CN104513200A - Substituted crotonamide maleate and crystal forms thereof - Google Patents
Substituted crotonamide maleate and crystal forms thereof Download PDFInfo
- Publication number
- CN104513200A CN104513200A CN201310680768.3A CN201310680768A CN104513200A CN 104513200 A CN104513200 A CN 104513200A CN 201310680768 A CN201310680768 A CN 201310680768A CN 104513200 A CN104513200 A CN 104513200A
- Authority
- CN
- China
- Prior art keywords
- maleate
- quinolyl
- dimethylamino
- ethynylanilino
- crystal formation
- 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.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
Abstract
The invention discloses a substituted crotonamide maleate, a crystal form thereof, a method for preparing all crystal forms of crystallized maleate, relevant compounds, and a medicinal composition including the compounds. (E)-N-{4-[3-acetylenylphenylamino]-3-cyan-7-ethoxy-6-quinolyl}}-4(dimethylamino)-2-crotonamide maleate, a crystal form I, a crystal form II or a crystal form III respectively have EGFR or ErbB2 kinase inhibition activity, can be used to prevent, treat or inhibit tumors, and can be especially to prepare drugs for preventing, treating or inhibiting epidermal growth factor receptor family related tumors.
Description
Technical field
The present invention relates to (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] } maleate form of-4-(dimethylamino)-2-butylene acid amides, prepare the method for crystalline form form, with relevant compound, and comprise their pharmaceutical composition.In addition, the invention still further relates to their pharmaceutical composition, and use them in treatment tumour, the application in the tumour of particularly following Epidermal Growth Factor Receptor Family kinases relevant.
Background technology
(E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] }-4-(dimethylamino)-2-butylene acid amides demonstrates anti-tumor biological, and this makes it be expected to there is a lot of application in the various different cancer for the treatment of.These cancers include but are not limited to the tumour of carcinoma of the pancreas, melanoma, lymphoma, carcinoma of parotid gland, the esophageal carcinoma, head and neck cancer, ovarian cancer, mammary cancer, epidermal carcinoma, major organs, as kidney, bladder, larynx, stomach, lung, Colon and rectum and prostate gland.Compound in example is open by WO2010151710, and display has anti-tumor activity.But the restriction of this compound is it can not be dissolved in the water with the form of free alkali.
Summary of the invention
The object of the invention is on the basis of existing technology, a class (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] be provided } maleate of-4-(dimethylamino)-2-butylene acid amides and crystallization thereof, preparation method and application.
Object of the present invention can be reached by following measures:
The present invention specifically discloses one (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] } maleate (formula I) of-4-(dimethylamino)-2-butylene acid amides, a kind of anhydrous form crystallization (crystal formation I), a kind of hydrate crystallization (crystal form II) and a kind of anhydrous form and monohydrate mixed form crystallization (crystal form II I).
The invention provides one (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] }-4-(dimethylamino)-2-butylene acid amides maleate crystal formation I, its X-ray diffracting spectrum is that 6.68 ± 0.2,8.58 ± 0.2,10.88 ± 0.2,13.36 ± 0.2,17.28 ± 0.2,20.10 ± 0.2,21.86 ± 0.2,23.32 ± 0.2,25.92 ± 0.2 and 28.58 ± 0.2 places have diffraction peak at 2 θ angles.
Further, the X-ray diffracting spectrum of crystal formation I is 5.42 ± 0.2 at 2 θ angles, 6.68 ± 0.2, 7.94 ± 0.2, 8.58 ± 0.2, 9.22 ± 0.2, 10.88 ± 0.2, 13.36 ± 0.2, 14.06 ± 0.2, 16.38 ± 0.2, 17.28 ± 0.2, 18.40 ± 0.2, 18.96 ± 0.2, 19.40 ± 0.2, 20.10 ± 0.2, 20.58 ± 0.2, 21.18 ± 0.2, 21.86 ± 0.2, 22.42 ± 0.2, 23.32 ± 0.2, 23.94 ± 0.2, 25.92 ± 0.2, 26.96 ± 0.2, 27.38 ± 0.2, 27.96 ± 0.2, 28.58 ± 0.2, 29.36 ± 0.2, there is diffraction peak at 30.64 ± 0.2 and 35.08 ± 0.2 places.Concrete, in independent test, anhydrous (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] }-4-(dimethylamino)-2-butylene acid amides maleate appears near position as above with the peak of the X-ray powder diffraction that 2 θ represent.
Further, crystal formation I crystallization has powder x-ray diffraction collection of illustrative plates as shown in Figure 1 substantially.This crystal formation shows starting to undergo phase transition and determine (its DSC endothermic transition is 117 DEG C of generations) in the scope of about 117 DEG C when being characterized by dsc (DSC), and meanwhile, its melting range is 123 ~ 128 DEG C.
The invention provides one (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] }-4-(dimethylamino)-2-butylene acid amides maleate crystal form II, its X-ray diffracting spectrum is that 8.00 ± 0.2,9.12 ± 0.2,18.30 ± 0.2,23.80 ± 0.2,24.50 ± 0.2 and 25.16 ± 0.2 places have diffraction peak at 2 θ angles.There is dehydration in this crystal formation, and show water content and count 3.0%-3.5% massfraction using compound as monohydrate in about 50 DEG C.
Further, the X-ray diffracting spectrum of crystal form II is 7.00 ± 0.2 at 2 θ angles, 8.00 ± 0.2, 9.12 ± 0.2, 9.88 ± 0.2, 10.74 ± 0.2, 12.18 ± 0.2, 13.20 ± 0.2, 13.56 ± 0.2, 14.02 ± 0.2, 14.72 ± 0.2, 15.24 ± 0.2, 16.36 ± 0.2, 17.70 ± 0.2, 18.30 ± 0.2, 19.36 ± 0.2, 20.74 ± 0.2, 21.38 ± 0.2, 22.30 ± 0.2, 23.80 ± 0.2, 24.50 ± 0.2, 25.16 ± 0.2, 26.06 ± 0.2, 26.52 ± 0.2, 27.24 ± 0.2, 28.30 ± 0.2, 28.72 ± 0.2, there is diffraction peak at 29.72 ± 0.2 and 30.72 ± 0.2 places.Concrete, in independent test, (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] }-4-(dimethylamino)-2-butylene acid amides maleate appears near position as above with the peak of the X-ray powder diffraction that 2 θ represent.
The infrared absorption spectrum of crystal form II about 3484.3,3400.5,3270.3,3190.9,3048.0,2993.7,2942.1,2216.7,2101.3,1681.1,1654.6,1622.3,1606.9cm
-1there is charateristic avsorption band at place.Particularly there is infrared spectra as shown in Figure 4 substantially.
Further, crystal form II crystallization has powder x-ray diffraction collection of illustrative plates as shown in Figure 3 substantially.The DSC endothermic transition of crystal form II is 113.6 DEG C of generations; Its melting range 119-125 DEG C.
The invention provides a kind of part water (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] } crystalline form (crystal form II I) of the determination of-4-(dimethylamino)-2-butylene acid amides maleate, this crystal formation is determined based on the water of this compound containing 0.8%-2.4% massfraction of having an appointment.
The invention provides a kind of preparation method of maleate: by water-alcohol solvent, under Elevated Temperature Conditions, mix (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl]-4-(dimethylamino)-2-butylene acid amides (free base) and toxilic acid prepare the method for maleate.Cool whole solution, solution contains (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] }-4-(dimethylamino)-2-butylene acid amides maleate.
The invention provides one (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] } preparation method of the maleate crystal form II of-4-(dimethylamino)-2-butylene acid amides: in water-alcohol solvent, at 40 DEG C ~ 60 DEG C, mix (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] }-4-(dimethylamino)-2-butylene acid amides (free base) and toxilic acid react, after reaction, cooling standing and reacting solution, isolates crystallization and get final product.
The invention provides one (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] } preparation method of the maleate crystal formation I of-4-(dimethylamino)-2-butylene acid amides: by (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] } the maleate crystal form II of-4-(dimethylamino)-2-butylene acid amides carries out vacuum-drying more than 30 DEG C, to obtain final product.The vacuum-drying time more than 10 hours, preferably about 12 to 48 hours.
The invention provides one and prepare (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] method of-4-(dimethylamino)-2-butylene acid amides maleate monohydrate crystal (crystal form II): with organic solvent and a certain amount of water suspendible anhydrous (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] }-4-(dimethylamino)-2-butylene acid amides maleate (crystal formation I), then filter the monohydrate crystal precipitated from mixed solution.
The invention provides one and prepare (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] method of-4-(dimethylamino)-2-butylene acid amides maleate monohydrate crystal (crystal form II): with organic solvent and a certain amount of water suspendible anhydrous (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] }-4-(dimethylamino)-2-butylene acid amides maleate (crystal formation I), add the organic solvent of the second containing certain water gaging, then filter the monohydrate crystal precipitated from mixed solution.
The invention provides one and prepare (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] method of-4-(dimethylamino)-2-butylene acid amides maleate monohydrate crystal (crystal form II): with organic solvent and a certain amount of water suspendible anhydrous (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] }-4-(dimethylamino)-2-butylene acid amides maleate (crystal formation I) a couple of days, then filter from suspension and obtain monohydrate crystal precipitation.
The invention provides a kind of pharmaceutical composition, said composition is with (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] } one or both in-4-(dimethylamino)-2-butylene acid amides maleate, crystal formation I, crystal form II or crystal form II I for main active ingredient, be aided with pharmaceutically acceptable auxiliary material.
The invention provides a kind of (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] by taking treatment effective dose }-4-(dimethylamino)-2-butylene acid amides maleate prevention, treatment, Tumor suppression method.User can be Mammals, especially, is people.Maleate can anhydrous form, monohydrate form or partially aqueous thing form be taken.One or more related compound discussed above can be taken in this way simultaneously.
Detailed Description Of The Invention
(E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] }-4-(dimethylamino)-2-butylene acid amides is that Her-2(is also known as ErbB-2 or neu) kinase whose irreversible inhibitor.Her-2 is EGF-R ELISA (EGFR) family member, and the generation development of EGFR family member and tumour and tumour patient poor prognosis have contacting closely.(E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] } the dissociate structure of base of-4-(dimethylamino)-2-butylene acid amides is as follows:
Compound (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] }-4-(dimethylamino)-2-butylene acid amides has description at patent WO2010151710.According to Biopharmaceutics Classification system (biopharmaceuticalclassification system, BCS), this compound is divided into IV level, low water solubility and weak perviousness.Under pH7 condition, the free solubleness of base in water is about 1 μ g/ml, and along with the reduction of pH value of solution, due to ionization, the solubleness of this compound increases.Under stomach pH condition, compound is water miscible, and stripping is non-speed limit.Therefore, improving the physicochemical property of compound is a problem anxious to be resolved.
For there is the medical compounds of solubleness or other problems, do salify, there are the preparation difficulty or ease for medicine in hydrate and/or any polymorph with certain specific crystalline form, stability, water-soluble, stability in storage, in the difficulty or ease of figuration and body, pharmacological characteristic has important decisive, but different salt, between hydrate or crystal, often nature difference is huge, sometimes, a kind of crystal formation or salt are in preparation difficulty or ease, stability, water-soluble and/or Pharmacokinetic Characteristics is better than another crystal formation or salt, but be not there is more excellent effect more time.
The invention provides one (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] }-4-(dimethylamino)-2-butylene acid amides forms the compound form of water-soluble salt with acid.Free base can with pharmacy can multiple sour salify, medicine be suitable for acid include but are not limited to: acetic acid, fumaric acid, toxilic acid, methylsulfonic acid, succsinic acid, sulfuric acid, tartrate, tosic acid.In order to the pharmaceutical salts form be optimized, have rated the salt that several acid and free base are formed, in table 1.
Table 1 (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] } the different salt of-4-(dimethylamino)-2-butylene acid amides physicochemical property
In 7 kinds of salt, acetic acid is lower due to acidity, cannot salify, the easy moisture absorption of phosphoric acid, hydrochloric acid, sulfuric acid product, the easy moisture absorption of benzene sulfonate, and becomes crystalline substance poor, and maleate shows good physicochemical property, becomes crystal formation, is not easy moisture absorption.In all salt, maleate has good solvability, and in addition, maleate very easily can prepare its monohydrate by recrystallization in water-containing solvent, be the crystalline form being very easy to filter, to preparation work below, there is obvious advantage.
In addition, (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] } maleate of-4-(dimethylamino)-2-butylene acid amides is crystallization, has better water-soluble with free Base comparison.It is as shown in table 2,
The solvability of base and maleate of dissociating table 2 compares
During pre-clinical trial, in rat body, carry out (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] } test of the systemic exposure of-4-(dimethylamino)-2-butylene acid amides.Analytical results shows, and in rat body, be in 5mg/kg weight range at dosage, the maleate AUC(area under concentration of compound, amasss below Plasma Concentration one time curve) be the twice of free base AUC.The bioavailability of the free base of compound is relatively low (20%), and can detect the compound of pronounced amount in ight soil, and this can explain the bioavailability that the free base of compound is relatively low.Maleate adds solvability, and therefore in rat body, its bioavailability also increases accordingly.But although several salt is in solubility test, the solubleness in water of hydrochloride is the highest, the bioavailability in body relatively in, maleate has higher bioavailability compared with hydrochloride.
Concrete pharmacokinetics test:
Healthy male SD rat 24, (body weight 200-265g), is divided into 4 groups, often organizes 6, respectively oral be equivalent to 5mg/kg free alkali free base (A), maleate (crystal formation I) (B), maleate (crystal form II) (C) and hydrochloride (D), namely wait mole administration.After administration, observe the vomiting reaction of rat.And gather plasma sample in different time points, after organic solvent process, adopt the concentration of free base in LC-MS/MS rat plasma, result represents with blood concentration-time.
Tested material is prepared before administration with the physiological saline containing 10% ethanol and 40% Macrogol 200.Overnight fasting before administration, administration gave feed after 4 hours.Before administration (0 hour), within after administration 0.25,0.5,1,1.5,2,4,6,24 hour, get blood through carotid artery intubate and be about 0.3ml, put K
2in EDTA centrifuge tube, centrifugal separation plasma.Plasma sample is except during analysis, and all samples is collected and is placed on-20 DEG C of Refrigerator stores.
Plasma sample treatment process:
1., after all samples melts completely, mix 10-30 second.
2. pipette in 100 microliters of sample to 96 orifice plates.
3. add 0.3ml containing interior target methanol solution, extraction of ocean eddies 3min.
4. by sample centrifugal 5min under 3200 turns, 4 DEG C conditions.
5. accurate absorption 100 RI of supernatant, add 100 microlitre 0.4% aqueous formic acids (pH3.2): acetonitrile=1:1, transfer to LC-MS/MS to analyze after vortex mixing.
Table 3 male SD rat is oral give two kinds of tested materials of 5mg/kg after the Plasma Concentration (ng/ml) of free base
Table 4 male SD rat is oral gives the generation number of animal vomiting after the tested material of 5mg/kg
Except poor water-soluble except, compound (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] } the free base of-4-(dimethylamino)-2-butylene acid amides and the nauseant acceptor interaction of stomach, cause mammal diarrhea.And (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] maleate of-4-(dimethylamino)-2-butylene acid amides, unexpectedly alleviate this problem and make to minimize with the interaction of nauseant acceptor in Mammals.
The preparation of maleate is by by (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] }-4-(dimethylamino)-2-butylene acid amides (free alkali) mixes with toxilic acid and is dissolved in by this mixture in the water-alcohol solution of heating and prepare.By the solution cooling generated, the solution of this cooling comprises (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] }-4-(dimethylamino)-2-butylene acid amides maleate.According to an embodiment, as shown in Scheme 1, by toxilic acid and free alkali are merged to prepare (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] in the solution of water and n-propyl alcohol }-4-(dimethylamino)-2-butylene acid amides maleate.
Route 1
In the preparation of maleate or crystal form II, the reaction of free alkali and toxilic acid occurs under the high temperature of about 40 DEG C ~ 60 DEG C, preferably about 40 DEG C ~ 50 DEG C.Water: the volumetric ratio of n-propyl alcohol can change, be such as about 1:10 to about 1:5, and water: the best ratio of n-propyl alcohol is about 1:9(i.e. 90% n-propyl alcohol-aqueous solution).Water-alcohol solution can comprise the water of about 5 volume % to about 20 volume % and the about 80 volume % alcohol to about 95% volume.Alcohol can be n-propyl alcohol.In one embodiment, water-alcohol solution comprises the water of about 10 volume % and the n-propyl alcohol of about 90 volume %.The volume of solvent solution can be about 8 to about 25 volumes, comprises about 10-10 volume.Use the toxilic acid of about 1.0-1.2 equivalent relative to the free alkali of every equivalent, preferably use the toxilic acid of about 1.03 equivalents relative to the free alkali of every equivalent.
In the preparation of maleate or crystal form II, the solution of the maleate of generation makes it clarify by filtering before cooling.Cooling step is sustainable to carry out until solution reaches about 45 DEG C or less than 40 DEG C or lower temperature, comprises and reach about 39 DEG C or lower temperature, more preferably reach about 30 DEG C or lower temperature.In one embodiment, be cooled to about room temperature, be preferably cooled to, after about 23 DEG C to about 25 DEG C, solution be filtered.Usually, when temperature reaches 37 DEG C or lower, maleate starts to crystallize out from solution.Solution can be made to leave standstill at least 12 hours under cooling, preferably about 12 to about 15 hours, then filter and wash, to reclaim crystalline form product.The filter cake obtained can with identical or different water-alcohol solution washing to obtain product.Can by dry for this product to obtain crystallization (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] }-4-(dimethylamino)-2-butylene acid amides maleate.Now, the form of the maleate being generally monohydrate form is recovered with the maleate products be separated.
Maleate crystal form II can carry out vacuum-drying under heating, and the yield of the yield with about 70% to about 95%, preferably about 80% to about 95% prepares the maleate (crystal formation I) of anhydrous form.This product has the purity exceeding about 98% usually, is generally about 99% pure.Usually, drying process carries out about 12 to about 48 hours, to obtain the conversion completely from the maleate (crystal form II) of monohydrate form to the maleate of anhydrous form.Usually the mixture of two kinds of crystallized forms is obtained shorter time of drying.This drying process is carried out usually at the temperature being greater than room temperature.In one embodiment, maleate drying be greater than about 30 DEG C, preferably about 40 DEG C carry out at the temperature of about 50 DEG C in another embodiment to about 60 DEG C.
(E) of the present invention-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] }-4-(dimethylamino)-2-butylene acid amides maleate is with three kinds of different isolated in crystalline form: anhydrous form (crystal formation I), monohydrate form (crystal form II) and partially hydrated thing form (crystal form II I), described partially hydrated form comprises the mixture of I shape and II shape.
The crystallized form of the separation of Maleic Acid, Anhydrous salt crystal formation I, shows the beginning temperature in the scope of about 117 DEG C when it is characterized by dsc (DSC), and fusing Sum decomposition occurs at such a temperature.Crystal formation I crystallization has powder x-ray diffraction collection of illustrative plates as shown in Figure 1 substantially.
There is dehydration in the crystalline form (crystal form II) of the determination of one water maleate, and show water content and count 3.0%-3.5% massfraction using compound as monohydrate in about 50 DEG C.Crystal form II crystallization has powder x-ray diffraction collection of illustrative plates as shown in Figure 3 substantially.This crystal formation at 113.6 DEG C, particularly adopts separately capillary melting point determination method to measure melt at about 120 DEG C by DSC.
Part water (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] } crystalline form (crystal form II I) of determination of-4-(dimethylamino)-2-butylene acid amides maleate, this crystal formation is by determining with the water of anhydrous compound containing have an appointment 0.8%-2.4% massfraction and about 1.5%-2.3% massfraction.
A kind of by water-alcohol solvent, under Elevated Temperature Conditions, mixing (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] }-4-(dimethylamino)-2-butylene acid amides (free base) and toxilic acid prepare the method for maleate.Cool whole solution, solution contains (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] }-4-(dimethylamino)-2-butylene acid amides maleate.
(E) is prepared by one-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] } method of-4-(dimethylamino)-2-butylene acid amides maleate monohydrate crystal (crystal form II): with organic solvent and a certain amount of water suspendible anhydrous (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] }-4-(dimethylamino)-2-butylene acid amides maleate (crystal formation I), then filter the monohydrate crystal precipitated from mixed solution.
(E) is prepared by one-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] } method of-4-(dimethylamino)-2-butylene acid amides maleate monohydrate crystal (crystal form II): with organic solvent and a certain amount of water suspendible anhydrous (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] }-4-(dimethylamino)-2-butylene acid amides maleate (crystal formation I), add the organic solvent of the second containing certain water gaging, then the monohydrate crystal precipitated from mixed solution is filtered.
(E) is prepared by one-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] } method of-4-(dimethylamino)-2-butylene acid amides maleate monohydrate crystal (crystal form II): with organic solvent and a certain amount of water suspendible anhydrous (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] }-4-(dimethylamino)-2-butylene acid amides maleate (crystal formation I) a couple of days, then filter from suspension and obtain monohydrate crystal precipitation.
I shape anhydrous form (crystal formation I) easily can be converted into II shape monohydrate (crystal form II) form.Under the relative humidity of the temperature of 20-25 DEG C and 50-60%, I shape partly can be converted into monohydrate along with time water suction.
The invention still further relates to a kind of medicine composition and comprise (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl]-4-(dimethylamino)-2-butylene acid amides maleate and relevant compound.One or more in these compounds can be found in the method for the invention in cooled solution.Because these compounds may not be separated with maleate, the pharmaceutical preparation therefore using this maleate to prepare may contain one or more such allied compound.
The invention still further relates to (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] comprising treatment effective dose of a kind of HER-2 of suppression kinase activity }-4-(dimethylamino)-2-butylene acid amides maleate and pharmacy thereof can connect
The pharmaceutical composition of the carrier be subject to.This pharmaceutical composition can comprise one or more above-mentioned related compound.Maleate can be anhydrous form, a water form and both combinations.
The invention still further relates to a kind of (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] by taking treatment effective dose }-4-(dimethylamino)-2-butylene acid amides maleate prevention, treatment, Tumor suppression method.User can be Mammals, especially, is people.Maleate can anhydrous form, monohydrate form or partially aqueous thing form be taken.One or more allied compound discussed above can be taken in this way simultaneously.
(E) of the present invention-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] }-4-(dimethylamino)-2-butylene acid amides maleate, crystal formation I, crystal form II or crystal form II I, there is EGFR or HER2 inhibit activities, can be applicable to prevention, treatment or Tumor suppression aspect, be particularly applied to prevention, treatment or suppress the tumour medicine with Epidermal Growth Factor Receptor Family kinases is relevant to prepare aspect.
Accompanying drawing explanation
Fig. 1 is (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] } the XRD scanning spectra of the anhydrous form (crystal formation I) of-4-(dimethylamino)-2-butylene acid amides maleate.
Fig. 2 is (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] } the DSC figure of the anhydrous form (crystal formation I) of-4-(dimethylamino)-2-butylene acid amides maleate.
Fig. 3 is (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] } the XRD scanning spectra of a water thing form (crystal form II) of-4-(dimethylamino)-2-butylene acid amides maleate.
Fig. 4 is (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] } infared spectrum of-4-(dimethylamino)-2-butylene acid amides maleate monohydrate form (crystal form II).
Fig. 5 is (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] } DSC of-4-(dimethylamino)-2-butylene acid amides maleate one water thing form (crystal form II) figure.
Embodiment
Describe the present invention more completely by conjunction with following specific embodiment, these specific embodiments are not construed as limiting scope of the present invention.Those skilled in the art can in illustrational method, according to the difference of processing parameter and equipment, carries out rearranging of step, merges, amendment or delete.
Embodiment 1: preparation (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] }-4-(dimethylamino)-2-butylene acid amides maleate, crystal form II
By crude product (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] }-4-(dimethylamino)-2-butylene acid amides free alkali (0.070kg, 0.159mol) dissolve with 1000ml90% n-propyl alcohol-aqueous solution suspendible, add the toxilic acid (0.0191kg with 100ml90% n-propyl alcohol-aqueous dissolution, 0.164mol), mixing is heated to rapidly 50-60 DEG C and keeps at least 15min, until obtain solution.Make hot solution make it clarify through the sand core funnel being preheating to 50-60 DEG C, and collect filtrate being preheating in the filter flask of 45-55 DEG C.Solution be cooled at least one hour 40 DEG C and keep 12 hours at such a temperature, then cool to room temperature (25 DEG C) at least 4 hours, and keeping at least 2 hours at such a temperature.Mixture is filtered on a buchner funnel, then uses n-propyl alcohol-aqueous solution rinsing and the washing of 90%.Filter cake compacting is also kept be drawn into dropping liquid substantially to stop.
Embodiment 2: preparation (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] }-4-(dimethylamino)-2-butylene acid amides maleate, crystal formation I
Dry (50 DEG C of the product (crystal form II) of embodiment 1 will be derived from, 10mmHg, 24h), obtain 94.4g(88% yield) crystallization, i.e. anhydrous (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] }-4-(dimethylamino)-2-butylene acid amides maleate (crystal formation I).
Claims (16)
1. (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] } the maleate crystal formation of-4-(dimethylamino)-2-butylene acid amides, it is characterized in that this crystallization is crystal formation I, its X-ray diffracting spectrum is that 6.68 ± 0.2,8.58 ± 0.2,10.88 ± 0.2,13.36 ± 0.2,17.28 ± 0.2,20.10 ± 0.2,21.86 ± 0.2,23.32 ± 0.2,25.92 ± 0.2 and 28.58 ± 0.2 places have diffraction peak at 2 θ angles.
2. maleate crystal formation according to claim 1, it is characterized in that its X-ray diffracting spectrum is 5.42 ± 0.2 at 2 θ angles, 6.68 ± 0.2, 7.94 ± 0.2, 8.58 ± 0.2, 9.22 ± 0.2, 10.88 ± 0.2, 13.36 ± 0.2, 14.06 ± 0.2, 16.38 ± 0.2, 17.28 ± 0.2, 18.40 ± 0.2, 18.96 ± 0.2, 19.40 ± 0.2, 20.10 ± 0.2, 20.58 ± 0.2, 21.18 ± 0.2, 21.86 ± 0.2, 22.42 ± 0.2, 23.32 ± 0.2, 23.94 ± 0.2, 25.92 ± 0.2, 26.96 ± 0.2, 27.38 ± 0.2, 27.96 ± 0.2, 28.58 ± 0.2, 29.36 ± 0.2, there is diffraction peak at 30.64 ± 0.2 and 35.08 ± 0.2 places.
3. maleate crystal formation according to claim 2, is characterized in that this crystallization has powder x-ray diffraction collection of illustrative plates as shown in Figure 1 substantially.
4. maleate crystal formation according to claim 1, is characterized in that its DSC endothermic transition is 117 DEG C of generations; Its melting range 123 ~ 128 DEG C.
5. (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] } the maleate crystal formation of-4-(dimethylamino)-2-butylene acid amides, it is characterized in that this crystallization is crystal form II, its X-ray diffracting spectrum is that 8.00 ± 0.2,9.12 ± 0.2,18.30 ± 0.2,23.80 ± 0.2,24.50 ± 0.2 and 25.16 ± 0.2 places have diffraction peak at 2 θ angles.
6. maleate crystal formation according to claim 5, it is characterized in that its X-ray diffracting spectrum is 7.00 ± 0.2 at 2 θ angles, 8.00 ± 0.2, 9.12 ± 0.2, 9.88 ± 0.2, 10.74 ± 0.2, 12.18 ± 0.2, 13.20 ± 0.2, 13.56 ± 0.2, 14.02 ± 0.2, 14.72 ± 0.2, 15.24 ± 0.2, 16.36 ± 0.2, 17.70 ± 0.2, 18.30 ± 0.2, 19.36 ± 0.2, 20.74 ± 0.2, 21.38 ± 0.2, 22.30 ± 0.2, 23.80 ± 0.2, 24.50 ± 0.2, 25.16 ± 0.2, 26.06 ± 0.2, 26.52 ± 0.2, 27.24 ± 0.2, 28.30 ± 0.2, 28.72 ± 0.2, there is diffraction peak at 29.72 ± 0.2 and 30.72 ± 0.2 places.
7. maleate crystal formation according to claim 5, it is characterized in that its infrared absorption spectrum about 3484.3,3400.5,3270.3,3190.9,3048.0,2993.7,2942.1,2216.7,2101.3,1681.1,1654.6,1622.3,1606.9cm
-1there is charateristic avsorption band at place.
8. maleate crystal formation according to claim 5, is characterized in that this crystallization has powder x-ray diffraction collection of illustrative plates as shown in Figure 3 substantially.
9. maleate crystal formation according to claim 5, is characterized in that its DSC endothermic transition is 113.6 DEG C of generations; Its melting range 119-125 DEG C.
10. (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] as shown in the formula (I) } maleate of-4-(dimethylamino)-2-butylene acid amides,
11. 1 kinds of pharmaceutical compositions, is characterized in that said composition with one or both crystallizations in claim 1 or 5 for main active ingredient, are aided with pharmaceutically acceptable auxiliary material.
(E)-N-{4-described in 12. 1 kinds of claims 5 [(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] } preparation method of maleate crystal formation of-4-(dimethylamino)-2-butylene acid amides, to it is characterized in that in water-alcohol solvent mixing (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] at 40 DEG C ~ 60 DEG C dissociate base and toxilic acid of-4-(dimethylamino)-2-butylene acid amides react, after reaction, cooling standing and reacting solution, isolates crystallization and get final product.
13. preparation methods according to claim 12, is characterized in that described alcohol is n-propyl alcohol, and the volume ratio of water and alcohol is 1:10 ~ 1:5; Temperature of reaction is 40 DEG C ~ 50 DEG C; Less than 40 DEG C are cooled to after reaction; Cooling time of repose is more than 12 hours.
(E)-N-{4-described in 14. 1 kinds of claims 1 [(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] } preparation method of maleate crystal formation of-4-(dimethylamino)-2-butylene acid amides, it is characterized in that (E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] the maleate crystal form II of-4-(dimethylamino)-2-butylene acid amides carries out vacuum-drying more than 10 hours more than 30 DEG C, to obtain final product.
15. preparation methods according to claim 14, it is characterized in that described vacuum drying temperature is 40 DEG C ~ 60 DEG C, the vacuum drying time is 12 hours ~ 48 hours.
(E)-N-{4-[(3-ethynylanilino)-3-cyano group-7-oxyethyl group-6-quinolyl] according to any one of 16. claims 1 ~ 10 } maleate of-4-(dimethylamino)-2-butylene acid amides or the application of its crystal formation in preparation prevention, treatment or Tumor suppression medicine, particularly in preparation prevention, treatment or suppress in the tumour medicine relevant with Epidermal Growth Factor Receptor Family kinases application.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310680768.3A CN104513200B (en) | 2013-09-26 | 2013-12-12 | Substituted crotonamide maleate and crystal forms thereof |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310446252 | 2013-09-26 | ||
| CN2013104462522 | 2013-09-26 | ||
| CN201310680768.3A CN104513200B (en) | 2013-09-26 | 2013-12-12 | Substituted crotonamide maleate and crystal forms thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104513200A true CN104513200A (en) | 2015-04-15 |
| CN104513200B CN104513200B (en) | 2017-05-03 |
Family
ID=52789104
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310680768.3A Active CN104513200B (en) | 2013-09-26 | 2013-12-12 | Substituted crotonamide maleate and crystal forms thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104513200B (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105175331A (en) * | 2015-08-14 | 2015-12-23 | 江苏苏中药业集团股份有限公司 | Preparation method for EGFR molecule targeting antitumor drug |
| WO2019096327A1 (en) * | 2017-11-20 | 2019-05-23 | Teligene Ltd | Maleate salts of (e)-n-(3-cyano-7-ethoxy-4-((4-phenoxyphenyl)amino) quinolin-6-yl)-4-(dimethylamino) but-2-enamide and crystalline forms thereof |
| CN112843060A (en) * | 2019-11-27 | 2021-05-28 | 江苏苏中药业集团股份有限公司 | Substituted butenamide pharmaceutical composition and preparation method thereof |
| WO2021104341A1 (en) | 2019-11-27 | 2021-06-03 | 江苏苏中药业集团股份有限公司 | Application of substituted crotonamide |
| CN113493413A (en) * | 2020-03-19 | 2021-10-12 | 江苏苏中药业集团股份有限公司 | Substituted butenamide-N-oxide, and preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1922146A (en) * | 2004-02-27 | 2007-02-28 | 莫茨药物股份两合公司 | Tetrahydroquinolones and their use as modulators of metabotropic glutamate receptors |
| JP2011063610A (en) * | 2007-10-17 | 2011-03-31 | Wyeth Llc | Maleate salt of (e)-n-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide and crystalline form thereof |
| CN102625797A (en) * | 2009-06-25 | 2012-08-01 | 迈德药物研发技术有限公司 | Substituted heterocyclic compounds as kinases inhibitors and method of use thereof |
-
2013
- 2013-12-12 CN CN201310680768.3A patent/CN104513200B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1922146A (en) * | 2004-02-27 | 2007-02-28 | 莫茨药物股份两合公司 | Tetrahydroquinolones and their use as modulators of metabotropic glutamate receptors |
| JP2011063610A (en) * | 2007-10-17 | 2011-03-31 | Wyeth Llc | Maleate salt of (e)-n-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide and crystalline form thereof |
| CN102625797A (en) * | 2009-06-25 | 2012-08-01 | 迈德药物研发技术有限公司 | Substituted heterocyclic compounds as kinases inhibitors and method of use thereof |
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105175331B (en) * | 2015-08-14 | 2019-04-26 | 江苏苏中药业集团股份有限公司 | A kind of preparation method of the molecular targeted anti-tumor drug of EGFR class |
| CN105175331A (en) * | 2015-08-14 | 2015-12-23 | 江苏苏中药业集团股份有限公司 | Preparation method for EGFR molecule targeting antitumor drug |
| US11034656B2 (en) | 2017-11-20 | 2021-06-15 | Teligene Ltd. | Maleate salts of (E)-N-(3-cyano-7-ethoxy-4-((4-phenoxyphenyl)amino) quinolin-6-yl)-4-(dimethylamino)but-2-enamide and crystalline forms thereof |
| WO2019096327A1 (en) * | 2017-11-20 | 2019-05-23 | Teligene Ltd | Maleate salts of (e)-n-(3-cyano-7-ethoxy-4-((4-phenoxyphenyl)amino) quinolin-6-yl)-4-(dimethylamino) but-2-enamide and crystalline forms thereof |
| CN111344280A (en) * | 2017-11-20 | 2020-06-26 | 苏州韬略生物科技有限公司 | (E) Maleate salts of (E) -N- (3-cyano-7-ethoxy-4- ((4-phenoxyphenyl) amino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide and crystalline forms thereof |
| JP2021503506A (en) * | 2017-11-20 | 2021-02-12 | テリジーン リミテッドＴｅｌｉｇｅｎｅ Ｌｔｄ． | Maleate of (E) -N- (3-cyano-7-ethoxy-4-((4-phenoxyphenyl) amino) quinoline-6-yl) -4- (dimethylamino) but-2-enamide and its thereof. Crystal morphology |
| CN111344280B (en) * | 2017-11-20 | 2022-08-12 | 苏州韬略生物科技股份有限公司 | (E) -N- (3-cyano-7-ethoxy-4- ((4-phenoxyphenyl) amino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide maleate and crystalline forms |
| WO2021104340A1 (en) | 2019-11-27 | 2021-06-03 | 江苏苏中药业集团股份有限公司 | Substituted crotonamide pharmaceutical composition and preparation method therefor |
| WO2021104341A1 (en) | 2019-11-27 | 2021-06-03 | 江苏苏中药业集团股份有限公司 | Application of substituted crotonamide |
| CN112843060A (en) * | 2019-11-27 | 2021-05-28 | 江苏苏中药业集团股份有限公司 | Substituted butenamide pharmaceutical composition and preparation method thereof |
| JP7356119B2 (en) | 2019-11-27 | 2023-10-04 | 蘇中薬業集団股▲ふん▼有限公司 | Substituted butenamide pharmaceutical composition and method for producing the same |
| JP7430890B2 (en) | 2019-11-27 | 2024-02-14 | 蘇中薬業集団股▲ふん▼有限公司 | Applications of substituted butenamides |
| CN113493413A (en) * | 2020-03-19 | 2021-10-12 | 江苏苏中药业集团股份有限公司 | Substituted butenamide-N-oxide, and preparation method and application thereof |
| CN113493413B (en) * | 2020-03-19 | 2024-03-26 | 苏中药业集团股份有限公司 | Substituted butenamide-N-oxide and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104513200B (en) | 2017-05-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2572848C2 (en) | Crystalline forms of 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-{ 6-[4-(4-ethylpiperazin-1-yl)-phenylamino]-pyrimidin-4-yl} -1-methylurea and its fractions | |
| US10035788B2 (en) | Maleate salts of (E)-N-{4[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide and crystalline forms thereof | |
| US9012464B2 (en) | Salts and polymorphic forms of Afatinib | |
| JP4836404B2 (en) | Novel crystal form of anticancer compound ZD1839 | |
| CN104513200A (en) | Substituted crotonamide maleate and crystal forms thereof | |
| CN106279127B (en) | Afatinib acid-addition salts and its crystal form, preparation method and pharmaceutical composition | |
| KR20230104186A (en) | Pharmaceutical Compositions of Kinase Inhibitors | |
| US20160046615A1 (en) | Novel Crystal Form of Dabrafenib Mesylate and Preparation Method Thereof | |
| JP2003525289A (en) | New salt forms and polymorphs | |
| RU2684278C1 (en) | Pyridilamine fumarate and its crystals | |
| WO2017215521A1 (en) | Plx3397 hydrochloride crystal form, preparation method therefor and use thereof | |
| AU2021221926B2 (en) | Maleate salts of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide and crystalline forms thereof | |
| RU2807142C1 (en) | Maleate salts of (e)-n-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide and their crystalline forms | |
| AU2013203571B2 (en) | Maleate salts of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl} -4-(dimethylamino)-2-butenamide and crystalline forms thereof | |
| CN103819461B (en) | N-[the chloro-4-of 3-(3-fluorine benzyloxy) phenyl]-6-[5-[[2-(methanesulfinyl) ethyl] amino] methyl]-2-furyl]-4-quinazoline amine polymorph and preparation method thereof | |
| US11731955B2 (en) | Crystal habit of quinoline derivative and preparation method for crystalline powder thereof | |
| CN115974878A (en) | Salt and crystal form of antitumor drug | |
| CN113717111A (en) | Crystal form of quinazoline compound and preparation method thereof | |
| NZ743660A (en) | Crystalline forms of hydrochloride salts of thienopyrimidine compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CP01 | Change in the name or title of a patent holder | ||
| CP01 | Change in the name or title of a patent holder |
Address after: No.1 Suzhong Road, Jiangyan District, Taizhou City, Jiangsu Province 225500 Patentee after: Suzhong Pharmaceutical Group Co.,Ltd. Address before: No.1 Suzhong Road, Jiangyan District, Taizhou City, Jiangsu Province 225500 Patentee before: JIANGSU SUZHONG PHARMACEUTICAL GROUP Co.,Ltd. |