RU2039058C1 - 4-aminopyridine derivatives - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: product: derivatives of 4-aminopyridine of the general formula (I)

where A means group

in which fragment CH at position "A" can be substituted with nitrogen atom; B means group (Ia)

or (IIa)

where broken line is nonobligatory double bond; R₃ hydrogen or fluorine at position "B"; Y₁ means CH₂, O or S; Y₂ means CH₂, CH, O or S; Y₃ means CH₂ or CH at condition that group (Ia) can contain double bond only if when Y₂ and Y₃ means CH, and at condition that when A means indicated group in which R₃ - hydrogen, and nitrogen is absent at position "A", only one of Y₁ and Y₂ means CH₂; q 1. EFFECT: improved method of synthesis. 3 cl, 1 tbl

Description

B где А означает группу R

в которой фрагмент СН в положении "а" может быть заменен атомом азота,
В означает группу

или

где прерывистая линия представляет необязательную двойную связь;
R₃ водород или фтор в положении "в",
Y₁ означает СН₂, О или S;
Y₂ означает СН₂, СН, О или S;
Y₃ означает СН₂ или СН, при условии, что группа формулы Ia может иметь двойную связь только в том случае, когда Y₂ и Y₃ означает СН, и при условии, что, когда А означает указанную группу, в которой R₃ водород и азот отсутствует в положении "а", только один из Y₁ и Y₂ означает СН₂;
q 1.The invention relates to derivatives of 4-aminopyridine of the general formula I
A

B where A is a group R

in which the CH moiety in position a can be replaced by a nitrogen atom,
B means a group

or

where the dashed line represents an optional double bond;
R ₃ hydrogen or fluorine in position "in",
Y ₁ means CH ₂ , O or S;
Y ₂ means CH ₂ , CH, O or S;
Y ₃ means CH ₂ or CH, provided that a group of formula Ia can have a double bond only when Y ₂ and Y ₃ means CH, and provided that when A means a specified group in which R _{3 is} hydrogen and nitrogen is absent in position "a", only one of Y ₁ and Y ₂ means CH ₂ ;
q 1.

 The compounds of formula 1 are useful in the treatment of various memory disorders caused by decreased cholinergic function, for example Alzheimer's disease. In addition, these compounds stimulate neuromuscular transmission, enhance excitation processes in excited tissues (nerves, smooth and striated muscles), and also restore conduction in nerves and neuromuscular synapses in case of damage. The compounds of the invention also exhibit antidepressant activity, which is especially useful for patients suffering from Alzheimer's disease. As a rule, the compounds according to the invention are less toxic and have a wider spectrum of therapeutic action than known compounds, for example tacrine and physotigmine, which makes them more therapeutically preferred.

 In the treatment of Alzheimer's disease, the dosage of the compounds according to the invention varies depending on the route of administration and the particular compound selected. In addition, the dosage varies depending on the particular patient, age, body weight and condition of the patient to be treated, as well as on the nature and severity of the symptoms. However, usually a dose is administered in the range of about 1-300 mg / day as a unit dose in divided doses. A preferred dose is in the range of about 1-150 mg / day in single or divided doses.

 Typically, treatment begins with small doses, significantly lower than the optimal dose of this compound. Then the dose is gradually increased by a small amount until the optimal effect is achieved.

 The compounds of the invention are used alone or in combination with pharmacologically acceptable carriers, a quantity of which is determined by the solubility and chemical nature of the compound, the chosen route of administration and standard medical practice. For example, they are administered orally in the form of capsules, tablets, suspensions or solutions, or they can be administered parenterally. Capsules and tablets are the preferred form of administration. For parenteral administration, the compounds according to the invention can be used in the form of a sterile solution containing also other dissolved substances, for example, salt or glucose in an amount sufficient to form an isotonic solution.

 Capsules and tablets with the compositions may contain the active ingredient in admixture with one or more pharmaceutical excipients suitable for the manufacture of capsules and tablets. Suitable pharmaceutical excipients are, for example, starch, milk sugar and certain types of clays. The tablets may be uncoated or they may be coated by known methods to slow down decomposition and absorption in the gastrointestinal tract, thereby providing a longer duration of action of the drug.

 Aqueous suspensions of the compounds of formula 1 contain the active ingredient in admixture with one or more pharmaceutical excipients suitable for the manufacture of aqueous suspensions. Suitable excipients are, for example, methyl cellulose, sodium alginate, gum arabic, lecithin and the like. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

 Non-aqueous suspensions may be prepared by suspending the active ingredient in vegetable oil, for example peanut oil, olive oil, sesame oil or coconut oil, or in mineral oil, for example liquid paraffin, and the suspension may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. These compositions may also contain a sweetening agent, fragrance and antioxidant.

 The following examples illustrate the preparation and properties of the compounds of the present invention. All melting points are not adjusted. Thin layer chromatography (TLC) was performed on silica gel.

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

A solution of anthranilonitrile (3.6 g, 30.0 mmol), norkamfara (3.3 g, 30.0 mmol) and n-toluenesulfonic acid (50 mg) in benzene (50 ml) is heated with reflux in a Dean-Stark apparatus. After heating for 18 hours the reaction mixture was cooled (25 ° ^C) and removing the separated water (about 1.5 mL). Then the excess benzene is distilled off in vacuo (1 mm Hg for 15 minutes). The thus obtained oily residue was dissolved in tetrahydrofuran (THF, 10 mL) and cooled ^to 0 ° C, then added a solution of lithium diisopropylamide in THF (1M, 36 mL, 36 mmol). Then this reaction mixture was stirred at 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 is washed with water (2x50 ml) and dried (anhydrous magnesium sulfate). Methylene chloride was distilled off in vacuo to give a residue, which was placed on a silica gel flash chromatography column. Elute 5% methanol in methylene chloride containing 1% triethylamine to give the title compound in an amount of 1.6 g (25%) as an oil which solidifies upon standing. Mp 185-186 ^about S.

 PRI me R 2. 9-amino-8-fluoro-1,2,3,4-tetrahydro-1,4-methanoacridine.

According to the method described in example 1, but with the replacement of anthranilonitrile with 2-amino-6-fluorobenzonitrile, the title compound is obtained, 23% mp 173 ^about S.

 PRI me R 3. 9-amino-7-chloro-1,2,3,4-tetrahydro-1,4-methanoacridine.

According to the method described in example 1, but with the replacement of anthranilonitrile with 2-amino-5-chlorobenzonitrile, the title compound was obtained, 14% mp 183-184 ^about S.

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

By the method described in example 1, but with the replacement of minkfara with 5-norbornen-2-one, the title compound was obtained, 26% mp 123 ^about S.

 PRI me R 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. By the end of this period, the reaction mixture was cooled (25 ° ^C), diluted aqueous sodium hydroxide solution (70 ml) and extracted with methylene chloride (4h60 mL). The combined organic phases are washed with water (2x100 ml) and dried (anhydrous magnesium sulfate). The organic solvents are removed in vacuo and a yellow residue is obtained, which is loaded onto a silica gel flash column. Elute 5% methanol in methylene chloride to give the title compound as yellow crystals, 155 mg, 31% mp. 195-196 ^about S.

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

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 120 ^° C for 20 minutes. The reaction mixture was cooled and the solid residue was filtered using ethyl ether (100 ml). The obtained orange solid (5.2 g) was placed in a beaker containing a saturated solution of EDTA (ethylenediaminetetraacetic acid) in the form (125 ml) and the pH was adjusted to 13 with a 12% aqueous sodium hydroxide solution. Then the aqueous phase is extracted with methylene chloride (4x5 ml) and the extract is washed with water (2x70 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 to give a pale yellow solid, 1.36 g, 29% mp. 205 ^{° C} (decomposed).

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

To a stirred ^-20 ° C solution of delta-valerolactone (1.0 g, 10.0 mmol) in methylene chloride (10 ml) was added 1M solution of titanium chloride (IV) in methylene chloride (20 mL). The reaction mixture becomes dark yellow and a mixture of triethylamine (2.0 g, 20 mmol) and anthranilonitrile (1.2 g, 10.0 mmol) in methylene chloride (30 ml) is added. The reaction mixture immediately became dark, it was allowed to warm to room temperature (about 25 ^C) and then stirred for 15 hours. At the end of this period, the reaction mixture was treated with 25% aqueous sodium hydroxide (40 ml) and methylene chloride (100 ml) and filtered through a 2 inch thick pad of diatomaceous earth (trade name Celite, Celit), which is 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 title compound as a white solid, 565 mg, 28%
¹ H-NMR (CDCl ₃ , 300 MHz, g): 2H, m, 2.02-2.18 ppm. 2H, T. 2.63 ppm. (J 6.0 Hz); 2H, T. 4.36 ppm. (J 6.0 Hz); 2H, s. 4.64 ppm 1H, T. 7.25 (J, 8.0 Hz); 1H, T. 7.5 (J, 8.0 Hz); 1H, g, 7.72 (J 8.0 Hz).

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

According to the procedure described in example 7, but with the replacement of anthranilonitrile with 2-amino-6-fluorobenzonitrile, the title compound was obtained, 8% mp. 195-196 ^about S.

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

According to the procedure described in example 7, but with the replacement of anthranilonitrile with 2-amino-5-chlorobenzonitrile, the title compound was obtained, 2% mp 278-279 ^about S.

 PRI me R 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 title compound was obtained, 8% mp 145 ^about S.

 PRI me R 11. 9-amino-2,3,7,8-tetrahydro-1H-cyclopenta (e) -6H-pyrano) - / 2 ', 3'-b / pyridine.

According to the method described in example 7, but with the replacement of anthranilonitrile with 2-amino-1-cyano-1-cyclopentene, the title compound was obtained, 22% mp 164 ^about S.

 PRI me R 12. 2,3-Dihydrothieno (3,2-b) quinolin-9-amine.

To a stirred ^-78 ° C solution of tetrahydrothiophene-3-one (1.1 g, 11 mmol) in methylene chloride (10 ml) was added 1M solution of titanium chloride (IV) 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 over 5 minutes to the reaction mixture. Thereafter, the reaction mixture was slowly warmed to room temperature and stirred for 2 h. Then the reaction mixture was added a tetrahydrothiophene-3-one (1 ml) and titanium chloride (IV) (1,0 ml) and the mixture was stirred at ²⁵ ° C for 16 hours. Then, a 12% aqueous sodium hydroxide solution (100 ml) was quickly poured into the reaction mixture, after which the reaction mixture was vigorously stirred with an additional amount of methylene chloride (300 ml). Then the reaction mixture is filtered through diatomaceous earth (trade name celite) and the organic phase is 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% triethylamine to give the title compound (1.3 g 64%), which crystallizes from chloroform, 560 mg, 32% mp. 208-210 ^about C.

 PRI me R 13. 9-amino-1,2,3,4,5,6,7,8-octahydro-1,4-methanoacridine.

To a stirred ^-20 ° C solution norkamfory (0.9 g, 8.2 mmol) in methylene chloride (8.0 ml) was added a mixture of triethylamine (1.7 g, 16.4 mmol) and 2-amino-1-cyano -1-cyclohexene (1.0 g, 8.2 mmol) in methylene chloride (24 mL) and the resulting mixture was stirred at ²⁵ ° C for 15 min. Then, a 12% aqueous sodium hydroxide solution (60 ml) was quickly poured into the reaction mixture and stirred vigorously with methylene chloride (60 ml). After that, the reaction mixture was filtered through a 2-inch-thick diatomaceous earth pad (trade name Celite). The organic phase is separated, washed with water (2x50 ml) and then dried (anhydrous magnesium sulfate). Methylene chloride was then removed under reduced pressure to give an oil which was triturated with pentane to give the title compound as an off-white solid, 225 mg, 13% mp. 131-133 ^about S.

 PRI me R 14. 9-amino-6-aza-1,2,3,4-tetrahydroacridine.

Titanium (IV) chloride (1.5 ml) is added to a stirred solution of 3-amino-4-cyanopyridine (500 mg, 4.2 mmol) and cyclohexanone (0.5 ml) in 1,2-dichloroethane (15 ml). The reaction mixture was kept at ⁹⁰ ° C for 12 hours. At the end of this period the reaction mixture was added cyclohexanone (2.0 mL) and 1,2-dichloroethane (5.0 mL) was added and heating continued for a further 12 hours. The An additional amount of cyclohexanone (2.0 ml) and titanium chloride (IV) (1,2 ml) and the reaction mixture was kept at ⁹⁰ ° C for 6 hours. The reaction mixture was cooled rapidly and poured thereto a 5% aqueous solution sodium hydroxide (250 ml) and vigorously stirred with methylene chloride (200 ml, 25 min). Then, the reaction mixture was worked up as described in Example 8, and the title compound (170 mg, 95% pure, 20%) was obtained after flash chromatography on silica gel (eluent 95: 5: 1 methylene chloride: methanol: ammonium hydroxide) . This material was further purified by chromatography to give the title compound, 75 mg, mp. 180-181 ^about S.

 PRI me R 15. 9-amino-5-aza-1,2,3,4-tetrahydroacridine.

By the method described in example 14, but with the replacement of 3-amino-4-cyanopyridine with 2-amino-3-cyanopyridine, the title compound was obtained, 38% mp 225-228 ^{° C} (decomposed).

¹ H-NMR (CDCl ₃ + CD ₃ OD, 300 MHz, δ): 4H, broad. from. 1.86 ppm 2H, br 2.5 ppm 2H, br 2.97 ppm 2H, br.s. 3.0-3.3 ppm 1H, dd. 7.2 ppm (J 8.0, 4.0 Hz); 1H, dd. 8.18 ppm (J 8.0, 1-2 Hz); 1H, dd. 8.77 ppm (J 4.0, 1-2 Hz).

 PRI me R 16. 9-amino-4,5-oxase-1,2,3,4-tetrahydroacridine.

Titanium (IV) chloride is added to a stirred solution of 2-amino-3-cyanopyridine (360 mg, 3.0 mmol) and delta-valerolactone (360 mg, 3.6 mmol) in 1,2-dichloroethane (7.0 ml) (0.9 mL) and the reaction mixture was kept at ⁹⁰ ° C for 18 hours. The reaction mixture was quenched by addition of 15% aqueous sodium hydroxide solution (200 ml) and stirred vigorously with methylene chloride (200 mL, 25 min). Then, the reaction mixture was worked up as described in Example 15, and the title compound was obtained, 8% mp. 269-270 ^{° C} (decomposed).

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

By the method described in example 16, but using 3-amino-4-cyanopyridine instead of 2-amino-3-cyanopyridine, the title compound was obtained, 16% mp. 237-238 ^about S.

 PRI me R 18. 9-amino-5-aza-1,2,3,4-tetrahydro-1,4-methanoacridine.

According to the method described in Example 16, but using instead norkamfory delta-valerolactone afforded the title compound (29% m.p. 243-244 ° ^C).

 PRI me R 19. 9-amino-6-aza-1,2,3,4-tetrahydro-1,4-methanoacridine.

By the method described in example 16, but using norkormora instead of delta-valerolactone and 3-amino-4-cyanopyridine instead of 2-amino-3-cyanopyridine, the title compound was obtained, 16% mp 236-237 ^about S.

 PRI me R 20. 9-Cyclohexylmethylamino-8-fluoro-4-oxa-1,2,3,4-tetrahydroacrid-in.

A mixture of sodium hydride (60% oil, 110 mg, 2.75 mmol) of the title compound of Example 6 (600 mg, 2.75 mmol), cyclohexylmethyl bromide (487 mg, 2.75 mmol) and dimethylformamide (3.0 ml ) was heated with stirring at ²⁵ ° C for 12 h, then at ⁶⁵ ° C for 12 hours. at the end of this period, the reaction mixture was quenched by pouring it into water (45 ml) and then the resulting mixture was extracted with ethyl acetate (3 x 35 ml ) The combined organic salts were washed with water (2 x 40 ml) 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 to give an oil that solidifies upon standing. Trituration of this solid with pentane gave the title compound (110 mg, 13%) as a tan crystalline solid, mp. 100 ^about S.

 PRI me R 21. 9-Cyclohexylethylamino-8-fluoro-4-oxa-1,2,3,4-tetrahydroacrid-in.

 According to the method described in example 20, but using cyclohexyl ethyl bromide instead of cyclohexyl methyl bromide, the title compound (34%) was obtained.

¹ H-NMR (CDCl ₃ , 300 MHz, δ): 2H, m, 0.8-1.02 ppm. 4H, m. 1.02-1.4 ppm. 2H, m. 1.44-1.56 ppm. 5H, broad d. 1.56-1.8 ppm. 2H, apt. 1.92-2.04 ppm (J 6.0 Hz); 2H, t, 2.8 ppm. (J 6 Hz); 2H, br 3.38 ppm 2H, t, 4.36 ppm. (J 6 Hz); 1H, broad d 5.6 ppm (J 20 Hz); 1H, dd. 6.38 dd 6.38 ppm (J 14.0, 7.5 Hz); 1H, dd. 7.24-7.38 ppm 1 H, 7.48 ppm. (J 8.2 Hz).

 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 title compound was obtained, 38% mp. 134-135 ^about S.

 PRI me R 23. 9-Phenethylamino-8-fluoro-4-oxa-1,2,3,4-tetrahydroacridine.

By the method described in example 20, but with the replacement of cyclohexylmethyl bromide with (2-bromoethyl) benzene, the title compound was obtained, 20% mp 125-126 ^about S.

 PRI me R 24. 9-Phenyropylamino-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 title compound (53% oil) was obtained.

¹ H-NMR (CDCl ₃ , 300 MHz, δ): 4H, m, 1.82-2.02 ppm. 4H, m. 2.62-2.78 ppm. 2H, broad from. 2.34 ppm 2H, t, 4.35 ppm. (J 6.0 Hz); 1H, broad d 5.7 ppm (J 20 Hz); 1H, dd. 6.86 ppm (J 14, 7.5 Hz); 6H, m. 7.04-7.4 ppm. 1H, d. 7.51 ppm. (J 8.2 Hz).

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

By the method described in example 20, but with the replacement of cyclohexylmethyl bromide with 1-bromo-3,3-diphenylpropane, the title compound was obtained, 32% mp. 134-135 ^about S.

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

According to the method described in example 7, but with the substitution of delta-valerolactone for delta-thiovalerolactone, the title compound was obtained, 4% mp. 190 ^about S.

 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 delta-valerolactone with 6-methyltetrahydropyran-2-one, the title compound was obtained, 23% mp. 202-203 ^about S.

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

According to the method described in example 7, but with the replacement of delta-valerolactone with 6-methyltetrahydropyran-2-one and anthragilonitrile with 2-amino-6-fluorobenzonitrile, the title compound was obtained, 13% mp 217-218 ^about S.

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

By the method described in example 7, but with the replacement of delta-valerolactone with tetrahydrothiopyran-4-one and anthranilonitrile with 2-amino-6-fluorobenzonitrile, the title compound was obtained, 19% mp. 175-176 ^about S.

 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 norkormora, the title compound was obtained, 20% mp 197-199 ^about S.

 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 title compound is obtained, mp. 300 ^about C (decomposes).

¹ H-NMR (CDCl ₃ , 300 MHz δ): 2H, t, 3.17 ppm. (J 8 Hz); 2H, broad from. 4.6 ppm. 2H, t. 4.69 ppm. (J 8 Hz); 1H, t, 7.28 ppm. (J 8 Hz); 1H, t, 7.53 ppm. (J 8 Hz); 1H, d. 7.62 ppm. (J 8 Hz); 1H, d. 7.77 ppm. (J 8 Hz).

 PRI me R 32. 6H- (1) Benzopyrano (4,3-b) quinolin-7-amine.

By the method described in example 7, but using 4-chromotmanone instead of delta-valerolactone, the title compound was obtained, 3% mp 275 ^{° C} (decomposed).

¹ H-NMR (DMSO, 300 MHz, δ): 2H, s. 5.3 ppm 1H, d, 6.97 ppm. (J 8.2 Hz); 1H, t. 7.08 ppm. (J 7.0 Hz); 2H, m, 7.15-7.4 ppm. 1H, t, 7.57 ppm. (J 7.0 Hz); 1H, d. 7.78 ppm. (J 7.0 Hz); 1H, d, 8.16 ppm. (J 8.0 Hz); 1H, dd. 8.24 ppm (J 7.0, 2.0 Hz).

 PRI me R 33. 6H- (1) -Benzothiopyrano (4,3-b) quinolin-7-amine.

By the method described in example 7, but using thiochroman-4-one instead of delta-valerolactone, the title compound was obtained, 13% mp 211-212 ^about S.

 PRI me R 34. 9-Methylamino-8-fluoro-4-oxa-1,2,3,4-tetrahydroacridine.

According to the method described in Example 20 but using cyclohexylmethyl bromide instead of iodomethane, the title compound (hydrochloride of m.p. 240 ° ^C).

¹ H-NMR (DMSO, 300 MHz, δ): 2H, m, 2.0 ppm. 2H t. 2.95 ppm. (J 6.5 Hz); 3H, broad d.3.3 ppm 2H, t. 4.53 ppm. (J 6.5 Hz); 1H, dd. 7.34 ppm (J 8.14 Hz); 1H, dd. 7.44 ppm (J8.0 Hz); 1H, m. 7.7-7.8 ppm. 1H, broad m. 7.94-8.06 ppm.

 PRI me R 35. 2,3-Dihydro-8-fluorothieno / 3,2-b / quinolin-9-amine (compound A) and 1,3-dihydro-8-fluorothieno / 3,4-b / quinoline-9-amine.

By the method described in Example 12, but using 2-amino-6-fluorobenzonitrile instead of anthranilonitrile, a 1: 1 mixture of both of the title compounds was obtained. Compound A, mp 137 ^{° C,} Compound B (m.p. 198 ^{° C} decomposed)
¹ H-NMR (CDCl ₃ , 300 MHz, δ): 2H, s. 4.09 ppm 2H s 4.38 ppm 2H, br.s. 5.3 ppm, 1H, dd. 7.0 ppm (J 7.3, 14.5 Hz); 1H, dd. 7.47 ppm (J 7.3, 10.5 Hz); 1H, d. 7.68 ppm. (J 10.5 Hz).

 PRI me 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 title compound was obtained, 11% mp. 240 ^C (decomposes).

¹ H-NMR (CDCl ₃ , 300 MHz, δ): 2H, quint. 2.31 ppm 4H mg. 2.8-2.95 ppm 2H, broad from. 4.95 ppm 1H, t, 7.29 ppm. (J 8.5 Hz); 1H, t. 7.64 ppm. (J 8.5 Hz); 1H, d. 7.74 ppm. (J 8.5 Hz); 1H, d, 8.2 ppm. (J 8.51 Hz).

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

To a stirred ^-20 ° C solution of cyclohexanone (1.0 g, 10.0 mmol) in methylene chloride (10 ml) was added 1M solution of titanium chloride (IV) in methylene chloride (20 mL). The reaction mixture turns yellow and a mixture of triethylamine (2.0 g, 20 mmol) and 2-amino-6-fluorobenzonitrile (1.36 g, 10.0 mmol) in methylene chloride (30 ml) is added. The reaction mixture immediately became dark in color and it was allowed to warm to room temperature (about 25 ^C) and stirred for a further 15 hours. At the end of this period, the reaction mixture was treated with 12% aqueous 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). Methylene chloride was removed in vacuo to give an oil which was triturated with ether to give the title compound as a white solid, 218 mg, 10% mp. 175 ^about S.

 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 title compound was obtained, 11% mp. 143-145 ^about S.

 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 title compound was obtained, 23% mp. 144-145 ^about S.

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

By the method described in example 37, but using cycloheptanone instead of cyclohexanone, the title compound was obtained, 22% mp. 203 ^about S.

 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 title compound was obtained, 11% mp. 194-195 ^about S.

 PRI me R 42. 4-amino-5-fluoro-2,3-trimethylene quinoline.

By the method described in example 37, but using cyclopentanone instead of cyclohexanone, the title compound was obtained, 6% mp. 179-181 ^about S.

 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 title compound was obtained, 15% mp 205 ^about S.

 PRI me R 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 title compound was obtained, 20% mp 177-179 ^about S.

¹ H-NMR (CDCl ₃ , 300 MHz, δ): 1H, d, 7.56 ppm. (J 7 Hz); 1H, t. 6.95 ppm. (J 7 Hz); 2H, broad from. 4.93 ppm 2H, t, 4.29 ppm (J 6 Hz); 3H, s. 2.89 ppm 2H, t. 2.52 ppm. (J 6 Hz); 2H, m. 2.08-2.11 ppm.

 PRI me R 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 title compound was obtained, 14% mp. 187-188 ^about S.

 PRI me R 46. 9-amino-8-methoxy-4-oxa-1,2,3,4-tetrahydroacridine.

By the method described in example 7, but using 2-amino-6-methoxybenzonitrile instead of anthranilonitrile, the title compound was obtained, 11% mp. 205-207 ^about S.

¹ H-NMR (CDCl ₃ , 300 MHz, δ): 2H, m, 7.33 ppm. 1H, dd. 6.57 ppm (J 3.6 Hz); 2H, broad from. 5.92 ppm 2H. t. 4.29 ppm (J 2.6 Hz); 3H, s. 3.95 ppm 2H, t. 2.5 ppm. (J 2.6 Hz); 2H, m. 2.13-2.07 ppm.

PRI me R 47. The ability of the compounds indicated in the headings of examples 1-16, 18, 26-29 and 35-46 to suppress brain acetylcholinesterase was determined spectrophotometrically by IZ / Ellman et al. (Biochemical Pharmacology, 7, 88 ( 1961)). For all compounds, the values of PK ₅₀ (in moles) were in the range of 5 μmol-01 μmol.

 The table shows the test data.

Claims (3)

1. 4-AMINOPYRIDINE DERIVATIVES of the General Formula

where is a group

in which the CH moiety in position a can be replaced by a nitrogen atom. B group:

where the dashed line represents an optional double bond;
R _{3 is} hydrogen or fluoro in position "b";
Y ₁ CH ₂ , O or S;
Y ₂ CH ₂ , CH, O or S;
Y ₃ CH ₂ or CH,
provided that the group of formula I a can have a double bond only when Y ₂ and Y ₃ CH, and provided that when A means the specified group, where R _{3 is} hydrogen and nitrogen is not in position "a" , only one of Y ₁ and Y ₂ CH ₂
q 1.  2. The derivatives according to claim 1, selected from the group comprising 9-amino-1,2,3,4, -tetrahydro-1,4-methanoacridine, 9-amino-8-fluoro-1,2,3,4, Tetrahydro -1,4-methanoacridine, 2,3-dihydrothieno (3,2-b) quinolin-9-amine, 2,3-dihydro-8-fluorothieno (3,2-b) -quinolin-9-amine, 1,3-dihydro-8-fluorothieno (3,4-b) quinolin-9-amine.  3. The derivatives according to claim 1, having anticholinesterase activity.

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