EP1030671A1 - Association de principes actifs, notamment de tetrahydropyridines et d'agents inhibiteurs de l'acetylcholinesterase, pour le traitement de la demence senile du type alzheimer - Google Patents
Association de principes actifs, notamment de tetrahydropyridines et d'agents inhibiteurs de l'acetylcholinesterase, pour le traitement de la demence senile du type alzheimerInfo
- Publication number
- EP1030671A1 EP1030671A1 EP98954538A EP98954538A EP1030671A1 EP 1030671 A1 EP1030671 A1 EP 1030671A1 EP 98954538 A EP98954538 A EP 98954538A EP 98954538 A EP98954538 A EP 98954538A EP 1030671 A1 EP1030671 A1 EP 1030671A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- trifluoromethylphenyl
- ethyl
- tetrahydropyridine
- biphenylyl
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- 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
-
- 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
-
- 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
-
- 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
-
- 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
Definitions
- the subject of the present invention is a pharmaceutical composition
- a pharmaceutical composition comprising a new combination of active principles, for the treatment of senile dementia of the Alzheimer type, consisting of derivatives of 1,2,3,6-tetrahydropyridines, optionally in the form of one of their pharmaceutically acceptable salts and of a compound active in the symptomatic treatment of senile dementia of the Alzheimer type, in particular of an acetylcholinesterase inhibitor, optionally in the form of one of its pharmaceutically acceptable salts and its use for the preparation of medicaments intended for the treatment of senile dementia of the Alzheimer type.
- Senile dementia of the Alzheimer type hereinafter called DAT (from English
- Impairia of Alzheimer's type is a neurodegenerative disease clinically characterized by the progressive decline of cognitive functions occurring in the elderly with an incidence that increases in relation to age. Given demographic trends, TAD will become an increasingly widespread disease.
- the only treatment for DAT currently available on the market consists of administering by acetylcholinesterase inhibitors which by reducing the hydrolysis of acetylcholine thus increase its bioavailability. It is therefore a symptomatic treatment.
- Tacrine sold under the brand COGNEX ®
- donepezil sold under the brand ARICEPT
- acetylcholinesterase inhibitors indicated for the symptomatic treatment of mild to moderate forms of DAT.
- Other products for the symptomatic treatment of TAD are being studied. Some of them also act on the availability of acetylcholine, others improve the symptomatic framework of patients affected by TAD by other mechanisms. So far, no drug available on the market has been able to slow the progression of the disease.
- EP-458696 describes the use of 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) - 1,2,3,6-tetr.ahydropyridine, known in the literature SR 57746, for the preparation drugs to fight neurodegenerative conditions, 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, nerve growth factor (NGF).
- NGF nerve growth factor
- WO 97/01536 describes new 4-substituted l-phenylalkyl-1,2,3,6-tetrahydropyridines having neurotrophic and neuroprotective activity similar to that of certain endogenous neurotrophins. Thanks to this activity, the compounds described in This patent application is said to be useful in the treatment of several pathologies of the central nervous system, including Alzheimer's disease.
- the activity in the treatment of nervous pathologies such as the DAT of the compound SR57746 and of the compounds described in WO 97/01536 is not intended to treat the symptoms but, by protecting the neurons, to modify the course of the disease and to reduce the progression.
- the subject of the present invention is a pharmaceutical composition containing as active principles a component (a) chosen from l- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -l, 2,3 , 6-tetrahydropyridine and a compound of formula (I),
- Ri represents hydrogen, a halogen, a CF 3 group, or (C1-C4) - dcoxyl
- R2 represents hydrogen, a halogen, a hydroxyl, a group CF 3 , (C3-C4) - alkyl or (Ci-C ⁇ alkoxyle;
- R3 and R4 each represent hydrogen or a (C ⁇ -C3) alkyl;
- a particularly advantageous component (a) is 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine (SR 57746), optionally in the form one of its pharmaceutically acceptable salts.
- SR 57746 A is a particularly preferred salt.
- An advantageous method for the preparation of SR 57746A provides for the reaction between 2- (2-bromoethyl) naphthalene and 4- (3-trifluoromethylphenyl) - 1,2,3,6- tetrahydropyridine and the isolation of l- hydrochloride (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine which is subsequently crystallized from an ethanol / water mixture by heating and cooling to 5 ° C with a cooling rate of 10 ° C / 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 microparticulate form, for example in an essentially amorphous form obtained by atomization or in a microcrystalline form obtained by micronization.
- Another particularly advantageous component (a) is 1- [2- (4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) - 1,2,3,6-tet.ahydropyridine, in particular its hydrochloride salt.
- the expression “active compound in the symptomatic treatment of DAT” designates a product which is capable of improving the symptomatological framework of patients suffering from DAT without intervening in the causes of the disease.
- Such compounds are for example acetylcholinesterase inhibitors, muscarinic agonists Mi, nicotinic agonists, receptor antagonists
- N-methyl-D-aspartate N-methyl-D-aspartate (NMDA), nootropics, acetylcholinesterase inhibitors being particularly advantageous.
- the invention relates to a pharmaceutical composition containing as active ingredient, a component (a), optionally in the form of one of its pharmaceutically acceptable salts, and a component (b) chosen from inhibitors of acetylcholinesterase, optionally in the form of one of its pharmaceutically acceptable salts.
- acetylcholinesterase inhibitors are tacrine and donepezil.
- acetylcholinesterase inhibitors which can be used are, for example, rivastigmine (SDZ-ENA-713), galanth.amine, metrifonate, eptastigmine, velnacrine, physostigmine (Drugs, 1997, 53 (5) : 752-768; The Merck
- acetylcholinesterase inhibitors are also 5,7-dihydro-3- [2- [l-
- acetylcholinesterase inhibitors are, for example, those described in 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 627400.
- Agonists of the Mi receptor are, for example, milamelin, besipiridine, talsaclidine, xanomelin, YM-796 and YM-954 (Eur. J. Pharmacol ., 1990, 187: 479-486), 3- [N- (2-diethylamino-2-methylpropyl) -6-phenyl-5-propyl] -pyridazinamine, also named SR-46559 (Biorg. Med. Chem.
- nicotinic 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).
- NMDA receptor antagonist for example memantine (Arzneim. Forsch., 1991, 41: 773-780).
- the present invention relates to the use of the compositions of the invention for the preparation of medicaments intended for the treatment of senile dementia of the Alzheimer type.
- the present invention also relates to a method of treating senile dementia of the Alzheimer type which consists in administering to a patient suffering from this disease an effective dose of component (a) above, possibly in the form one of its pharmaceutically acceptable salts and an effective dose of a component (b), in particular of an acetylcholinesterase inhibitor, optionally in the form of one of its pharmaceutically acceptable salts, said administrations being simultaneous, sequential or spread over time and the effective doses of the active principles which can be contained in separate unit administration forms or, when the active principles are administered simultaneously, the two active principles advantageously being contained in a single pharmaceutical form.
- the active ingredients according to the present invention are preferably administered orally.
- the active ingredients can be administered in unit forms administration, mixed with conventional pharmaceutical carriers, animals and humans for the treatment of the above conditions.
- Suitable unit dosage forms include, for example, possibly scored tablets, capsules, powders, granules and oral solutions or suspensions.
- the main active ingredient is mixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
- a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
- the tablets can be coated with sucrose or other suitable materials or they can be treated so that they have a prolonged or delayed activity and that they continuously release a predetermined quantity of active principle.
- a preparation in 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 sweetener, preferably calorie-free, methylparaben and propylparaben as antiseptics, as well as a flavoring agent and an appropriate color.
- a sweetener preferably calorie-free, methylparaben and propylparaben as antiseptics, as well as a flavoring agent and an appropriate color.
- Water dispersible powders or granules may contain the active ingredient in admixture with dispersing agents or wetting agents, or suspending agents, such as polyvinylpyrrolidone, as well as with sweeteners or correctors taste.
- the active principle can also be formulated in the form of microcapsules, optionally with one or more carriers or additives.
- the active principle can also be in the form of an inclusion complex in cyclodextrins, their ethers or their esters.
- the amount of active ingredient to be administered depends, as always, on the degree of progression of the disease as well as on the age and weight of the patient.
- the doses of the two active ingredients are analogous to those normally used in the art for the isolated administration of each of these active ingredients.
- compositions according to the invention therefore contain doses recommended for non-combined treatments, for example from 0.5 to 700 mg of component (a) or of a pharmaceutically acceptable salt thereof and 0.1 to 50 mg of component ( b) or a pharmaceutically acceptable salt thereof or lower doses, since the combination exerts a synergistic effect.
- compositions include, for example, 0.5 to 5 mg of SR 57746 or one of its pharmaceutically acceptable salts and 0.1 to 50 mg of an acetylcholinesterase inhibitor or one of its pharmaceutically acceptable salts.
- Preferred compositions include 0.5 to 5 mg of SR 57746 or a pharmaceutically acceptable salt thereof, especially 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 in non-salified form.
- composition according to the invention has been demonstrated using a specific model for the septo-hyppocampal cholinergic system, on lesions caused by the injection of vincristine.
- this model we evaluate the effects of the products tested on amnesia induced by the injection of vincristine which induces biochemical alterations similar to the alterations present in Alzheimer's disease.
- the rats have stable and lasting 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 po, a dose which is not sufficient to allow functional recovery in terms of memory in rats subjected to this test (the effective dose being 10 mg / kg as described in EP 655247).
- the dose of 1 mg / kg i.p. tacrine is then administered to the two groups of rats.
- the control group having received solvent and tacrine, shows no recovery of memory while the group having been treated with SR 57746A (sub-effective dose) and tacrine shows a significant recovery of memory deficits.
- the results of this test make it possible to recognize a synergistic action with the association of the present invention.
- the composition of the invention allows a effective treatment of DAT in all its forms.
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR9714324 | 1997-11-14 | ||
FR9714322A FR2771007B1 (fr) | 1997-11-14 | 1997-11-14 | Association de principes actifs pour le traitement de la demence senile du type alzheimer |
FR9714324A FR2771006B1 (fr) | 1997-11-14 | 1997-11-14 | Association de principes actifs pour le traitement de la demence senile du type alzheimer |
FR9714322 | 1997-11-14 | ||
PCT/FR1998/002384 WO1999025363A1 (fr) | 1997-11-14 | 1998-11-09 | Association de principes actifs, notamment de tetrahydropyridines et d'agents inhibiteurs de l'acetylcholinesterase, pour le traitement de la demence senile du type alzheimer |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1030671A1 true EP1030671A1 (fr) | 2000-08-30 |
Family
ID=26233932
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP98954538A Withdrawn EP1030671A1 (fr) | 1997-11-14 | 1998-11-09 | Association de principes actifs, notamment de tetrahydropyridines et d'agents inhibiteurs de l'acetylcholinesterase, pour le traitement de la demence senile du type alzheimer |
Country Status (27)
Country | Link |
---|---|
EP (1) | EP1030671A1 (ko) |
JP (1) | JP2001523642A (ko) |
KR (1) | KR100599350B1 (ko) |
CN (1) | CN1243540C (ko) |
AU (1) | AU743228B2 (ko) |
BG (1) | BG64819B1 (ko) |
BR (1) | BR9814035A (ko) |
CA (1) | CA2309966A1 (ko) |
CO (1) | CO4980891A1 (ko) |
DZ (1) | DZ2649A1 (ko) |
EA (1) | EA003255B1 (ko) |
EE (1) | EE04235B1 (ko) |
HU (1) | HUP0100098A3 (ko) |
ID (1) | ID24933A (ko) |
IL (2) | IL136122A0 (ko) |
IS (1) | IS5482A (ko) |
MY (1) | MY120461A (ko) |
NO (1) | NO20002450L (ko) |
NZ (1) | NZ504420A (ko) |
OA (1) | OA11464A (ko) |
PL (1) | PL194597B1 (ko) |
SA (1) | SA98190747B1 (ko) |
SK (1) | SK286040B6 (ko) |
TR (1) | TR200001262T2 (ko) |
TW (1) | TW585766B (ko) |
UY (1) | UY25247A1 (ko) |
WO (1) | WO1999025363A1 (ko) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100375619C (zh) * | 2002-06-14 | 2008-03-19 | 富山化学工业株式会社 | 改善脑功能的药物组合物及其用途 |
PT1529116E (pt) * | 2002-08-07 | 2009-09-10 | Novartis Ag | Métodos para o tratamento da demência com base no genótipo da apo e |
CN1520818A (zh) * | 2003-02-09 | 2004-08-18 | 山东绿叶天然药物研究开发有限公司 | 治疗老年性痴呆的胆碱酯酶抑制剂药物组合物 |
JP2008525313A (ja) | 2004-12-27 | 2008-07-17 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 抗痴呆薬の安定化方法 |
DK3498692T3 (da) | 2014-01-31 | 2022-05-16 | Cognition Therapeutics Inc | Isoindolin-sammensætninger og fremgangsmåder til behandling af neurodegenerativ sygdom og makulær degeneration |
BR112019023851A2 (pt) * | 2017-05-15 | 2020-08-18 | Cognition Therapeutics, Inc. | compostos, suas composições farmacêuticas e métodos para tratamento de doenças neurodegenerativas |
WO2019182319A1 (ko) * | 2018-03-20 | 2019-09-26 | (주)인벤티지랩 | 인지 장애 관련 질병의 예방 또는 치료용 약학적 조성물의 제조 방법 및 이의 제조 방법으로 제조된 인지 장애 관련 질병의 예방 또는 치료용 약학적 조성물 |
KR102224917B1 (ko) | 2018-03-20 | 2021-03-09 | (주)인벤티지랩 | 인지 장애 관련 질병의 예방 또는 치료용 약학적 조성물의 제조 방법 및 이의 제조 방법으로 제조된 인지 장애 관련 질병의 예방 또는 치료용 약학적 조성물 |
CN109265391B (zh) * | 2018-11-13 | 2021-11-19 | 枣庄学院 | 联苯多取代1,2,5,6-四氢吡啶化合物及其合成方法与应用 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2662355B1 (fr) * | 1990-05-22 | 1994-11-10 | Sanofi Sa | Utilisation de la 1-[2-(2-naphtyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine pour la preparation de medicaments destines au traitement de troubles cerebraux et neuronaux. |
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 |
CN1126546C (zh) * | 1995-03-06 | 2003-11-05 | 英特纽隆制剂药有限公司 | 使用胞磷胆碱减少梗塞面积 |
FR2736053B1 (fr) * | 1995-06-28 | 1997-09-19 | Sanofi Sa | Nouvelles 1-phenylalkyl-1,2,3,6-tetrahydropyridines |
-
1998
- 1998-10-26 CO CO98062479A patent/CO4980891A1/es unknown
- 1998-10-28 TW TW087117874A patent/TW585766B/zh not_active IP Right Cessation
- 1998-11-09 AU AU11609/99A patent/AU743228B2/en not_active Ceased
- 1998-11-09 SK SK711-2000A patent/SK286040B6/sk unknown
- 1998-11-09 KR KR1020007005231A patent/KR100599350B1/ko not_active IP Right Cessation
- 1998-11-09 BR BR9814035-3A patent/BR9814035A/pt not_active Application Discontinuation
- 1998-11-09 TR TR2000/01262T patent/TR200001262T2/xx unknown
- 1998-11-09 PL PL98340500A patent/PL194597B1/pl not_active IP Right Cessation
- 1998-11-09 EE EEP200000290A patent/EE04235B1/xx not_active IP Right Cessation
- 1998-11-09 CN CNB988130947A patent/CN1243540C/zh not_active Expired - Fee Related
- 1998-11-09 HU HU0100098A patent/HUP0100098A3/hu unknown
- 1998-11-09 EP EP98954538A patent/EP1030671A1/fr not_active Withdrawn
- 1998-11-09 EA EA200000412A patent/EA003255B1/ru not_active IP Right Cessation
- 1998-11-09 IL IL13612298A patent/IL136122A0/xx not_active IP Right Cessation
- 1998-11-09 ID IDW20000860A patent/ID24933A/id unknown
- 1998-11-09 CA CA002309966A patent/CA2309966A1/en not_active Abandoned
- 1998-11-09 NZ NZ504420A patent/NZ504420A/en unknown
- 1998-11-09 JP JP2000520796A patent/JP2001523642A/ja not_active Withdrawn
- 1998-11-09 WO PCT/FR1998/002384 patent/WO1999025363A1/fr not_active Application Discontinuation
- 1998-11-11 DZ DZ980259A patent/DZ2649A1/xx active
- 1998-11-12 UY UY25247A patent/UY25247A1/es not_active IP Right Cessation
- 1998-11-14 SA SA98190747A patent/SA98190747B1/ar unknown
- 1998-11-14 MY MYPI98005180A patent/MY120461A/en unknown
-
2000
- 2000-05-09 IS IS5482A patent/IS5482A/is unknown
- 2000-05-11 NO NO20002450A patent/NO20002450L/no unknown
- 2000-05-11 BG BG104428A patent/BG64819B1/bg unknown
- 2000-05-12 OA OA1200000141A patent/OA11464A/en unknown
- 2000-05-14 IL IL136122A patent/IL136122A/en unknown
Non-Patent Citations (1)
Title |
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See references of WO9925363A1 * |
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