JPH03151366A - 9-aminoacetylaminotetrahydroacridine derivative - Google Patents

Abstract

NEW MATERIAL:9-Aminoacetylaminotetrahydroacridine derivative of formula I [R<1> is H; R<2> is a group of formula II (R<3> is alkyl; R<4> is H or alkyl), or R<1> and R<2> mutually combine to form a group of formula III (R<5> is H or alkyl) together with the N; A is a group of formula IV (R<6> is H or halogen) or a group of formula V (R<7> is H or alkyl); B is a group of formula VI (R<8> is H or alkyl), VII or VIII], an optical antipode thereof or an acid adduct thereof. EXAMPLE:N-[(1,2,3,4-Tetrahydroacridin-9-yl)aminocarbonylmethyl]-L-alanine ethyl ester. USE:Useful as a drug for treating dysmnesia such as senile dementia or Alzheimer's disease. PREPARATION:A compound of formula IX (R<9> is 1-4C alkyl) is heated together with 1-10 equivalents of urea to prepare the compound of formula I wherein NR<1>R<2> is a group of formula III.

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-aminoacetylaminotetrahydroacridine 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).
397 (1978). Furthermore, JP-A-61-148154, JP-A-6
3-141980, JP 63-225358, JP 63-238063, JP 63-239271
No., JP-A-63-284175, JP-A-63-297
No. 367, JP-A-64-73, JP-A-1-13256
No. 6, EP-A-268871, International Publication No. 88702
It is reported in each publication of No. 256 that a specific 9-aminotetrahydroacridine derivative has an acetylcholinesterase inhibitory effect and is effective in treating Alzheimer's disease. Summers also published The New England Journal of Medicine (The New England Journal of Medicine).
New England Journal of Med
icine), 315.1241 (1986) 9
-Amino-1,2,3,4 tetrahydroacridine (Tafrin) has been reported to be effective in treating Alzheimer's disease in humans when used in combination with lecithin. However, sufficient improvement has not been achieved and side effects have become a problem.
It is hoped that new treatments will emerge.

On the other hand, as an example of known 9-acylaminotetrahydroacridine, the Journal of Chemical Society (J
Our own of Chemical 5ociet
y), 634 (1947) describes 9-acetylaminotetrahydroacridine, and Chem.

1isty), 51.1907 (1957) 9-
Chloroacetylaminotetrahydroacridine and 9-
Diethylaminoacetylaminotetrahydroacridine is described, and it is noted that the latter has a local anesthetic effect. In addition, the Journal of Medicinal Chemistry
Chemistry).

Tan, 1056 (1975) describes the structure-activity relationship of acetylcholinesterase inhibitory activity of 9-aminotetrahydroacridine derivatives, and 9-acetylaminotetrahydroacridine and 9-benzoylaminotetrahydroacridine are 9-aminotetrahydroacridine derivatives. It is noted that the activity is 1/1000 compared to that of Also, the above-mentioned patent (Japanese Unexamined Patent Publication No. 63-16
No. 6881, JP-A-63-203664, JP-A-63
-238063, JP-A-63 +239271,
JP-A No. 63-284175, JP-A No. 64-73, and JP-A No. 1-132566) include 9-acylaminotetrahydroacridine derivatives in their claims. However, 9-
Specific synthesis examples and pharmacological activities of compounds having an aminoacetylamino group are not described.

(Means for Solving the Problems) As a result of various studies aimed at providing a therapeutic agent for senile dementia including Alzheimer's disease, the present inventors discovered that a specific 9-aminoacetylaminotetrahydroacridine Derivatives, their antipodes, or pharmaceutically acceptable acid addition salts thereof can serve as drugs that improve memory disorders such as Alzheimer's disease through a mechanism different from that of conventional compounds that inhibit acetylcholinesterase. This discovery led to the completion of the present invention.

That is, the gist of the present invention is represented by the following general formula (I) (R3 represents an alkyl group, R4 represents a hydrogen atom or an alkyl group), or R1, R2, and R1 are connected to each other, -NkR2 in formula (I) represents an atom or a halogen atom. ) or aminotetrahydroacridine derivatives, their antipodes, or pharmaceutically acceptable acid addition salts thereof.

To explain the present invention below, the 9-aminoacetylaminotetrahydroacridine derivative of the present invention has the general formula (
I). In formula (I), R3-R6, R
As the alkyl group represented by 7 and R8, 01 to C
6 alkyl group, preferably methyl group, ethyl group, n-
C1 of propyl group, isopropyl group, n-butyl group, isobutyl group, 5ee-butyl group, tert-butyl group, etc.
-04 alkyl group is mentioned. Examples of the halogen atom represented by R6 include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

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

(1) R1 represents a hydrogen atom, and R2 represents -CH-C
A substituent represented by 0OR'3, in which R3 is a methyl group or an isopropyl group, and R4 is a hydrogen atom, a methyl group, or an ethyl group. Or a substituent in which R1 and R2 are connected to each other, and R6 is a hydrogen atom, a methyl group, or an isopropyl group.

Specific examples of the compounds of the present invention having such preferred substituents are shown in Table 1 below.

Table 1 Among the compounds of the present invention, particularly preferred compounds are the above-mentioned compound No. 1.3.5.10.11.12.2
1.22.24.26.27.28.31 and 32.

The salts of the compound represented by formula (I) are preferably physiologically acceptable salts, such as inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, and phosphate; and organic acid salts such as oxalate, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, methanesulfonate, and camphorsulfonate. 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) Except for the case where R1 and R2 are connected to each other in the formula (I) above, Japanese Patent Application No. 63-283351, Japanese Patent Application No. 63-305799, and Japanese Patent Application No. 137645
It can be produced by a method similar to that described in No.

(2) The following ( III) A compound of formula (I) can be produced.

The compound of formula (II) as a raw material is
No. 3351, Japanese Patent Application No. 1983-305799 and Japanese Patent Application No. 1998
It can be produced by a method similar to that described in No.-137645.

As the reaction solvent, inert polar solvents such as dimethylsulfoxide, dimethylformamide, dimethylacetamide, and N-methylpyrrolidone are preferred. The reaction temperature is 1
It is carried out at a temperature of 20 to 190°C, preferably 140 to 170°C.

The following (IV
) formula % formula % ) (b) Collection of Czec Chemical Communications (Collect, Czec
h, Chem.

Commun, ), board, 2802 (1977) (e)
Acta Chemipower Scandinavian Power (ActaChe
mica 5candinavica), B, 33
．． 313 (1979), or a method analogous thereto.

Also, JP-A-61-148154, JP-A-63-14
1980, JP-A-63-166881, JP-A-63-203664, JP-A-63-225358,
JP 63-238063, JP 63-23927
No. 1, JP-A-63-297367, JP-A-64-73
No., JP-A-1-132566 and EP-A-2688
It can also be synthesized according to the methods described in each publication of No. 71.

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 depends on the compound's solubility, chemical properties, route of administration,
Determined by administration schedule, 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 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. Excipients used in producing solid preparations include, for example, lactose, sucrose, starch, talc, cellulose, dextrin, kaolin, calcium carbonate, and the like. Liquid preparations for oral administration, ie, emulsions, syrups, suspensions, solutions, etc., contain commonly used inert diluents such as water or vegetable oils. In addition to inert diluents, the formulations may also contain adjuvants such as wetting agents, suspending agents, sweetening agents, flavoring agents, coloring agents, or preservatives. Liquid preparations may be enclosed in capsules of absorbable material such as gelatin. Examples of solvents or suspending agents used in the production of parenteral preparations, ie, injections, etc. 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, but it is more preferably increased or decreased 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:
It may be administered once a day, divided into two or three times a day at appropriate intervals, or administered 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. ~50mg.

The compound of the present invention represented by the general formula (I) obtained in this manner is a compound of 9-aminotetrahydroacridine which is known to have an acetylcholinesterase inhibitory effect.
Although it is weak (less than 0), it can activate the presynabtic side of cholinergic nerves and increase nerve transmission. Specifically, AF64A (ethylcholineaziridinium ion: ethylcholineazirid
inium 1on) [Journal of Pharmacology and Experimental Therapeutics (J,
Pharmacol, Exp, Ther, )
, 222, 140 (1982): 0 Neuropharmacol.

26, 361 (1982) improves the high-affinity choline uptake ability of the hippocampal sinusoids of rats administered intracerebroventricularly (Test Example 1). This effect is not observed with 9-aminotetrahydroacridine.

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

(Effects of the Invention) The compound represented by the general formula (I) of the present invention is a valuable pharmacologically active 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 Fibre-y-(Fisher)
[(J.

Pharmacol, Exp, Ther, ),
222, 140 (1982)] and] Leventer) [(Neuropharm
acol, ).

26, 361 (1987)], selectively and long-term damage to cholinergic nerves and AF
Memory and learning deficits were observed in rats administered with 64A [
Brain Research (Brain Res), 3
21, 91 (1984)] and 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.

(Examples) 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 N-[(1,2,3,4-tetrahydroacridine-9
-yl)aminocarbonylmethyl]-L-alanine ethyl ester (Compound No. 3 in Table 1) Synthesis 9-
Add 22 g of L-alanine ethyl ester to 5 g of chloroacetylamino-1,2,3,4-tetrahydroacridine and react at 100°C for 30 minutes. After cooling to room temperature, 100 ml of chloroform and 100 ml of water are added and stirred. The chloroform layer was dried over anhydrous sodium sulfate, purified by silica gel column chromatography (chloroform-methanol), and recrystallized from chloroform-n-hexane to obtain 5.9 g of the target compound.

Melting point 101-102°C0 Example 2 N-[(1,2,3,4-tetrahydroacridine-9
-yl)aminocarbonylmethyl]-L-alanine (Compound No. 1 in Table 1) 2 g of the compound obtained in Example 1 was added to 12 ml of IN-sodium hydroxide aqueous solution at room temperature and reacted for 2 hours. When 15 ml of IN hydrochloric acid is added to this at 15° C. or lower, white crystals are precipitated. This was taken in a furnace, washed with 10 ml of water, and then dried to obtain 1.42 g of the target compound.

Melting point 238-242°C0 decomposition.

Examples 3 to 5 The compounds shown in Table 2 below were synthesized in the same manner as in Example 1 or 2.

Example 6 2-((S)-5-methyl-2,4-imidazolidinion-1-yl)-N-(1,2,3,4-tetrahydroacridin-9-yl)acetamide (Table 1 Synthesis of Compound No. 22) 3.9 g of the compound obtained in Example 1 was dissolved in 9 ml of N-methylpyrrolidone, 2.64 g of urea was added, and the mixture was heated at 160°C.
Let it react for 1 hour. Cool to 80°C and add 100% water
Add m1 and count the number of crystals to precipitate. This was dissolved in 5 ml of methanol and 150 ml of chloroform, dried over anhydrous sodium sulfate, and concentrated to dryness. Recrystallization from ethanol-ethyl acetate yielded 2.44 g of the target compound.

Melting point: 260-263°C0 Examples 7-13 The compounds shown in Table 3 below were synthesized in the same manner as in Example 6.

Table 3 Test Example I Effect on Na+-dependent high affinity choline uptake (HACU) in AF64A-treated rat brain (method) AF64A was tested using the method from Fischer (J, Pha
rm, Expert.

Ther, 222, 140 (1982))
Adjusted from AF64 according to the following. AF64A (1,5
nmol/1.5 pl/5ide) is injected into bilateral rat ventricles. After -weeks, the head is decapitated and only the hippocampus is removed. 0
．． 32 Homogenized with M sucrose, 100
Centrifuge at 0 g for 10 minutes, and the supernatant is further centrifuged at 20,000 g.
Centrifuge at g for 20 minutes to obtain the crude synaptic fraction. The crude synaptic fraction and the compound of the invention are incubated at 37°C for 30 minutes, [3H]choline (1 μM) is added and further incubated at 37°C for 10 minutes. As a control, a crude synapse fraction incubated for 37°010 minutes was used. What is the reaction?
Stopped by suction filtration onto a man GF/B filter. The radioactivity on the filter was measured using a liquid scintillation counter, and this was designated as HACUfN. The protein amount is determined by Bradford's protein content.
Ord)'s method [Anal Biochem, 72.

248 (quantified in accordance with June 1976). The test results are shown in Table 4.

Procedural amendment (voluntary) Case indication 1999 Patent Application No. 29091 Title of invention 9-aminoacetylaminotetrahydroacridine derivative Person making amendment

Claims (1)

[Claims] (1) The following general formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1 represents a hydrogen atom, R^2 is a ▲mathematical formula,
There are chemical formulas, tables, etc. ▼ (R^3 represents an alkyl group, R^4 represents a hydrogen atom or an alkyl group), or R^1 and R^2 are connected to each other, In formula (I), ▲There are mathematical formulas, chemical formulas, tables, etc.▼ represents ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (R^5 represents a hydrogen atom or an alkyl group.) ▲There are mathematical formulas, chemical formulas, and tables.
R^7 represents a hydrogen atom or an alkyl group. ), ▲ has mathematical formulas, chemical formulas, tables, etc. ▼ has ▲ mathematical formulas, chemical formulas, tables, etc. ▼ (R^8 represents a hydrogen atom or an alkyl group), ▲ has mathematical formulas, chemical formulas, tables, etc. Represents ▼ or ▲, which includes mathematical formulas, chemical formulas, tables, etc. ), its optical antipode or a pharmaceutically acceptable acid addition salt thereof.