JPH03218361A - 9-acylaminotetrahydroacridine derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [R<1> is alkyl or CH2-N(R<2>)R<3> (R<2> is H or acetyl; R<3> is alkyl, cycloalkyl, etc., or forming five-membered ring with R<2>); ring A is of formula II, formula III, formula IV, etc.; ring B is of formula V, formula VI, formula VII (R<15> is H or alkyl), etc.; when ring B is of formula V, formula VI or formula VII, ring A is not of formula IV and R<7> is not H], its optical antipode or its acid-added salt. EXAMPLE:N-(3-Methyl-5,6,7,8-tetrahydro-thieno[2,3-b]quinoline-4-yl)but anamide. USE:A therapeutic agent for geriatric dementia including Alzheimer's disease. PREPARATION:For example, a compound of formula VIII (R<5> and R<6> are each H or alkyl) is allowed to react with urea to obtain one of the objective compounds of the formula I, a compound of formula IX.

Description

Detailed Description of the Invention (Industrial Field of Application) The present invention provides a method for activating cholinergic nerves with decreased function.
The present invention relates to novel and useful 9-acylaminotetrahydride acridine derivatives, their antipodes, or pharmaceutically acceptable acid addition salts thereof.

(Problems to be solved by conventional techniques and inventions) Alzheimer's disease
Attempts have been made to increase the content of acetylcholine in the brain using acetylcholinesterase inhibitors as a treatment for various memory disorders characterized by decreased cholinergic nerve function, such as se). For example, studies using physostigmine have been conducted in neurology (Neurology).
(1978). Furthermore, JP-A-61-148154, JP-A-6
No. 3-141980, JP-A-63-22535
No. 8, JP-A-63-238063, JP-A-63-
239271, JP-A-63 + 284175, JP-A-63 + 297367, JP-A-64-73
No., JP-A-1132566, EP-A-26887
1, International Publication No. 887 02256,
It has been reported that a specific 9-aminotetrahydride acridine derivative has an acetylcholinesterase inhibitory effect and is effective in treating Alzheimer's disease.

Summers also wrote The New England Journal of Medicine.
Land Journal of Medicine)
, 315. 1241 (1986) reported that 9-amino-1,2,3,4-tetrahydroacridine (tacrine) is effective against Alzheimer's disease in humans in combination with lecithin. However, sufficient improvement has not been achieved and side effects have been a problem, and new treatment methods are desired.

On the other hand, as an example of a known 9-acylaminotetrahydride acridine, the Journal of Chemical Society (
Journal of Chemical Society
9-acetylaminotetrahydroacridine-6- is described in Chem. ty), 634 (1947), and Chem.
sty), Dan, 1907 (1957) describes 9-chloroacetylaminotetrahydro-acridine and 9-diethylaminoacetylamino-tetrahydro-acridine, and notes that the latter has a local anesthetic effect. In addition, the Journal of Medicinal Chemistry (Journal of Medicinal C
Hemistry), Kawa, 1056 (1975) describes the structure-activity relationship of the acetylcholinesterase inhibitory activity of 9-aminotetrahydroacnodine derivatives, and 9-acetylaminotetrahydroacridine and 9-penzoylaminotetrahydroacridine are ,
The activity is 1/1 compared to 9-aminotetrahydroacridine.
It is written that it will be 1000. In addition, the above-mentioned patent publications (JP-A-63-166881, JP-A-63-2
No. 03664, JP-A-63-238063, JP-A-6
3-239271, JP 63-284175, JP 64-73, and JP 1-132566.
Some of the publications in the above-mentioned publications include 9-acylaminotetrahydride acridine derivatives in their claims, but none of them include specific examples of compounds having a -7- 9-acylamino group. Synthetic examples and pharmacological activities are not described.

(Means for Solving the Problems) As a result of various studies aimed at providing a therapeutic drug for senile dementia including Alzheimer's disease, the present inventors discovered that a specific 9-acylaminotetrahydroacridine derivative discovered that its optical antipode or its pharmaceutically acceptable acid addition salt can serve as a drug that improves memory disorders such as Alzheimer's disease through a mechanism different from that of conventional compounds that inhibit acetylcholinesterase. , we have completed the present invention.

That is, the gist of the present invention is the following general formula (I) 0=C-Rl 1 [wherein R1 is an alkyl group or (II) formula 8- {(II) where R2 is a hydrogen atom or an acetyl group and R3 is an alkyl group, a cycloalkyl group, or -
CH-COOR5 (R4O.J: R5 represents an independent L'' (water R4 represents a hydrogen atom or an alkyl group).

Does not represent child. 9-acylaminotetrahydride acridine derivatives represented by the following formula, its optical antipodes, or pharmaceutically acceptable acid addition salts thereof.

The present invention will be described below. The 9-acylaminotetrahydride acridine derivative of the present invention is represented by the general formula (I). In formula (I), Rl is an 02-C6 alkyl group, preferably an ethyl group, n-propyl group, isopropyl group, n-butyl group, see-butyl group, tert
- represents a C2-C4 alkyl group such as a butyl group, or a group represented by formula (II).

In formula (II), the alkyl group represented by R3 is an 01-C6 alkyl group, preferably a methyl group,
Examples include 01 to C4 alkyl groups such as ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, see-butyl group, tert-butyl group, and cycloa-9 (R6 is a hydrogen atom or represents an alkyl group.) each independently represents a hydrogen atom or an alkyl group; R9 stands for a hydrogen atom or an alkyl group;

), each independently representing an alkyl group or connected to each other as a cyclobutyl group, -10 cyclobutyl group; 03-
Examples include C6 cycloalkyl groups.

The alkyl group represented by R4 to R6 is C■ to C
6 alkyl group, preferably methyl group, ethyl group, n
- Probyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, etc.
Examples include 1 to C4 alkyl groups.

Furthermore, in formula (I), al? represented by R7 to R14? Examples of the group include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, se
Examples include 01-C4 alkyl groups such as e-butyl group and tert-butyl group.

In formula (I), the aralkyl group represented by Rl5 includes a phenyl group substituted with a C2 to C4 alkyl group such as a benzyl group and a phenethyl group.

Among the compounds represented by formula (I) of the present invention, preferred examples of substituents include the following.

(1) Rl represents an n-probyl group or isoprobyl group, or R2 represents a hydrogen atom, or a group in which R2 and R3 are bonded to each other.

The salts of the compound represented by formula (I) are preferably physiologically acceptable salts, such as hydrochloric acid-13-salt, hydrobromide, hydroiodide, sulfate, phosphate, etc. Inorganic acid salts and organic acid salts such as oxalate, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, methanesulfonate, camphorsulfonate, etc. Can be mentioned. Since the compound of formula (I) and its salts may exist in the form of hydrates or solvates, these hydrates and solvates are also included in the compounds of the present invention.

Next, a method for producing the compound of the present invention will be explained.

The compound of the present invention can be produced, for example, by any of the following methods.

(1) Rl is represented by formula (II), and R2 and R
3 excludes each other as 0, Japanese Patent Application No. 1983-283351, Japanese Patent Application No. 1983
- No. 305799 or Unexamined Japanese Patent Publication No. 1 + 13764
It can be produced by a method similar to that described in No. 5.

(2) Rl is represented by formula (II), and R2 and R
When 3 and -14= are combined with each other, the compound of the present invention represented by formula (IV) can be produced according to the following reaction formula.

(III) As defined in (IV). ) That is, by heating a compound of formula (III) with 1 to 10 equivalents of urea in the presence of a solvent or without a solvent, a compound of formula (IV) is obtained.

The starting compound of formula (III) can be obtained by the method described in item (1) above.

As the reaction solvent, inert polar solvents such as dimethylsulfoxide, dimethylformamide, dimethylacetamide, and N-methylpyrrolidone are preferred.

The reaction temperature is 120-190°C, preferably 140-190°C.
The range is 70°C.

The compound of formula (V) below, which is a raw material for the methods (1) and (2) above, is, for example, (a) Tetrahedron Letters (Tetrahe
drone Letters, 1277 (1963) (
b) Collection of Czech Chemical Communications (Collect. Czech.
Chem. Commun. ), 42, 2802 (1
977) (c) Acta Chemica Scandinavian Power (Ac
ta Chemica Scandinavica),
B, 33, 313 (1979), or a similar method.

Also, JP-A-61-148154, JP-A-63-
141980, JP-A-63-166881, JP-A-63-203664, JP-A-63-2253
No. 58, JP-A-63-238063, JP-A-63
- No. 239271, JP-A-63-297367
It can also be synthesized according to the methods described in the following publications: JP-A No. 64-73, JP-A-1-132566, and EP-A-268871.

Table 1 below shows specific examples of raw material compounds for the compound of the present invention represented by formula (V) synthesized according to the method described in the above literature.

Table 1 -17- -18- When the compounds of the present invention are used as therapeutic agents, they are administered alone or in combination with a pharmaceutically acceptable carrier. Its composition is determined by the compound's solubility, chemical properties, route of administration, regimen, etc. For example, it may be administered orally in the form of granules, fine granules, powders, tablets, hard capsules, soft capsules, syrups, emulsions, suspensions, or liquids, or intravenously as an injection. It may also be administered internally, intramuscularly, or subcutaneously.

It may also be used as a powder for injection. Pharmaceutical organic or inorganic, solid or liquid carriers or diluents suitable for oral, enteral, parenteral or topical administration can be used with the compounds of this invention. Examples of excipients used in producing solid preparations include lactose, sucrose, starch, talc, cellulose, dextrin, kaolin, calcium carbonate, and the like. Liquid preparations for oral administration, i.e. emulsions, syrups, suspensions, solutions, etc., are prepared using commonly used inert diluents,
For example, it includes water or vegetable oil. In addition to the inert diluent, this preparation may contain adjuvants such as wetting agents, suspending agents, sweetening agents,
Flavoring agents, coloring agents, preservatives, etc. may be included.

Liquid preparations may be enclosed in capsules of absorbable material such as gelatin. Solvents or suspending agents used in the manufacture of parenteral preparations, i.e. injections, etc.
Examples include water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin, and the like.

The formulation may be prepared by conventional methods.

Clinical dosages for a compound of the invention for adults when used by oral administration are generally 1 to 10 daily doses.
00 mg, preferably 1 to 100 mg,
It is more preferable to increase or decrease the amount as appropriate depending on age, medical condition, symptoms, and presence or absence of simultaneous administration. The daily dose of the compound of the present invention is 1
Once a day, or 2 or 3 times a day at appropriate intervals
It may be administered in divided doses or intermittently.

When used as an injection, the daily dose of the compound of the present invention for adults is 0.1 to 100 mg, preferably 0.1 to 50 mg.

The thus obtained compound of the present invention represented by the general formula (I) has an acetylcholinesterase inhibitory effect that is 1/1 that of the known 9-aminotetrahydroacridine.
Although it is weak (less than 00), it can activate the presynaptic side of cholinergic nerves and increase nerve transmission. Specifically, AF64A (ethylcholine aziridinium ion: ethylcholine aziridinium ion)
[Journal of Pharmacogenetics and Experimental Therapeutics (J
．． Pharmacol. Exp. Ther. ).
222, 140 (1982): 2. :L-
0 7 7-7 Cozy (Neuropharm
acol. ), 26, 361 (1982) improves the ability of hippocampal synaptosomes to take up high-affinity choline in rats intracerebroventricularly administered (Test Example 1). This effect is not observed with 9-aminotetrahydroacridine.

In addition, the compound of the present invention is much less toxic and has fewer side effects than 9-aminotetrahydride acridine, so
It can be a useful therapeutic agent for memory disorders such as Alzheimer's disease.

(Effect of the invention) The compound represented by the general formula (I) of the present invention has pharmacological-2
1- It is a chemically active and valuable compound. In particular, these compounds have the effect of directly activating damaged cholinergic nerves, and therefore are useful as pharmaceuticals that can be used to treat memory disorders such as senile dementia and Alzheimer's disease.

In senile dementia, especially Alzheimer's disease, the function of cholinergic nerves in the brain decreases, and there is a good correlation between this decrease and the degree of memory impairment.

On the other hand, AF64A is Fisher
[ (J. Pharmacol. Exp. Ther.
．． ), 222, 140 (1982 and Leventer [(Neuropharm
acol. ), 26, 361 (as reported in 1987, cholinergic nerves were selectively and long-term impaired, and memory-learning deficits were observed in rats administered AF64A [Brain Res.
), 321. 91 (1984)], is a good model for Alzheimer's disease. Therefore, the compound of the present invention, which can directly activate the function of cholinergic nerves in the brain that has been decreased by administration of AF64A, is considered to be useful in the treatment of senile dementia including Alzheimer's disease.

(Example) -22- Hereinafter, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to the following Examples unless the gist thereof is exceeded.

Example I Synthesis of N-(3-methyl-5.6,7.8-tetrahydrocheno[2.3-b]quinolin-4-yl)butanamide 4-amino-3-methyl-5. 6, 7.
8-tetrahydrocheno[2.3-b]quinoline 4
．． 37 g to 8 ml of pyridine and 12.7 g of anhydrous n-monobutyric acid.
g and heated under reflux for 13 hours.

The reaction solution was dried under reduced pressure, dissolved in 170 ml of methanol and 40 ml of ethanol, and 70 ml of concentrated ammonia water was added.
React at 65°C for 1.5 hours.

Concentrate the solvent under reduced pressure and add 100 ml of chloroform and 100 ml of water.
ml and 5 ml of concentrated ammonia water are added and stirred, and the chloroform layer is dried over anhydrous sodium sulfate.

The chloroform solution was concentrated, purified by silica gel column chromatography (chloroform methanol), and recrystallized from chloroform-diethyl ether.
5.11 g of the target compound was obtained. Melting point 200-202°C
0 Examples 2 to 18 The compounds shown in Table 2 below were synthesized in the same manner as in Example 1.

Table 2 0=C-C3H7 -25- Example 19 Synthesis of N-(2,3-dimethyl-5.6,7.8-tetrahydrofuro[2,3-bl quinolin-4-yl)isobutanamide The title compound was obtained in the same manner as in Example 13, except that -i-butyric anhydride was used instead of -i-butyric anhydride. Melting point 245-246°C Example 20 2-(2-oxopi-lysin-1-yl)-N-(3-
Methyl-5. 6, 7. Synthesis of 8-tetrahydrocheno[2.3-bl quinolin-4-yl)acetamide 1.26 g of sodium hydride (60% content) was suspended in 15 ml of N-methylpi-26-lolidone and the 4-amino 3-methyl-5, 6, 7. 8-tetrahydrocheno[
2.3-b] Add 3.28 g of quinoline. After heating to 50°C and stirring for 40 minutes, 4.72 g of 2-oxo-1-pyrrolidine acetic acid methyl ester was added dropwise at 50°C over 30 minutes. After stirring at 50°C for 20 minutes, cool to 15°C and add 130ml of an aqueous solution of 13.5g of ammonium chloride.
Pour into l.

Extract with 100 ml of chloroform, dry over anhydrous sodium sulfate, dry under reduced pressure, add ethyl acetate, crush, and take off. The crude crystals were recrystallized from chloroform-ethyl acetate to obtain 4.31 g of the target compound.

Melting point: 244-246°co Examples 21-37 The compounds shown in Table 3 below were synthesized in the same manner as in Example 20. However, Example No. The raw material compounds for No. 26 include 9-amino-2-methylene-1, 2, 3.
4-tetrahydroacridine (compound No. 13 in Table 1) was used, in which the double bond had been moved depending on the reaction conditions.

Table-3 -29- Reference example 1 2-chloro-N-(3-methyl-5.6, 7.8
Synthesis of tetrahydrocheno[2.3-bl quinolin-4-yl)acetamide 4-amino-3-methyl-5. 6, 7. 40 ml of chloroacetyl chloride was added to 12.7 g of 8-tetrahydrocheno[2,3-bl quinoline, and the mixture was heated under reflux for 40 minutes. Remove the oil bath and add 1,2-dichloroethane 5
0 ml was added, cooled to 25°C, and the precipitated crystals were filtered and washed with 1,2-dichloroethane. The crystals were mixed with 250 ml of chloroform, 55 ml of water, and 60 ml of ethanol.
1 of the mixture, and add 4.3 ml of concentrated aqueous ammonia. Heat to 40°C to dissolve most of the crystals.

-30- Dry the chloroform layer with anhydrous sodium sulfate and dry for about 10 minutes.
Concentrate to 0ml. To this was added n-heptane 4 (jm1) and cooled, and the crystals were filtered to obtain 8.2 g of the target compound. -dimethyl-5. 6, 7
．． 8-Tetrahydrof[2,3-b]quinoline-
Synthesis of 4-yl)acetamide 4-amino-2,3-dimethyl-5. 6, 7. 8
-tetrahydrofu [2.3-bl quinoline 12.0
14.5 g of the target compound was obtained in the same manner as in Reference Example 1, except that g was used as the raw material. Melting point 219-222°C Example 38 2-cyclopropylamino-N-(3-methyl-5,6
, 7,8 Synthesis of tetrahydrocheno(2.3-bl quinolin-4-monyl)acetamide 2.1 g of the compound synthesized in Reference Example 1 was mixed with 1 t-butanol.
In addition to 2 ml and 25 ml of dimethylformamide, 9 ml of cycloprobylamine was added and reacted at 100°C for 30 minutes.

The reaction solution was concentrated to dryness under reduced pressure, and 100 ml of chloroform, 30 ml of water and 5 ml of concentrated aqueous ammonia were added and stirred.

The chloroform layer was dried over anhydrous sodium sulfate, purified by silica gel column chromatography (chloroform-methanol), and recrystallized from ethyl acetate to obtain 1.52 g of the target compound.

Melting point: 141-144°C0 Examples 39-47 The compounds shown in Table 4 below were synthesized in the same manner as in Example 38.

Table 4 33-Example 48 2-(imidazolin-1-yl)-N-(2.3-dimethyl-5, 6, 7.8 Tetrahydrof [2.
3-b] Synthesis of quinolin-4-yl)acetamide 1.5 g of the compound synthesized in Reference Example 2 was added to 10 ml of i-propanol, 2.1 g of imidazole was added, and the mixture was heated under reflux for 2 hours. After concentrating the reaction solution under reduced pressure, 15 ml of water and 5 ml of concentrated ammonia are added. The precipitated crystals were harvested and recrystallized from methanol-water to yield 1.2 g of the target compound.
I got it. Melting point: 243-247°C0 Example 49 2-((S)-5-methyl-2,4-imidazolidinedione-1-yl)-N-(3-methyl-5.
6, 7. 8 Tetrahydrocheno [2,3-bl
Synthesis of quinolin-4-yl)acetamide 2.5 g of the compound of Example 39 was added to N-methylpyrrolidone 8
ml, add 8 g of urea, and react at 160°C for 40 minutes. Cool the reaction solution to 80°C and add 90ml of water.
The mixture is further cooled to 25°C, and the precipitated crystals are filtered. The crystals were recrystallized from methanol-water to obtain 0.84 g of the target compound 34-. Melting point 273-277°C0 Examples 50-53 The compounds shown in Table 5 below were synthesized in the same manner as in Example 49.

Table 5 Example 54 2-acetylmethylamino-N-(2.3-dimethyl-
5.6,7.8 Synthesis of Tetrahydrofuro[2,3-bl quinolin-4-monyl)acetamide Dissolve 1.3 g of the compound of Example 43 in 10 ml of chloroform, add 5 ml of acetic anhydride, and heat at 25°C. Let it react for 30 minutes. After the reaction solution was concentrated to dryness under reduced pressure, 50 ml of chloroform, 30 ml of water, 5 ml of concentrated ammonium water were added, and the mixture was stirred. The chloroform layer was dried over anhydrous sodium sulfate and recrystallized from chloroform diethyl ether to obtain 1.4 g of the target compound. Melting point 206-209°
co Compounds shown in Tables 6 and 7 below can be synthesized by the same method as in the above examples.

Table-6 0,. C-Rl -37 -38= Table 7 42-45- 46- 49-50 -53- -54- Test Example I Effect on Na+-dependent high affinity choline uptake (HACU) in AF64A-treated rat brain (Method ) AF64A was determined by the method of Fischer et al. (J. Phar
m. Expert. Ther. , 222, 140
(1982) ) from AF64. AF
64A (1.5 nmol/1.5 pi
/side) into bilateral ventricles of the rat. One week later, the animals are decapitated and only the hippocampus is removed. Homogenize with 0.32 M sucrose, centrifuge at 1000 g for 10 minutes, and centrifuge the supernatant at 20000 g for 20 minutes.
Obtain the crude synabus fraction. The crude synaptic fraction and the compound of the present invention were incubated at 37°C for 30 minutes and
] Add choline (1 μM) and incubate for an additional 10 minutes at 37°C. As a control, a crude synaptic fraction incubated at 37°C for 10 minutes was used. The reaction was stopped by suction filtration onto a Whatman GF/B filter. The radioactivity on the filter was measured using a liquid scintillation counter, and this was taken as the amount of HACU. The protein amount was determined by the Bradford method [Anal.
．． 72,248 (quantitated according to June 1976).

Test results are shown in Table-8-57- hand Continued Neho Positive book summer Display of incidents 1990 Patent Application No. 300862 3 person who makes corrections

Claims (7)

[Claims] (1) The following general formula (I) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) [In the formula, R^1 is an alkyl group or formula (II) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) {In formula (II), R^2 represents a hydrogen atom or an acetyl group, and R^3 represents an alkyl group, a cycloalkyl group, or ▲a numerical formula, a chemical formula, a table, etc.▼(R^4 and R^
5 each independently represents a hydrogen atom or an alkyl group. ). In addition, in formula (II), ▲There are mathematical formulas, chemical formulas, tables, etc.▼, R^2 and R^3 are connected to each other, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲Mathematical formulas, chemical formulas, tables, etc. Yes ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R^6
represents a hydrogen atom or an alkyl group. ) may be formed. ). ▲Contains mathematical formulas, chemical formulas, tables, etc.▼
▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ Mathematical formulas, chemical formulas, There are tables, etc. ▼ (R^7 and R^8 each independently represent a hydrogen atom or an alkyl group.), ▲
There are mathematical formulas, chemical formulas, tables, etc. ▼ (R^9 and R^1
^0 each independently represents a hydrogen atom or an alkyl group. ), ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ Mathematical formulas, chemical formulas,
There are tables, etc. ▼ (R^1^1 represents a hydrogen atom or an alkyl group), ▲ there are mathematical formulas, chemical formulas, tables, etc. ▼ means ▲ there are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ mathematical formulas, chemical formulas , tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, {R^1^2 and R^1^3 each independently represent an alkyl group, or are connected to each other to form a ▲mathematical formula, chemical formula , tables, etc. ▼ (n represents an integer of 2 to 6) or ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (m represents an integer of 2 or 3) may be formed. }
, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R^1^4 represents a hydrogen atom or an alkyl group.), ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( R^1^5 represents a hydrogen atom or an alkyl group.) or ▲There are mathematical formulas, chemical formulas, tables, etc.▼. However, when ▲There are mathematical formulas, chemical formulas, tables, etc.▼ represents ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or ▲There are mathematical formulas, chemical formulas, tables, etc.▼▲Mathematical formula , chemical formulas, tables, etc. ▼ is ▲ mathematical formula,
There are chemical formulas, tables, etc., but it does not represent ▼, and R^7 does not represent a hydrogen atom. ] A 9-acylaminotetrahydroacridine derivative, its optical antipode or a pharmaceutically acceptable acid addition salt thereof. (2) R^1 is an alkyl group, -CH_2-NHR^3(
R^3 is the same as the above definition), ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R
^6 is the same as the above definition) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ is ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲
There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼,
▲There are mathematical formulas, chemical formulas, tables, etc.▼(R^7 and R^
8 is the same as the above definition), ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R^9 and R^1^0 are the same as the above definition), ▲
There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Represents ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ is ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ Mathematical formulas, chemical formulas, There are tables, etc.▼ or ▲mathematical formulas, chemical formulas,
2. The compound according to claim 1, which is represented by ▼ (R^1^2 and R^1^3 are the same as defined above). (3) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ represents ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ represents ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ The compound according to claim 2, characterized in that: (4) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ represents ▲There are mathematical formulas, chemical formulas, tables, etc.▼, and ▲There are mathematical formulas, chemical formulas, tables, etc.▼ is ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (
3. The compound according to claim 2, wherein R^1^2 and R^1^3 are the same as defined above. (5) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ represents ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (R^7 and R^8 are the same as the above definitions), and ▲There are mathematical formulas, chemical formulas, tables, etc. ▼
▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R^1^2 and R^1^3 are the same as the above definitions )
3. A compound according to claim 2, characterized in that it represents (6) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ represents ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼ is ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or ▲ 3. The compound according to claim 2, which is represented by a mathematical formula, a chemical formula, a table, etc. (R^1^2 and R^1^3 are the same as defined above). (7) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ represents ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R^9 and R^1^0 are the same as the definitions above), ▲ Mathematical formulas, chemical formulas, tables, etc. There is ▼ ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R^1^2 and R^1^3 are the above 3. A compound according to claim 2, characterized in that it represents (same as in the definition).