JP2007022984A - Hydrobromide salt of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine or crystal thereof - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a salt of donepezil ä1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine} with hydrogen bromide or a crystal thereof useful as a therapeutic agent or a prophylactic agent for diseases caused by acetylcholine esterase inhibitory actions. <P>SOLUTION: The hydrobromide salt of the donepezil or a crystal of a solvate thereof has diffraction peaks at 6.6° and 26.9° diffraction angles (2θ±0.2°), etc., in powder X-ray diffraction. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a salt of Donepezil and hydrogen bromide or crystals thereof useful as a preventive or therapeutic agent for various senile dementias and the like having an acetylcholine esterase inhibitory action.

Donepezil Hydrochloride (chemical name: 1-benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yl] methylpiperidine hydrochloride) is a senile dementia that has an inhibitory action on acetylcholine esterase It is extremely useful as a prophylactic or therapeutic agent for Alzheimer-type senile dementia (Patent Document 1).
As the salt of donepezil, hydrochloride of 1-benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yl] methylpiperidine and its crystal are known (Patent Document 2). No hydrobromide salt of -benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yl] methylpiperidine has been found.
JP-A-64-79151 International Publication No. 97/46527 Pamphlet

  Salts and crystals used as pharmaceutical active ingredients are required to have properties that are easy to handle in industrial production.

  As a result of diligent research, the present inventors have found the following novel salt and completed the present invention. That is, the present invention relates to a salt of donepezil and hydrogen bromide, a solvate thereof, or a crystal thereof.

That is, the present invention includes the following.
(1)
1-benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yl] methylpiperidine hydrobromide or a solvate thereof,
(2)
1-benzyl-4-[(5,6-dimethoxy-1-indanone)-, which has diffraction peaks at diffraction angles (2θ ± 0.2 °) of 6.6 ° and 26.9 ° in powder X-ray diffraction 2-yl] methylpiperidine hydrobromide or a solvate thereof,
(3)
In the powder X-ray diffraction, the crystal according to (2) further having diffraction peaks at diffraction angles (2θ ± 0.2 °) of 21.1 ° and 21.6 °,
(4)
1-benzyl-4-[(5,6-dimethoxy-1-indanone)-having diffraction peaks at diffraction angles (2θ ± 0.2 °) of 21.5 ° and 24.4 ° in powder X-ray diffraction 2-yl] methylpiperidine hydrobromide or a solvate thereof,
(5)
In the powder X-ray diffraction, the crystal according to (4), further having diffraction peaks at diffraction angles (2θ ± 0.2 °) of 10.2 ° and 18.2 °,
(6)
Crystallization using the solvent of 1 or 2 selected from the group consisting of an alcohol solvent and water, The method for producing a crystal according to (4),
(7)
A pharmaceutical comprising the salt according to any one of (1) to (5) or a solvate thereof, or a crystal thereof,
(8)
A preventive or therapeutic agent for a disease having an effective acetylcholinesterase inhibitory effect, comprising the salt according to any one of (1) to (5) or a solvate thereof or a crystal thereof as an active ingredient,
(9)
An agent for preventing or treating senile dementia, comprising the salt according to any one of (1) to (5) or a solvate thereof or a crystal thereof as an active ingredient,
(10)
An agent for preventing or treating Alzheimer's disease, comprising the salt according to any one of (1) to (5) or a solvate thereof or a crystal thereof as an active ingredient,
(11)
Pharmaceutical composition containing the salt of any one of said (1)-(5), its solvate, or those crystals.

  Since the salt of Donepezil and hydrogen bromide of the present invention or a solvate thereof, or a crystal thereof has an excellent acetylcholine esterase inhibitory action, it is a pharmaceutical, particularly various senile dementia caused by the acetylcholine esterase inhibitory action, etc. It is useful as a prophylactic or therapeutic agent.

  Hereinafter, the contents of the present invention will be described in detail.

In the present specification, the structural formula of a compound may represent a certain isomer for convenience, but the present invention includes all optical isomers generated in the structure of the compound and is limited to the description of the formula for convenience. It may be any one isomer or a mixture. Accordingly, the salt of the present invention may exist in an optically active form and a racemic form, but is not limited in the present invention and includes both.
In addition, the crystal of the salt or solvate thereof of the present invention may have a crystal polymorph, but is not limited in the same manner, and even a single substance of any crystal form is a mixture. Also good.

  Hereinafter, the meaning of terms, symbols, and the like described in the present specification will be described, and the present invention will be described in detail.

  “Donepezil” means 1-benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yl] methylpiperidine.

  In general, since the diffraction angle (2θ) in powder X-ray diffraction can cause an error within a range of ± 0.2 °, the value of the diffraction angle includes a numerical value within a range of about ± 0.2 °. Need to be understood. Therefore, the present invention includes not only a crystal in which the diffraction angle of the peak in powder X-ray diffraction completely coincides but also a crystal in which the diffraction angle of the peak coincides with an error of about ± 0.2 °.

“Alcohol solvent” means C _1-6 alkyl alcohol, and specific examples include methanol, ethanol, isopropanol, n-propanol and the like.

The “ether solvent” means diC _1-6 alkyl ether or cyclic ether, and specific examples include dimethyl ether, diisopropyl ether, t-butylmethyl ether, tetrahydrofuran and the like.

  The solvation in “1-benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yl] methylpiperidine hydrobromide or solvate thereof” refers to the salt of the present invention and the solvation. Although it will not specifically limit if it forms, It is a form in which a solvent forms a solvation by appropriate ratio of 0.1-5 molecule with respect to the said compound 1 molecule. The solvent in the solvation is not particularly limited, and examples thereof include solvents (alcohol solvents, ether solvents, etc.) and water used in the production of salts and crystals thereof, preferably water, diisopropyl ether and ethanol. 1 to 3 solvents selected from the group consisting of (in the case of a plurality of combinations, a mixture in an arbitrary ratio) and the like, more preferably solvation with water and the like.

  In the salt of the present invention, the ratio of donepezil to hydrogen bromide is not particularly limited, but hydrogen bromide is 0.5 to 2 molecules per molecule of donepezil (preferably about 1 molecule per molecule of the compound). A salt is formed at a ratio of

  The salt of the present invention or a solvate thereof and crystals thereof can be produced by the method described below. However, the production method of the salt of the present invention or a solvate thereof and crystals thereof is not limited thereto.

Production method
[Production of salt of donepezil and hydrogen bromide]

  In the production method of the present invention, donepezil (1-benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yl] methylpiperidine) used as a starting material is disclosed in Patent Document (International Publication No. It can be produced by the method described in the 29668 pamphlet).

(Operation 1)
Donepezil, solvent and hydrogen bromide are mixed and dissolved at room temperature or under heating. In this dissolution step, the order in which donepezil, solvent and acid are added is not particularly limited, and can be performed under stirring or standing.

(Operation 2)
After the mixed solution is dissolved, a salt of donepezil and hydrogen bromide can be obtained by the following method or the like.
(1) The solvent is distilled off from the mixture under normal pressure or reduced pressure.
(2) The mixture is stirred or left at the temperature at the time of dissolution.
(3) The mixture is cooled from the temperature at the time of dissolution and stirred or allowed to stand.
(4) A poor solvent is added to the mixture at the temperature at the time of dissolution, and the mixture is stirred or left standing.
(5) Add a poor solvent to the mixture, cool, and stir or leave.

(Operation 3)
When the salt of donepezil and hydrogen bromide is obtained as a precipitate, a solid, or the like, the precipitate or the like can be appropriately washed with a solvent. Further, the obtained precipitates and residues can be dried under normal pressure or reduced pressure at room temperature or under heating as necessary.

  Although the time of the process (the said operation 2) for obtaining the salt of these donepezil and hydrogen bromide is not specifically limited, Preferably it is 1 hour-3 days, More preferably, it is 1 to 24 hours. The cooling temperature and cooling rate for obtaining the salt of donepezil and hydrogen bromide are not particularly limited.

[Production of salt crystals of donepezil and hydrogen bromide]

The salt of donepezil and hydrogen bromide can also be obtained as crystals by performing the above (Operation 1) to (Operation 3).
In addition, a salt of donepezil and hydrogen bromide and a solvent are mixed and dissolved, and then (1) the mixture is distilled off under normal pressure or reduced pressure. (2) The mixture is dissolved at the temperature at the time of dissolution. (3) The mixture is cooled from the temperature at the time of dissolution and stirred or left to stand. (4) The poor solvent is added to the mixture at the temperature at the time of dissolution and stirred or left to stand. A salt of donepezil and hydrogen bromide can be obtained as crystals by adding a poor solvent to the mixture, cooling, stirring or standing.

  Hydrogen bromide may be either a gas or a solution thereof, but is preferably a hydrogen bromide solution, and more preferably an aqueous solution of hydrogen bromide.

  Examples of the solvent include, but are not limited to, water, alcohol (eg, methanol, ethanol, isopropyl alcohol, etc.), ester (eg, methyl acetate, ethyl acetate, etc.), ketone (eg, acetone, etc.). , Nitrile (eg, acetonitrile, etc.), benzene, toluene, cyclic ether (eg, dioxane, tetrahydrofuran, etc.), N, N-dimethylformaldehyde, dimethyl sulfoxide, carbon halide (eg, methylene chloride, etc.) One or more solvents. When using a some solvent, you may add as a mixed solvent or may add each solvent separately.

  Although the heating temperature at the time of melt | dissolution of a mixture with donepezil, hydrogen bromide, and a solvent is not specifically limited, Preferably it is 20-80 degreeC.

  The cooling temperature after dissolution of the mixture of donepezil, hydrogen bromide and solvent is not particularly limited, but is preferably -20 to 40 ° C.

  The amount of the solvent used is not particularly limited, but it can be appropriately selected with the lower limit of the amount of donepezil dissolved by heating and the upper limit of the amount that does not significantly reduce the yield of crystals, more preferably the weight with respect to donepezil. The volume ratio is 4 to 30 times (v / w).

  The amount of hydrogen bromide used is not particularly limited as long as it is equal to or more than donepezil, but is preferably 1 to 3 times the molar ratio with donepezil, and more preferably about 1-1. 5 times the amount.

  When a salt of donepezil and hydrogen bromide is obtained as a crystal, a seed crystal (a crystal of the desired donepezil hydrobromide salt) may be added before crystal precipitation. The temperature at which the seed crystal is added is not particularly limited, but is preferably 60 ° C. or lower, more preferably 10 ° C. to 40 ° C.

A poor solvent (such as diethyl ether, isopropyl ether, t-butyl methyl ether, hexane, heptane, octane, or a mixed solvent thereof) can be appropriately added before or after the crystals are precipitated.
The crystals precipitated in the mixture can be collected by filtration to obtain the desired donepezil and hydrogen bromide salt.

  The obtained crystal can be washed with the same solvent as the dissolved solvent, if necessary. Further, the obtained crystals can be dried under normal pressure or reduced pressure at room temperature or under heating as necessary.

  For example, (i) a salt of donepezil and hydrogen bromide with a solvent (for example, water, alcohol (for example, methanol, ethanol, isopropyl alcohol, etc.), ester (for example, methyl acetate, ethyl acetate, etc.), ketone (for example, acetone) Etc.), nitriles (eg acetonitrile), benzene, toluene, cyclic ethers (eg dioxane, tetrahydrofuran, etc.), N, N-dimethylformaldehyde, dimethyl sulfoxide, carbon halides (eg methylene chloride, etc.) or mixtures thereof Solvent etc.) is added and heated to 20-80 ° C. to dissolve. (Ii) Diethyl ether, isopropyl ether, t-butyl methyl ether, hexane, heptane, octane or the like is added to the mixture. (Iii) The mixture is cooled to −20 to 40 ° C., and the resulting precipitate is collected by filtration, whereby a salt of donepezil and hydrogen bromide can be obtained as crystals.

  The salt of Donepezil with hydrogen bromide or a solvate thereof according to the present invention or a crystal thereof can be used for various types of senile dementias; Cerebrovascular disorders associated with trauma, etc .; Treatment of encephalitis sequelae, decreased attention due to cerebral palsy, speech disorder, decreased motivation, attention deficit / hyperactivity disorder, emotional disorder, memory disorder, hallucination-delusional state, behavioral abnormality It is effective for prevention, remission, improvement, etc.

  Furthermore, since the salt of Donepezil with hydrogen bromide or a solvate thereof or a crystal thereof according to the present invention has a potent and highly selective anticholinesterase action, it is also useful as a medicament based on these actions. In particular, the donepezil salt or a solvate thereof or a crystal thereof according to the present invention is useful for Alzheimer-type senile dementia, for example, Huntington's disease, Pick's disease, late onset abnormalities and the like.

When the salt of Donepezil with hydrogen bromide or a solvate thereof or a crystal thereof according to the present invention is used as a medicine, the salt of the present invention or a solvate thereof or a crystal thereof and an appropriate additive are usually used. Use blended and formulated products. However, the above does not deny that the salt of the present invention or a solvate thereof or a crystal thereof is used as a raw material as a medicine.
Examples of the additive include excipients, binders, lubricants, disintegrating agents, coloring agents, flavoring agents, emulsifiers, surfactants, solubilizers, suspending agents, etc. Examples include tonicity agents, buffering agents, preservatives, antioxidants, stabilizers, absorption promoters, and the like, and these can be used in appropriate combinations as desired.

  When the salt of donepezil with hydrogen bromide or a solvate thereof or a crystal thereof according to the present invention is used as these pharmaceuticals, it is administered orally or parenterally. The dose varies depending on the degree of symptom; patient age, sex, body weight, sensitivity difference; administration method; timing of administration, interval, nature of pharmaceutical preparation, preparation, type; type of active ingredient, etc., but is not particularly limited The dose is usually about 0.1 to 300 mg, preferably about 1 to 100 mg per day for an adult, and is usually administered once or twice to 4 times a day.

  In order to formulate the salt of Donepezil with hydrogen bromide or a solvate thereof or crystals thereof according to the present invention, injections, suppositories, sublingual tablets, tablets, capsules in the usual manner in the technical field of preparation The dosage form is such as a drug or transdermal agent. When preparing injections, add pH adjusters, buffers, suspending agents, solubilizers, solubilizers, tonicity agents, preservatives, etc. as necessary to the main drug, Subcutaneous and intramuscular injection. At that time, if necessary, a freeze-dried product can be obtained by a conventional method.

  Examples of the suspending agent include methyl cellulose, polysorbate 80, hydroxyethyl cellulose, gum arabic, tragacanth powder, sodium carboxymethyl cellulose, polyoxyethylene sorbitan monolaurate and the like.

  Examples of the solubilizer include polyoxyethylene hydrogenated castor oil, polysorbate 80, nicotinic acid amide, polyoxyethylene sorbitan monolaurate, tuna gol, castor oil fatty acid ethyl ester, and the like.

  Examples of the stabilizer include sodium sulfite, sodium metasulfite, and ether. Examples of the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, sorbic acid, phenol, cresol, and chlorocresol. Can do.

  Donepezil hydrogen bromide or a solvate thereof or a crystal thereof according to the present invention can be produced, for example, by the method described in the following examples. It can be confirmed by the method described in JP-A-64-79151). However, these are only examples, and the present invention is not limited to the following specific examples in any case, and may be changed without departing from the scope of the present invention.

  “Room temperature” in the following Reference Examples and Examples usually indicates about 10 ° C. to about 35 ° C. % Indicates weight percent unless otherwise specified.

Example 1
240 ml of ethanol was added to 30 g of donepezil, and the mixture was heated (external temperature 50 ° C.) and dissolved. Subsequently, 16.5 g of hydrobromic acid (47% aqueous solution) and 60 ml of ethanol were added to the mixture with stirring at an internal temperature of 34 ° C. The mixture was further stirred at room temperature for 12 hours and 20 minutes, and the precipitate was collected by filtration. The precipitate was washed with 70 ml of ethanol and then dried under reduced pressure at 50 ° C. for 7 hours to obtain 35.2 g (yield 96.7%) of crystals of donepezil hydrobromide.

Example 2
15 ml of a water-methanol mixture (50:50) was added to 1.5 g of donepezil hydrobromide, and the mixture was heated (external temperature 70 ° C.) and dissolved. The mixture was then left at an external temperature of 5 ° C. for about 5 minutes. Furthermore, it was left overnight at an external temperature of 3 ° C., and the precipitate was collected by filtration. The precipitate was washed with 1 ml of cold water and then dried under reduced pressure at room temperature for 6 hours to obtain 0.883 g (yield 58.9%) of donepezil hydrobromide crystals.

Example 3
50 ml of a water-methanol mixture (50:50) was added to 1.8 g of donepezil hydrobromide, and the mixture was dissolved by applying ultrasonic waves under heating (external temperature 70 ° C.). About 4 ml of the mixture was dried under reduced pressure under vacuum, and 20 ml of ethanol was added and dissolved. The mixture was then left overnight at an external temperature of 3 ° C., and the precipitate was collected by filtration. The precipitate was washed with 1 ml of cold water and dried at 60 ° C. overnight to obtain crystals of donepezil hydrobromide.

Measurement of Powder X-ray Diffraction Pattern Powder X-ray diffraction measurement of the crystals obtained in each Example was performed under the following measurement conditions in accordance with the powder X-ray diffraction measurement method described in the general test method of the Japanese Pharmacopoeia.
(apparatus)
Science X-ray DTA system: RINT-2000 (manufactured by Rigaku Corporation)
(Method of operation)
The sample was measured under the following conditions.
X-ray used: CuKα tube voltage: 40 kV
Tube current: 200 mA
Divergent slit: 1/2 deg
Receiving slit: 0.3mm
Scattering slit: 1/2 deg
Scanning speed: 2 ° / min Scanning step: 0.02 ° Measuring range (2θ): 5-40 °

  The powder X-ray diffraction pattern of the crystal obtained in Example 2 is shown in FIG. 1, and the powder X-ray diffraction pattern of the crystal obtained in Example 3 is shown in FIG.

  The diffraction angle (2θ) peak and intensity of the crystal obtained in Example 2 are shown in Table 1, and the diffraction angle (2θ) peak and intensity of the crystal obtained in Example 3 are shown in Table 2.

4 is a diagram illustrating a powder X-ray diffraction pattern of crystals obtained in Example 2. FIG. 6 is a diagram illustrating a powder X-ray diffraction pattern of crystals obtained in Example 3. FIG.

Claims (6)

  1-Benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yl] methylpiperidine hydrobromide or a solvate thereof.   1-benzyl-4-[(5,6-dimethoxy-1-indanone)-, which has diffraction peaks at diffraction angles (2θ ± 0.2 °) of 6.6 ° and 26.9 ° in powder X-ray diffraction 2-yl] methyl piperidine hydrobromide or a solvate thereof.   The crystal according to claim 2, further comprising diffraction peaks at diffraction angles (2θ ± 0.2 °) of 21.1 ° and 21.6 ° in powder X-ray diffraction.   1-benzyl-4-[(5,6-dimethoxy-1-indanone)-having diffraction peaks at diffraction angles (2θ ± 0.2 °) of 21.5 ° and 24.4 ° in powder X-ray diffraction 2-yl] methyl piperidine hydrobromide or a solvate thereof.   The crystal according to claim 4, further comprising diffraction peaks at diffraction angles (2θ ± 0.2 °) of 10.2 ° and 18.2 ° in powder X-ray diffraction.   The method for producing a crystal according to claim 4, wherein crystallization is performed using one or two solvents selected from the group consisting of an alcohol solvent and water.

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