KR20060109085A - Huperzine-tacrine hybrids and process for preparing them - Google Patents

Abstract

Huperzine-tacrine hybrids and preparing process thereof is provided to improve inhibiting activity of acetylcholine esterase(AChE) associated with occurrence of neurodegenerative disease, and enhance their production yield. The huperzine-tacrine hybrid derivatives represented by the formula(1) having neurodegenerative disease-treating effect are provided, wherein X is hydrogen, halogen group or C1-C6 alkyl group, m is 1 to 3 and n is 1 or 2; and the neurodegenerative disease is dementia. The precursors of the huperzine-tacrine hybrid derivatives represented by the formula(6) are provided. The process for preparing the huperzine-tacrine hybrid derivatives comprises the steps of: (1) treating chloro acrydine represented by the formula(2) with hydroxylamine to prepare hydroxy compounds represented by the formula(3); (2) oxidizing the compounds of the formula(3) with an oxidizing agent selected from pyridinium chlorochromate(PCC), pyridinium dichromate(PDC), Jone's reagent and manganese dioxide to prepare aldehyde compounds represented by the formula(4); (3) condensing the aldehyde compounds of the formula(4) with pyridineamine represented by the formula(5) by using a molecular sieve to prepare immine, and reducing it to prepare compounds represented by the formula(6); and (4) deprotecting the compounds of the formula(6) by using trimethylsilyl iodide(TMSI).

Description

Huperzine-Tacrine Hybrids and process for preparing them}

The present invention relates to a huperzine-tacrine hybrid of the following formula (1) and a method for preparing the same, and more particularly, using a chloro acridine compound of the following formula (2) as a starting material, After oxidizing the alcohol obtained by substituting the chloride with the amine to synthesize the aldehyde compound of the following formula (4) as a reaction intermediate, it is synthesized through a series of preparation process by reacting it with the pyridineamine of the formula (5), Huperzine-tacrine hybrid derivatives and methods for their preparation are disclosed.

In the above, X is hydrogen, a halogen group or a C ₁ to C ₆ alkyl group, m is 1 to 3, n is 1 or 2.

Drugs developed and marketed for the treatment of AChE include Tacrine, Aricept; Donepezil, Rivastigmine, and Galantamine. Of these, tacrine has excellent efficacy, but is rarely used because of hepatotoxicity and gastrointestinal disorders. Aricept has a structural activity relationship (SAR) by compound selection method at Eisai, Japan. It is developed by the company and has the largest market acquisition rate. Also, Huperzine A is a licopodium alkaloid isolated from Chinese moss ( Huperzia serrata ) [ Can. J. Chem . 1986 , 64 , 837-839], potent, selective and reversible AChE inhibitors. J. Neurosci. Res . 1989 , 24 , 276-285.] Hooperzine A is an excellent drug with long-term persistence and high potency than tacrine or aricept, and is particularly capable of penetrating the brain blood barrier (BBB). It is also known that Hoofed B has a slightly lower drug efficacy than Hoofed A, but has a longer duration and better efficacy than Hoofed A. Acta Pharmacol. Sin. 1987 , 8 , 117; J. Org. Chem. 1993 , 58 , 7660-7669] However, since hoppers are obtained from natural products, they are limited in supply for commercial use, and A, which is now a drug, is sold as a health supplement.

Thus, derivatives of similar structures tacrine duplexes, hybrids of tacrine and pyridones, duplexes of fupurin and tacrine have been published. Bioorg. Med. Chem. Lett. 1999 , 7 , 351-357. Bioorg. Med. Chem. 1999 , 7 , 2335-2338. Bioorg. Med. Chem. Lett. 2001 , 11 , 1779-1782. J. Med. Chem. 2005 , 1701-1704]

The present inventors have synthesized a novel compound consisting of a mixed structure of tacrine and hoopin compounds, which are known to be effective in treating dementia, a neurodegenerative disease, and also have a high yield of structuring materials in which hoopin and tacrine are mixed. Efforts have been made to develop a novel preparation method that can be synthesized in an efficient manner, and as a result, the present invention has been completed by synthesizing a novel compound represented by Chemical Formula 1.

Accordingly, an object of the present invention is to provide a hoopsin-tacrine hybrid derivative of the formula (1).

Another object of the present invention is to provide a method for producing a hoopsin-tacrine hybrid.

The present invention provides a hoopin-tacrine derivative represented by the following formula (1) and a method for preparing the same.

[Formula 1]

In Formula 1, X is hydrogen, a halogen group or a C ₁ ~ C ₆ alkyl group, m is 1 to 3, n is 1 or 2.

The novel compounds representing the compound represented by Formula 1 according to the present invention are as follows.

1) 13-[(E)-(±) -ethylidene-11-methyl-6- (1,2,3,4-tetrahydro-9-acridinylamino) hexylamino] -6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-5-one (Formula 1; X = H, m = 2, n = 1)

2) 13-[(E)-(±) -ethylidene-11-methyl-1-6- (7,8,9,10-tetrahydro-6H-cyclohepta [b] quinolin-11-ylamino) Hexylamino]-6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-5-one (1, X = H, m = 3 , n = 1)

3) 11- [6- (2,3-dihydro-1H-cyclopenta [b] quinolin-9ylamino) hexylamino] -3-[(E)-(±) -ethylidene] -11-methyl -6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-5-one (1, X = H, m = 1, n = 1 )

4) 13-[(E)-(±) -ethylidene-6- (8-fluor-1,2,3,4-tetrahydro-9-acridinylamino) hexylamino] -11-methyl-6 Azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-5-one (1, X = F, m = 2, n = 1)

5) 13-[(E)-(±) -ethylidene-6- (7-fluoro-1,2,3,4-tetrahydro-9-acridinylamino) hexylamino] -11-methyl-6 Azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-5-one (1, X = F, m = 2, n = 1)

6) 13-[(E)-(±) -ethylidene-6- (8-chloro-1,2,3,4-tetrahydro-9-acridinylamino) hexylamino] -11-methyl-6 Azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-5-one (1, X = Cl, m = 2, n = 1)

7) 13-[(E)-(±) -ethylidene-6- (7-chloro-1,2,3,4-tetrahydro-9-acridinylamino) hexylamino] -11-methyl-6 Azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-5-one (1, X = Cl, m = 2, n = 1)

8) 13-[(E)-(±) -ethylidene-6- (6-chloro-1,2,3,4-tetrahydro-9-acridinylamino) hexylamino] -11-methyl-6 Azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-5-one (1, X = Cl, m = 2, n = 1)

9) 13-[(E)-(±) -ethylidene-6- (5-methyl-1,2,3,4-tetrahydro-9-acridinylamino) hexylamino] -11-methyl-6 Azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-5-one (1, X = CH ₃ , m = 2, n = 1)

10) 13-[(E)-(±) -ethylidene-7- (7-fluor-1,2,3,4-tetrahydro-9-acridinylamino) heptylamino] -11-methyl-6 Azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-5-one (1, X = F, m = 2, n = 2)

11) 13-[(E)-(±) -ethylidene-7- (6-chloro-1,2,3,4-tetrahydro-9-acridinylamino) heptylamino] -11-methyl-6 Azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-5-one (1, X = Cl, m = 2, n = 2)

In addition, the present invention provides a precursor of the hoopsin-tacrine hybrid derivative (Formula 1) represented by the following formula (6).

[Formula 6]

In Formula 6, X is hydrogen, a halogen group or a C ₁ ~ C ₆ alkyl group, m is 1 to 3, n is 1 or 2.

The novel compounds representing the compounds represented by Formula 6 according to the present invention are as follows.

12) N1- [6- (1,2,3,4-tetrahydro-9-acridinyl amino) hexyl] -13-[(E)-(±) -ethylidene-5-methoxy-11- Methyl-6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-1-amine (Formula 6, X = H, m = 2, n = 1)

13) N1- [6- (2,3-Dihydro-1H-cyclopenta [b] quinolin-9-yl amino) hexyl] -13-[(E)-(±) -ethylidene-5-methoxy -11-methyl-6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-1-amine (6, X = H, m = 1 , n = 1)

14) N1- [6- (8-chloro-1,2,3,4-tetrahydro-9-acridinyl amino) hexyl] -13-[(E)-(±) -ethylidene-5-meth Toxy-11-methyl-6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-1-amine (6, X = Cl, m = 2, n = 1)

15) N1- [6- (7-chloro-1,2,3,4-tetrahydro-9-acridinyl amino) hexyl] -13-[(E)-(±) -ethylidene-5-meth Methoxy-11-methyl-6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-1-amine (6, X = Cl, m = 2, n = 1)

16) N1- [6- (6-chloro-1,2,3,4-tetrahydro-9-acridinyl amino) hexyl] -13-[(E)-(±) -ethylidene-5-meth Methoxy-11-methyl-6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-1-amine (6, X = Cl, m = 2, n = 1)

17) N1- [6- (8-Pluor-1,2,3,4-tetrahydro-9-acridinyl amino) hexyl] -13-[(E)-(±) -ethylidene-5- Methoxy-11-methyl-6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-1-amine (6, X = F, m = 2, n = 1)

18) N1- [6- (7-Pluor-1,2,3,4-tetrahydro-9-acridinyl amino) hexyl] -13-[(E)-(±) -ethylidene-5- Methoxy-11-methyl-6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-1-amine (6, X = F, m = 2, n = 1)

19) N1- [6- (5-methyl-1,2,3,4-tetrahydro-9-acridinyl amino) hexyl] -13-[(E)-(±) -ethylidene-5-meth Toxy-11-methyl-6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-1-amine (6, X = CH ₃ , m = 2, n = 1)

20) N11-6- [13 [(E)-(±) -ethylidene-5-methoxy-11-methyl-6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7 ), 3,5,10-tetraen-1-ylamino] hexyl-7,8,9,10-tetrahydro-6H-cyclohepta [b] quinolin-11-amine (6, X = H, m = 3, n = 1)

21) N1- [7- (1,2,3,4-tetrahydro-9-acridinyl amino) heptyl] -13-[(E)-(±) -ethylidene-5-methoxy-11- Methyl-6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-1-amine (6, X = H, m = 2, n = 2)

22) N1- [7- (7-Pluor-1,2,3,4-tetrahydro-9-acridinyl amino) heptyl] -13-[(E)-(±) -ethylidene-5- Methoxy-11-methyl-6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-1-amine (6, X = F, m = 2, n = 2)

23) N1- [7- (6-chloro-1,2,3,4-tetrahydro-9-acridinyl amino) heptyl] -13-[(E)-(±) -ethylidene-5-meth Methoxy-11-methyl-6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-1-amine (6, X = Cl, m = 2, n = 2)

In addition, the present invention includes a method for preparing a hoopsin-tacrine hybrid derivative represented by the formula (1),

1) treating the chloroacridine of formula 2 with hydroxyamine to prepare a hydroxy compound of formula 3;

2) preparing an aldehyde compound of Formula 4 by oxidizing the hydroxy compound of Formula 3;

3) condensing the aldehyde compound of Formula 4 with pyridineamine of Formula 5 to form imine and then reducing the compound to prepare a compound of Formula 6;

4) deprotecting the methyl group of Chemical Formula 6;

It provides a method for producing a hoopsin-tacrine hybrid derivative characterized in that.

Scheme 1

In Scheme 1, X is hydrogen, a halogen group or C ₁ ~ C ₆ alkyl group, m is 1 to 3, n is 1 or 2.

The preparation method of the present invention according to Scheme 1 will be described in more detail by dividing each process as follows.

First, a primary alcohol represented by Chemical Formula 3 is prepared by substituting an amine for a chloride at position C9 of the chloro acridine compound of Chemical Formula 2 with an amine. That is, in the amination process of the present invention, a hydroxy compound is prepared by treating the compound represented by Chemical Formula 2 with hydroxyamine. As the reaction solvent, 1-pentanol or a phenol solvent may be used, but 1-pentanol is most preferred.

Then, the hydroxy compound represented by Chemical Formula 3 is oxidized under moisture removal with an oxidizing agent to prepare an aldehyde compound represented by Chemical Formula 4. The oxidizing agent used in the aldehyde reaction in the alcohol may be used pyridinium chloro chromate (PCC), pyridinium dichromate (PDC), Jones reagent, manganese dioxide (MnO ₂ ), preferably PCC is the best fit. Molecular Sieve powder was used to remove moisture, and dichloromethane was used as a reaction solvent.

In the process of condensation reaction of the aldehyde compound represented by Formula 4 with pyridineamine of Formula 5 to form imine, sodium acetate and molecular sieve 4 Å were used, and the molecular sieve was reacted by effectively removing water as a reaction by-product. To promote this. In the process of reducing the imine to prepare a compound represented by the following formula (6), the reducing agent is sodium borohydride (NaBH ₄ ), sodium cyanoborohydride (NaBH ₃ CN) and the like, preferably sodium borohydride Is suitable. In addition, solvents include anhydrous methanol and ethanol, but methanol is most suitable.

Then, the deprotection reaction of the methyl group attached to the pyridine of the hybrid compound represented by the formula (6) to prepare a hoopin-tacrin hybrid derivative represented by the formula (1) of the present invention. The deprotection reaction for removing the methyl protecting group can be carried out using trimethylsilyl iodide (TMSI).

On the other hand, the pyridineamine compound of the formula (5) used as a condensation material of the present invention is a known compound synthesized in the present laboratory [Reference: Tetrhedron. Lett. 2004, 285-287. Application No. 2004-0025267 The amine compound can be easily synthesized by a known organic synthesis method.

In the following scheme 2, the chloro acridine represented by the formula (2) used as a starting material in the present invention is known from amino benzoic acid [Ref. J.Med.Chem. 2002 , 45 , 2277-2282 shows an example of the synthesis.

Scheme 2

In the preparation method according to Scheme 2, first, the substituted amino benzoic acid represented by Formula (A) is treated with cycloalkanone (B), phosphooxyl chloride (POCl ₃ ), and is represented by Formula ( 2 ). 9-chloro compound was obtained in 75-80% yield [Ref J. Med. Chem., 2002, 45, 2277-2282].

Scheme 3

In the preparation method according to Scheme 3, when the cycloalkenone represented by Chemical Formula (C) is first treated with sodium azide (NaN ₃ ) in a concentrated hydrochloric acid solution, oximes are generated and rearrangement is performed under acidic conditions. Wake up and lactam (D) is obtained in high yield. Ring this lactam with Boc anhydride to obtain Boc-substituted amino acid (E), and then react with ethyl chloroformate under a base to reduce the mixed anhydride with a reducing agent to obtain an alcohol (F). Removal with trifluoro acetic acid (TFA) yielded 7-amino-1-heptanol or 8-amino-octanol (G) from known methods. [Ref. J. Ame. Chem. Soc ., 1954 (76). 2317-2322. Syn. Comm., 1996 , 2641-2649. J. Med. Chem ., 1996 . 1664-1675].

The present invention as described above will be described in more detail based on the following examples, but the present invention is not limited thereto.

Example 1: Azocan-2-one (D)

Cycloheptanone (5.00 g, 44.6 mmol) was dissolved in concentrated hydrochloric acid (23.0 mL), and then NaN ₃ (4.47 g, 68.7 mmol) was added immediately at 0 ° C., stirred for about 15 minutes, and further stirred at room temperature for about 3 hours. Saturated sodium carbonate solution is added until the reaction is basic, the resulting inorganic substance is dissolved in water, extracted with chloroform, dried over anhydrous sodium sulfate, filtered and concentrated to azocaine-2-one D (5.12 g, 90%). Got.

_{^{1 H NMR (200MHz, CDCl 3}} ) δ 6.74 (brs, 1H), 3.26 (t, J = 3.0 Hz, 2H) 2.36 (t, J = 3.5Hz, 2H), 1.75 (d, J = 4.0 Hz, 2H ), 1.53 (brs, 6 H).

Example 2: 7- (tert-butoxycarbonyl) octanoic acid (E)

Azocan-2-one in a two-neck flask (Formula D: 5.00 g, 39.3 mmol) and 5M NaOH (43.2 mL, 216.2 mmol) were added thereto, and the mixture was stirred at reflux for about 5 hours while maintaining an internal temperature of 110 ° C. After cooling to room temperature, water (43.2 mL) was added, and then Di-tert-butyl dicarbonate (9.30 g, 42.8 mmol) dissolved in 1,4-oxane (86.4 mL) was slowly added thereto, and stirred at room temperature for about 2 hours. When the reaction was completed, the mixture was concentrated and diluted with ethyl acetate, pH 2 was adjusted with 0.5MH ₂ SO ₄ solution, and the water layer was extracted with ethyl acetate (3 x 15 mL). The extracted organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. After drying for about 10 minutes, hot hexane (20.0 mL) was added and ethyl acetate was added until the layers were not separated. The crystals produced by standing overnight at -5 ° C or less were filtered and dried to obtain Compound E (4.40 g, 46%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.85 (brs, 1H), 4.59 (brs, 1H), 3.08 (brs, 2H), 2.34 (t, J = 7.0 Hz, 2H), 1.62 (d, J = 7.0 Hz, 2H), 1.57-1.33 (m, 15H).

Example 3: tert-Butyl 7-hydroxyheptylcarbamate (F)

Dissolve 7- (tert-butoxycarbonyl) octanoic acid (Formula E: 3.00 g, 12.2 mmol) and N-Methylmorpholine (1.5 mL, 13.5 mmol) in dry THF (60 mL), then dry THF (60 mL) Ethyl chloroformate (1.28 mL, 13.5 mmol) dissolved in was slowly added at 0 ° C. After stirring at 0 ° C. for about 90 minutes, LiBH ₄ (20.0 mL, 40.3 mmol, 2.0 M in THF) was slowly added to the filtered solution. After raising the solution to room temperature and stirring for 4 hours, the solvent was removed under reduced pressure. The concentrate was dissolved in ethyl acetate, washed three times with water and once with brine, dried over anhydrous magnesium sulfate, filtered and the solvent was removed. F (2.70 g, 96%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 4.47 (brs, 1H), 3.62 (m, 12H), 3.08 (m, 2H), 1.25-1.58 (m, 19H).

Example 4: 7-amino 1-heptenol (G)

tert_butyl 7-hydroxyheptylcarbamate (Formula F: 1.80 g, 7.78 mmol) was dissolved in dry dichloromethane (45.0 mL), and trifulluor acetic acid (45.0 mL) was added thereto, and stirred at room temperature for 2 hours. After completion of the reaction, the solvent was removed and the resulting impure target compound G was used for hydroxylation.

Example 5 9-chloro-2,3-dihydrodo-1H-cyclopenta [b] quinoline (Formula 2, X = H, m = 1)

Cyclohexanone (3.22 mL, 36.5 mmol) was added to 2-aminobenzoic acid (Formula A: 5.00 g, 36.5 mmol), and phosphooxychloride (POCl ₃ , 25 mL) was slowly added at 0 ° C, followed by stirring under reflux for 2 hours. Was done. After cooling to room temperature excess POCl ₃ was removed and the residue was dissolved in ethyl acetate and slowly added until weak basic with saturated potassium carbonate solution in ice bath. The residue obtained by extraction with ethyl acetate (3 x 20 mL), washed once with brine, dried over anhydrous potassium carbonate and concentrated by filtration was purified by silica gel flash column chromatography (hexane: ethyl acetate = 4: 1) to obtain the title compound. (Formula 2: 4.10 g, 61%) was obtained.

¹ H NMR (300MHz, CDCl ₃ ) δ 8.16 (d, J = 8.3 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.68 (ddd, J = 8.3, 6.9, 1.4 Hz, 1H), 7.55 (ddd, J = 8.2, 7.0 , 1.2 Hz, 2H), 3.23 (t, J = 7.7 Hz, 2H), 3.17 (t, J = 7.5 Hz, 2H), 2.25 (quint, J = 7.6 Hz, 2H).

Example 6 9-Chloro-1,2,3,4-tetrahydroacridine (2, X = H, m = 2)

2-aminobenzoic acid The reaction was carried out in the same manner as in Example 5, except that (5.00 g, 36.5 mmol), cyclohexanone (3.78 mL, 36.0 mmol), and phosphooxychloride (25 mL) were used. Purification by silica gel flash column chromatography (hexane: ethyl acetate = 4: 1) afforded the target compound (7.02 g, 88%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.13 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.65 (ddd, J = 8.4, 6.7, & 1.4 Hz, 1H ), 7.56 (ddd, J = 8.3, 7.0, & 1.2 Hz, 1H), 3.11 (t, J = 5.9 Hz, 2H), 2.98 (t, J = 5.9 Hz, 2H), 1.94-1.88 (m, 4H).

Example 7 : 9-chloro-8-fluor-1,2,3,4-tetrahydroacridine (2, X = F, m = 2)

6-fluoro 2-aminobenzoic acid The reaction was carried out in the same manner as in Example 5, except that (1.00 g, 6.40 mmol), cyclohexanone (668 mL, 6.40 mmol), and phosphooxychloride (5 mL) were used. Purification by silica gel flash column chromatography (hexane: ethyl acetate = 4: 1) afforded the target compound (1.13 g, 74%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.77 (d, J = 8.4 Hz, 1H), 7.54 (td, J = 8.4, 5.4 Hz, 1H), 7.16 (dd, J = 7.8, 0.9 Hz, 1H), 3.09, 2.98 (2br, 4H), 1.94 (quint, J = 3.3 Hz, 4H).

Example 8 9-chloro-7-fluor-1,2,3,4-tetrahydroacridine (2, X = F, m = 2)

5-Fluoro 2-aminobenzoic acid (1.00 g, 6.40 mmol), cyclohexanone (668 mL, 6.40 mmol), and POCl 3 (5 mL) were used in the same manner as in Example 5, except that the reaction was carried out. Purification by silica gel flash column chromatography (hexane: ethyl acetate = 4: 1) to obtain the target compound (1.28 g, 85%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.16 (dd, J = 9.3, 6.0 Hz, 1H), 7.60 (dd, J = 9.9, 2.6 Hz, 1H), 7.31 (td, J = 9.9, 2.6 Hz, 1H ), 3.11 (brs, 2H), 3.00 (brs, 2H), 2.01-1.91 (m, 4H).

Example 9 : 8,9-dichloro-1,2,3,4-tetrahydroacridine (2, X = Cl, m = 2)

6-chloro 2-aminobenzoic acid The reaction was carried out in the same manner as in Example 5, except that (1.00 g, 5.83 mmol), cyclohexanone (572 mg, 5.83 mmol), and POCl ₃ (5 mL) were used. Purification by silica gel flash column chromatography (hexane: ethyl acetate = 4: 1) afforded the target compound (1.02 g, 69%).

¹ H NMR (200 MHz, CDCl ₃ ) δ7.94 (d, J = 8.1 Hz, 1H), 7.61 (d, J = 6.1 Hz, 1H), 7.54 (q, J = 8.0 Hz, 1H), 3.11 (brs, 2H), 3.02 (brs, 2H), 1.97 (m, 4H).

Example 10 : 7,9-dichloro-1,2,3,4-tetrahydroacridine (2, X = Cl, m = 2)

5-chloro-2-aminobenzoic acid The reaction was carried out in the same manner as in Example 5, except that (5.00 g, 29.0 mmol), cyclohexanone (3.0 mL, 29.0 mmol), and POCl ₃ (5 mL) were used. Purification by silica gel flash column chromatography (hexane: ethyl acetate = 4: 1) afforded the target compound (4.95 g, 68%).

¹ H NMR (200 MHz, CDCl ₃ ) δ7.92 (d, J = 2.3 Hz, 1H), 7.80 (d, J = 9.0 Hz, 1H), 7.47 (dd, J = 9.0, 2.3 Hz, 1H), 7.45 (dd, J = 9.0, 2.0 Hz, 1H), 3.50 (t, J = 6.3 Hz, 2H), 3.46 (t, J = 7.2 Hz, 2H), 3.03 (brs, 2H), 2.68 (brs, 2H), 1.94-1.90 (m, 4H), 1.71-1.52 (m, 4H), 1.44-1.38 (m, 4H).

Example 11 6,9-dichloro-1,2,3,4-tetrahydroacridine (2, X = Cl, m = 2)

The reaction was carried out in the same manner as in Example 5, except that 4-chloro 2-aminobenzoic acid (5.00 g, 29.0 mmol) and cyclohexanone (2.86 g, 29.0 mmol) were used. Purification by silica gel flash column chromatography (hexane: ethyl acetate = 4: 1) afforded the target compound (6.02 g, 82%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.06 (d, J = 9.0 Hz, 1H), 7.95 (d, J = 2.0 Hz, 1H), 7.45 (dd, J = 9.0, 2.0 Hz, 1H), 3.09 (brs, 2H), 2.97 (brs, 2H), 2.00-1.91 (m, 4H ).

Example 12 9-chloro-5-methyl-1,2,3,4-tetrahydroacridine (2, X = CH ₃ , m = 2)

3-Methyl 2-aminobenzoic acid (5.00 g, 33.1 mmol), cyclohexanone (3.40 mL, 33.1 mmol), and POCl ₃ (25 mL) were reacted in the same manner as in Example 5 above. Purification by silica gel flash column chromatography (hexane: ethyl acetate = 4: 1) gave the target compound (3.00 g, 39%).

¹ H NMR (200 MHz, CDCl ₃ ) δ7.93 (brs, 1 H), 7.87 (d, J = 9.5 Hz, 1H), 7.50 (dd, J = 8.8, 1.5 Hz, 1H), 3.11 (brs, 2H), 3.06-2.98 (m, 2H), 2.56 (s, 3H), 1.95 (quint, J = 3.3 Hz, 4H ).

Example 13 : 11-Chloro-7,8,9,10-tetrahydro-6H-cyclohepta [b] quinolin (2, X = H, m = 3)

2-aminobenzoic acid The reaction was carried out in the same manner as in Example 5, except that (5.00 g, 36.5 mmol), cyclohexanone (4.3 mL, 36.5 mmol), and POCl ₃ (25 mL) were used. Purification by silica gel flash column chromatography (hexane: ethyl acetate = 4: 1) gave the target compound (7.01 g, 83%).

¹ H NMR (300MHz, CDCl ₃ ) δ 8.16 (d, J = 8.3 Hz, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 3.25-3.19 (m, 4H), 1.89-1.70 (m, 6H).

Example 14 6- (2,3-Dihydro-1H-cyclopenta [b] quinolin-9-yl amino) hexane-1-ol (Formula 3, X = H, m = 1, n = 1)

Compound 9-chloro-2,3-dihydrodo-1 H -cyclopenta [b] quinoline (Formula 2: 500 mg, 2.70 mmol) was dissolved in 1-pentanol (15 mL) and then 6-amino 1-hexa Knoll (954 mg, 8.14 mmol) was added and stirred at reflux overnight. When the reaction was completed, the resultant was concentrated and purified by silica gel flash column chromatography (dichloromethane: methanol = 4: 1) to obtain the target compound (540 mg, 70%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.29 (d, J = 8.6 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.59 (t, J = 7.7 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 3.70 (t, J = 7.3 Hz, 2H), 3.60 (dd, J = 6.3, 2.0 Hz, 4H), 3.19-3.14 (m, 2H), 2.16 (quint, J = 7.6 Hz, 2H), 1.74 (brs, 2H), 1.57 (t, J = 6.0 Hz, 2H), 1.59-1.55 (m, 2H), 1.43 (brs, 2H)

Example 15 6- (1,2,3,4-tetrahydroacridin-9-yl amino) hexane-1-ol (3, X = H, m = 1, n = 1)

The reaction was carried out in the same manner as in Example 14, except that the compound (500 mg, 2.30 mmol) prepared in Example 6 and 6-amino-1-hexanol (807 mg, 6.90 mmol) were used. Purification by silica gel column chromatography (dichloromethane: methanol = 4: 1) gave the target compound (602 mg, 88%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.10 (d, J = 8.7 Hz, 1H), 8.00 (d, J = 8.7 Hz, 1H), 7.59 (ddd, J = 8.5, 6.9, & 1.2 Hz, 1H) , 7.36 (ddd, J = 8.3, 7.2, & 1.2 Hz, 1H), 3.93 (brs, 2H), 3.75 (t, J = 7.0 Hz, 2H), 3.50 (td, J = 6.3, 1.2 Hz, 2H) , 3.29 (brs, 2H), 3.02 (brs, 2H), 1.82-1.68 (m, 6H), 1.50-1.34 (m, 6H).

Example 16 6- (8-Fluoro-1,2,3,4-tetrahydro acridin-9-yl amino) hexane-1-ol (3, X = F, m = 2, n = 1 )

Compound prepared in Example 7 The reaction was carried out in the same manner as in Example 14, except that (300 mg, 1.27 mmol) and 6-amino 1-hexanol (448 mg, 3.82 mmol) were used. Purification by silica gel flash column chromatography (dichloromethane: methanol = 4: 1) to obtain the target compound (305 mg, 76%).

¹ H NMR (300MHz, CDCl ₃ ) δ 7.72 (d, J = 8.4 Hz, 1H), 7.42 (dd, J = 14.1, 7.9 Hz, 1H), 6.98 (dd, J = 14.9, 7.7 Hz, 1H), 3.63 (t, J = 6.5 Hz, 2H), 3.33 (t, J = 6.3 Hz, 2H), 3.06 (t, J = 6.5 Hz, 2H), 2.76 (t, J = 6.1 Hz, 2H), 1.95-1.85 (m, 2H), 1.82- 1.79 (m, 2H), 1.65-1.54 (m, 4H), 1.40-1.38 (m, 4H).

Example 17 6- (7-Fluoro-1,2,3,4-tetrahydro acridin-9-yl amino) hexane-1-ol (3, X = F, m = 2, n = 1 )

Compound prepared in Example 8 The reaction was carried out in the same manner as in Example 14, except that (500 mg, 2.12 mmol) and 6-amino 1-hexanol (746 mg, 6.36 mmol) were used. Purification by silica gel flash column chromatography (dichloromethane: methanol = 4: 1) to obtain the target compound (640 mg, 96%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.61 (d, J = 8.4 Hz, 1H), 7.33 (dd, J = 8.0, 6.0 Hz, 1H), 6.89 (dd, J = 14.8, 7.6 Hz, 1H), 3.55 (t, J = 6.5 Hz, 2H), 3.33 (td, J = 7.3, 1.6 Hz, 2H), 2.97 (t, J = 6.6 Hz, 2H), 2.68 (t, J = 6.1 Hz, 2H), 1.90-1.82 (m, 2H), 1.72 (quint, J = 6.0 Hz, 2H), 1.57-1.46 (m, 4H), 1.34-1.29 (m, 4H).

Example 18 6- (8-Chloro-1,2,3,4-tetrahydro acridin-9-yl amino) -hexane-1-ol (3, X = Cl, m = 2, n = One)

Compound prepared in Example 9 (500 mg, 1.98 mmol) and 6-amino 1-hexanol (697 mg, 5.95 mmol) were reacted in the same manner as in Example 14, except that. Purification by silica gel flash column chromatography (dichloromethane: methanol = 4: 1) to obtain the target compound (520 mg, 81%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.85 (dd, J = 7.3, 2.5 Hz, 1H), 7.38 (dd, J = 12.2, 7.7 Hz, 1H), 7.36 (brs, 1H), 5.92 (brs, 1H ), 3.63 (t, J = 6.3 Hz, 2H), 3.24-3.15 (m, 2H), 3.05 (t, J = 6.5 Hz, 2H), 2.76 (t, J = 6.1 Hz, 2H), 2.04-1.75 (m, 4H), 1.70-1.46 (m, 4H), 1.43-1.26 (m, 4H).

Example 19 6- (7-Chloro-1,2,3,4-tetrahydro acridin-9-yl amino) hexane-1-ol (3, X = Cl, m = 2, n = 1 )

Compound prepared in Example 10 The reaction was carried out in the same manner as in Example 14, except that (500 mg, 1.98 mmol) and 6-amino 1-hexanol (697 mg, 5.95 mmol) were used. Purification by silica gel flash column chromatography (dichloromethane: methanol = 4: 1) afforded the target compound (630 mg, 96%).

¹ H NMR (200 MHz, CDCl ₃ ) δ7.92 (d, J = 2.3 Hz, 1H), 7.80 (d, J = 9.0 Hz, 1H), 7.47 (dd, J = 9.0, 2.3 Hz, 1H), 3.50 (t, J = 6.3 Hz, 2H), 3.46 (t, J = 7.2 Hz, 2H), 3.03 (brs, 2H), 2.68 ( brs, 2H), 1.94-1.90 (m, 4H), 1.71-1.52 (m, 4H), 1.44-1.38 (m, 4H).

Example 20 6- (6-Chloro-1,2,3,4-tetrahydro acridin-9-yl amino) hexane-1-ol (3, X = Cl, m = 2, n = 1 )

The reaction was carried out in the same manner as in Example 14, except that the compound (500 mg, 1.98 mmol) prepared in Example 11 and 6-amino-1-hexanol (697 mg, 5.95 mmol) were used. Purification by silica gel flash column chromatography (dichloromethane: methanol = 4: 1) afforded the target compound (300 mg, 46%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.92 (d, J = 2.2 Hz, 1H), 7.91 (d, J = 9.0 Hz, 1H), 7.27 (dd, J = 9.0, 2.2 Hz, 1H), 3.65 (t, J = 6.4 Hz, 4H), 3.52 (t, J = 7.2 Hz, 2H), 3.05 (brs, 2H), 2.66 (brs, 2H), 1.94-1.90 (m, 4H), 1.76-1.49 (m, 4H), 1.69 (quint, J = 6.9 Hz, 2H), 1.58 (quint, J = 6.9 Hz, 2H), 1.46-1.40 (m, 4H).

Example 21 6- (5-methyl-1,2,3,4-tetrahydro acridin-9-yl amino) hexane-1-ol

(3, X = CH ₃ , m = 2, n = 1)

Compound prepared in Example 12 The reaction was carried out in the same manner as in Example 14, except that (500 mg, 2.16 mmol) and 6-amino 1-hexanol (758 mg, 6.47 mmol) were used. Purification by silica gel flash column chromatography (dichloromethane: methanol = 4: 1) afforded the target compound (540 mg, 80%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 7.80 (d, J = 8.2 Hz, 1H), 7.42 (d, J = 6.9 Hz, 1H), 7.22 (d, J = 8.2 Hz, 1H), 7.28 (brs, 1H), 3.64 (t, J = 6.3 Hz, 2H), 3.46 (t, J = 7.2 Hz, 2H), 3.09 (brs, 2H), 2.76 (s, 3H), 1.98-1.89 (m, 4H), 1.67-1.51 (m, 6H), 1.45-1.38 (m, 4H).

Example 22 6- (7,8,9,10-tetrahydro-6H-cyclohepta [b] quinolin-11-yl amino) hexane-1-ol (3, X = H, m = 3, n = 1)

The reaction was carried out in the same manner as in Example 14, except that the compound (500 mg, 2.16 mmol) and 6-amino-1-hexanol (760 mg, 6.50 mmol) prepared in Example 13 were used. Purification by silica gel flash column chromatography (dichloromethane: methanol = 4: 1) afforded the target compound (430 mg, 64%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.07 (d, J = 8.3 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.70 (t, J = 7.7 Hz, 1H), 7.60 (t, J = 7.7 Hz, 1H), 3.61 (t, J = 6.3 Hz, 2H), 3.39 (t, J = 7.2 Hz, 2H), 3.23-3.19 (m, 2H), 2.92-2.88 (m, 2H), 1.88-1.70 (m, 8H), 1.56 (quint, J = 6.6 Hz, 2H), 1.41-1.36 (m, 4H).

Example 23 7- (1,2,3,4-tetrahydroacridin-9-yl amino) heptane-1-ol (3, X = H, m = 2, n = 2)

The reaction was carried out in the same manner as in Example 14, except that the compound (500 mg, 2.30 mmol) prepared in Example 6 and 7-amino-1-heptanol (905 mg, 6.90 mmol) were used. Purification by silica gel flash column chromatography (dichloromethane: methanol = 4: 1) afforded the target compound (530 mg, 74%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 8.15 (d, J = 9.3 Hz, 1H), 8.12 (d, J = 9.3 Hz, 1H), 7.67 (t, J = 7.5 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 3.92-3.86 (m, 2H), 3.14 (t, J = 5.7 Hz, 2H), 2.54 (t, J = 6.3 Hz, 2H), 1.90-1.79 (m, 4H), 1.55-1.38 (m, 10 H).

Example 24: 7- (7-Fluoro-1,2,3,4-tetrahydro-acridin-9-ylamino) -heptane-1-ol (3, X = F, m = 2, n = 2)

Compound prepared in Example 8 The reaction was carried out in the same manner as in Example 14, except that (300 mg, 1.27 mmol) and 7-amino 1-heptanol (500 mg, 3.82 mmol) were used. Purification by silica gel flash column chromatography (dichloromethane: methanol = 4: 1) to obtain the target compound (340 mg, 81%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.19 (dd, J = 9.3, 5.2 Hz, 1H), 7.84 (dd, J = 10.4, 2.4 Hz, 1H), 7.49 (dd, J = 9.0, 2.5 Hz, 1H ), 3.92-3.83 (m, 2H), 3.62 (t, J = 6.3 Hz, 2H), 3.13 (t, J = 6.0 Hz, 2H), 2.59 (t, J = 6.0 Hz, 2H), 1.94-1.91 (m, 4H), 1.82 (quint, J = 7.2 Hz, 2H), 1.57-1.51 (m, 2H), 1.46-1.30 (m, 6H).

Example 25: 7- (6-Chloro-1,2,3,4-tetrahydro-acridin-9-ylamino) -heptane-1-ol (3, X = Cl, m = 2, n = 2)

Compound prepared in Example 11 The reaction was carried out in the same manner as in Example 14, except that (500 mg, 1.98 mmol) and 7-amino 1-heptanol (781 mg, 5.95 mmol) were used. Purification by silica gel flash column chromatography (dichloromethane: methanol = 4: 1) to obtain the target compound (510 mg, 74%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.11 (d, J = 9.0 Hz, 1H), 8.05 (brs, 1H), 7.26 (d, J = 7.7 Hz, 1H), 3.79 (t, J = 7.1 Hz, 2H), 3.64 (t, J = 6.3 Hz, 2H), 3.10 (brs, 2H), 2.66 (brs, 2H), 1.89 (brs, 4H), 1.83-1.78 (m, 2H), 1.56-1.53 (m , 2H), 1.41-1.31 (m, 6H).

Example 26 6- (2,3-Dihydro-1 H -cyclopenta [b] quinolin-9-yl amino) hexan (Formula 4, X = H, m = 2, n = 1)

Compound prepared in Example 14 (Formula 3: 200 mg, 0.703 mmol) was dissolved in dry dichloromethane (20 mL), and then PCC (227 mg, 1.05 mmol) and 4 분자 molecular sieve (Molecular Sieve, 1.0 g) were added, followed by stirring for 3 hours. Filtered through dichloromethane, the solvent was removed under reduced pressure and the residue was purified by silica gel flash column chromatography (dichloromethane: methanol = 10: 1) to give aldehyde (56 mg, 28%). .

Example 27 6- (1,2,3,4-tetrahydroacridin-9-yl amino) hexan (4, X = H, m = 2, n = 1)

In the same manner as in Example 26, except that the compound (200 mg, 0.670 mmol), PCC (288 mg, 1.34 mmol), and 4 ′ powder molecular sieve (300 mg) prepared in Example 15 were used. Reacted. Purification by silica gel flash column chromatography (dichloromethane: methanol = 10: 1) to obtain the target compound (130 mg, 65%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 9.70 (s, 1H), 8.24 (brs, 2H), 7.57 (brs, 1H), 7.36 (brs, 1H), 6.7 (brs, 1H), 3.88 (brs, 2H ), 3.18 (brs, 2H), 2.69 (brs, 2H), 2.43 (brs, 2H), 1.81 (brs, 4H) 1.43 (brs, 2H), 1.21 (brs, 2H).

Example 28 6- (8-Fluoro-1,2,3,4-tetrahydro acridin-9-yl amino) hexan (4, X = F, m = 2, n = 1)

The reaction was carried out in the same manner as in Example 26, except that the compound (146 mg, 0.461 mmol), PCC (300 mg, 1.38 mmol), and 4 ′ powder molecular sieve (300 mg) prepared in Example 16 were used. I was. Purification by silica gel flash column chromatography (dichloromethane: methanol = 10: 1) afforded the target compound (102 mg, 69%).

¹ H NMR (300MHz, CDCl ₃ ) δ 9.81 (s, 1H), 8.03 (brs, 1H), 7.54 (brs, 1H), 7.16-7.05 (m, 1H), 3.48 (brs, 2H), 3.26 (brs, 2H), 2.85 (brs, 2H ), 2.49 (brs, 2H), 1.99-1.90 (m, 4H), 1.73 (brs, 4H), 1.50-1.48 (m, 2H).

Example 29 6- (7-Fluoro-1,2,3,4-tetrahydro acridin-9-yl amino) hexan (4, X = F, m = 2, n = 1)

In the same manner as in Example 26, except that the compound (200 mg, 0.634 mmol) and PCC (547 mg, 2.54 mmol) prepared in Example 17 were used, and 4 μg powder molecular sieve (140 mg) was used. Reacted. Purification by silica gel flash column chromatography (dichloromethane: methanol = 10: 1) gave an impure target compound (167 mg).

Example 30 6- (8-chloro-1,2,3,4-tetrahydro acridin-9-yl amino) hexan (4, X = Cl, m = 2, n = 1)

The reaction was carried out in the same manner as in Example 26, except that the compound (300 mg, 0.90 mmol) prepared in Example 18 and PCC (291 mg, 1.35 mmol) were used. Purification by silica gel flash column chromatography (dichloromethane: methanol = 10: 1) afforded an impure target compound (120 mg, 40%), which was used in the next reaction.

Example 31 6- (7-chloro-1,2,3,4-tetrahydro acridin-9-yl amino) hexan (4, X = Cl, m = 2, n = 1)

The reaction was carried out in the same manner as in Example 26, except that the compound (400 mg, 1.20 mmol) prepared in Example 19 and PCC (387 mg, 1.80 mmol) were used. Purification by silica gel flash column chromatography (dichloromethane: methanol = 10: 1) afforded an impure target compound (200 mg, 34%), which was used in the next reaction.

¹ H NMR (200 MHz, CDCl ₃ ) δ 9.73 (s, 1H), 7.90 (brs, 2H), 7.44 (d, J = 4.8 Hz, 1H), 3.46 (brs, 2H), 3.00 (brs, 2H), 2.43 (t, J = 6.6 Hz, 2H), 1.86 (m, 4H) 1.68-1.62 (m, 4H), 1.39 (brs, 2H).

Example 32 6- (6-Chloro-1,2,3,4-tetrahydro acridin-9-yl amino) hexan (4, X = Cl, m = 2, n = 1)

The reaction was carried out in the same manner as in Example 26, except that the compound (200 mg, 0.60 mmol) prepared in Example 20, PCC (194 mg, 0.90 mmol), and 4 ′ powder molecular sieve (200 mg) were used. . Purification by silica gel flash column chromatography (dichloromethane: methanol = 10: 1) afforded an impure target compound (60 mg, 30%), which was used in the next reaction.

Example 33 6- (5-Methyl-1,2,3,4-tetrahydro acridin-9-yl amino) hexan (4, X = Cl, m = 2, n = 1)

The reaction was carried out in the same manner as in Example 26, except that the compound (200 mg, 0.64 mmol), PCC (207 mg, 0.96 mmol) and 4 ′ powder molecular sieve (1.0 g) prepared in Example 21 were used. . Purification by silica gel flash column chromatography (dichloromethane: methanol = 10: 1) gave an impure target compound (151 mg, 76%).

Example 34: 6- (7,8,9,10-tetrahydro -6 H - cyclohepta [b] quinolin-11-ylamino) hexanal (4, X = H, m = 3, n = 1)

The reaction was carried out in the same manner as in Example 26, except that the compound (200 mg, 0.640 mmol) prepared in Example 22, PCC (206 mg, 0.96 mmol), and 4 ′ powder molecular sieve (1.0 g) were used. . Purification by silica gel flash column chromatography (dichloromethane: methanol = 10: 1) afforded an impure target compound (160 mg, 80%), which was used in the next reaction.

Example 35 7- (1,2,3,4-tetrahydroacridin-9-yl amino) heptanal (4, X = H, m = 2, n = 2)

The reaction was carried out in the same manner as in Example 26, except that the compound (270 mg, 0.864 mmol), PCC (279 mg, 1.29 mmol) and 4 ′ powder molecular sieve (100 mg) prepared in Example 23 were used. . Purification by silica gel flash column chromatography (dichloromethane: methanol = 10: 1) gave an impure target compound (268 mg, 30%) in the next reaction.

Example 36 7- (7-Fluoro-1,2,3,4-tetrahydroacridin-9-yl amino) heptanal (4, X = F, m = 2, n = 2)

The reaction was carried out in the same manner as in Example 26, except that the compound (200 mg, 0.605 mmol) prepared in Example 24, PCC (196 mg, 0.980 mmol), and 4 ′ powder molecular sieve (100 mg) were used. . Purification by silica gel flash column chromatography (dichloromethane: methanol = 10: 1) afforded an impure target compound (192 mg, 97%), which was used in the next reaction.

Example 37 : 7- (6-Chloro-1,2,3,4-tetrahydroacridin-9-yl amino) heptanal (4, X = Cl, m = 2, n = 2)

Compound 25 (400 mg, 1.15 mmol) was dissolved in dry dichloromethane (20 mL), and PCC (373 mg, 1.73 mmol) and 4 Å molecular sieve (300 mg) were added and stirred for 2 hours. After filtering with dichloromethane using Celite 545, the filtrate was concentrated under reduced pressure and purified by column chromatography (dichloromethane: methanol = 10: 1) to obtain the target compound (125 mg, 31%).

Example 38 N1- [6- (1,2,3,4-tetrahydro-9-acridinyl amino) hexyl] -13-[(E)-

( ± ) -ethylidene-5-methoxy-11-methyl-6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraene-1- Amine (Formula 6, X = H, m = 2, n = 1)

pyridine amine (Formula 5: 50 mg, 0.195 mmol) was dissolved in dry MeOH (5 mL), and the compound prepared in Example 27 (Formula 4: 86.7 mg, 0.293 mmol), NaOAc (32 mg, 0.390 mmol), 4 μg powder molecular sieve (300 mg) was added and stirred overnight at room temperature. After completion of the reaction, methanol was concentrated and removed, water was added, extracted with dichloromethane (3 X 5 mL), dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, dried over anhydrous methanol (5 mL), and dried over NaBH. ₄ (14.8 mg, 0.39 mmol) was added and the mixture was stirred overnight at room temperature. After completion of the reaction, methanol was concentrated to remove the solution, added with water, extracted with dichloromethane (3 X 5 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, followed by silica gel column chromatography (dichloromethane: methanol = 10). : 1) to obtain the target compound (68 mg, 65%).

¹ H NMR (300MHz, CDCl ₃ ) δ 8.05 (d, J = 8.4 Hz, 1H), 7.98 (d, J = 8.4 Hz, 2H), 7.64 (t, J = 7.6 Hz, 2H), 7.58 (t, J = 7.6 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 6.57 (d, J = 8.5 Hz, 1H), 5.39 (m, 1H), 5.35 (q, J = 6.9 Hz, 1H), 3.88 (s, 3H), 3.62 (m, 1H), 3.55 (t, J = 7.1 Hz, 2H), 3.12 (brs, 2H), 2.92 (dd, J = 16.6, 4.5 Hz, 1H), 2.79 (d, J = 16.2 Hz, 1H), 2.67 (brs, 2H), 2.44-2.38 (m, 2H), 2.23 (d, J = 16.0 Hz, 1H), 2.09-2.06 ( m, 2H), 1.98 (brs, 4H), 1.72 (d, J = 6.8 Hz, 3H), 1.74-1.63 (m, 2H), 1.47 (s, 3H), 1.45-1.32 (m, 5H).

Example 39 N1- [6- (2,3-Dihydro-1H-cyclopenta [b] quinolin-9-yl amino) hexyl] -13-[(E)-( ± ) -ethylidene-5- Methoxy-11-methyl-6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-1-amine (6, X = H, m = 1, n = 1)

Compound prepared in Example 26 (Formula 4: 56 mg, 0.198 mmol), pyridine amine (Formula 5: 34 mg, 0.133 mmol), sodium acetate (21.7 mg, 0.265 mmol), and 4 ′ powder molecular sieve (200 mg The reaction was carried out in the same manner as in Example 37, except that it was used. Purification by silica gel flash column chromatography (dichloromethane: methanol = 10: 1) afforded the target compound (48 mg, 70%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.02 (d, J = 8.4 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H). 7.54 (t, J = 7.5 Hz, 1H), 7.36 (t, J = 7.5 Hz, 1H), 6.58 (d, J = 8.4 Hz, 1H), 5.43-5.38 (m, 2H), 3.88 (s, 3H ), 3.62 (brs, 2H), 3.17-3.07 (m, 3H), 2.96 (dd, J = 16.2, 4.8 Hz, 1H), 2.80 (d, J = 16.2 Hz, 1H), 2.42-2.29 (m, 2H), 2.14-2.04 (m, 4H), 1.73 (d, J = 6.6 Hz, 3H), 1.47 (s, 3H), 1.72-1.68 (m, 1H), 1.58-1.48 (m, 4H), 1.40 (brs, 2 H), 1.23 (m, 2 H).

Example 40 N1- [6- (8-Fluoro-1,2,3,4-tetrahydro-9-acridinyl amino) hexyl] -13-[(E)-( ± ) -ethylidene-5 -Methoxy-11-methyl-6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-1-amine (6, X = F, m = 2, n = 1)

Compound prepared in Example 28 (Formula 4: 102 mg, 0.325 mmol), pyridine amine (Formula 5: 56 mg, 0.217 mmol), sodium acetate (36.0 mg, 0.434 mmol), and 4 ′ powder molecular sieve (300 mg) The reaction was carried out in the same manner as in Example 37, except that was used. Purification by silica gel flash column chromatography (dichloromethane: methanol = 10: 1) afforded the target compound (75 mg, 62%).

¹ H NMR (300MHz, CDCl ₃ ) δ 7.68 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.45-7.38 (m, 1H), 6.96 (dd, J = 15.0, 7.7 Hz, 1H), 6.57 ( d, J = 8.5 Hz, 1H), 5.39 (m, 1H), 5.35 (q, J = 6. 8 Hz, 1H), 3.87 (s, 3H), 3.62 (brs, 1H), 3.30-3.26 (m , 2H), 3.05 (t, J = 6.6 Hz, 2H), 2.96 (dd, J = 17.0, 4.6 Hz, 1H), 2.78 (d, J = 17.0 Hz, 1H), 2.76 (t, J = 6.0 Hz , 2H), 2.40-2.33 (m, 1H), 2.22 (d, J = 16.5 Hz, 1H), 2.10-2.03 (m, 2H), 1.98-1.92 (m, 2H), 1.82-1.79 (m, 2H ), 1.74-1.68 (m, 2H), 1.72 (d, J = 6.7 Hz, 3H), 1.65-1.55 (m, 2H), 1.51-1.40 (m, 2H), 1.48 (s, 3H), 1.35- 1.30 (m, 3 H).

Example 41 N1- [6- (7-Fluoro-1,2,3,4-tetrahydro-9-acridinyl amino) hexyl] -13-[(E)-( ± ) -ethylidene-5 -Methoxy-11-methyl-6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-1-amine (6, X = F, m = 2, n = 1)

The compound prepared in Example 29 (Formula 4: 50.2 mg, 0.234 mmol), pyridine amine (Formula 5: 40 mg, 0.156 mmol), sodium acetate (25.6 mg, 0.312 mmol), and 4 ′ powder molecular sieve (200 mg) The reaction was carried out in the same manner as in Example 38, except that was used. Purification by silica gel flash column chromatography (dichloromethane: methanol = 10: 1) afforded the target compound (74 mg, 86%).

¹ H NMR (300MHz, CDCl ₃ ) δ 7.97 (q, J = 4.6 Hz, 2H), 7.64 (t, J = 8.3 Hz, 2H), 7.38-7.27 (m, 1H), 6.58 (d, J = 8.0 Hz, 1H), 5.39-5.36 ( m, 2H), 3.90 (s, 3H), 3.63 (brs, 1H), 3.50-3.36 (m, 2H), 3.07 (brs, 2H), 2.93 (d, J = 4.0 Hz, 2H), 2.70 (brs , 2H), 2.44-2.06 (m, 4H), 1.93 (s, 8H), 1.74-1.61 (m, 3H), 1.48 (s, 3H), 1.74-1.27 (m, 4H).

Example 42 N1- [6- (8-chloro-1,2,3,4-tetrahydro-9-acridinyl amino) hexyl] -13-[(E)-( ± ) -ethylidene-5 -Methoxy-11-methyl-6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-1-amine (6, X = Cl, m = 2, n = 1)

Compound prepared in Example 30 (Formula 4: 120 mg, 0.362 mmol), pyridine amine (Formula 5: 46.0 mg, 0.181 mmol), NaOAc (30.0 mg, 0.362 mmol), and 4 ′ powder molecular sieve (300 mg) The reaction was carried out in the same manner as in Example 38, except that was used. Purification by silica gel flash column chromatography (dichloromethane: methanol = 10: 1) afforded the target compound (69.0 mg, 66%).

¹ H NMR (300MHz, CDCl ₃ ) δ 7.88 (dd, J = 9.2, 5.7 Hz, 2H), 7.66 (d, J = 8.5 Hz, 1H), 7.56 (dd, J = 10.7, 2.7 Hz, 1H), 7.32 (td. J = 8.6, 2.7 Hz, 1H), 6.57 (d, J = 8.6 Hz, 1H), 5.39 (m, 1H), 5.35 (q, J = 6.6 Hz, 1H), 3.89 (s, 3H), 3.62 (brs, 1H) , 3.42 (t, J = 7.2 Hz, 2H), 3.04 (brs, 2H), 2.97 (dd, J = 16.5, 4.6 Hz, 1H), 2.79 (d, J = 16.0 Hz, 1H), 2.71 (brs, 2H), 2.43-2.29 (m, 1H), 2.23 (d, J = 16.0 Hz, 1H), 2.11-2.04 (m, 2H), 1.92 (m, 4H), 1.72 (d, J = 6.6 Hz, 3H ) 1.69-1.59 (m, 3H), 1.48 (s, 3H), 1.45-1.30 (m, 5H).

Example 43 N1- [6- (7-Chloro-1,2,3,4-tetrahydro-9-acridinyl amino) hexyl] -13-[(E)-( ± ) -ethylidene-5 -Methoxy-11-methyl-6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-1-amine (6, X = Cl, m = 2, n = 1)

The compound prepared in Example 31 (Formula 4: 110.0 mg, 0.330 mmol) and pyridine amine (Formula 5: 43.0 mg, 0.170 mmol), sodium acetate (28.0 mg, 0.330 mmol), and 4 ′ powder molecular sieve (300 mg) The reaction was carried out in the same manner as in Example 38, except that was used. Purification by silica gel flash column chromatography (dichloromethane: methanol = 10: 1) afforded the target compound (61.4 mg, 62%).

¹ H NMR (300MHz, CDCl ₃ ) δ 7.93 (d, J = 2.1 Hz, 1H), 7.89 (d J = 9.0 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.48 (dd, J = 9.0, 1.8 Hz, 1H), 6.57 (d, J = 8.5 Hz, 1H), 5.39-5.36 (m, 2H), 3.88 (s, 3H), 3.67 (brs, 1H), 3.47 (t, J = 7.1 Hz, 2H), 3.05 (brs , 2H), 2.96 (dd, 17.0, 4.8 Hz, 1H), 2.79 (d, J = 16.9 Hz, 1H), 2.66 (brs, 2H), 2.44-2.38 (m, 1H), 2.22 (d, J = 16.9 Hz, 1H), 2.12-2.04 (m, 2H), 1.90 (brs, 4H), 1.72 (d, J = 6.6 Hz, 3H), 1.71-1.64 (m, 2H), 1.47 (brs, 5H), 1.37-1.33 (m, 4 H).

Example 44 N1- [6- (6-Chloro-1,2,3,4-tetrahydro-9-acridinyl amino) hexyl] -13-[(E)-( ± ) -ethylidene-5 -Methoxy-11-methyl-6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-1-amine (6, X = Cl, m = 2, n = 1)

The compound prepared in Example 32 (Formula 4: 60.0 mg, 0.18 mmol) and pyridine amine (Formula 5: 31.0 mg, 0.120 mmol), sodium acetate (20.0 mg, 0.180 mmol), and 4 ′ powder molecular sieve (300 mg) The reaction was carried out in the same manner as in Example 38, except that was used. Purification by silica gel flash column chromatography (dichloromethane: methanol = 10: 1) afforded the target compound (54.0 mg, 79%).

¹ H NMR (300MHz, CDCl ₃ ) δ 7.88 (dd, J = 5.5, 3.6 Hz, 2H), 7.64 (d, J = 8.6 Hz, 1H), 7.28-7.24 (m, 1H), 6.57 (d, J = 8.6 Hz, 1H), 5.38 (brs, 1H), 5.35 (q, J = 6.9 Hz, 1H), 3.88 (s, 3H), 3.66 (s, 1H), 3.62 (brs, 1H), 3.50-3.43 (m, 2H), 3.02- 2.93 (m, 3H), 2.79 (d, J = 16.8 Hz, 1H), 2.65 (brs, 2H), 2.41-2.20 (m, 3H), 2.11-1.98 (m, 3H), 1.91 (brs, 5H) , 1.72 (d, J = 6.9 Hz, 3H), 1.71-1.64 (m, 2H), 1.47 (brs, 5H), 1.37-1.33 (m, 4H).

Example 45 N1- [6- (5-Methyl-1,2,3,4-tetrahydro-9-acridinyl amino) hexyl] -13-[(E)-( ± ) -ethylidene-5 -Methoxy-11-methyl-6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-1-amine (6, X = CH3, m = 2, n = 1)

The compound prepared in Example 33 (Formula 4: 91.0 mg, 0.293 mmol), pyridine amine (Formula 5: 50.0 mg, 0.195 mmol), sodium acetate (32.0 mg, 0.390 mmol), and 4 ′ powder molecular sieve (300 mg) The reaction was carried out in the same manner as in Example 38, except that was used. Purification by silica gel flash column chromatography (dichloromethane: methanol = 10: 1) afforded the target compound (50.0 mg, 46%).

^OneH NMR (300MHz, CDCl₃) δ 7.80 (d,J= 8.3 Hz, 1H), 7.65 (dJ= 8.3 Hz, 1H), 7.41 (d,J = 6.8 Hz, 1H), 7.23 (d,J= 8.2 Hz, 1H), 6.57 (d,J = 8.5 Hz, 1H), 5.39-5.34 (m, 2H), 3.88 (s, 3H), 3.62 (brs, 1H), 3.45-3.40 (m, 2H), 3.11 (brs, 2H), 2.96 (dd, 17.0, 4.8 Hz, 1H), 2.76 (s, 3H), 2.82-2.63 (m, 4H), 2.43-2.20 (m, 2H), 2.10-1.99 (m, 2H), 1.91 (brs, 4H), 1.71 (d,J = 6.6 Hz, 3H), 1.70-1.59 (m, 3H), 1.48 (s, 3H), 1.49-1.41 (m, 1H), 1.39-1.30 (m, 3H).

Example 46: N11-6- [13 [(E)-( ± ) -ethylidene-5-methoxy-11-methyl-6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-1-ylamino] hexyl-7,8,9,10-tetrahydro-6H-cyclohepta [b] quinolin-11-amine (6, X = H, m = 3, n = 1)

The compound prepared in Example 34 (Formula 4: 73.0 mg, 0.257 mmol), pyridine amine (Formula 5: 44.0 mg, 0.171 mmol), sodium acetate (28.0 mg, 0.34 mmol), and 4 ′ powder molecular sieve (300 mg) The reaction was carried out in the same manner as in Example 38, except that was used. Purification by silica gel flash column chromatography (dichloromethane: methanol = 10: 1) afforded the target compound (72 mg, 79%).

¹ H NMR (300MHz, CDCl ₃ ) δ 8.11 (d, J = 8.3 Hz, 1H), 7.95 (d, J = 8.3 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.41 (t, J = 8.6 Hz, 1H), 6.58 (d, J = 8.6 Hz, 1H), 5.38 (q, J = 6.5 Hz, 2H), 3.88 (s, 3H), 3.64 (brs, 2H), 3.38 (t, J = 7.2 Hz, 2H), 3.26-3.22 (m, 2H), 2.97 (dd, J = 16.4, 4.8 Hz, 1H), 2.90-2.86 (m, 1H), 2.79 (dd, J = 16.5 , 1.6 Hz, 1H), 2.44-2.27 (m, 2H), 2.12-2.03 (m, 2H), 1.88-1.69 (m, 9H), 1.72 (d, J = 6.8 Hz, 3H) 1.48 (s, 3H ), 1.53-1.32 (m, 5H).

Example 47 N1- [7- (1,2,3,4-tetrahydro-9-acridinyl amino) heptyl] -13-[(E)-

( ± ) -ethylidene-5-methoxy-11-methyl-6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraene-1- Amines (6, X = H, m = 2, n = 2)

pyridine amine (Formula 5: 22.0 mg, 0.086 mmol) was dissolved in dry MeOH (3 mL) and then 7- (1,2,3,4-Tetrahydro-acridine-9-ylamino) -heptanal (40.0 mg, 0.129 mmol) Sodium acetate (14.0 mg, 0.172 mmol) and 4x powder molecular sieve (500 mg) were added and stirred at room temperature for 4 days. After completion of the reaction, MeOH was concentrated and removed, water was added and extracted with dichloromethane (3 x 2 mL), dried over anhydrous magnesium sulfate to remove the solvent, dried and dissolved in anhydrous methanol (3 mL), followed by NaBH ₄ ( 7.00 mg, 0.172 mmol) and stirred overnight at room temperature. After completion of the reaction, methanol was removed, water was added, extracted with dichloromethane (3 x 2 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, followed by silica gel column chromatography (dichloromethane: methanol = 10 : 1) to obtain the target compound (21.0 mg, 45%).

¹ H NMR (300MHz, CDCl ₃ ) δ 8.17 (brs, 1 H), 8.10 (d, J = 8.5 Hz, 1 H), 7.69 (d, J = 8.5 Hz, 1 H), 7.65 (t, J = 7.7 Hz, 1 H), 7.44-7.38 (m, 1H), 6.59 (d, J = 8.5 Hz, 1H), 5.38-5.31 (m, 2H), 3.89 (s, 3H), 3.75 (t, J = 7.0 Hz, 2H), 3.67-3.63 (m, 1H ), 3.16 (brs, 2H), 2.90 (dd, J = 16.5, 4.6 Hz 1H), 2.77 (d, J = 17 Hz, 1H), 2.61 (brs, 2H), 2.43-2.04 (m, 4H), 1.91 (.s, 4H), 1.73 (d, J = 6.6 Hz, 3H), 1.48 (s, 3H), 1.77-1.25 (m, 10H).

Example 48 N1- [7- (7-Fluoro-1,2,3,4-tetrahydro-9-acridinyl amino) heptyl] -13-[(E)-( ± ) -ethylidene-5 -Methoxy-11-methyl-6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-1-amine (6, X = F, m = 2, n = 2)

Compound prepared in Example 36 (Formula 4: 57.0 mg, 0.175 mmol), pyridine amine (Formula 5: 30.0 mg, 0.120 mmol), sodium acetate (20.0 mg, 0.240 mmol), and 4 ′ powder molecular sieve (300 mg) The reaction was carried out in the same manner as in Example 38, except that was used. Purification by silica gel flash column chromatography (dichloromethane: methanol = 10: 1) afforded the target compound (18.0 mg, 26%).

¹ H NMR (300MHz, CDCl ₃ ) δ 7.87 (d, J = 7.5 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.43-7.35 (m, 2H), 6.57 (d, J = 8.5 Hz, 1H), 5.38 (m, 1H), 5.36 (q, J = 6.6 Hz, 1H), 3.89 (s, 3H), 3.66-3.62 (brs, 2H) 3.22 (t, J = 7.2 Hz, 2H), 3.07 (t, J = 6.6 Hz , 2H), 2.97 (dd, J = 16.5, 4.5 Hz, 1H), 2.81-2.74 (m, 3H), 2.43-2.35 (m, 1H), 2.23 (d, J = 16.0 Hz, 1H), 2.11- 2.04 (m, 2H), 1.98-1.93 (m, 3H), 1.83-1.71 (m, 3H), 1.72 (d, J = 6.6 Hz, 3H), 1.66-1.57 (m, 3H), 1.48 (s, 3H), 1.43-1.34 (m, 4H).

Example 49: N1- [7- (6-Chloro-1,2,3,4-tetrahydro-9-acridinyl amino) heptyl] -13-[(E)-( ± ) -ethylidene-5 -Methoxy-11-methyl-6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-1-amine (6, X = Cl, m = 2, n = 2)

The compound prepared in Example 37 (Formula 4: 125 mg, 0.362 mmol) and pyridine amine (Formula 5: 62 mg, 0.242 mmol), sodium acetate (40 mg, 0.484 mmol), and 4 ′ powder molecular sieve (500 mg Was reacted in the same manner as in Example 37, except that was used. Purification by silica gel flash column chromatography (dichloromethane: methanol = 10: 1) afforded the target compound (45 mg, 32%).

¹ H NMR (300MHz, CDCl ₃ ) δ 7.93 (d, J = 2.1 Hz, 1H), 7.89 (d, J = 9.0 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.48 (dd, J = 9.0, 1.8 Hz, 1H) , 6.57 (d, J = 8.5 Hz, 1H), 5.39-5.36 (m, 2H), 3.88 (s, 3H), 3.67 (brs, 1H), 3.47 (t, J = 7.1 Hz, 2H), 3.05 ( brs, 2H), 2.96 (dd, J = 17.0, 4.8 Hz, 1H), 2.79 (d, J = 16.9 Hz, 1H), 2.66 (brs, 2H), 2.44-2.38 (m, 1H), 2.22 (d , J = 16.9 Hz, 1H), 2.12-2.04 (m, 2H), 1.90 (brs, 4H), 1.72 (d, J = 6.6 Hz, 3H), 1.71-1.64 (m, 2H), 1.47 (brs, 5H), 1.37-1.33 (m, 4H).

Example 50 13-[(E)-( ± ) -ethylidene-11-methyl-6- (1,2,3,4-tetrahydro-9-acridinylamino) hexylamino] -6-aza Tricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-5-one (Formula 1; X = H, m = 2, n = 1)

The compound prepared in Example 38 (Formula 6; 50.0 mg, 0.093 mmol) was dissolved in dry chloroform (5.0 mL), TMSI (68.5 mL, 0.465 mmol) was added at room temperature under argon atmosphere, and the mixture was stirred under reflux for 5 hours. After the reaction was completed, the mixture was cooled, concentrated under reduced pressure, and the residue was dissolved in methanol (5 mL), followed by stirring under reflux for 18 hours. After completion of the reaction, the solvent was removed, 10% NaHCO ₃ and dichloromethane were added, the organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and silica gel flash column chromatography (dichloromethane: methanol = 4: 1 ) To give the target compound (38 mg, 78%).

¹ H NMR (300MHz, CDCl ₃ ) δ 8.37 (d, J = 8.7 Hz, 1H), 8.11 (d, J = 8.6 Hz, 1H), 7.64 (t, J = 7.7 Hz, 1H), 7.59 (d, J = 9.4 Hz, 1H), 7.42 (t, J = 7.7 Hz, 1H), 6.43 (d, J = 9.3 Hz, 1H), 5.37 (brs, 1H), 5.33 (q, J = 6.5 Hz, 1H), 5.15 (brs, 1H), 3.84 -3.75 (m, 2H), 3.69 (t, J = 5.7 Hz, 1H), 3.57 (brs, 1H), 3.39 (dd, J = 5.3, 3.0 Hz, 1H), 2.27-2.24 (m, 1H), 2.86 (dd, J = 16.9, 4.3 Hz, 1H), 2.68-2.61 (m, 3H), 2.49-2.40 (m, 2H), 2.17-2.11 (m, 2H), 1.92-1.86 (m, 4H), 1.80-1.78 (m, 2H) , 1.67 (d, J = 6.7 Hz, 3H), 1.52 (s, 3H), 1.49-1.32 (m, 5H).

Example 51 : 11- [6- (2,3-Dihydro-1H-cyclopenta [b] quinolin-9ylamino) hexylamino] -3-[(E)-( ± ) -ethylidene] -11 -Methyl-6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-5-one (1, X = H, m = 1, n = 1)

The reaction was carried out in the same manner as in Example 50, except that the compound prepared in Example 39 (Formula 6: 30 mg, 0.057 mmol) and TMSI (42 mL, 0.287 mmol) were used. Purification by silica gel flash column chromatography (dichloromethane: methanol = 4: 1) to obtain the target compound (26.0 mg, 90%).

¹ H NMR (300MHz, CDCl ₃ ) δ 11.31 (s, 1H), 8.41 (d, J = 8.5 Hz, 1H), 7.85-7.71 (m, 2H), 7.62-7.57 (m, 1H), 7.51 (d, J = 9.5 Hz, 2H), 6.14 (d, J = 9.5 Hz, 1H), 5.39-5.32 (m, 2H), 3.67-3.65 (m, 3H), 3.50-3.20 (s, 2H), 3.10 (t, J = 7.8 Hz , 4H), 3.50-3.07 (m, 9H), 2.29-1.91 (m. 4H), 1.60 (d, J = 6.7 Hz, 3H), 1.47 (s, 3H), 1.72-1.23 (m, 8H).

Example 52 : 13-[(E)-( ± ) -ethylidene-6- (8-fluor-1,2,3,4-tetrahydro-9-acridinylamino) hexylamino] -11-methyl -6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-5-one (1, X = F, m = 2, n = 1 )

The reaction was carried out in the same manner as in Example 50, except that the compound (Formula 6; 40.0 mg, 0.072 mmol) prepared in Example 40 and TMSI (51 mL, 0.361 mmol) were used. Purification by silica gel flash column chromatography (dichloromethane: methanol = 10: 1) afforded the target compound (21.0 mg, 54%).

¹ H NMR (300MHz, CDCl ₃ ) δ 8.15 (d, J = 8.5 Hz, 1H), 7.62 (d, J = 9.4 Hz, 1H), 7.54 (dd, J = 8.1, 5.9 Hz, 1H), 7.09 (dd, J = 15.0, 7.8 Hz, 1H), 6.44 (d, J = 9.4 Hz, 1H), 5.37-5.33 (m, 2H), 3.56-3.51 (m, 3H), 3.26 (t, J = 6.5 Hz, 2H), 2.84-2.81 (m , 3H), 2.70 (d, J = 16.0 Hz, 1H), 2.49-2.45 (m, 1H), 2.20-2.17 (m, 2H), 2.12-2.04 (m, 1H), 1.98-1.91 (m, 2H) , 1.83-1.80 (m, 2H), 1.68 (d. J = 6.6 Hz, 3H), 1.70-1.64 (m. 2H), 1.51 (s, 3H), 1.54-1.47 (m, 2H), 1.39-1.36 (m, 2 H), 1.26 (s, 2 H).

Example 53 13-[(E)-( ± ) -ethylidene-6- (7-fluor-1,2,3,4-tetrahydro-9-acridinylamino) hexylamino] -11-methyl -6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-5-one (1, X = F, m = 2, n = 1 )

The reaction was carried out in the same manner as in Example 50, except that the compound (Formula 6; 50.0 mg, 0.090 mmol) prepared in Example 41 and TMSI (66 mL, 0.450 mmol) were used. Purification by silica gel flash column chromatography (dichloromethane: methanol = 4: 1) to obtain the target compound (30.0 mg, 61%).

¹ H NMR (300MHz, CDCl ₃ ) δ 8.34 (dd, J = 9.0, 5.4 Hz, 1H), 7.84 (dd, J = 10.5, 2.7 Hz, 1H), 7.65 (d, J = 9.3 Hz, 1H), 7.49 (td, J = 9.0, 2.1 Hz, 1H), 6.43 (d, J = 9.3 Hz, 1H), 5.38-5.33 (m, 2H), 3.81 (t, J = 7.2 Hz, 2H), 3.60 (brs, 1H), 3.23-3.19 (m , 2H), 2.91-2.80 (m, 1H), 2.66-2.45 (m, 5H), 2.19-2.03 (m, 4H), 1.92-1.79 (m. 7H), 1.71 (d, J = 6.6 Hz, 3H ), 1.53 (s, 3 H), 1.50-1.42 (m, 3 H).

Example 54 13-[(E)-( ± ) -ethylidene-6- (8-chloro-1,2,3,4-tetrahydro-9-acridinylamino) hexylamino] -11-methyl -6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-5-one (1, X = Cl, m = 2, n = 1 )

The reaction was carried out in the same manner as in Example 50, except that the compound (Formula 6; 45.0 mg, 0.078 mmol) prepared in Example 42 and TMSI (56.0 mL, 0.392 mmol) were used. Purification by silica gel flash column chromatography (dichloromethane: methanol = 4: 1) afforded the target compound (38.0 mg, 86%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.35 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 9.3 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.45 (dd, J = 7.5, 1.2 Hz, 1H), 6.46 (d, J = 9.4 Hz, 1H), 5.41-5.36 (m, 2H), 3.58-3.50 (m, 3H), 3.28 (t, J = 6.3 Hz, 2H ), 2.93-2.72 (m, 4H), 2.53-2.44 (m, 1H), 2.25-2.19 (m, 2H), 2.08-2.03 (m, 2H), 1.95-1.90 (m, 2H), 1.84-1.79 (m, 2H), 1.75-1.70 (m, 2H), 1.68 ( d. J = 6.6 Hz, 3H ), 1.63-1.57 (m, 2H), 1.51 (s, 3H), 1.39-1.36 (m, 5H).

Example 55 13-[(E)-( ± ) -ethylidene-6- (7-chloro-1,2,3,4-tetrahydro-9-acridinylamino) hexylamino] -11-methyl -6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-5-one (1, X = Cl, m = 2, n = 1 )

The reaction was carried out in the same manner as in Example 50, except that the compound (Formula 6; 40.0 mg, 0.070 mmol) prepared in Example 43 and TMSI (51 mL, 0.350 mmol) were used. Purification by silica gel flash column chromatography (dichloromethane: methanol = 10: 1) afforded the target compound (33.0 mg, 85%).

¹ H NMR (300MHz, CDCl ₃ ) δ 8.26 (d, J = 9.0 Hz, 1H), 8.15 (d, J = 1.8 Hz, 1H), 7.70 (d, J = 9.3 Hz, 1H), 7.58 (dd, J = 9.1, 1.8 Hz, 1H) , 6.46 (d, J = 9.3 Hz, 1H), 5.41-5.37 (m, 2H), 3.82 (t, J = 7.1 Hz, 2H), 3.59 (brs, 1H), 3.20-3.16 (m, 2H), 2.87 (dd, J = 9.3, 3.9 Hz, 1H), 2.70-2.65 (m, 4H ), 2.57-2.47 (m, 3H), 2.25-2.04 (m, 4H), 1.92-1.81 (m, 5H), 1.69 (d. J = 6.7 Hz, 3H) , 1.52 (s, 3H), 1.58-1.51 (m, 2H), 1.47-1.39 (m, 3H).

Example 56 13-[(E)-( ± ) -ethylidene-6- (6-chloro-1,2,3,4-tetrahydro-9-acridinylamino) hexylamino] -11-methyl -6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-5-one (1, X = Cl, m = 2, n = 1 )

The reaction was carried out in the same manner as in Example 50, except that the compound (Formula 7; 40.0 mg, 0.070 mmol) prepared in Example 44 and TMSI (51 mL, 0.350 mmol) were used. Purification by silica gel flash column chromatography (dichloromethane: methanol = 10: 1) afforded the target compound (30.0 mg, 76%).

¹ H NMR (300MHz, DMSO-d ₆ ) δ 8.33 (d, J = 9.0 Hz, 1H), 7.80 (d, J = 2.0 Hz, 1H), 7.55 (d, J = 9.2, 2.0 Hz, 1H), 6.18 (d, J = 9.0 Hz, 1H) , 5.38-5.33 (m, 2H), 3.71 (brd, J = 5.1 Hz, 2H), 3.53-3.49 (m, 2H), 2.95 (brs, 2H), 2.74 (brs, 3H), 1.98-1.92 (m , 2H), 1.92 (brs, 3H), 1.64 (d. J = 6.6 Hz, 1H), 1.68-1.60 (m, 2H), 1.50 (s, 3H), 1.53-1.49 (m, 2H), 1.29- 1.25 (m, 6 H).

Example 57 13-[(E)-( ± ) -ethylidene-6- (5-methyl-1,2,3,4-tetrahydro-9-acridinylamino) hexylamino] -11- Methyl-6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-5-one (1, X = CH ₃ , m = 2, n = 1)

The reaction was carried out in the same manner as in Example 50, except that the compound (Formula 6; 40.0 mg, 0.072 mmol) prepared in Example 45 and TMSI (51 mL, 0.362 mmol) were used. Purification by silica gel flash column chromatography (dichloromethane: methanol = 10: 1) afforded the target compound (30 mg, 77%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.09 (d, J = 8.7 Hz, 1H), 7.69 (d, J = 9.3 Hz, 1H), 7.52 (d, J = 7.2 Hz, 1H), 7.36 (dd, J = 8.7, 7.3 Hz, 1H), 6.45 (d, J = 9.3 Hz, 1H), 5.40-5.36 (m, 2H), 3.89 (t, J = 7.1 Hz, 2H), 3.58 (brs, 1H), 3.38 (brs, 2H), 2.91-2.84 (m, 1H), 2.85 (s, 3H), 2.72-2.65 (m, 3H), 2.49-2.02 (m, 5H), 1.88 (brs, 7H), 1.68 ( d. J = 6.6 Hz, 3H ), 1.51 (s, 3H), 1.55-1.50 (m, 3H), 1.40 (brs, 3H).

Example 58 13-[(E)-( ± ) -ethylidene-11-methyl-1-6- (7,8,9,10-tetrahydro-6 H -cyclohepta [b] quinoline-11- Monoamino) hexylamino]-6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-5-one (Formula 1, X = H , m = 3, n = 1)

The reaction was carried out in the same manner as in Example 50, except that the compound (Formula 6; 50 mg, 0.091 mmol) prepared in Example 46 and TMSI (67 mL, 0.454 mmol) were used. Purification by silica gel flash column chromatography (dichloromethane: methanol = 10: 1) afforded the target compound (38 mg, 78%).

¹ H NMR (300MHz, CDCl ₃ ) δ 8.21 (d, J = 8.3 Hz, 1H), 8.14 (d, J = 8.3 Hz, 1H), 7.62 (d, J = 9.5 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.40 (t, J = 7.7 Hz, 1H), 6.38 (d, J = 9.4 Hz, 1H), 5.32- 5.23 (m, 2H), 3.63 (t, J = 7.1 Hz, 2H), 3.51 (brs, 1H) , 3.26-3.21 (m, 2H), 2.84-2.59 (m, 5H), 2.78 (dd, J = 17.0, 4.9 Hz, 1H), 2.59 (d, J = 16.8 Hz, 1H), 2.43-2.34 (m , 1H), 2.16 (d, J = 16.5 Hz, 1H), 2.07-1.96 (m, 2H), 1.83-1.69 (m, 4H), 1.61 (d, J = 6.9 Hz, 3H), 1.44 (s, 3H), 1.33-1.25 (m, 2H), 1.22-1.11 (m, 5H).

Example 59 : 13-[(E)-( ± ) -ethylidene-7- (7-fluor-1,2,3,4-tetrahydro-9-acridinylamino) heptylamino] -11-methyl -6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-5-one (1, X = F, m = 2, n = 2 )

The reaction was carried out in the same manner as in Example 50, except that the compound (Formula 7; 20.0 mg, 0.035 mmol) prepared in Example 48 and TMSI (25.0 mL, 0.175 mmol) were used. Purification by silica gel flash column chromatography (dichloromethane: methanol = 4: 1) afforded the target compound (15.0 mg, 77%).

¹ H NMR (300MHz, CDCl ₃ ) δ 8.37 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 9.5 Hz, 1H), 7.51 (t, J = 7.9 Hz, 1H), 7.46 (t, J = 6.6 Hz, 1H), 6.45 (d, J = 9.4 Hz, 1H), 5.40-5.33 (m, 2H), 3.57 (brs, 1H), 3.53-3.48 (m, 2H), 3.29 (t, J = 6.6 Hz, 1H), 2.88 ( dd, J = 17.0, 4.8 Hz, 1H), 2.69 (d, J = 17.1 Hz, 1H), 2.51-2.43 (m, 1H), 2.20-2.04 (m, 2H), 1.99-1.80 (m, 7H) , 1.68 (d. J = 6.6 Hz, 3H), 1.71-1.68 (m. 1H), 1.58-1.49 (m, 3H), 1.51 (s, 3H), 1.41-1.35 (m, 4H).

Example 60 13-[(E)-( ± ) -ethylidene-7- (6-chloro-1,2,3,4-tetrahydro-9-acridinylamino) heptylamino] -11-methyl -6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-5-one (1, X = Cl, m = 2, n = 2 )

The reaction was carried out in the same manner as in Example 50, except that the compound prepared in Example 49 (Formula 6; 40 mg, 0.070 mmol) and TMSI (51 mL, 0.35 mmol) were used. Purification by silica gel flash column chromatography (dichloromethane: methanol = 4: 1) afforded the target compound (32 mg, 82%).

¹ H NMR (300MHz, CDCl ₃ ) δ 8.20 (d, J = 9.2 Hz, 1H), 8.10 (d, J = 2.10 Hz, 1H), 7.70 (d, J = 9.2, 2.0 Hz, 1H), 6.45 (d, J = 9.3 Hz, 1H) , 5.37 (q, J = 6.6 Hz, 2H), 3.86 (t, J = 7.1 Hz, 2H), 3.60 (brs, 1H), 3.15 (brs, 2H), 2.91-2.81 (m, 5H), 2.67 (d, J = 5.1 Hz, 3H), 2.49-2.43 (m, 1H), 2.24 (d, J = 16.5 Hz, 1H), 2.18-2.11 (m, 1H), 1.92-1.77 (m , 5H), 1.70 (d. J = 6.9 Hz, 3H), 1.53 (s, 3H), 1.45-1.31 (m, 7H).

The pharmacological action of the compounds of Formula 1 and Formula 6 according to the present invention was examined by performing the following experiment.

Experimental Example 1 Evaluation of Acetylcholinesterase Enzyme Activity

In order to determine whether the compounds of Formulas 1 and 6 according to the present invention has a cognitive improvement action, the following experiment was performed.

0.2 U in 100 ul of working solution containing Amplex Red reagent, Hoserradish peroxidase (HRP) and choline oxidase / mL Acetylcholinesterase solution (100 ul) and the test drug prepared in Examples 40-60 were added and incubated at room temperature for 30 minutes, followed by FlexStation at 563 nm (excitation) and 587 nm (emission). Enzyme activity was measured by measuring the fluorescence using. The total volume of the above experiments was 300 ul and performed on a 96-well plate. Enzymes, substrates, and assay buffers used in the experiments were purchased from Molecular Probes (Eugene, OR, USA) and used. Details are shown in the table below.

Bioactive results for the compounds are shown in Table 1 below.

TABLE 1 Pharmacological activity data of compounds

As shown in Table 1, Example 55 shows better efficacy than tacrine or racemic hupaerzine A, and Examples 50, 53, 55, 56, and 60 show similar efficacy with tacrine. Indicated.

As described above, the compound represented by the formula (1) according to the present invention shows excellent medicinal activity as a mixture of Hooper's A compound and tacrine, which is known to be excellent in the treatment of dementia, a degenerative neurological disease.

Hooperzine-tacrine hybrid derivatives of the formula (1) according to the present invention is a novel compound having excellent activity against acetylcholinesterase (AChE) and is expected to have an excellent effect in treating dementia, a neurodegenerative disease. In preparing the compound of Formula 1, it is expected that its medicinal utility will be high by using an efficient and high yielding method.

Claims (8)

The hoopsin-tacrine hybrid derivative represented by the following formula (1). [Formula 1]

(In Formula 1, X is hydrogen, a halogen group or an alkyl group of C ₁ ~ C ₆ , m is 1 to 3, n is 1 or 2.) The method of claim 1, Compound of Formula 1 is 13-[(E)-(±) -ethylidene-11-methyl-6- (1,2,3,4-tetrahydro-9-acridinylamino) hexylamino] -6-azatricyclo [7.3 .1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-5-one, 13-[(E)-(±) -ethylidene-11-methyl-1- 6- (7,8,9,10-tetrahydro-6H-cyclohepta [b] quinolin-11-ylamino) hexylamino]-6-azatricyclo [7.3.1.0-2,7-] trideca -2 (7), 3,5,10-tetraen-5-one, 11- [6- (2,3-dihydro-1H-cyclopenta [b] quinolin-9ylamino) hexylamino] -3 -[(E)-(±) -ethylidene] -11-methyl-6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraene- 5-one, 13-[(E)-(±) -ethylidene-6- (8-fluor-1,2,3,4-tetrahydro-9-acridinylamino) hexylamino] -11-methyl -6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-5-one, 13-[(E)-(±) -ethylidene -6- (7-Fluoro-1,2,3,4-tetrahydro-9-acridinylamino) hexylamino] -11- Tyl-6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-5-one, 13-[(E)-(±) -ethyl Lidene-6- (8-chloro-1,2,3,4-tetrahydro-9-acridinylamino) hexylamino] -11-methyl-6-azatricyclo [7.3.1.0-2,7-] Trideca-2 (7), 3,5,10-tetraen-5-one, 13-[(E)-(±) -ethylidene-6- (7-chloro-1,2,3,4- Tetrahydro-9-acridinylamino) hexylamino] -11-methyl-6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraene- 5-one, 13-[(E)-(±) -ethylidene-6- (6-chloro-1,2,3,4-tetrahydro-9-acridinylamino) hexylamino] -11-methyl -6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-5-one, 13-[(E)-(±) -ethylidene -6- (5-methyl-1,2,3,4-tetrahydro-9-acridinylamino) hexylamino] -11-methyl-6-azatricyclo [7.3.1.0-2,7-] tri Deca-2 (7), 3,5,10-tetraen-5-one, 13-[(E)-(±) -ethylidene-7- (7-fluor -1,2,3,4-tetrahydro-9-acridinylamino) heptylamino] -11-methyl-6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-5-one or 13-[(E)-(±) -ethylidene-7- (6-chloro-1,2,3,4-tetrahydro-9-acridinyl Amino) heptylamino] -11-methyl-6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-5-one Hooperzine-tacrine hybrid derivatives selected from among. Precursor of the hoopsin-tacrine hybrid derivative represented by the following formula (6). [Formula 6]

(In Formula 6, X is hydrogen, a halogen group or a C ₁ ~ C ₆ alkyl group, m is 1 to 3, n is 1 or 2.) The method of claim 3, wherein Compound of Formula 6 is N1- [6- (1,2,3,4-tetrahydro-9-acridinyl amino) hexyl] -13-[(E)-(±) -ethylidene-5-methoxy-11-methyl- 6-Azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-1-amine, N1- [6- (2,3-dihydro-1H -Cyclopenta [b] quinolin-9-yl amino) hexyl] -13-[(E)-(±) -ethylidene-5-methoxy-11-methyl-6-azatricyclo [7.3.1.0-2 , 7-] trideca-2 (7), 3,5,10-tetraen-1-amine, N1- [6- (8-chloro-1,2,3,4-tetrahydro-9-acry Dinyl amino) hexyl] -13-[(E)-(±) -ethylidene-5-methoxy-11-methyl-6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7 ), 3,5,10-tetraen-1-amine, N1- [6- (7-chloro-1,2,3,4-tetrahydro-9-acridinyl amino) hexyl] -13-[( E)-(±) -ethylidene-5-methoxy-11-methyl-6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraene -1-amine, N1- [6- (6-chloro-l, 2,3,4-tetrahydro-9-acridinyl amino) hexyl] -13-[(E)-(±)- Thilidene-5-methoxy-11-methyl-6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-1-amine, N1- [6- (8-Fluoro-1,2,3,4-tetrahydro-9-acridinyl amino) hexyl] -13-[(E)-(±) -ethylidene-5-methoxy-11- Methyl-6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-1-amine, N1- [6- (7-pulluor-1 , 2,3,4-tetrahydro-9-acridinyl amino) hexyl] -13-[(E)-(±) -ethylidene-5-methoxy-11-methyl-6-azatricyclo [7.3 .1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-1-amine, N1- [6- (5-methyl-1,2,3,4-tetrahydro- 9-acridinyl amino) hexyl] -13-[(E)-(±) -ethylidene-5-methoxy-11-methyl-6-azatricyclo [7.3.1.0-2,7-] trideca -2 (7), 3,5,10-tetraen-1-amine, N11-6- [13 [(E)-(±) -ethylidene-5-methoxy-11-methyl-6-azatri Cyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-1-ylamino] hexyl-7,8,9,10-tetrahydro Rho-6H-cyclohepta [b] quinolin-11-amine, N1- [7- (1,2,3,4-tetrahydro-9-acridinyl amino) heptyl] -13-[(E)-( ±) -ethylidene-5-methoxy-11-methyl-6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-1-amine , N1- [7- (7-fluoro-1,2,3,4-tetrahydro-9-acridinyl amino) heptyl] -13-[(E)-(±) -ethylidene-5-methoxy -11-methyl-6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-1-amine or N1- [7- (6-chloro -1,2,3,4-tetrahydro-9-acridinyl amino) heptyl] -13-[(E)-(±) -ethylidene-5-methoxy-11-methyl-6-azatricyclo [7.3.1.0-2,7-] trideca-2 (7), 3,5,10-tetraen-1-amine Precursor of hoopsin-tacrine hybrid derivatives selected from among. 1) treating the chloroacridine of formula 2 with hydroxyamine to prepare a hydroxy compound of formula 3; 2) preparing an aldehyde compound of Formula 4 by oxidizing the hydroxy compound of Formula 3; 3) condensing the aldehyde compound of Formula 4 with pyridineamine of Formula 5 to form imine and then reducing the compound to prepare a compound of Formula 6; 4) deprotecting the methyl group of Chemical Formula 6; Method for producing a hoopsin-tacrine hybrid derivative represented by the formula (1) characterized in that.

(X is a hydrogen, a halogen group or a C ₁ -C ₆ alkyl group, m is 1 to 3, n is 1 or 2.) The method of claim 5, The oxidation of step 2) is performed by using one or more oxidants selected from pyridinium chloro chromate (PCC), pyridinium dichromate (PDC), Jones reagent and manganese dioxide. -Method for preparing tacrine hybrid derivatives. The method of claim 6, Method of producing a fuperazine-tacrine hybrid derivative, characterized in that during the condensation of step 3) using sodium acetate and molecular sieve (molecular sieve). The method of claim 6, The deprotection reaction of step 4) is a method for producing a hoopsin-tacrine hybrid derivative, characterized in that using trimethylsilyl iodide (TMSI).