharmaceutical Co., Ltd. Address before: 100083 No. 38, Haidian District, Beijing, Xueyuan Road Patentee before: Liu Wei |