WO1991001974A1

WO1991001974A1 - Acridine derivatives

Info

Publication number: WO1991001974A1
Application number: PCT/GB1990/001187
Authority: WO
Inventors: Oswald Morton; George Thomas Baxter Frost
Original assignee: Trifree Limited
Priority date: 1989-08-01
Filing date: 1990-07-31
Publication date: 1991-02-21
Also published as: NZ234731A; IL95246A0; AU6047290A; ZA906004B; AU652719B2; GB8917568D0; CA2064736A1; IE902764A1; EP0485419A1

Abstract

The present invention relates to compounds comprising a 1,2,3,4-tetrahydroacridinyl group coupled via an ester functionality to a dimethylaminoethyl group, and the acid addition salts thereof, and to processes for their preparation and pharmaceutical composition containing them. The compounds are suitable for use in the treatment of Alzheimer's Disease or other conditions related to cholinergic dysfunction.

Description

ACRIDINE DERIVATIVES

The present invention relates to novel acridine derivatives, processes for their preparation and

pharmaceutical compositions containing them.

There are a number of neurological and mental illnesses whose clinical manifestations are thought to be due, at least in part, to a malfunction within certain acetylcholine (AcCh) neurotransmitter systems of the brain. Such conditions include Alzheimer's disease, Huntingdon's Chorea, tardive diskinesia, hyperkinesia, mania and Tourette's syndrome.

The most common of these disorders is Alzheimer's disease, a slow progressive condition in which brain function gradually declines and which is characterised by a marked deterioration in the cognitive functions of the brain, most notably memory, followed eventually by death from debilitating disease, generally in 6 to 12 years.

A deficit in the cholinergic system in the

Alzheimer brain is now well established, a specific degeneration of cholinergic neurons and a reduction in the activity of choline acetyl transferase (CAT) having been demonstrated.

CAT is the enzyme responsible for the synthesis of AcCh and the diminished AcCh levels may be further reduced by the action of choline esterases within the brain. Post-synaptic AcCh receptor sites are however generally preserved and may be susceptible to

stimulation by exogenous AcCh agonists. Thus the cholinergic system is open to modification in a number of ways, making available a number of options for the treatment of Alzheimer's Disease.

For example, AcCh precursor treatment, analogous to the effective use of L-dopa in the treatment of

Parkinson's disease, was the first approach to be tried, although so far only limited success has been reported in studies using lecithin or choline chloride.

In a different approach, a number of centrally acting AcCh receptor agonists have been reported. EP-A-126654 for example describes novel

tetrahydroisoxazolo[4,5-c] pyridine derivatives capable of penetrating the blood brain barrier (BBB) and

exhibiting potent AcCh agonist activity. Similarly EP-A-239309 describes novel oxadiazole derivatives which are potent AcCh agonists and have good CNS

penetrability.

It is clear from such studies that for an agonist to be of any value in the treatment of Alzheimer's disease it must be able to penetrate the BBB following peripheral, e.g. oral, administration and be stable within the brain. These requirements have imposed a severe limitation on the number of useful compounds and this approach has not been as successful as had

originally been hoped.

As an alternative, rather than trying to mimic the action of AcCh, attempts have been made to maintain the reduced concentrations of AcCh already present within the Alzheimer brain by administration of centrally- acting anticholinesterase drugs, and this has proved to be the most successful strategy to date. A number of anticholinesterases are known, for example physostigmine and neostigmine. More recently, encouraging results have been reported for tacrine, (1,2,3,4-tetrahydro-9-amino acridine), particularly in the early stages of the disease. However tacrine has been shown to be

hepatotoxic and at higher doses it may exhibit unwanted peripherally-mediated cholinergic side effects such as gastro-intestinal tract disturbance or hypotension. As a result caution has been urged in the use of tacrine in the long-term treatment of Alzheimer's disease.

Thus there exists a need for more effective and/or safer treatment for Alzheimer's disease and other diseases related to cholinergic dysfunction.

We now propose the use of certain novel 1,2,3,4-tetrahydroacridine derivatives as inhibitors of acetylcholine esterase activity and as AcCh agonists and thus for use in the treatment of Alzheimer's and related conditions.

Thus, according to one aspect the present invention provides a compound comprising a 1,2,3,4-tetrahydroacridinyl group coupled via an ester

functionality to a dimethylaminoethyl group, and the acid addition salts thereof.

Preferred compounds of the invention include those of formula I

[wherein Y at at least one of positions 1 to 8

represents a hydrogen atom or a C_1-4 straight or branched alkyl or alkenyl group; and X which is bonded to a ring carbon of the tricyclic 1,2,3,4-tetrahydroacridinyl group represents a bond, a group -N(R¹)R²- (in which R¹ represents a hydrogen atom or a group -R²- COOCH₂CH₂N(CH₃)₂, and each R² which may be the same or different represents a bond or a divalent organic group, for example a straight or branched C_1-8 alkylene chain optionally interrupted by a phenylene group),

or a group -NH-CO-R²

(in which R is as hereinbefore defined) ] and the acid addition salts thereof.

Especially preferred compounds according to the invention include those where the tetrahydroacridinyl group is unsubstituted by groups Y which are other than hydrogen, or is mono-, di-, tri- or tetra- substituted by methyl groups at positions, 1-,4-,5- or 8-; and

X is a bond at position 4- or 9-, or

X is a group

(wherein each R² which may be the same or different, is a C_1-4 alkylene group) or a group

-NH-CO-R²- (wherein R² is a bond or a C_1-4 alkylene group), bonded at position 9 of the tetrahydroacridinyl group, and the salts thereof .

Particularly preferably, the tetrahydroacridinyl group is unsubstituted by non-hydrogen Y groups or is mono-substituted by a methyl group at position 4; and

X is a bond or a group or -NH-CO- at

position 9.

Further preferred compounds according to the invention include those of formula lb

(wherein Y¹ at at least one of positions 1 to 8

represents a hydrogen atom or an amino or nitro group, or a C_1-4 straight or branched alkyl or alkenyl group or at positions 1 to 4 represents an oxo group or at position 9 represents a C_1-4 alkanoylamino (preferably acetylamino) group; and

X¹ which is attached to a ring carbon of the tricyclic 1,2,3,4-tetrahydroacridinyl group (especially the 1, 4 or 9 position) represents a bond or a C_1-12 mono or polyazaalkylene group optionally substituted by C_1-4 alkyl, amino or C_1-4 alkylamino groups and, at carbons adjacent aza nitrogens by oxo, imino or C_1-4 alkylimino groups) and the acid addition salts thereof.

In formula lb, X¹ preferably represents a bond or a group of formula

(where n is an integer of 0 to 4 (preferably 0 or 1 in the (CH₂)_n moiety bonded to the tricyclic moiety and preferably 1,2 or 3 in the other (CH₂)_n moiety);

y is 0 or 1; and

R³ is hydrogen or C_1-4 alkyl, preferably methyl),

-CO-NR₃- (CH₂) _n-NR³-CO- (CH₂) _n- or

(where R³ and n are as defined above and where a carbonyl group of X¹ is bonded to the tricyclic moiety),

and Y¹ preferably represents a hydrogen atom, an

acetylamino group in the 9-position or an oxo group in the 1-position.

Particularly preferred compounds of formula lb include those of formulae Ic, Id and Ie

(where Y" is hydrogen or C_1-4 alkanoylamino, especially acetylamino; n' is 1 to 3, especially 2; and Y"' is hydrogen or oxo, especially oxo).

Especially preferred compounds according to the invention include compounds of formulae If and Ig

(where n' is 1 to 3 , especially 2) and acid addition salts thereof, especially hydrochloride salts or salts with weak organic acids such as the citrate, tartrate and, particularly, the ascorbate salts.

Particularly preferred compounds of the invention include:

4-OXO-4- (1,2,3,4-tetrahydroacridine-5-amino)butanoic acid-β-dimethylaminoethyl ester;

1,2,3,4,-tet.rahydroacridine-9-carboxylic acid,

dimethylaminoethyl ester;

4-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid, dimethylaminoethyl ester; and 9- (2 , 5-diaza-12-dimethylamino-10-oxa-1,6,9-trioxo-dodecyl)-1,2,3,4-tetrahydroacridine; and the salts thereof. Viewed from a further aspect, the present invention provides a process for the preparation of a compound of formula I or lb which process comprises at least one of the following steps: (a) reacting a compound of formula II

(wherein Y² is as hereinbefore defined for Y or Y ' , Hal is a leaving group, for example a hydroxyl group, a halogen atom or an ethoxy group and X² is as hereinbefore defined for X or X¹ but where CO-Hal is attached to a nitrogen that nitrogen may carry a further CO-Hal group, e.g. X² may represent a bond, a group -NH-R²-, -NH-CO-R²- or a group -N(R²COHal) R²-)

with 2-dimethylamino-ethanol; condensing a compound of formula III

(where R⁶ is an amino, optionally activated

carboxylic acid or aminoalkylcarboxamide group) with a compound of formula VIII

(CH₃)₂ N C₂H₄ OOC X³ - R⁸ (VIII)

(where X³ is a C_1-12 alkylene group optionally

interrupted by phenylene or aza groups and

optionally substituted by alkyl, oxo, amino,

alkylamino, imino or alkylimino groups; and R⁸ is an amino or alkylamino group where R⁶ is an optionally activated carboxylic acid group or R⁸ is an

optionally activated carboxylic acid group where R⁶ activated carboxylic acid group or R⁸ is an

optionally activated carboxylic acid group where R⁶ is an amino or aminoalkylcarboxamide group); c) (to produce a compound of formula lb wherein Y¹ is amino) reducing a compound of formula lb wherein Y¹ is nitro, e.g. with sodium dithionate; and d) converting a compound of formula I or lb into an acid addition salt thereof, particularly a

physiologically acceptable acid addition salt thereof with organic or inorganic acids.

The reaction of step (a) is conveniently carried out in a solvent or mixture of solvents such as benzene, acetone, diethylether, methylformamide, tetrahydrofuran at temperatures up to the boiling point of the mixture, preferably at ambient temperature.

The compounds of formula I or lb obtained may also be converted into the acid addition salts, thereof particularly into physiologically acceptable organic or inorganic acid addition salts. Suitable acids include, for example, hydrochloric, hydrobromic, sulphuric, phosphoric, acetic, lactic, citric, tartaric, succinic, maleic, fumaric and, particularly, ascorbic acids.

The compounds used as starting materials are known from the literature in some cases or may be obtained using methods known per se.

Thus for example a starting compound of formula II may be obtained by reacting a corresponding 1,2,3,4-tetrahydroacridine carboxylic acid with oxalyl- or thionyl chloride, the corresponding acid which is itself required for this being obtained by reacting a suitably substituted isatin (indole-2,3-dione) derivative with a suitably substituted cyclohexanone following known procedures, for example such as those described by

Sandmeyer (Helv. Chim. Acta, 1919, 2 , 234-42) and by Martinet and Coisset (Compt. Rend., 1921, 172, 1234-6).

The corresponding carboxylic acids referred to above are either known compounds or may be produced by standard techniques, e.g. by reaction of a corresponding 1,2,3,4-tetrahydroacridinyl amine, optionally after partial protection of the amine group, with a

glyconitrile, a cyclic acid anhydride or with a halo carboxylic acid e.g. an α- or ω- halo carboxylic acid. The carboxymethyl amides may thus be produced using formaldehyde, potassium cyanide and a 1,2,3,4-tetrahydroacridine amine (e.g. tacrine) using the method of Roscoe-Smith et al. J. Organic Chemistry 14 (1949) 355-361. Where in formula I X represents a group NR¹R²- in which R² is a bond, a starting material of formula II in which Hal is an ethoxy group may be obtained by reacting a 1,2,3,4-tetrahydroacridinyl amine with ethyl

chloroformate (CH₃CH₂OOCCl) . Alternatively it may be possible to reach the end product directly by reaction of the amine with dimethylaminoethyl chloroformate.

Where an amine is used as a starting product there may be several by-products formed and the desired intermediate or end product may be isolated from the byproducts by chromatography.

Particularly preferably the compounds of the invention are prepared from 9-amino or 9-carboxylic acid reagents of formula IIlb

(where R⁶ is an amino, carboxylic acid or carboxylic acid amide, especially aminoethylcarboxamide, group) for example as described below.

The compounds of formula Illb where R⁶ is a

carboxylic acid or amide group are novel and such compounds and their salts from a further aspect of the invention. These novel compounds of formula Illb may be prepared by reaction of an isatin compound of formula IV with a cyclohexanone compound of formula V

(where one of Y³ and Y⁴ is a group Y² or a protected Y² group and the other is hydrogen or a group Y² or a protected Y² group) in the presence of an alkali or an amine (especially an alkyldiamine or a diaminoalkanoic acid, e.g. ethylene diamine or L-arginine), and

subsequently if necesary removing any protecting group used.

The amine used is conveniently one of formula VI or

VII

HNR³-(CH₂)_n-NR³H (VI)

HNR³-(CHR⁷)_n COOH (VII)

(where each R⁷ is independently a hydrogen atom or a NR³ or protected NR³ ₂ group). The starting material of formula VIII used in step (b) may be prepared by condensing dimethylaminoethanol with an aminocarboxylic acid or a dicarboxylic acid, preferably in an activated form, e.g. the anhydride. A particularly preferred compound, dimethylaminoethyl hemi succinate may be prepared by reaction of

dimethylamihoethanol with succinic anhydride.

In the reactions to produce the compounds of the invention, if protecting group are used those should of course be subsequently removed.

As previously mentioned, the compounds of formula I and lb and the physiologically acceptable acid addition salts thereof have valuable pharmacological properties, particularly as cholinesterase inhibitors or AcCh agonists.

Thus viewed from a still further aspect the present invention provides a pharmaceutical composition

comprising a compound of formula I or lb or a

physiologically acceptable acid addition salt thereof, together with at least one pharmaceutical carrier or excipient.

In view of their pharmacological properties, the compounds according to the invention are suitable for the treatment of Alzheimer's disease and other diseases related to cholinergic dysfunction.

Thus, viewed from a yet further aspect the present invention provides a method of treatment of the human or non-human animal, preferably mammalian, body to combat Alzheimer's disease or other cholinergic dysfunction related conditions, said method comprising administering to said body a compound of formula I or lb or a

physiologically acceptable acid addition salt thereof. Furthermore, in a yet still further aspect of the invention there is provided use of a compound of formula I or lb or a physiologically acceptable acid addition salt thereof for the manufacture of a therapeutic agent for use in the treatment of Alzheimer's disease or other cholinergic dysfunction related conditions.

The dosage required to achieve this effect is conveniently 0.01 to 10 mg/kg body weight, preferably 2-8 mg/kg body weight, more preferably 4-6 mg/kg body weight, e.g administered orally, parentally or rectally 1 to 4 times a day.

The compounds of the invention may be incorporated, optionally together with other active substances, with one or more conventional carriers and/or diluents e.g.with cornstarch, lactose, glucose, magnesium ,

polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol,

water/polyethyleneglycol, propyleneglycol,

carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof to produce conventional galenic preparations such as tablets, coated tablets, capsules, powders, suspensions, drops, ampoules, syrups or suppositories.

The following non-limiting examples are provided to illustrate the invention (all percentages and ratios are by weight unless otherwise specified).

EXAMPLES

Intermediate 1 4,7-Dimethylisatin

To 15.77g (1.0 mol) 2,5-dimethylaniline hydrochloride in 150ml of water, 6.95g (0.1 mol) hydroxylamine

hydrochloride was added and the solution was brought to boiling. 16.54g (0.1 mol) Chloral hydrate in 130ml of water was added in small aliquots and boiling was maintained for 10 minutes after the final addition; the 2,5-dimethyl-isonitrosoacetanilide separated out on cooling, mp 150ºC. On heating this compound with 70g sulphuric acid (98%) at 80ºC for 15 minutes, followed by cooling and the addition of an excess of ice and water, 4,7-dimethylisatin precipitated as an orange-yellow product, mp 250ºC.

Intermediate 2 1,2,3,4-Tetrahydroacridine-9-carboxylic acid

Isatin (14.7g, 0.1 mol) dissolved in 30% aqueous

potassium hydroxide (60ml) was added to an excess of cyclohexanone (30g, 0.3 mol) dissolved in ethanol

(120ml) and the mixture was refluxed for 12 hours. The cooled reaction product was transferred to a rotary evaporator to remove most of the ethanol, then diluted with water and the solution filtered by gravity. The filtrate was treated with acetic acid until a

considerable excess was present and the technically pure product which crystallized out was filtered off and washed with a little ethanol to remove residual

cyclohexanone. Yield 88%: recrystallization from boiling ethanol gave a product melting with

effervescence at 283-285ºC.

Intermediate 3

1,2,3,4-Tetrahydroacridine-9-carbonyl chloride

Oxalyl chloride (12.70g, 0.10 mol) was dissolved in anhydrous benzene (40ml) in a flask fitted with a condenser and moisture trap and a magnetic stirring system. 1,2,3,4-Tetrahydroacridine-9-carboxylic acid (4.58g, 0.02 mol) was added in small aliquots over about 15 minutes followed by heating to gentle reflux until most of the solid had dissolved; the liquid was filtered through a dry sinter and any residue washed with

aliquots of benzene (2× 20ml). The reaction mixture was evaporated to dryness on a rotary evaporator and two aliquots of benzene (30ml) were added and distilled off to remove traces of oxalyl chloride.

Intermediate 4

1,2,3,4-Tetrahvdro-5,8-dimethyl-acridine-9-carbonyl chloride

This is obtained analogously to the compound of

Intermediate 3 from the compound of Intermediate 1.

Using methyl and dimethyl cyclohexanones, the 1,5,8-trimethyl, 4,5,8-trimithyl and 1,4,5,8-tetramethyl analogues of the title compound may be obtained.

Intermediate 5 Dimethylaminoethyl hemisuccinate

Succinic anhydride (20. Og, 0.2 mol) was weighed into a suitable container with stirring facilities and N,N'-dimethylaminoethanol (18.72g, 0.21 mol) was added. The exotherm generated by the addition of the amine was maintained using a water bath held at 70-80ºC and maintaining the reaction system under anhydrous

conditions. On cooling, the almost colourless

crystalline mush was treated with dry diethyl ether to remove unreacted dimethylaminoethanol and the

hemisuccinate was exposed to a stream of dry air to remove solvent, then dried in vacuum over phosphorus pentoxide.

Intermediate 6

1,2,3,4-Tetrahydroacridine-9-aminoethylcarboxamide

Isatin (16.8g, 0.11 mol) was weighed into a suitable flask fitted with reflux condenser and stirrer.

Cyclohexanone (33g, 0.34 mol) was added, followed by water (25ml) and ethanol (25ml). With adequate

stirring, ethylenediamine (20ml, 0.30 mol) was added over one minute. The exotherm produced was augmented by heating to gentle reflux for 12 hours. The cold

contents of the flask were filtered on a Whatman No. 50 paper and the solid was carefully washed with small aliquots of 50% ethanol to remove most of the colour, with a final wash with 2 × 10ml methanol. The product was dried in a stream of nitrogen and finally held in a vacuum desiccator over phosphorus pentoxide.

Intermediate 7 1,2,3,4-Tetrahydroacridine-9-arginylcarboxamide

Isatin (4.6g, 0.2 mol) was weighed into a suitable flask fitted with reflux condenser and stirrer. L-arginine, free amino acid, (7.0g, 0.40 mol) and

cyclohexanone (10.0g, 0.10 mol) were added, followed by ethanol (20ml) and water (10ml). Heating and stirring were applied and the flask contents developed a purple colouration. Heating was continued for 10 hours, when the colour had changed, with the formation of an off-white precipitate. Heating was stopped and water (60ml) was added, with continual stirring. The product, which was rather sticky, was dissolved in warm methanol (180ml), treated with activated charcoal to remove most of the colour, evaporated on a Buchi Rotovapor and triturated with dry diethylether to give an off-white friable powder. (3.9g, 33% based on isatin).

Intermediate 8

5-Nitroisatin Isatin (14.7g, 0.1 mol) was dissolved in

concentrated sulphuric acid in a suitable container held in an ice-bath. Nitric acid (70%, 8.1g) was added at 0ºC dropwise, with stirring and the mixture was stirred for 40 minutes. The mixture was poured onto cracked ice (700g) with stirring. The solid precipitate was

filtered on a glass sinter and washed with water until the pH of the effluent was ca pH 6. The crude product was dried in vacuum over anhydrous calcium chloride and recrystallized from 50% aqueous methanol. Yield 17.6g (92%), m.p. 254-255ºC.

Intermediate 9

7-nitro-1,2,3,4-tetrahydroacridine-9-carboxylic acid

This is obtained analogously to the compound of Intermediate 2 from the compound of Intermediate 8.

Intermediate 10

9-amino-1,2,3,4-tetrahydroacridine (Tacrine)

Anthranilonitrile (2-aminobenzonitrile) (23.63g, 0.2 mol) was heated in an excess of cyclohexanone containing anhydrous zinc chloride (27.26g, 0.2 mol) to reflux. A complex of the 9-amino-1,2,3,4-tetrahydroacridine separated within 10 to 15 minutes. On cooling this 1:1 complex was filtered off and sucked dry on a Buchner funnel. The complex was then dispersed in water and treated with a slight excess of sodium hydroxide and the product extracted into benzene from which the product was obtained on evaporation. Yield 35.6g (90%) m.p.

182-184ºC. TLC shows one major spot, one minor (ca 1%) solvent system: chloroform: methanol: 4:1.

Intermediate 11

3-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid

Isatin (14.7g, 0.1 mol) was dissolved in a solution of potassium hydroxide (18g, 0.32 mol) in water (60ml) contained in a suitable vessel fitted with a reflux condenser and stirring facilities. The mixture was brought to reflux and heating and stirring was contained for 12 hours. When cold, the reaction mixture was evaporated to remove ethanol then acetic acid was added to pH ca. 2.0. The free carboxylic acid separated as beige powder which was filtered off, washed well with water and sucked dry. It was carefully washed with cold methanol, which removed some colour giving an off-white powder, after finally heating with ethanol (50ml) followed by filtrate and drying in vacuum over

phosphorous pentoxide.

Example 1 1,2,3,4-Tetrahydroacridine-9-carboxylic acid,

dimethylaminoethyl ester, hydrochloride

1,2,3,4-Tetrahydroacridine-9-carbonyl chloride (4.58g) (Intermediate 3) was dissolved in anhydrous benzene (60ml) and treated dropwise with a solution of dimethyl- aminoethanol (3.75g, 0.04 mol) in anhydrous benzene (60ml). The mixture was left at ambient temperature for 12 hours, with occasional stirring, then evaporated to dryness on a rotary evaporator. The title compound

obtained as the hydrochloride, was soluble in water. Example 2

1,2,3,4-Tetrahydro-5,8-dimethyl-acridine-9-carboxylic acid, dimethylaminoethyl ester This is obtained analogously to the compound of Example 1 using the compound of Intermediate 4.

Example 3 4-Oxo-4-(1,2,3,4-tetrahvdroacridine-9-amino)butanoic acid β-dimethylaminoethyl ester (hydrochloride salt)

Dimethylaminoethyl hemisuccinate (1.89g, 0.01 mol)

(Intermediate 5) previously dried over phosphorus pentoxide was weighed into a suitable container and

N,N'-carbonyldiimidazole (1.62g, 0.01 mol) was added, followed by dry dichloromethane (50ml) . The contents of the container were stirred, using a magnetic stirring bar, under anhydrous conditions. A rapid evolution of CO₂ followed by the rapid formation of a clear solution signified the formation of the active intermediate imidazolide. At this point, 1,2,3,4-tetrahydro-9-aminoacridine (1.98g, 0.01 mol), thoroughly dried, was added to the contents of the flask and stirring was continued for ten hours. During this period the amine dissolved slowly and a crystalline precipitate of imidazole formed, which was removed by filtration at the end of the reaction. The filtrate was evaporated to near dryness and the product was isolated by the addition of dry diethylether. No attempt was made to isolate the amine, which was neutralized with 2M

hydrochloric acid, diluted with water, treated with activated carbon, filtered and evaporated to dryness and crystallised from acetone.

Example 4

1,2,3,4-Tetrahydroacridine-9-carboxylic acid,

dimethylaminoethyl ester (citrate salt)

1,2,3,4-Tetrahydroacridine-9-carboxylic acid (1.14g, 0.005 mol) (Intermediate 2) was weighed into a suitable dry flask fitted with a stirrer and reflux condenser and N,N'-carbonyldiimidazole (0.81g, 0.005 mol) was added, followed by dry dichloromethane (20 ml). The contents of the flask were stirred well and the solids slowly dissolved with liberation of CO₂. Stirring was continued for ten minutes then N,N'-dimethylethanolamine (1.00g, 0.011 mol) was added and stirring was continued at ambient temperature. After 30 minutes, the contents of the flask were brought to reflux temperature and held there for six hours. The reaction stood overnight and the white precipitate of imidazole was filtered off and the filtrate was evaporated to remove volatiles to yield an oily liquid which was treated with diethyl ether (25ml) and left overnight. The ether layer was decanted and the off-white crystalline product was treated with further ether (15ml) and the product was filtered off. The compound was neutralized with citric acid in aqueous solution, treated with activated carbon, filtered and evaporated on a Buchi Rotovapor to crystallize. The final product was off-white.

Example 5 9-(8-Amino-2,4-diaza-3-imino-12-dimethylamino-10-oxa-1,9-dioxo)-1,2,3,4-tetrahydrocridine

1,2,3,4-tetrahydroacridine-9-arginylcarboxamide (Intermediate 7) is acetylated using acetic anhydride and the resulting product is esterified with

dimethylamino-ethanol in the presence of N,N'-carboxyldiimidazole, analogously to Example 4.

Example 6

7-nitro-1,2,3,4-tetrahydroacridine-9-carboxylic acid, dimethylaminoethyl ester

This is obtained analogously to the compound of Example 4 using 7-nitro-1,2,3,4-tetrahydroacridine-9-carboxylic acid (Intermediate 9). Example 7

7-amino-1,2,3,4-tetrahydroacridine-9-carboxylic acid , dimethylaminoethyl ester This is obtained by reducing the nitro group of the compound of Example 6 using sodium dithionite.

Example 8 1,2,3,4-tetrahydroacridine-9-carboxylic acid,

2(dimethylamino)ethyl ester

1,2,3,4-tetrahydroacridine-9-aminoethylcarboxamide

(Intermediate 6) (2.6g, 0.01 mol) was weighed into a suitable flask fitted with a stirrer and reflux

condenser and 2 (dimethylamino) ethyl acrylate (l.60g, 0.011 mol) added together with ethanol (120ml).

Stirring was started and the flask contents were heated to 70-80ºC and held in this range for one hour. A red colour developed and the solid dissolved to form a clear solution. Heating was stopped and the flask contents were stirred for 4-5 days. The solution was treated with activated charcoal, filtered and the lightly coloured filtrate was evaporated to remove all solvent leaving the little compound. This may subsequently be converted to any desired salt form.

Example 9

3-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid, dimethylaminoethyl ester

This is obtained analogously to the compound of Example 4 using the compound of Intermediate 11.

Formulation Example I

Tablets containing 15 mg of 1,2,3,4-tetrahydroacridine-9-carboxylic acid, dimethylaminoethyl ester (Citrate salt)

Each tablet contains:

Active substance 15 mg

Powdered lactose 84 mg

Corn starch 40 mg

Colloidal silica 10 mg

Polyvinylpyrrolidone 10 mg

Magnesium stearate 1 mg

160 mg

Formulation Example II

Ampoules containing 5 mg of 1,2,3,4-tetrahydroacridine-9-carboxylic acid, dimethylaminoethyl ester,

(hydrochloride salt) per 5ml 5 mg of active substance is dissolved in water up to a volume of 5 ml. After sterilising by filtration the solution is transferred into suitable ampoules and sterilised.

Claims

1. A compound comprising a 1,2,3,4-tetrahydroacridinyl group coupled via an ester functionality to a

dimethylaminoethyl group, or an acid addition salt thereof.

2. A compound as claimed in claim 1 being a compound of formula I

[wherein Y at at least one of positions 1 to 8

represents a hydrogen atom, or an amino or a nitro group or a C_1-4 straight or branched alkyl or alkenyl group; and X which is bonded to a ring carbon of the tricyclic 1,2,3,4-tetrahydroacridinyl group represents a bond, a group -N(R¹)R²- (in which R¹ represents a hydrogen atom or a group -R²-COOCH₂CH₂N(CH₃)₂, and each R² which may be the same or different represents a bond or a divalent organic group) or a group -NH-CO-R² (in which R² is as hereinbefore defined)] or an acid addition salt thereof.

3. A compound as claimed in claim 2 wherein the tetrahydroacridinyl group is unsubstituted by groups Y which represent other than hydrogen, or is mono-, di-, tri- or tetra- substituted by methyl groups at

positions, 1-,4-,5- or 8-; and

X is a bond at position 4- or 9-, or X is a group

(wherein each R² which may be the same or different, is a C_1-4 alkylene group) or a group -NH-CO-R²- (wherein R² is a bond or a C_1-4 alkylene group), bonded at position 9 of the tetrahydroacridinyl group, or an acid addition salt thereof.

4. A compound as claimed in claim 1 being a compound of formula lb

(wherein Y¹ at at least one of positions 1 to 8

represents a hydrogen atom or a C_1-4 straight or branched alkyl or alkenyl group or at positions 1 to 4 represents an oxo group or at position 9 represents a C_1-4

alkanoylamino group; and

X¹ which is attached to a ring carbon of the tricyclic 1,2,3,4-tetrahydroacridinyl group represents a bond or a C_1-12 mono or polyazaalkylene group optionally substituted by C_1-4 alkyl, amino or C_1-4 alkylamino groups and, at carbons adjacent aza nitrogens by oxo, imino or C_1-4 alkylimino groups) or an acid addition salt thereof.

5. A compound as claimed in claim 4 wherein X¹

represents a bond or a group of formula

(where n is an integer of 0 to 4

y is 0 or 1; and

R³ is hydrogen or C_1-4 alkyl),

-CO-NR₃- (CH₂) _n-NR³-CO- (CH₂) _n- or

and Y¹ represents a hydrogen atom, an acetylamino group in the 9-position or an oxo group in the 1-position, or an acid addition salt thereof.

6. A compound as claimed in claim 1 being a compound of formula Ic, Id, Ie, If or Ig

(where Y" is hydrogen or C_1-4 alkanoylamino, n' is 1 to 3; and Y"' is hydrogen or oxo) or an acid addition salt thereof.

7. A compound as claimed in claim 6 being

4-oxo-4-(1,2,3,4-tetrahydroacridine-5-amino)butanoic acid-β-dimethylaminoethyl ester;

1,2,3,4,-tetrahydroacridine-9-carboxylic acid,

dimethylaminoethyl ester;

4-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid, dimethylaminoethyl ester; or

9-(2,5-diaza-12-dimethylamino-10-oxa-1,6,9-trioxo- dodecyl)-1,2,3,4-tetrahydroacridine; or an acid addition salt thereof.

8. A process for the preparation of a compound of formula I or lb which process comprises at least one of the following steps:

(a) reacting a compound of formula II

(wherein Y² is as defined in any one of claims 1 to 7 for Y or Y¹ , Hal is a displaceable leaving group, and X² is as defined in any one of claims 1 to 7 for X or X¹ but where CO-Hal is attached to a nitrogen that nitrogen may carry a further CO-Hal group) with 2-dimethylamino-ethanol;

(b) condensing a compound of formula III

(where R⁶ is an amino, optionally activated

carboxylic acid or aminoalkylcarboxamide group) with a compound of formula VIII

(CH₃) ₂NC₂H₄OOC-X³-R⁸ (VIII)

(where X³ is a C_1-12 alkylene group optionally interrupted by phenylene or aza groups and

optionally substituted by alkyl, oxo, amino, alkylamino, imino or alkylimino groups; and R⁸ is an amino or alkylamino group where R⁶ is an optionally activated carboxylic acid group or R⁸ is an

optionally activated carboxylic acid group where R⁶ is an amino or aminoalkylcarboxamide group);

(c) (to produce a compound of formula lb wherein Y¹ is amino) reducing a compound of formula lb wherein Y¹ is nitro;

(d) converting a compound of formula I or lb into an acid addition salt thereof, particularly a

9. A process as claimed in claim 10 wherein said amine of formula VIII is prepared by condensing

dimethylaminoethanol with an aminocarboxylic acid or a dicarboxylic acid.

10. An intermediate compound of formula Illb

(where R⁶ represents a carboxylic acid or carboxylic acid amide group and Y² is as defined in claim 8) or a salt thereof.

11. A process for the preparation of a compound of formula Illb which process comprises reacting an isatin compound of formula IV with a cyclohexanone compound of formula V

(where one of Y³ and Y⁴ is a group Y² or a protected Y² group and the other is hydrogen or a group Y² or a protected Y² group and Y² is as defined in claim 8) in the presence of an alkali or an amine, and subsequently if necessary removing any protecting group used.

12. A process as claimed in claim 11 wherein said amine is one of formula VI or VII

HNR³-(CH₂)_n-NR³H (VI)

HNR³-(CHR⁷)_n COOH (VII) (where each R⁷ is independently a hydrogen atom or a NR³ or protected NR³, group and R³ is as defined in claim 5).

13. A pharmaceutical composition comprising a compound of formula I or lb (as defined in any one of claims 1 to 7) or a physiologically acceptable acid addition salt thereof, together with at least one pharmaceutical carrier or excipient.

14. A method of treatment of the human or non-human animal body to combat Alzheimer's disease or other cholinergic dysfunction related conditions, said method comprising administering to said body a compound of formula I or Ib or a physiologically acceptable acid addition salt thereof.

15. Use of a compound of formula I or Ib or a

physiologically acceptable acid addition salt thereof for the manufacture of a therapeutic agent for use in the treatment of Alzheimer's disease or other

cholinergic dysfunction related conditions.