HU209674B - Apparatus for burning fat, mainly of animal origin - Google Patents

Abstract

The present invention relates to a compound of formula (I): wherein X is hydrogen or halogen, R is hydrogen, benzyl or alkanoyl of 2 to 12 carbon atoms, with the proviso that OR may not be at the 1-position of the ring system and R1 and \ t R 2 is hydrogen or R 1 and R 2 together form = CH-NR 3 R 4, wherein R 3 and R 4 are independently C 1-6 alkyl and are pharmaceutically acceptable acid addition salts thereof. The compounds of formula (I) are also used as active ingredients of pharmaceutical compositions which are acetylcholinesterase inhibitors. EN 208 674 B

Description

The present invention relates to a process for the preparation of compounds of the formula I wherein

X is hydrogen or halogen,

R is hydrogen, benzyl or C 2 -C 12 alkanoyl, with the proviso that OR cannot be in position 1 of the ring system and

Ri and _R2 are hydrogen, or

R 1 and R ₂ together form = CH-NR ₃ R ₄ , wherein R ₃ and R ₄ are each independently C 1 -C 6 alkyl and the pharmaceutically acceptable acid addition salts thereof. The compounds of formula (I) are also used as active ingredients in pharmaceutical compositions which are acetylcholinesterase inhibitors.

HU 208 674 B

HU 208,674 Β

This invention relates to hydroxy-1,2,3,4-tetrahydroaminoacridines and to pharmaceutical compositions containing them. The compounds of formula I according to the invention are prepared wherein X is hydrogen or halogen.

R is hydrogen, benzyl or C2-C12 alkanoyl, provided that

The OR group cannot be in position 1 of the ring system and

R 1 and R _{2 are} hydrogen, or

R 1 and R _{2 taken} together may form = CH-NR ₃ R ₄ wherein

R ₃ and R ₄ are each independently C 1-4 alkyl.

The compounds of formula I are useful in the treatment of various memory disorders characterized by reduced cholinergic function, such as Alzheimer's disease.

Compounds of formula (I) include stereochemically and optically active isomers, where such isomers are present, and addition salts and solvates, such as hydrates, of pharmaceutically acceptable acids.

The term lower alkyl as used herein refers to straight or branched C 1 -C 6 alkyl, such as methyl, ethyl, η-propyl, isobutyl, pentyl or hexyl.

By halogen is meant fluorine, chlorine, bromine or iodine.

The compounds of this invention are prepared by one or more of the following steps. Η During the synthesis, X, R, R, and R ₂ is defined as above.

Procedure 1

The 2-ol of formula Ic is prepared as follows:

step la)

In Scheme 1, an aminonitrile compound is reacted with a cyclic ketone to give the compound of formula II.

The reaction is carried out in the presence of a Lewis acid such as zinc chloride and a suitable solvent such as nitrobenzene, toluene or 1,2-dichloroethane at 80-150 ° C.

Step lb)

A compound of formula IVa wherein R 1 and R _{2 are} hydrogen and aryl lower alkyl is subjected to hydrogenolysis in a known manner to form a compound of formula V. A preferred catalyst for this reaction is palladium on charcoal, see Scheme 4.

step le)

A compound of Formula V is reacted with an aryl chloride of Formula VI or an ester of Formula VIa wherein R ₅ is C 1 -C 11 alkyl and R ⁶ is C 1 -C 2 alkyl. The reaction is carried out in a manner known per se to give compound VII: Scheme 5.

Step ld)

A compound of formula (V) is reacted with a formamide acetal of formula (VIII) wherein R ₂ , R ₄ and R ₇ are lower alkyl, and the reaction is carried out in a manner known per se to give compound (IX).

Process 2 Preparation of 9-amino-1,2,3,4-tetrahydroacridin-3-ols of formula Id

An aminonitrile shown in Scheme 7 is reacted with a cyclic ketone to give compound (X). The reaction is carried out in a similar manner to Step 1a).

Step 2b)

A compound of formula XIII wherein R 1 and R ₂ is hydrogen is subjected to hydrogenolysis as described in step ld) to give compound XIII according to Scheme 10.

Step 2c)

A compound of formula (XIII) is reacted with R ₃ COC1 acyl chloride of formula substantially as described in Step Ie) and (XIV) the compound obtained all. according to the reaction scheme.

Process 3: Preparation of 4-ols of formula XV

the step

A compound of formula (XVI) is reacted with acetic anhydride in a known manner to give a compound of formula (XVII) according to Scheme 12.

Step b)

A compound of formula XVII is first hydrolyzed in a known manner to provide the corresponding alcohol which is reacted with benzyl bromide in the presence of a strong base such as sodium hydride to give compound XVIII according to Scheme 13.

Step 3c)

A compound of Formula XVIII is reacted with ammonia in a suitable medium such as phenol in a manner known per se to form a compound of Formula XIX.

The compounds of formula (I) are useful in the treatment of various memory disorders characterized by reduced cholinergic function, such as Alzheimer's disease.

This useful property can be demonstrated by determining the ability of the compounds to inhibit the enzyme acetylcholinesterase activity and thereby increase acetylcholine levels.

An attempt to inhibit cholinesterase

The inhibition of acetylcholinesterase by Ellmann et al., Biochem. pharmacol. 7, 88 (1961)].

The results obtained with the compound of the invention are shown in Table 1 together with the results obtained with some reference compounds.

HU 208,674 Β

Table 1

Inhibition of acetylcholinesterase

Compound IC50 (molar concentration) 2-benzyloxy-1,2,3,4-tetrahydro-9akridinamin Ι, ΟχΚΓ ³ 9-amino-l, 2,3,4-tetrahydroacridin-2- ol maleate 5.3x1 (T ⁶ 2-acetoxy-l, 2,3,4-tetrahydro-9akridinamin 6.5x10 ⁶ 2-hexanoyloxy-1,2,3,4-tetrahydro-9akridinamin fumarate l, 9x10 " ⁵ 2-heptanoyloxy-l, 2,3,4-tetrahydro-9- acridinamine fumarate 3, lxl {T ⁵ 2-lauroyloxy-l, 2,3,4-tetrahydro-9- acridinamine l, 6x10 ~ ⁴ 2-decanoyloxy-1,2,3,4-tetrahydro-9akridinamin fumarate Ι, ΟχΚΓ ³ 2-nonanoyl-l, 2,3,4-tetrahydro-9- acridinamine fumarate Ι, ΟχΚΓ ³ 4-benzyloxy-l, 2,3,4-tetrahydro) dihydro-9- acridinamine Ι, ΟχΚΓ ³ 2-butyryloxy-l, 2,3,4-tetrahydro-9- acridinamine fumarate 8.2x10 ⁴ Octanoyl-2-oxy-1,2,3,4-tetrahydro-9akridinamin fumarate 4.8x10 ⁶ 2-valeryl-oxy-l, 2,3,4-tetrahydro-9- acridinamine fumarate ⁵ 1,2χΚΓ 9-amino-1,2,3,4-tetrahydroacridinamine-4-ol hemifumarate ⁶ 1.9Χ10- 2-hydroxy-N- (dimethylamino-methylene) - l, 2,3,4-tetrahydro-9-acridinamine 1.0x10 ³ (Reference compound) 9-amino-l, 2,3,4-tetrahydroacridine ⁷ 3,1χΚΓ physostigmine 6.0x10 ^-9

We can also provide this useful property by determining the ability of compounds to restore darkness avoidance! experiment with cholinergic deficient memory. In this experiment, mice are tested to recall an unpleasant stimulus over a 24 hour period. A mouse is placed in a chamber containing a dark portion, and a strong glowing light is introduced into the dark portion, where an electric shock is applied to the floor through metal plates. The animal is removed from the test apparatus and re-examined 24 hours later to see if it remembers the electric shock.

When used as a memory enhancer anticholinergic scopolamine, which is administered before the animal is initially exposed to the test chamber, the animal enters the dark area again shortly after being placed in the test chamber 24 hours later.

With scopolamine, this effect is inhibited by an active test compound, and as a result, the time it takes for the animal to re-enter the dark room is increased.

The results obtained with the active ingredient are expressed as a percentage of the group of animals in which the scopolamine effect is blocked and is manifested in the increased interval between placement in the test chamber and re-entering the darkroom. The results of the obtained darkness avoidance test with some representative compounds of the invention and the test results obtained with the reference compounds are shown in Table 2.

An attempt to avoid darkness

Table 2

Compound Dose in mg / kg body weight subcutaneously Scopolamine-Induced Decreased Met- reversal of memory in% of animals 9-amino-l, 2,3,4-tetrahydro- acridine-2-ol maleate 5.0 20% 2-acetoxy-1,2,3,4-tetrahydro-9-acridinamine 5.0 29% 2-propionyloxy-1,2,3,4 tetrahydro-9-akridinamin- fumarate hemihydrate 5.0 13% 2-oxy-1,2,3,4-hexanoyl tetrahydro-9-akridinamin- fumarate 0.63 25% (Reference) physostigmine 0.31 20%

An effective amount of the compounds of the present invention is administered to a patient by a variety of methods, for example, orally, in capsule or tablet form, parenterally in the form of sterile solutions or suspensions, and in some cases intravenously in the form of sterile solutions. The free base end products are also effective in themselves, but can be formulated and added in the form of their pharmaceutically acceptable acid addition salts for convenient crystallization, increased solubility.

Pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid and organic acids such as tartaric acid, citric acid, acetic acid, succinic acid, maleic acid, oxalic acid.

The compounds may be administered orally, for example, in admixture with an inert diluent or edible carrier, or compressed into a gelatin capsule or tablet. For oral administration, the active compounds are mixed with various excipients and used in the form of pills, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like. The formulations will contain at least 0.5% of active ingredient, but may also vary depending on the formulation and may be in the range of 4 to 70% by weight. The amount of active ingredient in such formulations is selected

In order to obtain a suitable dose. The hourly dosage form of the preferred compositions will contain from 1 to 300 mg of the active ingredient.

Tablets, pills, capsules, troches, and the like. they may also contain the following ingredients: a binder such as microcrystalline cellulose, gum tragacanth or gelatin, an excipient such as starch or lactose, a disintegrant, alginic acid, progel, corn starch, and the like. A lubricant such as magnesium stearate or Sterotex, a glidant such as colloidal silicon dioxide, a sweetener such as sucrose or saccharin, a flavoring agent such as frothormentate, methyl salicylate or orange flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as fatty oil. Other dosage unit forms may also contain various substances which affect the physical form of the dosage unit, for example, as a coating. The tablets or pills may be coated with sugar, shellac, or other enteric coating agents. A syrup may contain, in addition to the active ingredient, sucrose as a sweetening agent and certain preservatives, dyes, colorings and flavors. The materials used to make the compositions are pharmaceutically pure and non-toxic, necessarily in the amounts used.

For parenteral therapeutic administration, the active ingredient may be formulated in a solution or suspension. These compositions contain at least 0.1% of active ingredient, but may be present in an amount of 0.5-30% by weight. Such formulations employ sufficient amounts of the active ingredient to provide a suitable dosage. Preferred compositions contain from 0.5 to 100 mg of active ingredient per parenteral dosage unit.

Examples of the compounds of the present invention include: 2-benzyloxy-1,2,3,4-tetrahydro-9-acridinamine;

9-amino-1,2,3,4-tetrahydroacridin-2-ol,

2-hydroxy-N- (dimethylamino-methylene) -l, 2,3,4-tetrahydro-9-acridinamine,

2-acetoxy-l, 2,3,4-tetrahydro-9-acridinamine,

2-propionyloxy-l, 2,3,4-tetrahydro-9-acridinamine,

2-butyryloxy-l, 2,3,4-tetrahydro-9-acridinamine,

VaIeroil-2-oxy-l, 2,3,4-tetrahydro-9-acridinamine,

2-hexanoyl-oxy-l, 2,3,4-tetrahydro-9-acridinamine,

Heptanoyl-2-oxy-l, 2,3,4-tetrahydro-9-acridinamine,

Octanoyl-2-oxy-l, 2,3,4-tetrahydro-9-acridinamine,

2-nonanoyl-oxy-l, 2,3,4-tetrahydro-9-acridinamine,

Decanoyl-2-oxy-l, 2,3,4-tetrahydro-9-acridinamine,

2-lauroyloxy-l, 2,3,4-tetrahydro-9-acridinamine,

4-benzyloxy-l, 2,3,4-tetrahydro-9-acridinamine,

9-amino-1,2,3,4-tetrahydroacridin-4-ol.

The invention is further illustrated by the following examples.

Example 1

2-Benzyloxy-l, 2,3,4-tetrahydro-9-acridinamine

14.86 g of 4-benzyloxycyclohexanone 'and 8.90 g of ant' j. Chem. Soc. Chem. Commun. 1984, 721.

ranilonitrile was dissolved in 100 ml of nitrobenzene, to which 0.9 g of fresh bulk zinc chloride was added. The reaction mixture was heated at 60 ° C for 90 minutes and then raised to 120 ° C for 3 hours. After this time, 200 ml of anhydrous diethyl ether are added and the mixture is left undisturbed overnight. The granular precipitate was filtered off, washed with diethyl ether and partitioned between aqueous ammonia and 2-butanone. The organic phase was dried, evaporated and the resulting solid was triturated with diethyl ether to give 17.19 g of product, mp 188-190 ° C. An analytical material is obtained after recrystallization from methanol / water, m.p. 190-191 ° C.

Analysis for C ₂₀ H ₂₀ N ₂ O:

Found: C, 78.92; H, 6.62; N, 9.21 Found: 78.86; 6.64; 9.24.

Example 2

9-Amino-1,2,3,4-tetrahydroacridin-2-ol maleate

18.75 g of 2-benzyloxy-1,2,3,4-tetrahydro-9-acridinamine are hydrogenated with 10% palladium on carbon in a solution of 1 liter of absolute ethanol and 56.83 ml of concentrated hydrochloric acid overnight at 4 atm. . pressure.

The reaction mixture was filtered through celite, dissolved in 100 mL deionized water, and 55 mL of 10% sodium hydroxide was added dropwise while stirring in an ice bath. The remaining solid was filtered, washed with deionized water, dried to give 11.82 g of the desired 9-amino-1,2,3,4-tetrahydroacridine. A portion of the product was converted to the maleate in methanol and recrystallized from a mixture of methanol and triethyl ether.

222-225 'C (dec.).

Calcd for C _{13 H] 2} N ₄ H ₄ O ₄ OXC _O4: Calculated: C% -61.81; H, 5.49; N, 8.48. Found: 61.64; 5.61; 8.42.

Example 3

2-Hydroxy-N- (dimethylaminomethylene) -1,2,3,4-tetrahydro-9-acridinamine

9-Amino-1,2,3,4-tetrahydroacridin-2-ol (10.97 g) was heated under reflux in 329 ml of dimethylformamide dimethylacetal for 2 hours. The reaction mixture was cooled to room temperature, diluted with 1 L of saturated potassium carbonate and extracted with ethyl acetate (2 x 600 mL). After stirring for half an hour in activated carbon, it was filtered through celite, dried over magnesium sulfate and evaporated to give a solid which was triturated with diethyl ether to give 5.68 g of product. Recrystallization from a mixture of methylene chloride in hexane and drying under high vacuum in 3-hexanone at reflux for 24 hours gives 4.37 g of a solid, m.p.

Analysis for C ₁₆ H ₉ N ₃ O:

Found: C, 71.35; H, 7.11; N, 15.60; Found: 70.86; 6.90; 15.40.

Example 4

2-acetoxy-l, 2,3,4-tetrahydro-9-acridinamine

HU 208,674 Β

10.97 g of 2-benzyloxy-1,2,3,4-tetrahydro-9-acridinamine are suspended in 500 ml of liquid ammonia at 65 ° C. Sodium (2.2 g) was then added in small portions until the blue color remained. The reaction was quenched by addition of solid ammonium chloride, then the ammonia was allowed to evaporate and the residue was washed well with ethyl acetate. The ethyl acetate wash was evaporated and contained 2-acetoxy-1,2,3,4-tetrahydro-9-acridinamine. This was passed through a silica gel column (5% triethylamine / ethyl acetate), and the fractions containing the product were evaporated and the residue was converted to the hydrochloride in ethereal hydrogen chloride. Recrystallization from methanol / triethyl ether gave 2.30 g of product, m.p. 178-181 ° C.

Analysis for C ₁₅ H ₁₆ N ₂ O ₂ HCl:

Found: C, 61.53; H, 5.85; N, 9.57. Found: 60.88; 5.71; 9.38.

Example 5

2-Propionyloxy-1,2,3,4-tetrahydro-9-acridinamide fumarate hemihydrate 9-amino-1,2,3,4-tetrahydroacridin-2-ol hydrochloride with 6.15 ml pyridine and 240 ml anhydrous Propionyl chloride (2.17 mL) was added dropwise to a suspension of N, N-dimethylformamide. After stirring at room temperature for 2 hours, an additional 1 ml of propionyl chloride was added and the reaction mixture was heated at 45 ° C for 64 hours.

The reaction mixture was cooled to room temperature, diluted with saturated sodium bicarbonate (400 mL) and deionized water (400 mL), and extracted with ethyl acetate (5 x 300 mL). The organic material was dried over magnesium sulfate and evaporated to give 4.03 g of crude product. It was purified by trituration with diethyl ether, flash chromatographed with 5% triethylamine and ethyl acetate and recrystallized from ethyl acetate. 1.88 g of product are obtained.

This is combined with another batch and the fumarate salt is prepared using isopropanol solvent. Recrystallization from ethyl acetate and drying under high vacuum, and refluxing in xylene for 36 hours, gave 2.7 g of whitish micro-needles, melting at 220 ° C with decomposition.

Analysis using the formula C ₁₆ Hi ₈ N ₂ O ₂ x C ₄ H ₄ O ₄ × 0.5 H ₂ O:

Calculated: C, 60.75; H, 5.86; N, 7.09; Found: 60.98; 5.47; 7.11.

Example 6

2-butyryl-oxy-l, 2,3,4-tetrahydro-9-acridinamine, fumarate

To a suspension of 8-g 9-amino-1,2,3,4-tetrahydroacridin-2-ol hydrochloride in 11.16 ml pyridine and 376 ml anhydrous dimethylformamide was added 4.67 ml butyryl chloride. The reaction mixture was stirred in an 80 ° C water preheated oil bath for 1/2 hour, then another 4.67 ml of butyryl chloride was added and the mixture was heated at 80 ° C for another 15 minutes. The reaction mixture was cooled to room temperature, diluted with 1 L of saturated potassium carbonate and extracted with 2 x 700 mL of ethyl acetate. The organic layer was washed with water (2 x 500 mL), dried over magnesium sulfate and concentrated to an oil. Purification by flash chromatography (1.5% triethylamine / ethyl acetate) and trituration with diethyl ether / hexane (1: 1) gave 2.67 g of product. The fumarate is prepared using an isopropanol solvent. Recrystallization from a mixture of ethanol and hexane gave 2.74 g of a white solid, m.p.

Calc'd for C ₁₇ H ₂ oN ₂ 0 ₂ x C ₄ H ₄ 0 ₄ calculated: C% = 62.99; % H, -6.04; N, 7.00;

Found: 62.66; 5.96; 6.98.

Example 7

2-Valeryloxy-1,2,3,4-tetrahydro-9-acridinamine fumarate 9-amino-1,2,3,4-tetrahydro-acridin-2-ol hydrochloride with 11.16 ml of pyridine and To a suspension of 5 ml of anhydrous Ν, Ν-dimethylformamide was added 5.43 ml of valeryl chloride. The reaction mixture was stirred in an 80 'C preheated oil bath for half an hour, an additional 5.43 ml of valeryl chloride was added and the mixture was stirred for another 20 minutes at 80' C. The reaction mixture was cooled to room temperature, diluted with 1 L of saturated potassium carbonate, extracted with 250 mL of ethyl acetate, and the organic phase was washed with water (2x350 mL), dried over magnesium sulfate and evaporated to an oil.

Purify by flash chromatography (1.5% triethylamine / ethyl acetate) and triturate with diethyl ether / hexane (1: 3). 3.85 g (41%) of product are obtained. The fumarate is obtained using an isopropanol solvent. Recrystallization from a mixture of methanol and diethyl ether and drying under high vacuum at reflux in xylene yields 4.54 g of solid, m.p. 210 DEG C. with decomposition. Calcd for _Ig H ₂₂ N ₂ O ₂ x C ₄ H ₄ O ₄ Calculated:% C = 63.75; H, 6.32; N, 6.76.

Found: 63.53; 6.31; 6.71.

Example 8

2-Hexanoyloxy-1,2,3,4-tetrahydro-9-acridinamide fumarate

To a suspension of 3.0 g of 9-amino-1,2,3,4-tetrahydroacridine-2-ol hydrochloride in 3.63 ml of pyridine and 141 ml of Ν, Ν-dimethylformamide is added dropwise 2.19 ml of hexanoyl chloride. The reaction mixture was stirred in a preheated 80 ° C oil bath for 1 hour, another 2.19 ml of hexanoyl chloride was added, the reaction mixture was heated for an additional hour and the reaction mixture was cooled to room temperature. The reaction mixture was diluted with 600 mL of saturated potassium carbonate, extracted with 400 mL of ethyl acetate, and the organic phase was washed with water (2 x 250 mL). Dry over magnesium sulfate and evaporate to an oil.

This oil was combined with another batch and purified by flash chromatography (1.5% triethylamine / ethyl acetate). Trituration with diethyl ether gave 2.35 g of product. Fumarate was prepared with 50 ml of isopropanol solvent. Recrystallized from a mixture of ethanol and diethyl ether, dried under high vacuum at reflux in xylenes

Boiling for 674 Β hours gives 2.41 g of a microcrystalline melting point at 205 ° C.

Analysis calculated for C C HH ^ NNjCj xC x ^^: C, 64.47; H, 6.59; N, 6.54.

Found: 64.34; 6.45; 6.55.

Example 9

Heptanoyl-2-oxy-1,2,3,4-tetrahydro-9-acridine-amine fumarate

To a suspension of 5.0 g of 9-amino-1,2,3,4-tetrahydroacridin-2-ol hydrochloride in 6.93 ml of pyridine and 235 ml of anhydrous Ν, Ν-dimethylformamide is added 432 ml of heptanoyl chloride. The reaction mixture was stirred at 80 ° C, preheated oil bath for 1/2 hour, additional heptanoyl chloride (4.32 ml) was added and heated for 5 hours. The reaction mixture was then stirred at room temperature overnight. The reaction mixture was diluted with saturated potassium carbonate (750 mL), extracted with ethyl acetate (660 mL), and the organic layer was washed with water (200 mL). Dry over magnesium sulfate, evaporate to give an oil.

Purification by flash chromatography (2.5% triethylamine / ethyl acetate) and trituration with diethyl ether / hexane (1: 1) gave 2.65 g of product. Fumarate was prepared with 30 ml of isopropanol solvent. Recrystallization from ethanol / hexane and refluxing with N-butyl acetate for 16 hours under high vacuum afforded 2.49 g of a microcrystalline solid. Op .: 195 "C.

Analysis by formula:

Found: C, 65.14; H, 6.83; N, 6.33.

Found: 64.86; 6.63; 6.24.

Example 10

2-Octanoyloxy-oxy-l, 2,3,4-tetrahydro-9-akridinaminfumarát

To a suspension of 9-amino-1,2,3,4-tetrahydroacridin-2-ol hydrochloride (8.0 g) in pyridine (11.16 ml) and Ν, kl-dimethylformamide (376 ml) was added dropwise octanoyl chloride (7.68 ml). . The reaction mixture is stirred in an 80 ° C preheated oil bath for 1/2 hour and then 7.68 ml of octanoyl chloride is added and the mixture is heated at 80 ° C for half an hour. The reaction mixture was further cooled to room temperature, diluted with 1 L of saturated potassium carbonate, extracted with 800 mL of ethyl acetate and the organic phase was washed with 2 x 250 mL of water. It was dried over magnesium sulfate, evaporated to give an oil which solidified overnight. Purification by trituration with a mixture of pentane and diethyl ether gave 2.83 g of product. The fumarate was prepared with isopropanol and recrystallized from methanol / diethyl ether under high vacuum in xylene under reflux for 19 hours to give 2.87 g of a white solid, m.p. 199 ° C. Analysis calculated for C21 H28 N2 O2 X C4 H4 O4: C, 65.77; H, 7.07; N, 6.14%;

Found: 65.68; 7.16; 6.15.

Example 11

2-Nonanoyloxy-1,2,3,4-tetrahydro-9-acridinamide fumarate 9-amino-1,2,3,4-tetrahydroacridine-2-ol hydrochloride 5.56 ml pyridine and 188 ml anhydrous, 4 ml of nonanoyl chloride was added dropwise to a suspension of ano-dimethylformamide. The reaction mixture was stirred in an 80 ° C preheated oil bath and another 4 ml of nonanoyl chloride was added and the mixture was heated for another half hour and then cooled to room temperature. The reaction mixture was combined with 1 g of a test reaction, diluted with 1 liter of saturated potassium carbonate, extracted with 250 ml of ethyl acetate and the organic phase was washed with water (2 x 500 ml), dried over magnesium sulfate and concentrated to an oil. Purification by flash chromatography (1.5% triethylamine / ethyl acetate) and trituration with pentane / diethyl ether gave 2.02 g of product, which was combined with a further 3 g of batch and the fumarate was prepared with isopropanol. Recrystallization from a mixture of ethanol and hexane and drying under high vacuum while refluxing in xylenes overnight afforded 3 g of a white solid, m.p.

Analysis calculated for C ₂₂ H ₃₀ N ₂ O ₂ • C ₄ H ₄ O ₄ : C, 66.36; H, 7.28; N, 5.95; Found: 66.23; 7.19; 6.91.

Example 72

Decanoyl-2-oxy-1,2,3,4-tetrahydro-9-akridinaminfumarát

To a suspension of 5.31 g of 9-amino-1,2,3,4-tetrahydroacridine-2-ol hydrochloride in 7.28 ml of pyridine and 247 ml of anhydrous N, N-dimethylformamide is added dropwise 6.02 ml of decanoyl chloride. The reaction mixture was stirred in an oil bath preheated to 45 ° C for 1/2 hour, decanoyl chloride (6.02 ml) was added and the mixture was stirred overnight at 45 ° C. The reaction mixture was heated to 60 ° C for 1/2 hour, cooled to room temperature, diluted with 700 mL of saturated potassium carbonate, extracted with 600 mL of ethyl acetate and washed with 500 mL of deionized water, dried over magnesium sulfate, evaporated to an oil. Purification by flash chromatography (2.5% triethylamine / hexane) and trituration with diethyl ether / hexane (1: 3) gave 3.67 g of product. The fumarate is prepared with isopropanol solvent. Recrystallization from a mixture of ethanol and hexane and drying under high vacuum while heating under reflux in xylene overnight afforded 3.8 g of a microcrystalline solid, m.p. Analysis calculated for C CJHJJN2O2OCCHHO4: C, 66.92; H, 7.49; N, 5.78.

found: 67.10; 7.47; 5.73.

Example 13

Lauroyl-2-oxy-1,2,3,4-tetrahydro-9-acridinamine

A suspension of 6.0 g of 9-amino-1,2,3,4-tetrahydroacridin-2-ol hydrochloride in 8.32 ml of pyridine and 282 ml of anhydrous dimethylformamide is added dropwise to 7.74 ml of lauroyl chloride. The reaction mixture was stirred in an oil bath preheated to 80 ° C for 1/2 hour and another 7.74 ml of lauroyl chloride was added. Heating was continued for 1 hour and the mixture was stirred at room temperature overnight. The reaction6

The mixture was diluted with 1200 ml of saturated potassium carbonate, extracted with 800 ml of ethyl acetate and washed with 500 ml of water, dried over magnesium sulphate and evaporated to give a gummy solid. The solid was purified by flash chromatography (5.5% triethylamine / ethyl acetate) and triturated with diethyl ether / hexane (1: 1) to give 5.25 g of product. Recrystallization from a mixture of diethyl ether, hexane and ethanol and drying under high vacuum at reflux with ethanol gave 18 g of solid, m.p. 115 ° C with decomposition.

Calcd C2jH ₃₆ N ₂ O ₂ wherein:

Found: C, 75.72; H, 9.15; N, 7.06; Found: 75.60; 9.19; 7.10.

Example 14

4-Acetoxy-9-chloro-1,2,3,4-tetrahydroacridine 40.12 g of 9-chloro-1,2,3,4-tetrahydroacridine N-oxide were heated at reflux in 200 ml of acetic anhydride. After 30 minutes, the acetic anhydride was evaporated and the reaction mixture was purified by preparative HPLC (20% ethyl acetate / hexane, two columns, two turns). Product containing fractions were evaporated and triturated with pentane to give 33.1 g of product, m.p. Recrystallization from hexane gives an analytical material, m.p. 85-87 ° C.

Analysis using the formula C ₁₃ H ₁₄ ClNO ₂ :

Found: C, 65.33; H, 5.12%; N, 5.08; Found: 65.51; 5.15; 5.07.

Example 75

4-Benzyloxy-9-chloro-1,2,3,4-tetrahydroacridine 20.78 g of 9-chloro-4-hydroxy-1,2,3,4-tetrahydroacridine are dissolved in 500 ml of dimethylformamide. Benzyl bromide (8 g) was added. Sodium hydride (4.80 g, 50% suspension) was added and the mixture was stirred for 2 hours at room temperature. The reaction mixture was partitioned between diethyl ether and water and the organic layer was separated, washed well with water, dried and evaporated. Trituration of the residue with pentane gave 19.60 g of product, m.p. Analysis of the pentane detergent by TLC showed that it still contained a significant amount of product, which was further purified by flash chromatography (10% ethyl acetate / hexane) to give an additional 7.42 g of product, m.p. 73-75 ° C. An analytical material is obtained which is recrystallized from pentane, m.p.

Analysis calculated for C ₂₀ H ₁₈ ClNO ₂ : C, 74.18; H, 5.60; N, 4.33;

Found: 74.12; 5.57; 4.29.

Example 76

4-Benzyloxy-1,2,3,4-tetrahydro-9-acridinamine 4-Benzyloxy-9-chloro-1,2,3,4-tetrahydroacridine (24.0 g) was dissolved in phenol (130 ml) at 130 ° C. and ammonia was added to the solution for 2 hours. The reaction mixture was partitioned between diethyl ether and 10% sodium hydroxide, and the organic phase was washed again with 10% sodium hydroxide and water. The organic layer was dried, evaporated and purified by flash chromatography (ethyl acetate). The product-containing fractions were evaporated and the residue was triturated with diethyl ether to give 10.12 g of product.

Analysis for C ₂₀ H ₂₀ N ₂ O:

Found: C, 78.92; H, 6.62; N, 9.20; Found: 78.67; 6.52; 9.09.

Example 17

9-Amino-1,2,3,4-tetrahydroacridin-4-ol, hemifumarate

6.0 g of 4-benzyl-1,2,3,4-tetrahydro-9-acridinamine are heated at reflux for 1 hour in a mixture of 50 ml of glacial acetic acid and 50 ml of concentrated hydrochloric acid. The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (5% triethylamine / ethyl acetate) to give 2.83 g of the free base. The fumarate was prepared in isopropanol by recrystallization from water to give 2.63 g of hemifumarate, melting at 225 ° C with decomposition.

Analysis for C ₁₃ H ₁₄ N ₂ OxO, 5 C ₄ H ₄ O ₄ :

Example 18

6-Chloro-2-benzyloxy-1,2,3,4-tetrahydro-9-acridinamine

To a mechanically stirred solution of 10.77 g of 4-benzyloxy-cyclohexanone ¹ and 7.93 g of 4-chloro-anthranilonitrile ^{2 in} 72.6 ml of nitrobenzene are added 7.9 g of freshly melted zinc chloride. The reaction mixture was heated at 60 ° C for 90 minutes and then heated at 120 ° C for a further 3 hours. After cooling to room temperature, 170 ml of anhydrous diethyl ether are added dropwise and the precipitate is filtered off, washed well with diethyl ether and dissolved in 200 ml of methanol. Saturated ammonium hydroxide (200 mL) was added dropwise while cooling in an ice bath. The resulting solid was filtered, washed sequentially with deionized water, then diethyl ether, and air dried to give 7.2 g of a white solid. A portion (4.86 g) was recrystallized from a mixture of ethanol and hexane, dried under high vacuum while heated under reflux in xylene. 3.5 g of product are obtained, m.p. 220 DEG C. with decomposition. Analysis calculated for C ₂₀ H ₁₉ N ₂ OC ₁ :

Calculated: C, 70.90; H, 5.65; N, 8.27. Found: 70.71; 5.60; 8.21.

Example 79

4-acetoxy-1,2,3,4-tetrahydro-9-acridinamine fumarate, hemihydrate

9-Amino-1,2,3,4-tetrahydroacridin-4-ol (2.40 g) was heated at reflux in acetic anhydride (20 ml) for 1 hour. The reaction mixture was then evaporated and partitioned between 2-butanone and sodium bicarbonate solution. The organic phase was evaporated to give a residue which was triturated with diethyl ether to give the crude product as the free base. Izo 'Chem. Soc., Chem. Commun. 1984,721 ² Amer. Chem. Soc. 1947, Vol. 89, 940.

Propanol is formed with propanol to give 1.82 g of fumarate hemihydrate during analysis which melts at 258 ° C with decomposition.

Analysis using the formula C ₁₅ H ₁₆ N ₂ O ₂ x C ₄ H ₄ O ₄ x0,5 H ₂ O:

Found: C, 59.83; H, 5.55; N, 7.35. Found: 59.95; 5.71; 6.99.

Claims (10)

PATENT CLAIMS A process for the preparation of compounds of formula I wherein X is hydrogen or halogen, R is hydrogen, benzyl or C 2 -C 12 alkanoyl, provided that -OR cannot be in position 1 of the ring system and R ₁ and R _{2 are} hydrogen, or R 1 and R ₂ together form = CH-NR ₃ R ₄ , wherein R ₃ and R ₄ are each independently C 1 -C 6 alkyl or a pharmaceutically acceptable acid addition salt thereof, characterized in that: a) reacting a compound of formula A with a compound of formula B to produce a compound of formula Γ, wherein X is as defined above, or b) reacting a compound of formula XVIII wherein X is as defined above with ammonia to form a compound of formula Γ, wherein X is as above c) optionally a compound of formula I where R is 2 or 3 is in the position R is benzyl, R _b R ₂ is hydrogen and X is as above - hydrogenolysis to give a compound of formula (I) wherein R is hydrogen, or d) optionally solvating a compound of formula I wherein the OR group is in the 4 position, R is benzyl, R _b R ₂ and X are as defined above to give a compound of formula I wherein R is hydrogen . e) optionally reacting a compound of formula I wherein R is hydrogen, R 1, R ₂ and X are as defined above with acyl chloride R ₅ COCl or an ester R ₅ COOR ₆ where R ₅ is C 1 -C 11 alkyl, R ₆ is C 1 -C 2 alkyl to form a compound of formula I wherein R is C 2 -C 12 alkanoyl, R _b R ₂ and X are as defined above and f) optionally reacting a compound of formula I wherein R is hydrogen, R _b R ₂ is hydrogen, lower alkyl or aryl lower alkyl, X is as defined above with Formamide VIII acetal, wherein R ₃ , R ₄ and R ₇ are C 1 -C 6 alkyl for the preparation of a compound of formula I wherein R 1 and R ₂ are = CH-NR ₃ R ₄ - wherein R ₃ and R ₄ are upper. A process according to claim 1, wherein the compounds of formula (I) are -OR is in position 2 or 4, characterized in that the appropriate starting materials are reacted. 3. A process according to claim _{2 for the} preparation of compounds of formula I wherein R _{b is} R ₂ and X is hydrogen, wherein the appropriate starting materials are reacted. A process according to claim 3 for the preparation of compounds of formula I wherein R is hydrogen or C2-C6 alkanoyl, wherein the appropriate starting materials are reacted. A process for the preparation of 9-amino-1,2,3,4-tetrahydroacridinamin-4-ol or a pharmaceutically acceptable acid addition salt thereof according to claim 1, which comprises reacting the appropriate starting materials. A process for the preparation of 9-amino-1,2,3,4-tetrahydroacridin-2-ol or a pharmaceutically acceptable acid addition salt thereof according to claim 1, wherein the appropriate starting materials are reacted. 7. A process according to claim 1 for the preparation of 2-acetoxy-1,2,3,4-tetrahydro-9-acridinamine or a pharmaceutically acceptable salt thereof, which comprises reacting the appropriate starting materials. 8. A process according to claim 1 for the preparation of 2-butyryloxy, 2,3,4-tetrahydro-9-acridinamine or a pharmaceutically acceptable acid addition salt thereof comprising reacting the appropriate starting materials. 9. A process according to claim 1 for the preparation of 2-hexanoyloxyl, 2,3,4-tetrahydro-9-acridinamine or a pharmaceutically acceptable acid addition salt thereof, which comprises reacting the appropriate starting materials. 10. A process for the preparation of a pharmaceutical composition comprising mixing a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof according to claim 1, wherein R _b R ₂ , X and R are pharmaceutically acceptable carriers as defined in claim 1, and converting it into a pharmaceutical composition. .