SA98190747B1 - A combination of active agents, particularly tetrahydropyridine and acetylcholinesterase inhibitors, for the treatment of senile dementia such as Alzheimer's - Google Patents

Abstract

Abstract: The invention relates to a pharmaceutical composition containing, as active agents: Component (a) selected from among: l-(2-napht-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridin and a compound ( I) and has: Y stands for -CH- or -N-; R1 is: hydrogen, halogen, hydroxyl, CF3, or alkyl group (C3-C4) or c4) alkoxyl-c1); and R2 stands for hydrogen , or CF3, or a c3-c4 (alkyl) or alkoxyl group (C1-C4); R3 and R4 each represent hydrogen or (C1- alkyl (c4; and X represents: (a) C3-C6) alkyl); or C3-C6) alkoxyl); or C3-C7) carboxyaltyl ); or C1-C4)alkoxycarbonyl)alkyl (C3-C6); or C3-C7) carboxyalkyl ); or c4) alkoxycarbonyl-C3-C6) alkoxyl (c1); or (b) a selective moiety from among C3-C7 (cycloalyl), or cycloalkyloxy (C3-C7); or C3-C7) cycloallkylmethyl), or C3-C7) cycloalkylamino and cyclohexenyl), and this moiety can be substituted with a halogen, hydroxy or C1-C4 (alkoxy), carboxy, or alkoxycarbonyl (C1-C4), or an amino, mono- or -di-(ClC4)alkyamino, or (c) a select group of among phenyl, phenoxy, and phenylamino groups; and -N-(C1-C3)alkyl phenyl-amino, phenylmethyl, phenylethyl, phenylcarbonyl', phenylthio, phenylsulphonyl, phenylsulphinyl, styryl, said group can have one or multiple substitutions on the phenyl -halogen group , CF3, C1-C4) alkyl, or C1-C4) alkoxy); or cyano , or amino , or mono- or -di-(C1 C4)alkydamino , or C1-C4) acylamino ), or carboxy , or C4) alkoxycarbonyl-C1), or aminocarbonyl , or mono- or di-(Cl- C4)alkylaminocarbonyl , or amino(C1-C4)alk yl , or hydroxy(C1-C4)alkyl , or halogeno(C1-C4)alkyl ;; optionally in the form of one of its pharmaceutically acceptable salts; and Ingredient (b) active in symptomatic treatment d DAT, optionally in the form of one of its pharmaceutically acceptable salts, provided that when component (a) is an ingredient other than :-(l-(2napht-2-ylethyl)-4-(3-trifluoromethylphenyl 1) ,2,3,6-tetrahydropyridin or one of its pharmaceutically acceptable salts, wherein Component (B) is an acetylcholinesterase inhibitory substrate.

Description

Y — _ combination of potent agents, particularly tetrahydropyridine and acetylcholinesterase inhibitors; for the treatment of senile die Jia alzheimer's dementia Full description Background Ad a) At least one embodiment of the present invention usefully presents a pharmaceutical formulation containing a new synergistic combination of Aads for the treatment of dementia of the Alzheimer type Alzheimer's; It consists of - derivatives, <1,2,3,6-tetrahydropyridine optionally in the form of one of its pharmaceutically acceptable salts and an active substance in the synergistic treatment of dementia of Alzheimer's type, and in particular an inhibitor of acetylcholinesterase «optionally in the form of one of Its salts are acceptable to catch and use to prepare medicines designed to treat dementia of Alzheimer's type. Spend Alzheimer's, later known as DAT ("dementia of the Alzheimer's type"), is a cilia of the nerves clinically characterized by a persistent decrease in cognitive functions; it occurs in the elderly and increases with age. In light of the J gall demographic DAT will become an increasingly widespread disease.You may notice a decrease in the level of various neurotransmitters, acetylcholine in particular, in patients with DAT and the only commercially available treatment now for DAT. DAT consists of administering dls acetylcholinesterase Vo inhibitors by reducing the hydrolysis of acetylcholine thus increasing its bioavailability.Hence it is only a symptomatic treatment.

Das and Tacrine Compounds; Sold under the brand name “COGNEX®” and “donepezil”; Sold under the brand name ARICEPT® are acetylcholinesterase inhibitors that are indicated for the symptomatic treatment of mild to moderate forms of DAT and other products for the symptomatic treatment of DAT are under study. Some also affect the availability of acetylcholine ¢ 0 and others improve symptoms in patients with DAT by other mechanisms. To date, “there is no commercially available drug that has been shown to be able to slow disease progression. EP No. 458696-EP describes the use of compound 1-(2- naphth-2-ylethyl)-4-(3- trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine ¢ Featured in References B 57746 “SR For a drug designed to combat neurodegenerative conditions including dementia and MS 0 Alzheimer's The neurotrophic effect of compound 57746 88 on the nervous system is similar to that of certain endogenous neurotrophins (Ja, nerve growth factor (NGF) for example). 1-phenylalkyl-1,2,3,6-tetrahydropyridines have new substitutions and have neuroprotective and neurotrophic activity similar to that of certain endogenous vo neurotrophins. As a result of this activity, the compounds described in this patent application are supposed to be useful in the treatment of various diseases of the central nervous system; Including Alzheimer's disease. The activity of compound 57746 88 and the compounds described in International Application No. 016 97/016796 in the treatment of neurological diseases such as DAT is not designed to treat symptoms but; to protect the nerves; © to modify the course of the disease and reduce its exacerbation. what

B p _ General description of the invention m um bin ‎NTR arte Lf se m 0 f i ~ . 7 J a al because the discovery that the combination of compounds (coe) and optionally in the form of one of its pharmaceutically acceptable salts with an effective compound in the symptomatic treatment of dementia of Alzheimer’s type, and in particular an enzyme inhibitor (acetylcholinesterase) and optionally in the form of one of its salts acceptable ° pharmacologically; BA indicates a complete and highly effective treatment for DAT disease and the combination shows an effect | Quick and complete. Therefore ¢ z J gad ada is the first of 1 to invent the current pharmaceutical formula that contains a synergistic combination of compound 0 (and compound (b) as active substances Cua with: oT compound 00) from: +S ya 51 -(2-naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine 01 Formula 0 ' EEE ge a for Been Bana eae L L eo Ema BEN ee ie a he Bhan ae L L Sean ed ie EG bal ne a ll EL and it is -011- R “—N— Ry is hydrogen or halogen or CF3 or the (C3-Cq) alkyl group i.e. alkoxy (0-) 0 meth is hydrogen or hydroxyl sl halogen Or the group “(C3-Cq) alkyl RI-N) ¢talkoxy Yo.

A

Q — _ ya and y both be hydrogen or (C1-Cy) alkyl ¢ kr be (J) for (J) ; father Toadaoui); i.e. (C3-Cpcarboxyalkyl NA meaning alkoxycarbonyl (C3-Cg) alkyl; or (C3-C7) carboxyalkyl ¢ or (N-N) alkoxycarbonyl (C;-Cg) alkoxy °¢ OR ( C5-C7) from the R-cycloalkyloxy sl “(C3-Cy) cycloalkyl moiety selected from among (<2) the 13a 5 ¢ cyclohexenyl moiety and (C3-Cy) cycloalkylamino or “cycloalkylmethyl” mentioned It can have an optional substitution with (C1-Cq) 4 “hydroxy 4” alkoxy halogen “or carboxy” or alkoxycarbonyl 0hm-n)-0 amino ¢ or mono - or di-(C1-Cy) alkylamino 1 « or N-(C;-C3) rho amino phenyl s « phenoxy and ¢ phenyl subset of (—) phenylcarbonyl s « phenylethyl 5 ¢ phenylmethyl 5 ¢ alkylphenylamino + and phenylsulphinyl 5 » phenylsulphonyl s ¢ phenylthio » and styryl; And said group can have one or more optional substituents on the phenyl group : ; or halogen with Vo , CFs, (C1-Cy) alkyl, (C,-C4) alkoxy, cyano, amino, mono- or di-(C;-Cs) alkylamino, (C1-Cy4) acylamino , carboxy, (C1-Cs4) alkoxycarbonyl, aminocarbonyl, mono- or ‎di-(C;-C4) alkylaminocarbonyl, amino (C;-Cs) alkyl, hydroxy (C;-Cs) alkyl or halogeno (C,- C4) alkyl

You

_a"_ optionally in the form of one of its pharmaceutically acceptable salts; - ingredient (b) active in the symptomatic treatment of (DAT) optionally in the form of one of its pharmaceutically acceptable salts; provided that when component (a) is a component other than 1-( 2-naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6- tetrahydropyridine ° or one of its salts that is acceptable for fishing; Component B is an acetylcholinesterase inhibitor. The compound 1-(2-naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6- (SR 57746) tetrahydropyridine is described in European Patent No. VIVA and described Compounds of formula (1) above in International Application No. 61677/597. 0 A particularly useful compound (a) is: 1-(2-Naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)-1, Optionally 2,3,6-tetrahydropyridine (SR) 57746 ¢ in the form of one of its acceptable salts at Sayd Alanya. Of the pharmaceutically acceptable salts of compound 57746 “SR the hydrochloride later named A 0 57746 .586 is a particularly preferred salt There is a distinctive way to prepare His 57746 SR consisting of the reaction between: 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridin 5 2-(2-bromoethyl)naphthalene and isolate:

1-(2-naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride which is then crystallized from an ethanol-water mixture by heating and cooling to at a cooling rate of 10 m/h and a stirring speed of 5080 cycles/AB to obtain a mixture of two crystalline forms at a ratio of about FE and it is preferable to use SR 57746 A in the form of small particles; For example, in an essentially amorphous form obtained by spray drying, or in the form of microcrystals by making the image micron-sized. The compound (a) AY that is particularly useful is: 1-[2-(4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine | 0 and in particular the hydrochloride salt thereof. Other useful compounds are: 1-[2-(3'-chloro-4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6- tetrahydropyridine; 1-[ 2-(2'-chloro-4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6- Vo tetrahydropyridine; 1-[2-(4'-chloro-4) -biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6- tetrahydropyridine;

A

A _—a name

1-[2-(4'-fluoro-4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6- tetrahydropyridine; 1-[2-(3'-trifluoromethyl-4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6- tetrahydropyridine; 1-[2-(4-cyclohexylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; ° 1-[2-(4-biphenylyl)ethyl]-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine; 1-[2-(4-biphenylyl)-2-methylpropyl]-4-(3-trifluoromethylphenyl)-1,2,3,6- tetrahydropyridine; 1-[2-(4-phenoxyphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; 1-[2-(4-benzylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; 01 1-[2-(4-n-butylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; 1-[2-(4-n-butoxyphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; 1-[2-(4-(4-ethoxycarbonylpropoxy)phenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6- tetrahydropyridine; 1-[2-(4-biphenylyl)ethyl]-4-(6-chloropyrid-2-yl)-1,2,3,6-tetrahydropyridine; Vo 1-[2-(2,3'-dichloro-4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6- tetrahydropyridine;

Yo.

A

_ q _ 1-[2-(3-chloro-4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6- tetrahydropyridine; 1-[2-(3",5'-dichloro-4-biphenylyl)ethyl]-4-(3-trifluoromethylhenyl)-1,2,3,6- tetrahydropyridine; 1-[2-(2',4') -dichloro-4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6- ° tetrahydropyridine;1-[2-(2-chloro-4-biphenylyl)ethyl]-4-(3 -trifluoromethylphenyl)-1,2,3,6- tetrahydropyridine; 1-[2-(3'-chloro-4-biphenyl)-2-methylpropyl]-4-(3-trifluoromethylphenyl)-1,2,3,6 - tetrahydropyridine; Ve 1-[2-(2-fluoro-4-biphenylyl)propyl]-4-(3-trifluoromethylphenyl)-1,2,3,6- tetrahydropyridine; 1-[2-(4-methoxy-3) -biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6- tetrahydropyridine;1-[2-(4'-methoxy-4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)- 1,2,3,6- Vo tetrahydropyridine;1-[2-(4'-hydroxy-4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6- tetrahydropyridine;

Vo. A

1. - - 1-[2-(4'-ethoxycarbonylbutoxy-4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6- tetrahydropyridine; 1-[2-( 3-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; 1-[2-(3'-chloro-4'-fluoro-4-biphenylyl)ethyl]- 4-(3-trifluoromethylphenyl)-1,2,3,6- tetrahydropyridine; ° 1-[2-(2'-trifluoromethyl-4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6- tetrahydropyridine; 1-[2-(3) ,4-diisobutylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6- tetrahydropyridine; 1-[2-(3,4-dipropylphenyl)ethyl]-4-(3- trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; \ 1-[2-(4-cyclohexylphenyl)ethyl]-4-(6-chloropyrid-2-yl)-1,2,3,6-tetrahydropyridine; 1-[2-(4-isobutylphenyl) propyl]-4-(6-chloropyrid-2-yl)-1,2,3,6-tetrahydropyridine and its pharmaceutically acceptable salts. Detailed description 1 and in the present description; The expression “compound effective in the symptomatic treatment of DAT” describes a product that can improve symptoms in patients with DAT without having an effect on Yo.

A

These compounds oa for example. acetylcholinesterase inhibitors, muscarinic adjuvants, nicotinic agonists, N-methyl-D-aspartate (NMDA) receptor antagonists; 5 Jal se psychological nutrition; And acetylcholinesterase inhibitors, which are useful, especially da. According to a preferred feature; The invention relates to a pharmaceutical composition containing as an active substance a compound ( ) optionally in the form of one of its acceptable salts Liana and a compound (b) selected from acetylcholinesterase inhibitors ¢ optionally in the form of one of its pharmaceutically acceptable salts. Sadall acetylcholinesterase inhibitors in particular are donepezil 5 Tacrine Other acetylcholinesterase inhibitors that may be used are for example: rivastigmine (SDZ-ENA-713), galanthamine, metrifonate, eptastigmine, velnacrine, Ve physostigmine (Drugs, 1997, 53 (5): 752-768 The Merck Index 12 ed.). 2-1[-1,2-benzisoxazol-6-one, also known as icopezil (J. Med. Chem., 1995, 38: 2802-2808),

MDL-73,745 or zifrosilone (Eur. J. Pharmacol., 1995, 276: 93-99), TAK-147 (J. Med. yo).

Chem., 1994, 37: 2292-2299). Others are for example those described in the following patent applications for acetylcholinesterase and inhibitors:

American Patent No. “foo / 85-l; and international patents No. vy / 04, 6 av / 12, pursuant to Y / Y 4, Japanese patent No. oo 9 / CACEAY, American Patent No. 4 + and European Patent No. 177; And the international patent No. 71877 / 9 and the American patent No. t¢ooVY¢o 0; the European patent No. Da and the international patent ° No. “YovY¢ / 41 ¢ and the international patent No. q YY “V1 and patent 6 American Patent No. 00:70 6, European Patent No. A-4, Japanese Patent No. 7 0 1 CEAYY) and European Patent No. 6A, European Patent No. 1 “6, Japanese Patent No. 77L0 and Japanese Patent No. 0 7/1 AMIVY, European Patent No. ¢NYVE sy, International Patent No. YAYVYY / 8 6, and American Patent No. 51. Yo and receptor cofactors (SR M; eg 6 melameline, besipiridine, talsaclidine, xanomeline, YM-796 and YM-954 (Eur.

J. Pharmacol., 1990, 187: 479-486), 3-[N-(2-diethylamino-2-methylpropyl)-6-phenyl-5-propyl]-pyridazinamine, also known as SR-46559 (Biorg.

Med.

Chem.

Let., 1992, 2: AF-102, CI-979, L-689,660, LU 25-109, 5-99 77-2, SB 202,026, thiopilocarpine, WAL 2014 (Pharmacol.

Toxicol., 1996, 78: 59-68). Yo and useful nicotine aids are, for example: (Japan J.

T - 588 «(Biorg.

Med.

Chem.

Let., 1995, 5 (14): 1495 - 1500). MKC - 231. (Br.

J.

Pharmacol., 1997, 120: 429 - 438 (ABT - 418 5 Pharmacol., 1993, 62: 81 - 86) and useful NMDA receptor antagonists are, for example: YO A

Y —_ \ — memantine (Arzneim.

Forsch., 1991, 41: 773-780). In a further aspect the present invention also relates to a method for the treatment of dementia of the Alzheimer type All Alzheimer© consisting of administering to a patient suffering from this disease an effective dose of compound (a) above; optionally in the form of one of its pharmaceutically acceptable salts and an effective dose of compound (b); and in particular acetylcholinesterase tafe "and optionally in the form of one of its pharmaceutically acceptable salts"; The said giving is instantaneous; or successively or alternately at effective intervals and doses of the active substances which may be contained in the formulations of separated units of administration or; When 0 the active substances are administered momentarily, it is beneficial to contain the two active substances in a pharmaceutical formulation and 2B aa. It is preferable to administer the active substances according to the invention Mad orally and in the pharmaceutical formulations of the present invention for oral administration; The active substances may be administered in unit formulations for administration ¢ in mixture with standard pharmaceutical carriers; For animals and humans to treat the aforementioned diseases. Unit forms suitable for administration include, for example, optionally divisible tablets; capsules; powders; and granules, cgranules, and solutions or suspensions to be taken by mouth. No preparation of a solid formulation in the form of tablets. The main active substance is mixed with a pharmaceutical carrier, gelatin ie ¢, starch, lactose ¢, or magnesium stearate, i.e. suspension or gum.

_ 1 —

Arabi; or something like that. Tablets may be coated with sucrose or other suitable materials

It is also processed so that it has an extended or delayed activity and so that it continuously releases a previous quantity

Determination of the active substance.

The capsules are prepared by mixing the active substance with a diluted ale and pouring the mixture obtained into soft or hard capsules.

The preparation in the form of a syrup or elixir may contain the active substance with

sweetening agent preferably without calories; and methylparaben and

propylparaben as antiseptic as well as a suitable flavoring agent and coloring matter.

Water dispersible powders or granules may contain the active substance in mixture with dispersing agents or wetting agents.” Or suspension agents, polyvinylpyrrolidone Jie ¢ as in the case of agents

sweetener or flavor corrector.

The active substance can also be formulated in the form of small capsules; Optionally with one or more

Carriers or additives.

and in pharmaceutical compositions according to the present invention; The active substance may also be in the form of a Vo containing complex in cyclodextrins, ethers or esters.

The amount of active substance to be administered, as in the case of Lely, depends on the fal degree of the disease

In addition to the age and weight of the patient.

- 1 and —

The doses of the two active substances are similar to those normally chosen in this field for administration

independent of each of these active substances.

Therefore the formulations according to the invention contain doses preferred for non-combinant treatments; on

for example; From 1.6 mg to 70010 mg of Compound (A) or one of its pharmaceutically acceptable salts; and from 1.1 M to 00 mg of Compound B or one of its pharmaceutically acceptable salts; even lower doses; And it is given

The combination has a synergistic effect.

Useful combinations contain for example between 4.0 to © mg of SR 57746 or one

Acceptable salts (LY dm) and from 1.1 to 00 mg of acetylcholinesterase inhibitor or al

Pharmaceutical acceptable salts.

0 and the preferred formulations contain between 1.5 to © mg of 57746 SR or one of its pharmaceutically acceptable salts, in particular hydrochloride; And from ? to 10 mg of donepezil or one of its pharmaceutically acceptable salts. The dosages shown in the present description refer to the active substances not incorporated in a salt formulation. The activity of the composition according to the invention was demonstrated by using a specific model of the verbal cholinergic system

ve of seahorse barrier on lesions caused by vincristine injection and in this model; The effects of the tested products on forgetfulness were evaluated by injection of vincristine, which produced biochemical changes similar to those found in Alzheimer's disease. the procedures used in this form; The lesions induced by vincristine in addition to the assessment of social memory are described in European Application No. 47 687. :

Evaluation of a Social Memory Test in the Rat: After the lesions were induced by injections of vincristine as described in ER 5077, the rats showed consistent and persistent forgetfulness. The rats were divided into two groups; One group received a solvent and the other group received SR 57746 A at a dose of [ane kg by mouth; This is the dose that would be insufficient to allow functional recovery in terms of memory in the rats subjected to this test (effective dose being 1 mg/kg as described in EP 625247) Then a dose of 1 mg/kg was administered intraperitoneally from Tacrine to the two groups of rats.The comparison group that received the solvent Tacrines showed no memory recovery, while the group treated with 57746 SR (subactive dose) lid Tacrines demonstrated significant memory retention. The results of this test are the synergistic action of the combination of the present invention. As a result of the complementary and synergistic effect of the components of the combination, which simultaneously guarantee protection as well as recovery from the nerves caused by the disease in addition to the immediate atl ale SU in the patient”, the combination of J Lachter | 2 Enables effective treatment of DAT in Alex Fig. 1 The reference to any prior art in this specification is not to be taken as an acknowledgment or suggestion that prior art forms part of the general information common in Australia.

Claims (1)

11 - - Elements of protection 1 1 Pharmaceutical composition containing a synergistic combination of compound (A) and compound (B) 7 as active substances, wherein it contains: Compound 0 is selected (from: 1-(2-naphth-2-ylethyl)-4-(3- trifluoromethylphenyl)-1,2,3,6- ¢ tetrahydropyridine ° 1 and compound of formula (I) Because A L A with 4 7 be “—N— J —CH- Ry Ve be chydrogen or halogen” or “CF; or an alkyl group (Ht-F) + or ¢ (C1-Cy) alkoxy 1 R, VY is <hydrogen or hydroxyl ; or (C5-Cy) alkyl group or (C1-Cy) alkoxy Vy ¢ Res Ry 1 each being (C1-C3) alkyl of hydrogen ¢ X Vo being (Cs-Cealkyl (J) 11 ¢ a (C3-Coalkoxyl ¢ i.e. (C3-Cy)carboxyalkyl; or (C1-Cyq) alkoxycarbonyl (C;-Cg) alkyl VV ¢ or (C3-C;) carboxyalkoxy; or alkoxycarbonyl (C3-Ce) alkoxy (-r0) ¢ 0 4 (b) moiety selected from among (C3-C7) cycloalkyl + or cycloalkyloxy (©-f) + or The - 18 « cyclohexenyl and (C3-C7) cycloalkylamino or « (C5-C7) cycloalkylmethyl Y. hydroxy sf « halogen and this moiety can be optionally substituted by 71 ¢ amino 0 « (C1-Cy4) alkoxycarbonyl – or carboxy or ¢ (C1-C4) alkoxy or ‘YY’ or — mono or YY or “di-(C;-Cy) alkylamino amino Y¢ —N » amino phenyl and ¢ “phenoxy.s” phenyl (c) a group selected from among Yo “phenylethyl” and “phenylmethyl” and “amino — phenyl — (C;-Cs) alkyl 4 “phenylsulphinyl 5” phenylsulphonyl and ¢ phenylthio and phenylcarbonyl 5 L; And the said group can have a single or multiple optional substitution styryls YA (C1-Cs) R (C1-C4)alkyl § «CF; i.e. “halogen but phenyl on Yq group” or “di-(C;-C4) alkylamino or mono- or ¢ amino or ¢ cyano or “alkoxy 4” ( from-R0), alkoxycarbonyl, ¢" carboxy (J-R0)-, acylamino 11 amino, ¢ di-(C;-Cy4) alkylaminocarbonyl, -mono, or ¢" aminocarbonyl YY and of ¢ -n) alkyl and ¢ halogen or hydroxy (C;-Cy) alkyl or ¢ (C1-Cy) alkyl TY optionally in the form of one of its commercially acceptable salts; vi optionally in A form of one of its salts, DAT, is an ingredient (b) effective in the occasional treatment of ro that is acceptable for fishing; Provided that when component 0 is a component other than 4 1-(2-naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6- vy tetrahydropyridine YA then component B is Enzyme inhibitory factor (Lana or one of the acceptor salts v4 . acetylcholinesterase gs 01 z - 1 - 1 "-. Composed according to claim (1); characterized as containing as active substances 1-(2-naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3 ,6- Y tetrahydropyridine v Optionally as one of its pharmaceutically acceptable salts in combination with an active compound in ¢ Optionally in Alzheimer's Synergistic treatment of dementia of Alzheimer type 0 as one of its pharmaceutically acceptable salts.‎ 1 1 *- A composition according to claim (1); it is characterized by the fact that it contains as active substances: () a compound of formula Y Re Lo r ¢ and in it Y . J —CH-solved ¢ (C3-Cy) alkyl 4c gana or “CF; or « halogen § ¢ hydrogen be R; . ¢ (C1-Cy) alkoxy i.e. v a CF; or a ¢ hydroxyl group or “halogen or hydrogen” being Ry R ¢C;-Cy) alkoxy (C3-Cy) alkyl ; ¢ (C1-C3) alkyl of hydrogen of which is JS and b is Rs 0 X 11 is x (a) (C3-Cg) alkoxy 4 ¢ (C3-Ce) alkyl ; carboxyalkyl J («©-j); or ¢ (C3-C7) carboxyalkoxy (MA-0); or alkoxycarbonyl (one-one) alkyl 'yr ,. J ¢ (C1-C4) alkoxycarbonyl (C3-Cg) alkoxy ie v 07. yo (b) moiety selected from among cycloalkyl yo cycloalkyloxy 4 ¢ or cycloalkylmethyl (Mt-Mn) or (C5-Cy) cyclohexenyl 5 cycloalkylamino VY ¢ and this said moiety can that ha has an optional substitution of halogen » or hydroxy ¢ or (C1-Cy) alkoxy + or carboxy 83 » or alkoxycarbonyl (m-rn) 0 di- of =~ mono 0 ¢ amino (C1-Cy) alkylamino Y.” or 4c sana (—) 71 selected from amino phenyl 5 » phenoxy s « phenyl » YY and phenylmethyl 5 ¢ N-(C;- C;3) alkylphenylamino « and phenylethyl « ¢ phenylsulphonyls ¢ phenylthios ¢ phenylcarbonyl s Yy » Y ¢ and phenylsulphinyl ; styryl s ¢ and said group may have a single or multiple optional substitution Yo on phenyl 4c sane with halogen “or” CF; YH or alkyl Z-Rn) or (C1-C4) alkoxy ¢ or cyano ¢ or amino ¢ L or mono- or di-(C;-C4) alkylamino « or (C1-C4) acylamino ¢ or carboxy YA “¢ or alkoxycarbonyl (NA-R0) – or L or mono Yq - or di-(C1-C4) alkylaminocarbonyl ¢ or alkyl (N-R0n) amino « or hydroxy (C1-Cs) alkyl v. or halogeno (C,-C4) alkyl f ; optionally in 1 form of one of its pharmaceutically acceptable salts; YY and vy - acetylcholinesterase inhibitor ¢ or in the form of one of its ve-salts that are pharmaceutically acceptable; Yo. A — vy — : a ;- . A composition according to claim (7) characterized by the fact that compound (1) is 1-[2-(4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6- Y tetrahydropyridine ¥ of it . hydrochloride and in particular the ¢ t salt of composition according to the claim (©); it is characterized by the fact that the compound ( ) is selected from <0 \ the following compounds: 1-[2-(3'-chloro-4-biphenylyl )ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6- ¥ tetrahydropyridine; ¢ 1-[2-(2'-chloro-4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)- 1,2,3,6-© tetrahydropyridine;1 1-[2-(4'-chloro-4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6- L tetrahydropyridine; A 1-[2-(4'-fluoro-4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6- A tetrahydropyridine; Ve 1-[2-(3'-) trifluoromethyl-4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)- 1 1,2,3,6-tetrahydropyridine; VY 1-[2-(4-cyclohexylphenyl)ethyl]-4-(3-trifluoromethylphenyl)- 1,2,3,6- \v tetrahydropyridine; Ve 1-[2-(4-biphenylyl)ethyl]-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine; Ve 1-[2- (4-biphenylyl)-2-methylpropyl]-4-(3-trifluoromethylphenyl)-1,2,3,6- 1 tetrahydropyridine; VY \ 5 [2;(4-phenoxyphenylethyl] -4-(3-trifluoromethylphenyl)-1,2,3,6- YA the tetrahydropyridine; 4 1-[2-(4-benzylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6- v tetrahydropyridine; 57 1-[2-(4-n-butylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6- vy tetrahydropyridine; vy 1-[2-(4-n-butoxyphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6- ve tetrahydropyridine; Yo 1-[2-(4-(4-ethoxycarbonylpropoxy)phenyl)ethyl]-4-(3- 11 trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; vv 1-[2-(4-biphenylyl)ethyl]-4-(6-chloropyrid-2-yl)-1,2,3,6-tetrahydropyridine; YA 1-[2-(2,3'-dichloro-4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6- Ya tetrahydropyridine; ve 1-[2-(3-chloro-4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-© tetrahydropyridine; YY 1-[2-(3',5'-dichloro-4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6- YY tetrahydropyridine; vi 1-[2-(2',4'-dichloro-4-biphenylyl)ethyl]-4-(3-trifluoromethyl-henyl)-1,2,3,6- Yeo tetrahydropyridine; 1 1-[2-(2-chloro-4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6- ry tetrahydropyridine, VA 1-[2-(3'-chloro-4) -biphenylyl)-2-methylpropyl]-4-(3-trifluoromethylphenyl)- va 1,2,3,6-tetrahydropyridine; Ee \ 5 [2,(2-fluoro-4-biphenylyl)propyl] -4-(3-trifluoromethylphenyl)-1,2,3,6- 3 — tetrahydropyridine saddle; ex 1-[2-(4-methoxy-3-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6- a tetrahydropyridine; tt 1-[2-(4'-methoxy-4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6- to tetrahydropyridine; 3 1-[2-(4'-hydroxy-4-biphenylyl)ethyl]-4-(3-trifluoromethyl-phenyl)-1,2,3,6- tv tetrahydropyridine; EA 1-[2-(4'-ethoxycarbonylbutoxy-4-biphenylyl)ethyl]-4-(3- £1 trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; or 1-[2-(3-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6- 51 tetrahydropyridine; oY 1-[2-(3'-chloro-4'-fluoro-4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)- ov of 1,2,3,6-tetrahydropyridine 1-[2-(2'-trifluoromethyl-4-biphenylyl)ethyl}-4-(3-trifluoromethylphenyl)- eo 1,2,3,6-tetrahydropyridine; ol 1-[2-(3,4-diisobutylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6- ov tetrahydropyridine; oA 1-[2-(3,4-dipropylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6- od tetrahydropyridine; 1 1-[2-(4-cyclohexylphenyl)ethyl]-4-(6-chloropyrid-2-y1)-1,2,3,6- 1 tetrahydropyridine; 1 1-[2-(4-isobutylphenyl)propyl]-4-(6-chloropyrid-2-yl1)-1,2,3,6- 17 1 tetrahydropyridine oo 1 and its pharmaceutically acceptable salts. 1 >- . Formulated according to claim (1); characterized by the active compound Y in the synergistic treatment of dementia of Alzheimer's type, selected from <M; muscarinic and ¢ acetylcholinesterase auxiliaries v coenzyme inhibitors and trophic factors NMDA nicotinic A3 receptor antagonists and auxiliaries Psychological .nootropic agents ° 1 "-. Formula according to claimant (7); characterized by compound (B) being bound to ¢ acetylcholinesterase enzyme Y 1 / - Ls formulation, for protective agent 71 ¢ It is characterized by the inhibitor of acetylcholinesterase 7 » is selected from Tacrine and donepezil 1 4- Formula according to the protective character oY) It is characterized by the inhibitor of galanthamine ¢ rivastigmine is selected from » acetylcholinesterase 7 physostigmine and velnacrine ¢ eptastigmine + metrifonate ¢ Y .zifrosilone + icozepil and ¢ 1 (2 formulation according to claim oY) are characterized as containing between 0.8 to 7 mg of compound (). Yo. A : Cove. 1 to 0.1 is characterized as containing between oY) a formulation according to claim 11 1 mg of compound (B). 1 to 0.5 is characterized as containing between oY) Composition according to claim VY 1: 11 7 mg of 1-(2-naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6- ¥ tetrahydropyridine t: Containing as active substances oY) in composition according to claim VY 1 1-(2-naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6- Y tetrahydropyridine ¥ or their acceptable salts Donepezil 5 ¢ : formulation according to claim (7) characterized by the fact that it contains as active substances 4 1 1-[2-(4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3 1,6-Y tetrahydropyridine or their pharmaceutically acceptable salts. donepezil s 0 ¢ : formulation as claimed (?); containing between 050.0 mg of 1-1 1-(2-naphth-2-ylethyl)- 4-(3-trifluoromethylphenyl)-1,2,3,6- Y tetrahydropyridine hydrochloride ¥ .donepezil 01 mg from ? to 3 Yo. A 1 1 Formula according to any of the above protective ingredients for die aging type Y Alzheimer's disease. VY 1 Use the combination in accordance with any of the foregoing claims to prepare Y drugs designed to treat Alzheimer's disease. : It is characterized by that compound (1) is selected from (VY) composition according to the claim —VA 1 1-(2-naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3 ,6- Y tetrahydropyridine and 1-[2-(4-biphenylyl)ethyl]-4-(3- ¥ trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine ¢ has the advantage that compound (b) is selected from ( VV) combination according to claim 4 7 -donepezil and Tacrine Y in the manufacture of (V1) to (1) the use of its composition in accordance with any of the elements of protection from Alzheimer's type 0*-*. : composition according to claim (10); It is characterized by the fact that compound (1) is selected from 1 71 1-(2-naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydro Y pyridine and 1-[2-( 4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6- v tetrahydropyridine : _— 7 7 _ YY 1 is a formulation according to claim (17); characterized by compound (B) being selected from donepezil 5 Tacrine Y . YY 1 Lana composition pursuant to claim (1) » as then described herein by Y primarily. YO A