CN113633637A - Azaspiroanone pharmaceutical composition and preparation method thereof - Google Patents
Azaspiroanone pharmaceutical composition and preparation method thereof Download PDFInfo
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- CN113633637A CN113633637A CN202110956004.7A CN202110956004A CN113633637A CN 113633637 A CN113633637 A CN 113633637A CN 202110956004 A CN202110956004 A CN 202110956004A CN 113633637 A CN113633637 A CN 113633637A
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- water
- solvent
- citrate
- dicarboximide
- bicyclo
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- 239000008194 pharmaceutical composition Substances 0.000 title abstract description 12
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- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 11
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- 208000019423 liver disease Diseases 0.000 description 1
- 230000005976 liver dysfunction Effects 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 230000036651 mood Effects 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 229940035363 muscle relaxants Drugs 0.000 description 1
- 230000036640 muscle relaxation Effects 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 208000011906 peptic ulcer disease Diseases 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 208000024335 physical disease Diseases 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229940023488 pill Drugs 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 230000004799 sedative–hypnotic effect Effects 0.000 description 1
- 239000000952 serotonin receptor agonist Substances 0.000 description 1
- 230000037321 sleepiness Effects 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000007779 soft material Substances 0.000 description 1
- 230000000392 somatic effect Effects 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/94—[b, c]- or [b, d]-condensed containing carbocyclic rings other than six-membered
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract
An azaspirone pharmaceutical composition and its preparation method, said azaspirone pharmaceutical composition comprises compound I and/or its citrate, compound II and/or its citrate and compound III and/or its citrate, it has effects of antianxiety, antidepressive, the bad reaction is small; the product prepared by the preparation method has high purity and low content of related substances.
Description
Technical Field
The invention relates to an azaspirone pharmaceutical composition and a preparation method thereof.
Background
Tandospirone belongs to azaspirone drugs and has the chemical name of (3a alpha, 4 beta, 7a alpha) -hexahydro-2- [4[4- (2-pyrimidinyl) -1- (piperazinyl) -butyl]-4, 7-methylene-1H-isoindole-1, 3(2H) -dione. It is a 5-hydroxytryptamine receptor agonist, belonging to 3 rd generation anxiolytic, and is mainly used for treating anxiety or other diseases accompanied with anxiety state. The tandospirone can be highly selectively distributed in the 5-HT of the cerebral marginal system and the sutural gland nucleus of hippocampus, septum, interpeduncular nucleus, amygdala and the like of emotional center1AReceptor binding, agonism of 5-HT1AAutoreceptors, exert anxiolytic effects. The tandospirone can also play a certain role in resisting depression.
Compared with buspirone which is a similar derivative, tandospirone has higher selective anxiolytic effect, which is similar to diazepam, but has less toxic and side effects in the aspects of nerve motility function damage, drug abuse and the like than diazepam. Due to the specificity of the action mechanism, the tandospirone has the advantages of high medication safety, less side effect, weak sedative-hypnotic effect, no muscle relaxation effect, no dependence or withdrawal phenomenon after stopping the drug, no accumulation in the body after long-term application and the like when being clinically used for treating the anxiety disorder. Long-term clinical practice proves that tandospirone has good curative effects on anxiety states caused by various neuroses, mild and moderate depression, and anxiety states and/or depression states accompanied by various somatic diseases such as hypertension, peptic ulcer and the like, and obviously improves the mental and physical symptoms of patients. As a basic medicine for physical and mental diseases, tandospirone has wide clinical application prospect.
At present, the citrate of tandospirone (namely, tandospirone citrate) is used for clinical treatment. Among 1451 patients 150 (10.3%) had adverse reactions, 43 cases of sleepiness (3.0%), gait toddlers (16.1%), nausea (13.9%), feeling of lassitude (1) (0.8%), poor mood (11 cases (0.8%), decreased appetite (10 cases (0.7%), and few patients had liver dysfunction with AST, ALT elevation, jaundice, etc. At present, no relevant documents report the causes of the adverse reactions.
Disclosure of Invention
The inventor finds that the quality control of tandospirone citrate has great significance in reducing the adverse reaction incidence rate of tandospirone citrate and improving the anxiolytic and antidepressant effects of tandospirone citrate.
The invention provides a tandospirone citrate composition and a preparation method thereof, and the composition comprises certain amounts of a compound I ((3 aalpha, 4 beta, 7 aalpha) -tetrahydro-2- [4- [4- (2-pyrimidinyl) -1-piperazinyl ] butyl ] -4, 7-methylene-1H-isoindole-1, 3(2H) -dione) and/or a citrate thereof, a compound II ((3aR,4R,7S,7aS) -hexahydro-2- [4- [4- (2-pyrimidinyl) -1-piperazinyl ] butyl ] -4, 7-methylene-1H-isoindole-1, 3(2H) -dione) and/or a citrate thereof, and a compound ((3aR,4S,7R,7aS) -tetrahydro-2- [4- [4- (2-pyrimidinyl) -1-piperazinyl ] butyl ] -4, 7-methylene-1H-isoindole-1, 3(2H) -dione) and/or its citrate salt, compounds i, ii and iii having the following structural formula:
the tandospirone citrate composition has the effects of antianxiety and antidepressant, and has small adverse reaction; the product prepared by the preparation method has high purity and low content of related substances.
The invention provides a tandospirone citrate composition which is characterized by comprising 0-0.5% of compound I and/or citrate thereof, 0-0.4% of compound II and/or citrate thereof and 0-0.2% of compound III and/or citrate thereof in percentage by weight.
Preferably, the content of compound i and/or its citrate is 0.001-0.4%, more preferably 0.001-0.2%.
Preferably, the content of compound II and/or its citrate is 0-0.3%, more preferably 0-0.2%.
Preferably, the content of compound III and/or its citrate is 0-0.1%, more preferably 0-0.05%.
Preferably, the content of the compound III and/or the citrate thereof in the tandospirone citrate composition is 0.
Preferably, the content of the compound II and/or the citrate thereof in the tandospirone citrate composition is 0.
Preferably, the content of tandospirone citrate in the tandospirone citrate composition is more than 98%, more preferably more than 98.5%, and even more preferably more than 99%.
The preparation method of the tandospirone citrate composition comprises the following steps of purifying cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide (IV):
the purification step comprises a step of dissolving cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide in a solvent and then precipitating the resulting solution.
Preferably, the purification step comprises adding a solvent to cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide, heating, cooling, filtering, and drying to obtain cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide.
More preferably, the purification process comprises the steps of:
(A) adding a solvent into cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide, heating, cooling to 50 +/-5 ℃, cooling to 35 +/-5 ℃, cooling to room temperature, filtering and drying to obtain cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide; or
(B) Adding a solvent into cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide, heating, cooling to room temperature, cooling to-10 +/-5 ℃, filtering, adding the solvent into a filter cake, heating, cooling to room temperature, cooling to 5 +/-5 ℃, filtering and drying to obtain the cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide.
Preferably, the solvent is at least one selected from the group consisting of water, alcohols, ketones, ethers, esters, halogenated hydrocarbons, amides, and sulfoxides.
Preferably, the alcohol solvent is methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, t-butanol, n-pentanol, isopentanol, n-hexanol, or the like.
Preferably, the ketone solvent is acetone, butanone, cyclohexanone or the like.
Preferably, the ether solvent is diethyl ether, isopropyl ether, tetrahydrofuran, 1, 4-dioxane, methyl tert-butyl ether, or the like.
Preferably, the ester solvent is methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate, ethyl propionate, propyl propionate, butyl propionate, or the like.
Preferably, the halogenated hydrocarbon solvent is dichloromethane, chloroform, tetrachloromethane, or the like.
Preferably, the amide solvent is DMF, DMAC or the like.
Preferably, the sulfoxide-based solvent is DMSO.
Preferably, the solvent is at least one selected from the group consisting of water, ethanol, methanol, isopropanol, butanol, acetone, and methyl ethyl ketone.
More preferably, the solvent is any one selected from the group consisting of methanol, ethanol, isopropanol, butanol, acetone, a mixed solution of ethanol and water, a mixed solution of methanol and water, a mixed solution of isopropanol and water, a mixed solution of butanol and water, and a mixed solution of acetone and water.
Further preferably, the solvent is selected from the group consisting of ethanol: 0.1-10: 1 of water, methanol: 0.1-10: 1 of water, isopropanol: 0.1-10: 1 of water, butanol: 0.1-10: 1 of water, acetone: water is a mixed solvent in a ratio of 0.2-5: 1.
Still more preferably, the solvent is selected from: ethanol: 0.5-4: 1 of water, methanol: 3-9: 1 of water, isopropanol: 0.2-2: 1 of water, butanol: 0.15-5: 1 of water, acetone: water is a mixed solvent in 1: 1.
Preferably, the above preparation method comprises the steps of: adding 1- (2-pyrimidyl) piperazine, 1, 4-dibromobutane, potassium carbonate, benzyltriethylammonium chloride and toluene into a reactor for reaction, then adding the purified cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide for reaction, purifying the reaction solution to obtain free alkali, and adding citric acid for reaction to obtain the product.
Preferably, the reaction solution purification step includes the steps of: adding the reaction solution into water, separating liquid, acidifying an organic layer until the pH value is less than or equal to 3.5, separating a water layer, adding an organic solvent for washing, separating liquid, adjusting the pH value of the water layer to be more than 9, filtering, and drying to obtain free alkali. Wherein, the reagent for acidifying or adjusting pH value of water layer to above 9 is conventional acidic or alkaline reagent, such as hydrochloric acid, sulfuric acid, nitric acid, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate; the organic solvent is conventional organic solvent, such as ethyl acetate, methyl acetate, dichloromethane, chloroform, tetrahydrofuran, diethyl ether, methyl tert-butyl ether.
More preferably, the above preparation method comprises the steps of: adding 1- (2-pyrimidyl) piperazine, 1, 4-dibromobutane, potassium carbonate, benzyltriethylammonium chloride and toluene into a reactor, carrying out reflux reaction for 3-4 hours, adding the purified cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide, carrying out reflux for 4-5 hours, cooling a reaction solution to room temperature, adding the reaction solution into water, carrying out liquid separation, adding a hydrochloric acid solution into an organic layer, acidifying until the pH value is less than or equal to 3.5, separating out an aqueous layer, adding an organic solvent, washing, separating out the aqueous layer, adding activated carbon, filtering, adjusting the pH value of a filtrate to be more than 9 by using a sodium hydroxide solution, filtering, drying to obtain a free alkali, adding a mixed solution of citric acid and ethanol, carrying out reflux for 0.5-1 hour, cooling, filtering, adding 5-10 times of ethanol into a filter cake, carrying out reflux for 0.5-1 hour, cooling, filtering and drying to obtain the product.
Preferably, the citric acid is in the form of monohydrate.
The invention also provides application of the tandospirone citrate composition in preparing antidepressant and/or anxiolytic medicaments.
Preferably, the antidepressant and/or anxiolytic drug also comprises pharmaceutically acceptable auxiliary materials or auxiliary components.
Preferably, the dosage form of the antidepressant and/or anxiolytic drug comprises liquid, gas, solid and semisolid preparations, preferably aromatic water, solution, injection, mixture, lotion, liniment, aerosol, spray, powder, pill, tablet, capsule, granule, film, ointment, suppository, paste and other common dosage forms, and more preferably capsule, tablet, granule and other forms.
The invention also provides application and a treatment method of the tandospirone citrate composition in treating depression and/or anxiety.
Through intensive research on related substances in the tandospirone citrate, the inventor surprisingly finds that the tandospirone citrate composition has an anxiolytic effect, obviously improves the clinical antidepressant effect and obviously reduces the adverse reaction. The purification process of the intermediate cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide uses environment-friendly, safe, low-toxicity/non-toxic reagents, and has the advantages of high yield and high purity. On the basis of improving the purity of the key intermediate, the preparation method does not need to separate the intermediate product generated by the reaction, greatly improves the industrial production efficiency, shortens the production period, and ensures that the prepared product has high purity and low content of related substances.
Detailed Description
The following describes in detail specific embodiments of the present invention. It should be understood that the embodiments described herein are illustrative only and are not limiting.
Example 1:
1. preparation of cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide
Cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide is prepared according to the method reported in the literature (new Chinese technical product: 2014,8,13), and the content of related substances is 2.7% by HPLC. Wherein, HPLC (high performance liquid chromatography) test conditions are as follows: octadecylsilane chemically bonded silica was used as a filler, 0.01mol/L potassium dihydrogen phosphate solution (pH adjusted to 7.5 with 10% sodium hydroxide solution) acetonitrile (80:20) was used as a mobile phase, the detection wavelength was 243nm, and the purity was 97.3%.
2. Purification of cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide
(i) Weighing 100.0g of cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide prepared in the step 1, adding a mixed solvent of 400mL of ethanol and 400mL of water, heating until the solvent flows back, stirring for 1h, cooling to 50 +/-5 ℃, stirring for 1h, cooling to 35 +/-5 ℃, stirring for 1h, naturally cooling to room temperature, standing for 2-3 h, filtering, collecting a filter cake, and drying at 45 +/-5 ℃ under reduced pressure for 3-4 h to obtain 98.5g of cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide with the yield of 98.5%. Purity by HPLC was more than 99.5%, and the detection conditions were the same as in the above step 1, wherein the content of impurity 1 (cis-exo-bicyclo [2.2.1] hept-5-ene-2, 3-dicarboximide) was 0.18%, the content of impurity 2 (cis-endo-bicyclo [2.2.1] heptane-2, 3-dicarboximide) was 0.12%, and the content of impurity 3 (cis-endo-bicyclo [2.2.1] hept-5-ene-2, 3-dicarboximide) was 0.009%.
(ii) Cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide was prepared according to the method of (i) above, the charge amounts were all 100g, and the specific conditions and the results of the detection of the relevant substances are shown in Table 1.
TABLE 1 refining methods and results
Note: in the table, the solvent ratios are volume ratios; "- -" indicates no detection.
3. Preparation of tandospirone citrate composition
Adding 164g of 1- (2-pyrimidyl) piperazine, 227g of 1, 4-dibromobutane, 345g of potassium carbonate, 20g of benzyltriethylammonium chloride and 2L of toluene into a reactor, stirring and refluxing for 3-4 hours, adding 165g of cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide purified in the step 2(i), stirring and refluxing for 4-5 hours, cooling the reaction solution to room temperature, adding the reaction solution into water, stirring, standing, separating, adding a hydrochloric acid solution into an organic layer for acidification until the pH value is less than or equal to 3.5, separating a water layer, adding ethyl acetate for washing, adding an appropriate amount of activated carbon into the separated water layer, fully stirring, filtering, adjusting the pH value of the filtrate to be more than 9 by using a sodium hydroxide solution, filtering, drying to obtain free alkali, adding a mixed solution of 210g of citric acid and 2L of ethanol, stirring and refluxing for 0.5-1 hour, cooling to room temperature, filtering, adding 5-10 times of ethanol into the filter cake, stirring and refluxing for 0.5-1 hour, cooling to room temperature, filtering, and drying to obtain 530g of product with yield of 92%.
And (3) carrying out HPLC detection on the obtained product, wherein the test conditions are as follows: octadecylsilane chemically bonded silica was used as a filler, 0.01mol/L potassium dihydrogen phosphate solution (pH adjusted to 7.5 with 10% sodium hydroxide solution) acetonitrile (60:40) was used as a mobile phase, and the detection wavelength was 243 nm. The content of the tandospirone citrate in the tandospirone citrate composition is measured to be more than 98.5 percent; the citrate content of the compound I is 0.07 percent, the citrate content of the compound II is 0.002 percent, and the citrate content of the compound III is 0.001 percent.
Example 2
The tandospirone citrate composition is prepared by taking cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide prepared under the conditions of 1-5 in the table 1 as a raw material according to the method, and the content of the tandospirone citrate is over 98.0 percent through HPLC detection, and the content of related substances is shown in the table 2.
TABLE 2 test results
Note: "- -" indicates no detection.
From the above, the purification process of cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide, an intermediate in examples 1 and 2, uses an environmentally friendly, safe, low-toxic/non-toxic reagent, and has the advantages of high yield and high purity; in addition, the preparation of the tandospirone composition adopts a two-step one-pot process, an intermediate product generated by the reaction does not need to be separated, the industrial production efficiency is greatly improved, the production period is shortened, and the content of related substances in the product prepared by the method is low.
Example 3:
1. cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide was prepared as in example 1, step 1.
2. Purification of cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide
(i) Weighing 100.0g of cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide prepared in the step 1, adding a mixed solvent of 400mL of ethanol and 400mL of water, heating to reflux the solvent, stirring for 1h, naturally cooling to room temperature, standing at-10 +/-5 ℃ for 2-3 h, carrying out suction filtration, adding a mixed solvent of 200mL of ethanol and 200mL of water into a filter cake, heating to reflux the solvent, stirring for 1h, naturally cooling to room temperature, standing at 5 +/-5 ℃ for 2-3 h, filtering, and drying the filter cake to obtain 99.5g of cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide with the yield of 99.5%. Purity by HPLC was more than 99.5%, the detection conditions were the same as in step 1 of example 1, wherein the content of impurity 1 (cis-exo-bicyclo [2.2.1] hept-5-ene-2, 3-dicarboximide) was 0.13%, and impurity 2 and impurity 3 were not detected.
(ii) Cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide was prepared according to the above method at a charge of 100g each, and the specific conditions and the results of the measurement of the relevant substances are shown in Table 3. According to the detection result, the total content of the impurities 1, 2 and 3 in the product obtained by the method is not higher than 0.2%.
TABLE 3 refining methods and results
Note: in the table, the proportions of the mixed solvents are volume ratios; "- -" indicates no detection.
3. Preparation of tandospirone citrate composition
Adding 164g of 1- (2-pyrimidyl) piperazine, 227g of 1, 4-dibromobutane, 410g of potassium carbonate, 22g of benzyltriethylammonium chloride and 2.5L of toluene into a reactor, stirring and refluxing for reaction for 3-4 hours, adding 165g of cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide purified in the step 2(i), stirring and refluxing for 4-5 hours, cooling the reaction solution to room temperature, adding the reaction solution into water, stirring, standing, separating liquid, adding a hydrochloric acid solution into an organic layer, acidifying to a pH value of less than or equal to 3.5, separating a water layer, adding dichloromethane for washing, adding an appropriate amount of activated carbon into the separated water layer, fully stirring, filtering, adjusting the pH value of the filtrate to be more than 9 by using a sodium hydroxide solution, filtering, drying to obtain a free base, adding a mixed solution of 210g of citric acid and 2.5L of ethanol, stirring and refluxing for 0.5-1 hour, cooling to room temperature, filtering, adding 5-10 times of ethanol into the filter cake, stirring and refluxing for 0.5-1 h, cooling to room temperature, filtering, and drying to obtain 541g of product with yield of 94%.
Performing HPLC detection on the obtained product, wherein the test conditions are the same as the step 3 in the example 1, and the content of the tandospirone citrate in the tandospirone citrate composition is more than 98.5 percent; the content of citrate in the compound I is 0.05 percent, and citrate in the compound II and citrate in the compound III are not detected.
Example 4
The tandospirone citrate composition is prepared by taking cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide prepared under the conditions in the table 3 as a raw material according to the method, and the tandospirone citrate content is over 98.5% through HPLC detection, wherein the tandospirone citrate content in the composition with the number of 3-5 is over 99.0%. The contents of the relevant substances are shown in Table 4.
TABLE 4 test results
Note: "- -" indicates detection.
From the above, the purification process of cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide, which is an intermediate in examples 3 and 4, uses environmentally friendly, safe, low-toxicity/non-toxic reagents, and has the advantages of high yield and high purity; in addition, the preparation of the tandospirone composition adopts a two-step one-pot process, an intermediate product generated by the reaction does not need to be separated, the industrial production efficiency is greatly improved, the production period is shortened, and the content of related substances in the product prepared by the method is low.
Comparative example 1
1. Cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide was prepared as in example 1, step 1.
2. Preparation of tandospirone citrate composition
485g of tandospirone citrate composition is prepared according to the method of step 3 in example 1 by using the cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide prepared in step 1 as a raw material and the feeding amount of 165 g. The HPLC detection conditions are the same as the step 3 of the example 1, and the citrate content of the compound I is 0.62 percent, the citrate content of the compound II is 0.46 percent, and the citrate content of the compound III is 0.25 percent.
As can be seen from the results of examples 1-4 and comparative example 1, the content of tandospirone citrate can be effectively increased by the method of the invention, and related substances are controlled within a lower limited range.
Example 5: the pharmaceutical composition of the invention
And (3) uniformly mixing the tandospirone citrate composition prepared in the embodiment 3 with starch by an equivalent incremental method, then uniformly mixing with microcrystalline cellulose, granulating, and encapsulating to obtain the capsule.
Example 6: the pharmaceutical composition of the invention
The raw and auxiliary materials are respectively sieved by a 100-mesh sieve. Uniformly mixing the tandospirone citrate composition of the group 1 in the number of Table 4 of example 4 and low-substituted hydroxypropyl methylcellulose to be prepared by an equivalent incremental method, sequentially adding mannitol and lactose starch, finally adding orange essence and magnesium stearate, uniformly mixing and tabletting to obtain the sublingual tablet.
Example 7: the pharmaceutical composition of the invention
Mixing the tandospirone citrate composition of the group 2 in the number of Table 4 of example 4, hydroxypropyl methylcellulose and lactose to be prepared, sieving, adding 75% ethanol solution to prepare soft mass, sieving with a 20-mesh sieve to prepare wet granules, drying at about 50 ℃, sieving with a 20-mesh sieve to complete granules, adding magnesium stearate and talcum powder, mixing uniformly, and tabletting to obtain the sustained-release tablet.
Example 8: the pharmaceutical composition of the invention
Mixing the tandospirone citrate composition of the group 3 in the number of Table 4 of example 4, microcrystalline cellulose, lactose and sodium carboxymethyl starch in a granulator, adding ethanol to prepare soft mass, vacuum drying, sieving, and bagging to obtain granules.
Example 9: the pharmaceutical composition of the invention
Uniformly mixing the tandospirone citrate composition of the group 4 in the table 4 of the example 4, microcrystalline cellulose, lactose and sodium carboxymethyl starch in a granulator, adding ethanol to prepare a soft material, vacuum drying, sieving, adding magnesium stearate, uniformly mixing, and tabletting to obtain the tablet.
The beneficial effects of the present invention are further illustrated by pharmacodynamic and clinical trials as follows:
the pharmaceutical composition capsules are prepared by the method of example 5 for the following groups, and the tandospirone citrate composition for each group is prepared by the method of: the original quality group was prepared from comparative example 1, quality improvement group 1 was prepared from group 2 in table 2 of example 2, quality improvement group 2 was prepared from group 3 in table 2 of example 2, quality improvement group 3 was prepared from group 6 in table 4 of example 4, and quality improvement group 4 was prepared from group 5 in table 4 of example 4.
Test 1: clinical efficacy test
Clinical trials of a multicenter randomized, double-blind, placebo parallel control study using the pharmaceutical composition of the invention, the patients were 120 in total, randomized into 3 groups of 24 to 65 years of age, with mild to moderate anxiety patients as a criteria for inclusion and compliance with at least one of conditions associated with digestive disorders, gastric mucosal damage or bleeding liability, over the age of 50 years. Patients were banned from other sedatives, anti-inflammatory agents, muscle relaxants, hypotensive agents, antipsychotic agents, antidepressants, or anxiolytic agents during the study. The placebo, the original mass group (citrate containing 0.62% of compound I, citrate containing 0.46% of compound II, citrate containing 0.25% of compound III), and the mass-increasing group 3 (citrate containing 0.05% of compound I) were administered to each group. After 30 days of administration, the treatment effect (anxiolytic treatment effect was evaluated according to Hamilton anxiety scale) and adverse reaction evaluation were performed. Wherein, the effective rate of the placebo group is 10 percent, and the incidence rate of adverse reactions is 5 percent; the effective rate of the original mass group is 65%, and the incidence rate of adverse reactions is 35%; the effective rate of the quality improvement group 3 is 75 percent, and the incidence rate of adverse reactions is 15 percent.
The clinical observation results show that the original quality group and the quality improvement group have obvious curative effects, and the incidence rate of the adverse drug reactions of the quality improvement group is obviously lower than that of the original quality group, which indicates that the quality improvement group not only has the anxiolytic effect, but also has obviously reduced adverse reactions.
Test 2: hepatotoxicity test
Serious adverse reactions of long-term use of the tandospirone citrate composition include damage to the liver, and the damage of the tandospirone citrate composition to the liver of different quality groups is examined through long-term administration experiments of mice.
120 male ICR mice with the weight of 18-22 g are randomly divided into 6 groups, each group comprises 20 mice, each administration group is continuously subjected to intragastric administration for 28 days according to the medicines and the doses shown in the table 5, the blank group is subjected to intragastric administration by using physiological saline for 1 time/day, the fasting time is 12 hours before blood taking, two blood taking parts are taken from the retrobulbar venous plexus on the 29 th day, and the transaminase AST and ALT concentrations in serum are respectively determined.
Mean. + -. standard deviation of test data
Data analysis was performed using SPSS software. Comparison between groups Using One-Way analysis of variance (One-Way ANOVA), with P<0.05 and P<0.01 is significantly different.
TABLE 5 Effect of Long-term administration on liver function
Comparison with blank control:#P<0.05，##P<0.01; comparison with the original quality group: p<0.05，**P<0.01。
Test results show that the concentration of AST and ALT in the serum of mice is obviously increased (# P <0.01) compared with the original quality group and the blank group by adopting the conventional dose of single administration every day; when the composition of tandospirone citrate with improved quality is taken every day, compared with the original quality group, the increase of AST and ALT concentration in the blood serum of mice is obviously reduced, especially the quality improvement groups 2,3 and 4 (P is less than 0.01); and the concentration of AST and ALT is reduced along with the reduction of the content of citrate of the compound I, citrate of the compound II and citrate of the compound III in the quality-improved group, which shows that the toxicity of the citric acid tandospirone composition on the liver after the use quality is improved is obviously reduced, and the medicine safety is higher.
Test 3: antidepressant animal model experiment
(1) Mouse tail suspension experiment (anti-depression experiment)
84 mice were randomly divided into 7 groups of 12 mice each and were gavaged once per group of drugs in Table 6. 1h after administration of each group of mice, the tail tip of each group of mice is pasted and inversely hung at a position of 1cm, the mice are fixed on a hook by using an adhesive tape to be in an inversely hung state, the head of each group of mice is 15cm away from an experimental table, each group of mice is operated one at a time, the despair behavior of the mice within 6min is recorded by using an animal behavior video analysis system, and the accumulated immobility time(s) within 4min after analysis is carried out. The standard for determining immobility is that the mouse stops struggling, is in an overhang state and is still.
The data of the test are expressed as mean. + -. standard deviation (X. + -. SD) and the data are analyzed by SPSS software. Group comparisons were significantly different using One-Way analysis of variance (One-Way ANOVA) with P <0.05 and P < 0.01.
TABLE 6 mouse Tail suspension test results
Comparison with blank control:#P<0.05,##P<0.01; comparison with the original quality group: p<0.05,**P<0.01。
The experimental result shows that the accumulative immobilization time of the mice in the positive drug group is obviously reduced compared with that in the blank control group (##P<0.01); the accumulated immobility time of the mice of the original quality group and the quality improvement groups 1, 2,3 and 4 is less than that of the blank control group, which shows that the original quality group and the quality improvement group have certain antidepressant effect; the cumulative immobility time was significantly reduced in the mass-improved groups 2,3, 4 mice compared to the original mass group (. about.P)<0.01), indicating thatThe quality-improved group had better antidepressant effect than the original quality group; from the results of the quality improvement groups 3 and 4, it can be seen that the cumulative immobility time of the mice decreased with the increase of the citrate content of the compound i, which is smaller than that of the quality improvement groups 1 and 2, indicating that within the scope of the present application, the antidepressant effect of the tandospirone citrate composition becomes better with the increase of the citrate content of the compound i.
(2) Forced swimming test of mouse (anti-depression test)
84 mice were randomly divided into 7 groups of 12 mice each and were gavaged once per group of drugs in the following table. 1h after administration of each group of mice, the mice are respectively placed into an organic glass jar with the height of 20cm and the diameter of 10cm, 25 +/-1 ℃ of water is filled into the organic glass jar, the height of 15cm is achieved, one mouse is operated each time, the swimming behavior of the mice within 6min is recorded by using an animal behavior video analysis system, and the cumulative immobile time(s) of forced swimming of the mice within 4min after analysis. The immobility time is judged that the animal stops struggling in the water and is in a floating state, and only small limbs move to keep the head floating on the water surface.
Mean. + -. standard deviation of test data
Data analysis was performed using SPSS software. Comparison between groups Using One-Way analysis of variance (One-Way ANOVA), with P<0.05 and P<0.01 is significantly different.
TABLE 7 results of forced swimming test for mice
Comparison with blank control:#P<0.05,##P<0.01; comparison with the original quality group: p<0.05,**P<0.01。
The experimental result shows that the accumulative immobilization time of the mice in the positive drug group is obviously reduced compared with that in the blank control group (##P<0.01); the cumulative immobility time of the mice in the original quality group and the quality improvement groups 1, 2,3 and 4 is less than that in the blank control group, which indicates that the mice in the original quality group are all smaller than that in the blank control groupHas certain antidepressant effect with the quality improving group; the cumulative immobility time was significantly reduced in the mass-improved groups 2,3, 4 mice compared to the original mass group (. about.P)<0.01); from the results of the quality improvement groups 3 and 4, it is clear that the cumulative immobility time of the mice increases with the decrease of the citrate content of the compound i, and is smaller than that of the quality improvement group 1, indicating that the antidepressant effect of the tandospirone citrate composition is better with the increase of the citrate content of the compound i within the scope of the present application.
The research results show that the drug effect of tandospirone citrate can be effectively improved and the toxic and side effects can be reduced within the limited range of the invention by controlling the index components.
The preferred embodiments of the present invention have been described in detail, however, the present invention is not limited to the specific details of the above embodiments, and various simple modifications may be made to the technical solution of the present invention within the technical idea of the present invention, and these simple modifications are within the protective scope of the present invention.
Claims (10)
1. The tandospirone citrate composition is characterized by comprising 0.001-0.5 wt% of compound I and/or citrate thereof, 0-0.4 wt% of compound II and/or citrate thereof, and 0-0.2 wt% of compound III and/or citrate thereof; the content of the compound I and/or citrate thereof is preferably 0.001-0.4%, more preferably 0.001-0.2%, further preferably 0.05-0.5%, further preferably 0.05-0.4%, further preferably 0.05-0.2%; the content of the compound II and/or citrate thereof is preferably 0-0.3%, more preferably 0-0.2%; the content of compound III and/or its citrate is preferably 0-0.1%, more preferably 0-0.05%,
2. the tandospirone citrate composition according to claim 1, characterized in that the content of compound iii and/or its citrate in the composition is 0.
3. Tandospirone citrate composition according to claim 1 or 2, characterized in that the content of compound ii and/or its citrate in the composition is 0.
4. The tandospirone citrate composition according to any of claims 1-3, wherein the tandospirone citrate content of the composition is more than 98%; preferably more than 98.5 percent; more preferably 99% or more.
5. A process for preparing tandospirone citrate composition according to any of claims 1-4, characterized in that it comprises a step of purifying cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide (IV):
the purification step comprises a step of dissolving cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide in a solvent and then precipitating the resulting solution. Preferably, the purification process comprises adding a solvent to cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide, heating, cooling, filtering, and drying to obtain cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide.
6. The method according to claim 5, wherein the purification step comprises the following two methods:
(A) adding a solvent into cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide, heating, cooling to 50 +/-5 ℃, cooling to 35 +/-5 ℃, cooling to room temperature, filtering and drying to obtain cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide;
or
(B) Adding a solvent into cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide, heating, cooling to room temperature, cooling to-10 +/-5 ℃, filtering, adding the solvent into a filter cake, heating, cooling to room temperature, cooling to 5 +/-5 ℃, filtering and drying to obtain the cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide.
7. The method of claim 5 or 6, comprising the steps of: adding 1- (2-pyrimidyl) piperazine, 1, 4-dibromobutane, potassium carbonate, benzyltriethylammonium chloride and toluene into a reactor for reaction, then adding the purified cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide for reaction, purifying the reaction solution to obtain free alkali, and adding citric acid for reaction to obtain the product. Preferably, the reaction solution purification process includes the steps of: adding the reaction solution into water, separating liquid, acidifying an organic layer until the pH value is less than or equal to 3.5, separating a water layer, adding an organic solvent for washing, separating liquid, adjusting the pH value of the water layer to be more than 9, filtering, and drying to obtain free alkali.
8. The method for preparing according to any one of claims 5 to 7, comprising the steps of: adding 1- (2-pyrimidyl) piperazine, 1, 4-dibromobutane, potassium carbonate, benzyltriethylammonium chloride and toluene into a reactor, carrying out reflux reaction for 3-4 hours, adding the purified cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide, refluxing for 4-5 hours, cooling the reaction solution to room temperature, adding the reaction solution into water, carrying out liquid separation, adding a hydrochloric acid solution into an organic layer for acidification until the pH value is less than or equal to 3.5, separating out an aqueous layer, adding an organic solvent for washing, separating out the aqueous layer, adding activated carbon, filtering, adjusting the pH value of the filtrate to be more than 9 by using a sodium hydroxide solution, filtering, drying to obtain free alkali, adding a mixed solution of citric acid and ethanol, refluxing for 0.5-1 hour, cooling, filtering, adding 5-10 times of ethanol into a filter cake, refluxing for 0.5-1 hour, cooling, filtering and drying to obtain the product.
9. The method according to claim 5 or 6, wherein the solvent is selected from the group consisting of: at least one of water, alcohols, ketones, ethers, esters, halogenated hydrocarbons, amides, and sulfoxide solvents; preferably, the alcohol solvent is preferably methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, t-butanol, n-pentanol, isopentanol, n-hexanol, or the like; preferably, the ketone solvent is preferably acetone, butanone, cyclohexanone, or the like; preferably, the ether solvent is preferably diethyl ether, isopropyl ether, tetrahydrofuran, 1, 4-dioxane, methyl tert-butyl ether, or the like; preferably, the ester solvent is preferably methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate, ethyl propionate, propyl propionate, butyl propionate, or the like; preferably, the halogenated hydrocarbon solvent is dichloromethane, chloroform, tetrachloromethane, or the like; preferably, the amide-based solvent is DMF, DMAC, or the like; preferably, the sulfoxide solvent is DMSO; preferably, the solvent is at least one selected from the group consisting of water, ethanol, methanol, isopropanol, butanol, acetone, and butanone; further preferably any one selected from methanol, ethanol, isopropanol, butanol, acetone, a mixed solution of ethanol and water, a mixed solution of methanol and water, a mixed solution of isopropanol and water, a mixed solution of butanol and water, and a mixed solution of acetone and water; further preferred is a compound selected from the group consisting of ethanol: 0.1-10: 1 of water, methanol: 0.1-10: 1 of water, isopropanol: 0.1-10: 1 of water, butanol: 0.1-10: 1 of water, acetone: water is a mixed solvent in a ratio of 0.2-5: 1; even more preferably selected from: ethanol: 0.5-4: 1 of water, methanol: 3-9: 1 of water, isopropanol: 0.2-2: 1 of water, butanol: 0.15-5: 1 of water, acetone: water is a mixed solvent in 1: 1.
10. Use of the tandospirone citrate composition according to any one of claims 1-4 for the preparation of antidepressant and/or anxiolytic drugs; preferably, the antidepressant and/or anxiolytic also comprises pharmaceutically acceptable auxiliary materials or auxiliary components; preferably, the dosage form of the antidepressant and/or anxiolytic comprises liquid preparation, gas preparation, solid preparation and semisolid preparation, preferably aromatic water, solution, injection, mixture, lotion, liniment, aerosol, spray, powder, pill, tablet, capsule, granule, film, ointment, suppository, paste and other common dosage forms, and more preferably capsule, tablet and granule.
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| US20100004249A1 (en) * | 2006-07-11 | 2010-01-07 | Takahiro Matsumoto | Bicyclic heterocyclic compound and use thereof |
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| US5521313A (en) * | 1994-05-05 | 1996-05-28 | Bristol-Myers Squibb Company | Process for preparing certain azapirones |
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