RU1816283C - Process for preparing 4-aminopyridine derivatives - Google Patents

Abstract

Compounds of formula (I), wherein R<1>, R<2>, A and B are defined hereinbelow. The compounds of the present invention inhibit brain acetylcholinesterase and are useful in the treatment of Alzheimer's disease.

Description

These properties make it possible to suggest their use in medicine.

An object of the present invention is to provide novel 4-aminopyridine derivatives having higher biological activity.

This objective is that the compound of formula II

CN

oo

where A and B are as defined above, are cyclized in the presence of a base.

Example. 9-amino-1,2,3,4-tetrahydro-1,4-methanoacridine.

A solution of anthranilonitrile (3.6 g, 30.0 mmol), mink headlights (3.3 g, 30.0 mmol) and p-toluenesulfonic acid (50 mg) in benzene (50 ml) are heated by boiling in a Dean device -Stark. After heating for 18 hours, the reaction mixture was cooled (25 ° C) and the separated water (approximately 1.5 ml) was removed. Then, excess benzene was distilled off in vacuo (1 mmHg, 15 minutes). The oily residue thus obtained was dissolved in tetrahydrofuran (THF, 10 ml) and cooled to 0 ° C, then a solution of lithium diisopropylamide in THF (1 M, 36 ml, 36 mmol) was added. Then this reaction mixture is stirred at a temperature of 0 ° C for 3 hours. At the end of this time, the reaction was stopped by adding 40 ml of water to the reaction mixture and the reaction mixture was extracted with methylene chloride (200 ml). The resulting organic phase was washed with water (2 x 50 ml) and dried (anhydrous magnesium sulfate). Methylene chloride was distilled off in vacuo to give a residue, which was placed on a flash chromatography silica gel column. 5% methanol in methylene chloride containing 1% triethylamine was eluted and the target product was obtained in an amount of 1.6 g (25%) as an oil that hardens upon standing. T. pl. 185-186 ° C.

Example 2. 9-amino-8-fluoro-1,2.3,4-tetrahydro-1,4-methanoacridine.

By the procedure described in Example 1, but with the replacement of anthranilonitrile with 2-amino-6-fluorobenzonitrile, the desired product is obtained. 23% mp 173 ° C.

Example 3. 9-amino-7-chloro-1,2,3,4-tetrahydro-1,4-methanoacridine.

By the method described in example 1, but with the replacement of anthranilonitrile with 2-amino-5-chlorobenzonitrile, the desired product is obtained, 14%, mp 183-184 ° C.

PRI me R 4. 9-amino-1,4-dihydro-1,4-methanoacridine

By the methodology described in example 1, but with the replacement of mink headlights with 5-norbornene-2- he received the target product 26%. t. pl. 123 ° C.

Example 5.9-Amino-2-oxa-1,2,3,4-tetrahydroacridine.

Anthranilonitrile (2.95 g, 25 mmol), zinc chloride (3.1 g, 25 mmol) and tetrahydro-4H-pyran-4-one were dissolved in toluene (40 ml) and heated with reflux for 2.5 days . TO

At the end of this period, the reaction mixture was cooled (25 ° C), diluted with an aqueous solution of sodium hydroxide (70 ml) and extracted with methylene chloride (4 x 60 ml). The combined organic phases are washed with water (2 x 100 ml) and dried (anhydrous magnesium sulfate). The organic solvents were removed in vacuo to give a yellow residue, which was loaded onto a silica gel flash chromatography column. Elute 5% methanol in methylene chloride to obtain the desired product in the form of yellow crystals, 155 mg, 31%, mp 195-196 ° C.

Example 6. 9-amino-2-thia-1,2,3,4-tet0 rahydroacridine.

Anthranilonitrile (2.6 g, 21.5 mmol), tetrahydrothiopyran-4-one (5.0 g, 43 mmol) and zinc chloride (2.54 g, 21.5 mmol) are combined and heated to a temperature of 120 ° C. for 20 minutes. The reaction mixture was cooled to a solid residue, filtered using ethyl ether (100 ml). The obtained orange solid (5.2 g) was placed in a beaker,

0 containing a saturated solution of EDTA (ethylenediaminetetraacetic acid) in water (125 ml) and the pH was adjusted to 13 with a 12% aqueous sodium hydroxide solution. The aqueous phase is then extracted with methylenex5 loride (4 x 50 ml) and the extract is washed with water (2 x 70 ml) and dried (magnesium sulfate). After removal of methylene chloride in vacuo, a yellow paste (2.0 g) is obtained, which is triturated with ether and filtered, a pale yellow solid, 1.36 g, 29%, mp. 205 ° C (decomposes). Example. 9-amino-4-oxa-1,2,3,4-tetrahydroacridine.

To mix at temperature

A solution of delta% valerolactone (1.0 g, 10.0 mmol) in methylene chloride (10 ml) was added with a 1 M solution of titanium (IV) chloride in methylene chloride (20 ml). The reaction mixture turned a dark yellow color, and a mixture of triethylamine (2.0 g, 20

mmol) and zntranilonitrile (1.2 g, 10.0 mmol) in methylene chloride (30 ml). The reaction mixture immediately darkens, it is allowed to warm to room temperature (approximately 25 ° C) and then stirred for 15 hours. At the end of this period, the reaction mixture was treated with a 25% aqueous solution of sodium hydroxide (40 ml) and methylene chloride (100 ml) and filtered through a 2 inch thick pad of diatomaceous earth (trade name Celite, Ceflt), which was washed with methylene chloride (50 ml) and water (100 ml). The organic layer was separated, washed once with water (30 ml) and dried (anhydrous magnesium sulfate). Methylene chloride was distilled off in vacuo to give an oil which was triturated with ether to give the desired product as a white solid, 565 mg, 28%.

1 H NMR (CDCI 3. 300 MHz, d); 2H, t, 2.02-2.18 ppm „-2H, t, 2.63 ppm (J 6.0Hz); 2H, t, 4.36 ppm. 0 6.0 Hz); 2H, S, 4.64 ppm; IH, t, 7.25 (f 9.0 Hz), IH. t, 7.5Q 8.0 Hz); IH, d, 7.72 (I - 8.0 Hz).

An example. 9-amino-8-fluoro-4-oxa-1,2,3,4-tetrahydroacridine.

By the method described in example 7. but with the replacement of anthranilonitrile with 2-amino-6-fluorobenzonitrile, the desired product is obtained, 8%, mp. 195-196 ° C.

PRI me R 9. 9-amino-7-chloro-4-oxa-1,2,3,4-tetrahydroacridine.

By the method described in example 7, but with the replacement of anthranilonitrile with 2-amino-5-chlorobenzonitrile, the desired product is obtained, 2%, mp. 2 78-279 ° C.

Example 10. 9-amino-4-oxa-1,2,3,4,5,6,7,8-octahydroacridine.

By the method described in example 7, but with the replacement of anthranilonitrile with 2-amino-1-cyano-1-cyclohexene, the target product is obtained, 8%, mp. 145 ° C.

Example 11.9-Amino-2,3,7,8-tetrahydro-1H-cyclopenta (e) -6H-pyrano (-) 2, 3-c) pyridine.

According to the method described in example 7, but with the replacement of anthranilonitrile with 2-amino-1-cyano-1-cyclopentene, the desired product is obtained, 22%, mp 164 ° C.

Example 12. 2,3-Dihydrothieno (3,2-c) quinolin-9-amine.

To a solution of tetrahydrothiophen-3-one (1.1 g, 11 mol) in methylene chloride (10 ml) stirred at -78 ° C was added a 1 M solution of titanium (IV) chloride in methylene chloride (11 ml). Then, a mixture of triethylamine (2.2 g, 22 mmol) and anthranilonitrile (1.2 g, 10.0 mmol) in methylene chloride (30 ml) was added to the reaction mixture over 5 minutes, after which the reaction mixture was slowly warmed to room temperature and stirred for 2 hours. Then, rahydrothiophen-3-one (1 ml) and titanium (IV) chloride (1.0 ml) were added to the tet5 reaction mixture, and the mixture was stirred at 25 ° C for 16 hours. Then a 12% aqueous solution of sodium hydroxide (100 ml) was quickly added to the reaction mixture,

0 after which the reaction mixture was vigorously stirred with an additional amount of methylene chloride (300 ml). The reaction mixture was then filtered through a diatomaceous earth (trade name Celite) and the organic phase was separated. The organic solvents were removed in vacuo to give a residue, which was loaded onto a flash chromatography column. Elute 5% methanol in methylene chloride containing 1%

0 triethylamine, and get the target product. (13 g, 64%), which crystallizes from chloroform, 560 mg, 32%. so pl. 208-210 ° C.

Example 13.9-amino-1,2,3,4.5,6,7,8-octahydro-1,4-methanoacridine

5 A mixture of triethylamine (1.7 g, 16.4 mmol) and 2-amino-1- was added to a solution of norkormora (0.9 g, 8.2 mmol) in methylene chloride (8.0 ml) stirred at -20 ° C. cyano-1-cyclohexene (1.0 g, 8.2

0 mmol) in methylene chloride (24 ml) and the resulting mixture was stirred at 25 ° C for 15 minutes. Then a 12% aqueous solution of sodium hydroxide (60 ml) was quickly poured into the reaction mixture and vigorously stirred with methylene chloride (60 ml). After that, the reaction mixture is filtered through a 2-inch-thick diatomaceous earth pad (trade name Celite). The organic phase is separated

0 was washed with water (2 x 50 ml) and then dried (anhydrous magnesium sulfate). Then, methylene chloride is removed under reduced pressure to give an oil, which is triturated with pentane to give the desired product in the form

5 whitish solid, 225 mg, 13%, mp. 131-133 ° C.

PRI me R 14.9-amino-6-aza-1,2,3,4-tetrahydroacridine.

Titanium (IV) chloride (1.5 ml) is added to

To a stirred solution of 3-amino-4-cyanopyridine (500 mg, 4.2 mmol) and cyclohexanone (0.05 ml) in 1,2-dichloroethane (15 ml). Then the reaction mixture was kept at a temperature of 90 ° C for 12 hours. TO

At the end of this period, cyclohexanone (2.0 ml) and 1,2-dichloroethane (5.0 ml) were added to the reaction mixture, and heating was continued for another 12 hours. Then additional quantities of cyclohexanone (2.0 ml) and titanium (IV) chloride (1.2 ml) were added and the reaction mixture was kept at 90 ° C for b hours. Then the reaction mixture was cooled and 5% was quickly added to it. aqueous sodium hydroxide solution (25 ml) and vigorously stirred with methylene chloride (200 ml, 25 min). Then the reaction mixture is treated as described in example 8, and the desired product (170 mg, 95% pure, 20%) is obtained after flash chromatography on silica gel (eluent 95: 5: 1 methylene chloride: methanol-ammonium hydroxide) . This material is further purified by chromatography and get the target product, 75 mg, so pl. 180-181 ° C.

PRI me R 15.9-Amino-5-aza-1,2,3,4-tetrahydroacridine

By the method described in example 12, but with the replacement of 3-amino-4-cyanopyridine with 2-amino-3-cyanopyridine, the desired product is obtained, 38%, mp. 225-228 ° C (decomposes).

W-NMR (CDCI3 + CD3OD, 300 MHz, d): 4H, bS, 1.8 bpm;

2H, Bt, 2.5 ppm; 2H, Bt, 2.97 ppm; 2H, veS, 3.0-3.3 ppm;

IH, dd, 7.2 ppm. 0 8.04.0 Hz); IH, dd, 8.18 ppm.

About 8.0. 1-2 Hz); IH, dd, 8.77 ppm. O - 4.0, 1-2 Hz).

Example 16. 9-amino-4,5-oxase-1,2,3,4-tetrahydroacridine

To a stirred solution of 2-amino-3-cyanopyridine (360 mg, 3.0 mmol) and delta-valerolactor (360 mg, 3.6 mmol) in 1,2-dichloroethane (7.0 ml), titanium chloride (IV) (0.9 ml), after which the reaction mixture was kept at a temperature of 90 ° C for 18 hours. After that, the reaction mixture was quickly cooled by adding 15% aqueous sodium hydroxide solution (200 ml) and stirred vigorously with methylene chloride (200 ml, 25 min). Then the reaction mixture is treated as described in example 15, and get the target product, 8%, so pl. 269-270 ° C (decomposes).

PRI me R 17. 9-amino-4,6-oxase-1,2,3,4-tetrahydroacridine

According to the method described in example 16, but using 3-amino-4-cyanopyridine instead of 2-amino-3-cyanopyridines, the target product is obtained, 16%, mp. 237-238 ° C.

PRI me R 18.9-Amino-5-aza-1,2,3,4-tetrahydro-1,4-methanoacridine

By the method described in example 16, but using norkormora instead of delta-valerolactone, the desired product is obtained (29%, mp 243-244 ° C).

Example 9.9-Amino-6-aza-1,2,3,4-tetrahydro-1,4-methanoacridine

According to the method described in example 16. but

using norkamfora instead of deltavalerolactone and 3-amino-4-cyanopyridine

instead of 2-amino-3-cyanopyridine get

target product (16%, mp 236-237 ° C).

PRI me R 20, 9-Cyclohexylmethylamino-8-fluoro-4-oxa-1,2,3,4-tetrahydroacridine

A mixture of sodium hydride (60% oil, 110 0 mg, 2.75 mmol), the title of Example 6 of the compound (600 mg, 2.75 mmol) of cyclohexylmethyl bromide (487 mg, 2.75 mmol) and dimethylformamide (3, 0 ml) is heated with stirring at a temperature of 25 ° C for 5 hours, then at a temperature of 65 ° C for 12 hours. At the end of this period, the reaction mixture was rapidly cooled, poured into water (45 ml) and then the resulting mixture was extracted with ethyl acetate (3 x 40 ml) 0 and dried (anhydrous magnesium sulfate). Ethyl acetate was distilled off in vacuo to give a residue, which was loaded onto a silica gel column for flash chromatography. Elute with ethyl acetate and 5 give an oil that solidifies on standing. Trituration of this solid with pentane gave the desired product (110 mg, 13%) as a tan crystalline solid, mp. 100 ° C. 0 Example 21.9-Cyclohexylethylamino-8-fluoro-4-oxa-1,2,3,4-tetrahydroacridine

By the method described in Example 20, but using cyclohexyl ethyl bromide instead of cyclohexyl methyl bromide, the desired product is obtained (34%).

IH-NMR (CD, 300 MHz, d): 2H, t, 0.8-1.02 ppm; 4H, t,

1.02-1.4 ppm; 2H, t, 1.44-1.56 ppm; 5H, Bd, 1.56-1.8 ppm; 2H, a, 1.92-2.04 ppm, O 0 6.0 Hz); 2H, t, 2.8 ppm. 0 6 Hz); 2H, in :, 3.33 ppm; 2H, t, 4.36 ppm. About 6 Hz); IH, Bd - 5.6 ppm. (1 20Hz); IH, dd, 6.38 ppm, O 14.0, 7.5 Hz); IH, dd, 7.24-7.38 ppm; IH.d, 7.48 ppm. 0 8.2 Hz). 5 PRI me R 22. 9-Benzylamino-8-fluoro-4-oxa-1,2,3,4-tetrahydroacridine

By the method described in example 20, but with the replacement of cyclohexylmethyl bromide with benzyl bromide, the desired product is obtained, 0 38%, mp 134-135 ° C.

PRI me R 23. 9-Phenetilamiyo-8-fluoro-4-oxa-1,2,3,4-tetrahydrozcridine

By the method described in example 20, but with the replacement of cyclohexylmethyl bromide with (2-5 bromoethyl) benzene, the desired product is obtained. 20% mp 225-126 ° C.

PRI me R 24. 9-Phenpropylamino-8-fluoro-4-oxa-1,2,3,4-tetrahydroacridine

By the method described in example 20, but with the replacement of cyclohexylmethyl bromide with 1 bromo-3-phenylpropane, the desired product is obtained (53% oil).

IH-NMR (CDCI.3, 300 MHz, b): 4H, t, 1.82-2.02 ppm; 4H, t,

2.62-2.78 ppm; 2H, b5, 2.34 ppm; 2H, t, 4.35 ppm.

O - 6.0 Hz); IH, VO. 5.7 ppm O - 20 Hz); IH, dd,

6.86 ppm (I - 14, 7.5 Hz); 6H, t, 7.04-7.4 ppm; IH, d

7.51 ppm (| -8.2 Hz).

PRI me R 25. 9- (3,3-Diphenylpropylamino) -8-fluoro-4-oxa-1,2,3,4-tetrahydroacridine

According to the method described in example 20, but with the replacement of cyclohexylmethyl bromide by 1-. bromo-3,3-diphenylpropane get the target product, 32%, so pl. 134-135 ° C.

PRI me R 26. 9-amino-4-thia-1,2, 3,4-tetrahydroacridine

According to the method described in example 7, but with the replacement of deltavalerolactone by deltovovalerolactone, the desired product is obtained 4%, mp. 190 ° C.

PRI me R 27. 9-amino-3-methyl-4-oxa-1,2,3,4-tetrahydroacridine

By the method described in example 7, but with the replacement of deltavalerolactone with 6-methyl-tetrahydropyran-2-one, the desired product is obtained, 23%, mp. 202-203 ° C.

PRI me R 28. 9-amino-3-methyl-8-fluoro-4-oxa-1,2,3,4-tetrahydroacridine

By the method described in example 7, but with the replacement of delta-valerolactone with 6-methyltetrahydropyran-2-one and anthranilo-nitrile with 2-amino-6-fluorobenzonitrile, the title compound was obtained, 13%, mp . 217-218 ° C.

PRI me R 29. 9-amino-8-fluoro-2-thia-1,2,3,4-tetrahydroacridine

According to the method described in Example 7, but with the replacement of delta-valerolactone with tetranitrothiopyran-4-one and anthranyl nitranyl with 2-amino-b-fluorobenzonitrile, ce is obtained. left product 19% mp 175-17b ° C.

PRI me R 30. 9-amino-1,2,3,4-tetrahydro-1,4-ethanoacridine

By the method described in example 1, but using dicyclo (2.2.2) octan-2-one, instead of minkfort, the target product is obtained, 20%, mp 197-199 ° C.

PRI me R 31. 2,3-Dihydrofuro (2,3-b) quinolin-4-amine

By the method described in example 7, but using gamma-butyrolactone instead of delta-valerolactone, the desired product is obtained, mp 300 ° C (decomposes).

1 H NMR (COC1CH, 300 MHz, d): 2H. t, 3.17 ppm. (Hz);

2H, b5, 4.6 ppm; 2H, t, 4.69 ppm. O - 8 Hz); IH, t,

7.28 ppm 0 8 Hz); IH, t, 7.53 ppm. fl 8 Hz); IH, d.

57.62 ppm (| 8 Hz); F, d. 7.77 ppm 0 8 Hz).

PRI me R 32. 6H- (1) Benzopyrano (4.3-c) quinolin-7-amine

0 By the method described in example 7, but using 4-chromanone instead of deltavalerolactone, the desired product is obtained. 3% mp 275 ° C (decomposes).

1 H NMR (DMSO, 300 MHz, d): 2H, S, 5 5.3 ppm; IH, d. 6.97 ppm

O 8.2 Hz); IH, t, 7-08 ppm O 7.0 Hz); 2H, t,

7.15-7.4 ppm; Ih. t, 7.57 ppm O 7.0 Hz); IH, d, 7.78 ppm.

0 (J 7.0 Hz); W, d, 8.16 ppm. (f 8.0 Hz); F, dd,

8.24 ppm 0 7.0, 2.0 Hz). PRI me R 33. 6H- (1) Benzothiopyrano (4,3-c) quinolin-7-amine.

5 By the method described in example 7, but using thiochroman-4-one instead of delta-valerolactone, the target product is obtained, 13%, mp 21b2126c.

Example 34. 9-Methylamino-8-fluoro-4-0 oxa-1,2,3,4-tetrahydroacridine

By the method described in Example 20, but using iodomethane instead of cyclohexylmethyl bromide, the desired product is obtained (for hydrochloride, mp 240 ° C). 5 IH-NMR (DMSO, 300 MHz, d): 2H, t, 2, Ohm d; 2H, t, 2.95 ppm.

About 6.5 Hz); ZN, Bd. 3.3 ppm; 2H, t. 4.53 ppm 0 6.5Hz);

IH, dd, 7.34 ppm. 0 8.14 Hz); IH, dd, 7.44 ppm.

O 8.0 Hz); W, t, 7.7-7.8 ppm; IH, Tue, 7.94-8.06 ppm.

PRI me R 35. 2,3-Dihydro-8-fluorotheno (3,2-b) quinolin-9-amine (compound A) and 5 1,3-dihydro-8-fluorothieno (3,) quinoline-9-amine

By the method described in Example 12, but using 2-amino-6-fluorobenzo-0 nitrile instead of anthracilonitrile, a 1: 1 mixture of both target products is obtained. Compound A, e.g. 137 ° C, compound B (mp. 198 ° C, decomposes):

1 H NMR (CDCfs. 300 MHz, d): 2H, S, 5 4.09 ppm, 2H. S

4.38 ppm; 2H. 5.5.5 ppm; W, dd, 7.0 ppm

O 7.3, 14.5 Hz); IH, dd, 7.47 ppm, 7.3, 10.5 Hz);

F, d, 7.68 ppm O-10.5 Hz).

P r m about r 36.

9-amino-1,2-dihydroacridin-4 (3H} -one

By the method described in example 1, but using 1,2-cyclohexanedione instead of norkormora, the target product is 11%, so pl. 240 ° C (decomposes).

1 H-NMR (COSl.s. ZOOMHz, 3): 2H, guln, 2.31 ppm;

4H, mt. 2.8-2.95 ppm; 2H, b5, 4.95 ppm; IH.t, 7.29 ppm.

O - 8.5 Hz) W; t, 7.64 ppm O - 8.5 Hz); IH, d, 7.74 ppm. .

O - 8.5 Hz); IH, d, 8.2 ppm. O - 8.51 Hz).

PRI me R 37. 8-Fluoro-9-amino-1,2,3,4-tetrahydroacridine

To mix at temperature

-20 ° C solution of cyclohexanone (1.0, 10.0

mmol) in methylene chloride (10 ml), a 1 M solution of titanium (IV) chloride in methylene chloride (20 ml) was added. The reaction mixture turns yellow and a mixture of triethylamine (2.0 g, 20 mmol) and 2-amino-b-fluorobenzonitrile (1i36 g, 10.0 mmol) in methylene chloride (30 ml) is added. The reaction mixture immediately turned dark and allowed to warm to room temperature (approximately 25 ° C) and was stirred for another 15 hours. At the end of this period, the reaction mixture was treated with a 12% aqueous solution of sodium hydroxide (100 ml) and methylene chloride (100 ml). The reaction mixture is then filtered through a 2 inch thick pad of diatomaceous earth (trade name Celite) and the pad is washed with methylene chloride (50 ml) and water (100 ml). The organic layer was separated, washed with water (1 x 30 ml) and dried (anhydrous magnesium sulfate). The methylene chloride was removed in vacuo to give the desired product as a white solid, 218 mg, 10%, mp. 175 ° C.

PRI me R 38. 9-amino-8-methyl-1,2,3,4-tetrahydroacridine

By the method described in example 37, but using 2-amino-6-methylbenzonitrile instead of 2-amino-6-fluorobenzonitrile, the desired product is obtained, 11%, mp. 143-145 ° C.

PRI me R 39. 9-amino-8-chloro-1,2,3,4-tetrahydroacridine

By the method described in example 37, but using 2-amino-6-chlorobenzonitrile instead of 2-amino-6-fluorobenzonitrile, the desired product is obtained, 23%, mp. 144-145 ° C.

PRI me R 40. 4-amino-5-fluoro-2,3-pentamethylene quinoline

By the method described in example 37, but using cycloheptanone instead

cyclohexanone receive the target product, 22%, so pl. 203 ° C.

PRI me R 41. 4-amino-5-chloro-2,3-pentamethylene quinoline

By the method described in example 37, but using cycloheptanone instead of cyclohexanone and 2-amino-6-chlorobenzonitrile instead of 2-amino-6-fluorobenzonitrile, the desired product is obtained, 11%, mp. 194 - 195 ° C.

Example 42. 4-amino-5-fluoro-2,3-trimethylenequinoline

By the method described in example 37, but using cyclopentanone instead of cyclohexanone, the desired product is obtained, 6% mp 179-18GS.

PRI me R 43. 9-amino-8-chloro-4-oxo-1,2,3,4-tetrahydroacridine

By the method described in example 7, but using 2-amino-6-chlorobenzonitrile instead of anthranilonitrile, the desired product is obtained, 1.5%, mp. 205 ° C.

Example 44. 9-amino-8-methyl-4-oxa-, 1,2,3,4-tetrahydroacridine By the method described in example 7, but using 2-amino-6-methylbenzonitrile instead of anthranilonitrile, the desired product is obtained , 20%, mp 177-179 ° C.

1 H NMR (CDCI 3, 300 MHz, d); IH, d, 7.56 ppm. 0 7 Hz);

IH, t, 6.95 ppm. 0 7 Hz); 2H, b, 5.4.93 ppm; 2H, t,

4.29 m, d. 0 6 Hz); ZN, S, 2.89 ppm; 2H, t, 2.52 ppm. 0 6Hz); 2H, t, 2.08-2.11 ppm.

Example 45. 9-amino-8-methoxy-1,2,3,4-tetrahydroacridine

By the method described in example 37,

but using 2-amino-6-methoxybenzonitrile instead of 2-amino-6-fluorobenzonitrile, the desired product is obtained, 14%, mp.

187-188 ° C.

PRI me R 46. 9-amino-8-methoxy-4-oxa-1,2,3,4-tetrahydroacridine According to the method described in example 7, but using 2-amino-6-methoxybenzo- nitrile instead of anthranilonitrile get the target product, 11%, so pl. 205 207 ° C. W-NMR (CDCIs, 300 MHz, d): 2H, t, 7.33 ppm; IH, dd,

6.57 ppm 0 3.6 Hz); 2H BS, 5.92 ppm; 2H, t, 4.29 ppm.

About 2.6 Hz); ZN, S, 3.95 ppm; 2H. t, 2.5 ppm O 2.6 Hz) 2H, t, 2.13-2.07 ppm.

Example 47. The ability of compounds 1-16, 18, 26-29 and 35-46 to suppress brain acetylcholinesterase was determined spectrophotometrically. For all

188 ± 16

500 ± 187

600 ± 163

230 ± 18

345 ± 18

272 ± 78

482 ± 147

318 ± 64

395 ± 118

308 ± 73

815 ± 335

700