JP2720549B2 - 9-aminoacetylaminotetrahydroacridine derivative - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a novel and useful 9-aminoacetylaminotetrahydroacridine derivative which activates a cholinergic nerve with reduced function, an optical antipode thereof or a pharmaceutically active substance. Pertains to its acceptable acid addition salts.

Acetylcholinesterase inhibitors have been used as treatments for various memory lifetimes characterized by impaired cholinergic nervous function, such as Alzheimer's disease, such as Alzheimer's disease. There has been an attempt to increase the acetylcholine content in the brain by using acetylcholine. For example, consider using physostigmine Neurology (Neurology), 8, 397
(1978). Further, JP-A-61-148154
No., JP-A-63-141980, JP-A-63-225358, JP-A-63-225358
63-238063, JP-A-63-239271, JP-A-63-284175
JP-A-63-297367, JP-A-64-73, JP-A-1-
No. 132566, EP-A-268871, and WO 88/02256 report that a specific 9-aminotetrahydroacridine derivative has an acetylcholinesterase inhibitory effect and is effective for treating Alzheimer's disease. ing.
Summers is also a member of The New England Journal of Medicine.
Journal of Medicine), 315 , 1241 (1986).
Amino-1,2,3,4 tetrahydroacridine (tacrine)
Report that it is effective in combination with lecithin in human Alzheimer's disease. However, sufficient improvement has not been achieved or the occurrence of side effects has become a problem, and the emergence of a new therapeutic method is desired.

On the other hand, as an example of known 9-acylaminotetrahydroacridine, 9-acetylaminotetrahydroacridine is described in Journal of Chemical Society, 634 (1947), and Chemikelisty (Chem.listy) , 51 , 1907 (1
957) describes 9-chloroacetylaminotetrahydroacridine and 9-diethylaminoacetylaminotetrahydroacridine, and describes that the latter has a local anesthetic effect. Also, the Journal of
Medicinal Chemistry (Journal of Medicinal
Chemistry), 18 , 1056 (1975) describes the structure-activity relationship of the acetylcholinesterase inhibitory activity of 9-aminotetrahydroacridine derivatives. It is described that the activity becomes 1/1000 as compared with aminotetrahydroacridine. The above-mentioned patents (JP-A-63-166881, JP-A-63-203664, JP-A-63-238063, JP-A-63-2392)
No. 71, JP-A-63-284175, JP-A-64-73 and JP-A-1-132566), the claims include 9-acylaminotetrahydroacridine derivatives. However, none of these publications describes a specific synthesis example and pharmacological activity of a compound having a 9-aminoacetylamino group.

(Means for Solving the Problems) The present inventors have conducted various studies with the aim of providing a therapeutic agent for senile dementia including Alzheimer's disease, and as a result, a specific 9-aminoacetylaminotetrahydroacridine was obtained. The derivative, its optical antipode or its pharmaceutically acceptable acid addition salt has a different mechanism from a compound having a conventional acetylcholinesterase inhibitory action,
The present inventors have found that it can be used as a drug for improving memory disorders such as Alzheimer's disease, and have completed the present invention.

That is, the gist of the present invention is represented by the following general formula (I) 中 (R ⁵ represents a hydrogen atom or an alkyl group.)

(R ⁶ represents a hydrogen atom or a halogen atom.) Or (R ⁷ represents a hydrogen atom or an alkyl group.) (R ⁸ represents a hydrogen atom or an alkyl group.), Represents ９ represents a 9-aminoacetylaminotetrahydroacridine derivative, an optical antipode thereof or a pharmaceutically acceptable acid addition salt thereof.

Hereinafter, the present invention will be described. The 9-aminoacetylaminotetrahydroacridine derivative of the present invention is represented by the general formula (I). In the formula (I), R ⁵ , R ⁷ and R ⁸
As the alkyl group represented by, a C _{1 to} C ₆ alkyl group, preferably a methyl group, an ethyl group, an n-propyl group,
Isopropyl group, n-butyl group, isobutyl group, sec-
Butyl group, an alkyl group of C ₁ -C _4, such as a tert- butyl group. Examples of the halogen atom represented by R ⁶ 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 of the compounds include the following.

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

Among the compounds of the present invention, particularly preferred are compounds No. 1, 2, 4, 6, 7, 8, 11 and 12 in Table 1 above.

As the salts of the compound represented by the formula (I), physiologically acceptable salts are preferable, for example, inorganic salts such as hydrochloride, hydrobromide, hydroiodide, sulfate and phosphate;
And oxalate, maleate, fumarate, lactate,
Organic acid salts such as malate, citrate, tartrate, benzoate, methanesulfonate, camphorsulfonate and the like can be mentioned. Since the compounds of formula (I) and salts thereof 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 described.

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

Formula (II) below In the presence or absence of a solvent, a compound represented by
By heating with 1 to 10 equivalents of urea, the compound of the formula (I) represented by the following formula (III) can be produced.

(Where And R ⁵ are as defined above. The compound of formula (II) as the starting material is disclosed in Japanese Patent Application No. 63-283351.
And Japanese Patent Application No. 63-305799 and Japanese Patent Application No. 1-137645.

As a reaction solvent, an inert polar solvent such as dimethylsulfoxide, dimethylformamide, dimethylacetamide, or N-methylpyrrolidone is preferable. The reaction temperature is
The reaction is carried out at a temperature of 120 to 190 ° C, preferably 140 to 170 ° C.

The compound of the following formula (IV), which is a basic material of the above method For example, (a) Tetrahedron Lette
rs), 1277 (1963) (b) Collection of Czechoslovak Chemical Communications (Collect.Czech.Chem.Commu)
n.), 42 , 2802 (1977) (c) Acta Chemic
a Scandinavica), B, 33 , 313 (1979) and the like, or a method analogous thereto.

Also, JP-A-61-148154, JP-A-63-141980, JP-A-63-166881, JP-A-63-203664, JP-A-63-22
No. 5358, JP-A-63-238063, JP-A-63-239271, JP-A-63-297367, JP-A-64-73, JP-A-1-132566
And EP-A-268871.

When the compound of the present invention is used as a therapeutic agent, it is administered alone or in combination with a pharmaceutically acceptable carrier. Its composition is
It is determined by the solubility, chemical properties, administration route, administration schedule and the like of the compound. For example, they may be orally administered in the form of granules, fine granules, powders, tablets, hard capsules, soft capsules, syrups, emulsions, suspensions or liquids, or intravenously as injections. Administration may be performed, intramuscular administration, or subcutaneous administration.

In addition, it may be used as powder for injection and adjusted for business use. 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 the present invention. As an excipient used for producing a solid preparation, for example, lactose, sucrose, starch, talc, cellulose, dextrin, kaolin, calcium carbonate and the like are used. Liquid preparations for oral administration, i.e., emulsions, syrups, suspensions, solutions and the like, are commonly used inert diluents,
For example, water or vegetable oil is included. This preparation contains, in addition to the inert diluent, auxiliary substances such as wetting agents, suspending aids, sweeteners,
It can include fragrances, colorants or preservatives and the like. Liquid preparations may be included in capsules of absorbable substances such as gelatin. Examples of the preparation for parenteral administration, that is, a solvent or a suspending agent used for producing an injection or the like include water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin and the like. The preparation of the preparation may be in accordance with a conventional method.

When used by oral administration, the clinical dose is generally 1 to 10 times a day as the compound of the present invention for adults.
The dose is 00 mg, preferably 1 to 100 mg, but it is more preferable to increase or decrease as appropriate according to age, medical condition, symptom, and presence or absence of simultaneous administration. The daily dose of the compound of the invention is 1
It may be administered twice or three times a day at appropriate intervals, or may be administered intermittently.

When used as an injection, the compound of the present invention for an adult is in a daily dose of 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) is 1/100 of 9-aminotetrahydroacridine known to have an acetylcholinesterase inhibitory action.
It can activate the presynaptic side of cholinergic nerves, albeit weaker, to enhance neurotransmission.
Specifically, AF64A (ethylcholine aziridinium ion) [Journal
Of Pharma Korozo and Ickx Peri mental Sera poi Politics (J.Pharmacol.Exp.Ther.), 222, 1
40 (1982): Neuropharmacology
ol.), 26 , 361 (1982)], improves the ability of hippocampal synaptosomes to take up high-affinity choline in rats intravenously (Test Example 1). This effect is not seen with 9-aminotetrahydroacridine.

In addition, the compound of the present invention has very low toxicity and has few side effects as compared with 9-aminotetrahydroacridine, and thus 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 is a pharmacologically active and valuable compound. In particular, since these compounds have an action of directly activating the inhibited cholinergic nerve, they are useful as pharmaceuticals that can be used for treating 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 is reduced, and there is a good correlation between this reduction and the degree of memory impairment.

AF64A, on the other hand, is based on Fisher [(J. Pharmac
ol. Exp. Ther.), 222 , 140 (1982)] and Venter (L.
Eventer) [(Neuropharmacol.), 26 , 361 (1987)] reported that cholinergic nerves were selectively and chronically impaired, and AF64A-treated rats were impaired in memory learning [Brain Research (Brain Res.), 3
21 , 91 (1984)], a good model for Alzheimer's disease. Therefore, the compound of the present invention, which can directly activate the function of cholinergic nerve in the brain reduced by the administration of AF64A, is considered to be useful for the treatment of senile dementia including Alzheimer's disease.

(Examples) Hereinafter, the present invention will be described more specifically with reference to Examples, but the present invention is not limited to the following Examples as long as the gist of the present invention is not exceeded.

Reference Example 1 Synthesis of N-[(1,2,3,4-tetrahydroacridin-9-yl) aminocarbonylmethyl] -L-alanine ethyl ester 9-chloroacetylamino-1,2,3,4-tetrahydroacridine 22 g of L-alanine ethyl ester is added to 5 g and reacted 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 desired compound.

 101-102 ° C.

Reference Example 2 Synthesis of N-[(1,2,3,4-tetrahydroacridin-9-yl) aminocarbonylmethyl] -L-alanine 2 g of the compound obtained in Reference Example 1 was dissolved in a 1N aqueous solution of sodium hydroxide at room temperature. Add to 12 ml and let react for 2 hours. In addition, 15
When 15 ml of 1N hydrochloric acid is added at a temperature below ℃, white crystals precipitate. This was collected by filtration, washed with 10 ml of water, and dried to obtain the desired compound 1.
42 g were obtained.

 238-242 ° C. Disassembly.

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

Example 1 2-((S) -5-methyl-2,4-imidazolidinon-1-yl) -N- (1,2,3,4-tetrahydroacridin-9-yl) acetamide (Table 1) Compound No. 2)
Synthesis of 3.9 g of the compound obtained in Reference Example 1 was carried out using 9 m of N-methylpyrrolidone.
and 2.64 g of urea are added and reacted at 160 ° C. for 1 hour. After cooling to 80 ° C., 100 ml of water is added, and the precipitated crystals are collected by filtration. 5 ml of methanol and 150 ml of chloroform
Dissolve in water, dry over anhydrous sodium sulfate and concentrate to dryness. Recrystallization from ethanol-ethyl acetate gave 2.44 g of the desired compound.

 260-263 ° C.

Examples 2 to 8 The compounds shown in Table 3 below were synthesized in the same manner as in Example 1.

Test Example 1 Effect of AF64A-treated rat brain on Na ⁺ -dependent high-affinity choline uptake (HACU) (Method) AF64A was prepared by the method of Fischer et al. (J. Pharm. Exper. Ther., 222 ,
140 (1982)). AF64A (1.5n
mol / 1.5 μl / side) is injected into the bilateral ventricles of the rat. One week later, the head is decapitated and only the hippocampus is removed. The mixture is homogenized with 0.32M sucrose, centrifuged at 1000 g for 10 minutes, and the supernatant is further centrifuged at 20,000 g for 20 minutes to obtain a crude synaptic fraction. The crude synaptic fraction and the compound of the present invention were incubated at 37 ° C. for 30 minutes, and [ ³ H] choline (1 μM) was added.
Incubate for another 10 minutes at 37 ° C. As a control, a crude synapse fraction incubated at 37 ° C. for 10 minutes was used. The reaction was stopped by suction filtration on Whatman GF / B filters. The radioactivity on the filter was measured with a liquid scintillation counter, and this was defined as the amount of HACU. The protein amount was quantified according to the method of Bradford (Anal. Biochem., 72 , 248 (1976)). Table 4 shows the test results.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Akihiro Tobe 1000 Kamoshita-cho, Midori-ku, Yokohama-shi, Kanagawa Prefecture Inside Mitsubishi Chemical Research Institute (72) Inventor Yasuhiro Morinaka 1000 Kamoshita-cho, Midori-ku, Yokohama-shi, Kanagawa Mitsubishi (56) References JP-A-1-132566 (JP, A) JP-A-1-250353 (JP, A)

Claims (1)

(57) [Claims] 1. A compound represented by the following general formula (I) 中 (R ⁵ represents a hydrogen atom or an alkyl group.) (R ⁶ represents a hydrogen atom or a halogen atom.) Or (R ⁷ represents a hydrogen atom or an alkyl group.) (R ⁸ represents a hydrogen atom or an alkyl group.), Represents A 9-aminoacetylaminotetrahydroacridine derivative represented by｝, an optical antipode or a pharmaceutically acceptable acid addition salt thereof.