BG64819B1 - Combination of tetrahydropyridins and acetylcholinesterase for treating senile dementia of alzheimer type - Google Patents

Abstract

The invention concerns a pharmaceutical composition for the preparation of medicamentous means designed for the treatment of senile dementia or Alzheimer type. The composition comprises as active component 4-substituted-1,2,3,6-tetrahydropyridin selected from 1-2-napht-2-yletil)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridin and 1-[2-(4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridin, optionally in the form of its pharmaceutically acceptable salts, and a compound which is in the symptomatic treatment of dementia of Alzheimer type, occasionally in the form of itspharmaceutically acceptable salts.

Description

The present invention relates to a pharmaceutical composition containing a novel combination of active ingredients for the treatment of senile dementia of the Alzheimer's type composed of derivatives of 1,2,3,6-tetrahydropyridine, optionally in the form of their pharmaceutically acceptable salts and active substance for symptomatic treatment of Alzheimer's type senile dementia, in particular an acetylcholine esterase inhibitor, optionally in the form of its pharmaceutically acceptable salts, and to the use of the composition for the preparation of medicaments, e.g. dnaznacheni for the treatment of senile dementia of the Alzheimer type.

BACKGROUND OF THE INVENTION

Senile Alzheimer's-type dementia, hereinafter referred to as DAT ("Alzheimer's-type dementia"), is a neurodegenerative disease characterized by clinical progressive degeneration of cognitive function, which occurs in adults with a prevalence that increases with age. Given the demographic trends, DAT is becoming more and more prevalent.

A decrease in the level of various neurotransmitters, in particular acetylcholine, has been observed in patients suffering from DAT.

The only treatment for DAT currently available in the market is the use of acetylcholinesterase inhibitors, which, by reducing the hydrolysis of acetylcholine, increase its bioavailability. It is therefore a symptomatic treatment.

Tacrine, commonly known as COGNEX®, and donepezil, marketed under the trademark ARICEPT®, are acetylcholinesterase inhibitors indicated for the symptomatic treatment of mild to moderate DAT. Other symptomatic treatment products for

DATs are under study. Some also act on the availability of acetylcholine, others improve the symptomatology of patients suffering from DAT through other mechanisms. So far, there is no commercially available drug capable of slowing the progression of the disease.

EP 458696 describes the use of 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine, referred to in the literature as SR 57746, for the preparation of medicaments designed to overcome neurodegenerative conditions, including senile dementia and Alzheimer's disease. The neurotropic effect of SR 57746 on the nervous system is similar to that of some endogenous neurotrophins such as, for example, nerve growth factor (NGF).

WO 1997/001536 discloses novel 420 substituted 1-phenylalkyl-1,2,3,6-tetrahydropyridines with neuroprotective and neurotrophic effects similar to some endogenous neurotrophins. As a result of this activity, it is suggested that the compounds described in this patent application would be useful for the treatment of certain diseases of the central nervous system, including Alzheimer's disease.

The activity of SR 57746 and the compounds described in WO 1997/001536 for the treatment of nervous diseases such as DAT is not intended to treat the symptoms but to protect the neurons, modify the course of the disease and reduce its progression.

SUMMARY OF THE INVENTION

It has now been found that a combination of the above compounds, optionally in the form of their pharmaceutically acceptable salts, with a compound 40 active in the symptomatic treatment of Alzheimer's type senile dementia, in particular an acetylcholinesterase inhibitor, in the form of its pharmaceutically acceptable salts, results in complete and very effective treatment of DAT, the combination exerts a rapid and complementary effect.

Thus, an object of the present invention is a pharmaceutical composition containing as active ingredients

- compound (a) selected from 1- (2-naphth-2 ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine, and a compound of formula (I)

wherein Y is -CH- or -N-;

R 1 represents hydrogen, halogen, CF ₃ , (C ₃ C ₄ ) alkyl or (C 1 -C ₄ ) alkoxy;

R ₂ represents hydrogen, halogen, hydroxy, CF ₃ , (C ₃ -C ₄ ) alkyl or (C 1 -C ₄ ) alkoxy;

R ₃ and R _{4 are} each hydrogen or (C 1 -C ₃ ) alkyl;

X is a) (C ₃ -C ₆ ) alkyl; (C ₃ -C ₆ ) alkoxy; (C ₃ C ₇ ) carboxyalkyl; (C ₁ -C ₄ ) alkoxycarbonyl (C ₃ C ₆ ) alkyl; (C ₃ -C ₇ ) carboxyalkoxy; or (C 1 -C ₄ ) alkoxycarbonyl (C ₃ -C ₆ ) alkoxy;

b) a radical selected from (C ₃ -C ₇ ) cycloalkyl, (C ₃ -C ₇ ) cycloalkyloxy, (C ₃ -C ₇ ) cycloalkylmethyl, (C ₃ -C ₇ ) cycloalkylamino and cyclohexenyl, which radical is optionally substituted by halogen, hydroxy, (C 1 -C ₄ ) alkoxy, carboxy, (C, C ₄ ) alkoxycarbonyl, amino, mono- or di- (C 1 -C ₄ ) alkylamino; or

c) a group selected from phenyl, phenoxy, phenylamino, N- (C 1 -C ₃ ) alkylphenylamino, phenylmethyl, phenylethyl, phenylcarbonyl, phenylthio, phenylsulfonyl, phenylsulfinyl or styryl, such as the phenyl group being optionally mono- or poly-mono- or poly halogen, CF ₃ , (C 1 -C ₃ ) alkyl, (C, C ₄ ) alkoxy, cyano, amino, mono- or di- (C 1 -C ₄ ) alkylamino, (C 1 -C ₄ ) acylamino, carboxy , (C, C ₄ ) alkoxycarbonyl, aminocarbonyl, mono- or di- (C 1 -C ₄ ) alkylaminocarbonyl, amino (C ₍ -C ₄ ) alkyl, hydroxy (C) -C ₄ ) alkyl or halo (C, C ₄ ) alkyl; optionally in the form of one of its pharmaceutically acceptable salts and

- compound (b) active in the symptomatic treatment of DAT, optionally in the form of one of its pharmaceutically acceptable salts, provided that when compound (a) is different from 1- (2-naphth-2-ylethyl) - 4- (3-Trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine or one of its pharmaceutically acceptable salts, compound (b) is an acetylcholinesterase inhibitor.

BER 101 381 describes 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine (SR 57746) and the compounds of formula (I) above are described in WO 1997/001536.

Particularly preferred compound (a) is 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine (SR 57746), optionally in the form of one of its pharmaceutically acceptable salts.

Of the pharmaceutically acceptable salts of SR 57746, hydrochloride, hereinafter referred to as SR 57746A, is a particularly preferred salt.

A preferred method for the preparation of SR 57746A consists in the interaction between 2 (2-bromoethyl) naphthalene and 4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine and the isolation of 1- (2-naphth-2-ylethyl) ) -4- (3-Trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride, which is then crystallized from a mixture of ethanol / water by heating and cooling to 5 ° C at a cooling rate of 10 ° C / h and stirring at a speed of 400 rpm to obtain a mixture of two crystalline forms in a ratio of about 66:34.

SR 57746A is preferably used in the form of microparticles, for example in substantially amorphous form obtained by spray drying or in microcrystalline form by microcrystallization.

Another particularly preferred compound (a) is 1- {2- (4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine, optionally in the form of its pharmaceutically acceptable salts, and especially its hydrogen chloride salt.

In particular, the present application relates to a pharmaceutical composition characterized in that it contains as active ingredients compound a) which is 4-substituted-1,2,3,6-tetrahydropyridine selected from 1- (2-napht- 2-ylethyl) -4 (3-trifluoromethyl phenyl) -1,2,3,6-tetrahydropyridine and 1- [2- (4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2, 3,6-tetrahydropyridine, optionally in the form of its pharmaceutically acceptable salts, and compound b), active in the symptomatic treatment of Alzheimer's type senile dementia, optionally in the form of its pharmaceutically acceptable and salts thereof.

Compound b), active in the symptomatic treatment of senile dementia of Alzheimer's type, is in particular an acetylcholinesterase inhibitor or a pharmaceutically acceptable salt thereof.

The acetylcholinesterase inhibitor is selected in particular from tacrine, donepezil and rivastigmine.

The pharmaceutical composition of the invention preferably contains from 0.5 to 700 mg of compound a) and from 0.1 to 50 mg of compound b).

A preferred composition according to the invention contains from 0.5 to 10 mg of 1- (2-naphth-2ylethyl) -4- (3-trifluoromethyl phenyl) -1,2,3,6-tetrahydropyridine or a pharmaceutically acceptable salt thereof.

Preferred compositions according to the invention which comprise 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine and donepezil or pharmaceutically acceptable salts thereof as active ingredients.

Also preferred are compositions containing 1- [2- (4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) -

1,2,3,6-tetrahydropyridine and donepezil or their pharmaceutically acceptable salts.

The amount of active ingredients in these compositions is 0.5 to 5 mg of 1- (2-naphth-2-ylethyl) 4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine and 2 to 10 mg of donepezil.

The compositions of the invention are suitable for use in the treatment of senile dementia of Alzheimer's type, for the purpose of which medicines are intended for the treatment of senile dementia of Alzheimer's type.

Particularly preferred are compositions according to the invention that contain 1- (2-naphth-2ylethyl) -4- (3-trifluoromegyl phenyl) -1,2,3,6-tetrahydropyridine or 1- [2- (4-biphenylyl) ethyl] -4 (3-Trifluoro-methylphenyl) -1,2,3,6-tetrahydropyridine, optionally in the form of their pharmaceutically acceptable salts, wherein the compound b) is selected from tacrine, donepezil and rivastigmine.

In the present invention, the expression "active in the symptomatic treatment of Alzheimer's type senile dementia" means a product which is capable of improving the symptomatology of patients suffering from DAT without having any effect on the cause of the disease.

Such compounds are, for example, acetylcholinesterase inhibitors, M, muscarinic agonists, nicotinic agonists, N-methyl-O-aspartate (NMDA) receptor antagonists, nootropics, with preferred acetylcholinesterase inhibitors.

According to a preferred aspect, the invention relates to a pharmaceutical composition comprising as active ingredient compound (a), optionally in the form of its pharmaceutically acceptable salt, and compound (b) selected from acetylcholinesterase inhibitors, optionally in the form of its pharmaceutically acceptable salts.

Particularly preferred acetylcholinesterase inhibitors are tacrine and donepezil.

Other acetylcholinesterase inhibitors that may be used are, for example, rivastigmine (SDZ-ENA-713), galantamine, metrifonate, eptastigmine, velnacrine, physostigmine (Drugs, 1997, 53 (5): 752-768; The Merck Index 12 ed .).

Other acetylcholinesterase inhibitors are 5,7-dihydro-3- {2- (1- (phenylmethyl) -4-piperidinyl) ethyl} -6H-naphtho (3,2-f) -1,2-benzisoxazol-6-one , also known as icopesil (J. Med. Chem. 1995, 38: 2802-2808), MDL-73, 745 or digitosilon (Eur. J. Pharmacol. 1995, 276: 9399), TAK-147 (J. Med. Chem., 1994, 37: 22922299).

Other acetylcholinesterase inhibitors are, for example, those described in patent application JP 09-095483, WO 1997/013754, WO 1997/021681, WO 1997/019929, ZA 96-04565, US 5 455 245, WO 1995/021822, EP 637 586, US 5 401 749, EP 742 207, US 5 547 960, WO 1996/020176, WO 1996/002524, EP 677 516, JP 07-188177, JP 07-133274, EP 649 846, EP 648 771, JP No. 07-048370, US 5,391,553, WO 1994/029272, EP 627,400.

M-receptor antagonists are, for example, myelamelin, besipyridine, talzaclidin, xanomelin, YM-796 and YM-954 (Eur. J. Pharmacol., 1990,187: 479-486), 3- {M- (2-diethylamino) -2-methylpropyl) -6-phenyl-5-propyl} pyridazinamine, also known as SR-46559 (Biog. Med. Chem. Let. 1992, 2: 833-838), AF-102, CI-979, L689 , 660, LU 25-109, S-99 77-2, SB 202,026, Thiopylcarpine, VAL 2014 (Pharmacol. Toxicol. 1996, 78: 59-68).

Preferred nicotine agonists are, for example, ISS-231 (Biorg. Med. Chem. Let., 1995, 5 (14): 1495-1500), T-588 (Japan J. Pharmacol., 1993, 62: 81-86). , ABT-418 (No. J.

Pharmacol., 1997, 120: 429-438).

A preferred NMDA receptor antagonist is, for example, memantine (Arzneim. Forsch., 1991, 41: 773-780).

In another aspect, the present invention relates to the use of the compositions of the invention for the preparation of medicaments for the treatment of senile dementia of Alzheimer's type.

According to another aspect, the present invention relates to a method of treating Alzheimer's type senile dementia, which comprises administering to the patient suffering from the disease an effective amount of compound (a) above, optionally in the form of one of its pharmaceutically acceptable salts and an effective amount of compound (b), in particular an acetylcholinesterase inhibitor, optionally in the form of one of one of its pharmaceutically acceptable salts, administering simultaneously, sequentially or alternatively, int and the effective amount of active ingredients contained in separate units of administration or, when the active ingredients are administered concomitantly, the two active ingredients are preferably contained in the same pharmaceutical form.

The active ingredients of the present invention are preferably administered orally.

In the pharmaceutical compositions of the present invention for oral administration, the active ingredients may be administered in unit dosage forms, in admixtures with standard pharmaceutical carriers, to animals and humans for the treatment of the diseases listed. Suitable unit dosage forms include, for example, divisible tablets, capsules, powders, granules and solutions or oral suspensions.

When the solid composition is formulated into tablets, the main active ingredient is mixed with pharmaceutical carriers such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets may be coated with sucrose or other suitable materials, or may be treated to have prolonged or delayed activity, and continuously release a predetermined amount of active ingredient.

Capsule preparation is performed by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard capsules.

In the preparation of the syrup or elixir forms, the active ingredient may be contained together with a sweetening agent, preferably calorie-free, methyl paraben and propyl paraben as antiseptics, as well as a flavoring agent and a suitable colorant.

Powders and granular dispersions in water may contain the active ingredient in admixture with dispersing agents or wetting agents, or suspending agents such as polyvinylpyrrolidone, as well as with sweetening agents or flavor enhancers.

The active ingredients may also be formulated as microcapsules, optionally with one or more carriers or additives.

In the pharmaceutical compositions of the present invention, the active ingredient may be in the form of a cyclodextrin complex, its ethers or their esters.

The amount of active substance to be administered depends, as always, on the degree of progression of the disease, as well as on the age and weight of the patient.

The doses of the two active ingredients are similar to those commonly selected in the area for the isolated administration of each of these active ingredients.

The compositions according to the invention contain the recommended doses for non-combination treatment, for example, 0.5 to 700 mg of compound (a) or one of its pharmaceutically acceptable salts and 0.1 to 50 mg of compound (b) or one of its pharmaceutically acceptable salts, or even lower doses given in such a way that the combination exerts a synergistic effect.

Preferred compositions contain, for example, 0.5 to 5 mg of SR 57746 or one of its pharmaceutically acceptable salts and 0.1 to 50 mg of an acetylcholinesterase inhibitor or one of its pharmaceutically acceptable salts.

Preferred compositions contain 0.5 to 5 mg of SR 57746 or one of its pharmaceutically acceptable salts, in particular hydrochloride, and 2 to 10 mg of donepezil or one of its pharmaceutically acceptable salts.

The dosages indicated in the present formulation refer to the active ingredients which have not been salt-converted.

The activity of the composition according to the invention is demonstrated by using a specific model for the septo-hippocampus cholinergic system on damage caused by injection of vincristine, which causes biochemical changes similar to the changes present in Alzheimer's disease.

The procedure used in this model, the vincristine lesions, and the assessment of social memory are described in EP 655247.

Evaluation of a social memory test in rats

After provoking lesions by injection of vincristine as described in EP 655247, the rats showed stable and persistent amnesia. Rats were divided into two groups, one group received solvent and the other group received SR 57746A at a dose of 5 mg / kg p.o., a dose that was insufficient to allow functional memory recovery in rats subjected to this test ( the effective dose is 10 mg / kg as described in EP 655247). A dose of 1 mg / kg p.o. tacrine to both groups of rats. The control group that received solvent and tacrine did not show memory regrowth, while the group treated with SR 57746A (sub-dose) and tacrine showed significant recovery of insufficient memory retention.

The results of this test indicate the synergistic action of the combination according to the present invention.

As a result of this complementary and synergistic effect on the components of the combination, while guaranteeing the protection and even healing of the neurons affected by the disease, as well as immediate improvement of the patient's symptoms, the composition of the invention enables effective treatment of DAT in all its forms .

Claims

Claims (10)

1,2,3,6-tetrahydropyridine or a pharmaceutically acceptable salt thereof, in particular a hydrogen chloride salt. 1,2,3,6-tetrahydropyridine or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising as active ingredients: compound a) which is 4-substituted-1,2,3,6-tetrahydropyridine selected from 1- (2-naphth-2-ylethyl) - 4 (3-Trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine and 1- [2- (4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine, optionally in the form of its pharmaceutically acceptable salts, and compound b) active in the symptomatic treatment of senile dementia of Alzheimer's type, optionally in the form of its pharmaceutically acceptable salts. A composition according to claim 1, wherein the compound b) active for symptomatic treatment of senile dementia of Alzheimer's type is an acetylcholinesterase inhibitor. Composition according to claim 1, characterized in that compound a) is 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethyl-phenyl) - Composition according to claim 1, characterized in that compound a) is 1- [2- (4biphenyl) ethyl] -4- (3-trifluoromethyl-phenyl) - A composition according to claims 1 to 4, characterized in that the acetylcholinesterase inhibitor is selected from tacrine, donepezil and rivastigmine. Composition according to claim 1, characterized in that it contains from 0.5 to 700 mg of compound a). 7. A composition according to claim 1, comprising 0.1 to 50 mg of compound b). Composition according to claim 1, characterized in that it contains from 0.5 to 10 mg of 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine or a pharmaceutically acceptable salt thereof. Composition according to claim 1, characterized in that it contains as active ingredients 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine and donepezil or their pharmaceutically acceptable salts. Composition according to claim 9, characterized in that it contains as active ingredients 0.5 to 5 mg of 1- (2-naphth-2-ylethyl) -4- (36 trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine and 2 to 10 mg donepezil. Composition according to claim 1, characterized in that it contains as active ingredients 1- [2- (4-biphenyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine and donepezil or pharmaceutically acceptable salts thereof. A composition according to any one of claims 1 to 11 for use in the treatment of senile dementia of Alzheimer's type. 13. Use of a composition according to which and any one of claims 1 to 12 for the preparation of medicaments for the treatment of senile dementia of Alzheimer's type. Use according to claim 13, at 5 which compound a) is selected from 1- (2-naphth-2ylethyl) -4- (3-trifluoromethyl phenyl) -1,2,3,6-tetrahydropyridine and 1- [2- (4-biphenylyl) ethyl] - 4- (3trifluoromethyl phenyl) -1,2,3,6-tetrahydropyridine. Use according to claim 13, at which compound b) is selected from tacrine and donepezil. Publication of the Patent Office of the Republic of Bulgaria