AU743228B2 - Combination of active principles, in particular of tetrahydropyridins and acetylcholinesterase inhibiting agents, for treating senile dementia such as Alzheimer dementia - Google Patents
Combination of active principles, in particular of tetrahydropyridins and acetylcholinesterase inhibiting agents, for treating senile dementia such as Alzheimer dementia Download PDFInfo
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- AU743228B2 AU743228B2 AU11609/99A AU1160999A AU743228B2 AU 743228 B2 AU743228 B2 AU 743228B2 AU 11609/99 A AU11609/99 A AU 11609/99A AU 1160999 A AU1160999 A AU 1160999A AU 743228 B2 AU743228 B2 AU 743228B2
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- tetrahydropyridine
- ethyl
- biphenylyl
- trifluoromethylphenyl
- alkyl
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Description
Advantageously at least one embodiment of the present invention provides a pharmaceutical composition containing a novel synergistic combination of active ingredients for the treatment of senile dementia of the Alzheimer type, constituted of 1, 2 3 ,6-tetrahydropyridine derivatives, optionally in the form of one of their pharmaceutically acceptable salts and a substance active "T in the symptomatic treatment of senile dementia of the Alzheimer type, in particular an acetylcholinesterase inhibitor, optionally in the form of one of its 10 pharmaceutically acceptable salts and, its use for the preparation of medicines designed for the treatment of senile dementia of the Alzheimer type.
Senile dementia of the Alzheimer type S 15 designated hereafter DAT ("dementia of the Alzheimer type") is a neurodegenerative disease characterized clinically by the progressive degeneration of cognitive functions, occurring in elderly people with an incidence which increases with age. In the light of demographic trends DAT will become an increasingly widespread disease.
A reduction of the level of several neurotransmitters, of acetylcholine in particular, has been observed in patients suffering from DAT.
The only treatment for DAT currently available commercially consists of administering S acetylcholinesterase inhibitors which by reducing the hydrolysis of acetylcholine thus increase its bioavailability. Hence it is a symptomatic treatment.
Tacrine, marketed under the trade mark COGNEX®, and donepezil, sold under the trade mark ARICEPT®, are acetylcholinesterase inhibitors indicated for the symptomatic treatment of mild to moderate forms of DAT. -Other products for the symptomatic treatment of DAT are under study. Some of them also act on the availability of acetylcholine, others improve the symptomatology of patients suffering from DAT by other mechanisms. Hitherto, no commercially available medicine has proved capable of slowing the progression of the disease.
EP-458696 describes the use of l-(2-naphth-2ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6tetrahydropyridine, designated in the literature SR 57746, for the preparation of medicines designed to combat neurodegenerative states, including senile dementia and Alzheimer's disease. The neurotrophic action of SR 57746 on the nervous system is similar to that of certain endogenous neurotrophins such as, for example, the nerve growth factor (NGF).
WO 97/01536 describes novel 4-substituted l-phenylalkyl-l,2,3,6-tetrahydropyridines having a neuroprotective and neurotrophic activity similar to that of certain endogenous neurotrophins. As a result of this activity, it is presumed that the compounds described in this patent application will be useful in the treatment of several diseases of the central nervous system, including Alzheimer's disease.
The activity of the compound SR 57746 and the compounds described in WO 97/01536 in the treatment of the nervous diseases such as DAT is not designed to treat the symptoms but, by protecting the neurons, to modify the course of the disease and to reduce its progression.
10 It has now been found that the combination of the above compounds, optionally in the form of one of their pharmaceutically acceptable salts, with a compound active in the symptomatic treatment of senile Sdementia of the Alzheimer type, in particular an acetylcholinesterase inhibitor, optionally in the form of one of its pharmaceutically acceptable salts, leads to a complete and very efficacious treatment of DAT, the combination exerting a rapid and complementary effect.
Thus, a first embodiment of the present invention provides a pharmaceutical composition containing a synergistic combination of a component (a) and a compound as active ingredients wherein component is selected from 1-(2-naphth-2ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6tetrahydropyridine and a compound of formula
N-CH
2
I
in which Y is -CH- or
R
1 is hydrogen, halogen, a CF 3
(C
3
-C
4 alkyl or (Cl-C 4 alkoxy group;
R
2 is hydrogen, halogen, hydroxyl, a CF 3
(C
3
-C
4 alkyl or (Cl-C 4 alkoxy group;
R
3 and R 4 are each hydrogen or (Cl-C 3 alkyl; X is
(C
3
-C
6 alkyl; (C 3
-C
6 alkoxy; (C 3
-C
7 carboxyalkyl; (Cl-C 4 alkoxycarbonyl (C 3
-C
6 alkyl; (C 3
-C
7 carboxyalkoxy; or (Cl-C 4 alkoxycarbonyl (C 3
-C
6 alkoxy; 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, said radical being optionally substituted by halogen, hydroxy, (Cl-C 4 alkoxy, carboxy, (Cl-C 4 alkoxycarbonyl, amino, mono- or di- (Cl-C 4 alkylamino; or a group selected from phenyl, phenoxy, phenylamino, N- (Cl-C 3 alkyiphenylamino, phenylmethyl, phenylethyl, phenylcarbonyl, phenylthio, phenylsulphonyl, phenylsuiphinyl and styryl, said phenyl group being optionally mono- or polysubstituted by halogen, CF 3 (Cl-C 4 alkyl, (Cl-C 4 alkoxy, cyano, amino, mono- or di- (Cl-C 4 alkylamino, (Cl-C 4 acylamino, carboxy,
(C
1
-C
4 alkoxycarbonyl, aminocarbonyl, mono- or di-(C 1
-C
4 alkylaminocarbonyl, amino (C 1
-C
4 alkyl, hydroxy (Ci-C 4 alkyl or halogeno (C 1
-C
4 alkyl; optionally in the form of one of its pharmaceutically acceptable salts and compound is active in the symptomatic treatment of DAT, optionally in the form of one of its pharmaceutically acceptable salts, provided that when compound is other than 1-(2naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6tetrahydropyridine or one of its pharmaceutically acceptable salts, compound is an acetylcholinesterase inhibitor.
15 1- (2-Naphth-2-ylethyl) (3-trifluoromethylphenyl)-1, 2 ,3,6-tetrahydropyridine (SR 57746) was described in EP 101 381 and the compounds of formula above are described in WO 97/01536.
A particularly advantageous compound 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, the hydrochloride designated hereafter SR 57746A is a particularly preferred salt.
An advantageous method for the preparation of SR 57746A consists of the reaction between 2-(2bromoethyl)naphthalene and 4-(3-trifluoromethylphenyl)- 1,2,3,6-tetrahydropyridine and the isolation of 1-(2naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6tetrahydropyridine hydrochloride which is then crystallized from an ethanol/water mixture by heating and cooling to 50C with a rate of cooling of 100C/hour and a stirring speed of 400 revolutions/minute, so as to obtain a mixture of two crystalline forms in a ratio of about 66/34.
SR 57746A is preferably used in a microparticulate form, for example in an essentially amorphous form obtained by spray drying or in a microcrystalline form by micronization.
Another particularly advantageous compound is 1-[2-(4-biphenylyl)ethyl]-4-(3trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine, in particular its hydrochloride salt.
Other advantageous compounds are the following: 1- [2-(3'-chloro-4-biphenylyl)ethyl] trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; 1-[2-(2'-chloro-4-biphenylyl)ethyl]-4-(3trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; 1-[2-(4'-chloro-4-biphenylyl)ethyl]-4-(3trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; 1- (4'1 -fluoro-4-biphenylyl) ethyl]1 (3trifluoromethyiphenyl) 6-tetrahydropyridine; 1- -trifluoromethyl.-4-biphenylyl)ethyl] (3trifluoromethyiphenyl) 6-tetrahydropyridine; 1- (4-cyclohexylphenyl)ethyl] (3trifluoromethyiphenyl) 6-tetrahydropyridine; 1- (4--biphenylyl)ethy1] (4-fluorophenyl) -1,2,3,6- Let rahydropyridine; 1 2- (4 -biphenylyl) 2 -methyipropyl] (3 trifluoromethyiphenyl) 6-tetrahydropyridine; 1- (4-phenoxyphenyl) ethyl] (3trifluoromethyiphenyl) 6-tetrahydropyridine; 1- (4-benzylphenyl) ethyl] (3trifluoromethyiphenyl) 6-tetrahydropyridine; 1-[2-(4-n-butylphenyl)ethyl]-4-(3trifluorornethyiphenyl) 6-tetrahydropyridine; 1- (4-n-butoxyphenyl)ethyl] (3trifluoromethylphenyl) 6-tetrahydropyridine; 1 2- (4 (4 ethoxycarbonylpropoxy) phenyl) ethyl]I 4- (3 trifluoromethyiphenyl) 6-tetrahydropyridine; 1- (4-biphenylyl) ethyl] (6-chloropyrid-2-yl) 1,2,3, 6-tetrahydropyridine; 1- 3' -dichloro-4-biphenylyl) ethyl] -4 (3trifluorornethyiphenyl) 6-tetrahydropyridine; 1- (3-chloro-4-biphenylyl) ethyl] (3trifluorornethyiphenyl) 6-tetrahydropyridine; 1- .5'-dichloro-4-biphenylyl) ethyl] (3trifluoromethylhenyl) 6 -tetrahydropyridine; 1- -dichloro-4-biphenylyl)ethyl] (3trifluoromethylphenyl) G-tetrahydropyridine; 1- 2 -(2-chloro-4-biphenylyl)ethyJ 4 3 trifluoromethylphenyl) G-tetrahydropyridine; 1- -chloro-4-biphenylyl) -2-methyipropyl] (3trifluoromethylphenyl) G-tetrahydropyridine; 1- 2 -fluoro-4-biphenylyl)propyl] (3trifluoromethylphenyl) 3 ,6-tetrahydropyridine; 1- (4-methoxy-3-biphenyly1)ethyl] (3trifluoromethylphenyl) G-tetrahydropyridine; 1- [2 (4 1 -methoxy-4 -biphenylyl) ethyl]1 -4 (3 trifluoromethylphenyl) G-tetrahydropyridine; 1- 2 -(4'-hydroxy-4-bphenylyl)ethyl- 4 3 trifluoromethylphenyl) G-tetrahydropyridine; 1- -ethoxycarbonylbutoxy4biphenll)ehl-(3 trifluoromethylphenyl) -lI 2 3 ,6-tetrahydropyridine; 1- 3 -biphenylyl)ethyl] 3 -trifluoromethylphenyl) 1,2,3, E-tetrahydropyridine; 1- [2 (3'1 chloro-4 I fluoro-4 -biphenylyl) ethyl]1 -4 (3 trifluoromethyphenl) -l 2 3 ,6-tetrahydropyridine; 1- [2-(2-rfurmehl4bpenllehl-4- (3trifluoromethylphel) G-tetrahydropyridine; l[ 2 -3,4-diisobutylpheny1)ethy] 4 3 trifluoromethylphel) G-tetrahydropyridine; 1-[2-(3,4-dipropylphenyl)ethyl]-4-(3trifluoromethylphenyl)-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 their pharmaceutically acceptable salts.
In the present description, .the expression "compound active in the symptomatic treatment of DAT" designates a product which is capable of improving the symptomatology of patients suffering from DAT without having an effect on the causes of the disease.
Such compounds are, for example, acetylcholinesterase inhibitors, MI muscarinic agonists, nicotinic agonists, N-methyl-D-aspartate (NMDA) receptor antagonists, nootropic agents, the acetylcholinesterase inhibitors being particularly advantageous.
In accordance with a preferred feature, the invention relates to a pharmaceutical composition containing as active ingredient a compound optionally in the form of one of its pharmaceutically acceptable salts, and a compound selected from the acetylcholinesterase inhibitors, optionally in the form of one of its pharmaceutically acceptable salts.
Particularly advantageous acetylcholinesterase inhibitors are tacrine and donepezil.
Other acetylcholinesterase inhibitors which may be used are for example rivastigmine (SDZ-ENA-713), galanthamine, metrifonate, eptastigmine, velnacrine, physostigmine (Drugs, 1997, 53 752-768; The Merck Index 12 ed.).
Other acetylcholinesterase inhibitors are 5,7-dihydro-3-[2-[l-(phenylmethyl)-4piperidinyl]ethyl]-6H-pyrrolo [3,2-f]-1,2-benzisoxazol- 6-one, also known as icopezil Med. Chem., 1995, 38: 2802-2808), MDL-73,745 or zifrosilone (Eur. J.
Pharmacol., 1995, 276: 93-99), TAK-147 Med. Chem., 1994, 37: 2292-2299).
Other acetylcholinesterase inhibitors are for example those which are described in the patent applications JP 09-095483, WO 97/13754, WO 97/21681, WO 97/19929, ZA 96-04565, US 5,455,245, WO 95-21822, EP 637 586, US 5,401,749, EP 742 207, US 5,547,960, WO 96/20176, WO 96/02524, EP 677 516, JP 07-188177, JP 07-133274, EP 649 846, EP 648 771, JP 07-048370, US 5,391,553, WO 94/29272, EP 627 400.
MI receptor agonists are, for example, milameline, besipiridine, talsaclidine, xanomeline, YM-796 and YM-954 (Eur. J. Pharmacol., 1990, 187: 479- 486), 3-[N-(2-diethylamino-2-methylpropyl)-6-phenyl-5propyl]-pyridazinamine, also known as SR-46559 (Biorg.
Med. Chem. Let., 1992, 2: 833:838), AF-102, CI-979, L-689,660, LU 25-109, S-99 77-2, SB 202,026, thiopilocarpine, WAL 2014 (Pharmacol. Toxicol., 1996, 78: 59-68).
Advantageous nicotine agonists are for example MKC-231 (Biorg. Med. Chem. Let., 1995, 5 (14): 1495-1500), T-588 (Japan J. Pharmacol., 1993, 62: 81- 86), ABT-418 (Br. J. Pharmacol., 1997, 120: 429-438).
An advantageous NMDA receptor antagonist is for example memantine (Arzneim. Forsch., 1991, 41: 773- 780).
In accordance with another feature, the present invention relates to the use of the compositions of the invention for the preparation of medicines designed for the treatment of senile dementia of the Alzheimer type.
In accordance with another feature the present invention also relates to a method for the treatment of senile dementia of the Alzheimer type which consists of administering to a patient suffering from this disease an efficacious dose of a compound (a) above, optionally in the form of one of its pharmaceutically acceptable salts and an efficacious dose of a compound in particular an acetylcholinesterase inhibitor, optionally in the form of one of its pharmaceutically acceptable salts, said administrations being simultaneous, sequential or alternating at intervals and the efficacious doses of the active ingredients being able to be contained in separate unit forms of administration or, when the active ingredients are administered simultaneously, the two active ingredients being advantageously contained in a single pharmaceutical form.
The active ingredients according to 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 forms of administration, in a mixture with standard pharmaceutical vehicles, to animals and to human beings for the treatment of the abovementioned diseases. The appropriate unit forms of administration include for example optionally divisible tablets, capsules, powders, granules and solutions or oral suspensions.
When a solid composition is prepared in the form of tablets, the principal active ingredient is mixed with a pharmaceutical vehicle 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 they may also be treated so that they have a prolonged or delayed activity and that they continuously release a predefined quantity of active ingredient.
A preparation of capsules is obtained by mixing the active ingredient with a diluent and by pouring the mixture obtained into soft or hard capsules.
A preparation in the form of a syrup or elixir may contain the active ingredient together with a sweetening agent, preferably calorie-free, methylparaben and propylparaben as antiseptics as well as a flavouring agent and a suitable colouring matter.
The powders or granules dispersible in water may contain the active ingredient in a mixture with dispersion agents or wetting agents, or suspension agents like polyvinylpyrrolidone, just as with sweetening agents or flavour correctors.
The active ingredient may also be formulated in the form of microcapsules, optionally with one or more vehicles or additives.
In the pharmaceutical compositions according to the present invention, the active ingredient may also be in the form of an inclusion complex in cyclodextrins, their ethers or their esters.
The quantity of active ingredient to be administered depends, as always, on the degree of advancement 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 usually selected in the state of the art for the isolated administration of each of these active ingredients.
The compositions according to the invention thus contain recommended doses for the uncombined treatments, for example, of 0.5 mg to 700 mg of compound or of one of its pharmaceutically acceptable salts and 0.1 to 50 mg of compound or of one of its pharmaceutically acceptable salts or even lower doses, given that the combination exerts a synergistic effect.
Advantageous compositions contain for example 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 the hydrochloride, and 2 to 10 mg of donepezil or one of its pharmaceutically acceptable salts.
The doses indicated in the present description refer to the active ingredients not combined in salt form.
The activity of the composition according to the invention was demonstrated by using a specific model for the septo-hippocampal cholinergic system on lesions caused by the injection of vincristine. In this model, the effects are evaluated of the products tested on amnesia induced by the injection of vincristine which induces biochemical alterations similar to the changes present in Alzheimer's disease.
The procedures used in this model, lesions caused by vincristine as well as the evaluation of the social memory are described in EP 655247.
Evaluation test of the social memory in the rat.
After lesions have been provoked by injection of vincristine as described in EP 655247 the rats exhibit a stable and durable amnesia. The rats are divided into two groups, one group receiving solvent and the other group receiving SR 57746A at a dose of 5 mg/kg a dose which is insufficient to permit functional recovery in terms of memory in the rats undergoing this test (the efficacious dose being mg/kg as described in EP 655247). The dose of 1 mg/kg i.p. of tacrine is then administered to the two groups of rats. The control group which has received solvent and tacrine shows no recovery of memory whereas the group which has been treated with SR 57746A (subefficacious dose) and tacrine shows a significant recovery of memory retention deficits.
The results of this test indicate a synergistic action of the combination of the present invention.
P:\OPER\KbU~ 1609-99 303 sp.do-021 101 -16- As a result of the complementary and synergistic effect of the constituents of the combination, simultaneously guaranteeing the protection and even cure of the neurones affected by the disease as well as the immediate improvement of the symptoms in the patient, the composition of the invention makes possible an efficacious treatment of DAT in all its forms.
The reference to any prior art in this specification is not, and should not be taken as, an 10 acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.
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Claims (23)
1. A pharmaceutical composition containing a synergistic combination of a component and a compound as active ingredients wherein component is selected from l-(2- naphth-2-ylethyl) 3 -trifluoromethylphenyl) -1,2,3,6- tetrahydropyridine and a compound (I) ~N-CH 2 I R 1 R 2 in which Y is -CHI- or R, is hydrogen, halogen, a CF 3 (C 3 -C 4 alkyl or (C 1 -C 4 alkoxy group; R 2 is hydrogen, halogen, hydroxyl, a CF 3 (C 3 -C 4 alkyl or (Cl-C 4 alkoxy group; R 3 and R 4 are each hydrogen or (Cl-C 3 alkyl; X is (C 3 -Cr 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; 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, said radical being optionally substituted by halogen, hydroxy, (C 1 -C 4 alkoxy, carboxy, (C 1 -C 4 alkoxycarbonyl, amino, mono- or di-(C-C 4 alkylamino; or a group selected from phenyl, phenoxy, phenylamino, N-(Ci-C 3 alkylphenylamino, phenylmethyl, phenylethyl, phenylcarbonyl, phenylthio, phenyl- sulphonyl, phenylsulphinyl and styryl, said phenyl group being optionally mono- or polysubstituted by halogen, CF 3 (Ci-C 4 alkyl, (C 1 -C 4 alkoxy, cyano, 1 0 amino, mono- or di-(C 1 -C 4 alkylamino, (C 1 -C 4 acylamino, carboxy, (C 1 -C 4 alkoxycarbonyl, aminocarbonyl, mono- or di-(C 1 -C 4 alkylaminocarbonyl, amino (C 1 -C 4 alkyl, hydroxy (CI-C 4 alkyl or halogeno (C 1 -C 4 alkyl; optionally in the form of one of its pharmaceutically 15 acceptable salts, and compound is active in the symptomatic 0 treatment of DAT, optionally in the form of one of its pharmaceutically acceptable salts, provided that when compound is other than 1-(2- naphth-2-ylethyl)-4-( 3 -trifluoromethylphenyl)-1,2,3,6- tetrahydropyridine or one of its pharmaceutically acceptable salts, compound is an acetylcholinesterase inhibitor.
2. 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, optionally in the form of one of its pharmaceutically acceptable salts in combination with a compound active in the symptomatic treatment of senile dementia of the Alzheimer type, optionally in the form of one of its pharmaceutically acceptable salts.
3. Composition according to Claim 1, characterized in that it contains as active ingredients a compound of formula (I) R 3 x N-CH 2 -C (I) RI R2 in which Y is -CH- or Ri is hydrogen, halogen, a CF3, (C 3 -C 4 alkyl or (C 1 -C 4 alkoxy group; R 2 is hydrogen, halogen, hydroxyl, a CF 3 (C 3 -C 4 alkyl or (Ci-C 4 alkoxy group; R 3 and R 4 are each hydrogen or (C 1 -C 3 alkyl; X is (C 3 -C 6 alkyl; (C 3 -C 6 alkoxy; (C 3 -C 7 carboxyalkyl; (CI-C 4 alkoxycarbonyl (C 3 -C 6 alkyl; (C 3 -C 7 carboxyalkoxy; or (C 1 -C 4 alkoxycarbonyl (C 3 -C 6 alkoxy; 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, said radical being optionally substituted by halogen, hydroxy, (C 1 -C 4 alkoxy, carboxy, (C 1 -C 4 alkoxycarbonyl, amino, mono- or di-(C 1 -C 4 alkylamino; or a group selected from phenyl, phenoxy, phenyl- amino, N-(C 1 -C 3 alkylphenylamino, phenylmethyl, phenylethyl, phenylcarbonyl, phenylthio, phenyl- sulphonyl, phenylsulphinyl and styryl, said phenyl group being optionally mono- or polysubstituted by halogen, CF 3 (C 1 -C 4 alkyl, (C 1 -C 4 alkoxy, cyano, amino, mono- or di-(CI-C 4 alkylamino, (C 1 -C 4 acylamino, carboxy, (C 1 -C 4 alkoxycarbonyl, aminocarbonyl, mono- or di-(C 1 -C 4 alkylaminocarbonyl, amino (C 1 -C 4 alkyl, hydroxy (C 1 -C 4 alkyl or halogeno (C 1 -C 4 alkyl; optionally in the form of one of its pharmaceutically acceptable salts, and an acetylcholinesterase inhibitor, or a pharmaceutically acceptable salt of the latter.
4. Composition according to Claim 3, characterized in that the compound is biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6- tetrahydropyridine or its hydrochloride salt.
Composition according to Claim 3, characterized in that compound is selected from the following compounds: 1- -chloro-4-biphenylyl) ethyl] (3- trifluoromethyiphenyl) 6-tetrahydropyridine; 1- -chloro-4-bipheriylyl) ethyl] (3- trifluoromethyiphenyl) 6-tetrahydropyridine; l-[2-(4'-chloro-4-biphenylyl)ethyl]-4-(3- trifluoromethyiphenyl) 6-tetrahydropyridine; 1- (4 '-fluoro-4-biphenylyl) ethyl] (3- trifluoromethyiphenyl) 6-tetrahydropyridine; 1- (3 1-trifluoromethyl-4-bipheiylyl) ethyl]1 (3- trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- (4-cyclohexylphenyl) ethyl] (3- trifluoromethylphenyl) 6-tetrahydropyridine; 1-[2-(4-biphenylyl)ethyl]-4-(4-fluorophenyl)-1,2,3,6- tetrahydropyridine; 1- (4-biphenylyl) -2-methylpropyl]-4-(3- trifluoromethyiphenyl) 6-tetrahydropyridine; 1- (4-phenoxyphenyl)ethyl] (3- trifluoromethylphenyl) 6-tetrahydropyridine; 1- (4-benzylphenyl)ethyl] (3- trifluorornethylphenyl) 6-tetrahydropyridine; 1- (4-n-butylphenyl)ethyl] (3- trifluoromethylphenyl) 6-tetrahydropyridine; 1- (4-n-butoxyphenyl) ethyl] (3- trifluoromethylphenyl) 6-tetrahydropyridine; 1 2- (4 (4 -ethoxycarbonylpropoxy) phenyl) ethyl]I 4- (3 trifluoromethylphenyl)
6-tetrahydropyridine; 1- (4-biphenylyl)ethyl] (6-chloropyrid-2-yl) 1,2,3, 6-tetrahydropyridine; l-[2-(2,3'-dichloro-4-biphenylyl)ethyl]-4-(3- trifluoromethyiphenyl) 6-tetrahydropyridine; 1-[2-(3-chloro-4-biphenylyl)ethyl]-4-(3- trifluorornethyiphenyl) 6-tetrahydropyridine; 1- (3 5'-dichloro-4-biphenylyl) ethyl] (3- trifluoromethyiphenyl) 6-tetrahydropyridine; 1- ,4 '-dichloro-4-biphenylyl)ethyl] (3- trifluoromethyl-henyl) 3,6-tetrahydropyridine; 1- (2-chloro-4-biphenylyl) ethyl] (3- trifluorornethylphenyl) 6-tetrahydropyridine; 1- -chloro-4-biphenylyl) -2-methyipropyl] (3- trifluoromethyiphenyl) 6-tetrahydropyridine; 1- [2-(2-fluoro-4-biphenylyl)propyl]-4-(3- trifluorornethyiphenyl) 6-tetrahydropyridine; 1- (4-methoxy-3-biphenylyl) ethyl] (3- trifluoromethyiphenyl) 6-tetrahydropyridine; 1- -methoxy-4-biphenylyl) ethyl] (3- trifluoromethyiphenyl) -1,2,3,6-tetrahydropyridine; 1- -hydroxy-4-biphenylyl) ethyl] (3- trifluoromethyl-phenyl) 6-tetrahydropyridine; 1- -ethoxycarbonylbutoxy-4-biphenylyl) ethyl] (3- trifluorornethyiphenyl) 6-tetrahydropyridine; 1- (3-biphenylyl)ethyl] (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 their pharmaceutically acceptable salts. 6. Composition according to Claim 1, characterized in that the compound active in the symptomatic treatment of senile dementia of the Alzheimer type is selected from acetylcholinesterase inhibitors, Mi muscarinic agonists, nicotinic agonists, NMDA receptor antagonists and nootropic agents
7. Composition according to Claim 6, characterized in that compound is an acetylcholinesterase inhibitor.
8. Composition according to Claim 7, characterized in that the acetylcholinesterase inhibitor is selected from tacrine and donepezil.
9. Composition according to Claim 7, characterized in that the acetylcholinesterase inhibitor is selected from rivastigmine, galanthamine, metrifonate, eptastigmine, velnacrine, physostigmine, icozepil and zifrosilone.
Composition according to Claim 1, characterized in that it contains from 0.5 to 700 mg of compound
11. Composition according to Claim characterized in that it contains from 0.1 to compound 1, 50 mg of
12. Composition according to Claim 2, 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.
13. Composition according to Claim 2, 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.
14. Composition according to Claim 3, characterized in that it contains as active ingredients 1-[2-(4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)- 1,2,3,6-tetrahydropyridine and donepezil or their pharmaceutically acceptable salts. Composition according to Claim 2 containing 0.5 to 5 mg of 1-(2-naphth-2-ylethyl)-4-(3- trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride and 2 to 10 mg of donepezil.
P:\OPER\Kbm\l 1609-99 303 spe.doc02/ 1/01
16. Composition according to any one of the preceding claims for the treatment of senile dementia of the Alzheimer type.
17. Use of the composition according to any one of the preceding claims for the preparation of medicines designed for the treatment of senile dementia of the Alzheimer type.
18. Use according to Claim 17, characterized in that the compound is selected from l-(2-naphth-2-ylethyl)-4- se 9 10 (3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine and 1- (4-biphenylyl) ethyl]-4- 3 -trifluoromethylphenyl) 1,2,3,6-tetrahydropyridine.
19. Use according to Claim 17, characterized in that the compound is selected from tacrine and donepezil. 15
20. A method of treating senile dementia of the Alzheimer type including administering a composition according to any one of Claims 1 to 16.
21. A method according to Claim 20 characterized in that the compound is selected from 1-(2-naphth-2- ylethyl)-4-(3-trifluoromethylphenyl) 3, 6- tetrahydropyridine and 1-[ 2 -(4-biphenylyl)ethyl]-4-(3- trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine.
22. A method according to Claim 20 characterized in that the compound is selected from tacrine and donepezil. PAOPER\Kb,,.UI609-99 303 spedoc02/11/01 26
23. A pharmaceutical composition according to Claim 1, substantially as hereinbefore described. DATED this 2nd day of November, 2001 Sanofi-Synthelabo By DAVIES COLLISON CAVE 10 Patent Attorneys for the Applicant C. S C C C C.. C C *CCC
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR97/14324 | 1997-11-14 | ||
| FR97/14322 | 1997-11-14 | ||
| FR9714322A FR2771007B1 (en) | 1997-11-14 | 1997-11-14 | COMBINATION OF ACTIVE INGREDIENTS FOR THE TREATMENT OF SENILE DEMENTIA OF THE ALZHEIMER TYPE |
| FR9714324A FR2771006B1 (en) | 1997-11-14 | 1997-11-14 | COMBINATION OF ACTIVE INGREDIENTS FOR THE TREATMENT OF SENILE DEMENTIA OF THE ALZHEIMER TYPE |
| PCT/FR1998/002384 WO1999025363A1 (en) | 1997-11-14 | 1998-11-09 | Combination of active principles, in particular of tetrahydropyridins and acetylcholinesterase inhibiting agents, for treating senile dementia such as alzheimer dementia |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU1160999A AU1160999A (en) | 1999-06-07 |
| AU743228B2 true AU743228B2 (en) | 2002-01-24 |
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| AU11609/99A Ceased AU743228B2 (en) | 1997-11-14 | 1998-11-09 | Combination of active principles, in particular of tetrahydropyridins and acetylcholinesterase inhibiting agents, for treating senile dementia such as Alzheimer dementia |
Country Status (27)
| Country | Link |
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| EP (1) | EP1030671A1 (en) |
| JP (1) | JP2001523642A (en) |
| KR (1) | KR100599350B1 (en) |
| CN (1) | CN1243540C (en) |
| AU (1) | AU743228B2 (en) |
| BG (1) | BG64819B1 (en) |
| BR (1) | BR9814035A (en) |
| CA (1) | CA2309966A1 (en) |
| CO (1) | CO4980891A1 (en) |
| DZ (1) | DZ2649A1 (en) |
| EA (1) | EA003255B1 (en) |
| EE (1) | EE04235B1 (en) |
| HU (1) | HUP0100098A3 (en) |
| ID (1) | ID24933A (en) |
| IL (2) | IL136122A0 (en) |
| IS (1) | IS5482A (en) |
| MY (1) | MY120461A (en) |
| NO (1) | NO20002450L (en) |
| NZ (1) | NZ504420A (en) |
| OA (1) | OA11464A (en) |
| PL (1) | PL194597B1 (en) |
| SA (1) | SA98190747B1 (en) |
| SK (1) | SK286040B6 (en) |
| TR (1) | TR200001262T2 (en) |
| TW (1) | TW585766B (en) |
| UY (1) | UY25247A1 (en) |
| WO (1) | WO1999025363A1 (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL165589A (en) * | 2002-06-14 | 2012-04-30 | Toyama Chemical Co Ltd | Pharmaceutical composition for improving cerebral function and use thereof |
| PT1529116E (en) * | 2002-08-07 | 2009-09-10 | Novartis Ag | Method for predicting the responsiveness to treatment with rivastigmine based on the apoe genotyp of dementia patients |
| CN1520818A (en) * | 2003-02-09 | 2004-08-18 | 山东绿叶天然药物研究开发有限公司 | Cholinesterase inhibitor pharmaceutical composition for senile dementia |
| BRPI0518396A2 (en) | 2004-12-27 | 2008-11-18 | Eisai R&D Man Co Ltd | Anti-Dementia Drug Stabilization Method |
| ES2721001T3 (en) | 2014-01-31 | 2019-07-26 | Cognition Therapeutics Inc | Isoindoline derivative, and compositions and methods to treat a neurodegenerative disease |
| CA3061787A1 (en) * | 2017-05-15 | 2018-11-22 | Cognition Therapeutics, Inc. | Compositions for treating neurodegenerative diseases |
| KR102224917B1 (en) | 2018-03-20 | 2021-03-09 | (주)인벤티지랩 | Production methods of preventing or treating cognitive impairment-related disease and preventing or treating cognitive impairment-related disease producing thereto |
| WO2019182319A1 (en) * | 2018-03-20 | 2019-09-26 | (주)인벤티지랩 | Method for preparing pharmaceutical composition for preventing or treating cognitive disorder-associated diseases, and pharmaceutical composition for preventing or treating cognitive disorder-associated diseases, prepared by preparation method |
| CN109265391B (en) * | 2018-11-13 | 2021-11-19 | 枣庄学院 | Biphenyl polysubstituted 1,2,5, 6-tetrahydropyridine compound and synthetic method and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997001536A1 (en) * | 1995-06-28 | 1997-01-16 | Sanofi | 4-aryl-1-phenylalkyl-1,2,3,6-tetrahydropyridines having neurotrophic and neuroprotective activity |
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| FR2662355B1 (en) * | 1990-05-22 | 1994-11-10 | Sanofi Sa | USE OF 1- [2- (2-NAPHTYL) ETHYL] -4- (3-TRIFLUOROMETHYLPHENYL) -1,2,3,6-TETRAHYDROPYRIDINE FOR THE PREPARATION OF MEDICINES FOR THE TREATMENT OF BRAIN AND NEURAL DISORDERS. |
| US5453428A (en) * | 1991-02-14 | 1995-09-26 | The Mount Sinai School Of Medicine Of The City Of New York | Method and composition for the treatment of apathy-amotivation syndrome |
| DE69634773T2 (en) * | 1995-03-06 | 2006-05-04 | Interneuron Pharmaceuticals, Inc., Lexington | REDUCTION OF INFECTIVE EXCHANGE USING CITICOLIN |
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1998
- 1998-10-26 CO CO98062479A patent/CO4980891A1/en unknown
- 1998-10-28 TW TW087117874A patent/TW585766B/en not_active IP Right Cessation
- 1998-11-09 WO PCT/FR1998/002384 patent/WO1999025363A1/en not_active Application Discontinuation
- 1998-11-09 SK SK711-2000A patent/SK286040B6/en unknown
- 1998-11-09 TR TR2000/01262T patent/TR200001262T2/en unknown
- 1998-11-09 HU HU0100098A patent/HUP0100098A3/en unknown
- 1998-11-09 PL PL98340500A patent/PL194597B1/en not_active IP Right Cessation
- 1998-11-09 CN CNB988130947A patent/CN1243540C/en not_active Expired - Fee Related
- 1998-11-09 NZ NZ504420A patent/NZ504420A/en unknown
- 1998-11-09 AU AU11609/99A patent/AU743228B2/en not_active Ceased
- 1998-11-09 KR KR1020007005231A patent/KR100599350B1/en not_active IP Right Cessation
- 1998-11-09 BR BR9814035-3A patent/BR9814035A/en not_active Application Discontinuation
- 1998-11-09 EP EP98954538A patent/EP1030671A1/en not_active Withdrawn
- 1998-11-09 EA EA200000412A patent/EA003255B1/en not_active IP Right Cessation
- 1998-11-09 EE EEP200000290A patent/EE04235B1/en not_active IP Right Cessation
- 1998-11-09 IL IL13612298A patent/IL136122A0/en not_active IP Right Cessation
- 1998-11-09 JP JP2000520796A patent/JP2001523642A/en not_active Withdrawn
- 1998-11-09 CA CA002309966A patent/CA2309966A1/en not_active Abandoned
- 1998-11-09 ID IDW20000860A patent/ID24933A/en unknown
- 1998-11-11 DZ DZ980259A patent/DZ2649A1/en active
- 1998-11-12 UY UY25247A patent/UY25247A1/en not_active IP Right Cessation
- 1998-11-14 SA SA98190747A patent/SA98190747B1/en unknown
- 1998-11-14 MY MYPI98005180A patent/MY120461A/en unknown
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2000
- 2000-05-09 IS IS5482A patent/IS5482A/en unknown
- 2000-05-11 BG BG104428A patent/BG64819B1/en unknown
- 2000-05-11 NO NO20002450A patent/NO20002450L/en unknown
- 2000-05-12 OA OA1200000141A patent/OA11464A/en unknown
- 2000-05-14 IL IL136122A patent/IL136122A/en unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997001536A1 (en) * | 1995-06-28 | 1997-01-16 | Sanofi | 4-aryl-1-phenylalkyl-1,2,3,6-tetrahydropyridines having neurotrophic and neuroprotective activity |
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