TW202104186A - Donepezil myristyloxymethyl ether or pharmaceutically acceptable salt thereof - Google Patents

Abstract

The present invention relates to novel donepezil myristyloxymethyl ether or a pharmaceutically acceptable salt thereof and a sustained release pharmaceutical composition comprising the same as a main ingredient. Donepezil myristyloxymethyl ether of the present invention may reduce the initial release of donepezil, which is an active ingredient, when administered into the body by introducing a myristyloxymethyl ether group into donepezil, thereby reducing the risk of side effects, such as drug toxicity and the like, and uniformly release donepezil in the body over a long period of time, thereby enhancing the therapeutic effect of the drug for patients with dementia.

Description

Donepezil myristyloxy methyl ether or its pharmacologically acceptable salt

The present invention relates to a novel donepezil myristyloxymethyl ether or its pharmacologically acceptable salt and a sustained-release pharmaceutical composition containing this substance as a main component. Specifically, the present invention relates to donepezil myristyloxymethyl ether or its pharmacologically acceptable salt and an injection composition containing the substance, which can continuously maintain donepezil when administered to the body The blood concentration of the active ingredient, and provides the active ingredient over a long period of time without the risk of side effects.

Dementia refers to a complex disease related to cognitive impairment, which manifests as amnesia, mental deterioration, personality changes, and abnormal behaviors. In other words, dementia is a degenerative cranial nerve disease, which is caused by the irreversible dysfunction of the neural network caused by the slow death of nerve cells that cause degenerative diseases of the central nervous system, which eventually leads to the permanent loss of related functions of the human body.

The development mechanism of dementia has not yet been fully elucidated. However, it is known that, compared with normal people, choline acetyltransferase (choline acetyltransferase) (hereinafter referred to as acetylcholine) (hereinafter referred to as "ACh") is synthesized in the brains of dementia patients "ChAT") reduced by about 20-30%. It is also known that the concentration of acetylcholine, which is a neurotransmitter, is reduced by about 16-30%. As a result of the above studies, studies have been conducted using inhibitors that inhibit acetylcholinesterase (hereinafter referred to as "AChE"), which is an enzyme that hydrolyzes the neurotransmitter acetylcholine. This method is Indirect treatment methods.

Acetylcholinesterase is an enzyme that hydrolyzes acetylcholine into choline and acetate. Acetylcholine is one of the neurotransmitters that mediate parasympathetic nerve activity in the human body. Acetylcholinesterase is formed in the endoplasmic reticulum membrane and transferred to the cell membrane to perform its function. Enzymes are mainly distributed in cholinergic nerves and their surrounding environment, especially at the junctions of muscle nerves, and are an important enzyme also found in plasma, liver and other tissues.

Most dementia treatment agents currently in use are acetylcholinesterase inhibitors, including donepezil (trade name: Aricept), tacrine (trade name: Cognex), rivastigmine (trade name: Exelon) ), Galantamine (trade name: Reminyl), etc.

The first generation of acetylcholinesterase inhibitors includes tacrine, which was the first drug approved as an anti-dementia therapeutic agent. However, the duration of the effect of tacrine is too short, so that it must be administered four times a day, and there is a problem of liver poisoning.

The second generation acetylcholinesterase inhibitor includes donepezil, which is a compound represented by the following formula. Donepezil was approved as a therapeutic agent for dementia in the United States in 1996 and is known as a therapeutic agent for mild, moderate or severe Alzheimer’s dementia, most of which are It is administered orally in the form of a lozenge.

However, it is known that oral administration of donepezil tablets in some patients causes gastrointestinal side effects, such as diarrhea, nausea, loss of appetite, muscle twitches and the like. In addition, the commercially available oral preparations of donepezil hydrochloride are usually administered at a starting dose of 5 mg per day for 4 to 6 weeks before going to bed, and then the dose is increased to 10 mg once a day. However, its disadvantage is that oral preparations exhibit poor drug compliance when treated in this way, because these preparations must be administered orally every day, especially for patients with dementia.

Recently, patients with dysphagia can purchase lozenges that disintegrate in the oral cavity. In addition, an ointment preparation for transdermal administration when oral administration is difficult has been proposed (Japanese Patent Publication (Pyung) No. 11-315016). In addition, in order to solve the situation that it is difficult to orally take drugs in a state where the symptoms of dementia are clearly developed, ointments and suppositories have been proposed. However, these formulations also have the problem of continuous administration of active ingredients over a long period of time.

In order to improve the convenience and compliance of patients by reducing the frequency of drug administration, and to maintain the drug concentration continuously and stably for a long period of time, there is a method of formulating sustained-release injections. However, when sustained-release injection is performed, it is difficult to ensure that the drug is continuously and uniformly released over a long period of time while maintaining biological activity in the body.

Specifically, in the case of sustained release injection, due to the high initial release of the drug (initial burst), which may cause side effects including toxic reactions, it is necessary to eliminate or at least minimize the high initial release.

Therefore, there is a need to develop a formulation capable of suppressing the high initial release of donepezil and continuously releasing donepezil for a long time.

Therefore, the present inventors developed the myristyl oxymethyl ether of Donepezil, which continuously and uniformly releases Donepezil in the body by introducing a myristyl oxymethyl ether group into Donepezil. Pai Qi, while reducing the initial release of Donai Pai Qi's height. Based on the above content, the present inventor has completed the present invention. Prior Art Document Patent documents

(Patent Document 1) Japanese Patent Publication (Pyung) No. 11-315016

technical problem

The present invention provides donepezil myristyloxymethyl ether or its pharmacologically acceptable salt and a pharmaceutical composition containing the substance, which can reduce the risk of side effects when administered to the body and enhance the drug compliance of patients with dementia Sex.

Specifically, the present invention provides donepezil myristyloxymethyl ether and a sustained-release pharmaceutical composition containing the substance, which can reduce the initial release of donepezil so as to reduce the risk of side effects, such as drug toxicity and It has a similar effect and uniformly releases donepezil in the body over a long period of time in order to enhance the drug treatment effect of patients with dementia. The solution to the problem

The present invention relates to donepezil myristyloxymethyl ether represented by the following formula 1 or a pharmacologically acceptable salt thereof. [Formula 1]

The chemical name of Donepezil myristyloxy methyl ether is "1-benzyl-4-((5,6-dimethoxy-3-((tetradecyloxy)methoxy)) -1 H -inden-2-yl)methyl)piperidine" and the compound in which the myristyloxymethyl ether group is introduced into donepezil in the present invention is called donepezil myristyl基oxymethyl ether.

The present invention relates to a sustained-release pharmaceutical composition containing donepezil myristyloxymethyl ether or a pharmacologically acceptable salt thereof.

Donepezil myristyloxy methyl ether can be prepared by reacting Donepezil free base with 1-(chloromethoxy)tetradecane.

The 1-(chloromethoxy)tetradecane of the present invention can be prepared by a method including the following steps: (i) mixing 1-tetradecyl alcohol, sodium chloroacetate, and sodium hydroxide to obtain 2-(decyl The step of sodium tetraalkyloxy)acetate; (ii) the step of reacting sodium 2-(tetradecyloxy)acetate with 2M aqueous HCl to obtain 2-(tetradecyloxy)acetic acid; and ( iii) A step of reacting 2-(tetradecyloxy)acetic acid with sulfite chloride.

The pharmaceutical composition of the present invention can be formulated into preparations for parenteral administration, such as intramuscular injection, intravenous injection, subcutaneous injection, intradermal injection, and intravenous drip, and can be preferably formulated for use A preparation for intramuscular injection.

The pharmaceutical composition of the present invention is preferably administered every 4 to 16 weeks, and more preferably every 8 to 12 weeks.

In addition, the pharmaceutical composition of the present invention can be administered to prevent or treat dementia. Effect of the invention

The Donepezil myristyloxymethyl ether or its pharmacologically acceptable salt and the sustained-release pharmaceutical composition containing this substance as a main component of the present invention reduce the initial release of Donepezil after administration to the body ( The initial burst) and has the effect of minimizing the risk of side effects including toxic reactions, and by maintaining the effective concentration of Donepezil in the blood for a long period of time so that the therapeutic effect can be exhibited only by a single administration, Thereby it has the effect of enhancing the drug compliance of patients with dementia.

1)製備2-（十四烷基氧基）乙酸鈉Hereinafter, the present invention is described in more detail through working examples. However, these examples are provided for illustrative purposes only to facilitate understanding of the present invention, but the scope of the present invention is not limited to the following examples. [Example 1] Synthesis of 1-(chloromethoxy)tetradecane (1-(chloromethoxy)tetradecane; MMS-Cl)

1) Preparation of sodium 2-(tetradecyloxy)acetate

After 220 g of 1-tetradecanol was added to the reaction zone, 60 g of sodium chloroacetate and 31 g of sodium hydroxide were added, and the mixture was heated to 80° C. and stirred for 63 hours. 600 mL of n-heptane was poured into the reaction solution and stirred at 80° C. for 1 hour, and then the reaction solution was filtered at the same temperature to obtain an off-white solid. The resulting solid and 1.5 L of MTBE (methyl tert -butyl ether; methyl tertiary - butyl ether) was added to the reaction zone and stirred at 50 ℃ 1 hour. The precipitated solid was filtered to obtain 134 g of sodium 2-(tetradecyloxy)acetate compound. ( ¹ H NMR (CD ₃ OD, 400 MHz) δ 3.83 (s, 2H), 3.48 (t, J = 6.9 Hz, 2H), 1.65 ~ 1.57 (m, 2H), 1.37 ~ 1.29 (m, 22H), 0.90 (t, J = 6.9 Hz, 3H)). 2) Preparation of 2-(tetradecyloxy)acetic acid

Add 134 g of 2-(tetradecyloxy) sodium acetate prepared in the above step 1) to 800 mL of ethyl acetate (EtOAc) in the reaction zone and after stirring, pour 800 mL of 2M HCl aqueous solution and stirred at ambient temperature for 2 hours. The organic layer was obtained by layer separation, followed by washing with 600 mL of saturated sodium chloride aqueous solution. An organic layer was obtained, then dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The concentrated compound was dissolved in 600 mL of n-hexane, followed by stirring at -15°C for 1 hour. The precipitated solid was filtered and washed with 120 mL of cold n-hexane to obtain 75.7 g of 2-(tetradecyloxy)acetic acid compound. ( ¹ H NMR (CDCl ₃ , 400 MHz) δ 4.11 (s, 2H), 3.56 (t, J = 6.7 Hz, 2H), 1.66 ~ 1.59 (m, 2H), 1.36 ~ 1.25 (m, 22H), 0.88 (t, J = 7.2 Hz, 3H)). 3) Preparation of 1-(chloromethoxy)tetradecane (1-(chloromethoxy)tetradecane; MMS-Cl)

Add 50.0 g of 2-(tetradecyloxy)acetic acid prepared in step 2) above to the reaction zone, then pour 100 mL of sulfite chloride into it, and heat the mixture to reflux temperature and stir 3 hour. After the reaction was completed, the solvent was removed by distillation under reduced pressure, and 150 mL of toluene was poured into it, and the distillation under reduced pressure was repeated three times to obtain 48.2 g of 1-(chloromethoxy)tetradecane Compound. ( ¹ H NMR (CDCl ₃ , 400 MHz) δ 5.51 (s, 2H), 3.68 (t, J = 6.7 Hz, 2H), 1.65 ~ 1.58 (m, 2H), 1.37 ~ 1.26 (m, 22H), 0.88 (t, J = 6.8 Hz, 3H)). [Example 2] Preparation of donepezil myristyloxymethyl ether (DMME) [1-benzyl-4-((5,6-dimethoxy-3-((tetradecane) Oxy)methoxy)-1 H -inden-2-yl)methyl)piperidine]

63.3 g of Donepezil free base (purchased from "Jinan Chenghui-Shuangda Chemical Co., Ltd") was added to the reaction zone, followed by pouring 380 mL of THF (tetrahydrofuran) and 253 mL of DMPU (1 , 3-dimethyl-3,4,5,6-tetrahydro -2 (1 H) -pyrimidinone; 1,3- dimethyl-3,4,5,6-tetrahydro -2 (1 H) - pyrimidinone ) To dissolve and cool to -78°C. Pour 183.5 mL of NaHMDS (1.0 M THF solution) into the reaction solution for 30 minutes and stir at -78°C for 1 hour. The reaction solution was heated to -20°C, and 48.2 g of 1-(chloromethoxy)tetradecane prepared in Example 1-3) above was dissolved in 60 mL of THF (tetrahydrofuran; tetrahydrofuran) and poured into The reaction solution lasted for 30 minutes, and then the mixture was stirred at the same temperature for 1 hour.

1)製備2-（十二烷基氧基）乙酸鈉630 mL of saturated ammonium chloride aqueous solution was poured into the reaction solution, and 630 mL of purified water was poured into it. The organic layer was obtained by layer separation, and then the aqueous layer was back-extracted twice with 630 mL of ethyl acetate (EtOAc). The organic layer was collected and concentrated under reduced pressure, and the concentrate was dissolved in 630 mL of IPE (diisopropyl ether; diisopropyl ether), and then washed with 630 mL of purified water. The organic layer was obtained by layer separation, and then washed twice with 300 mL of purified water, and then washed once with 300 mL of saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by a silica column and then recrystallized from 480 mL of n-heptane to obtain 42.8 g of Donepezil myristyloxymethyl ether. ( ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.31 ~ 7.22 (m, 5H), 6.96 (s, 1H), 6.95 (s, 1H), 5.11 (s, 2H), 3.90 (s, 3H), 3.88 (s, 3H), 3.77 (t, J = 6.7 Hz, 2H), 3.48 (s, 2H), 3.14 (s, 2H), 2.88 ~ 2.85 (m, 2H), 2.37 (d, J = 7.2 Hz, 2H), 1.92 (td, J = 11.7, 2.3 Hz, 2H), 1.67 ~ 1.60 (m, 4H), 1.55 ~ 1.45 (m, 1H), 1.41 ~ 1.25 (m, 24H), 0.88 (t, J = 6.9 Hz, 3H)). [Example 3] Synthesis of 1-(chloromethoxy)dodecane (1-(chloromethoxy)dodecane; LMS-Cl)

1) Preparation of sodium 2-(dodecyloxy)acetate

64 g of 1-dodecanol was added to the reaction zone, followed by 20 g of sodium chloroacetate and 10.3 g of sodium hydroxide, and the mixture was heated to 70° C. and stirred for 63 hours. The mixture was cooled to ambient temperature, and 300 mL of dichloromethane and 300 mL of purified water were poured into it and stirred for 1 hour. The reaction solution was filtered and washed with 50 mL of ethyl acetate (EtOAc) and 100 mL of n-heptane to obtain 37.3 g of 2-(dodecyloxy) sodium acetate compound. ( ¹ H NMR (CD ₃ OD, 400 MHz) δ 3.83 (s, 2H), 3.47 (t, J = 6.9 Hz, 2H), 1.64 ~ 1.57 (m, 2H), 1.37 ~ 1.29 (m, 18H), 0.90 (t, J = 6.9 Hz, 3H)). 2) Preparation of 2-(dodecyloxy)acetic acid

Add 37.3 g of 2-(dodecyloxy) sodium acetate prepared in step 1) above to 220 mL of ethyl acetate (EtOAc) in the reaction zone and stir, then pour 220 mL into it. mL of 2M HCl aqueous solution and stirred at ambient temperature for 2 hours. The organic layer was obtained by layer separation, and then the aqueous layer was back-extracted again with 160 mL of ethyl acetate (EtOAc). The organic layer was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The concentrated compound was dissolved in 200 mL of n-hexane, followed by stirring at -15°C for 1 hour. The precipitated solid was filtered and washed with 30 mL of cold n-hexane to obtain 30.8 g of 2-(dodecyloxy)acetic acid compound. ( ¹ H NMR (CDCl ₃ , 400 MHz) δ 4.11 (s, 2H), 3.56 (t, J = 6.7 Hz, 2H), 1.66 ~ 1.59 (m, 2H), 1.36 ~ 1.25 (m, 18H), 0.87 (t, J = 6.9 Hz, 3H)). 3) Preparation of 1-(chloromethoxy)dodecane (1-(chloromethoxy)dodecane; LMS-Cl)

10.0 g of 2-(dodecyloxy)acetic acid prepared in step 2) above was added to the reaction zone, and then 20 mL of sulfite chloride was poured into it, and the mixture was heated to reflux temperature and stirred for 3 hour. After the reaction was completed, the solvent was removed by distillation under reduced pressure, and 30 mL of toluene was poured into it, and the distillation under reduced pressure was repeated three times to obtain 9.6 g of 1-(chloromethoxy)dodecane Compound. ( ¹ H NMR (CDCl ₃ , 400 MHz) δ 5.51 (s, 2H), 3.68 (t, J = 6.7 Hz, 2H), 1.65 ~ 1.58 (m, 2H), 1.37 ~ 1.26 (m, 18H), 0.88 (t, J = 6.8 Hz, 3H)). [Example 4] Preparation of donepezil lauryloxymethyl ether (DLME) [1-benzyl-4-((3-((dodecyloxy)methoxy)-5 ,6-Dimethoxy- 1H -inden-2-yl)methyl)piperidine]

10.4 g of Donepezil free base was added to the reaction zone, followed by pouring 80 mL of THF (tetrahydrofuran; tetrahydrofuran) to dissolve, and cooling to -78°C. Pour 40.9 mL of NaHMDS (1.0 M THF solution) into the reaction solution for 30 minutes and stir at -78°C for 1 hour. At the same temperature, 9.6 g of 1-(chloromethoxy)dodecane prepared in the above example 3-3) was dissolved in 20 mL of THF (tetrahydrofuran; tetrahydrofuran) and poured into the reaction solution for 30 minutes Then, the mixture was gradually heated to ambient temperature and stirred for 15 hours.

1)製備2-（癸氧基）乙酸鈉The saturated aqueous ammonium chloride solution was poured into the reaction solution, and 100 mL of purified water was poured into it. The organic layer was obtained by layer separation, and then the aqueous layer was back-extracted once with 100 mL of ethyl acetate (EtOAc). The combined organic layer was washed once with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by a silica column and then recrystallized from n-heptane to obtain 1.95 g of donepezil lauryloxy methyl ether. ( ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.31 ~ 7.21 (m, 5H), 6.95 (s, 1H), 6.94 (s, 1H), 5.10 (s, 2H), 3.90 (s, 3H), 3.88 (s, 3H), 3.77 (t, J = 6.7 Hz, 2H), 3.48 (s, 2H), 3.14 (s, 2H), 2.86 (d, J = 11.7, 2H), 2.37 (d, J = 7.2 Hz, 2H), 1.91 (t, J = 10.6 Hz, 2H), 1.65 ~ 1.60 (m, 4H), 1.53 ~ 1.47 (m, 1H), 1.36 ~ 1.25 (m, 20H), 0.87 (t, J = 6.9 Hz, 3H)). [Example 5] Synthesis of 1-(chloromethoxy)decane (1-(chloromethoxy)decane; DMS-Cl)

1) Preparation of sodium 2-(decyloxy)acetate

81.5 g of 1-decanol was added to the reaction zone, followed by 30 g of sodium chloroacetate and 15.5 g of sodium hydroxide, and the mixture was heated to 75° C. and stirred for 88 hours. The mixture was cooled to ambient temperature, and 500 mL of dichloromethane and 300 mL of purified water were poured into it and stirred for 1 hour. The reaction solution was filtered and washed with 150 mL of IPE (diisopropyl ether; diisopropyl ether) to obtain 41.1 g of 2-(decyloxy) sodium acetate compound. ( ¹ H NMR (CD ₃ OD, 400 MHz) δ 3.83 (s, 2H), 3.47 (t, J = 6.9 Hz, 2H), 1.64 ~ 1.57 (m, 2H), 1.37 ~ 1.30 (m, 14H), 0.90 (t, J = 6.8 Hz, 3H)). 2) Preparation of 2-(decyloxy)acetic acid

Add 41.1 g of 2-(decyloxy) sodium acetate prepared in step 1) above to 300 mL of ethyl acetate (EtOAc) in the reaction zone and stir, then pour 300 mL of 2M into it HCl aqueous solution and stirred at ambient temperature for 1 hour. The organic layer was obtained by layer separation, and then the aqueous layer was back-extracted again with 200 mL of ethyl acetate (EtOAc). The organic layer was washed with a saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The concentrated compound was dissolved in 200 mL of n-hexane, followed by stirring at -15°C for 1 hour. The precipitated solid was filtered and washed with 50 mL of cold n-hexane to obtain 33.1 g of 2-(decyloxy)acetic acid compound. ( ¹ H NMR (CDCl ₃ , 400 MHz) δ 4.10 (s, 2H), 3.56 (t, J = 6.5 Hz, 2H), 1.67 ~ 1.59 (m, 2H), 1.37 ~ 1.26 (m, 14H), 0.88 (t, J = 6.0 Hz, 3H)). 3) Preparation of 1-(chloromethoxy)decane (1-(chloromethoxy)decane; DMS-Cl)

11.0 g of 2-(decyloxy)acetic acid prepared in step 2) above was added to the reaction zone, then 22 mL of sulfite chloride was poured into it, and the mixture was heated to reflux temperature and stirred for 3 hours. After the reaction was completed, the solvent was removed by distillation under reduced pressure, and 30 mL of toluene was poured into it, and the distillation under reduced pressure was repeated three times to obtain 10.5 g of 1-(chloromethoxy)decane compound . ( ¹ H NMR (CDCl ₃ , 400 MHz) δ 5.51 (s, 2H), 3.68 (t, J = 6.7 Hz, 2H), 1.65 ~ 1.58 (m, 2H), 1.37 ~ 1.26 (m, 14H), 0.88 (t, J = 6.8 Hz, 3H)). [Example 6] Preparation of donepezil decyloxymethyl ether (DDME) [1-benzyl-4-((3-((decyloxy)methoxy)-5,6-di Methoxy- 1H -inden-2-yl)methyl)piperidine]

12.9 g of Donepezil free base was added to the reaction zone, followed by pouring 100 mL of THF (tetrahydrofuran; tetrahydrofuran) to dissolve, and cooling to -78°C. Pour 50.9 mL of NaHMDS (1.0 M THF solution) into the reaction solution for 30 minutes and stir at -78°C for 1 hour. At the same temperature, 10.5 g of 1-(chloromethoxy)decane prepared in Example 5-3) above was dissolved in 20 mL of THF (tetrahydrofuran; tetrahydrofuran) and poured into the reaction solution for 30 minutes, The mixture was then gradually heated to ambient temperature and stirred for 15 hours.

1)製備2-（辛氧基）乙酸鈉The saturated aqueous ammonium chloride solution was poured into the reaction solution, and 100 mL of purified water was poured into it. The organic layer was obtained by layer separation, and then the aqueous layer was back-extracted once with 100 mL of ethyl acetate (EtOAc). The combined organic layer was washed once with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by a silica column, and then recrystallized from n-heptane to obtain 4.05 g of donepezil decyloxy methyl ether. ( ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.31 ~ 7.21 (m, 5H), 6.96 (s, 1H), 6.95 (s, 1H), 5.11 (s, 2H), 3.90 (s, 3H), 3.88 (s, 3H), 3.77 (t, J = 6.7 Hz, 2H), 3.48 (s, 2H), 3.14 (s, 2H), 2.86 (d, J = 11.7 Hz 2H), 2.37 (d, J = 7.2 Hz, 2H), 1.92 (td, J = 11.7, 2.3 Hz, 2H), 1.67 ~ 1.60 (m, 4H), 1.54 ~ 1.46 (m, 1H), 1.39 ~ 1.26 (m, 16H), 0.88 (t, J = 6.9 Hz, 3H)). [Example 7] Synthesis of 1-(chloromethoxy)octane (1-(chloromethoxy)octane; OMS-Cl)

1) Preparation of 2-(octyloxy) sodium acetate

67 g of 1-octanol was added to the reaction zone, followed by 30 g of sodium chloroacetate and 15.5 g of sodium hydroxide, and the mixture was heated to 70° C. and stirred for 63 hours. The mixture was cooled to ambient temperature, and 300 mL of dichloromethane and 300 mL of purified water were poured into it and stirred for 1 hour. The reaction solution was filtered and washed with 100 mL of IPE (diisopropyl ether; diisopropyl ether) to obtain 28.1 g of 2-(octyloxy) sodium acetate compound. ( ¹ H NMR (CD ₃ OD, 400 MHz) δ 3.83 (s, 2H), 3.47 (t, J = 6.9 Hz, 2H), 1.64 ~ 1.57 (m, 2H), 1.39 ~ 1.30 (m, 10H), 0.90 (t, J = 6.9 Hz, 3H)). 2) Preparation of 2-(octyloxy)acetic acid

Add 40.3 g of 2-(octyloxy) sodium acetate prepared in step 1) above to 300 mL of ethyl acetate (EtOAc) in the reaction zone and stir, then pour 300 mL of 2M into it HCl aqueous solution and stirred at ambient temperature for 1 hour. The organic layer was obtained by layer separation, and then the aqueous layer was back-extracted again with 200 mL of ethyl acetate (EtOAc). The organic layer was washed with a saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The concentrated compound was dissolved in 200 mL of n-hexane, followed by stirring at -15°C for 1 hour. The precipitated solid was filtered and washed with 50 mL of cold n-hexane to obtain 28.1 g of 2-(octyloxy)acetic acid compound. ( ¹ H NMR (CDCl ₃ , 400 MHz) δ 4.11 (s, 2H), 3.56 (t, J = 6.7 Hz, 2H), 1.66 ~ 1.59 (m, 2H), 1.37 ~ 1.27 (m, 10H), 0.88 (t, J = 6.9 Hz, 3H)). 3) Preparation of 1-(chloromethoxy)octane (1-(chloromethoxy)octane; OMS-Cl)

10.0 g of 2-(octyloxy)acetic acid prepared in step 2) above was added to the reaction zone, then 20 mL of thiol chloride was poured into it, and the mixture was heated to reflux temperature and stirred for 3 hours. After the reaction was completed, the solvent was removed by distillation under reduced pressure, and 30 mL of toluene was poured into it, and the distillation under reduced pressure was repeated three times to obtain 9.5 g of 1-(chloromethoxy)octane compound . ( ¹ H NMR (CDCl ₃ , 400 MHz) δ 5.51 (s, 2H), 3.68 (t, J = 6.7 Hz, 2H), 1.65 ~ 1.58 (m, 2H), 1.37 ~ 1.26 (m, 10H), 0.88 (t, J = 6.8 Hz, 3H)). [Example 8] Preparation of donepezil octyloxymethyl ether (DOME) [1-benzyl-4-((5,6-dimethoxy-3-((octyloxy)methyl) Oxy)-1 H -inden-2-yl)methyl)piperidine]

13.4 g of Donepezil free base was added to the reaction zone, and then dissolved by pouring 100 mL of THF (tetrahydrofuran; tetrahydrofuran), and cooled to -78°C. Pour 53.1 mL of NaHMDS (1.0 M THF solution) into the reaction solution for 30 minutes and stir at -78°C for 1 hour. At the same temperature, 9.5 g of 1-(chloromethoxy)octane prepared in Example 7-3) above was dissolved in 20 mL of THF (tetrahydrofuran; tetrahydrofuran) and poured into the reaction solution for 30 minutes, The mixture was then gradually heated to ambient temperature and stirred for 15 hours.

The saturated aqueous ammonium chloride solution was poured into the reaction solution, and 100 mL of purified water was poured into it. The organic layer was obtained by layer separation, and then the aqueous layer was back-extracted once with 100 mL of ethyl acetate (EtOAc). The combined organic layer was washed once with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by silica column and then recrystallized from n-heptane to obtain 3.74 g of donepezil octyloxymethyl ether. ( ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.31 ~ 7.21 (m, 5H), 6.95 (s, 1H), 6.95 (s, 1H), 5.11 (s, 2H), 3.90 (s, 3H), 3.88 (s, 3H), 3.77 (t, J = 6.7 Hz, 2H), 3.48 (s, 2H), 3.14 (s, 2H), 2.86 (d, J = 11.4 Hz, 2H), 2.37 (d, J = 7.2 Hz, 2H), 1.91 (t, J = 10.6 Hz, 2H), 1.67 ~ 1.60 (m, 4H), 1.53 ~ 1.47 (m, 1H), 1.37 ~ 1.27 (m, 12H), 0.87 (t, J = 6.9 Hz, 3H)). [Example 9] Preparation of donepezil palmitate (DP) [2-((1-benzylpiperidin-4-yl)methyl)-5,6-dimethoxy-1 H- Inden-3-yl palmitate]

3.0 g of Donepezil free base was added to the reaction zone, followed by dissolving by pouring 36 mL of THF (tetrahydrofuran; tetrahydrofuran), and cooling to -78°C. Pour 11.9 mL of LiHMDS (1.0 M THF solution) into the reaction solution for 30 minutes and stir at -10°C for 50 minutes. The mixture was cooled to -78°C again, and 3.26 g of palmitoyl chloride was dissolved in 9 mL of THF (tetrahydrofuran; tetrahydrofuran) and poured into the reaction solution for 30 minutes, then the mixture was gradually heated to ambient temperature and Stir for 15 hours.

A saturated aqueous ammonium chloride solution was poured into the reaction solution, and purified water was poured therein. The organic layer was obtained by layer separation, and then the aqueous layer was back-extracted twice with 40 mL of ethyl acetate (EtOAc). The combined organic layer was washed twice with 100 mL of saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by silica column to obtain 435 mg of Donepezil palmitate. ( ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.32 ~ 7.21 (m, 5H), 6.96 (s, 1H), 6.57 (s, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.47 (s, 2H), 3.24 (s, 2H), 2.86 (d, J = 11.5 Hz, 2H), 2.59 (t, J = 7.5 Hz, 2H), 2.26 (d, J = 7.1 Hz, 2H), 1.90 (t, J = 10.6 Hz, 2H), 1.83 ~ 1.75 (m, 2H), 1.51 ~ 1.26 (m, 29H), 0.88 (t, J = 6.9 Hz, 3H)). [Example 10] Preparation of Donepezil composition

實例9 (DP)  

實例2 (DMME)  

實例4 (DLME)  

實例6 (DDME)  

實例8 (DOME)  

The solution phase composition uses Donepezil (D), Example 9 (DP), Example 2 (DMME), Example 4 (DLME), Example 6 (DDME), and Example 8 (DOME) having the structure of Table 1 below. To prepare. [Table 1] Types of structure Donepezil (D), 2-((1-benzylpiperidin-4-yl)methyl)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one

Example 9 (DP)

Example 2 (DMME)

Example 4 (DLME)

Example 6 (DDME)

Example 8 (DOME)

Mix the main ingredients (D, DP, DMME, DLME, DDME, and DOME) in Table 1 above, castor oil, and benzyl benzoate in the composition and contents of Table 2 below and stir at ambient temperature for 0.5 -3 hours to prepare the solution phase composition. [Table 2] (Unit: mg) D DP DMME DLME DDME DOME Main ingredients* 137 223 218 208 198 188 castor oil 1,200 1,200 1,200 1,200 1,200 1,200 Benzyl benzoate 1,800 1,800 1,800 1,800 1,800 1,800 *Corresponds to the equivalent dose of donepezil [Experimental Example 1] Pharmacokinetic evaluation

The composition prepared in Example 10 above was injected intramuscularly into 4 male SD rats with an average weight of 300 g at a dose corresponding to 4 mg donepezil/kg.

The concentration of donepezil in plasma samples of SD rats after intramuscular injection was analyzed using LC-MS/MS, and the results are shown in Table 3 and Figures 1 to 6 below. [table 3] D DP DMME DLME DDME DOME C max (ng/mL) 27.5 2.4 0.6 3.3 2.8 4.3 AUC _last (ng•d/mL) 367.6 213.3 459.1 389.8 806.6 713.1

As shown in Table 3 and Figure 1 above, when donepezil (D) is administered, the initial release (initial burst) is very high as 27.5 ng·d/mL and may cause side effects or toxicity. It is confirmed that it is not suitable as a sustained-release composition because the release is completed within one day.

In addition, as shown in Table 3 and Figure 2, when Example 9 (DP) was administered, the initial release (initial burst) was 2.4 ng·d/mL, which was four times higher than that of Example 2 (DMME). Confirm that it is likely to cause side effects or toxicity.

On the other hand, as shown in Table 3 and Figure 3, when Example 2 (DMME) was administered, the initial release (initial burst) was 0.6 ng·d/mL, which was the lowest value. Confirm that there is a small difference between the maximum blood concentration (Cmax) and the maintenance concentration. In addition, unlike the administration of Donepezil (D), it was confirmed that Example 2 (DMME) even maintained effective blood concentration for 8 weeks or longer by a single administration.

In addition, as shown in Table 3 and Figure 4, when Example 4 (DLME) was administered, the initial release (initial burst) was 3.3 ng·d/mL, which was at least five times higher than Example 2 (DMME). It was confirmed that the period of maintaining effective blood concentration was shorter than that of Example 2 (DMME).

In addition, as shown in Table 3 and Figure 5, when Example 6 (DDME) was administered, the initial release (initial burst) was 2.8 ng·d/mL, which was at least four times higher than Example 2 (DMME). It was confirmed that the period of maintaining effective blood concentration was shorter than that of Example 2 (DMME).

In addition, as shown in Table 3 and Figure 6, when Example 8 (DOME) was administered, the initial release (initial burst) was 4.3 ng·d/mL, which was at least seven times higher than Example 2 (DMME). It was confirmed that the period of maintaining effective blood concentration was shorter than that of Example 2 (DMME).

Therefore, it can be found that Donepezil myristyloxy methyl ether (DMME) exhibits a better release pattern than Donepezil and Donepezil palmitate. In addition, it can be found that among the fatty alcohol ethers of donepezil, the myristyloxymethyl ether of donepezil has a low initial release concentration and maintains a sustained release for a longer period of time, and therefore, has a maximum The excellent properties of reducing the risk of side effects (including toxic reactions) and maintaining the effective concentration of the therapeutic drug for a long period of time only by a single administration.

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Figure 1 shows the results of measuring the blood concentration of donepezil (donepezil; D) after administration of donepezil to rats.

Figure 2 shows the results of measuring the blood concentration of donepezil after administering donepezil palmitate (DP) to rats.

Figure 3 shows the results of measuring the blood concentration of donepezil after administering donepezil myristyloxymethyl ether (DMME) to rats.

Figure 4 shows the results of measuring the blood concentration of donepezil after administering donepezil lauryloxymethyl ether (DLME) to rats.

Figure 5 shows the results of measuring the blood concentration of donepezil after administering donepezil decyloxymethyl ether (DDME) to rats.

Figure 6 shows the results of measuring the blood concentration of donepezil after administering donepezil octyloxymethyl ether (DOME) to rats.

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Claims (6)

A 1-benzyl-4-((5,6-dimethoxy-3-((tetradecyloxy)methoxy)-1 H -inden-2-yl) represented by the following formula 1 (Methyl) piperidine or its pharmacologically acceptable salt. [Formula 1]

A sustained-release pharmaceutical composition for the prevention or treatment of dementia, which comprises 1-benzyl-4-((5,6-dimethoxy-3-((tetradecyl) represented by the following formula 1 ) methoxy) -1 H - inden-2-yl) methyl) piperidine or the pharmacologically acceptable salt thereof. [Formula 1]

The sustained-release pharmaceutical composition for preventing or treating dementia according to claim 2, characterized in that the composition is for injection administration every 8 to 12 weeks. The sustained-release pharmaceutical composition for preventing or treating dementia according to claim 3, which is characterized in that the composition is used for intramuscular injection. A kind for the preparation of 1-benzyl-4-((5,6-dimethoxy-3-((tetradecyloxy)methoxy)-1 H -inden-2-yl)methyl) The piperidine method includes the step of reacting donepezil free base with 1-(chloromethoxy)tetradecane. For the preparation of 1-benzyl-4-((5,6-dimethoxy-3-((tetradecyloxy)methoxy)-1 H -indene-2 as described in claim 5 -(Yl)methyl)piperidine is characterized in that 1-(chloromethoxy)tetradecane is prepared by a process including the following steps: (i) 1-tetradecanol, sodium chloroacetate, and The step of mixing sodium hydroxide to obtain sodium 2-(tetradecyloxy)acetate; (ii) reacting sodium 2-(tetradecyloxy)acetate with 2M aqueous HCl to obtain 2-(tetradecane The step of oxy)acetic acid; and (iii) the step of reacting 2-(tetradecyloxy)acetic acid with sulfite chloride.

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