AU684880B2

AU684880B2 - Use of a tricyclic compound for obtaining medicinal products intended for the treatment of memory/cognitive disorders

Info

Publication number: AU684880B2
Application number: AU13488/95A
Authority: AU
Inventors: Bruno Delalleau; Antoine Deslandes; Annie Kamoun
Original assignee: ADIR SARL
Current assignee: ADIR SARL
Priority date: 1994-02-25
Filing date: 1995-02-24
Publication date: 1998-01-08
Anticipated expiration: 2015-02-24
Also published as: NO950714L; CA2143251A1; FR2716623B1; NO950714D0; AU1348895A; JPH07258089A; NZ270566A; ZA951575B; FR2716623A1; FI950725A0; FI950725A; CN1119100A; CN1051226C; EP0671173A1

Description

Regulation 3,2(2)

AUSTRALIA

Patents Act 1990

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT *o *o o *r Application Number: Lodged: Invention Title: USE OF A TRICYCLIC COMPOUND FOR OBTAINING MEDICINAL PRODUCTS INTENDED FOR THE TREATMENT OF MEMORY/COGNITIVE DISORDERS e The following statement is a full description of this invention, including the best method of performing it known to us C~U~I_ The invention relates to the use of a tricyclic compound for obtaining medicinal products intended for the treatment of memory/cognitive disorders.

More specifically, the invention relates to the use of the compound of formula

CH

3

I

Cl

S-N

Cl j isomer (I)

HN-(CH

2 6

-CO

2

H

as well as its addition salts with a pharmaceutically acceptable acid or base, for obtaining medicinal products intended for memory/cognitive disorders.

According to this invention, there is provided a method of treating memory/cognitive disorders including administering to a patient requiring such treatment an effective amount of the isomer of a compound of formula or one of its additional salts, with a pharmaceutically effective acid or base.

As a base capable of salifying the compounds of formula sodium, Si'" potassium, calcium or aluminium hydroxide, alkali metal or alkaline-earth metal carbonates or organic bases such as triethylamine, benzylamine, 15 diethanolamine, tert-butylamine, dicyclohexylamine, arginine, and the like, may be used.

Among acids which may be added to the compounds of formula to obtain an addition salt, hydrochloric, sulfuric, phosphoric, tartaric, malic, maleic, furmaric, oxalic, methanesulfonic, ethanesulfonic, camphoric, citric, and the like, acids may be mentioned without implied limitation.

The compound of formula which is preferentially useable according to the invention is the isomer of tianeptine in the form of the sodium salt, or sodium (+)-7-[(3-chloro-6-methyl-6,1 1-dihydrodibenzo[c,f][1,2]thiazepin-11-yl) amino]heptanoate Tianeptine is described in French Patent FR 2,104,728 (Example 3).

Patent FR 2,104,728 claims the use of tianeptine and its derivatives in the treatment of psychoneurotic disorders, pain and cough. French Patent FR 2,635,461 describes the use of tianeptine and its derivatives in the treatment of stress.

Recent work has shown that tianeptine has significant effects on memory.

z- These are described by: S.E. File et al. in: Drug Development Research, 1991, 23, 47-56:

I-

R. Jaffard et al. in: Journal de Psychiatrie Biologique et Thdrapeutique, 1989, special No., March, 37-39; R. Jaffard et al. in: Abstracts of the XVI th CINP Congress, Munich (Germany), 5-19 August 1988; Psychophannacology, 1988, 96 (suppl), 31.02.32, p.

2 7 R. Jaffard et al. in: Behavioural Pharmacology, 1991, 2, 37-46 C. Lebrun et al. in: European Psychiatry, 1993, 8 (suppl.2), 81s-88s R. Jaffard et al. in: Presse Mdicale, 1991, 20, 37, 1812-1816.

The applicant has now discovered that, surprisingly, the isomer of tianeptine displays pharmacological properties markedly superior to those observed for tianeptine. Thesf properties enable it to be used in the treatment of memory and cognitive disorders aifid neuro-behavioral disorders associated with cerebral aging and with acute or chronic degenerative diseases of the nervous system, such as Alzheimer's disease, Pick's disease, Korsakoffs syndrome, stroke, spinal trauma, amyotrophic lateral sclerosis or multiple sclerosis.

s The results obtained in mice might be obtained in man. In effect, if it is postulated that the rate of forgetting is determined by encoding strategies associated with the hippocampus, it appears S that a memory test which would employ essentially the representation of similar successive experiences in a specific context might be suitable for evaluating the effects of aging on long-term forgetfulness in man Lebrun et al. European Psychiatry, 1993, 8 (suppl.2), 81s-88s). It would appear, moreover, that some basic cerebral mechanisms involved in normal and pathological long-term forgetfulness are common to man, monkeys and rodents (Squire, Psychological Review, 1992, 99, 195-231).

Moreover, the enantiomer displays a satisfactory toxicological and pharmacokinetic S profile. In rats, the bioavailability of the isomer is 29%, whereas the bioavailability of the iJ racemate is only 11%. Its absorption is rapid (tmax 0.5 h) after oral adminstration. Its half-life is 1.8 h. Lastly, in contrast to the enantiomer and the racemate which decrease in a dose-dependent manner 10 and 15 mg/kg) the number of feces expelled and the tremor, the enantiomer has no significant effect. Thus, the enantiomer hence has no effect on serotoninergic transmission, in contrast to the racemate and the enantiomer.

The compounds of the formula or their pharmaceutically acceptable salts will be presented in pharmaceutical dosage forms suitable for oral and parenteral, and in particular intravenous, per- or transcutaneous, nasal, rectal, perlingual, ocular or respiratory, adminstration, and in particular injections, aerosols, eye or nose drops, tablets, sublingual tablets, preparations to be XIIIII~llplaced under the tongue, capsule including hard gelatin capsule, troches, suppositories, creams, ointments, skin gels, and the like.

The dosage varies according to the patient's age and weight, the administration route and the nature of the therapeutic indication and of associated treatments, and ranges from 0.1 mg to 100 mg per dose or per application.

The examples which follow illustrate the invention and in no wa-y limit it.

Example 1: Stereospecific synthesis of sodium (+)-7-[(3-chloro-6-methyl-6,11-dihydrodibenzo[c,fj][,2]thiazepin-11-yl)amino]heptanoate 5,5-dioxide (or isomer of tianeptine) The isomer of tianeptine was obtained by resolving 1 1-amino-3-chloro-6-methyl-6, 1-dihydrodibenzo[c,f] [1,2]thiazepine 5,5-dioxide, condensing S the isomer with ethyl 7-bromoheptanoate and then saponifying the ester obtained.

Stage A: 1 1-amino-3-chloro-6-methyl-6,11-dihydrodibenzo[cf][1,2]thiazepine (-)-dibenzoyltartarate 162 mmol of (-)-dibenzoyltartaric acid monohydrate dissolved in 400 ml of 96% ethanol are added to 162 mmol of 1-amino-3-chloro-6-methyl-6,1l-dihydro-dibenzo[c,f][1,2]thiazepine suspended in 600 ml of 96% ethanol. The mixture is stirred for 3 hours at room temperature. After the precipitate obtained has been filtered off and dried, it is recrystallized twice in 96% ethanol and yields the expected product.

Isomeric purity: 99% 0* Stage B: Ethyl (+)-7-[(3-chloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2] thiazepin-ll-yl)amino]heptanoate 43.5 mmol of the compound obtained in the preceding stage are mixed with 0.5 M sodium carbonate and extracted with dichloromethane. The organic phase is dried and evaporated. To the white solid thereby obtained, 200 ml of anhydrous ethanol and then 10 g of anhydrous potassium carbonate are added. The mixture is brought to reflux and 65.4 mmol of ethyl 7-bromoheptanoate are added dropwise. The mixture is kept refluxing for 3 days under a nitrogen atmosphere and protected from light. After the reaction medium has been filtered and sT1 B~C~B~IP~B 7 the filtrate evaporated, the residue is taken up with ethyl ether. The insoluble matter is filtered off and the filtrate is evaporated. The oil thereby obtained is taken up with isopropyl ether, and yields the expected product after the precipitate formed has been filtered off and dried.

Sttage C: Sodium (+)-7-[(3-chloro-6-methyl-6,11-dihydrodibenzo[c,f] 1,2]thiazepin-11-yl) amino]heptanoate 42 mmol of the compound obtained in the preceding stage are placed in a mixture containing ml of 96% ethanol and 45 ml of 1N sodium hydroxide. The mixture is stirred overnight at room temperature and, after evaporation of the ethanol and washing with dichloromethane, the aqueous phase is neutralized with 45 ml of 1N hydrochloric acid. The corresponding acid is then extracted with dichloromethane, the organic phase is dried and evaporated and the acid is purified by chromatography on a silica column using a dichloromethan/methanol (98:2) mixture as eluent. It is then converted to the corresponding sodium salt by dissolution in a stoichiometric amount of 1N sodium hydroxide. After the addition of 50 ml of water, the '*1s5 expected product is lyophilized.

Optical rotation: [o]D 20 9.20 (c 5.0 mg/ml, 95% ethanol) Elemental microanalysis: C% H% N% calculated 54.96 5.27 6.10 S: found 55.08 5.49 6.16 The enantiomeric purity is verified by liquid chromatography.

Column: L 15 cm, internal diameter: 4.6 mm Mobile phase: 20 mM KI1 2

PO

4 pH 6.1/ethanol, 8:2 Flowrate: 0.9 ml/min Temperature: room temperature Detection: UV 220 nm Solution: 0.5 mg/ml in a potassium phosphate buffer, pH 6.1 Injection: 2 pl Under these conditions, the enantiomeric purity of the compound is greater than 99%.

s a -41 C-_CIC I C Example 2: Pharnacological study of the isomer of tianeptine Comparison of the effects of tianeptine and of the isomer of the latter on spontaneous alternation, acquisition and retention of a simple spatial discrimination (T-shaped aze) in mice Earlier results showed that tianeptine facilitated, in mice, at a dose of 10 mg/kg, spontaneous alternation, acquisition and retention of a simple discrimination determined in a T-shaped maze. The facilitatory effects of tianeptine had been observed in two independent experiments using an identical apparatus but placed in a different environment (room), the experiments being carried out by different investigators (Jaffard et al. Behav. Pharmacol., 1991, 2, 37-46).

The object of this experiment is, using the same tests, to compare the effects of tianeptine with those of the isomer.

The principle of the test is based on the inate tendency possessed by mammals confronted with a choice between two directions to take, to go and explore the place less familiar to them.

An animal placed several times in succession at the entrance to a T-shaped maze will preferably head for the arm it has not visited before. In order for this behavior to become apparent, it is obviously necessary for the animal to recollect the last arm visited. This recollection involves so-called working memory. The mouse is subjected to a learning phase S (acquisition), during which it has to choose several times in succession between the two arms, S until it has opted five times in succession for one arm determined by the investigator. To assess whether the animal has indeed retained what it has learned during the acquisition test, it is put back 24 hours later into the same situation. The degree of retention will be measured by the number of tests undergone before achieving success in five consecutive tries.

Techniques and methods Animals: 36 14- to 16-week-old male BALB/c line mice not previously subjected to any experiments are used. 15 days before the beginning of the experiments, they are placed in individual cages (air-conditioned (22°C) animal house provided with a 12-hour artificial light-darkness cycle (7 a.m. ON)).

Apparatus: This is a T-shaped maze made from gray Plexiglas. The central passageway and the two finishing arms measure 35 cm in length, 10 cm in width and 20 cm in height. The starting sC' compartment (10 12 cm) is separated from the central passageway by a vertically sliding door. The entrance to each arm is also provided with a door. The apparatus used is semiautomatic: the supply to the feeders and the opening and closing of the doors are controlled by a microcomputer according to the preestablished protocol, Protocol: All the tests take place between 9 a.m. and. 4 p.m. and over 4 days (from D1 to D4) without interruption. The animals' feed ration is reduced so as to achieve a body weight of 83-84% of the ad libitum weight for the habituation tests (D1 and D2) and 87-88% in the alternation and spatial discrimination tests (D3 and D4).

Habituation (D1-D2): The experiment proper is preceded by two 10-minute habituation sessions (free exploration, one session per day). The animal is simply placed in the apparatus with all the doors open.

Spontaneous alternations and acquisition of discrimination (D3): S" These two tests take place the next day without interruption. They are designed to measure the Y'1"5 alternation (first 6 tries) and the rate of acquisition of spatial discriminaion (following tries).

During the first 6 tries, food is arranged at the end of each of the two arms. During each try, the animal is placed in the starting compartment for 30 seconds (interval between tries). The door giving access to the central passageway is opened and the mouse can choose between the two arms, where it remains shut in for 30 seconds. A normal animal is found to alternate its *20 successive choices (approximately 65% alternation). From the 6th try onwards, food is now arranged in one arm only, always the same one; the arm chosen is the one which has been visited less during the first 6 tries. The test is then continued "ntil the animal achieves a criterion of 5 correct responses in 5 consecutive tries.

Retention of spatial discrimination (D4): This takes place under the same conditions as acquisition (same arm reinforced), and is continued for a minimum of 10 tries, or beyond, until the criterion of 5/5 is achieved. The number of tries is limited to Treatments and groups: The 36 animals are divided into 3 groups of 12 subjects receiving, depending on the group, one of the products tested during the execution of the experiment: tianeptine, the isomer or placebo. The treatments are administered intraperitoneally 30 minutes before the tests on day 3 (alternation acquisition) and on day 4 (retention) at a dose of 10 mg/kg for each of the products. The control group receives the solvent ml/ 10 g of physiological -aline).

Ib Analysis of the results: All the values are expressed as means together with their standard error. The results relating to alternation (percentage), the number of tries needed for achieving the criteria for acquisition and for retention, and the number of correct responses in the first 5 and in the first 10 tries of retention are compared between groups (TREATMENT effect) by analyses of variance (ANOVA) followed by comparisons of the groups taken in pairs (Fisher's F test). The acquisition performances between groups were compared by taking the number of correct responses recorded in the first 20 tries, or the equivalent for animals which had achieved the criterion in fewer than 20 tries.

Results: 1. Acquisition of discrimination: Number of correct responses in the first 20 tries of the test 0.77 14.83 0.75 13.58 0.86 The results obtained with the isomer are superior to those obtained with the control group and to those obtained with racemic tianeptine.

2. Retention of discrimination: Tries to meet the criterion: There is a significant difference between groups. The experimental groups have performances superior to those of the placebo group. The greatest improvement is observed with the isomer: 8.58 0.60 tries 7.83 0.74 tries 1.07 tries The results obtained with the isomer are statistically superior (p 0.01) to those obtained with the control group.

Correct responses in 5 and 10 tries: The treatment effect is significant from the first five tries onwards and during the first ten tries of retention.

In the first 5 tries, only the isomer has performances significantly superior (p<0.01) to those of the placebo group (3.92 0.15 vs. 3.0 0.21). Tianeptine has no effect.

I1F~P~L~L~ssar~ecr~ rP-s ~I -p In the first ten responses, the experimental groups have performances superior (p<0.0 5 to those of the placebo group. The isomer has performances superior to those of the tianeptine group.

Conclusion: During a pharmacological test recognized as predictive of the promnesic activity of a compound, the isomer showed efficacy: in respect of acquisition, the isomer tends to increase the number of correct responses; in respect of retention: tries to meet the criterion, correct responses in the first 5 or the to first 10 tries, the isomer has a positive effect and an effect superior to that of racemic tianeptine.

The isomer is capable of increasing animals' memory, and is hence likely to improve memory disorders in man.

Example 3: Pharmaceutical composition ::f5 Tablets containing a 12.5 mg dose of isomer of tianeptine Preparation formula for 1000 tablets Isom er of tianeptine 12.5 g W heat starch 15 g M aize starch 65 g M agnesium stearate 2 g Silica 1 g g -il 9 Iq- -P I -4Yqil~s

Claims

1. A method of treating memory/cognitive disorders including administering to a patient requiring such treatment an effective amount of the isc "nr of a compound of formula or of one of its addition salts with a pharmaceutically acceptable acid or base, CH 3 i CI SO -N. isomer (I) HN- (CH 2 6 -CO 2 H

2. A method according to claim 1, including the administration of an addition salt of the compound of formula wherein the addition salt is sodium salt. o

3. A pharmaceutical composition for the treatment of memory/cognitive disorders, containing as active principle the isomer of the compound of formula as claimed in claim 1, or one of its addition salts with a pharmaceutically acceptable acid or base.

4. A method of preparing a composition as claimed in claim 3, including admixing, in a pharmaceutically acceptable ratio, an effective amount of the isomer of the compound of formula as claimed in claim 1 or one of its addition salts with a pharmaceutically acceptable acid or base. DATED this 21st day of August, 1997. ADIR ET COMPAGNIE WATERMARK PATENT TRADEMARK ATTORNEYS 290 BURWOOD ROAD HAWTHORN VICTORIA 3122 AUSTRALIA LCG:PJM:GL DOC 016 AU1348895.WPC LI L- ~~rs~a~T~L1 C ABSTRACT USE OF A TRICYCLIC COMPOUND FOR OBTAINING MEDICINAL PRODUCTS INTENDED FOR THE TREATMENT OF MEMORY/COGNITIVE DISORDERS ADIR ET COMPAGNIE 1 rue Carle HIbert 92415 COURBEVOIE Cedex C C C C CC The invention relates to the use of a tricyclic compound for obtaining medicinal products intended for the treatment of memory/cognitive disorders. Medicinal products. I ^-s~IIP~y