KR900007243B1 - 4-aminopyridine derivative - Google Patents

Abstract

No content.

Description

4-aminopyridine derivative

The present invention relates to 4-aminopyridine derivatives.

The compounds of the present invention inhibit acetylcholinesterase in the brain and are useful for the treatment of Alzheimer's disease.

Tetrahydro-aminoacridine with cholinesterase inhibitory activity has been reported to show improved performance in mental tests in patients suffering from Alzheimer's disease (WKSummers et al. The New England Journal of Medicine, 315, 1241-1245 (1986). It has been reported that anticholinesterase physostigmine has also been used experimentally in the treatment of Alzheimer's disease (see Neurobiol. Aging 4, 139-145 (1983) , SDBrinkman et al. ).

The compounds described in the following four documents are claimed to have cholinesterase inhibitory activity.

US Pat. No. 4,652,567 refers to benzo (c) -1,5-naphthyridine for the treatment of Alzheimer's disease.

US Pat. No. 4,631,286 mentions 9-amino-1,2,3,4-tetrahydroacridin-1-ol and related compounds for the treatment of Alzheimer's disease.

U.S. Patent No. 4,550,113 discloses 9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta (b) for the treatment of neuritis, peripheral nervous system disorders, hereditary neuromuscular diseases and disseminated sclerosis.

Quinoline monohydrate hydro-chloride is mentioned.

U.S. Patent 4,578,394 mentions dihydropyridine for the treatment of Alzheimer's disease.

US Patent No. 4,540,564 mentions dihydropyridine for delivering drugs to the brain.

J. Med . Chem ., 9 , 483-488 (1966) to GK Patnaik et al., 4-substituted 2,3 having analgesic, local anesthesia, excitement (tongue) and respiratory stimulatory actions. Polymethylenequinoline is mentioned.

In the British patents nos. 1,186,061, 1,186,062 and 1,186.063, benzonaphthyridine derivatives are mentioned.

The present invention relates to compounds of the general formula (I) and pharmaceutically acceptable salts thereof.

Wherein A is selected from the group consisting of the following general formulas (1), (2), (3), (4) and (5)

Wherein one of the CH residues at positions a, b, c and d of Formula (I) is substituted with a nitrogen atom, or each of the CH residues at positions a and d, a and c or b and d is nitrogen May be substituted with an atom: B is selected from the group consisting of the following general formulas (6), (7), (8), (9) and (10)

Where the dashed lines each represent an optional double bond: R ¹ is hydrogen or C ₁ -C ₆ alkyl: R ³ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C _1- C ₆ alkanoyl, di (C ₁ -C ₆ alkylamino) -C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl, halogen (e.g. blue auro, chloro, bromo or io Hydroxy, nitoro, phenyl, substituted phenyl, pentyl-C ₁ -C ₆ alkyl, substituted phenyl-C ₁ -C ₆ alkyl, diphenyl-C ₁ -C ₆ alkyl, wherein One or both may be substituted with substituted phenyl group, furyl-C ₁ -C ₆ alkyl, thienyl-C ₁ -C ₆ alkyl, phenyloxy, substituted phenyloxy, NHCOR ⁵ and NR ⁶ R ⁷ ) a is independently selected from the group consisting of, wherein the phenyl moieties on said substituted phenyl and substituted phenylalkyl groups are halogen (e.g., fluoro, chloro, bromo or iodo), C ₁ -C ₆ alkyl, trifluoromethyl Romethyl, C ₁ -C ₆ Alkoxy-C ₁ -C ₆ Al Substituted with one or more substituents (preferably one or two substituents) selected from the group consisting of Kil, hydroxy and nitro, wherein R ⁵ , R ⁶ and R ⁷ are C ₁ -C ₆ alkyl and C ₁ -C Independently selected from ₆ alkane oil: R ² is 1,4-dihydropyridyl-C ₁ -C ₆ alkane oil, C ₁ -C ₆ alkyl-1,4-dihydropyridyl-C ₁ -C ₆ Are independently selected from the group consisting of the above definitions for alkanoyl and R ³ , wherein R ² cannot be hydroxy, halogen, C ₁ -C ₆ alkoxy, phenyloxy or substituted phenyloxy: R ⁴ is independently selected from the above definitions for R ³ , with R ^{4 not} being halogen, nitoro, NHCOR ⁵ or NR ⁶ R ⁷ : n is 1,2 or 3 and Z ¹ is NH, O, S or NR ⁸ , wherein R ⁸ is C ₁ -C ₆ alkyl or C ₁ -C ₆ alkanoyl: Z ² is O or S and Z ³ and Z ⁴ are (CH ₂ ) _p With O, S, S = O and SO ₂ Are independently selected, provided that at least one of Z ³ and Z ⁴ is (CH ₂ ) _p and Z ⁵ is CH ₂ , O, S, S = O or SO ₂ and Z ⁶ is O, S, S = O or SO ² and: p is 1,2 or 3 and: q is 1 or 2 and: Y ¹ is CH ₂ , CHOH, O, C = O, S, S = O or SO ₂ and: Y ² is CH ₂ , CH, O, S, S = O or SO ₂ and: and Y ³ is CHOH, CH ₂ , CH or C = O, provided that the group of formula (8) is when Y ² and Y ³ are both CH Y ¹ with a double bond, A is a group of formula (I) wherein R ³ is hydrogen and no nitrogen at the a, b, c or d position or A is a group of formula (3) or (4) And only one of Y ² may be CH ₂ , and when A is a group of formula (1) in which R ³ is hydrogen and no nitrogen at a, b, c or d position, only one of Z ³ and Z ⁴ is (CH ₂ ) _{p may} be.

The invention also. A pharmaceutical composition for treating Alzheimer's disease comprising a compound of formula (I) and a use of the compound of formula (I) for treating Alzheimer's disease.

The present invention also relates to a method for producing the general formula (I) compound.

Specific embodiments of the present invention include those wherein R ¹ , R ² , A and B are as defined above for Formula (I). General formula wherein only one of Y ¹ and Y ² is CH ₂ when A is a group of formula (1) without nitrogen at the a, b, c or d position or A is a group of formula (3) or (4) (I) compounds and their pharmaceutically acceptable salts. Some of these embodiments include that Y ³ is CH ₂ , at least one of Z ³ and Z ⁴ is CH ₂ , provided that A is a group of formula (I) wherein R ³ is hydrogen, a, b, c or when there is no nitrogen at the d position, only one of Z ³ and Z ⁴ relates to a compound which is (CH ₂ ) _p .

Preferred embodiments of the invention are those in which A, B, Z ¹ , Z ² , Z ³ .Z ⁴ , Z ⁵ , Z ⁶ and Y ³ are as defined above for general formula (I): ^R 1, R ² and R ⁴ is hydrogen, R ³ is hydrogen or halogen, provided that A is a group of formula (1) without nitrogen at the a, b, c or d position or A is a group of formula (3) or (4) When only one of Y ¹ and Y ² is CH ₂ , and a pharmaceutically acceptable salt thereof. When R ³ is halogen, the halogen is preferably fluorine.

Another preferred embodiment of the invention is that A is a group of formula (1) wherein one of the CH moieties at positions a and b of formula (1) may be replaced by a nitrogen atom, or In the formula (3): B, R ¹ , R ² , R ³ , R ⁴ , Z ³ , Z ⁴ , Z ⁵ , Y ³ and g are as defined above for formula (I): n is 1 or 2: Z ⁶ is S: P is 1 or 2, provided that (a) when A is a group of general formula (1) without nitrogen at the a or b position, Z ³ is O, S or CH ₂ and: R ⁴ is hydrogen or C ₁ -C ₆ alkyl: Z ⁴ is (CH ₂ ) _P (where P is 1 or 2) or S and: Y ¹ is CH ² , C═O, Is O or S: Y ₂ is CH ₂ , O or S, provided that only one of Y ¹ and Y ² can be CH ₂ , and (b) in Formula (1) where A is nitrogen at either a or b When Y ¹ is O, S or CH ₂ and Y ² is CH ₂ : and (c) when A is a group of formula (3), Y ¹ is O or S and Y ² is CH ₂ General formula ( ) Compounds and to the pharmaceutically acceptable salts thereof. In a more preferred embodiment, R ¹ , R ² and R ⁴ are hydrogen and R ³ is hydrogen or halogen. When R ³ is halogen, the halogen is preferably fluorine.

Another preferred embodiment of the invention is that B is a group of formula (7) or (8), wherein A, R ¹ , R ² , R ³ , Z ¹ , Z ² , q, Y ¹ , Y ² and Y ³ for the general formula (ⅰ) as defined above but, a is a, b, c, or or a group of the formula (1) does not have nitrogen at the d position a is represented by the general formula (3) or (4) When the group, only one of Y ¹ and Y ² relates to the general formula (I) compound and CH ₂ pharmaceutically acceptable salts thereof. More preferred embodiments are where R ¹ and R ² are hydrogen and R ³ is hydrogen or halogen. When R ³ is halogen, the halogen is preferably fluorine.

Particularly preferred embodiments of the invention are those in which A is a group of formula (1), wherein one of the CH residues at positions a and b may be substituted by a nitrogen atom or is a group of formula (3): Is a group of formula (7) or (8): R ¹ , R ² , R ³ , q, Y ¹ , Y ² and Y ³ are as defined for formula (I) and n is 1 or 2 Provided that (a) when A is a group of formula (1) without nitrogen at the a or b position, Y ¹ is CH ₂ , C = O, O or S and Y ² is CH ₂ , O or S And only one of Y ¹ and Y ² may be CH ₂ : (b) when A is a group of general formula (1) with nitrogen in a or b position, Y ¹ is O, S or CH ₂ and Y ² Is CH ₂ and: and (c) when A is the group of formula (3), Y ¹ is O or S and Y ² is CH ₂ , will be. In a more preferred embodiment R ¹ , R ² and R ⁴ are hydrogen and R ³ is hydrogen or halogen. When R ³ is halogen, the halogen is preferably fluorine.

Another preferred embodiment of the invention A is a group of formula (1) (wherein R ³ is as defined above for formula (Ⅰ), but R ³ is may be only d position of formula (1) And R ¹ , R ² and B are related to the general formula (I) compound and pharmaceutically acceptable salts thereof as defined for the general formula (I). In a more preferred embodiment, R ³ is halogen, preferably fluorine.

Another preferred embodiment of the invention is that A is a group of formula (1) wherein R ³ is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, hydroxy, nitro, NHCOR ^5, NR ⁶ R ⁷ or trifluoromethyl)

)r 의 그룹(이때 r은 2,3 또는 4이다)이며, R¹,R²,R⁵,R⁶및 R⁷은 일반식(Ⅰ)에 대해 정의한 바와 같은 일반식(Ⅰ)의 화합물 및 그의 약학적으로 허용되는 염에 관한 것이다. 상기 화합물들중에서 보다 바람직한 화합물은 R³가 일반식(1)의 d 위치에 있거나 R³가 할로겐인 화합물이다.And B is a general formula

) is a group of r wherein r is 2, 3 or 4, and R ¹ , R ² , R ⁵ , R ⁶ and R ⁷ are compounds of general formula (I) as defined for general formula (I) and To pharmaceutically acceptable salts thereof. More preferred among these compounds are those wherein R ³ is at the d position of formula (1) or R ³ is halogen.

Particularly preferred compounds are when R ³ is halogen in the d position. When R ³ is halogen, the halogen is preferably fluorine.

Specific compounds preferred in the present invention are as follows: 9-amino-4-oxa-1,2,3,4-tetrahydroacridine: 9-amino-1,2,3,4-tetrahydro-1, 4-Methanoacridine: 9-amino-8-fluoro-1,2,3,4-tetrahydro-1,4-methanoacridine: 9-amino-2-oxa-1,2,3, 4-tetrahydroacridine: 9-amino-2-thia-1,2,3,4-tetrahydroacridine: 9-amino-8-fluuro-4-oxa-1,2,3,4 Tetrahydroacridine: 9-amino-4-oxa-1,2,3,4,5,6,7,8-octahydroacridine: 2,3-dihydrothieno [3,2- b] quinolin-9-amine: 9-amino-5-aza-1,2,3,4-tetrahydroacridine: 2,3-dihydro-8-fluoro-thieno1,3-dihydro -8-fluoro-thieno [3,2-b] quinolin-9-amine: 9-amino-1,2-dihydroacridin-4 (3H) -one: 1,3-dihydro-9 -Fluoro-thieno [3,4-b] quinolin-9-amine: 9-amino-4-thia-1,2,3,4-tetrahydroacridine: 8- By Luo-9-amino-1,2,3,4-tetrahydro-acridine: A and 9-Amino-8-thiazol-2-wool plug-1,2,3,4-tetrahydro-acridine.

Other compounds of the invention are as follows: 9-amino-4,5-thiaza-1,2,3,4-tetrahydroacridine: 9-amino-4-thia-1,2,3,4 , 5,6,7,8-octahydroacridine: 9-amino-2-thia-1,2,3,4,5,6,7,8-octahydroacridine: 9-amino-2 -Oxa-1,2,3,4,5,6,7,8-octahydroacridine; 9-amino-5,7-diaza-1,2,3,4-tetrahydroacridine: 9-amino-3-methyl-7-phenyl-4-oxa-1,2,3,4-tetra Hydro-acridine: 9-amino-6-trifluoromethyl-1,4-methano-1,2,3,4-tetrahydroacridine: 9-amino-5,8-diaza-1 , 4-Metano-1,2,3,4-tetrahydroacridine: 9-amino-1-thia-1,2,3,4-tetrahydroacridine: 9-amino-3-thia- 1,2,3,4-tetrahydroacridine: 4-amino-5,6,7,8-tetrahydro-1H-imidazo [4,5-b] -quinoline: 4-amino-5,6 , 7,8-tetrahydro-oxazolo [4,5-b] quinoline: 4-amino-5,6,7,8-tetrahydro-thiazolo [4,5-b] quinoline: 9-amino-1 , 2,3,4-tetrahydroacridin-4-ol: 9-amino-6-trifluoromethyl-4-oxa-1,2,3,4-tetrahydroacridine: 9-amino- 6-trifluoromethyl-1-hydroxy-4-oxa-1,2,3,4-tetrahydroacridine: and 9-amino-1-hydroxy-4-oxa-1,2,3 , 4-tetrahydroacridine.

Preferred compositions of the present invention include the above preferred compounds. More preferred compositions of the present invention include those more preferred compounds and preferred specific compounds.

The compound of the present invention can be prepared as follows.

As shown in Scheme I, the inonitrile of formula (II) (where A is as defined above) is reacted with a ketone of formula (III) (where B is as defined above) to formula (IV) To prepare ketimine. This reaction is carried out in an inert solvent, preferably an aromatic solvent (eg benzene or toluene), in the presence of an acid, preferably a strong acid (eg p-toluenesulfonic acid). The temperature should be at least about 100 ° C. but it does not matter much. In general, this reaction is carried out at the reflux temperature of the reaction mixture, for example by refluxing the reaction mixture in a Dean Stark apparatus, preferably for about 6 to about 16 hours and periodically removing water. The reaction pressure is not very important. As a rule, the reaction is carried out at about 0.5 to about 2 atmospheres, preferably at ambient pressure (about 1 atmosphere in liquid).

The impure ketimine (IV) obtained after the removal of the solvent is combined with a base (e.g., lithium diisopropylamide) in an inert solvent, preferably anhydrous ether (e.g. tetrahydrofuran) at a temperature of about 0 ° C to about 25 ° C. React.

Pressure is not important in this reaction. Generally this reaction is carried out at about 0.5 to about 2 atmospheres, preferably at ambient pressure (usually about 1 atmosphere).

The first method works particularly well when all carbon ketones are used in the reaction. Azeotropic removal of water from the benzene solution of norcampo (or all carbon ketones) and anthranironitrile (80 ° C., PTSA, 15 hours) yields the corresponding ketimine, which is treated with lithium diisopropylamide in tetrahydrofuran. (0 ° C, 4 hours) to give the compound of Example 1 in 25% yield. This procedure is illustrated for preparing the compounds of Examples 2,3,4,30 and 36.

The first method is generally limited because it is difficult to form ketimine from carbonyl compounds containing nitrogen or oxygen atoms.

Titanium (IV) chloride has been used to prepare ketimines due to its high affinity for oxygen (see H. Weingarten et al. J. Org. Chem ., 32 , 3246 (1967)). This observation was used to condense the appropriate 0-aminonitrile with various carbonyl constituents in one step to synthesize 9-ino-1,2,3,4-tetrahydroacridine derivatives.

Therefore, in the second method of preparing the compound of the present invention, a compound of formula (II), wherein A is as defined above, is a carbonyl-containing compound of formula (III), wherein B is defined above As shown).

The carbonyl-containing compound may be a ketone, lactone or the like. This reaction is carried out in an inert solvent in the presence of a Lewis acid (e.g. titanium (IV) chloride) and, if necessary, in the presence of a base, preferably an amine base (e.g. triethylamine).

Suitable solvents include aromatic solvents (eg benzene or toluene) and chlorinated solvents (eg methylene chloride or 1,2-dichloroethane). The reaction temperature should be at least about 0 ° C., and preferably about 25 to about 120 ° C. The reaction pressure is not important. Generally, this reaction is carried out at about 0.5 to about 2 atmospheres, preferably at ambient pressure (approximately about 1 atmosphere).

Thus, for example, delta-valerolactone in methylene chloride was condensed with titanium (IV) chloride in the presence of anthranironitrile and triethylamine (2 equivalents) at 25 ° C. to give the compound of Example 7 (28%). . This method was used to synthesize the compounds of Examples 7-19,26-29,31-33,35 and 37-46. The compounds of Examples 5 and 6 were prepared by condensing anthranironitrile in the presence of anhydrous zinc chloride at an appropriate ketone and elevated temperature (140 ° C.).

Monosubstitution of amine groups in the compounds of the present invention provides the ability of compounds of the general formula R ⁹ X (wherein R ⁹ is the same as R ² but not hydrogen and X is a halogen such as chloro, bromo or iodo). Performed by heating with halides. This reaction can also be carried out in the presence of sodium hydride in dimethylformamide. This reaction is illustrated in the synthesis of the compounds of Examples 20-25 and 34.

Compounds of general formula (I) may form acid addition salts with pharmaceutically acceptable acids. Acid addition salts are prepared by reacting the base form of a suitable compound of general formula (I) with one equivalent, preferably with an excess of a suitable acid in an organic solvent such as diethylether or ethanol diethylether mixture. Acids suitable for forming these salts are usually inorganic acids, such as halogenic acid, sulfuric acid or phosphoric acid: organic acids such as ascorbic acid, citric acid, lactic acid, aspartic acid or tartaric acid, or pHs of 5.5 or higher. Aqueous solutions adjusted to below: and acids, such as pamo acid or tannic acid or carboxymethyl cellulose, which are slightly soluble in body fluids and which cause them to release slowly when the corresponding salts are formed. Preferred salts are hydrochlorides.

Compounds of formula (I) and their pharmaceutically acceptable salts are useful for the treatment of various memory dysfunctions associated with reduced cholinergic function, such as Alzheimer's disease. In addition, when the compounds are damaged by nerve and neuromuscular synapses, the compounds not only restore their delivery, but also stimulate stimulation of neuromuscular transmission and strengthening excitatory tissues (nerve, smooth muscle and rhabdomyo). The compound of the present invention also has an anti-inhibitory effect which is particularly beneficial for patients suffering from Alzheimer's disease. Compounds of the present invention are therapeutically preferred because they are generally less toxic and have a broader therapeutic range than known compounds such as tacrine and physostigmine.

When treating Alzheimer's disease, the dose of a compound of the invention will vary depending on the dosage form and the particular compound selected. Moreover, this dose depends on the nature and extent of the condition as well as the age, weight and condition of the particular patient, ie the patient to be treated. However, doses in the range of about 1 to about 300 mg / day are usually administered in a single dose or in divided doses. Preferred doses are in the range of about 1 to about 150 mg / day in a single or full dose.

In general, treatment begins with a dose substantially less than the optimal dose. Then increase the dose of small seed until the optimum effect is obtained.

The compounds of the present invention may be used alone or in combination with pharmacologically acceptable carriers, the proportion of which is determined by the solubility and chemical properties of the compound, the chosen route of administration and standard medical practice. For example, the present compounds can be administered orally or parenterally in the form of capsules, tablets, suspensions or solutions. Capsules and tablets are preferred dosage forms. For parenteral administration, the compound of the present invention is another solute. For example, the solution may be in the form of a sterile solution containing saline or glucose sufficient to make an isotonic solution.

Capsules and tablets compositions contain a medicament in admixture with one or more pharmaceutical excipients suitable for the manufacture of capsules and tablets. Suitable pharmaceutical excipients are, for example, starch, milk sugar and certain types of clay. Tablets may be uncoated or coated in a known manner to slow disintegration and absorption in the gastrointestinal tract so that they can have a longer lasting effect.

Aqueous suspensions of compounds of formula (I) contain the active ingredient in admixture with one or more pharmaceutical excipients suitable for the manufacture of aqueous suspensions. Suitable excipients are, for example, methylcellulose, sodium alginate, gum acacia, lecithin and the like. Aqueous suspensions may also include one or more preservatives, one or more pigments, one or more flavorings, and one or more sweeteners.

Water-insoluble suspensions can be prepared by suspending the active substance in vegetable oils (eg, arachis oil, olive oil, sesame oil or coconut oil) or mineral oils (eg liquid paraffin). This suspension may also contain thickening agents, for example beeswax, solid paraffin or cetyl alcohol. The composition may also include sweeteners, fragrances and antioxidants.

The following examples illustrate the preparation and properties of the compounds of the present invention. All melting points were uncorrected and thin layer chromatography (TLC) was performed on silica gel.

Example 1

9-amino-1,2,3,4-tetrahydro-1,4-methanoacridine

A solution of anthranironitrile (3.6 g, 30.0 mmol), norcampo (3.3 g, 30.0 mmol) and para-toluenesulfonic acid (50 mg) in benzene (50 ml) was heated to reflux using a Diyne Stark apparatus. After heating for 18 hours, the reaction mixture was cooled (25 ° C.) and the separated water (ca. 1.5 ml) was discarded. Then excess benzene was removed in vacuo (1 mmHg, 15 min). The oily residue thus obtained was dissolved in tetrahydrofuran (THF, 10 ml), cooled to 0 ° C., and a solution of lithium diisopropylamide in THF (1 M, 36 ml, 36 mmol) was added. The reaction mixture was stirred at 0 ° C. for 3 hours. After stirring, the reaction mixture was quenched with 40 ml of water and extracted with methylene chloride (200 ml). The resulting organic phase was washed with water (2 × 50 ml) and dried (anhydrous MgSO ₄ ). Methylene chloride was removed in vacuo to give a residue, which was applied on a silica gel flash chromatography column. Elution with 5% methanol in methylene chloride containing 1% triethylamine gave 1.6 g (25%) of the title compound as an oil which was left to solidify. Melting point 185-186 ° C.

Example 2

9-amino-8-fluoro-1,2,3,4-tetrahydro-1,4-methanoacridine

Except for using 2-amino-6-fluorobenzonitrile instead of anthraninilnitrile, the procedure of Example 1 was followed to prepare the title compound (23%, melting point of 173 ° C).

Example 3

9-amino-7-chloro-1, 2,3,4-tetrahydro-1, 4-methanoacridine

The title compound was prepared in the same manner as in Example 1, except that 2-amino-5-chlorobenzonitrile was used instead of anthranironitrile. 14%, melting point 183-184 ° C.

Example 4

9-amino-1,4-dihydro-1,4-methanoacridine

The title compound was prepared in the same manner as in Example 1, except that 5-norborneon-2-one was used instead of norcampo. 26%, melting | fusing point 123 degreeC.

Example 5

9-amino-2-oxa-1,2,3,4-tetrahydroacridine

Anthranironitrile (25 mmol, 2.95 g), zinc chloride (3.2 g, 25 mmol) and tetrahydro-4H-pyran-4-one were dissolved in toluene (40 ml) and heated to reflux for 2.5 days. After this period, the reaction mixture was cooled (25 ° C.), quenched with aqueous sodium hydroxide solution (70 ml) and extracted with methylene chloride (4 × 60 ml). The combined organic phases were washed with water (2 × 100 ml) and dried (anhydrous MgSO ₄ ). The organic solvent was removed in vacuo to give a yellow residue which was applied on a silica gel flash chromatography column. Elution with 5% methanol in methylene chloride gave the title compound as yellow crystals. 155 mg, 31%, melting point 195-196 ° C.

Example 6

9-amino-2-thia-1,2,3,4-tetrahydroacridine

Anthranironitrile (2.6 g, 21.5 mmol), tetrahydrothiopyran-4-one (5.0 g, 43 mmol) and zinc chloride (2.54 g, 21.5 mmol) were combined and heated to 120 ° C. for 20 minutes. The reaction mixture was cooled and the solid residue was filtered using ethyl ether (100 ml). The resulting orange solid (5.2 g) was placed in a beaker containing a saturated solution of EDTA (ethylene diaminetetraacetic acid) in water (125 ml) to adjust the pH to 13 by adding 12% NaOH. The aqueous phase was then extracted with methylene chloride (4 x 50 ml), washed with water (2 x 70 ml) and dried (MgSO ₄ ). Methylene chloride was removed in vacuo to give a yellow paste (2.0 g), which was triturated with ether and filtered to give 1.36 g (29%) of a pale yellow solid. Melting Point 205 ℃ (Decomposition)

Example 7

Methylene chloride in a stirred solution of delta-valerolactone (1.0 g, 10.0 mmol) in methylene chloride (10 ml) at 9-amino-4-oxa-1,2,3,4-tetrahydroacrydine at -20 ° C. A solution of titanium (IV) chloride 1N in (20 ml) was added. The reaction mixture turned dark yellow to which a mixture of triethylamine (2.0 g, 20 mmol) and anthranironitrile (1.2 g, 10.0 mmol) in methylene chloride (30 ml) was added. The reaction mixture immediately turned to dark color, which was allowed to warm up to room temperature (about 25 ° C.) and stirred further for 15 hours. At the end of stirring, the reaction mixture was treated with 25% aqueous NaOH solution (40 ml) and methylene chloride (100 ml), filtered through a 2 inch diatomaceous earth pad (trade name Celite) and washed with methylene chloride (50 ml) and water (100 ml). The organic layer was separated, washed once with water (30 ml) and dried (anhydrous MgSO ₄ ). Methylene chloride was removed in vacuo to give an oil which was triturated with ether to give 565 mg (28%) of the title compound as a white solid.

¹ H-NMR (CDC ₁₃ , 300 MHz, ∂): 2H, m, 2.02-2.18 ppm; 2H, t, 2.63 ppm (J = 6.0 Hz); 2H, t, 4.36 ppm (J = 6.0 Hz); 2H, s, 4.64 ppm; 1H, t, 7.25 ppm (J = 8.0 Hz); 1H, t, 7.55 ppm (J = 8.0 Hz); 1H, d, 7.72 ppm (J = 8.0 Hz).

Example 8

9-amino-8-fluoro-4-oxa-1,2,3-4-tetrahydroacridine

The title compound was obtained in the same manner as in Example 7, except that 2-amino-6-fluorobenzonitrile was used instead of anthranironitrile. 8%, melting point 195-196 캜.

Example 9

9-amino-7-chloro-4-oxa-1,2,3-4 -tetrahydroacridine

The title compound was obtained in the same manner as in Example 7, except that 2-amino-5-chlorobenzonitrile was used instead of anthranironitrile. 2%, melting | fusing point 278-279 degreeC.

Example 10

9-amino-4-oxa-1,2,3,4,5,6,7,8-octahydroacridine

Except for using 2-amino-1-cyano-1-cyclohexene in place of anthraninilnitrile, the procedure of Example 7 was followed to obtain the title compound (8%, melting point of 145 ° C.).

Example 11

9-amino-2,3,7,8-tetrahydro-1H-cyclopenta [e] 6H-pyrano- [2 ', 3'-b] pyridine

Except for using 2-amino-1-cyano-1-cyclopentene instead of anthraninilnitrile, the procedure of Example 7 was carried out as it was, to prepare the title compound (22%, melting point of 164 ° C).

Example 12

2,3-dihydrothieno [3,2-b] quinolin-9-amine

To a stirred solution of tetrahydrothiophen-3-one (1,1 g, 11 mmol) in methylene chloride (10 ml) was added a 1M solution of titanium (IV) chloride in methylene chloride (11 ml) at -78 ° C. A mixture of triethylamine (2.2 g, 22 mmol) and anthranironitrile (1.2 g, 10.0 mmol) in methylene chloride (30 ml) was added to the reaction mixture over 5 minutes. The reaction mixture was then slowly warmed to room temperature and stirred for 2 hours. Tetrahydrothiophen-3-one (1 ml) and titanium (IV) chloride (1.0 ml) were added to the reaction mixture, and the mixture was stirred at 25 ° C for 16 hours. The reaction mixture was then quenched with 12% aqueous NaOH solution (100 ml) and additional methylene chloride (300 ml) was added to the reaction mixture and stirred vigorously. The reaction mixture was filtered through diatomaceous earth (trade name Celite) and the organic phase was separated. The residue obtained by removing the organic solvent in vacuo was applied on a flash chromatography column. Elution with 5% methanol in methylene chloride containing 1% triethylamine gave the title compound (1.3 g, 64%) which was crystallized from chloroform to give 560 mg (32%, melting point 208-210 ° C.). .

Example 13

9-amino-1,2,3,4,5,6,7,8-octahydro-1,4-methanoacridine

Triethylamine (1.7 g, 16.4 mmol) and 2-amino-1-cyano- in methylene chloride (24 ml) to a stirred solution of norcampo (0.9 g, 8.2 mmol) in methylene chloride (8.0 ml) at -20 ° C. A mixture of 1-cyclohexene (1.0 g, 8.2 mmol) was added and the resulting mixture was stirred at 25 ° C. for 15 hours. The reaction mixture was then quenched with 12% aqueous NaOH solution (60 ml) and vigorously stirred with mephilene chloride (60 ml). The reaction mixture was filtered through a 2 inch pad of diatomaceous earth (Celite). The organic phase was separated, washed with water (2 x 50 ml) and dried (anhydrous MgSO ₄ ). The oil obtained by removing methylene chloride under reduced pressure was then ground with pentane to give 225 mg (13%) of the title compound as an off-white solid. Melting Point 131-133 ℃

Example 14

9-amino-6-aza-1,2,3,4-tetrahydroacridine

Titanium (IV) chloride (1.5 ml) was added to a stirred solution of 3-amino-4-cyano-pyridine (500 mg, 4.2 mmol) and cyclohexanone (0.5 ml) in 1,2-dichloroethane (15 ml). The reaction mixture was then maintained at 90 ° C. for 12 hours. At the end of this period cyclohexanone (2.0 ml) and 1,2-dichloroethane (5.0 ml) were added to the reaction mixture and heating was continued for another 12 hours. Additional cyclohexanone (2.0 ml) and titanium tetrachloride (1.2 ml) were added and the reaction mixture was kept at 90 ° C. for 6 hours. The reaction mixture was then cooled, quenched with 5% aqueous NaOH solution (250 ml) and vigorously stirred with methylene chloride (200 ml, 25 min). The reaction mixture was treated as in Example 8 to give flash chromatography on silica gel (eluant: 95: 5: 1 methylene chloride: methanol: ammonium hydroxide) to give the title compound (170ml, 95% purity, 20%). This material was further purified by chromatography to yield 75 mg of the title compound (melting point 180-181 ° C.).

Example 15

9-amino-5-aza-1,2,3,4-tetrahydroacridine

Except for using 2-amino-3-cyano-pyridine instead of 3-amino-4-cyanopyridine, Example 14 was carried out as is to obtain the title compound. 38%, melt 225-228 degreeC (this year).

¹ H-NMR (CDCl ₃ + CD ₃ OD, 300MHz, ∂): 4H, bs, 1.86ppm: 2H, bt, 2.5ppm: 2H, bt, 2.97ppm: 2H, vbs, 3.0-3.3ppm: 1H, dd 7.2 ppm (J = 8.0,4.0 Hz): 1 H, dd, 8.18 ppm (J = 8.0, 1-2 Hz): 1 H, dd, 8.77 ppm (J = 4.0, 1-2 Hz).

Example 16

9-amino-4, 5-oxa-1,2,3,4-tetrahydroacridine

Titanium (IV) chloride (0.9) in a stirred solution of 2-amino-3-cyano-pyridine (360 mg, 3.0 mmol) and delta-valerolactone (360 mg, 3.6 mmol) in 1,2-dichloroethane (7.0 ml) ml) was added and the reaction mixture was kept at 90 ° C. for 18 hours. The reaction mixture was quenched with 15% aqueous NaOH solution (200 ml) and stirred vigorously with methylene chloride (200 ml, 25 min). The reaction mixture was then treated as in Example 15 to yield the title compound (8%, melting point 269-270 ° C. degradation).

Example 17

9-amino-4,6-oxaza-1,2,3,4-tetrahydroacridine

Except for using 3-amino-4-cyano-pyridine instead of 2-amino-3-cyano-pyridine, the method of Example 16 was carried out as is to obtain the title compound (16%, melting point 237-238 ° C.). Obtained.

Example 18

9-amino-5-aza-1,2,3,4-tetrahydro-1,4-methanoacridine

Example 16 The procedure was carried out as is, except that norcampo was used instead of telta-valerolactone to give the title compound (29%, melting point 243-244 ° C.).

Example 19

9-amino-6-aza-1,2,3,4-tetrahydro-1,4-methanoacridine

Example 16 method is carried out as is, except that norcancampo is used in place of delta-valerolactone and 3-amino-4-cyano-pyridine is used instead of 2-amino-3-cyano-pyridine. The title compound (16%, melting point 236-237 ° C.) was obtained.

Example 20

9-cyclohexylmethylamino-8-fluoro-4-oxa-1,2,3,4-tetrahydroacridine

Sodium hydride (60% oil, 110 mg, 2.75 mmol), the title compound of Example 6 (600 mg, 2.75 mmol), cyclohexylmethyl bromide (60% oil, 110 mg 2.75 mmol), the title compound of Example 6 at 25 ° C. Stir heated at 12 h at 65 ° C. for 12 h. After this period, the reaction mixture was quenched by pouring into water (45 ml) and the resulting mixture was extracted with ethyl acetate (3 × 35 ml). The organic layers were combined, washed with water (2 x 40 ml) and dried (anhydrous MgS0.). The residue obtained by removing ethyl acetate in vacuo was applied to a flash chromatography column filled with silica gel. Elution with ethyl acedate gave an oil which prevented and solidified. The solid was triturated with pentane to give the title compound (110 mg, 13%) in the form of a tan crystalline solid (melting point 100 ° C.).

Example 21

9-cyclohexylethylamino-8-fluoro-4-oxa-1,2,3,4-tetrahydroacridine

Except for using cyclohexylethyl bromide instead of cyclohexylmethyl bromide, the Example 20 method was followed to yield the title compound (34%).

¹ H-NMR (CDC1 ₃ , 300 MHz): 2H, m, 0.8-1.02 ppm: 4H, m, 1.02-1.4 ppm: 2H, m, 1.44-1.56 ppm; 5H, bd, 1.56-1.8 ppm: 2H, q, 1.92-2.04 ppm (J = 6.0 Hz); 2H, t, 2.8ppm (J = 6Hz): 2H, bt, 3.33ppm: 2H, t, 4.36ppm (J = 6Hz): 1H, bd, 5.6ppm (J = 20Hz): 1H, dd, 6.38ppm ( J = 14.0, 7.5 Hz): 1H, dd, 7.24-7.38 ppm: 1H, d, 7.48 ppm (J = 8.2 Hz).

Example 22

9-benzylamino-8-fluoro-4-oxa-1,2,3,4-tetrahydroacridine

Except for using benzyl bromide instead of cyclohexylmethyl bromide, the method of Example 20 was followed to obtain the title compound (38%, melting point 134-135 ° C.).

Example 23

9-phenethylamino-8-fluoro-4-oxa-1,2,3,4-detrahydroacridine

Except for using (2-bromoethyl) benzene instead of cyclohexylmethyl bromide, the method of Example 20 was carried out as it was to obtain the title compound (20%, melting point 125-126 ° C.).

Example 24

9-phenpropylamino-8-fluoro-4-oxa-1,2,3,4-tetrahydroacridine

Except for using 1-bromo-3-phenylpropane instead of cyclohexylmethyl bromide, the procedure of Example 20 was followed to yield the title compound (53% oil).

¹ H-NMR (CDCl ₃ , 300NIHz, ∂): 4H, m, 1.82-2.02ppm: 4H, m, 2.62-2.78ppm: 2H, bs, 2.34ppm: 2H, t, 4.35ppm (J = 6.0Hz) : 1H, bd, 5.7 ppm (J = 20 Hz): 1 H, dd, 6.86 ppm (J = 14,7.5 Hz): 6H, m, 7.04-7. 4 ppm: 1H, d, 7.51 ppm (J = 8.2 Hz).

Example 25

9- (3,3diphenylpropylamino) -8-fluoro-4-oxa-1,2,3,4-tetrahydroacridine

Except for using 1-bromo-3,3-diphenylpropane instead of cyclohexylmethyl bromide, the method of Example 20 was carried out as is to obtain the title compound (32%, melting point of 134-135 ° C.).

Example 26

9-amino-4-thia-1,2,3,4-tetrahydroacridine

Except for using delta-thiovalerolactone instead of delta-valerolactone, the procedure of Example 7 was followed to yield the title compound (4%. Melting point: 190 ° C.).

Example 27

9-amino-3-methyl-4-oxa-1,2,3,4-tetrahydroacridine

Except for using 6-methyl-tetrahydropyran-2-one instead of delta-valerolactone, the procedure of Example 7 was followed to yield the title compound (23%, melting point 202-203 ° C.).

Example 28

9-amino-3-methyl-8-luoro-4-oxa-1,2,3,4-tetrahydroacridine

The method of Example 7, except that 6-methyl-tetrahydropyran-2-one is used instead of delta-valerolactone and 2-amino-6-fluorobenzonitrile is used instead of anthranironitrile. The title compound (13%, melting | fusing point 217-218 degreeC) was obtained as it was.

Example 29

9-amino-8-fluoro-2-thia-1,2,3,4-tetrahydroacridine

Except for using tetrahydrothiopyran-4-one instead of delta-valerolactone and 2-amino-6-fluoro benzonitrile instead of anthranironitrile, The title compound (19%, melting point 175-176 ° C.) was obtained.

Example 30

9-amino-1,2,3,4-tetrahydro-1,4-ethananoacridine

Except for using bicyclo [2,2,2] octan-2-one instead of norcampo, the procedure of Example 1 was followed to yield the title compound (20%, melting point 197-199 ° C.).

Example 31

2,3-dihydrofuro [2,3-b] quinolin-4-amine

The title compound was obtained in the same manner as in Example 7 except that gamma-butyrolactone was used instead of delta-valerolactone. Melting point 300 ° C. (decomposition).

¹ H-NMR (CDCl ₃ , 300MHz, ∂): 2H, t, 3.17ppm (J = 8Hz0: 2H, t, 4.69ppm (J = 8Hz); 1H, t, 7.28ppm (J = 8Hz): 1H, t, 7.53 (J-8 Hz); 1 H, d, 7.62 ppm (J = 8 Hz); 1 H, d, 7.77 ppm (J-8 Hz).

Example 31

6H- [1] benzopyrano [4,3-b] quinolin-7-amine

The title compound (3%, melting point of 275 ° C. (decomposition)) was obtained by performing the method of Example 7 as it was except that 4-chromanone was used instead of delta-valerolactone.

¹ H-NMR (DMSO, 300 MHz, ∂): 2H, s, 5.3 ppm: 1H, d, 6.97 ppm (J = 8.2 Hz); 1H, t, 7.08 ppm (J = 7.0 Hz); 2H, m, 7.15-7.4 ppm; 1H, t, 7.57 ppm (J = 7.0 Hz); 1H, d, 7.78 ppm (J = 7.0 Hz); 1H, d, 8.16 ppm (J = 8.0 Hz); 1H, dd, 8.24 ppm (J = 7.0, 2.0 Hz).

Example 33

6H- [1] benzothiopyrano [4,3-b] quinolin-7-amine

Except for using thiochroman-4-one instead of delta-valerolactone, the procedure of Example 7 was followed to yield the title compound (13%, melting point 211-212 ° C.).

Example 34

9-methylamino-8-fluoro-4-oxa-1,2,3,4-tetra-hydroacridine

Except for using iodomethane instead of cyclohexylmethyl bromide, the method of Example 20 was followed to obtain the title compound (melting point 240 ° C. for HC1 salt).

¹ H-NMR (DMSO, 300 MHz, ∂): 2H, m, 2.0 ppm; 2H, t, 2.95 ppm (J = 6.5 Hz); 3H, bd, 3.3 ppm; 2H, t, 4.53 ppm (J = 6.5 Hz); 1H, dd, 7.34 (J = 8.14 Hz); 1H, dd, 7.44 (J = 8.0 Hz); 1H, m, 7.7-7.8 ppm; 1 H, bm, 7.94-8.06 ppm.

Example 35

2,3-dihydro-8-fluorothieno [3,2-b] quinolin-9-amine (Compound A) and 1,3-dihydro-8-fluorothieno [3,4-b] Quinolin-9-amine (Compound B)

Except for using 2-amino-6-fluorobenzonitrile instead of anthranilo nitoryl, the method of Example 12 was followed to obtain a 1: 1 mixture of the two title compounds.

Compound A (melting point 137 ℃), compound B (melting point 198 ℃ ^{decomposition): 1 H-NMR (CDC1} 3, 300MHz, ∂): 2H, s, 4.09ppm: 2H, s, 4.38ppm; 2H, bs, 5.3 ppm; 1 H, dd, 7.0 ppm (J = 7.3, 14.5 Hz): 1 H, dd, 7.47 ppm (J = 7.3, 10.5 Hz); 1H, d, 7.68 ppm (J = 10.5 Hz)

Example 36

9-amino-1,2-dihydroacridin-4 (3H) -one

Except for using 1,2-cyclohexanedione instead of norcampo, the method of Example 1 was followed to obtain the title compound (11%, melting point of 240 ° C.).

¹ H-NMR (CDCl ₃ , 300 MHz, ∂): 2H, quin, 2.31 ppm; 4H, mt, 2.8-2.95 ppm; 2H, bs, 4.95 ppm; 1H, t, 7.29 ppm (J = 8.5 Hz); 1H, t, 7.64 ppm (J = 8.5 Hz); 1H, d, 7.74 ppm (J = 8.5 Hz); 1H, d, 8.2 ppm (J = 8.5 Hz).

Example 37

8-fluoro-9-amino-1,2,3,4-tetrahydroacridine

To a stirred solution of cyclohexanone (1.0 g, 10.0 mmol) in methylene chloride (10 ml) at -20 ° C was added a 1M solution of chloride of titanium (IV) in methylene chloride (20 ml). When the reaction mixture turned yellow, triethylamine (2.0 g, 20 mmol) and 2-amino-6-fluoro-benzonitrile (1.36 g. 10.0 mmol) in methylene chloride (30 ml) were added thereto. The color of the reaction mixture immediately darkened and it was allowed to warm up to room temperature (about 25 ° C.) and stirred further for 15 hours. At the end of this period the reaction mixture was treated with 12% aqueous NaOH solution (100 ml) and methylene chloride (100 ml). The reaction mixture was then filtered through a 2-inch diatomaceous earth pad (top surface Celite) and washed with methylene chloride (50 ml) and water (100 ml). The organic layer was separated and washed with water (1 × 30 ml) to dryness (anhydrous MgSO ₄ ). Removal of methylene chloride in vacuo gave an oil which was triturated with ether to give 218 mg (10%) of the title compound as a white solid. Melting point 175 캜.

Example 38

9-amino-8-methyl-1,2,3,4-tetrahydroacridine

The title compound was obtained in the same manner as in Example 37, except that 2-amino-6-methylbenzonitrile was used instead of 3-amino-60fluorobenzonitrile. 11%, Melting Point 143-145 ° C

Example 39

9-amino-8-chloro-1,2,3,4-tetrahydroacridine

Except for using 2-amino-6-chlorobenzonitrile instead of 2-amino-6-fluorobenzonitrile, the method of Example 37 was carried out as is, to obtain the title compound (23%, melting point of 144-145 ° C). Obtained.

Example 40

4-amino-5-fluoro-2,3-pentamethylenequinoline

Except for using cycloheptanone instead of cyclohexanone, the same procedure as in Example 37 was carried out to obtain the title compound (22%, melting point of 203 ° C).

Example 41

4-amino-5-chloro-2,3-pentamethylenequinoline

Except for using cycloheptanone instead of cyclohexanone and using 2-amino-6-chlorobenzonitrile instead of 2-amino-6-fluoro-benzonitrile, the method of Example 37 was carried out as is. Compound (11%, melting point 194-195 ° C.) was prepared.

Example 42

4-amino-5-fluoro-2,3-trimethylenequinoline

Except for using cyclopentanone instead of cyclohexanone, the method of Example 37 was followed to yield the title compound (6%, melting point of 179-181 ° C.).

Example 43

9-amino-8-chloro-4-oxo-1,2,3,4-tetrahydroacridine

Except for using 2-amino-6-chlorobenzonitrile instead of anthraninilnitrile, the procedure of Example 7 was followed to yield the title compound (15%, melting point of 205 ° C.).

Example 44

9-amino-8-methyl-4-oxa-1,2,3,4-tetrahydroacridine

Except for using 1-amino-6-methylbenzonitrile in place of anthranironitrile, the method of Example 7 was followed to yield the title compound (20%, melting point 177-179 ° C.).

_{^{1 H-NMR (CDC1 3,}} 300MHz, ∂): 1H, d, 7.56ppm (J = 7Hz): 1H, t, 7.31ppm (J = 7Hz):

1H, d, 6.95 ppm (J = 7 Hz); 2H, bs, 4.93 ppm; 2H, t, 4.29 ppm (J = 6 Hz); 3H, s, 2.89 ppm; 2H, t, 2.52 ppm (J = 6 Hz); 2H, m, 2.08-2.11 ppm.

Example 45

9-amino-8-methoxy-1,2,3,4-tetrahydroacridine

Except for using 2-amino-6-methoxybenzonitrile instead of 2-amino-6-fluorobenzonitrile, the method of Example 37 was carried out as is, and the title compound (14%, melting point: 187-188 ° C.) was obtained. Obtained.

Example 46

9-amino-8-methoxy-4-oxy-1,2,3,4-tetrahydroacridine

Except for using 2-amino-6-methoxybenzonitrile in place of anthraninilnitrile, the procedure of Example 7 was followed to yield the title compound (11%, melting point 205-207 ° C.).

_{^{1 H-NMR (CDC1 3,}} 300MHz, ∂): 2H, m, 7.33ppm: 1H, dd, 6.57ppm (J = 3.6Hz): 2H, bs, 5.92ppm: 2H, t, 4.29ppm (J = 1.6 Hz): 3H, s, 3.95 ppm: 2H, t, 2.5 ppm (J = 2.6 Hz): 2H, m, 2.13-2.07 ppm.

Example 47

The ability of the title compounds of Examples 1-16, 18, 26-29, and 35-46 to inhibit acetylcholinesterase in the brain was measured by spectrometry such as rat. GLEllman. (See Biochemical, Pharmacology, 7, 88 (1961).) All compounds showed IC ₅₀ (molar) values between 5 μM and 0.1 μM.

Claims (10)

The compound of formula (I) and a pharmaceutically acceptable salt thereof.

Wherein A is selected from the group consisting of the following general formulas (1), (2), (3), (4) and (5)

Wherein one of the CH residues at positions a, b, c and d of Formula (1) is substituted with a nitrogen atom, or each of the CH residues at positions a and d, a and c or b and d is nitrogen May be substituted with an atom): B is selected from the group consisting of the following general formulas (6), (7), (8), (9) and (10)

(Wherein, the dotted lines each represent an arbitrary double bond); R ¹ is hydrogen or C ₁ -C ₆ alkyl; R ³ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C _{6 al} Khan oil, di (C ₁ -C ₆ alkylamino) -C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl, halogen, hydroxy, nitro, phenyl, substituted phenyl, phenyl-C ₁ -C ₆ alkyl, substituted phenyl-C ₁ -C ₆ alkyl, diphenyl-C ₁ -C ₆ alkyl, where one or both of the phenyl groups are substituted, furyl-C ₁ -C ₆ alkyl, thienyl-C ₁ -C ₆ alkyl, phenyloxy, substituted phenyloxy, NHCOR ⁵ and NR ⁶ R ⁷ may be substituted with a) a is independently selected from the group consisting of, wherein the substituted phenyl and the phenyl moieties on the substituted phenylalkyl group is a halogen, C ₁ -C ₆ alkyl, trifluoromethyl, C ₁ - C ₆ alkoxy-C ₁ -C ₆ is substituted with one or more substituents selected from the group consisting of alkyl, hydroxy and nitro, wherein R ^5, R ⁶ and R ⁷ are C ₁ -C ₆ alkyl and C ₁ -C Independently selected from ₆ alkanes; R ² is the above for 1,4-dihydropyridyl-C ₁ -C ₆ alkanoyl, C ₁ -C ₆ alkyl-1,4-dihydropyridyl-C ₁ -C ₆ -alkanoyl and R ³ Are independently selected from the group consisting of definitions, provided that R ² cannot be hydroxy, halogen, C ¹ -C ⁶ alkoxy, phenyloxy or substituted phenyloxy; R ⁴ is independently selected from the above definitions for R ³ provided that R ⁴ is not halogen, nitro, NHCOR ⁵ or NR ⁶ R ⁷ ; n is 1,2 or 3; Z ¹ is NH, O, S or NR ⁸ , wherein R ⁸ is C ₁ -C ₆ alkyl or C ₁ -C ₆ alkanoyl; Z ² is O or S; Z ³ and Z ⁴ are independently selected from (CH ₂ ) _p , O, S, S═O and SO ₂ , provided that at least one of Z ³ and Z ⁴ is (CH ₂ ) _p ; Z ⁵ is CH ₂ , O. S, S═O or SO ₂ ; Z ⁶ is O, S, S = O or SO ₂ ; p is 1,2, or 3; q is 1 or 2 and Y ¹ is CH ₂ , CHOH, O, C═O, S, S═O or SO ₂ ; Y ² is CH ₂ , CH, O, S, S═O or SO ₂ ; And Y ³ is CHOH, CH ₂ , CH or C═O, provided that the group of formula (8) has a double bond only when both Y ² and Y ³ are CH, A is R ³ is hydrogen and a, b When one of the groups of formula (1) without nitrogen at position c or d or A is a group of formula (3) or (4), only one of Y ¹ and Y ² may be CH ₂ , and A is R ³ And a group of formula (1) without nitrogen in a, b, c or d positions, only one of Z ³ and Z ⁴ may be (CH ₂ ) _p . 2. A compound according to claim 1, wherein A is a group of formula (1) without nitrogen at the a, b, c or d position, or only one of Y ¹ and Y ² when A is a group of formula (3) or (4) This CH ₂ may be a compound. 3. A compound according to claim 1 or 2, wherein the compounds mentioned are those in which A is a group of formula (1) wherein one of the CH moieties at positions a and b of formula (1) is replaced by a nitrogen atom Or A is a group of general formula (3); B, R ¹ , R ² , R ³ , R ⁴ , Z ³ , Z ⁴ , Z ⁵ , Y ³ and q are as defined in claim 1; n is 1 or 2; Z ⁶ is S; p is 1 or 2, provided that (a) when A is a group of the general formula (1) without nitrogen at the a or b position, Z ³ is O, S or CH ₂ ; R ₄ is hydrogen or C ₁ -C ₆ alkyl; Z ⁴ is (CH ₂ ) _P (where p is 1 or 2) or S; Y ¹ is CH ₂ , C═O, O or S; Y _² CH ^2, O or S, and the only one of the stages, Y ¹ and Y ² are CH ₂ days; (b) when A is a group of formula (1) with nitrogen at the a or b position, Y ¹ is O, S or CH ₂ and Y ² is CH ₂ ; And (c) when A is a group of formula (3), Y ¹ is selected from the group consisting of a compound of formula (I) and pharmaceutically acceptable salts thereof, wherein Y ¹ is O or S and Y ² is CH ₂ Compound made into. The compound according to any one of claims 1 to 3, wherein B is a group of formula (7) or (8). The compound of claim 4, wherein R ¹ , R ² and R ⁴ are hydrogen and R ³ is hydrogen or halogen. The method of claim 1 wherein, A is a group of formula (1) (wherein R ³ is as defined above for formula (Ⅰ), but R ³ may be present Evan c position of the general formula (1)) and , R ¹ , R ² and B are as defined in claim 1. The compound of claim 1, wherein A is a group of formula (1) wherein R ³ is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, hydroxy, nitoro, NHCOR ⁵ , NR ⁶ R ⁷ or Trifluoromethyl, and R ⁵ , R ⁶ and R ⁷ are as defined in claim 1; B is a general formula

A compound that is a group of r wherein r is 2, 3 or 4. The compound according to claim 1, wherein the compound mentioned is 8-fluoro-9-amino-1,2,3,4-tetrahydroacridine or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising the compound of claim 1. A compound according to claim 1 for the treatment of Alzheimer's disease.