CN1285742A - Combination of active principles for treating senile dementia such as alzheimer dementia - Google Patents
Combination of active principles for treating senile dementia such as alzheimer dementia Download PDFInfo
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- CN1285742A CN1285742A CN98813094A CN98813094A CN1285742A CN 1285742 A CN1285742 A CN 1285742A CN 98813094 A CN98813094 A CN 98813094A CN 98813094 A CN98813094 A CN 98813094A CN 1285742 A CN1285742 A CN 1285742A
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- tetrahydropyridine
- trifluoromethyl
- ethyl
- alkyl
- amino
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- 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
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- 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
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- 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
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Abstract
The invention concerns a pharmaceutical composition containing as active principles: a constituent (a) selected between 1-(2-napht-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridin and a compound (I) in which: Y represents -CH- or -N-; R1 represents hydrogen, a halogen, a hydroxyl, a CF3, a (C3-C4)alkyl or (C1-C4) alkoxyl group; R2 represents hydrogen, a halogen, a hydroxyl, a CF3, (C3-C4) alkyl or( C1-C4)alkoxyl group; R3 and R4 represent each hydrogen or a (C1-C4)alkyl; X represents (a) a (C3-C6)alkyl; a (C3-C6)alkoxyl; a (C3-C7)carboxyalkyl; a (C1-C4)alkoxycarbonyl(C3-C6-)alkyl; a (C3-C7)carboxyalkoxyl; or a (C1-C4)alkoxycarbonyl(C3-C6)alkoxyl; (b) a radical selected among a (C3-C7)cycloalkyl, (C3-C7)cycloalkyloxy, (C3-C7)cycloalkylmethyl, (C3-C7)cycloalkylamino and cyclohexenyl, said radical capable of being substituted by a halogen, hydroxy, (C1-C4)alkoxy, carboxy, (C1-C4)alkoxycarbonyl, amino, mono- or di-(C1-C4)alkyamino or (c) a group selected among phenyl, phenoxy, phenylamino, N-(C1-C3)alkyl-phenyl-amino, phenylmethyl, phenylethyl, p henylcarbonyl, phenylthio, phenylsulphonyl, phenylsulphinyl and styryl, said group capable of being mono- or polysubstituted on the phenyl group by a halogen, CF3, (C1-C4)alkyl, (C1-C4)alkoxy, cyano, amino, mono- or di-(C1-C4)alkylamino, (C1-C4)acylamino, carboxy, (C1-C4)alkoxycarbonyl, aminocarbonyl, mono- or di-(C1-C4)alkylaminocarbonyl, amino(C1-C4)alk yl, hydroxy(C1-C4)alkyl, or halogeno(C1-C4)alkyl; optionally in the form of one of its pharmaceutically acceptable salts; and an constituent (b) active in the symptomatic treatment of DAT, optionally in the form of one of its pharmaceutically acceptable salts, provided that when constituent (a) is other than 1-(2napht-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridin or one of its pharmaceutically acceptable salts, the constituent (b) is an acetylcholinesterase inhibiting agent.
Description
The present invention relates to contain the pharmaceutical composition of the new combination of active component that is used for the treatment of Alzheimers type alzheimer disease, wherein said combination is by optional 1 of its a kind of pharmaceutical acceptable salt that is, 2,3, the 6-5,6-tetrahydropyridine derivative and choose in the symptom treatment of Alzheimers type alzheimer disease activated material wantonly, the acetylcholinesteraseinhibitors inhibitors that especially is its a kind of pharmaceutical acceptable salt forms, the invention still further relates to described pharmaceutical composition and be used for the treatment of application in the medicine of Alzheimers type alzheimer disease in preparation.
The Alzheimers type alzheimer disease that is called DAT (" Alzheimers type dementia ") hereinafter is a neurodegenerative disease, and its Clinical symptoms is that cognitive function carries out sexual involution, usually occur among the old people, and sickness rate increases with age growth.According to the demographic trend, DAT has become very general disease gradually.
The level of having observed several neurotransmitteies, especially acetylcholine neurotransmitter in DAT patient reduces.
For DAT, unique treatment of adopting comprises the acetylcholinesteraseinhibitors inhibitors administration that can reduce acetylcholine hydrolyzation and increase its bioavailability thus usually.Therefore this is a symptom treatment.
With trade name COGNEX
Commercially available tacrine and with trade name APICEPT
Commercially available donepezil is the acetylcholinesteraseinhibitors inhibitors that is used for gently arriving moderate DAT symptom treatment.Other product that is used for the DAT symptom treatment is in conceptual phase.Some of them also act on the utilizability aspect of acetylcholine, and other is a symptom of improving DAT patient by other mechanism.Up to now, be proved to be the process that to slow down this disease without any marketed drugs.
EP-458696 has described 1-(2-naphthalene-2-ethyl)-4-(3-trifluoromethyl)-1,2,3,6-tetrahydropyridine (being called SR 57746 in the document) is used for the treatment of application in the medicine of neurodegenerative disorders in preparation, and described neurodegenerative disorders comprises alzheimer disease and Alzheimer.57746 pairs of neural neurotrophic effects of SR and some endogenous neurotrophins for example effect of nerve growth factor (NGF) are similar.
WO 97/01536 has described the 4-that has with similar neuroprotective of some endogenous neurotrophins and neurotrophic activity and has replaced 1-phenylalkyl-1,2,3,6-tetrahydropyridine.Owing to have this activity, the chemical compound of describing in this patent application can be used for treating several central nervous system disease that comprise Alzheimer by inference.
Except being used to neuroprotective unit, compound S R 57746 and the chemical compound in WO 97/01536, described the treatment sacred disease for example the activity among the DAT be not used to treat symptom, change the course of disease of sacred disease and alleviate its development.
Have been found that now, the optional above-claimed cpd that is its a kind of pharmaceutical acceptable salt, with the optional combination of activated chemical compound, especially acetylcholinesteraseinhibitors inhibitors in the symptom treatment of Alzheimers type alzheimer disease that is its a kind of pharmaceutical acceptable salt can be fully and treat DAT, the rapid and complementary effect of this combination results very effectively.
Therefore, the objective of the invention is, the pharmaceutical composition that contains following active component be provided:
-be selected from 1-(2-naphthalene-2-ethyl)-4-(3-trifluoromethyl)-1,2,3, the chemical compound (a) of 6-tetrahydropyridine and formula I chemical compound:
Wherein
Y is-CH-or-N-;
R
1Be hydrogen, halogen, CF
3, (C
3-C
4) alkyl or (C
1-C
4) alkoxyl;
R
2Be hydrogen, halogen, hydroxyl, CF
3, (C
3-C
4) alkyl or (C
1-C
4) alkoxyl;
R
3And R
4Be respectively hydrogen or (C
1-C
3) alkyl;
X is
(a) (C
3-C
6) alkyl; (C
3-C
6) alkoxyl; (C
3-C
7) carboxyalkyl; (C
1-C
4) alkoxy carbonyl (C
3-C
6) alkyl; (C
3-C
7) the carboxyl alkoxyl; Or (C
1-C
4) alkoxy carbonyl (C
3-C
6) alkoxyl;
(b) be selected from (C
3-C
7) cycloalkyl, (C
3-C
7) cycloalkyloxy, (C
3-C
7) methyl cycloalkyl, (C
3-C
7) group of cycloalkyl amino and cyclohexenyl group, wherein said group is optional by halogen, hydroxyl, (C
1-C
4) alkoxyl, carboxyl, (C
1-C
4) alkoxy carbonyl, amino, (a C
1-C
4) alkyl amino or two (C
1-C
4) the alkyl amino replacement; Or
(c) be selected from phenyl, phenoxy group, phenyl amino, N-(C
1-C
3) group of alkyl phenyl amino, phenyl methyl, phenylethyl, phenylcarbonyl group, thiophenyl, benzenesulfonyl, benzenesulfinyl or styryl, wherein said phenyl is optional by halogen, CF
3, (C
1-C
4) alkyl, (C
1-C
4) alkoxyl, cyano group, amino, (a C
1-C
4) alkyl amino, two (C
1-C
4) alkyl amino, (C
1-C
4) acylamino-, carboxyl, (C
1-C
4) alkoxy carbonyl, amino carbonyl, (a C
1-C
4) alkyl amino-carbonyl, two (C
1-C
4) alkyl amino-carbonyl, amino (C
1-C
4) alkyl, hydroxyl (C
1-C
4) alkyl or halo (C
1-C
4) alkyl list or polysubstituted;
Wherein chemical compound (a) is chosen wantonly and is its a kind of pharmaceutical acceptable salt,
With
-optional be its a kind of pharmaceutical acceptable salt, in the symptom treatment of DAT activated chemical compound (b),
Condition is, when chemical compound (a) is not 1-(2-naphthalene-2-ethyl)-4-(3-trifluoromethyl)-1,2,3, during a kind of officinal salt of 6-tetrahydropyridine or its, chemical compound (b) is an acetylcholinesteraseinhibitors inhibitors.
1-(2-naphthalene-2-ethyl)-4-(3-trifluoromethyl)-1,2,3,6-tetrahydropyridine (SR-57746) is described among the EP 101381, and above-mentioned formula (I) chemical compound is described among the WO 97/01536.
Particularly suitable chemical compound (a) is optional 1-(2-naphthalene-2-the ethyl)-4-(3-trifluoromethyl)-1,2,3 that is its a kind of pharmaceutical acceptable salt, 6-tetrahydropyridine (SR 57746).
In the middle of the officinal salt of SR 57746, its hydrochlorate is particularly preferred, and its hydrochlorate is called SR 57746A hereinafter.
The proper method of preparation SR 57746A comprises, with 2-(2-bromoethyl) naphthalene and 4-(3-trifluoromethyl)-1,2,3, the reaction of 6-tetrahydropyridine, separate 1-(2-naphthalene-2-ethyl)-4-(3-trifluoromethyl)-1,2,3,6-tetrahydropyridine hydrochlorate, then it is cooled to 5 ℃, stirs with 400 rev/mins speed and carry out recrystallization simultaneously by heating and with 10 ℃/hour speed in ethanol/water mixture, the ratio that obtained is about two kinds of crystal formation mixture of 66/34.
SR 57746A preferably uses with the microparticle form, for example with obtain by spray drying be basically unbodied form or by micronization obtain microcrystalline form use.
Another particularly suitable chemical compound (a) is 1-{2-(4-xenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3,6-tetrahydropyridine, especially its hydrochlorate.
Other chemical compound that is fit to is as follows:
1-{2-(3 '-chloro-4-xenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(2 '-chloro-4-xenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(4 '-chloro-4-xenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(4 '-fluoro-4-xenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(3 '-trifluoromethyl-4-xenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(4-cyclohexyl phenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(4-xenyl) ethyl }-4-(4-fluorophenyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(4-xenyl)-2-methyl-propyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(4-Phenoxyphenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(4-benzyl phenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(4-n-butylphenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(4-n-butoxy phenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(4-(4-ethoxy carbonyl propoxyl group) phenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(4-xenyl) ethyl }-4-(6-chloropyridine-2-yl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(2,3 '-two chloro-4-xenyls) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(3-chloro-4-xenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(3 ', 5 '-two chloro-4-xenyls) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(2 ', 4 '-two chloro-4-xenyls) ethyl }-4-(3-trifluoromethyl)-1,2,3,6-tetrahydrochysene pyrrole is fixed;
1-{2-(2-chloro-4-xenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(3 '-chloro-4-xenyl)-2-methyl-propyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(2-fluoro-4-xenyl) propyl group }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(4-methoxyl group-3-xenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(4 '-methoxyl group-4-xenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(4 '-hydroxyl-4-xenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(4 '-ethoxy carbonyl butoxy-4-xenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(3-xenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(3 '-chloro-4 '-fluoro-4-xenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(2 '-trifluoromethyl-4-xenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(3,4-diisobutyl phenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(3,4-dipropyl phenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(4-cyclohexyl phenyl) ethyl }-4-(6-chloropyridine-2-yl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(4-isobutyl phenenyl) propyl group }-4-(6-chloropyridine-2-yl)-1,2,3, the 6-tetrahydropyridine;
With their officinal salt.
In this manual, " activated chemical compound in the symptom treatment of DAT " be meant, can improve DAT patient symptom, but the cause of disease of DAT not have the chemical compound that acts on.
These chemical compounds are for example acetylcholinesteraseinhibitors inhibitors, M
1Muscarinic agonist, nicotinic agonist, N-methyl-D-aspartate (NMDA) receptor antagonist, psychotropic thing, acetylcholinesteraseinhibitors inhibitors is particularly suitable.
Aspect preferred, the present invention relates to contain and optionally be the chemical compound (a) of its a kind of pharmaceutical acceptable salt and be selected from the pharmaceutical composition of the chemical compound (b) of the optional acetylcholinesteraseinhibitors inhibitors that is its a kind of pharmaceutical acceptable salt as active component.
Particularly suitable acetylcholinesteraseinhibitors inhibitors is tacrine and donepezil.
Other operable acetylcholinesteraseinhibitors inhibitors is rivastigmine (SDZ-ENA-713), galantamine, metrifonate, eptastigmine, Velnacine, Fysostigmin (" medicine " (Drugs), 1997,53 (5): 752-768 for example; " Merck index " (The Merck Index) the 12nd edition).
Other acetylcholinesteraseinhibitors inhibitors is 5,7-dihydro-3-{2-(1-(phenyl methyl)-4-piperidyl) ethyl }-6H-pyrrolo-(3,2-f)-1,2-benzoisoxazole-6-ketone (being also referred to as icopezil) (" pharmaceutical chemistry magazine " (J.Med.Chem.), 1995,38:2802-2808), MDL-73,745 or zifrosilone (" European pharmacology's magazine " (Eur.J.Pharmacol.), 1995,276:93-99), TAK-147 (" pharmaceutical chemistry magazine " (J.Med.Chem.), 1994,37:2292-2299).
Other acetylcholinesteraseinhibitors inhibitors is the acetylcholinesteraseinhibitors inhibitors of for example describing in following patent publications: JP 09-095483, WO 97/13754, WO 97/21681, WO 97/19929, ZA 9604565, US 5455245, WO 95-21822, EP 637586, US 5401749, EP742207, US 5547960, WO 96/20176, WO 96/02524, EP 677516, JP07-188177, JP 07-133274, EP 649846, EP 648771, JP 07-048370, US 5391553, WO 94/29272, EP 627400.
The M1 receptor antagonist is milameline for example, besipirdine, talsaclidine, account for Nuo Meilin, YM-796 and YM-954 are (" European pharmacology's magazine " (Eur.J.Pharmacol.), 1990,187:479-486), 3-{N-(2-diethylamino-2-methyl-propyl)-6-phenyl-5-propyl group } pyridazine amine (being also referred to as SR-46559) (Biorg.Med.Chem.Let., 1992,2:833-838), AF-102, CI-979, L-689660, LU 25109, S-99 77-2, SB 202026, thiopilocarpine, WAL 2014 (Pharmacol.Toxicol., 1996,78:59-68).
The nicotinic agonist that is fit to is MKC-231 (Biorg.Med.Chem.Let. for example, 1995,5 (14): 1495-1500), T-588 (" Folia Pharmacologica Japonica " (Japan J.Pharmacol.), 1993,62:81-86), ABT-418 (" Britain pharmacology magazine " (Br.J.Pharmacol.), 1997,120:429-438).
The nmda receptor antagonist that is fit to be for example Memantine hydrochloride (Arzneim.Forsch., 1991,41:773-780).
On the other hand, the present invention relates to the present composition and be used for the treatment of application in the medicine of Alzheimers type alzheimer disease in preparation.
On the other hand, the invention still further relates to the other method of treatment Alzheimers type alzheimer disease, comprise the optional above-claimed cpd (a) that is its a kind of pharmaceutical acceptable salt with effective dose, the optional chemical compound (b) that is its a kind of pharmaceutical acceptable salt with effective dose, especially acetylcholinesteraseinhibitors inhibitors is to suffering from patient's administration of this disease, described administration can be simultaneously, in proper order, or certain hour hockets at interval, the active component of effective dose can be included in the unit form of administration separately, perhaps when active component administration simultaneously, these two kinds of active components preferably are contained in the same pharmaceutical dosage form.
Active component preferred oral of the present invention administration.
Be used for the pharmaceutical composition of the present invention of oral administration, can with active component in the unit form of administration, with the mixture of standard pharmaceutical carrier in above-mentioned disease is treated in animal and human's administration.Suitable unit form of administration comprises for example optional dispersible tablet, capsule, powder, granule and solution or oral suspension.
When preparing solid composite with tablet form, for example gelatin, starch, lactose, magnesium stearate, Talcum, arabic gum etc. mix with pharmaceutical carrier with active component.Available sucrose or other suitable material are perhaps handled tablet coating making it have the active or delay release activity of slow release, and are made it continue to discharge the active substance of scheduled volume with tablet.
By with active component and mixing diluents, and pack into the gained mixture soft or hard capsule in can make capsule.
Syrup or elixir can contain active component and sweeting agent, the sweeting agent that does not preferably contain heat, as methyl parahydroxybenzoate and propyl p-hydroxybenzoate and the flavoring agent and the appropriate colouring agent of antiseptic.
Can be in water dispersive powder and granule can contain active component and dispersant or wetting agent or suspending agent such as polyvinylpyrrolidone or sweeting agent or flavoring agent.
Active component can be chosen wantonly with one or more carriers or additive and be made microcapsule.
In pharmaceutical composition of the present invention, active component and cyclodextrin, its ether or ester can be made inclusion complex.
The dosage of active component depends on the order of severity and the patient's age and the body weight of disease all the time.
The dosage of two kinds of active components is similar to their selected in the prior art next individually dosed common doses.
Therefore, the present composition contains the recommended dose of non-therapeutic alliance, for example 0.5mg-700mg chemical compound (a) or its a kind of officinal salt and 0.1-50mg chemical compound (b) or its a kind of officinal salt or even low dosage more so that this combination results synergism.
The compositions that is fit to contains for example 0.5-5mg SR 57746 or its a kind of officinal salt and 0.1-50mg acetylcholinesteraseinhibitors inhibitors or its a kind of officinal salt.
Preferred compositions contains 0.5-5mg SR 57746 or its a kind of officinal salt and 2-10mg donepezil or its a kind of officinal salt.
The described dosage of this description is meant the amount of the active component that is not salt form.
By confirmed the activity of the present composition with following particular model, be Hippocampus every the cholinergic system damage model, wherein said damage be by injection can induce with Alzheimer in the similarly biochemical vincristine that changes of the variation that exists cause.
The operation of in this model, using, the damage that causes by vincristine and the evaluation of Social Memory is described among the EP 655247.
The Social Memory evaluation test of in rat, carrying out
Cause after the damage that by injection vincristine as described in EP 655247 rat shows stable and persistent dementia.Rat is divided into 2 groups, and a winding is subjected to solvent, the SR 57746A of another group oral administration 5mg/kg, and this underdosage is so that the memory function of rat recovery (effective dose of describing in EP 655247 is 10mg/kg) in this test.Give the tacrine of administration 1mg/kg in these two groups of rat peritoneums then.The matched group of accepting solvent and tacrine does not show any reminiscence, and the memory defects of the rats in test groups for the treatment of with SR 57746A (effective dose following dosage) and tacrine shows remarkable recovery.
This result of the test shows that combination of the present invention has synergism.
The complementation and the synergistic result of the component of the present invention combination be, can protect or even cure the neuron that this disease influences, and can improve patient's symptom again, and the present composition can be treated the DAT of form of ownership effectively.
Claims (19)
1. the pharmaceutical composition that contains following active component:
-be selected from 1-(2-naphthalene-2-ethyl)-4-(3-trifluoromethyl)-1,2,3, the chemical compound (a) of 6-tetrahydropyridine and formula I chemical compound:
Wherein
Y is-CH-or-N-;
R
1Be hydrogen, halogen, CF
3, (C
3-C
4) alkyl or (C
1-C
4) alkoxyl;
R
2Be hydrogen, halogen, hydroxyl, CF
3, (C
3-C
4) alkyl or (C
1-C
4) alkoxyl;
R
3And R
4Be respectively hydrogen or (C
1-C
3) alkyl;
X is
(a) (C
3-C
6) alkyl; (C
3-C
6) alkoxyl; (C
3-C
7) carboxyalkyl; (C
1-C
4) alkoxy carbonyl (C
3-C
6) alkyl; (C
3-C
7) the carboxyl alkoxyl; Or (C
1-C
4) alkoxy carbonyl (C
3-C
6) alkoxyl;
(b) be selected from (C
3-C
7) cycloalkyl, (C
3-C
7) cycloalkyloxy, (C
3-C
7) methyl cycloalkyl, (C
3-C
7) group of cycloalkyl amino and cyclohexenyl group, wherein said group is optional by halogen, hydroxyl, (C
1-C
4) alkoxyl, carboxyl, (C
1-C
4) alkoxy carbonyl, amino, (a C
1-C
4) alkyl amino or two (C
1-C
4) the alkyl amino replacement; Or
(c) be selected from phenyl, phenoxy group, phenyl amino, N-(C
1-C
3) group of alkyl phenyl amino, phenyl methyl, phenylethyl, phenylcarbonyl group, thiophenyl, benzenesulfonyl, benzenesulfinyl or styryl, wherein said phenyl is optional by halogen, CF
3, (C
1-C
4) alkyl, (C
1-C
4) alkoxyl, cyano group, amino, (a C
1-C
4) alkyl amino, two (C
1-C
4) alkyl amino, (C
1-C
4) acylamino-, carboxyl, (C
1-C
4) alkoxy carbonyl, amino carbonyl, (a C
1-C
4) alkyl amino-carbonyl, two (C
1-C
4) alkyl amino-carbonyl, amino (C
1-C
4) alkyl, hydroxyl (C
1-C
4) alkyl or halo (C
1-C
4) alkyl list or polysubstituted;
Wherein chemical compound (a) is chosen wantonly and is its a kind of pharmaceutical acceptable salt,
With
-optional be its a kind of pharmaceutical acceptable salt, in the symptom treatment of DAT activated chemical compound (b),
Condition is, when chemical compound (a) is not 1-(2-naphthalene-2-ethyl)-4-(3-trifluoromethyl)-1,2,3, during a kind of officinal salt of 6-tetrahydropyridine or its, chemical compound (b) is an acetylcholinesteraseinhibitors inhibitors.
2. the compositions of claim 1, it is characterized in that, described compositions contains optional 1-(2-naphthalene-2-the ethyl)-4-(3-trifluoromethyl)-1 that is its a kind of pharmaceutical acceptable salt, 2,3, the 6-tetrahydropyridine and optional be its a kind of pharmaceutical acceptable salt, in the symptom treatment of Alzheimers type alzheimer disease activated chemical compound in conjunction with as active component.
3. the compositions of claim 1 is characterized in that, described compositions contains following active component:
-formula I chemical compound:
Wherein
Y is-CH-or-N-;
R
1Be hydrogen, halogen, CF
3, (C
3-C
4) alkyl or (C
1-C
4) alkoxyl;
R
2Be hydrogen, halogen, hydroxyl, CF
3, (C
3-C
4) alkyl or (C
1-C
4) alkoxyl;
R
3And R
4Be respectively hydrogen or (C
1-C
3) alkyl;
X is
(a) (C
3-C
6) alkyl; (C
3-C
6) alkoxyl; (C
3-C
7) carboxyalkyl; (C
1-C
4) alkoxy carbonyl (C
3-C
6) alkyl; (C
3-C
7) the carboxyl alkoxyl; Or (C
1-C
4) alkoxy carbonyl (C
3-C
6) alkoxyl;
(b) be selected from (C
3-C
7) cycloalkyl, (C
3-C
7) cycloalkyloxy, (C
3-C
7) methyl cycloalkyl, (C
3-C
7) group of cycloalkyl amino and cyclohexenyl group, wherein said group is optional by halogen, hydroxyl, (C
1-C
4) alkoxyl, carboxyl, (C
1-C
4) alkoxy carbonyl, amino, (a C
1-C
4) alkyl amino or two (C
1-C
4) the alkyl amino replacement; Or
(c) be selected from phenyl, phenoxy group, phenyl amino, N-(C
1-C
3) group of alkyl phenyl amino, phenyl methyl, phenylethyl, phenylcarbonyl group, thiophenyl, benzenesulfonyl, benzenesulfinyl or styryl, wherein said phenyl is optional by halogen, CF
3, (C
1-C
4) alkyl, (C
1-C
4) alkoxyl, cyano group, amino, (a C
1-C
4) alkyl amino, two (C
1-C
4) alkyl amino, (C
1-C
4) acylamino-, carboxyl, (C
1-C
4) alkoxy carbonyl, amino carbonyl, (a C
1-C
4) alkyl amino-carbonyl, two (C
1-C
4) alkyl amino-carbonyl, amino (C
1-C
4) alkyl, hydroxyl (C
1-C
4) alkyl or halo (C
1-C
4) alkyl list or polysubstituted;
Wherein chemical compound (a) is chosen wantonly and is its a kind of pharmaceutical acceptable salt,
With
-acetylcholinesteraseinhibitors inhibitors or its officinal salt.
4. the compositions of claim 3 is characterized in that, chemical compound (a) is 1-{2-(4-xenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3,6-tetrahydropyridine or its hydrochlorate.
5. the compositions of claim 3 is characterized in that, chemical compound (a) is selected from following chemical compound:
1-{2-(3 '-chloro-4-xenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(2 '-chloro-4-xenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(4 '-chloro-4-xenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(4 '-fluoro-4-xenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(3 '-trifluoromethyl-4-xenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(4-cyclohexyl phenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(4-xenyl) ethyl }-4-(4-fluorophenyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(4-xenyl)-2-methyl-propyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(4-Phenoxyphenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(4-benzyl phenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(4-n-butylphenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(4-n-butoxy phenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(4-(4-ethoxy carbonyl propoxyl group) phenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(4-xenyl) ethyl }-4-(6-chloropyridine-2-yl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(2,3 '-two chloro-4-xenyls) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(3-chloro-4-xenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(3 ', 5 '-two chloro-4-xenyls) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(2 ', 4 '-two chloro-4-xenyls) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(2-chloro-4-xenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(3 '-chloro-4-xenyl)-2-methyl-propyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(2-fluoro-4-xenyl) propyl group }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(4-methoxyl group-3-xenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(4 '-methoxyl group-4-xenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(4 '-hydroxyl-4-xenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(4 '-ethoxy carbonyl butoxy-4-xenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(3-xenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(3 '-chloro-4 '-fluoro-4-xenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(2 '-trifluoromethyl-4-xenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(3,4-diisobutyl phenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(3,4-dipropyl phenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(4-cyclohexyl phenyl) ethyl }-4-(6-chloropyridine-2-yl)-1,2,3, the 6-tetrahydropyridine;
1-{2-(4-isobutyl phenenyl) propyl group }-4-(6-chloropyridine-2-yl)-1,2,3, the 6-tetrahydropyridine;
With their officinal salt.
6. the compositions of claim 1 is characterized in that, described in the symptom treatment of Alzheimers type alzheimer disease activated chemical compound be selected from acetylcholinesteraseinhibitors inhibitors, M
1Muscarine (muscarinic) agonist, nicotine (nicotinic) agonist, nmda receptor antagonist and parent's spirit (nootropic) medicine.
7. the compositions of claim 6 is characterized in that, chemical compound (b) is an acetylcholinesteraseinhibitors inhibitors.
8. the compositions of claim 7 is characterized in that, described acetylcholinesteraseinhibitors inhibitors is selected from tacrine and donepezil.
9. the compositions of claim 7, it is characterized in that described acetylcholinesteraseinhibitors inhibitors is selected from rivastigmine, galantamine (galanthamine), metrifonate, eptastigmine, Velnacine (velnacrine), Fysostigmin (phystostigmine), icopezil and zifrosilone.
10. the compositions of claim 1 is characterized in that, described compositions contains 0.5-700mg chemical compound (a).
11. the compositions of claim 1 is characterized in that, described compositions contains 0.1-50mg chemical compound (b).
12. the compositions of claim 2 is characterized in that, described compositions contains 0.5-10mg1-(2-naphthalene-2-ethyl)-4-(3-trifluoromethyl)-1,2,3,6-tetrahydropyridine.
13. the compositions of claim 2 is characterized in that, described compositions contains 1-(2-naphthalene-2-ethyl)-4-(3-trifluoromethyl)-1,2,3, and 6-tetrahydropyridine and donepezil or their officinal salt are as active component.
14. the compositions of claim 3 is characterized in that, described compositions contains 1-{2-(4-xenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3,6-tetrahydropyridine and donepezil or their officinal salt are as active component.
15. the compositions of claim 2 is characterized in that, described compositions contains 0.5-5mg1-(2-naphthalene-2-ethyl)-4-(3-trifluoromethyl)-1,2,3,6-tetrahydropyridine and 2-10mg donepezil.
16. be used for the treatment of each the compositions of aforementioned claim of Alzheimers type alzheimer disease.
17. each compositions of aforementioned claim is used for the treatment of application in the medicine of Alzheimers type alzheimer disease in preparation.
18. the application of claim 17 is characterized in that, chemical compound (a) is selected from 1-(2-naphthalene-2-ethyl)-4-(3-trifluoromethyl)-1,2,3,6-tetrahydropyridine and 1-{2-(4-xenyl) ethyl }-4-(3-trifluoromethyl)-1,2,3, the 6-tetrahydropyridine.
19. the application of claim 17 is characterized in that, chemical compound (b) is selected from tacrine and donepezil.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9714322A FR2771007B1 (en) | 1997-11-14 | 1997-11-14 | COMBINATION OF ACTIVE INGREDIENTS FOR THE TREATMENT OF SENILE DEMENTIA OF THE ALZHEIMER TYPE |
| FR97/14322 | 1997-11-14 | ||
| FR9714324A FR2771006B1 (en) | 1997-11-14 | 1997-11-14 | COMBINATION OF ACTIVE INGREDIENTS FOR THE TREATMENT OF SENILE DEMENTIA OF THE ALZHEIMER TYPE |
| FR97/14324 | 1997-11-14 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1285742A true CN1285742A (en) | 2001-02-28 |
| CN1243540C CN1243540C (en) | 2006-03-01 |
Family
ID=26233932
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB988130947A Expired - Fee Related CN1243540C (en) | 1997-11-14 | 1998-11-09 | Combination of active principles for treating senile dementia such as alzheimer dementia |
Country Status (27)
| Country | Link |
|---|---|
| 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) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004069246A1 (en) * | 2003-02-09 | 2004-08-19 | Shandong Luye Natural Drugs Research And Develop Company Ltd. | Drug compositions comprising inhibitors of cholinesterase for treating senile dementia |
| CN109265391A (en) * | 2018-11-13 | 2019-01-25 | 枣庄学院 | The polysubstituted 1,2,5,6- 5,6-tetrahydropyridine compounds of biphenyl and its synthetic method and application |
Families Citing this family (7)
| 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 |
| WO2004015140A1 (en) * | 2002-08-07 | 2004-02-19 | Novartis Ag | Methods for the treatment of dementia based on apo e genotype |
| US8481565B2 (en) | 2004-12-27 | 2013-07-09 | Eisai R&D Management Co., Ltd. | Method for stabilizing anti-dementia drug |
| AU2015210852B2 (en) | 2014-01-31 | 2019-01-24 | Cognition Therapeutics, Inc. | Isoindoline compositions and methods for treating neurodegenerative disease |
| CA3061787A1 (en) | 2017-05-15 | 2018-11-22 | Cognition Therapeutics, Inc. | Compositions for treating neurodegenerative diseases |
| 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 |
| KR102224918B1 (en) | 2018-03-20 | 2021-03-09 | (주)인벤티지랩 | Pharmaceutiical composition comprising memantine and donepezil for preventing or treating cognitive impairment-related disease and preparation method thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| PT813416E (en) * | 1995-03-06 | 2005-10-31 | Interneuron Pharma | REDUCING VOLUME OF FUNGUS USING CITICOLIN |
| FR2736053B1 (en) * | 1995-06-28 | 1997-09-19 | Sanofi Sa | NEWS 1-PHENYLALKYL-1,2,3,6-TETRAHYDROPYRIDINES |
-
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 EE EEP200000290A patent/EE04235B1/en not_active IP Right Cessation
- 1998-11-09 ID IDW20000860A patent/ID24933A/en unknown
- 1998-11-09 AU AU11609/99A patent/AU743228B2/en not_active Ceased
- 1998-11-09 CA CA002309966A patent/CA2309966A1/en not_active Abandoned
- 1998-11-09 CN CNB988130947A patent/CN1243540C/en not_active Expired - Fee Related
- 1998-11-09 TR TR2000/01262T patent/TR200001262T2/en unknown
- 1998-11-09 SK SK711-2000A patent/SK286040B6/en unknown
- 1998-11-09 WO PCT/FR1998/002384 patent/WO1999025363A1/en not_active Application Discontinuation
- 1998-11-09 PL PL98340500A patent/PL194597B1/en not_active IP Right Cessation
- 1998-11-09 EA EA200000412A patent/EA003255B1/en not_active IP Right Cessation
- 1998-11-09 EP EP98954538A patent/EP1030671A1/en not_active Withdrawn
- 1998-11-09 KR KR1020007005231A patent/KR100599350B1/en not_active IP Right Cessation
- 1998-11-09 IL IL13612298A patent/IL136122A0/en not_active IP Right Cessation
- 1998-11-09 NZ NZ504420A patent/NZ504420A/en unknown
- 1998-11-09 HU HU0100098A patent/HUP0100098A3/en unknown
- 1998-11-09 JP JP2000520796A patent/JP2001523642A/en not_active Withdrawn
- 1998-11-09 BR BR9814035-3A patent/BR9814035A/en not_active Application Discontinuation
- 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
-
2000
- 2000-05-09 IS IS5482A patent/IS5482A/en unknown
- 2000-05-11 NO NO20002450A patent/NO20002450L/en unknown
- 2000-05-11 BG BG104428A patent/BG64819B1/en unknown
- 2000-05-12 OA OA1200000141A patent/OA11464A/en unknown
- 2000-05-14 IL IL136122A patent/IL136122A/en unknown
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004069246A1 (en) * | 2003-02-09 | 2004-08-19 | Shandong Luye Natural Drugs Research And Develop Company Ltd. | Drug compositions comprising inhibitors of cholinesterase for treating senile dementia |
| CN109265391A (en) * | 2018-11-13 | 2019-01-25 | 枣庄学院 | The polysubstituted 1,2,5,6- 5,6-tetrahydropyridine compounds of biphenyl and its synthetic method and application |
| 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 |
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