JP2546919B2 - 9-acylaminotetrahydroacridine derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel and useful 9-acylaminotetrahydroacridine derivative, which activates a depressed cholinergic nerve, its optical antipode or pharmaceutically acceptable Acid addition salts thereof which can be

(Problems to be Solved by Conventional Techniques and Inventions) Acetylcholinesterase inhibitors are used as a treatment method for various memory disorders such as Alzheimer's disease characterized by a decline in cholinergic nerve function. There is an attempt to increase the acetylcholine content in the brain. For example, consider using physostigmine Neurology (Neurology), 8, 397
(1978). Further, JP-A-61-148154
JP-A-63-141980, JP-A-63-225358, JP-A-SHO
63-238063, JP-A-63-239271, JP-A-63-284175
JP-A-63-297367, JP-A-64-73, JP-A-1-
132566, EP-A-286871, and WO 88/02256 each report that a specific 9-aminotetrahydroacridine derivative has an acetylcholinesterase inhibitory action and is effective for the treatment of Alzheimer's disease. ing.

Also, Summers is the New England Journal of Medicine.
Journal of Medicine), 315 , 1241 (1986) reported that 9-amino-1,2,3,4 tetrahydroacridine (tacrine) in combination with lecithin is effective for human Alzheimer's disease. However, sufficient improvement has not been achieved, and the occurrence of side effects has become a problem, and the advent of new therapeutic methods is desired.

On the other hand, as an example of the known 9-acylaminotetrahydroacridine, as an example, Journal of Chemical Society, 634 (1947)
9-acetylaminotetrahydroacridine is described in Chem.listy, 51 , 1907.
(1957) describes 9-chloroacetylaminotetrahydroacridine and 9-diethylaminoacetylamino-tetrahydroacridine, the latter having a local anesthetic effect. Also, the Journal of Medicin
al Chemistry), 18 , 1056 (1975), the structure-activity relationship of the acetylcholinesterase inhibitory activity of 9-aminotetrahydroacridine derivatives is described, and 9-acetylaminotetrahydroacridine and 9-benzoylaminotetrahydroacridine are -It is noted that the activity is 1/1000 compared to aminotetrahydroacridine. Further, the above-mentioned patent publication (JP-A-63-166881)
JP-A-63-203664, JP-A-63-238063, JP-A-SHO
63-239271, JP-A-63-284175, JP-A-64-73 and JP-A-1-132566), a 9-acylaminotetrahydroacridine derivative is included in the claims. Some of them are included, but no specific synthetic examples and pharmacological activities of compounds having a 9-acylamino group are described therein.

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

That is, the gist of the present invention is the following general formula (I) [In the Formula, R ¹ is an Alkyl Group or Formula (II) {In the formula (II), R ² represents a hydrogen atom or an acetyl group, R ³ represents an alkyl group, a cycloalkyl group or (R ⁴ and R ⁵ each independently represent a hydrogen atom or an alkyl group.

Also, in the formula (II) In, R ² and R ³ are connected to each other Or (R ⁶ represents a hydrogen atom or an alkyl group). } Is represented.

(R ⁷ and R ⁸ each independently represent a hydrogen atom or an alkyl group.), (R ⁹ and R ¹⁰ each independently represent a hydrogen atom or an alkyl group.) (R ¹¹ represents a hydrogen atom or an alkyl group), {R ¹² and R ¹³ each independently represent an alkyl group or are linked to each other. (N represents an integer of 2 to 6) or (M represents an integer of 2 or 3) may be formed. ｝, (R ¹⁴ represents a hydrogen atom or an alkyl group.) (R ¹⁵ represents a hydrogen atom or an alkyl group.) Or Represents However, When represents And R ⁷ does not represent a hydrogen atom. ] The 9-acylaminotetrahydroacridine derivative represented by the above, its optical antipode, or a pharmaceutically acceptable acid addition salt thereof.

The 9-acylaminotetrahydroacridine derivative of the present invention is represented by the above general formula (I). (I) In formula, the alkyl group of R ¹ is C ₂ -C _6, preferably an ethyl group, n- propyl group, an isopropyl group, n- butyl group, sec- butyl group, C ₂ ~ such as tert- butyl It represents an alkyl group of C ₄ or a group represented by the formula (II).

In the formula (II), the alkyl group represented by R ³ is a C _{1 to} C ₆ alkyl group, preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group,
C ₁ such as isobutyl group, sec-butyl group, tert-butyl group
To C ₄ alkyl group, and examples of the cycloalkyl group include C _{3 to} C ₆ cycloalkyl groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group.

The alkyl group represented by R ^{4 to} R ⁶ is a C _{1 to} C ₆ alkyl group, preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, sec-butyl. Group, and a C ₁ -C ₄ alkyl group such as a tert-butyl group.

In formula (I), the alkyl group represented by R ^{7 to} R ¹⁴ includes a methyl group, an ethyl group, an n-propyl group,
Isopropyl group, n-butyl group, isobutyl group, sec-
Examples thereof include C _{1 to} C ₄ alkyl groups such as a butyl group and a tert-butyl group.

In formula (I), examples of the aralkyl group represented by R ¹⁵ include a phenyl group substituted with a C _{1 to} C ₄ alkyl group such as a benzyl group and a phenethyl group.

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

(1) R ¹ is represented by an n-propyl group, an isopropyl group or a formula (II), and in the formula (II), In, R ² represents a hydrogen atom, or R ² and R ³ are bonded to each other. A substituent represented by.

Is a substituent.

Is a substituent.

The salts of the compound represented by the formula (I) are preferably physiologically acceptable salts, for example, inorganic salts such as hydrochloride, hydrobromide, hydroiodide, sulfate and phosphate. , And oxalate, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate,
Examples thereof include organic acid salts such as methane sulfonate and camphor sulfonate. Since the compound of the formula (I) and salts thereof may exist in the form of hydrate or solvate, these hydrates and solvates are also included in the compound 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 any of the following methods.

(1) R ¹ is represented by the formula (II), and R ² and R ³ are connected to each other. Except when the group represented by
No. 63-305799 or JP-A-1-137645.

(2) R ¹ is represented by the formula (II), and R ² and R ³ are connected to each other. When the group represented by is represented by (I
The compound of the present invention represented by the formula V) can be produced.

(In the above formula, R ⁵ and R ⁶ are as defined above. That is, the compound of formula (IV) is obtained by heating the compound of formula (III) in the presence of a solvent or without solvent with 1 to 10 equivalents of urea.

The compound of the formula (III) as a raw material can be obtained by the method of the above item (1).

The reaction solvent is preferably an inert polar solvent such as dimethyl sulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone.

The reaction temperature is in the range of 120 to 190 ° C, preferably 140 to 170 ° C.

The compound of the following formula (V), which is a raw material for the above methods (1) and (2), is, for example, (A) Tetrahedron Letters
ers, 1277 (1963) (b) Collection of Czechoslovak Chemical Communications (Collect.Czech.Chem.Com
mun.), 42 , 2802 (1977) (c) Acta Chemi
ca Scandinavica), B, 33 , 313 (1979) etc.,
Alternatively, it can be easily synthesized by a method according to this.

Further, JP-A-61-148154, JP-A-63-141980, JP-A-63-166881, JP-A-63-203664, and JP-A-63-22.
5358, JP-A-63-238063, JP-A-63-239271, JP-A-63-297367, JP-A-64-73, JP-A-1-132566.
It can also be synthesized according to the method described in each publication of JP-A-No. EP-A-268871.

Table 1 below shows specific examples of the starting compound for the compound of the present invention represented by the formula (V), which was synthesized according to the method described in the above document.

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 of the compound, chemical properties, administration route, administration schedule and the like. For example, granules, fine granules, powders, tablets, hard capsules, soft capsules, syrups, emulsions,
It may be orally administered in the form of a suspension or liquid, or may be administered as an injection intravenously, intramuscularly or subcutaneously.

Alternatively, it may be powdered for injection and adjusted for use. A pharmaceutical organic or inorganic solid or liquid carrier or diluent suitable for oral, enteral, parenteral or topical administration can be used with the compounds of the present invention. Examples of the excipient used when producing the solid preparation include lactose, sucrose, starch, talc, cellulose, dextrin, kaolin, calcium carbonate and the like. Liquid preparations for oral administration, that is, emulsions, syrups, suspensions, solutions, etc., are commonly used inert diluents,
For example, it includes water or vegetable oil. In addition to an inert diluent, this formulation may include auxiliary agents such as wetting agents, suspension auxiliary agents, sweetening agents,
Fragrances, colorants or preservatives may be included. It may be made into a liquid formulation and included in a capsule of an absorbable substance such as gelatin. Examples of the formulation for parenteral administration, that is, a solvent or 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 method may be a conventional method.

When used by oral administration, the clinical dose is generally 1 to 10 per day as a compound of the present invention for adults.
The amount is 00 mg, preferably 1 to 100 mg, but it is more preferable to appropriately increase or decrease depending on age, medical condition, symptom, and presence / absence of simultaneous administration. The daily dose of the compound of the present invention is 1
It may be administered once or twice or three times a day at appropriate intervals, or may be 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
It is 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 which is known to have an acetylcholinesterase inhibitory action.
Although weaker than the following, it can activate the presynaptic side of cholinergic nerves and enhance neurotransmission.
Specifically, AF64A (ethylcholine aziridinium
Ion: ethylcholine aziridinium ion) [Journal of Pharmacology and Experimental Therapoitics (J.Pharmacol.Exp.Ther.). twenty two
2 , 140 (1982): Neuropharmacology
macol.), 26, 361 (1982)] is intraventricularly administered to improve the high affinity choline uptake ability of hippocampal synaptosomes (Test Example 1). This effect is not seen with 9-aminotetrahydroacridine.

In addition, the compound of the present invention is much less toxic than 9-aminotetrahydroacridine and has few side effects, and thus can be a useful therapeutic drug 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 valuable compound. In particular, since these compounds have an action of directly activating the impaired 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, particularly Alzheimer's disease, the function of cholinergic nerves in the brain is decreased, and this decrease and the degree of memory impairment have a good correlation.

On the other hand, the AF64A is based on Fisher [(J.Pharmac
ol.Exp.Ther.), 222, 140 ( 1982)] and Rebenta (Leventer) [[Neuropharmacol.), 26, 361 ( 198
[7]] reported that, after selective and long-term damage to cholinergic nerves, AF64A-administered rats showed impaired memory learning [Brain Research (Brain Research
s.), 321 , 91 (1984)], which is a good model for Alzheimer's disease. Therefore, the compound of the present invention, which is capable of directly activating the function of cholinergic nerve in the brain which is decreased by 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 in more detail with reference to examples, but the present invention is not limited to the following examples as long as the gist thereof is not exceeded.

Example 1 Synthesis of N- (3-methyl-5,6,7,8-tetrahydro-thieno [2,3-b] quinolin-4-yl) butanamide 4-amino-3-methyl-5,6,7 , 8-Tetrahydro-
To 4.37 g of thieno [2,3-b] quinoline, 8 ml of pyridine and 12.7 g of anhydrous -n-butyric acid are added, and the mixture is heated under reflux for 13 hours. The reaction solution is dried under reduced pressure, dissolved in 170 ml of methanol and 40 ml of ethanol, added with 70 ml of concentrated aqueous ammonia, and reacted at 65 ° C for 1.5 hours.

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

The chloroform solution was concentrated and purified by silica gel column chromatography (chloroform-methanol),
Recrystallization from chloroform-diethyl ether gave 5.11 g of the desired compound. 200-202 ° C.

Examples 2 to 18 The compounds shown in Table 2 below were synthesized in the same manner as in Example 1.

Example 19 Synthesis of N- (2,3-dimethyl-5,6,7,8-tetrahydro-furo [2,3-b] quinolin-4-yl) isobutanamide In Example 13, the reaction of -n-butyric anhydride Instead anhydrous-
The title compound was obtained in a similar manner except that i-butyric acid was used.
Melting point 245-246 ° C Example 20 2- (2-oxopyrrolidin-1-yl) -N- (3-
Synthesis of methyl-5,6,7,8-tetrahydro-thieno [2,3-b] quinolin-4-yl) acetamide 1.26 g of sodium hydride (60% content) was suspended in 15 ml of N-methylpyrrolidone at room temperature. 4-amino-3-methyl-5,6,7,8-tetrahydro-thieno [2,3-b] quinoline
Add 3.28g. Warm up to 50 ° C and stir for 40 minutes to obtain 4.72 g of 2-oxo-1-pyrrolidineacetic acid methyl ester at 50 ° C.
At 30 minutes. After stirring at 50 ° C for 20 minutes, the mixture is cooled to 15 ° C and poured into 130 ml of an aqueous solution of 13.5 g of ammonium chloride.

Extract with 100 ml of chloroform, dry over anhydrous sodium sulfate and dry under reduced pressure. Add ethyl acetate, grind and collect. The crude crystals were recrystallized from chloroform-ethyl acetate to obtain 4.31 g of the objective compound.

 Melting point 244-246 ° C.

Examples 21 to 37 The compounds shown in Table 3 below were synthesized in the same manner as in Example 20. However, as the raw material compound of Example No. 26, 9-amino-2-methylene-1,2,3,4-tetrahydroacridine (compound of No. 13 in Table 1) was a double bond depending on the reaction conditions. I used the one that moved.

Reference Example 1 Synthesis of 2-chloro-N- (3-methyl-5,6,7,8tetrahydro-thieno [2,3-b] quinolin-4-yl) acetamide 4-amino-3-methyl-5, 40 ml of chloroacetyl chloride is added to 12.7 g of 6,7,8 tetrahydro-thieno [2,3-b] quinoline, and the mixture is heated under reflux for 40 minutes. Remove the oil bath,
50 ml of 1,2-dichloroethane is added, cooled to 25 ° C., the precipitated crystals are filtered and washed with 1,2-dichloroethane. The crystals were added to chloroform 250 ml, water 55 ml and ethanol 6
Suspend in 0 ml of the mixture and add 4.3 ml of concentrated aqueous ammonia. 40
Warm up to ° C to dissolve most of the crystals.

Dry the chloroform layer over anhydrous sodium sulfate and
Concentrate to 0 ml. To this, 40 ml of n-heptane was added and cooled, and the crystals were filtered to obtain 8.2 g of the desired compound. Melting point 23
3-236 ° C.

Reference Example 2 Synthesis of 2-chloro-N- (2,3-dimethyl-5,6,7,8-tetrahydro-furo [2,3-b] quinolin-4-yl) acetamide 4-amino-2,3 14.5 g of the target compound was obtained in the same manner as in Reference Example 1 except that 12.0 g of -dimethyl-5,6,7,8-tetrahydro-furo [2,3-b] quinoline was used as a starting material. Melting point 2
19-222 ° C Example 38 2-Cyclopropylamino-N- (3-methyl-5,6,7,
8 Synthesis of tetrahydro-thieno [2,3-b] quinolin-4-yl) acetamide 2.1 g of the compound synthesized in Reference Example 1 was added to 12 ml of t-butanol.
In addition to 25 ml of dimethylformamide and 9 ml of cyclopropylamine, the mixture is reacted at 100 ° C. for 30 minutes.

The reaction mixture was concentrated under reduced pressure to dryness, chloroform 100 ml, water 30 m.
Add 1 ml of concentrated aqueous ammonia and stir. The chloroform layer was dried over anhydrous sodium sulfate, purified by silica gel caral chromatography (chloroform-methanol), and recrystallized from ethyl acetate to obtain 1.52 g of the desired compound.

 Melting point 141-144 ° C.

Examples 39 to 47 The compounds shown in Table 4 below were synthesized in the same manner as in Example 38.

Example 48 2- (Imidazolin-1-yl) -N- (2,3-dimethyl-5,6,7,8 tetrahydro-furo [2,3-b] quinolin-
Synthesis of 4-yl) acetamide 1.5 g of the compound synthesized in Reference Example 2 was added to i-propanol 10
In addition to ml, 2.1 g of imidazole is added, and the mixture is heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure and then 15 ml of water and 5 m of concentrated ammonia
add l The precipitated crystals were collected and recrystallized from methanol-water to obtain 1.2 g of the objective compound. Melting point 243-247
° C.

Example 49 2-((S) -5-Methyl-2,4-imidazolidindione-1-yl) -N- (3-methyl-5,6,7,8tetrahydro-thieno [2,3-b Synthesis of quinolin-4-yl) acetamide 2.5 g of the compound of Example 39 is dissolved in 8 m of N-methylpyrrolidone, 8 g of urea is added, and the mixture is reacted at 160 ° C. for 40 minutes. The reaction solution is cooled to 80 ° C., 90 ml of water is added and further cooled to 25 ° C., and the precipitated crystals are passed through. Methanol-
Recrystallization from water gave 0.84 g of the desired compound. Melting point 273 ~
277 ° C.

Examples 50 to 53 The compounds shown in Table 5 below were synthesized in the same manner as in Example 49.

Example 54 2-Acetylmethylamino-N- (2,3-dimethyl-5,
Synthesis of 6,7,8 tetrahydro-furo [2,3-b] quinolin-4-yl) acetamide 1.3 g of the compound of Example 43 was dissolved in 10 ml of chloroform,
Add 5 ml of acetic anhydride and react at 25 ° C for 30 minutes. After the reaction solution is concentrated to dryness under reduced pressure, chloroform (50 ml), water (30 ml) and concentrated ammonium water (5 ml) are added and the mixture is 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 20
6-209 ° C.

The following Table-6 and Table-
The compound of 7 can be synthesized.

Test Example 1 Effect of AF64A-treated rat brain on Na ⁺ -dependent high-affinity choline uptake (HACU) (Method) AF64A is the method of Fischer et al. (J.Pharm.Exper.Ther., 222 ,
140 (1982)) and adjusted from AF64. AF64A (1.5n
mol / 1.5 μl / side) is injected into the rat bilateral ventricles. One week later, the animal is decapitated and only the hippocampus is removed. Homogenize with 0.32 M sucrose, centrifuge at 1000 g for 10 minutes, and further centrifuge the supernatant for 20 minutes at 20000 g to obtain a crude synapse fraction. The crude synaptic fraction and the compound of the present invention were incubated at 37 ° C. for 30 minutes, [ ³ H] choline (1 μM) was added,
Incubate at 37 ° C for 10 minutes. 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 taken as the HACU amount. The amount of protein was quantified according to the method of Bradford [Analytical Biochemistry (Anal.Biochem.), 72 , 248 (1976)]. The test results are shown in Table-8.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Akihiro Tobe 1000 Kamoshida-cho, Midori-ku, Yokohama-shi, Kanagawa Mitsubishi Kasei Co., Ltd. (72) Inventor Yashiro Morinaka 1000 Kamoshida-cho, Midori-ku, Yokohama, Kanagawa Mitsubishi Kasei Chemical Research Institute (72) Inventor Tomoko Bessho 1000 Kamoshida-cho, Midori-ku, Yokohama-shi, Kanagawa Mitsubishi Kasei Research Institute (72) Haruko Harada 1000 Kamoshida-cho, Midori-ku, Yokohama, Kanagawa Mitsubishi Kasei Corporation (56) Reference JP 63-225358 (JP, A) JP 1-250353 (JP, A) JP 3-66670 (JP, A)

Claims (4)

(57) [Claims] 1. The following general formula (I a) [In the Formula, R ¹ is a C _{2 to} C ₆ Alkyl Group or (II) Formula {In the formula (II), R ² represents a hydrogen atom or an acetyl group,
R ³ is a C ₁ -C ₆ alkyl group or (R ⁴ and R ⁵ each independently represent a hydrogen atom or a C ₁ -C ₆ alkyl group). Also, in the formula (II) In, R ² and R ³ are connected to each other (R ⁶ may represent a hydrogen atom or a C ₁ -C ₆ alkyl group). R ⁹ and R ¹⁰ each independently represent a C ₁ -C ₄ alkyl group. (R ¹⁵ represents a C ₁ -C ₄ alkyl group substituted with a phenyl group.) Or Represents ] The 9-acyl amino tetrahydro acridine derivative represented by these, its optical antipode, or its pharmaceutically acceptable acid addition salt. 2. R ¹ is a C ₂ -C ₆ alkyl group, —CH ₂ —NHR ₃ (R ³
Is the same as the above definition), 9. The 9-acylaminotetrahydroacridine derivative according to claim 1, wherein R ⁶ is the same as defined above, its optical antipode or a pharmaceutically acceptable acid addition salt thereof. (3) The 9-acylaminotetrahydroacridine derivative represented by the formula, its optical antipode, or a pharmaceutically acceptable acid addition salt thereof. 4. A memory disorder-improving agent comprising the 9-acylaminotetrahydroacridine derivative according to any one of claims 1 to 3 or its optical antipode or a pharmaceutically acceptable acid addition salt thereof as an active ingredient. .