FI93117B - Analogous Process for the Preparation of Therapeutically Useful 9-Aminotetrahydroacridine Derivatives - Google Patents

Abstract

Compounds of formula (I), wherein R<1>, R<2>, A and B are defined hereinbelow. The compounds of the present invention inhibit brain acetylcholinesterase and are useful in the treatment of Alzheimer's disease.

Description

93117

Analogous process for the preparation of therapeutically useful 9-aminotetrahydroacridine derivatives

The present invention relates to an analogous process 5 for the preparation of therapeutically useful 9-aminotetrahydroacridine derivatives of formula I

v n

1ST

R 3 J J (I) wherein R 3 is hydrogen or halogen and Y 1 is O or S and pharmaceutically acceptable salts thereof.

These compounds are therapeutically useful; they inhibit brain acetylcholinesterase and are useful in the treatment of Alzheimer's disease.

Tetrahydroaminoacridine, which has anticholin-20 terase activity, has been shown to be more effective in psychological experiments in patients with Alzheimer's disease [W.K. Summers et al. The New England Journal of Medicine, 315, 1241-1245 (1986)]. Anticholinesterase physo-stigmine has also been reported in the experimental treatment of Alzheimer's disease (S.D. Brinkman et al., Neurobiol.

: Aging, 4, 139-145 (1983)].

The compounds disclosed in the following four documents have been shown to be anticholinergically active: U.S. Patent 4,652,567 refers to benzo (C) -30 1,5-naphthyridines in the treatment of Alzheimer's disease.

U.S. Patent No. 4,631,286 refers to 9-amino-1,2,3,4-tetrahydroacridin-1-ol and related compounds in the treatment of Alzheimer's disease.

U.S. Patent 4,550,113 refers to 9-amino-35 2,3,5,6,7,8-hexahydro-1H-cyclopenta (b) quinoline monohydrate hydrochloride in the treatment of neurite outgrowth, peripheral nervous system damage, and hereditary neuromuscular disorders. in widespread sclerosis.

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

U.S. Patent 4,540,564 refers to dihydropyridines as a drug for use in the brain.

G.k. Patnaik et al., J. Med. Chem., 9, 483-488 (1966) refers to 4-substituted 2,3-polymethylenequinolines having analgesic, local anesthetic, analeptic and respiratory stimulating activity.

GB patents 1,186,061, 1,186,062 and 1,186,063 refer to benzonaphthyridine derivatives.

When R 3 in the present invention is halogen it is, for example, fluorine, chlorine, bromine or iodine, preferably it is fluorine.

Particularly preferred compounds of formula I are: 9-amino-4-oxa-1,2,3,4-tetrahydroacridine; 9-Amino-8-fluoro-4-oxa-l, 2,3,4-tetrahydroacridine; and 9-amino-4-thia-1,2,3,4-tetrahydroacridine.

The analogous process according to the invention for the preparation of therapeutically useful compounds of the formula X and their pharmaceutically acceptable salts is characterized in that

a) subjecting to aminonitrile of formula II

. - -cc

wherein R 3 is as defined above, to react with a compound of formula III

3 9311 7 y (III) 5 wherein Y1 is as defined above, and

b) cyclizing a ketimine of formula IV

10, r ^ NTCN

- | (IV) wherein R 3 and Y 1 are as defined above, and if desired are reacted with a pharmaceutically acceptable acid.

By this method, certain 9-amino-1,2,3,4-tetrahydroacridine derivatives can be prepared in one step by condensing the appropriate o-aminonitriles with various carbonyl components.

In the process, the aminonitrile of formula II is reacted with a carbonyl-containing compound of formula III, which may be a ketone, lactone or the like. The reaction is carried out in an inert solvent in the presence of a Lewis-φ25 acid (e.g. titanium (IV) chloride) and, if necessary, a base, preferably an amine base (e.g. triethylamine) is present. Suitable solvents include aromatic solvents (e.g. benzene or toluene) and chlorinated solvents (e.g. methylene chloride or 1,2-dichloroethane). The reaction temperature should be at least about 0 ° C and is preferably about 25 to 120 ° C. The reaction pressure is not critical. The reaction is usually carried out at a pressure of 0.5 to 2 atmospheres, preferably at ambient pressure (usually about 1 atm).

Thus, for example, condensation of delta-valerolactone with anthranilonitrile in methylene chloride with titanium (IV) → 4 93117 chloride at 25 ° C in the presence of triethylamine (2 equivalents) gave the compound of Example 1 (28%).

The compounds of formula I may form acid addition salts with pharmaceutically acceptable acids. Acid addition salts may be prepared by reacting the appropriate base form of a compound of formula I with one or more equivalents, preferably an excess, of a suitable acid in an organic solvent, for example diethyl ether or ethanol-diethyl ether. Suitable acids for the formation of these salts include the usual mineral acids, for example hydrogen halides, sulfuric and phosphoric acid; organic acids, for example ascorbic, citric, lactic, aspartic or tartaric acid or aqueous solutions thereof, the pH of which has been adjusted to 5.5 or less; and acids which are sparingly soluble in body fluids and which transfer slow-release properties to their corresponding salts, for example, pamoic or tannic acid or carboxymethylcellulose. The preferred salt is the hydrochloride salt.

The compounds of formula I and their pharmaceutically acceptable acid addition salts are useful in the treatment of various memory disorders associated with reduced cholinergic activity, such as Alzheimer's disease. In addition, said compounds cause stimulation of neuro-25 muscle transfer, increased tension in tense tissues (nerve and smooth and striated muscles), as well as improvement in the function of nerves and neuromuscular synapses when they are damaged. The compounds of formula I also have antidepressant activity, which is particularly advantageous in patients suffering from Alzheimer's disease. The compounds of formula I are generally less toxic and have a wider range of activity than known compounds such as tacrine and physotigmine, so that they are therapeutically advantageous.

5 93117

The ability of the compounds prepared according to Examples 1-4 to inhibit brain acetylcholinesterase was determined by Ellman et al. by spectrophotometric method [Biochemical Pharmacology, 7, 88 (1961)]. IC50 (molar) values for all compounds ranged from 5 to 0.1 pmol.

When the above experiment compared the activity of the novel compounds of formula I with the activity of some of the compounds known from U.S. Patents 4,550,113 and 5,631,286, the results shown in the following table were obtained:

Table

Example AChE IC ^ n 1 345 ± 13 2 272 ± 78 15 4 308 ± 73 U.S. Pat. No. 4,550,113,700 nh2 Co 60 U.S. Pat. No. 4,631,286,200

In the treatment of Alzheimer's disease, the dosages of the compounds of formula I will vary depending on the mode of administration and the compound selected. In addition, the dose will vary according to the particular subject, as well as the age, weight and condition of the subject being treated, and also the nature and extent of the symptoms. Usually, however, the dose will be in the range of about 1 to 300 mg / day, taken as a single dose or in divided doses. The preferred dose is in the range of about 1 to about 150 mg / day in single or divided doses.

Generally, treatment is initiated with small dosages which are substantially less than the optimum dose of the compound. The dose is then increased in small increments until the best effect is obtained under these conditions.

The compounds of formula I are used alone or in combination with pharmacologically acceptable carriers 10 and their proportion is determined according to the solubility and the chemical nature of the compound, depending on the mode of administration and standard pharmaceutical practice. For example, they are administered orally in the form of capsules, tablets, suspensions or solutions, or may be injected parenterally.

Capsules and tablets are the preferred route of administration. For parenteral administration, they may be used as a sterile solution containing other ingredients, such as sufficient salt or glucose to make the solution isotonic.

A capsule or tablet may contain the active ingredient in admixture with one or more pharmaceutical excipients suitable for the manufacture of capsules or tablets. Suitable pharmaceutical additives are, for example, starch, milk sugar or certain types of clays. The tablets may be uncoated or they may be coated according to known methods to provide delayed disintegration or absorption in the gastrointestinal tract and to provide a sustained action over a long period of time.

Aqueous suspensions of the compounds of formula I contain the active ingredient in admixture with one or more pharmaceutical excipients suitable for the manufacture of aqueous suspensions. Suitable additives are, for example, methyl cellulose, sodium alginate, acacia, lecithin, etc.

93117 7

Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

Non-aqueous suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil, for example liquid paraffin, and in the form of a paraffin, e.g. These compositions may additionally contain a sweetener, flavoring and antioxidant.

The following examples illustrate the invention. All melting points are uncorrected. Silica gel was used for thin layer chromatography (TLC).

Example 1 9-Amino-4-oxa-1,2,3,4-tetrahydroacridine To a stirred solution of delta-Valero-lactone (1.0 g, 10.0 mmol) in methylene chloride (10 mL) at -20 ° C. , a solution of 1M titanium (IV) in a solution of chloro-20 in methylene chloride (20 ml) was added. The reaction mixture turned dark yellow in color and a mixture of triethylamine (2.0 g, 20 mmol) and anthranilonitrile (1.2 g, 10.0 mmol) in methylene chloride (30 mL) was added. The reaction mixture immediately turned dark in color and was allowed to warm to room temperature (about 25 ° C) and stirred for a further 15 hours. After this time, the reaction mixture was treated with 25% aqueous NaOH (40 mL) and methylene chloride (100 mL) and filtered using a 5.08 cm pad of diatomaceous earth [Celite (trade name)] and this was washed with methylene chloride (50 mL) and water (100 mL). mL). The organic layer was separated, washed once with water (30 ml) and dried (anhydrous MgSO 4). The methylene chloride was removed in vacuo to give an oil which was triturated with ether to give the title compound as a white solid, 565 mg, 28%. 1 H-NMR (CDCl 3, 300 MHz, δ): c

P

93117 δ 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 (J = 8.0 Hz); 1H, t, 7.5 (J = 8.0 Hz); 1H, d, 7.72 (J = 8.0 Hz).

Example 2 9-Amino-8-fluoro-4-oxa-1,2,3,4-tetrahydroacridine Following the procedure of Example 1, but substituting anthranilonitrile for 2-amino-6-fluorobenzonitrile, the title compound, 8%, was obtained. mp. 195-196 ° C.

Example 3 9-Amino-7-chloro-4-oxa-1,2,3,4-tetrahydroacridine Following the procedure of Example 1, but substituting anthranilonitrile for 2-amino-5-chlorobenzonitrile, the title compound, 2%, m.p. . 178-179 ° C.

Example 4 9-Amino-4-thia-1,2,3,4-tetrahydroacridine Following the procedure of Example 1, but using delta-thiovalerolactone instead of delta-valerolactone, the title compound, 4%, m.p. 190 ° C.

Claims (3)

An analogous process for the preparation of therapeutically useful compounds of formula I wherein R 3 is hydrogen or halogen and Y 1 is O or S, and pharmaceutically acceptable salts thereof, characterized in that a) reacting an aminonitrile of formula II aCN NH 2 wherein R 3 is the same as above, with a compound of formula III 25. III (III) where Y Wherein R 3 and Y 1 are the same as above, and 12 9 5 ΐ 17 if desired, react with a pharmaceutically acceptable acid. 2. A process according to claim 1, wherein 9-amino-8- fluoro-4-oxa-1,2,3,4-tetrahydroacridine or a pharmaceutically acceptable salt thereof can be prepared. A process according to claim 1, characterized in that 9-amino-4-oxa-1,2,3,4-tetrahydroacridine or a pharmaceutically acceptable salt thereof is prepared.