JPH02180871A - Hydroxy-1,2,3,4-tetrahydroaminoacrydine and preparation thereof - Google Patents

Abstract

NEW MATERIAL: A compd. represented by formula I [wherein (n) is 1 or 2; X is H, lower alkyl, lower alkoxy, halogen, OH, NO₂ or CF₃; R is H, benzyl or 2-12C alkanoyl (but a group-OR is not present at a first position of a tricyclic system); R₁ and R₂ are each H, lower alkyl, aryl-lower alkyl (but both of them are not aryl-lower alkyl at the same time) and combined to form a group represented by formula II (R₃ and R₄ are each lower alkyl)], its stereoisomer and its acid addition salt.

EXAMPLE: 9-Amino-1,2,3,4-tetrahydroacridineamin-4-ol.

USE: A medicine characterized by the lowering of choline acting function and useful for treating various memory function failures, for example, an Alzheimer's disease.

PROCESS: For example, a compd. represented by formula III and a compd. represented by formula IV are reacted to obtain a compd. represented by formula V being one of compds. represented by formula I.

COPYRIGHT: (C)1990,JPO

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is a compound of the formula halogen, hydroxy, nitro or trifluoromethyl that is useful for treating various memory dysfunctions characterized by decreased cholinergic function, such as Alzheimer's disease. is hydrogen, benzyl or alkanoyl having 2 to 12 carbon atoms, provided that the group -OR is
R, and R1 shall each independently be hydrogen, lower alkyl, or aryl lower alkyl, but cannot both be aryl lower alkyl at the same time, or alternatively R and R
2 together represent a group /''-NR1R2 (f: dashi formula,
R3 and R1 are each independently lower alkyl.

Included in the above compounds are the following formulas 1a and I
b [In the formula, n is 1 or 2, and X is a compound of hydrogen, lower alkyl, or lower alkoxy.

The chemical formulas or names given throughout this specification and the appended claims include all stereoisomers, geometric and optical isomers, where isomers exist, and pharmaceutically acceptable forms thereof. Acid addition salts and their solvates such as hydrates are meant to be included.

The following definitions shall apply throughout this specification and the appended claims.

Unless stated or indicated otherwise, the term lower alkyl refers to straight or branched chain alkyl groups having 1 to 6 carbon atoms. Examples of such lower alkyl include methyl, ethyl, n-propyl, isobutyl, pentyl and hexyl.

Unless otherwise stated or indicated, the term cycloalkyl refers to a cycloaliphatic hydrocarbon radical containing 3 to 7 carbon atoms. Examples of such cycloalkyls include cyclopropyl, cyclohexyl and cycloheptyl.

Unless otherwise stated or indicated, the term halogen shall mean fluorine, chlorine, bromine; and iodine.

Unless stated or indicated otherwise, the term aryl refers to an unsubstituted phenyl group or one, two or three substituted phenyl groups, each independently lower alkyl, lower alkoxy, halogen, hydroxy or trifluoromethyl. shall mean a phenyl group substituted with a group.

Compounds of the invention are prepared using one or more of the steps described below.

With respect to the description of the synthetic steps, unless otherwise stated or indicated, the definitions of n, X, R, R, and R2 are as given above.

Scheme 1 Preparation of a 2-ol having the following formula I (c) m-1 or 2 Step 1 (a) The amino nitrile compound shown below is reacted with the cyclic ketone shown below to obtain a compound of formula (1).

or 80° to 15 in the presence of 1,2-dichloroethane
It is carried out at a temperature of 0°C.

Step 1 (b) Compound ■ (in the formula, X is not 0■) with formula R1'
# (In the formula, W is C4, Br, I or 0S03
When the compound is reacted with the compound (CHs (mesyloxy)), the compound (2) is obtained. Typically, the above reaction is carried out in a suitable organic solvent such as dichloromethane, chloroform,
benzene, toluene, etc., in a two-phase system containing a strongly alkaline aqueous phase, such as 50% aqueous sodium hydroxide, a starting compound, and a correlated transfer catalyst, such as tetrabutylammonium hydrogen sulfate, and at a temperature of about 0'' to 50°C. .

The above reaction is carried out using a Lewis acid such as zinc chloride and a suitable solvent such as nitrobenzene, toluene and when X is OH. The compounds can be prepared, for example, by subjecting them to a cleavage reaction using pyridine hydrochloride, which is carried out at a temperature of about 180°0.

Step 1 (c) Compound ■ is converted into formula R,
When reacted with a compound of W, a compound of formula (2) is obtained.

lower alkyl or aryl lower alkyl)
Compounds of formula V are obtained by hydrogenolysis by conventional methods known in the art. The preferred catalyst for this reaction is palladium-carbon.

Step 1 (d) Formula IVa (where R1 and R1 are hydrogen) Step L (e) Compound V is converted to formula IV by a conventional method known in the art.
acyl chloride or formula Via (where ■ and Vi
A compound of formula can get.

9-amino-1,2,3, having the following formula 1(d)
Production of 4-tetrahydroacridin-3-ol (■) (V ) + Ri -C-ORs-> (■) (Vla
) Step 1 (f) Compound V is converted to formula ■ by conventional methods known in the art.
(wherein R3, R4 and R7 are lower alkyl), a compound of formula (2) is obtained.

l-N Rs R4 Step 2(a) The aminonitrile compound shown below is reacted with the cyclic ketone shown below to obtain the compound of formula X.

This reaction is carried out in substantially the same manner as in step 1(a).

(IX) Scheme Step 2(b) Compound X is reacted with compounds R and W in substantially the same manner as in Step 1(b) to obtain a compound of formula (1).

R1\/H and lower alkyl or aryl lower alkyl)
A compound of formula xm is obtained by hydrogenolysis carried out in substantially the same manner as in step 1(d).

Step 2(c) Compound 1 is reacted with compounds R and W in substantially the same manner as in Step 1(c) to obtain a compound of formula 2.

Step 2(d) 2I) la (wherein, if R1 and R3 are hydrogen, R
1\/RI Step 2(e) Compound x■ is reacted with acyl chloride R, GOCI2 in substantially the same manner as in Step 1(a) to form formula XI
Compound V is obtained.

R,\/Rz Scheme 3 Process for producing 4-thiol below 3(a) A compound of formula X■ is reacted with acetic anhydride in a conventional manner known in the art to obtain a compound of formula X■.

This reaction is known as the Polonovsky reaction.

Step 3(b) Compound Reaction with benzyl bromide in the presence of sodium gives the compound of formula X■.

('1 Step 3(c) Compound X■ is reacted with ammonia in a suitable medium such as phenol by conventional methods known in the art to give a compound of formula Xrx.

Compound XX is reacted with compounds R, W in substantially the same manner as in step 1(c) to provide a compound of formula XII.

Step 3(d) Compound X■ is reacted with compound RIW in substantially the same manner as in Step 1(b) to provide a compound of formula XX.

1"\/H Step 3(r) Formula XIIa (wherein RI and R3 are hydrogen and lower alkyl or aryl lower alkyl)
When a compound of formula xn is subjected to a solvolysis reaction, a compound of formula xn is obtained. Typically the solvolysis reaction is carried out in the presence of hydrogen chloride and acetic acid.

Step 3 (e) R, pH, R, +1 (, X≠O)! Step 3(g) Compound XX1 is reacted with the acyl chloride RCOCl2 in substantially the same manner as in Step 1(e) to form formula
A compound of Xm is obtained.

It can be used to treat various memory dysfunctions characterized by a decrease in R.\/R., such as Alzheimer's disease.

This utility is confirmed by measuring the ability of these compounds to inhibit the activity of the enzyme acetylcholinesterase, thereby increasing brain acetylcholine concentrations.

Assay test for cholinesterase inhibitory effect The ability to inhibit acetylcholinesterase was determined by Nillman et al.
Biochem, pharma-co1. Vol. 7, p. 88 (1961)]. Results for several compounds of the invention are shown in Table 1 below, along with results for several reference compounds.

The compounds of formula (I) of the present invention have cholinergic function Table 1 Compound IC. (Molar Concentration) (Inhibition of Acetylcholinesterase) Fumarate Monorurate Malate Fumarate Fumarate Marate Marate Marate-Lurate Acridine Physostigmine 6.0XI
Efficacy here can be confirmed by measuring the ability of these compounds to restore cholinergic deficient memory in the dark avoidance test. In this test mice are tested for their ability to remember unpleasant stimuli for 24 hours. A mouse is placed in a room with a dark partition, and a strong incandescent light is directed at the mouse to drive it into the dark partition, where it is given an electric shock through a metal plate on the floor. Remove the animal from the test apparatus and
They are then tested again 24 hours later for their ability to remember the electric shock.

If scopolamine, an anticholinergic agent known to impair memory, was first administered before the animal was placed in the test room, the animal was placed in the test room 24 hours later; Reenter that dark partition. This effect of scopolamine is blocked by the active test compound, thus increasing the interval before re-entering the dark compartment.

The results for the active compound are expressed as the percentage of the group of animals in which the action of scopolamine is blocked, as evidenced by the lengthening of the interval between entry into the test chamber and re-entry into its dark compartment. . The results of the dark avoidance test for representative compounds of the invention and reference compounds are shown in Table 2.

Dark Avoidance Test Table Amine Leate, Fumarate Effective amounts of the compounds of the present invention can be administered in a variety of ways, for example, orally in the form of capsules or tablets, parenterally in the form of a sterile solution or suspension; If so, it can be administered to the patient intravenously in the form of a sterile solution. While the final products, which are free bases, are effective in their own right, it is difficult to formulate and administer them in the form of their pharmaceutically acceptable acid addition salts for reasons of stability, convenience of crystallization, increased solubility, etc. can do.

Acids useful for preparing the pharmaceutically acceptable acid addition salts of this invention include inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric and perchloric acids, and organic acids such as tartaric, citric and , acetic acid, succinic acid, maleic acid, fumaric acid and oxalic acid.

The active compounds of the invention can be administered orally, for example with an inert diluent or an edible carrier, or they can be enclosed in gelatin capsules, and they can also be compressed into tablets. . For therapeutic oral administration, the active compounds of the invention may be mixed with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums, etc. Can be done. These preparations should contain at least 0.5% of active compound, but
This can vary depending on the particular form and is conveniently from 4% to about 70% by weight of the dosage unit. The amount of active compound in such compositions is such that a suitable dosage will be obtained. Preferred compositions and formulations according to the invention are prepared such that the oral dosage unit form contains from 1.0 to 300 μ of active compound.

Tablets, powders, capsules, troches, etc. can also contain the following ingredients: binders such as microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, brimogel, corn starch, etc.; lubricants such as magnesium stearate or sterotex; lubricants such as colloidal Silicon dioxide, sweeteners such as sucrose or saccharin can be added, and flavoring agents such as peppermint, methyl salicylate or orange flavor can be added. When the dosage unit form is a capsule, it can contain, in addition to the materials enumerated above, a liquid carrier such as a fatty oil.

Other dosage unit forms can contain various other materials that modify the physical form of the dosage unit, such as coatings.

For example, tablets or powder may be coated with sugar, shellac, or other enteric coatings. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes, colorings and flavors. The materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used.

For therapeutic parenteral administration, the active compounds of the invention can be made into solutions or suspensions. These formulations should contain at least 0.1% of active compound, but can vary between 0.5 and about 30% by weight thereof. The amount of active compound in such compositions is such that a suitable dosage will be obtained. Preferred compositions and formulations according to the invention have a parenteral dosage unit of 0.5
~ioOmsr of active compounds.

Examples of the compounds of the present invention include the following compounds.

2-benzyloxy-1,2,3,4-tetrahydro-
9-acridinamine, 9-amino-1,2,3,4-tetrahydroacridin-2-ol, 2-hydroxy-N-(dimethylaminomethylene)-1
, 2,3,4-tetrahydro-9-acridineamine, 2-acetoxy-1,2,3,4-tetrahydro-9-
Acridinamine, 2-propionyloxy-1,2,3,4-tetrahydro-9-acridineamine 2-butyryloxy-1,2,3,4-tetrahydro-
9-acridinamine, 2-valeroyloxy-1,2,3,4-tetrahydro-9-acridinamine, 2-hexanoyloxy-1,2,3,4-tetrahydro-9-acridinamine, 2-hepta Noyloxy-1,2,3,4-tetrahydro-9-acridineamine, 2-ctanoyloxy-1,2,3,4-tetrahydro-9-acridineamine, 2-nonanoyloxy-1,2,3,4- Tetrahydro-9-acridineamine, 2-decanoyloxy-1,2,3,4-tetrahydro-9-acridineamine, 2-lauroyloxy-1,2,3,4-tetrahydro-9-acridineamine, 4- Benzyloxy-1,2,3,4-tetrahydro-
9-acridinamine, 9-amino-1,2,3,4-tetrahydroacridin-4-ol.

In order to further understand the present invention, the present invention will be explained by giving examples below.

Example 1 2-benzyloxy-1,2,3,4-tetrahydro-
9-acridineamine 4-benzyloxycyclohexanone (14°86g
) and anthranylonitrile (8,90 g) are dissolved in 100 mα of nitrobenzene and then freshly molten zinc chloride (0,99) is added thereto.

The reaction mixture is heated at 60" for 90 minutes, then the temperature is increased to 120" and held at this temperature for 3 hours. At the end of this time anhydrous diethyl ether 200
Add 1 IQ and let the mixture sit undisturbed overnight. The granular precipitate thus obtained is then filtered off, washed thoroughly with diethyl ether and partitioned between aqueous ammonia and 2-butanone. dry the organic phase;
Concentration gave a solid that was thoroughly triturated with diethyl ether to give the product 17.199 (III+)-
188-190°) is obtained. Analytically pure material is obtained by recrystallization from methanol/water (m
p, 190-191').

Elemental analysis (for Ct.HzsNzO) Calculated value: 7
8.92%C6, 62%H9, 21%N actual value near 8.
86%C6, 64%H9, 24%N J, Chem,
Soc, Chem, Con+mun, page 721 (1
984) Example 2 9-Amino-1,2,3,4-tetrahydroacridin-2-ol, maleate 2-benzyloxy-1,2,3,4-tetrahydro-
9-Acridineamine (18,759) was prepared using 10% palladium-carbonate in a solution prepared from absolute ethanol (1 liter) and concentrated hydrochloric acid (56,83 mff).
Hydrogenate overnight at Qpsi.

The reaction mixture was filtered through Celite, concentrated, dissolved in deionized water (llo+m(2), and then the mixture was stirred in a water bath with 10% sodium hydroxide (5
Add 5 m (2) dropwise. The resulting solids are filtered, washed with deionized water, and dried to yield the desired 9-amino-
11.82 g of 1,2,3,4-tetrahydroacridin-2-ol are obtained.

A portion of the product is converted to the maleate salt in methanol,
and recrystallized from methanol/diethyl ether (
mp, 225' (decomposition)].

Calculated value for elemental analysis CC15H1aNtO-C4H404: 61.81%c 5.49%H8,48
%N actual value: 61.64%C5, 61%H8°42%
N Example 3 2-Hydroxy-N-(dimethylaminomethylene)-1
, 2,3,4-tetrahydro-9-acridinamine 9-amino-1,2,3,4-tetrahydroacridin-2-ol (10,979) was refluxed in dimethylformamide dimethylacecool (329 mQ) for 2 hours. do. The reaction mixture was cooled to room temperature, diluted with saturated potassium carbonate (1 liter) and diluted with ethyl acetate (2X 600 m
Extract with Q), stir for half an hour with activated charcoal, filter through Celite, dry (magnesium sulfate) and concentrate to obtain a solid. Trituration of this solid in diethyl ether gives product 5.689. Recrystallization from methylene chloride/hexane and drying under high vacuum with refluxing 3-hexanone for 24 hours yields 4.37 g solid (mp, 158' (dec)).

Elemental analysis (for C+sH+*NsO) Calculated value: 7
1.35%C7, 11%H15, 60%N Actual value: 7
0.86%C6, 90%H15, 40%N Example 4 2-acetoxy-1,2,3,4-tetrahydro-9-
Acridinamine 2-Benzyloxinol 1.2.3.4-Tetrahydro-9-acridineamine (10,97 g) is suspended in liquid ammonia 500+12 at -65°. Next, add sodium little by little until the blue color does not disappear (2, 29 used). The reaction is stopped by adding solid ammonium chloride, then the ammonia is evaporated, the residue is washed thoroughly with ethyl acetate and filtered off. When the ethyl acetate washing solution is concentrated, 2-acetoxy-1,2,3,4-
It is shown to contain tetrahydro-9-acridineamine. This is applied to a column of silica gel and eluted (5% triethylamine/ethyl acetate), then the 7-lactone containing the product is concentrated and the residue is converted to its hydrochloride in ethereal hydrogen chloride. Recrystallization from methanol/diethyl ether gives product 2.309
(101), 178-181') are obtained.

Elemental analysis (for C+sH+1NzOz・HCl2)
Calculated value: 61.53%C5, 85%H9-57%N Actual value: 60.88%C5, 71%H9, 38%N Example 5 2-propionyloxy-1,2,3,4-tetrahydro- 9-Acridinamine fumarate hemihydrate viridi7 (6,15 mff) and 9-amino-1,2.3.4-tetrahydroacridine- in anhydrous N,N-cymaleformamide (240 mQ) Propionyl chloride (
2.17 mQ) is added dropwise. The reaction mixture was heated at room temperature for 2
Stir for 1 hour and add 1. omff
is added and the reaction mixture is held at 45° for 64 hours.

The reaction mixture was cooled to room temperature, saturated sodium bicarbonate (400+ mQ) and deionized water (400 mff
) and diluted with ethyl acetate (5X 300 mff
) to extract. Dry the mixture overnight (with magnesium sulfate),
After concentration, 4.03 g of crude product is obtained. Purification by trituration (diethyl ether), flash chromatography (5% triethylamine/ethyl acetate) and recrystallization from ethyl acetate gives the product 1.889.

This operation is repeated one more time to combine the products and use Improper Tools as the solvent to produce the hexamarate salt. Recrystallization from ethyl acetate and drying under high vacuum with refluxing xylene for 36 hours gives slightly off-white microneedles 2.79 (mp, 220'' (decomposed)).

Elemental analysis (C+ *H+ 5 Nioz -C4H404
”0.5HtOi= Calculated value: 60.75%
C5,86%H7,09%N Actual value: 60.98%C
5,47%H7,11%NExample 6 2-Butyryloxy-1,2,3,4-tetrahydro-
9-Acridineamine, fumarate pyridine (11,
i6mff) and butyryl chloride (4 , 67 ml is added. The reaction mixture is stirred in a preheated oil bath (80° C.) for half an hour, more butyryl chloride 4-67raQ is added, and heating is continued at 80° C. for 15 minutes. The reaction mixture was cooled to room temperature, diluted with saturated potassium carbonate (1 liter), extracted with ethyl acetate (2 x 700 mQ), the organic phase was washed with water (2 x 500 mff), dried (magnesium sulfate) and concentrated. An oil is obtained.

Purification by flash chromatography (1,5% triethylamine/ethyl acetate) and trituration (diethyl ether/hexane, (1:1)) gives 2.67 g of product.

Generate the fumarate salt using Impropatool as a solvent. Recrystallization from ethanol/hexane gives 2.74 g of a white solid (mp, 222° C. (decomposed)).

Elemental analysis (C+y)lx. N80.・Calculated value for C, H, O: 62.99%C6,04%8 7.
00%N actual value: 62.66%C5, 96%8 6.
98%N Example 7 2-valeryloxy-1,2,3,4-tetrahydro-
9-Acridineamine, fumarate pyridine (11,
16mff) and 9-amino-1,2,3.4-tetrahydroacridin-2-ol hydrochloride (8,09) in dry N,N-dimethylformamide (376y+ff)
Add valeryl chloride (5,43+Q) to the suspension. The reaction mixture is stirred for half an hour in a preheated oil bath (80°O), a further 5.43+mα of valeryl chloride is added and heating is continued for 20 minutes at 80°C. The reaction mixture was cooled to room temperature, diluted with saturated potassium carbonate (1 liter), extracted with ethyl acetate (750+12), the organic phase was washed with water (2X 35011Q), dried (magnesium sulfate) and concentrated. An oil is obtained.

Purification by flash chromatography (1.5% triethylamine/ethyl acetate) followed by trituration (diethyl ether/hexane (1:3)) gives 3.85 g (41%) of the product. . Generate the fumarate salt using Impropatool as a solvent. Recrystallization from methanol/diethyl ether and drying under high vacuum with refluxing xylene for 48 hours resulted in a solid content of 4.
．． 54 Cmp, 210°C (decomposition)] is obtained.

Elemental analysis (for C+aH*zNxOz・C,H,O,) Calculated value: 63.75%C6, 32%8 6.76
%N actual value: 63.53%C6, 31%H6, 71%
N Example 8 2-hexanoyloxy-1,2,3,4-tetrahydro-9-acridinamine, fumarate pyridine (3
,63m(2) and 9-amino-1,2.3.4-tetrahydroacridin-2-ol hydrochloride (3,09) in dry N,N-dimethylformamide (141mI2)
Hexanoyl chloride (2,19i) is added dropwise to the suspension. The reaction mixture was heated in a preheated oil bath (80°C) for 1 hour.
Stir for an hour and add 2.19 mf of hexanoyl chloride.
f is added, heating is continued for 1 hour, and the reaction mixture is cooled to room temperature.

The reaction mixture is diluted with saturated potassium carbonate (60 h+ff), extracted with ethyl acetate (400 mL), the organic phase is washed with water (2X 250 a+g), dried (magnesium sulfate) and concentrated to give an oil.

This operation was repeated once again to combine both products and subjected to flash chromatography (1,5% triethylamine/
Purify by ethyl acetate).

Trituration (diethyl ether) gives the product 2.359. The fumarate salt is produced using Impropatool (50 ml) as a solvent. Recrystallized from ethanol/diethyl ether and dried for 52 hours under high vacuum with refluxing xylene, resulting in fine crystals of 2.419 (mp
, 205°C (decomposition)] is obtained.

Elemental analysis (for C+JaaNtOx・C4H,O) Calculated values: 64.47%G 6.59%H6,54
%N actual value: 64.34%C6,45%H6,55%
N Example 9 2-heptanoyloxy-1,2,3,4-tetrahydro-9-acridinamine, fumarate pyridine (6
, 93 mQ) and heptanoyl chloride (4, 32wrQ) was added dropwise. The reaction mixture was stirred for half an hour in a preheated oil bath (80°C) and further added 4.32 ml of heptanoyl chloride.
Add m+Q and continue heating for 5 hours, then stir the reaction mixture at room temperature overnight.

The reaction mixture is diluted with saturated potassium carbonate (750+A4), extracted with ethyl acetate (660ml), the organic phase is washed with water (700mA), dried (magnesium sulfate) and concentrated to give an oil. .

Purification by flash chromatography (2.5% triethylamine/ethyl acetate) and trituration (diethyl ether/hexane (1:1)) gives 2.65 g of product. The 7-malate salt is produced using Impropatool (30I) as a solvent. Recrystallization from ethanol/hexane and drying under high vacuum for 16 hours with refluxing n-butyl acetate gives fine crystals 2.49
g(mp.

195°C (decomposition) is obtained.

Elemental analysis CCtoHzsNzOx 'c, H, o, l
Calculated value: 65.14%C6, 83%H6,
33%N actual value: 64.86%G 6.63%H6
, 24%N Example 10 2-octanoyloxy-1,2,3,4-tetrahydro-9-acridinamine, 7marate viridi 7 (
11,16+ff) and 9-amino-1,2,3.
4-tetrahydroacridin-2-ol salt M salt (8,
Octanoyl chloride (7,68+1
12) is added dropwise. This reaction mixture was heated in a preheated oil bath (8
0°C) for half an hour, add another 7.68+llQ of octanoyl chloride and continue heating at 80°C for half an hour. The reaction mixture was cooled to room temperature, diluted with saturated potassium carbonate (1 liter) and ethyl acetate (800 liters).
+1IQ) and the organic phase was extracted with water (2X 250+1f
f), drying (magnesium acid) and concentration to give an oil which solidifies on standing overnight.

Purification by trituration (pentane/diethyl ether) gives 2.85 g of product.

The fumarate salt is produced using infropanol as a solvent. Recrystallized from methanol/diethyl ether,
Then, drying for 19 hours under high vacuum while refluxing xylene resulted in a white solid content of 2-87g (mp, 199°0(
decomposition)] is obtained.

Elemental analysis (for C□HXaN201・C,H40,) Calculated value: 65.77%C7,07%8 6.14%
N actual value: 65.68%C7, 16%H6, 15%N
Example 11 2-nonanoyloxy-1,2,3,4-tetrahydro-9-acridinamine, fumarate pyridine (5,
56 + 112) and nonanoyl chloride (4, Omff ) is added dropwise. The reaction mixture was preheated for 1 hour in an oil bath (80°C).
Stir for an hour, add another 4.0 raQ of nonanoyl chloride, continue heating for half an hour, and cool the reaction mixture to room temperature.

This reaction mixture was combined with 1.09 of the preliminary test reaction, diluted with saturated potassium carbonate (1 liter) and ethyl acetate (7 liters).
501), the organic phase is washed with water (2 x 500 md), dried (magnesium sulfate) and concentrated to give an oil. Flash chromatography (1
, 5% triethylamine/ethyl acetate),
and upon trituration (pentane/diethyl ether) the product 2.029 is obtained. Repeat this one more time (3, Og
) to form the fumarate salt using isopropanol as a solvent. Recrystallization from ethanol/hexane and drying under high vacuum overnight with refluxing xylene yielded a white solid, 3.0 g (m
p, 203°C (decomposition)] is obtained.

Elemental analysis (C!!8!.N,O,・C,H,04) Calculated value: 66.36%C7,28%H5,95%
N actual value: 66.23%C7, 19%H5, 91%N
Example 12 2-decanoyloxy-1,2,3,4-tetrahydro-9-acridinamine, fumarate pyridine (7,
28+Q) and dry N,N-dimethylformamide (
Decanoyl chloride (6,02 tQ) is added dropwise to a suspension of 9-amino-1.2.3.4-tetrahydroacridin-2-ol hydrochloride (5,319) in 247 ml (247 ml). The reaction mixture is stirred in a preheated oil bath (45°C) for half an hour, more decanoylcluride a, o2mQ is added, and heating is continued at 45°C overnight. The reaction mixture was heated to 80 °C for 1 h, cooled to room temperature, diluted with saturated potassium carbonate (700 + 12) and ethyl acetate (6
Extract with 0.00 liters of water (500+4), wash with deionized water (500+4), dry [magnesium acid], and concentrate to give an oil. Flash chromatography (2,
5% triethylamine/hexane).

and triturate (diethyl ether/hexane (1:3)
)) and product 3.679 are obtained. The fumarate salt is produced using Impropatool as a solvent. Recrystallization from ethanol/hexane and drying under high vacuum overnight with refluxing xylene yields fine crystals 3.89
(mp, 212°C (decomposition)) is obtained.

Elemental analysis (for CzJ3*Nz0t・Ca H404) Calculated value: 66.92%C7,49%)I 5.
78%N actual value: 67.10%G 7.47%) [
5,73% N Example 13 2-lauroyloxy-1,2,3,4-tetrahydro-9-acridinaminepyridine (8,32 mff) and 9-amino/9-aminopropylamide in dry N,N-dimethylformamide (282 mff) -1
, 2,3,4-tetrahydroacridin-2-ol hydrochloride (6,0 g) was added with lauroyl chloride (7,
74 mff) was added dropwise. The reaction mixture was stirred in a preheated oil bath (80°0) for half an hour and then added lauroyl chloride. , 74 mff are added and heating is continued for 1 hour, after which the reaction mixture is stirred at room temperature overnight.

The reaction mixture was diluted with saturated potassium carbonate (1200 kg), extracted with ethyl acetate (800 mff), and water (
Wash with 500mff) and dry with magnesium sulfate).
, and when concentrated, a gummy solid is obtained.

This solid was removed by flash chromatography (2.5%
Purification by triethylamine/ethyl acetate) and trituration (diethyl ether/hexane (1:1)) gives the product 5.259.

Recrystallized from diethyl ether/hexane/ethanol and dried under high vacuum for 18 hours with refluxing ethanol to a solids content of 4.09 (mp.

115°C (decomposition)] is obtained.

Elemental analysis (for CxgHs*Nz island) calculated value near 5
゜72%c 9.15%H7,06%N Actual value: 7
5.60%C9, 19%H7, 10%N Example 14 4-acetoxy-9-chloro-1,2,3,4-tetrahydroacridine 9-chloro-1,2,3,4-tetrahydroacridine N- Oxide (40,129) is refluxed in 20 olQ acetic anhydride for 30 minutes. At the end of this time, the acetic anhydride was evaporated and the reaction mixture was purified by preparative high performance liquid chromatography (HPLC, 20% ethyl acetate/hexane,
Purification is performed twice using two columns). The fractions containing the product were concentrated and triturated with pentane to give the product 33.19 (mp, 83-85 °C
) is obtained. Analytically pure material is obtained by recrystallization from hexane (mp, ss ~ 87°C).

Elemental analysis (for C+ sHr ac4NOz) Calculated values: 65.33%c 5.12%H5, 08%N Actual values: 65.51%C5, 15%H5, 07%N Example 15 4-benzyloxy-9 -Chloro-1,2,3,4-tetrahydroacridine 9-Chloro-4-hydroxy-1,2,3,4-tetrahydroacridine (20,78 g) was dissolved in dimethylformamide 50 (1+<2, then Add benzyl bromide (30,89) to it. Sodium hydride (5
0% suspension 4.809) is added and the reaction mixture is stirred for 2 hours at room temperature. At the end of this time, the reaction mixture is partitioned between diethyl ether and water, then the organic phase is separated, washed thoroughly with water, dried and concentrated. Trituration of the residue with pentane yields the product 19.609
(mp-73 to 75°C) is obtained. TLC showed that the pentane wash still contained a significant amount of product, so it was further purified by flash chromatography (10% ethyl acetate/hexane), yielding an additional 7.429 products (mp , 74-75°C). Analytically pure material is obtained by recrystallization from pentane (mp, 74-76°0).

Elemental analysis (for CZ. HracQNOz) Calculated values:
74, 18% C5, 60% H4, 33% N actual values:
74.12%c 5.57%H4, 29%N Example
16 4-benzyloxy-1,2,3,4-tetrahydro-
9-Acridineamine 4-benzyloxy-9-chloro-1,2,3,4-tetrahydroacridine (24,0 g) is dissolved in 50+ff of phenol at 130 DEG C. and ammonia is passed through the solution for 2 hours. At the end of this time the reaction mixture was partitioned between diethyl ether and 10% sodium hydroxide and the organic phase was washed again with 10% sodium hydroxide and then with water.

The organic phase is dried, concentrated and then purified by 7 column chromatography (ethyl acetate). The fractions containing the product are concentrated and the residue is triturated with diethyl ether to give the product 10.129.

Elemental analysis (CZ.H2°N, O) Calculated value Near 8
．． 92%C6, 62%H9, 20%N actual value: 78.
67%C6,52%H9,09%NExample 17 9-amino-1,2,3,4-tetrahydroacridinamine-4-ol, hemifumarate 4-benzyloxy-1,2,3,4-tetrahydro- 9-Acridinamine (6.0 g) was mixed with 50 μl of glacial acetic acid and 50 μ+ concentrated hydrochloric acid.
Reflux in the mixture of Q for 1 hour. At the end of this time the reaction mixture is concentrated under reduced pressure and the residue is purified by flash chromatography (5% triethylamine/ethyl acetate) to yield the free base 2.839.

The fumarate was produced in an inproper tool and recrystallized from water to yield 2.639 m
p-225°C (decomposition)] is obtained.

Elemental analysis (for CI3H14N!0.0.5C, H, O,) Calculated values: 66.16%G 5.92%H1
0.29%N actual value: 65.80%G 5.88%
H10,16%N Example 18 6-Chloro-2-benzyloxy-1,2,3,4-tetrahydro-9-acridineamine 4-benzyloxycyclohexanone (10,779) in nitrobenzene (72,6 mQ) and Freshly molten zinc chloride (7,99) is added to a mechanically stirred solution of 4-chloroanthranilonitrile (7,939). The reaction mixture is heated at 60 °C for 90 min, then 1
Heat at 20°C for 3 hours. The reaction mixture was cooled to room temperature, anhydrous diethyl ether (170 mQ) was added dropwise,
The precipitate is filtered, washed thoroughly with diethyl ether and dissolved in methanol (200 mQ). The mixture was cooled in a water bath with saturated ammonium hydroxide (200
m12) is added dropwise. The resulting solid is filtered, washed sequentially with deionized water and diethyl ether, and air dried to yield 7.2 g of a white solid.

Part (4,869) was recrystallized from ethanol/hexanes and dried under high vacuum with refluxing xylene to yield the product 3.59 C+++p, 220°C (decomposition)]
is obtained.

Elemental analysis (for CzoH+*Nz0C4) calculated values:
70.90%C5, 65%H8, 27%N Actual value near 0. C%C5, 60%H8, 21%N end J, Cham
, Soc, Chem, Commun, p. 721, 1
984.

Honsue J, Amer, Chen+, Soc, vol. 69, p. 940, 1947.

Example 19 4-acetoxy-1,2,3,4-tetrahydro-9-
Acridinamine-fumarate, hemihydrate 9-Amino-1,2,3,4-tetrahydroacridin-4-ol (2,40 g) is refluxed in 20+ mu acetic anhydride for 2 hours. The reaction mixture is then partitioned between 2-butanone and sodium bicarbonate solution. Concentration of the organic phase gives a residue, which is triturated with diethyl ether to give the crude product as the free base. When the fumarate is produced in ilpropatur, it is 1.829
A salt was obtained which was determined by analysis to be the heptamarate hemihydrate (n+p, 25 g' (decomposed)).

Claims (1)

[Claims] 1) The following formula I ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) [In the formula, n is 1 or 2, and X is hydrogen, lower alkyl, lower alkoxy, halogen,
hydroxy, nitro or trifluoromethyl, R is hydrogen, benzyl or alkanoyl having 2 to 12 carbon atoms, with the proviso that the group -OR is a tricyclic 1
and R_1 and R_2 shall each independently be hydrogen, lower alkyl, or aryl lower alkyl, but not both at the same time, or R_1 and R_2 together. A compound, its stereoisomer or its pharmaceutical Acceptable acid addition salts. 2) Compounds according to claim 1, wherein n is 2 and the group OR is present in the 2- or 4-position. 3) A compound according to claim 2, wherein R_1, R_2 and X are hydrogen. 4) The compound according to claim 3, wherein R is hydrogen or C_2-C_■-alkanoyl. 5) The compound according to claim 1, which is 9-amino-1,2,3,4-tetrahydroacridinamine-4-ol, or a pharmaceutically acceptable acid addition salt thereof. 6) The compound according to claim 1, which is 9-amino-1,2,3,4-tetrahydroacridin-2-ol, or a pharmaceutically acceptable acid addition salt thereof. 7) 2-acetoxy-1,2,3,4-tetrahydro-
2. The compound according to claim 1, which is 9-acridine amine, or a pharmaceutically acceptable acid addition salt thereof. 8) The compound according to claim 1, which is 2-butyryloxy-1,2,3,4-tetrahydro-9-acridinamine, or a pharmaceutically acceptable acid addition salt thereof. 9) The compound according to claim 1, which is 2-hexanoyloxy-1,2,3,4-tetrahydro-9-acridinamine, or a pharmaceutically acceptable acid addition salt thereof. 10) A pharmaceutical composition containing a compound according to claim 1 as an active ingredient and a suitable carrier therefor. 11) Use of the compound according to claim 1 for producing a medicament having memory dysfunction alleviation activity. 12) In producing the compound according to claim 1, the compound of a) formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ A_1) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (However, n is 1 or 2) to form the formula I ′ ▲There are mathematical formulas, chemical formulas, tables, etc. ▼ I ′ (where X and n are as defined)
or a_2) React with a compound of formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ to obtain the compound of formula I ″ ▲There are mathematical formulas, chemical formulas, tables, etc.▼ I ″ (However, in the formula, X is not defined. or b) Formula XVIII ▲ Numerical formula, chemical formula, table, etc. ▼
react with ammonia to obtain a compound of formula I ″′ ▲ Mathematical formula, chemical formula, table, etc. ▼ I ″′, c) optionally with the above formula I ′, I ″ or I ″′ (
However, in the formula, X is not OH).
(However, in the formula, W is Cl, Br, I or -OSO_3
CH_3 and R_1 is as defined above) to form a compound of formula I (wherein
R is benzyl, R_1 is as defined above, X is as defined above with the exception of OH, and n is 1 or 2) or d) optionally of the formula I, where R is benzyl, R_1 is as defined above, R_2 is hydrogen, and X is as defined above but OH
and n is 1 or 2) of the formula R_2W, where W is as defined in step c) and R_2 is as defined above) to obtain a compound of formula I, where R is benzyl and R_1, R_2, X and n are as defined, provided that X is not OH. or e) optionally of the formula I (wherein the OR group is present in the 2- or 3-position, R is benzyl, and R_1 and R
_2 is hydrogen, lower alkyl or aryl lower alkyl, and X and n are as defined above)
or f) optionally a compound of formula I in which n is 2 and O
The R group is present in the 4-position, R is benzyl, R_1, R
_2 and X are as defined, but X is not OH) are subjected to a solvolysis reaction to obtain a compound of formula I, where R is hydrogen. , g) optionally of the formula I (wherein R is hydrogen,
R_1, R_2, and R_6 is C_1-C_2-alkyl) of formula I, where R is C_2-C_2-alkyl.
_1_2-alkanoyl, and R_1, R_2
, X and n are as defined above, and h) optionally a compound of formula I in which R is hydrogen;
R_1 and R_2 are hydrogen, lower alkyl or aryl lower alkyl, and X and n are as defined. is alkyl) by reacting with the formamide acetal of the formula
Claim 1 consisting of obtaining a compound of the formula I in which R_1 and R_2 together constitute the group =CH-NR_3R_4, in which R_3 and R_4 are as defined. Methods for producing the described compounds.