KR0128975B1 - 9-acylamino-tetrahydroacridine derivatives and memory euhancing agent containing said derivative as active ingredient - Google Patents

Abstract

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Description

A memory promoter comprising 9-acylamino-tetrahydroacridine derivatives and derivatives thereof as an active ingredient.

The present invention provides a novel and readily available 9-acylamino-tetrahydroacridine derivative and its optical colonic or pharmacologically acceptable acid addition salts and present derivative compounds that improve the reduced function of cholinergic nerves. A memory promoter comprising the active ingredient.

In the treatment of various memory disorders, such as Alzheimer's disease, which is characterized by decreased cholinergic function, attempts have been made to increase the acetylcholine content of the furnace using acetylcholine esterase inhibitors. For example, studies using physostigmine are described in Neurology Vol. 8, P. 377 (1978).

Furthermore, Japanese Patent Laid-Open Nos. 148154/1986, 1414/1988, 1166881/1988, 203664/1988, 225358/1988, 238063/1988 and 239271/1988: EP- A-268,871 and International Patent Publication No. 88/02256 report that certain 9-amino-tetrahydroacridine derivatives have an acetylcholine esterase inhibitory effect and are effective in treating Alzheimer's disease. In addition, in The New Bagland Journal of Medicine, Vol. 315, p. 1241 (1986), summers are used with 9-amino-1,2,3,4-tetrahydroacrynin (tacrine) in combination with lecithin. Reported to be effective against Alzheimer's disease. However, the above methods do not yet provide sufficient treatment, and in some cases harmful reactions can be caused, so new treatments are desired.

Meanwhile as an example of a known 9-acylamino-tetrahydroacrydine, 9-acetylamino-tetrahydroacridine is described in Journal of Chemical Society., P634 (1947), and 9-chloroacetylamino-tetra Hydroacridine and 9-diethylaminoacetylamino-tetrahydroacridine are described in Chem. listy, Vol. 51, p. 1056 (1957), the latter also describes local anesthesia. The Journal of Medicinal Chemistry, Vol. 18, p. 1056 (1975) also describes the relationship of structural activity to the acetylcholine esterase inhibitory action of 9-amino-tetrahydroacridine. It is also described that the activity of tetrahydroacridine and 9-benzoylamino-tetrahydroacridine is 1/1000 compared to the activity of 9-amino-tetrahydroacridine. In addition, 9-acylamino-tetrahydroa is disclosed in the above-mentioned special places (Japanese Patent Laid-Open Nos. 166881/1988, 203664/1988, 225358/1988, 238063/1988 and 239271/1988). Although a glycine derivative is claimed, specific synthesis examples and pharmacological activities of compounds containing 9-acylamino groups are not described in each of the specific places.

The inventors of the present invention have conducted extensive research aimed at providing a therapeutic agent for senile dimentia, including Alzheimer's disease, and as a result, certain 9-acylamino-tetrahydroacridine derivatives and their optical colon or pharmacological The present invention has been completed by finding that an acceptable acid addition salt thereof is a therapeutic agent for treating memory disorders such as Alzheimer's disease in a mechanism different from conventional compounds exhibiting acetylcholine esterase inhibitory action.

That is, the present invention contains 9-acylamino-tetrahydroacridine derivatives represented by the following general formula (I), optically the colon or pharmacologically acceptable acid addition salts thereof, and the present compound as active ingredients. Includes memory accelerators.

Where

R represents an alkyl group, an aralkyl group or a group represented by the following general formula (II):

In formula (II), R1 is a hydrogen atom or an alkyl group,

(여기서, R³는 수소원자 또는 알킬기임)R ² is a hydrogen atom,

Wherein R ³ is a hydrogen atom or an alkyl group

이고;

는 R¹및 R²가 서로 결합되어or

ego;

R ¹ and R ² are bonded to each other

을 형성하기도 하며;

Also forms;

(여기서, R⁴는 수소원자, 할로겐원자, 알킬기, 알콕시기 또는 수산기임) 또는

(여기서, R5는 수소원자 또는 알킬기임)이며:

(여기서, R6은 수소원자, 알킬기또는 수산기임),

(여기서, R⁷은 수소원자, 알킬기, 아르알킬기,

또는

(여기서, R⁸은 수소 또는 알킬기)임)

(여기서, R⁹은 수소원자 또는 알킬기임),

또는

또는

이다.n is 1 or 2:

(Wherein R ⁴ is a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group or a hydroxyl group) or

Wherein R 5 is a hydrogen atom or an alkyl group:

(Wherein R 6 is a hydrogen atom, an alkyl group or a hydroxyl group),

(Wherein R ⁷ is a hydrogen atom, an alkyl group, an aralkyl group,

or

Wherein R ⁸ is hydrogen or an alkyl group

(Wherein R ⁹ is a hydrogen atom or an alkyl group),

or

or

to be.

The invention is described in more detail below.

In the present invention, the 9-acylamino-tetrahydroacridine derivative is represented by the general formula (I).

In general formula (I), R is an alkyl group containing 2 to 8 carbon atoms, preferably an ethyl group, n-propyl group, isopropyl group, n-butyl group, secondary-butyl group and tert-butyl group Alkyl groups such as alkyl groups containing 2 to 4 carbon atoms; aralkyl groups such as — (CH ₂ ) N ′ where n ′ = 1 to 3; Or a group represented by General Formula (II).

In general formula (II), the alkyl groups represented by R ¹ and R ³ are alkyl groups containing 1 to 6 carbon atoms, preferably methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group and secondary- It may also include alkyl groups containing 1 to 4 carbon atoms, such as butyl.

In addition, in general formula (I), the halogen atom, alkyl group, alkoxy group, or aralkyl group represented by R <^4> -R <^7> may be as follows. That is, halogen atoms include fluorine, chlorine, bromine or iodine atoms; Alkyl groups include alkyl groups containing 1 to 4 carbon atoms such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, secondary-butyl group and the like: alkoxy group is methoxy group, ethoxy group, n- Alkoxy groups containing 1 to 4 carbon atoms such as propoxy group, isopropoxy group, n-butoxy group, secondary-butoxy group and the like; aralkyl group includes benzyl group, phenethyl group and the like.

Among the compounds represented by the general formula (I), examples of preferred substituents of the compound include the following ones.

(1) As R, group represented by n-propyl group, isopropyl group, or general formula (II).

이며; n이 1인 화합물Particularly preferred is R is a group of formula (II),

Is; n is 1

로서는,

또는

인 화합물(2)

As

or

Phosphorus compounds

로서는,

또는

인 화합물(3)

As

or

Phosphorus compounds

Specific examples of the compounds of the present invention are described in Tables 1 and 2.

TABLE 1

Particularly preferred compounds of the present invention are compounds 1, 2, 3, 11, 19, 20, 23, 26, 28, 30, 32, 34, 37, 39, 41, 44, 45, 54, in Table 1 and Table 2 above. 61, 63, 64, 66-69, 72, 73, 77-80, 83, 84, 88, 89 and 92-94.

As salts of the compounds represented by the general formula (I), physiologically obtainable salts are preferable, and such salts include inorganic acid salts such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, and the like: and oxalate, maleate And organic acid salts such as fumarate, lactate, succinate, citrate, tartarate, benzoate, methane sulfonate and the like. Since the compounds of the general formula (I) or salts thereof also exist in the form of hydrates or solvates, the hydrates and solvates are also included in the compounds of the invention.

The following describes a method for preparing the compound of the present invention.

The compounds of the present invention can be prepared by any of the following methods.

(1) The compound of general formula (III) can be reacted with the reactive derivative of the compound of general formula (IV) to obtain a compound of general formula (I):

Where

및

는 상기 일반식(Ⅰ)에서 정의된 바와 같고,

And

Is as defined in the general formula (I),

R ¹⁰ is an alkyl group or an aralkyl group represented by R in General Formula (I).

As the reactive derivative of the compound of the general formula (IV), symmetric acid anhydrides and acid halides (particularly acid chlorides) are preferable. The reaction is carried out in the presence of an inert solvent such as benzene, toluene, xylene, 1,2-dichloroethane, 1,1,2,2, -tetrachloroethane or by using a large amount of symmetric acid anhydride or acid halide as a solvent. .

If symmetric acid anhydrides are used, tertiary amines such as pyridine are used. The reaction is carried out at 30 to 150 ° C, preferably 50 to 120 °.

(2) A sodium salt is prepared by treating the compound of formula (III) with an equimolar amount or more sodium hydride, and then reacting the salt with an ester compound of formula (V) to give a general formula (I). Obtain the compound of:

또는

이며, R¹²는 메틸기 또는 에틸기이다.In which R ¹¹ is

or

And R ¹² is a methyl group or an ethyl group.

Preferred as the solvent are tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide and the like. The reaction is carried out at 10 to 30 ° C, preferably 30 to 60 ° C.

(3)

및

는 일반식(Ⅰ)에서 정의된 바와 같고; 일반식(Ⅷ)의 R¹³은 1 내지 4개의 탄소 원자를 갖는 직선형 또는 측쇄형 알킬기: 또는

는 1내지 4개의 탄소원자를 지닌 알킥리임)이며; 일반식(Ⅸ)중의 R¹⁴는Wherein X is a chlorine atom or a bromine atom; m is 1 or 2;

And

Is as defined in formula (I); R ¹³ in general formula is a straight or branched chain alkyl group having 1 to 4 carbon atoms: or

Is an alkyri having 1 to 4 carbon atoms; R ¹⁴ in general formula

이다.

to be.

By the two-step reaction scheme, the compound of general formula (I) can be synthesized.

That is, the acyl halide compound of general formula (VI) is reacted with the compound of general formula (III), and compound of general formula (VII) is obtained [step (a)].

Thereafter, a compound of formula (VII) is reacted with a compound of formula (IV) or imidazole, or a compound which is a sodium salt obtained by treating compound of formula (IV) with sodium hydride is reacted. (b)], the corresponding compound (I) can be obtained.

Step (a) is carried out at 50 to 150 ° C., preferably 70 to 120 ° C., using a large amount of acyl halide as a solvent, or benzene, toluene, xylene, 1,2-dichloroethane, 1,1,2, It is carried out using an inert solvent such as 2, -tetrachloroethane.

Step (b) is carried out at 0 to 150 ° C., preferably 20 to 100 ° C., using a large amount of amine as a solvent, alcohol solvents such as methanol, ethanol, n-propanol, isoprotanol, n-butanol or tetrahydro It is carried out using a solvent such as furan, dioxane, acetonitrile, dimethylformamide, dimethyl sulfoxide and the like. When the sodium salt of the compound of the formula (III) is reacted, solvents such as tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, and dimethyl sulfoxide may be used at 0 to 120 ° C, preferably 20 to 80 ° C. To carry out the reaction.

(4)

및

는 앞에서 정의한 바와 같다.Where x, m

And

Is as defined above.

Using the compound of formula (iii), the compound of general formula (I) can be obtained through the three-step reaction.

That is, sodium azide is reacted with a compound of formula (VII) to obtain an azide compound of formula (VII), and the compound is reduced by hydrogenolysis using a catalyst such as palladium. [Step (d)] to obtain a primary amine compound of Formula (XI), and then acylated [Step (e)] or Carbamoylated [Step (f)] to obtain a compound of Formula (I). To obtain.

Step (c) is carried out in a solvent such as dimethylformamide, dimethyl sulfoxide, acetonitrile, methanol, ethanol, n-propanol, isopropanol or a mixed solvent of water and water at 0 to 80 캜, preferably 10 to 50 캜. Is performed in

Step (d) is carried out in solvents such as methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, dioxane, acetonitrile and the like at 0 to 80 ° C, preferably 10 to 40 ° C. Step (e) is carried out by reacting with an acyl halide compound or a symmetric acid anhydride, for example, under conventional acylation reaction conditions such as the presence of a tertiary amine.

Step (f) is carried out under conventional carbamoylation reaction conditions.

)의 화합물을 알킬 이소시안산과 반응시키는 경우에는, 알킬-치환된 우레아가 수득되고, 동 화합물을 아세트산 내에서 이소시안산 나트륨으로 반응시키는 경우에는, 우레아 유도체가 수득될 수 있다.For example, the general formula (

When the compound of) is reacted with alkyl isocyanic acid, an alkyl-substituted urea is obtained, and when the compound is reacted with sodium isocyanate in acetic acid, a urea derivative can be obtained.

(5) As a method of converting one of the compounds of the general formula (I) to the other compound contained in the general formula (I), there are the following methods.

) 및 (XIII)의 R 및

는 상기 일반식(Ⅰ)에서 정의된 바와 같다.In the above formula, the general formula (

) And (XIII) R and

Is as defined in the general formula (I) above.

Namely, N-benzylamine of general formula (XIII) was debenzylated by hydrogenolysis using palladium as catalyst [step (g)], and thus acylated secondary amine of general formula (XIII) obtained [Step (h)] or Carbamoylation [Step (i)].

Step (g) can be carried out by conventional methods, for example by hydrolysis using palladium-carbon as catalyst and adding hydrochloric acid.

Step (b) and step (i) may be performed in the same manner as in step (e) and step (f) of the above (4), respectively.

Compounds of the general formula (III) as starting materials of the preparation method of (1) to (3) are (a) Tetrahedron Letters, p. 1277 (1963); (b) Collection of Czechoslovak Chemical Communications, Vol. 42, p. 2802 (1977); (c) Acta Chemica Scandinavica, B, Vol. 33, p. 313 (1970); It can easily synthesize | combine by the method as described in these etc., or its equivalent.

Japanese Patent Application Laid-Open Nos. 148154/1986, 14-14 / 1988, 166881/1988, 203664/1988, 225358/1988, 238063/1988 and 239271/1988; And EP-A-268,871, respectively.

When the compounds of the present invention are used as therapeutic agents, they may be administered alone or as complexes formulated with pharmaceutically acceptable carriers. The composition is determined by the solubility, chemical nature, route of administration, dosing schedule, etc. of the compound. Therapeutic agents of the present compounds may be administered orally as granules, microparticles, powders, tablets, rigid capshules, soft capshules, syrups, emulsions, suspensions or liquid forms, or intravenously, intramuscularly or subcutaneously.

Injectable powders may also be used as an injection just before use. Solid or liquid organic or inorganic carriers, or diluents, which are pharmacologically acceptable for oral, rectal, parenteral or topical administration, may also be used in combination with the compounds of the present invention. As excipients used in the preparation of solid preparations, lactose, sugar, starch, taic, cellulose, dextrin, kaolin, calcium carbonate and the like are used. Emulsions, syrups, suspensions, liquids, and the like, which are liquid preparations for oral administration, include inert diluents commonly used, such as water or cooking oil. In addition to inert diluents, the formulations may also contain auxiliaries such as wetting agents, suspending aids, sweeteners, fragrances, colorants or preservatives. The adjuvant is prepared as a liquid formulation and placed in a capsche rate of a well absorbent material such as gelatin. Solvents or suspensions used for oral administration formulations, i.e. infusion preparations, include water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleic acid, lecithin and the like. The preparation method of a formulation follows a conventional method.

In clinical dosages, for oral administration, the daily dosage is generally from 1 to 1000 mg, preferably from 1 to 100 mg of the compound of the present invention per adult, but the age, the severity of the disease, the condition of the patient and the simultaneous administration It may change depending on the presence or absence. The daily doses of the compounds of the invention presented above are administered once per day, or two to three times per day, as appropriate, or intermittently.

In addition, when used in the form of infusion, the compound of the present invention per adult is used at 0.1 to 100 mg, preferably 0.1 to 50 mg per day.

The compound of formula (1) prepared according to the present invention has a weak acetylcholine esterase inhibition of 1/100 compared to the known 9-amino-tetrahydroacridine, whereas the presynaptic site of cholinergic Newton Can activate neurotransmission. More specifically, AF64A (ethylcholine aziradinium ion) in the ventricle [Journal of Pharmacolgy and Experimental Therapeutics, Vol. 222, p. 140 (1982); Neuropharmacology, Vol. 26, p. 361 (1987)] may enhance high affinity-choline uptake in the Heppinus synaptosomes of rats injected. (See 1 in the test). This activity could not be found in 9-amino-tetrahydroacridine.

In addition, the compound of the present invention is extremely weak in toxicity compared to 9-amino-tetrahydroacridine and has little side effects, and thus can be used as a treatment for memory disorders such as Alzheimer's disease.

Compounds of formula (1) of the present invention are physiologically active and valuable compounds. In particular, the compound has a function of directly activating the degraded cholinergic nervous system, so it can be used as a pharmaceutical preparation for treating memory disorders such as Alzheimer's disease.

In senile dysfunction, especially Alzheimer's disease, the cholinergic Newtonian function of the brain is reduced, and there is a good correlation between the disease and the degree of memory impairment.

On the other hand, in Fischer [Journal of Pharmacolgy and Experimental Therapeutics, Vol. 222, p. 140 (1982)] and Leven [Neuropharmacology, Vol. 26, p. 361 (1987), AF64A selectively causes long-term damage to cholinergic neurons. In mice injected with AF64A, defects in memory and learning can be detected and described in Brain Research, Vol. 321, p. 91 (1984)], therefore this is a good example of Alzheimer's disease.

Therefore, it is believed that the compounds of the present invention that can directly activate the cholinergic neuronal function of the brain degraded by injecting AF64A can be used as an anti-aging agent including Alzheimer's disease.

EXAMPLE

In the following, the invention is described in more detail, but the invention is not limited by the following examples unless departing from the summary of the invention.

Example 1

N- (1,2,3,4-tetrahydroacridin-9-yl) butanamide. Synthesis of (Compound No. 2 in Table 1).

To 4 ml of pyridine was added 2 g of 9-amino-1,2,3,4-tetrahydroacridine. 3.3 ml of n-butyric anhydride was added to the mixture and refluxed for 8 hours. The solvent was then removed under reduced pressure and 10 ml of methanol was added to give a residue. Concentrated aqueous ammonia was added to the mixture and refluxed for 1 hour. After the solvent was removed under reduced pressure, water was added and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue obtained was purified by silica gel column chromatography and recrystallized from chloroform / ether to give 1.57 g of N- (1,2,3,4-tetrahydroacridin-9-yl) butanamide. Melting point: 202-204 ° C,

The compound of Table 3 was synthesized in the same manner as in Example 1.

Reference Example 1

In the same manner as in Example 1, the compound of Reference Example 1 was synthesized as shown in Table 3.

TABLE 3

Example 14

Synthesis of 2- (2-oxopyrrolidin-1-yl) -N- (1,2,3,4-tetrahydroacridin-9-yl) acetamide hydrochloride (Compound No. 26 in Table 1) .

4.4 g of sodium hydride (content: 60%) was suspended in 50 ml of N-methylpyrrolidone, and 10.4 g of 9-amino-1,2,3,4-tetrahydroacridine was added to the suspension at room temperature. Stir for 1 hour. Thereafter, the temperature of the reaction system was raised to 50 ° C., and 17.4 g of methyl 2-oxo-1-pyrrolidine acetate was added dropwise to the mixture over 30 minutes. After cooling to 10 ° C., the mixture was poured into 300 ml of an aqueous solution containing 40 g of ammonium chloride and extracted with 300 ml of chloroform. The chloroform solution was evaporated to dryness and recrystallized from isopropanol to yield 14.9 g of crystals. Melting point: 233 to 236 ° C.

This crystal was suspended in 120 ml of isopropane, to which 10 ml of a 26% hydrogen chloride-isopropane solution was added. The mixture was stirred at room temperature for 1 hour and then filtered to yield 15.2 g of 2- (2-oxopyrrolidin-1-yl) acetamide hydrochloride. Melting point: 230-235 ° C. (decomposition).

In the same manner as in Example 14, the compounds shown in Table 4 below were synthesized.

TABLE 4

Example 34

2- (2,4-imidizolidinedione-3-yl) -N- (1,2,3,4-tetrahydroacridin-9-yl) acetamide (Compound No. 37 in Table 1) synthesis.

0.8 g of sodium hydride (content: 60%) was suspended in 20 ml of dimethylformamide, 3 g of 2,4-imidazolidinedione was added to the suspension, and the mixture was stirred at room temperature for 30 minutes. Then, 2.75 g of 9-chloroacetylamino-1,2,3,4-tetrahydroacrydine (described in Chem. Listy, Vol 51, p. 1906 (1957)) was added to the mixed solution, and over 30 minutes. The reaction was carried out while heating to 80 ° C. After cooling to 10 ° C., the mixed solution was poured into 100 ml of an aqueous solution containing 8 g of ammonium chloride. The precipitated crystals were collected by filtration, washed with water and dried. The crystals were recrystallized from methanol-chloroform to give 2- (2--4-imidazolidione-3-yl) -N- (1,2,3,4-tetrahydroacridin-9-yl) acetamide 2.5 g were obtained. Melting Point: 302-304 ° C (Decomposition)

In the same manner as in Example 34, the compounds shown in Table 5 were synthesized.

TABLE 5

Example 39

Synthesis of 9-[(2-methylamino) acetyl-amino] -1,2,3,4-tetrahydroacridine (Compound No. 11 in Table 1).

1.4 g of 9-chloroacetylamino-1,2,3,4-tetrahydroacrydine was added to 30 ml of a 40% methyl amine-methanol solution, and the mixed solution was reacted at room temperature for 2 hours and at 50 ° C for 30 minutes. Thereafter, 60 ml of water and 80 ml of chloroform were added to extract the mixed liquid. The chloroform solution was condensed and purified via silica gel column chromatography (chloroform-methanol), and then recrystallized from isopropanol-diethyl ether to give 9-[(2-methylamino) acetyl-amino] -1,2,3, 0.89 g of 4-tetrahydroacridin was obtained. Melting Point: 152 ~ 155 ℃

In the same manner as in Example 39, the compounds of Examples 40 and 41 were synthesized. In addition, the compound of Example 39 was acetylated by a conventional method using acetic anhydride-pyridine to synthesize the compound of Example 42 below. The melting point of this compound is shown in Table 6.

TABLE 6

Example 43

Synthesis of 9-[(2-amino) acetyl-amino] -1,2,3,4-tetrahydroacrydine (compound number 10 in Table 1).

2.84 g of sodium azide was suspended in 40 ml of dimethylformamide, and 10 g of 9-chloroacetylamino-1,2,3,4-tetrahydroacridine was added thereto, and the mixture was reacted at room temperature for 2 hours. . 32 ml of water was added to the mixed solution, and the precipitated crystals were filtered to give 9.7 g of 9-azidoacetylamino-1,2,3,4-tetrahydroacridin. Melting point: 190 ° C. (decomposition).

The crystals were suspended in 500 ml of methanol, and hydrolysis was carried out at room temperature for 1 hour by adding 0.5 g of palladium black. After the catalyst was filtered off, the filtrate was condensed and recrystallized and filtered from methanol-isopropanol to give 9-[(2-amino) acetyl-amino] -1,2,3,4-tetrahydroacrydine 7.4 g Obtained. Melting point: 225-230 degreeC.

The compound of Example 43 was acylated or carbamoylated in a conventional manner to synthesize the compound shown in Table 7 below.

TABLE 7

Example 48

2- (2-oxopyrrolidin-1-yl) -N- (1,2,3,4-tetrahydrobenzo [b] [1,6] naphthyridin-10-yl) acetamide maleic acid ( 1: 1) (Compound No. 67 in Table 2).

Dissolve 10.2 g of the free base of the compound of Example 21 in a mixed solvent of 200 ml of ethanol and 100 ml of acetic acid, and add 6 ml of 30% hydrogen chloride-ethanol solution and 1.5 g of 5% palladium-carbon to obtain 6 at atmospheric pressure and 50 ° C. Hydrolysis reaction was carried out for a time. The catalyst was filtered off, the solvent was evaporated to dryness, and the remaining solid was recrystallized from ethanol to obtain 8.7 g of crude crystals. This crystal was added to 100 ml of saturated aqueous sodium hydrogen carbonate solution and 150 ml of chloroform and stirred. After drying the chloroform solution over sodium sulfate, chloroform was removed and the residue was dissolved in 60 mL methanol. Thereafter, 60 ml of a methanol solution containing 2.6 g of maleic acid was added to the solution, and the precipitated crystals were filtered to give 2- (2-oxopyrrolidin-1-yl) -N- (1,2,3 7.5 g of, 4-tetrahydrobenzo [b], [1,6] naphthyridin-10-yl) acetamide maleic acid (1: 1) was recovered. Melting point: 192-198 ° C. (decomposition).

The free base of the compound of Example 48 was acylated or carbamoylated in a conventional manner to synthesize the compound shown in Table 8 below.

TABLE 8

Example 52

Synthesis of N- (3,4-dihydroacridin-2 (1H) -9-yl) butanamide (Compound No. 76 in Table 2).

3.6 g of the compound of Reference Example 1 was dissolved in 30 ml of acetone, and 7 ml of 2N hydrochloric acid was added, and the mixture was reacted at 50 ° C for 3 hours. The solvent was removed under reduced pressure, and 100 ml of chloroform and 30 ml of 10% aqueous potassium carbonate solution were added to the residue, followed by stirring the mixture. The chloroform layer was separated, dried over sodium sulfate, condensed and crystallized from chloroform-diethyl ether to give 2.4 g of N- (3,4-dihydroacridin-2 (1H) -9-yl) butanamide. Obtained. Melting point: 213-217 캜 (decomposition).

Example 53

Synthesis of N- (1,2,3,4-tetrahydroacridin-2-ol-9-yl) butanamide.

(Compound No. 8 in Table 1)

1 g of the compound of Example 52 was dissolved in 20 ml of methanol, and 0.14 g of sodium borohydride was added to the solution and reacted at room temperature for 12 hours. After the solvent was removed under reduced pressure, 30 ml of chloroform and 30 ml of water were added to the residue, followed by stirring. The chloroform layer was separated and dried over sodium sulfate, then condensed and crystallized from chloroform-ethyl acetate to give 0.77 g of N- (1,2,3,4-tetrahydroacridin-2-ol-9-yl) butanamide. Obtained. Melting point: 260 to 265 ° C. (decomposition).

Reference Example 2

Synthesis of 4-amino-5,6,7,8-tetrahydro-thieno- [2,3, -b] -quinoline.

Cyclohexa was added to 45 ml of 7.54 g of zinc chloride and 5.56 g of 2-amino-3-cyanothiophene and reacted at 100 to 110 ° C. for 2 hours. After the reaction system was cooled to 20 ° C, 20 ml of ethyl acetate was added and the crystals were filtered off. This crystal was suspended in 100 ml of chloroform and 17 ml of concentrated aqueous ammonia was added and stirred. The chloroform solution was dried over sodium sulfate, condensed and crystallized from chloroform-n-heptane to give 6.11 g of 4-amino-5,6,7,8-tetrahydro [2,3, -b] thienoquinoline. Melting point: 159-161 degreeC.

Reference Example 3

Synthesis of 10-amino-1 H-3,4-dihydro-pyrano [4,3, -b] -quinoline.

A mixture of 5.04 g of tetrahydro-4H-pyran-4- and 8.92 g of zinc chloride with 5.95 g of 2-amino benzonitrile was reacted at 90 ° C. for 1 hour.

After cooling to room temperature, 20 ml of toluene was added to the resulting solid, and the solid was ground and filtered. This solid was suspended in 180 ml of chloroform, and 22 ml of concentrated aqueous ammonia was added and stirred. From this the chloroform solution was separated, dried over sodium sulfate, condensed and crystallized from chloroform-n-heptane to give 10-amino-1H-3,4-dihydro-pyrano [4,3-b] -quinoline 5.84 g was obtained. Melting Point: 199 to 202 ° C

Reference Example 4

Synthesis of 4-amino-5H-7,8-dihydro-pyrano [4,3-b] thieno [3,2-e] pyridine.

The compound was synthesized in the same manner as in Reference Example 3. Melting Point: 199 to 202 ° C

Reference Example 5

Synthesis of 10-amino-2-benzyl-1,2,3,4-tetrahydro-benzo (b) (1,6) naphthyridine.

55 g of isatin, 76.2 g of N-benzyl-4-piperidone, and 86.5 g of ammonium acetate were added to 400 ml of dimethylformamide, and the mixture was reacted at 120 ° C. for 3 hours. After removing the solvent under reduced pressure, 200 ml of acetone and 200 ml of water were added to the residue, and the insolubles were collected by filtration. This insoluble material was suspended in 400 ml of ethanol, washed and filtered to give 67.8 g of 20benzyl-10-carbamoyl-1,2,3,4-tetrahydro-benzo [b], [1,6] naphthyridine. Obtained. Melting point: 234-237 degreeC.

After dissolving 20.2 g of sodium hydroxide in 250 ml of water and dropping 22.2 g of bromine at -5 ° C, the mixture to which 40 g of the carboxamide of the compound was added was sufficiently stirred for 4 hours while raising the temperature to 80 ° C. . After cooling the mixture to 20 ° C., the precipitated crystals were collected by filtration, washed and recrystallized from methanol to give 10-amino-2-benzyl-1,2,3,4-tetrahydro-benzo [b], [1, 6] 13 g of naphthyridine were obtained. Melting point: 193-196 degreeC.

Reference Example 6

Synthesis of 10-amino-2-methyl-1,2,3,4-tetrahydro-benzo [b], [1,6] naphthyridine.

The compound was synthesized in the same manner as in Reference Example 5. Melting Point: 169 to 171 ° C

Reference Example 7

Synthesis of 10-amino-2-methyl-1,3-propano-1,2,3,4-tetrahydro-benzo [b], [1,6] naphthyridine.

A mixture of 4.36 g of 2-aminobenzonitrile and 7 g of hydrogen chloride pseudofeletierin was mixed with 5.53 g of zinc chloride was reacted at 150 ° C. for 2.5 hours. After cooling to room temperature, the resulting solid was triturated by adding 10 ml of isopropanol and filtered. This solid was suspended in 100 ml of chloroform and stirred with addition of 22 ml of concentrated aqueous ammonia. From this the chloroform solution was separated, condensed, purified via silica gel column chromatography (chloroform-methanol) and recrystallized from ethyl acetate to give 10-amino-2-methyl-1,3-propano-1,2,3, 1.2 g of 4-tetrahydro-benzo [b], [1,6] naphthyridine were obtained. Melting point: 220-240 ° C. (decomposition).

Reference Example 8

Synthesis of 4-amino-5,8-ethano-5,6,7,8-tetrahydro-thieno [2,3-b] [1,5] naphthyridine.

A mixture of 5 g of 2-amino-3-cyanothioene and 30 quinucridinone hydrogen chloride with 6.04 g of zinc chloride was reacted at 110 ° C. for 1 hour. After cooling to room temperature, the resulting solid was triturated by adding 100 ml of chloroform, and 30 ml of concentrated aqueous ammonia and 10 ml of methanol were added and stirred. The insolubles were filtered off, from which the chloroform layer was separated, condensed, purified via silica gel column chromatography and recrystallized from ethyl acetate to 4-amino-5,8-ethano-5,6,7,8 0.59 g of tetrahydro-thieno [2,3-b] [1,5] naphthyridine was obtained. Melting point: 265 to 268 ° C (decomposition).

[Test Example 1]

Effect on Na + dependent high affinity choline uptake (HACU) of hippocampus of AF64A-treated rats.

(Way)

Fischer company's method [J. Pharm. Exper. Ther., Vol. 222, p. 140 (1982)], AF64A was prepared from AF64. AF64A (1.5 nmole / 1.5 μl / side) was injected into both ventricles of mice. One week later, the rats were cut off and only the hippocampus was extracted. This was homogenized with 0.3 M sugar solution and centrifuged at 1000 g for 10 minutes, and then the supernatant was further centrifuged at 20,000 g for 20 minutes to obtain a crude synaptosome fraction. The crude synaptosome fraction and drug were incubated at 37 ° C. for 30 minutes and (3H) choline (1 μm) was added followed by further incubation at 37 ° C. for 10 minutes.

As a control, the crude synaptosome fraction was incubated at 37 ° C. for 30 minutes, [3H] choline (1 μm) was added, followed by further incubation at 37 ° C. for 10 minutes.

The reaction was stopped by filtering on Whatman GF / B filters.

Radioactivity on the filter was measured with a liquid scintillation counter, which was taken as the HACU amount. Protein amount was determined by Bradford method [Analytical Biochemistry, Vol. 72, p. 248 (1976). The test results are shown in Table 9.

TABLE 9

Improved rain (% contrast)

(* P <0.05, ** P <0.01)

Comparative Example ⁺ : 9-amino-1,2,3,4-retrahydroacridine

[Test Example 2]

Acute Toxicity Test.

The compound of the present invention was injected orally into a mouse (mouse) to determine the acute toxicity value.

The results are shown in Table 10.

TABLE 10

Claims (3)

9-acylamino-tetrahydroacridine derivatives represented by formula (I)

Wherein R is an alkyl group having 2 to 8 carbon atoms, an aralkyl group or a group represented by the following general formula (II):

In formula (II), R ¹ is a hydrogen atom or an alkyl group, R ² is a hydrogen atom,

(Wherein R ³ is a hydrogen atom or an alkyl group) or

R ¹ and R ² are bonded to each other

or

To form; n is 1 or 2. A compound according to claim 1, wherein R is represented by formula (II). A memory promoter comprising, as an active ingredient, the 9-acylamino-tetrahydroacridine derivative of formula (I) as defined in claim 1, the optical colon of the derivative or a pharmacologically acceptable acid addition salt thereof.