FI90872B - Method for production of therapeutically active 1,2,3a,4,5,6-hexahydro[1,3]oxazino[6,5,4-kl]acridine derivative - Google Patents

Description

90872

Process for the preparation of therapeutically active 1,2,3a, 4,5,6-hexahydro [1,3] oxazino [6,5,4-cl] acridine derivatives 5 Separated from patent application 895605

The invention relates to a process for the preparation of compounds of formula (I) 10

X

HN 0 20 wherein R is hydrogen or halogen, and stereoisomers and pharmaceutically acceptable acid addition salts thereof.

These compounds are useful in the treatment of various memory disorders characterized by reduced cholinergic function in 25 countries, such as Alzheimer's disease.

The chemical formula or name set forth throughout the specification and appended claims is intended to include all stereoisomers, geometric and optical isomers, where such isomers exist, as well as pharmaceutically acceptable acid addition salts of the compound and solvates thereof, such as hydrates.

Compounds of formula I according to the invention are prepared by reacting a compound of formula (V) 2 NH 2 oh, cCo with a compound of formula 10 / = \ 15 This reaction may be carried out with morpholine and a suitable solvent, for example an aromatic hydrocarbon such as in the presence of toluene. Typically, this reaction is performed at a temperature of 100 to 150 ° C.

The starting materials used in the process of the invention may be prepared using one or more of the reaction steps described below.

Step A:

The compound of formula II is reacted with 25,3-cyclohexanedione to give the compound of formula III. Typically, this reaction is performed in a suitable solvent such as benzene or toluene at a temperature of about 50 to 150 ° C.

O

30 j? X ^ CN. ---- _ ^ || || ° f

35 H

(II) (III)

II

3,90872

Step B:

A compound of formula IV is prepared by cyclizing a compound of formula III using a metal halide such as cuprous chloride, cuprobromide or cuproiodide and the like as a catalyst. in the presence of, for example, potassium carbonate, potassium hydrogencarbonate, sodium carbonate, sodium hydrogencarbonate, etc., at a temperature of about 30 to 100 ° C.

NHj p 15 ^ “rm 20

Step C:

A compound of formula V is prepared by reacting a compound of formula IV with a suitable metal hydride such as LiAlH 4 in an ether solvent such as tetrahydrofuran, diethyl ether, dioxane or mixtures thereof at a temperature of about -20 to + 20 ° C and then hydrolysing the product.

30 NH2 OH

(iv) + L1AIH4 -►- 35 (V) 4

The compounds (I) prepared according to the invention can be used for the treatment of various memory disorders characterized by reduced cholinergic function as in the treatment of Alzheimer's disease of Example 5.

The utility of the compounds can be demonstrated by determining their ability to inhibit the activity of the acetylcholinesterase enzyme, thereby increasing acetylcholine levels in the brain.

10 Cholinesterase Inhibition Assay

The ability to inhibit acetylcholinesterase was determined by the photometric method described by

Ellman et al., Biochem. Pharmacol. 7, 88 (1961). The results obtained with some of the compounds of the invention, together with the results obtained with the reference compounds, are shown in Table 1 below.

TABLE 1 Cholinesterase Inhibition 20 Compound ICJ0 (molar conc.) 2-phenyl-1,2,3a, 4,5,6-hexahydro- [1,3] -oxazino [6,5,4-cl] acridine 3, 6x10'5 2- (4-fluorophenyl) -1,2,3a, 4,5,6-hexahydro- [1,3] oxazino [6,5,4-cl] acridine 2,1x10'5 (Reference Compounds) 9-amino-1,2,3,4-tetrahydroacridine 3,1x10'7

Physostigmine 6.0x10'9 35 _

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90872 5 Usefulness can also be demonstrated by determining the ability of compounds to restore cholinergically decreased memory in a dark avoidance assay. This experiment tests the ability of mice to remember an unpleasant stimulus for 24 hours. The mouse is placed in a booth with a dark compartment; a strongly dazzling light drives it into a dark compartment where it is given an electric shock through the metal plates of the floor. The animal is removed from the test device and its ability to remember the electric shock is retested 24 hours later.

10 If an animal is given an anticholinergic scopolamine known to cause memory impairment before it is first introduced into the experimental enclosure, the animal will return to the dark compartment shortly after being restarted in the experimental enclosure 24 hours later. The active compound blocks the action of scopolamine, resulting in an extended time interval before the mouse goes into the dark compartment again.

The test results obtained with the active compound are expressed as a percentage of the percentage of animals in the group in which the action of scopolamine has been inhibited, as shown by the prolonged interval between introduction into the test chamber and return to the dark compartment. The results obtained in the dark avoidance test with the representative compounds of the invention and the reference compound are shown in Table 2.

25 TABLE 2 Dark avoidance test

Compound Dose% of animals mg / kg body weight scopolamine-kg induced memory deficiency 30 reverses 2-phenyl-1,2,3a, 4,5,6-hexahydro- [1,3] oxazino- Sino [ 6,5,4-cl] acridine 5.0 27% 35

Physostigmine (reference compound) 0.31 20% 6

Effective doses of the compounds of formula (I) may be administered to a patient by various methods, for example orally as capsules or tablets, parenterally in the form of sterile solutions or suspensions, and in some cases intravenously as sterile solutions. The final products in the form of the free base, which are themselves active, can be formulated into pharmaceutical preparations and administered as pharmaceutically acceptable acid addition salts due to their better stability, easier crystallization, better solubility, and the like.

Suitable acids for the preparation of pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and perchloric acid, as well as organic acids such as tartaric acid, citric acid, silicic acid, acetic acid, acetic acid, acetic acid,

The active compounds of the invention may be administered orally, for example, in association with an inert diluent or edible carrier 20, or may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the compounds may be incorporated with excipients in tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums, etc. These preparations should contain at least 0.5% of active compound, but may be varied depending upon and is suitably from 4 to about 70% by weight of the unit. The amount of active compound in such compositions is such that a suitable dosage will be obtained. Preferred compositions are prepared so that an oral dosage unit form contains between 1.0 mg and 300 mg of active compound.

Tablets, pills, troches, and the like may also contain the following ingredients: a binder such as microcrystalline cellulose, gum tragacanth, or gelatin; filler,

II

90872 7 such as starch or lactose, a disintegrant such as alginic acid, Primogel, corn starch and the like; a lubricant such as magnesium stearate or steroxy; a glidant such as colloidal silica; a sweetening agent such as sucrose or saccharin may also be added or a flavoring agent such as peppermint oil, methyl lisalylate or orange flavoring may be added. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as edible oil. Other dosage unit forms may contain other various materials for modifying the physical form of the dosage unit, for example, as coatings. Tablets and pills may thus be coated with sugar, shellac or enteric coating agents. The syrup may contain, in addition to the active ingredient, certain preservatives, dyes and flavors. The materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used.

Example 1 2-Phenyl-1,2,3a, 4,5,6-hexahydro [1,3] oxazino- [6,5,4-cl] acridine 9-Amino-1,2,3,4-tetrahydroacridide -1-ol (15.0 g) was refluxed in toluene (1 L) containing 12.28 g of morpholine and 9.29 g of benzaldehyde (vas-stained with K 2 CO 3). The reaction mixture was refluxed overnight, then allowed to cool. The crude product was filtered and purified by flash chromatography (20% isopropanol / ethyl acetate) to give, after crystallization from methanol / water, 8.07 8: 80:20 diastereomers. Recrystallization from dimethylformamide / water gave a 60:40 mixture of diastereomers, m.p. 225-235 ° C.

Analysis:

Calculated for C 2 OH 18 N 2 O: 79.44% C 6.00% H 9.27% N

Found: 79.37% C 5.98% H 9.26% N

8

Example 2 2- (4-Fluorophenyl) -1,2,38,4,5,6-hexahydro [1,3] oxazino [6,5,4-cl] acridine 9-amino-1,2,3 A mixture of 1,4-tetrahydroacridin-1-ol (7.77 g), 5-fluorobenzaldehyde (5.9 g) and morpholine (6.3 ml) in 400 ml of xylene was boiled for 16 hours while removing water.

The solvent was then removed and the desired product was purified by flash chromatography (20% isopropanol-ethyl-10 acetate) to give 3.5 g of a yellow solid, m.p. 220-234 ° C (dec.). It was crystallized from methanol / water to give 2.3 g of a yellow solid, m.p. 238-241 ° C (dec.).

Analysis:

15 Calculated, C 20 H 17 FN 2 O: 74.98% C 5.35% H 8.74% N

Found: 74.93% C 5.47% H 8.71% N.

li

Claims (3)

A process for the preparation of therapeutically active 1,2,3a, 4,5,6-hexahydro [1,3] oxazino [6,5,4-cl] acr indine derivatives of formula (I) R (C) (I) where R is hydrogen or halogen, and stereoisomers and pharmaceutically acceptable acid addition salts thereof, characterized in that a compound of formula (V) 20 nh 2 pH Cu) (v> 25 reacted with a compound of formula wherein R is the same as above. 2. A process according to claim 1, characterized in that 2-phenyl-1,2,3a, 4,5,6-hexahydro [1,3] oxazino [6,4,5-chloro] acridine is prepared. or a pharmaceutically acceptable acid addition salt thereof. A process according to claim 1, characterized in that 2- (4-fluorophenyl) -1,2,3a, 4,5,6-hexahydro [1,3] oxazino [6,4] is prepared. , 5-chloroacridine or a pharmaceutically acceptable acid addition salt thereof. IN!