Donepezil derivative and use thereof

Abstract

The present invention relates to a donepezil derivative of general formula (I) or a pharmaceutically acceptable salt thereof, wherein R in the formula is as disclosed herein; and a method for preparation thereof; and a composition comprising an effective amount of a compound of the general formula (I) or a pharmaceutically acceptable salt thereof. The present invention also relates to use of a compound of the general formula (I) or a pharmaceutically acceptable salt thereof in preparing a medicament for treating a disease resulted from an abnormality in acetylcholinesterase activity. ##STR00001##

Claims

1. A compound of formula (I): ##STR00006## or a pharmaceutically acceptable salt thereof, wherein R is C.sub.7 alkyl group.

2. A method of treating dementia in a patient, comprising: administering a compound according to claim 1 or a pharmaceutically acceptable salt thereof to said patient.

3. A pharmaceutical composition, comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

4. The pharmaceutical composition of claim 3, wherein the excipient is selected from one or more of castor oil, soybean oil, sesame oil, arachis oil, corn oil, cottonseed oil, or glycerides.

5. The pharmaceutical composition of claim 3, further comprising a hydrotropic agent, the hydrotropic agent being selected from one or more of benzyl benzoate or alcohols.

6. The pharmaceutical composition according to claim 3, further comprising a pain relief agent, the pain relief agent being selected from benzyl alcohol.

7. The pharmaceutical composition of claim 4, wherein the excipient is castor oil.

8. The pharmaceutical composition of claim 5, wherein the hydrotropic agent is benzyl benzoate.

Description

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

(1) FIG. 1 shows the relationship between drug concentration in plasma and time in the group of rats administered with donepezil.

(2) FIG. 2 shows the relationship between drug concentration in plasma and time in the group of rats administered with compound 1.

(3) FIG. 3 shows the relationship between drug concentration in plasma and time in the group of rats administered with compound 3.

(4) FIG. 4 shows the relationship between drug concentration in plasma and time in the group of rats administered with compound 4.

(5) FIG. 5 shows the relationship between drug concentration in plasma and time in the group of rats administered with compound 6.

DETAILED DESCRIPTION OF THE INVENTION

(6) In order to describe the present invention in more detail, the following preparation examples are given. However, the scope of the present invention is not limited thereto.

Example 1

(7) Compound 1: Preparation of Donepezil Acetate

(8) Donepezil (50.0 g, 132 mmol) was added to a 2,000 ml three-neck round-bottom flask (equipped with an argon protection, a thermometer, a mechanical stirrer, and a constant pressure dropping funnel), the air was replaced with nitrogen, and 600 ml of anhydrous tetrahydrofuran was added and stirred to dissolve. Then cool the system temperature to 60 to 78 C. Lithium bis(trimethylsilyl)amide (200 ml, 1.0 mol/L, 200 mmol) was added to a constant pressure dropping funnel through a double-ended needle rapidly at once time. After stirring at 60 to 78 C. for 15 to 30 minutes, the temperature was naturally raised to 0 to 10 C. The system temperature was then lowered to 60 to 78 C. Acetic anhydride (20.4 g, 200 mmol) was dissolved in 200 ml of anhydrous tetrahydrofuran and added to a constant pressure dropping funnel rapidly at once time. After stirring at 60 to 78 C. for 30 minutes, the temperature was naturally raised to room temperature (2030 C.). Examine complete reaction by TLC. The reaction system was placed in an iced water bath and 250 ml of saturated ammonium chloride solution was added dropwise. After completing the dropwise addition, the mixture was transferred to a separatory funnel and removal of the aqueous layer, and then wash once with 250 ml of 20% sodium chloride solution. Wash with 250 ml of saturated sodium chloride solution and then the mixture was transferred to a separatory funnel and removal of the aqueous layer. The organic phase was dried by anhydrous sodium sulfate and the solvent is removed under reduced pressure. Crystallization was done by using 500 ml of isopropanol, and 41 g of a white solid (yield: 73.7%) was obtained. HPLC (aera): 95.71%.

(9) Mass spectrum (m/z): [M+H].sup.+=422.3.

(10) .sup.1H-NMR (CDCl.sub.3) : 7.33-7.29 (4H, d), 7.25-7.27 (1H, m), 6.99 (1H, s), 6.62 (1H, s), 3.90 (3H, s), 3.90 (3H, s), 3.50 (2H, s), 3.27 (2H, s), 2.88-2.91 (2H, d), 2.36 (3H, s), 2.29-2.31 (2H, d), 1.92-1.97 (2H, t), 1.66-1.69 (2H, d), 1.51-1.52 (1H, m), 1.29-1.35 (2H, m).

Example 2

(11) Compound 2: Preparation of Donepezil Hexanoate

(12) Donepezil (25.0 g, 65.9 mmol) was added to an 1,000 ml three-neck round-bottom flask (equipped with an argon protection, a thermometer, a mechanical stirrer, and a constant pressure dropping funnel), the air was replaced with nitrogen, and 300 ml of anhydrous tetrahydrofuran was added and stirred to dissolve. Then the system temperature was cooled to 60 to 78 C. Lithium bis(trimethylsilyl)amide (100 ml, 1.0 mol/L, 100 mmol) was added to a constant pressure dropping funnel through a double-ended needle rapidly at once time. After stirring at 60 to 78 C. for 15 to 30 minutes, the temperature was naturally raised to 0 to 10 C. The system temperature was then lowered to 60 to 78 C. Then caproic anhydride (21.4 g, 100 mmol) was dissolved in 100 ml of anhydrous tetrahydrofuran and added to a constant pressure dropping funnel rapidly at once time. After stirring at 60 to 78 C. for 30 minutes, the temperature was naturally raised to room temperature (2030 C.). Examine complete reaction by TLC. The reaction system was placed in an iced water bath and 250 ml of saturated ammonium chloride solution was added dropwise. After completing the dropwise addition, the mixture was transferred to a separatory funnel and removal of the aqueous layer, and then wash once with 250 ml of 20% sodium chloride solution. Wash with 250 ml of saturated sodium chloride solution and then the mixture was transferred to a separatory funnel and removal of the aqueous layer. The organic phase was dried by anhydrous sodium sulfate and the solvent was removed under reduced pressure. 29.3 g of oily substance was obtained (yield: 93%). Insolubles were removed from the oily substance by heating and dissolving in 225 ml of n-heptane and then filtrating. Subsequently, 22.5 ml of ethanol was added and subjected to cooling crystallization. Keep temperature under 5 to 10 C. for 1 hour and then perform filtration. Wash with 50 ml of cold n-heptane/ethanol (10:1) and drain. Perform vacuum drying to obtain 21.0 g of grey solid (yield: 66.7%), with HPLC (aera): 99.08%.

(13) Mass spectra (m/z): [M+H].sup.+=478.4.

(14) .sup.1H-NMR (CDCl.sub.3) : 7.32-7.31 (4H, d), 7.25-7.27 (1H, m), 6.98 (1H, s), 6.60 (1H, s), 3.89 (6H, s), 3.49 (2H, s), 3.26 (2H, s), 2.86-2.89 (2H, d), 2.60-2.64 (2H, t), 2.28-2.29 (2H, d), 1.91-1.93 (2H, t), 1.81-1.84 (2H, t), 1.65-1.68 (2H, t), 1.20-1.60 (7H, m), 0.95-0.97 (3H, t).

Example 3

(15) Compound 3: Preparation of Donepezil Heptanoate

(16) The preparation process was the same as that of Example 2. Donepezil (40.0 g, 105.4 mmol) was reacted with heptanoic anhydride (38.82 g, 242.4 mmol) to obtain 42.30 g of donepezil heptanoate (yield: 81.7%) with HPLC (aera): 98.2%.

(17) Mass spectrum (m/z): [M+H].sup.+=492.4.

(18) .sup.1H-NMR (CDCl.sub.3) : 7.32-7.31 (4H, d), 7.26-7.27 (1H, m), 6.98 (1H, s), 6.59 (1H, s), 3.89 (3H, s), 3.90 (3H, s), 3.50 (2H, s), 3.26 (2H, s), 2.87-2.89 (2H, d), 2.60-2.64 (2H, t), 2.27-2.29 (2H, d), 1.90-1.93 (2H, t), 1.80-1.83 (2H, t), 1.65-1.68 (2H, t), 1.20-1.60 (9H, m), 0.90-0.96 (3H, t).

Example 4

(19) Compound 4: Preparation of Donepezil Octanoate

(20) The preparation process was the same as that of Example 2. Donepezil (46.16 g, 121.6 mmol) was reacted with octanoic anhydride (38.82 g, 242.4 mmol) to obtain 46.0 g of donepezil octanoate (yield: 74.8%) with HPLC (aera): 98.2%.

(21) Mass spectrum (m/z): [M+H].sup.+=506.4.

(22) .sup.1H-NMR (CDCl.sub.3) : 7.32-7.31 (4H, d), 7.26-7.27 (1H, m), 6.98 (1H, s), 6.59 (1H, s), 3.89 (3H, s), 3.90 (3H, s), 3.49 (2H, s), 3.26 (2H, s), 2.86-2.89 (2H, d), 2.60-2.63 (2H, t), 2.27-2.29 (2H, d), 1.90-1.96 (2H, t), 1.80-1.83 (2H, t), 1.65-1.68 (2H, t), 1.10-1.60 (11H, m), 0.90-0.96 (3H, t).

Example 5

(23) Compound 5: Preparation of Donepezil Nonanoate

(24) The preparation process was the same as that of Example 2. Donepezil (19.0 g, 50.1 mmol) was reacted with nonanoic anhydride (22.7 g, 76.2 mmol), and subjected to post-processing. Insolubles were removed by filtration before crystallization, and the crystallization temperature was 15 to 20 C. 17.8 g of the compound donepezil nonanoate was obtained (yield: 68.3%) with HPLC (area): 98.15%.

(25) Mass spectrum (m/z): [M+H].sup.+=520.4.

(26) .sup.1H-NMR (CDCl.sub.3) : 7.32-7.31 (4H, d), 7.25-7.26 (1H, m), 6.98 (1H, s), 6.59 (1H, s), 3.896 (3H, s), 3.889 (3H, s), 3.49 (2H, s), 3.26 (2H, s), 2.86-2.89 (2H, d), 2.60-2.63 (2H, t), 2.27-2.29 (2H, d), 1.91-1.96 (2H, t), 1.81-1.85 (2H, t), 1.65-1.68 (2H, t), 1.18-1.65 (13H, m), 0.88-0.91 (3H, t).

Example 6

(27) Compound 6: Preparation of Donepezil Decanoate

(28) The preparation process was the same as that of Example 2. Donepezil (25.0 g, 65.9 mmol) was reacted with decanoic anhydride (32.6 g, 100 mmol), and subjected to post-processing. Insolubles were removed by filtration before crystallization. 21.9 g of the compound donepezil decanoate was obtained (yield: 62.2%) with HPLC (area): 98.15%.

(29) Mass spectrum (m/z): [M+H].sup.+=534.4.

(30) .sup.1H-NMR (CDCl.sub.3) : 7.32-7.31 (4H, d), 7.26-7.28 (1H, m), 6.98 (1H, s), 6.59 (1H, s), 3.891 (3H, s), 3.899 (3H, s), 3.49 (2H, s), 3.26 (2H, s), 2.86-2.89 (2H, d), 2.60-2.63 (2H, t), 2.27-2.29 (2H, d), 1.90-1.94 (2H, t), 1.80-1.83 (2H, t), 1.65-1.68 (2H, t), 1.30-1.62 (15H, m), 0.89-0.93 (3H, t).

Example 7

(31) Compound 7: Preparation of Donepezil Dodecanoate

(32) The preparation process was the same as that of Example 2. Donepezil (15.0 g, 39.5 mmol) was reacted with dodecanoic anhydride (23.0 g, 60.0 mmol), and subjected to post-processing. Insolubles were removed by filtration before crystallization. 14.3 g of the compound donepezil dodecanoate was obtained (yield: 64.4%) with HPLC (area): 98.15%.

(33) Mass spectrum (m/z): [M+H].sup.+=562.4.

(34) .sup.1H-NMR (CDCl3) : 7.32-7.30 (4H, d), 7.26-7.27 (1H, m), 6.98 (1H, s), 6.59 (1H, s), 3.890 (3H, s), 3.899 (3H, s), 3.50 (2H, s), 3.26 (2H, s), 2.87-2.90 (2H, d), 2.59-2.63 (2H, t), 2.27-2.29 (2H, d), 1.91-1.97 (2H, t), 1.79-1.83 (2H, t), 1.65-1.68 (2H, t), 1.28-1.49 (19H, m), 0.90-0.92 (3H, t).

Example 8

(35) Compound 8: Preparation of Donepezil Tetradecanoate

(36) The preparation process was the same as that of Example 2. Donepezil (2.00 g, 5.27 mmol) was reacted with tetradecanoaic anhydride (3.5 g, 8.00 mmol), and subjected to post-processing. Insolubles were removed by filtration before crystallization. 1.93 g of the compound donepezil tetradecanoate was obtained (yield: 62.0%) with HPLC (area): 98.15%.

(37) Mass spectrum (m/z): [M+H].sup.+=590.5.

(38) .sup.1H-NMR (CDCl3) : 7.32-7.30 (4H, d), 7.26-7.27 (1H, m), 6.98 (1H, s), 6.59 (1H, s), 3.890 (3H, s), 3.899 (3H, s), 3.51 (2H, s), 3.26 (2H, s), 2.87-2.90 (2H, d), 2.60-2.63 (2H, t), 2.27-2.29 (2H, d), 1.91-1.97 (2H, t), 1.81-1.83 (2H, t), 1.65-1.68 (2H, t), 1.28-1.49 (23H, m), 0.88-0.92 (3H, t).

Example 9

(39) Compound 9: Preparation of Donepezil Hexadecanoate

(40) The preparation process was the same as that of Example 2. Donepezil (30.0 g, 79.1 mmol) was reacted with hexadecanoic anhydride (58.7 g, 119 mmol), and subjected to post-processing. Insolubles were removed by filtration before crystallization. 38.0 g of the compound donepezil hexadecanoate was obtained (yield: 79.5%) with HPLC (area): 98.15%.

(41) Mass spectrum (m/z): [M+H].sup.+=618.5.

(42) .sup.1H-NMR (CDCl3) : 7.32-7.31 (4H, d), 7.25-7.27 (1H, m), 6.98 (1H, s), 6.59 (1H, s), 3.90 (3H, s), 3.89 (3H, s), 3.49 (2H, s), 3.26 (2H, s), 2.86-2.89 (2H, d), 2.60-2.63 (2H, t), 2.28-2.29 (2H, d), 1.90-1.96 (2H, t), 1.80-1.83 (2H, t), 1.65-1.68 (2H, t), 1.28-1.55 (29H, m), 0.88-0.92 (3H, t).

Example 10

(43) Compound 10: Preparation of Donepezil Octadecanoate

(44) The preparation process was the same as that of Example 2. Donepezil (2.00 g, 5.27 mmol) was reacted with octadecanoic anhydride (4.40 g, 8.00 mmol), and subjected to post-processing. Insolubles were removed by filtration before crystallization. 2.13 g of the compound donepezil octadecanoate was obtained (yield: 62.6%) with HPLC (area): 98.15%.

(45) Mass spectrum (m/z): [M+H].sup.+=646.5.

(46) .sup.1H-NMR (CDCl3) : 7.32-7.30 (4H, d), 7.25-7.27 (1H, m), 6.98 (1H, s), 6.59 (1H, s), 3.890 (3H, s), 3.898 (3H, s), 3.50 (2H, s), 3.26 (2H, s), 2.87-2.89 (2H, d), 2.60-2.63 (2H, t), 2.27-2.29 (2H, d), 1.91-1.96 (2H, t), 1.81-1.83 (2H, t), 1.66-1.68 (2H, t), 1.28-1.60 (31H, m), 0.88-0.92 (3H, t).

Example 11

(47) Formulation:

(48) TABLE-US-00001 Component Formulation amount compound 4 100 mg benzyl benzoate 200 mg benzyl alcohol 100 mg castor oil .sup.1 ml

(49) Preparation Process:

(50) Compound 4, benzyl alcohol, and benzyl benzoate of respective formulation amounts were dissolved in castor oil. Stir until the substances were completely dissolved. 0.22 m filter membrane was used for filter sterilization. Stopper and cap to obtain oily preparations.

Example 12

(51) Pharmacokinetic Properties of Compounds of the Present Invention Administered to Rats

(52) In the present embodiment, male SD rats (SPF grade), aged 9 months and weighing 180 to 220 g, were purchased from Shanghai Slack laboratory Animal Co., Ltd. Throughout the process of the experiment, give the rats free access to food and water.

(53) Adopting grouping of random grouping design, the SD rats for experiments were grouped according to gender and body weight. They were divided into donepezil group, compound 1 group, compound 3 group, compound 4 group, and compound 6 group. Rats of each group were administered by intramuscular injection (i.m.) with the dose set at 90 mg/kg (based on donepezil). The samples were dissolved in oil solvent at a concentration of 90 mg/ml (based on donepezil).

(54) At 4 h, 8 h, 24 h (2 days), 3 days, 4 days, 5 days, 7 days, 9 days, 12 days after administration, 0.5 ml of venous blood was collected from ocular fundus venous plexuses and placed into a pre-labeled EDTA (4 mM) anticoagulated EP tube. The whole blood was collected and placed on ice, followed by centrifugation at 4 C., 8000 rpm and 5 mM to collect plasma The plasma was transferred to a 96-well plate and stored at 20 C. until LC-MS/MS examination. Drug concentrations in EDTA (4 mM) anticoagulated plasma of SD rats were determined using LC/MS/MS (Agilent6460). Concentration v.s. time curves of each group are shown in FIGS. 1-5. Using WinNonlin 5.2 software, calculate respective relevant pharmacokinetic parameters of each group at each time point after administration according to statistical moment theory. See Table 1 for the details.

(55) TABLE-US-00002 TABLE 1 com- com- com- com- donepezil pound 1 pound 3 pound 4 pound 6 group group group group group T.sub.1/2, hr 13.34 22.76 314.18 426.92 287.47 T.sub.max, hr 0.67 6.00 18.00 18.00 24.00 C.sub.max, ng/ml 361.10 243.17 44.11 30.80 41.60 C.sub.max and T.sub.max were represented in measured values. t.sub.1/2 was calculated by the formula t.sub.1/2 = 0.693/z; z is an end elimination rate constant derived from the logarithmic concentration - the straight part of the end of time curve, which can be derived from the slope of the logarithmic concentration - the straight part of the end of time curve.

(56) Conclusion: From the above experimental results, it can be seen that the compounds of the present invention have the advantages of long half-life and avoiding rapid increase of plasma drug concentration.

(57) The foregoing are only preferred embodiments of the present invention. It ought to be noted that several improvements and modifications may be made by those skilled in the art without departing from the principles of the present invention. These improvements and modifications should be regarded as the scope of protection by the present invention.