CA2153399A1 - Use of idazoxan and its derivatives in the treatment of alzheimer-type senility - Google Patents
Use of idazoxan and its derivatives in the treatment of alzheimer-type senilityInfo
- Publication number
- CA2153399A1 CA2153399A1 CA002153399A CA2153399A CA2153399A1 CA 2153399 A1 CA2153399 A1 CA 2153399A1 CA 002153399 A CA002153399 A CA 002153399A CA 2153399 A CA2153399 A CA 2153399A CA 2153399 A1 CA2153399 A1 CA 2153399A1
- Authority
- CA
- Canada
- Prior art keywords
- treatment
- alzheimer
- radical
- derivatives
- type
- 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.)
- Abandoned
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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Neurology (AREA)
- Epidemiology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
~o 94/1~603 ~ 1 5 3 3 q 9 PCT/FR94/00014 UTILISATION DE L'IDAZOXAN ET SES DERIVES POUR LE TRAITEMENT DE DEMENCE
SENILE DU TYPE A U HEIMER.
La présente illvellLion a pour objet l'lltilis~tion de l'i~7.c~n et de ses dérivés pour obtenir un médicament neuro-protecteur, destiné au traitement 6 de démence sénile du type ~l7heimer et du syndrome pré ~17h~imer ainsi que leur ~ l ession.
La maladie d'Alzheimer est une maladie neurodégénérative progressive affectant particulièrement mais non e~clusivement le système çholin~rgique central (Nucleus basalis de Meynert) se traduisant par une perte des facultés cognitives, une perte des capacités intellect~lelles, des troubles du comportement et de la personnalité.
Il n'e~iste pas actuellement de traitement satisfaisant ni pour le traitement des symptômes, ni pour ralentir sa progression. Le diagnostic de la maladie est difficile, et c'est en particulier l'analyse anatomo-histologique pratiquée post mortem par, entre autres, la mise en évidence de plaques séniles e2~traneuronales et d'ench~v~ ents neurofibrillaires intraneuronaux, qui peut permettre de diagnostiquer sans ambiguité la m~ lie d'~l7.heimer. Lui sont associées également une perte de corps cellulaires et une déplétion de ne~ lsmetteurs, en particulier l'acétylcholine.
Il est connu que l'irl~7.o~n 2-(1,4-benzodioxan-2-yl)-2-imidazoline possède des propriétés antagonistes sur les récepteurs ct2-adrénergiques. Ce composé est décrit dans le brevet EP-0 033 655 ainsi que son application thérapeutique en tant que médicament antidépresseur.
D'autres dérivés de l'i-1~7o~n sont également décrit dans EP-0 092 328 et GB-2 092 139.
L'irl~7.0~P.n a également été étudié en clinique humaine dans le traitement de la dépression à des doses variant de 5 à
40 mg,3 fois par jour sur 4 semaines et a montré une amélioration significative sur l'échelle de Hamilton contre placebo (Drug of the Future 10, N 9,782 (1985)).
La présente invention concerne l'utilisation de l'idazoxan et ses dérivés pour la préparation d'un médicament destiné au traitement de démence sénile du type Alzheimer et du syndrome pré-~17heimer ainsi que leur progres-sion.
/
WO 94/15603 ~ o 94/1 ~ 603 ~ 1 5 3 3 q 9 PCT / FR94 / 00014 USE OF IDAZOXAN AND DERIVATIVES THEREOF FOR THE TREATMENT OF DEMENTIA
SENILE OF THE HEIMER TYPE.
The present illvellLion relates to the use of the ~ 7.c ~ n and its derivatives to obtain a neuroprotective drug, intended for treatment 6 of senile dementia of the type ~ l7heimer and of the syndrome pre ~ 17h ~ imer as well as their ~ l ession.
Alzheimer's disease is a neurodegenerative disease progressive particularly but not exclusively affecting the system çholin ~ rgique central (Nucleus basalis de Meynert) resulting in a loss cognitive faculties, loss of intellectual capacity, impaired behavior and personality.
There is currently no satisfactory treatment either for the treatment of symptoms, nor to slow its progression. The diagnosis of disease is difficult, and this is particularly the anatomo-histological analysis practiced post mortem by, among other things, the identification of plaques senile e2 ~ traneuronales and intraneuronal neurofibrillary auctions, which can be used to make an unambiguous diagnosis of ~ l7.heimer's disease. Him cell loss and depletion of do ~ lsmitters, especially acetylcholine.
It is known that ir ~ 7.o ~ n 2- (1,4-benzodioxan-2-yl) -2-imidazoline has antagonistic properties on ct2-adrenergic receptors. This compound is described in patent EP-0 033 655 as well as its application therapeutic as an antidepressant drug.
Other derivatives of i-1 ~ 7o ~ n are also described in EP-0 092 328 and GB-2,092,139.
Irl ~ 7.0 ~ Pn has also been studied in human clinics in the treatment of depression at doses varying from 5 to 40 mg, 3 times daily for 4 weeks and showed significant improvement on the Hamilton scale versus placebo (Drug of the Future 10, N 9,782 (1985)).
The present invention relates to the use of idazoxan and its derivatives for the preparation of a medicament for the treatment of dementia senile Alzheimer's type and pre- 17heimer syndrome and their progress if we.
/
WO 94/15603
2 1 5 3 3 9 9 PCT/FR94100014 Par idazoxan et ses dérivés, on entend composé de formule générale I:
5 ~XO~
dans laquelle R représente un atome d'hydrogène, un radical alkyle linéaire ou r~mifié en C 1-C4 ou un radical alcoxy linéaire ou ramifié en C 1-C4 et ses o sels thérapeutiquement acceptables, son racémique ou ses isomères optiquement actifs.
D'une manière préférentielle, R représente un atome d'hydr-ogène, un radical étho2~y ou un radical n-propyle.
1. ETUDE PHARMACOLOGIQUE
Une étude pharm~Mloeique a mis en évidence le rôle neuroprotec-teur de l'i-1~70~n après une lésion du système noradrénergique et une lésion ne~u- kJxique du sy~è~e cholinergique.
La destruction du système cholinergique a été provoquée chez le rat par injection stéréotaxique bilatérale de l'acide iboténique dans le noyau de base de Meynert (nbM).
Quatre groupes d'~nim~ ont été constitués.
Groupe A: représente le groupe de rats non traités Groupe B: l'ir1~7~qn a été atimini~tré à des rats témoin~.
Groupe C: les rats subissent une lésion du système noradrénergique ainsi qu'une injection stéréotaxique bilatérale avec l'acide iboténique dans le nbM et représente le groupe de rat ayant une déficience du système noradrénergique et cholinergique (groupP-p~t~loloEique).
GrouPe D: les rats sont traités comme pour le groupe C et l'i~70~n a été ~lminictré
-fEUl~LE REC~IFIEE (REG~E 91) WO 941156û3 215 3 3 9 9 PCT/FR94/00014 Le degré de destruction cholinergique a été déterminé en mesurant l'activité de l'enzyme choline-acétyltransférase (ChAT) qui marque les terminaisons cholinergiques et dont l'activité est 5 proportionnelle à leur nombre (C.G. Gottfries, J. Neurosci. Res. 27, 541, (1990) et E. Perry Br. Med. J. 1457 (1978) et G.L. Wenk Brain Res. 293, 184, (1984)).
Groupe expérimental Diminution provoquée par la lésion Activité de ChAT
C ---D
0 = absence de diminution de l'activité basale de l'enzyme ChAT
- à - - - = échelle de rliminlltion de l'activité basale de l'enzyme ChAT.
Il est observé que le traitement réitéré avec l'i(~ n a un effet neuroprotecteur en atténuant la perte des neurones cholinergique, 25 mesurée par l'enzyme provoquée par l'acide iboténique (groupe D par rapport au groupe C).
Il est ainsi montré que le traitement par l'irl~:o~n atténue la perte de performance mnésique qui avait été induite par la lésion des systèmes noradrénergiques et cholinergiques (groupe D par rapport au 30 groupe C).
WO 94/15602 1 5 3 3 9 9 PCT / FR94100014 By idazoxan and its derivatives is meant a compound of formula general I:
5 ~ XO ~
in which R represents a hydrogen atom, a linear alkyl radical or r ~ mified in C 1-C4 or a linear or branched alkoxy radical in C 1-C4 and its o therapeutically acceptable salts, its racemic or its isomers optically active.
Preferably, R represents a hydrogen atom.
ogen, an etho2 ~ y radical or an n-propyl radical.
1. PHARMACOLOGICAL STUDY
A pharm ~ Mloeique study has highlighted the neuroprotective role i-1 ~ 70 ~ n after an injury to the noradrenergic system and a ne ~ u- kJxique lesion of the cholinergic sy ~ è ~ e.
The destruction of the cholinergic system was caused in the rat by bilateral stereotaxic injection of ibotenic acid into the nucleus Meynert base (nbM).
Four groups of ~ nim ~ were formed.
Group A: represents the group of untreated rats Group B: ir1 ~ 7 ~ sn was atimini ~ tré to control rats ~.
Group C: Rats suffer damage to the noradrenergic system as well as a bilateral stereotaxic injection with the acid ibotenic in nbM and represents the group of rats having a deficiency in the noradrenergic and cholinergic system (groupP-p ~ t ~ loloEique).
GROUP D: Rats are treated as for group C and i ~ 70 ~ na summer ~ limited -fEUl ~ LE REC ~ IFIEE (REG ~ E 91) WO 941156û3 215 3 3 9 9 PCT / FR94 / 00014 The degree of cholinergic destruction was determined in measuring the activity of the enzyme choline acetyltransferase (ChAT) which marks cholinergic endings and whose activity is 5 proportional to their number (CG Gottfries, J. Neurosci. Res. 27, 541, (1990) and E. Perry Br. Med. J. 1457 (1978) and GL Wenk Brain Res. 293, 184, (1984)).
Experimental group Decrease caused by lesion ChAT activity At 0 VS ---D
0 = no decrease in basal enzyme activity Cat - to - - - = scale of reduction of the basal activity of the enzyme ChAT.
It is observed that the repeated treatment with i (~ has an effect neuroprotective by reducing the loss of cholinergic neurons, 25 measured by the enzyme caused by ibotenic acid (group D by compared to group C).
It is thus shown that treatment with ir ~: o ~ n attenuates the loss of memory performance which had been induced by lesion of noradrenergic and cholinergic systems (group D versus 30 group C).
WO 94/1560
3 215 3 3 9 9 PCT/FR94/00014 2. ETUDE GALENIQUE
Les compositions pharmaceutiques sont ~lministrées par voie orale sous forme de gélules ou de comprimés dosés de 1 à 200 mg de principe actif, plus particulièrement de 5,10,20 et 40 mg par comprimé,ou parvoie intraveineuse sous forme de soluté injectable dosé de 0,1 à 10 mg d'iti~- Y~n 3. ETUDE CLINIQUE
20 sujets diagnostiqués comme souffrant d'une démence pré-~l~heimer et 20 sujets diagnostiqués comme souffrant de la maladie d'~l7heimer ont été traités par 20 mg d'i-l~7.0~n 3 fois par jour par voie orale pendant 9 mois. L'efficacité a été mesurée sur la progression de la symptomatologie globale et a montré un effet bénéfique (groupes "améliorés" et Ufaiblement améliorés" dans sept cas de démence pré-~l7heimer et cinq cas de la m~l~rlie d'~l7heimer). 3,215 3 3 9 9 PCT / FR94 / 00014 2. GALENIC STUDY
The pharmaceutical compositions are ~ administered by the oral in the form of capsules or tablets containing 1 to 200 mg of active ingredient, more particularly 5,10,20 and 40 mg per tablet, or intravenously as an injectable solution, 0.1 to 10 mg of iti ~ - Y ~ n 3. CLINICAL STUDY
20 subjects diagnosed with pre-dementia ~ l ~ heimer and 20 subjects diagnosed as suffering from the disease of ~ l7heimer were treated with 20 mg of i-l ~ 7.0 ~ n 3 times a day oral for 9 months. Efficacy was measured on the progression of overall symptomatology and showed a beneficial effect (groups "improved" and Weakly improved "in seven cases of pre-~ l7heimer and five cases of ~ l7heimer's disease).
Claims (4)
dans laquelle R représente un atome d'hydrogène, un radical alkyle linéaire ou ramifié en C1-C4 ou un radical alcoxy linéaire ou ramifié en C1-C4 et ses sels thérapeutiquement acceptables, son racémique ou ses isomères optiquement actifs, pour la préparation d'un médicament destiné au traitement de démence sénile du type Alzheimer et du syndrome pré-Alzheimer ainsi que leur progression. 1/ Use of a compound of general formula I:
in which R represents a hydrogen atom, a linear alkyl radical or branched C1-C4 or a linear or branched C1-C4 alkoxy radical and its salts therapeutically acceptable, its racemate or its optically isomers active ingredients, for the preparation of a medicament intended for the treatment of dementia senile of the Alzheimer type and pre-Alzheimer syndrome as well as their progress.
représente un atome d'hydrogène. 2 / Use according to claim 1, characterized in that R
represents a hydrogen atom.
représente un radical ethoxy. 3 / Use according to claim 1, characterized in that R
represents an ethoxy radical.
représente un radical n-propyle. 4 / Use according to claim 1, characterized in that R
represents an n-propyl radical.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR93/00084 | 1993-01-07 | ||
FR9300084A FR2700113B1 (en) | 1993-01-07 | 1993-01-07 | Use of Idazoxan and its derivatives for the manufacture of medicaments intended for the treatment of neurodegenerative diseases and in particular the evolution of Alzheimer's disease. |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2153399A1 true CA2153399A1 (en) | 1994-07-21 |
Family
ID=9442871
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002153399A Abandoned CA2153399A1 (en) | 1993-01-07 | 1994-01-06 | Use of idazoxan and its derivatives in the treatment of alzheimer-type senility |
Country Status (8)
Country | Link |
---|---|
EP (1) | EP0678024A1 (en) |
JP (1) | JPH08505154A (en) |
AU (1) | AU680463B2 (en) |
CA (1) | CA2153399A1 (en) |
FR (1) | FR2700113B1 (en) |
NZ (1) | NZ259531A (en) |
WO (1) | WO1994015603A1 (en) |
ZA (1) | ZA9469B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8188126B2 (en) | 2002-05-16 | 2012-05-29 | Pierre Fabre Medicament | Imidazolic compounds and use thereof as alpha-2 adrenergic receptors |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PH16249A (en) * | 1980-02-04 | 1983-08-16 | Reckitt & Colmann Prod Ltd | Imidazoline derivatives,its pharmaceutical composition and method of use |
NZ199469A (en) * | 1981-01-30 | 1984-03-16 | Reckitt & Colmann Prod Ltd | Benzodioxanyl-2-imidazoline derivatives and pharmaceutical compositions |
NZ203680A (en) * | 1982-04-17 | 1985-08-16 | Reckitt & Colmann Prod Ltd | Imidazolines and pharmaceutical compositions |
GB2174087A (en) * | 1985-04-23 | 1986-10-29 | Glaxo Group Ltd | Heterocyclic amino compounds |
GB8903437D0 (en) * | 1989-02-15 | 1989-04-05 | Erba Carlo Spa | Imidazolyl derivatives of 3,4-dihydro-2h-1-benzothiopyran |
-
1993
- 1993-01-07 FR FR9300084A patent/FR2700113B1/en not_active Expired - Fee Related
-
1994
- 1994-01-06 JP JP6515752A patent/JPH08505154A/en active Pending
- 1994-01-06 ZA ZA9469A patent/ZA9469B/en unknown
- 1994-01-06 NZ NZ259531A patent/NZ259531A/en unknown
- 1994-01-06 WO PCT/FR1994/000014 patent/WO1994015603A1/en not_active Application Discontinuation
- 1994-01-06 EP EP94904203A patent/EP0678024A1/en not_active Withdrawn
- 1994-01-06 CA CA002153399A patent/CA2153399A1/en not_active Abandoned
- 1994-01-06 AU AU58354/94A patent/AU680463B2/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
AU5835494A (en) | 1994-08-15 |
EP0678024A1 (en) | 1995-10-25 |
NZ259531A (en) | 1997-04-24 |
WO1994015603A1 (en) | 1994-07-21 |
JPH08505154A (en) | 1996-06-04 |
FR2700113A1 (en) | 1994-07-08 |
FR2700113B1 (en) | 1995-03-24 |
ZA9469B (en) | 1996-02-01 |
AU680463B2 (en) | 1997-07-31 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
FZDE | Dead |