WO2005094797A2

WO2005094797A2 - Use of ampa-receptor antagonists for treating dementia

Info

Publication number: WO2005094797A2
Application number: PCT/EP2005/002305
Authority: WO
Inventors: Kurt LINGENHÖHL; Ferenc Martenyi
Original assignee: Novartis Ag; Novartis Pharma Gmbh
Priority date: 2004-03-05
Filing date: 2005-03-04
Publication date: 2005-10-13
Also published as: WO2005094797A3; GB0405034D0

Abstract

The present invention relates to a method for the treatment and/or prevention dementia comprising the step of administering to a warm-blooded animal, including a human, in need thereof an effective amount of AMPA receptor antagonist alone or in combination with nootropics.

Description

Novel Use of A PA-receptor antagonists

The present invention relates to methods and materials for the treatment of dementia.

Surprisingly, it has been found that dementia can be treated by administration of an AMPA receptor antagonist alone or in combination with nootropics. Hence, the present invention relates to a method for the treatment and/or prevention dementia comprising the step of administering to a warm-blooded animal, including a human, in need thereof an effective amount of AMPA receptor antagonist alone or in combination with nootropics.

The term "AMPA receptor antagonists" as used herein includes, but is not limited to the quinoxaline-dione aminoalkylphosphonates of formula I

wherein

Ri represents hydroxy or an aliphatic, aryl aliphatic or aromatic group,

X represents an aliphatic, cycloaliphatic, cycloaliphatic aliphatic, aryl aliphatic, heteroar l aliphatic or aromatic group,

R₂ represents hydrogen or an aliphatic or aryl aliphatic group, alk stands for C1-C7alkylene, and

R₃, R₄ and R₅ represent independently of each other hydrogen, C1-C7alkyl, halogen, trifluoromethyl, cyano or nitro, and wherein the radicals have the meanings as defined in WO 98/17672.

The term "dementia" as used herein includes, but is not restricted to, Alzheimer's dementia with or without psychotic symptoms. In particular, the methods and materials described herein are suitable for the treatment of behavioral disturbances observed with such types of dementia. The term "nootropics" as used herein includes, but is not limited to nootropical plant extracts, calcium antagonists, cholinesterase inhibitors, dihydroergotoxin, nicergoline, piracetame, purine derivates, pyritinol, vincamine and vinpocetine. In a preferred embodiment of the invention, the combination partner is a cholinesterase inhibitor.

The term "nootropical plant extracts" as used herein includes, but is not limited to extracts from Ginkgo leafs. The term "calcium antagonists" as used herein includes, but is not limited to cinnarizine and nimodipine. The term "cholinesterase inhibitors" as used herein includes, but is not limited to donepezil hydrochloride, rivastigmine and galantamine hydrobromide. The term "purine derivates" as used herein includes, but is not limited to pentifyllin.

Extracts from Ginkgo leafs can be administered, e.g., in the form as marketed, e.g. under the trademark Ginkodilat™ according to the information provided by the package insert. Cinnarizine can be administered, e.g., in the form as marketed, e.g. under the trademark Cinnarizin forte-ratiopharm™. Nimodipine can be administered, e.g., in the form as marketed, e.g. under the trademark Nimotop™. Donepezil hydrochloride can be administered, e.g., in the form as marketed, e.g. under the trademark Aricept™. Rivastigmine can be prepared as disclosed, in US 5,602,176. It can be administered, e.g., in the form as marketed, e.g. under the trademark Exelon™. Galantamine hydrobromide can be administered, e.g., in the form as marketed, e.g. under the trademark Reminyl™. Dihydroergotoxin can be administered, e.g., in the form as marketed, e.g. under the trademark Hydergin™. Nicergoline can be administered, e.g., in the form as marketed, e.g. under the trademark Sermion™. Piracetam can be administered, e.g., in the form as marketed, e.g. under the trademark Cerebroforte™. Pentifyllin can be administered, e.g., in the form as marketed, e.g. under the trademark Cosaidon™. Pyritinol can be administered, e.g., in the form as marketed, e.g. under the trademark Encephabol™. Vinpocetin can be administered, e.g., in the form as marketed, e.g. under the trademark Cavinton™.

The structure of the active ingredients identified by code nos., generic or trade names mentioned herein may be taken from the actual edition of the standard compendium "The Merck Index" or from databases, e.g. Patents International (e.g. IMS World Publications). The corresponding content thereof is hereby incorporated by reference. Any person skilled in the art is fully enabled to identify the active ingredients and, based on these references, likewise enabled to manufacture and test the pharmaceutical indications and properties in standard test models, both in vitro and in vivo.

Hence, in one aspect the invention relates to a combination, such as a combined preparation or pharmaceutical composition, which comprises at least one AMPA receptor antagonist and at least one nootropic, in which the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt and optionally at least one pharmaceutically acceptable carrier; for simultaneous, separate or sequential use.

The term "a combined preparation", as used herein defines especially a "kit of parts" in the sense that the first and second active ingredient as defined above can be dosed independently or by use of different fixed combinations with distinguished amounts of the ingredients, i.e., simultaneously or at different time points. The parts of the kit of parts can then, e.g., be administered simultaneously or chronologically staggered, that is at different time points and with equal or different time intervals for any part of the kit of parts. Very preferably, the time intervals are chosen such that.the effect on the treated disease in the combined use of the parts is larger than the effect which would be obtained by use of only any one of the active ingredients. The ratio of the total amounts of the active ingredient 1 to the active ingredient 2 to be administered in the combined preparation can be varied, e.g., in order to cope with the needs of a patient sub-population to be treated or the needs of the single patient which different needs can be due to age, sex, body weight, etc. of the patients. Preferably, there is at least one beneficial effect, e.g., a mutual enhancing of the effect of the first and second active ingredient, in particular a synergism, e.g. a more than additive effect, additional advantageous effects, less side effects, a combined therapeutic effect in a non- effective dosage of one or both of the first and second active ingredient, and especially a strong synergism the first and second active ingredient.

It will be understood that in the discussion of methods, references to the active ingredients are meant to also include the pharmaceutically acceptable salts. If these active ingredients have, for example, at least one basic center, they can form acid addition salts. Corresponding acid addition salts can also be formed having, if desired, an additionally present basic center. The active ingredients having an acid group (for example COOH) can also form salts with bases. The active ingredient or a pharmaceutically acceptable salt thereof may also be used in form of a hydrate or include other solvents used for crystallization. A pharmaceutical combination which comprises at least one AMPA receptor antagonist and at least one nootropic in which the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt, if at least one salt-forming group is present, will be referred to hereinafter as a COMBINATION OF THE INVENTION.

The pharmacological activity of an AMPA receptor antagonist or a COMBINATION OF THE INVENTION may, for example, also be demonstrated in a clinical study. Such clinical studies are preferably randomized, double-blind, clinical studies in patients with Alzheimer's Disease. Such studies demonstrate, in particular, the synergism of the active ingredients of the COMBINATIONS OF THE INVENTION. The beneficial effects on Alzheimer's Disease can be determined directly through the results of these studies or by changes in the study design which are known as such to a person skilled in the art. The studies are, in particular, suitable to compare the effects of a monotherapy using the active ingredients and a COMBINATION OF. THE INVENTION.

A further benefit is that lower doses of the active ingredients of the COMBINATION OF THE INVENTION can be used, for example, that the dosages need not only often be smaller but are also applied less frequently, or can be used in order to diminish the incidence of side effects. This is in accordance with the desires and requirements of the patients to be treated. The COMBINATIONS OF THE INVENTION can be used, in particular, for the treatment of dementia which is refractory to monotherapy.

In one embodiment of the invention, the AMPA receptor antagonists used in the present invention are competitive AMPA receptor antagonists.

Preferably, the COMBINATION OF THE INVENTION comprises an AMPA receptor antagonist, which is a quinoxalinedione aminoalkylphosphonate, in particular a quinoxalinedione aminoalkylphosphonate of formula I

wherein

R-i represents hydroxy or an aliphatic, aryl aliphatic or aromatic group,

X represents an aliphatic, cycloaliphatic, cycloaliphatic aliphatic, aryl aliphatic, heteroaryl aliphatic or aromatic group,

R₃, R and R₅ represent independently of each other hydrogen, C1-C7alkyl, halogen, trifluoromethyl, cyano or nitro, and wherein the radicals have the meanings as defined in WO 98/17672.

In another embodiment of the present invention, the AMPA receptor antagonists is selected from EGIS 8332 (7-acetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1 ,3- dioxolo[4,5-h][2,3]benzodiazepine-8-carbonitrile), GYKI 47261 4-(7-chloro-2-methyl- 4H-3,10,10a-triaza-benzo[f|azulen-9-yl)-phenylamine), irampanel (BUR 561 ; N,N- dimethyI-2-[2-(3-phenyl-1 ,2,4-oxadiazol-5-yl)phenoxy]ethanamine), KRP 199 (7-[4- [[[[(4-carboxyphenyl)-amino]carbonyl]oxy]methyl]-1 H-imidazol-1-yl]-3,4-dihydro-3-oxo- 6-(trifluoromethyl)-2-qϋTnoxalinecarboxylic acid), NS 1209 (2-[[[5-[4-[(dimethylamino)- sulfonyl]phenyl]-1 ,2,6,7,8,9-hexahydro-8-methyl-2-oxo-3H-pyrrolo[3,2-h]isoquinolin-3- ylidene]amino]oxy]-4-hydroxybutanoic acid monosodium salt, e.g. prepared as described in WO 98/14447), topiramate (TOPAMAX, 2,3:4,5-bis-O-(1-methyl- ethylidene)-beta-D-fructopyranose sulfamate, preparation, e.g. as described in US 535475) and talampanel (LY-300164, (R)-7-acetyl-5-(4-aminophenyl)-8,9-dihydro-8- methyl-7H-1 ,3-dioxolo[4,5-h][2,3]benzo-diazepine, preparation, e.g. as described in EP 492485), YM90K (6-imidazol-1-yl-7-nitro-1 ,4-dihydro-quinoxaline-2,3-dione), S-34730 (7-chloro-6-sulfamoyl-2-(1H)-quinolinone-3-phosphonic acid), Zonampanel (YM-872; (7-imidazol-1-yl-6-nitro-2,3-dioxo-3,4-dihydro-2H-quinoxalin-1-yl)-acetic acid), GYKI- 52466 (4-(8-methyl-9H-1 ,3-dioxa-6,7-diaza-cyclohepta[f]inden-5-yl)-phenylamine), ZK- 200775 (MPQX, (7-morpholin-4-yl-2,3-dioxo-6-trifluoromethyl-3,4-dihydro-2H- quinoxalin-1-ylmethyl)-phosphonic acid), CP-465022 (3-(2-chloro-phenyl)-2-[2-(6- diethylaminomethyl-pyridin-2-yl)-vinyl]-6-fluoro-3H-quinazolin-4-one), SYM-2189 (4-(4- amino-phenyl)-6-methoxy-1-methyl-1 H-phthalazine-2-carboxylic acid propylamide), SYM-2206 (8-(4-amino-phenyl)-5-methyl-5H-[1 ,3]dioxolo[4,5-g]phthalazine-6-carboxylic acid propylamide, RPR-117824 ((4-oxo-2-phosphono-5,10-dihydro-4H-imidazo[1 ,2- a]indeno[1 ,2-e]pyrazin-9-yl)-acetic acid), LY-293558 (6-[2-(1H-tetrazol-5-yl)-ethyl]- decahydro-isoquinoline-3-carboxylic acid).

It is one objective of this invention to provide a pharmaceutical composition comprising a quantity, which is jointly therapeutically effective against dementia, comprising at least one AMPA receptor antagonist, at least one nootropic and at least one pharmaceutically acceptable carrier. In this composition, the first and second active ingredient can be administered together, one after the other or separately in one combined unit dosage form or in two separate unit dosage forms. The unit dosage form may also be a fixed combination.

The pharmaceutical compositions according to the invention can be prepared in a manner known per se and are those suitable for enteral, such as oral or rectal, and parenteral administration to mammals (warm-blooded animals), including man, comprising a therapeutically effective amount of at least one pharmacologically active ingredient, alone or in combination with one or more pharmaceutically acceptable carries, especially suitable for enteral or parenteral application. The preferred route of administration of the dosage forms of the present invention is orally.

The novel pharmaceutical composition contain, for example, from about 10 % to about 100 %, preferably from about 20 % to about 60 %, of the active ingredients. Pharmaceutical preparations for the combination therapy for enteral or parenteral administration are, for example, those in unit dosage forms, such as sugar-coated tablets, tablets, capsules or suppositories, and furthermore ampoules. If not indicated otherwise, these are prepared in a manner known per se, for example by means of conventional mixing, granulating, sugar- coating, dissolving or lyophilizing processes. It will be appreciated that the unit content of active ingredient or ingredients contained in an individual dose of each dosage form need not in itself constitute an effective amount since the necessary effective amount can be reached by administration of a plurality of dosage units. ln preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils or alcohols; or carriers such as starches, sugars, microcristalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for exam le, powders, capsules and tablets. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed.

Furthermore, the present invention relates to the use of a COMBINATION OF THE INVENTION for the preparation of a medicament for the treatment of dementia.

Additionally, the present invention provides a method of treating a warm-blooded animal having dementia comprising administering to the animal a COMBINATION OF THE INVENTION in a quantity which is jointly therapeutically effective against dementia and in which the compounds can also be present in the form of their pharmaceutically acceptable salts.

Moreover, the present invention provides a commercial package comprising as active ingredients COMBINATION OF THE INVENTION, together with instructions for simultaneous, separate or sequential use thereof in the treatment of dementia.

In one preferred embodiment of the invention, the COMBINATION OF THE INVENTION is used for the treatment of dementia which is refractory to monotherapy.

In particular, a therapeutically effective amount of each of the active ingredients of the COMBINATION OF THE INVENTION may be administered simultaneously or sequentially and in any order, and the components may be administered separately or as a fixed combination. For example, the method of treatment of dementia according to the invention may comprise (i) administration of the first active ingredient in free or pharmaceutically acceptable salt form and (ii) administration of the second active ingredient in free or pharmaceutically acceptable salt form, simultaneously or sequentially in any order, in jointly therapeutically effective amounts, preferably in synergistically effective amounts, e.g. in daily dosages corresponding to the amounts described herein. The individual active ingredients of the COMBINATION OF THE INVENTION can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. Furthermore, the term administering also encompasses the use of a pro-drug of an active ingredient that convert in vivo to the active ingredient. The instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly.

The effective dosage of each of the active ingredients employed in the COMBINATION OF THE INVENTION may vary depending on the particular compound or pharmaceutical composition employed, the mode of administration, the severity of the condition being treated. Thus, the dosage regimen the COMBINATION OF THE INVENTION is selected in accordance with a variety of factors including the route of administration and the renal and hepatic function of the patient. A physician, clinician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the single active ingredients required to prevent, counter or arrest the progress of the condition. Optimal precision in achieving concentration of the active ingredients within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the active ingredients' availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of the active ingredients.

When the combination partners employed in the COMBINATION OF THE INVENTION are applied in the form as marketed as single drugs, their dosage and mode of administration can take place in accordance with the information provided on the packet leaflet of the respective marketed drug in order to result in the beneficial effect described herein, if not mentioned herein otherwise. In particular,

Cinnarizine may be administered to a patient in a total daily dosage of between about 75 to about 150 mg.

Nimodipine may be administered to a patient in a total daily dosage of between about 60 to about 120 mg.

Donepezil hydrochloride may be administered to a patient in a total daily dosage of between about 5 mg and 10 mg. Rivastigmine may be administered to a patient in a total daily dosage of between about 6 and about 12 mg.

Galantamine may be administered to a patient in a total daily dosage of between about 12 and 24 mg, e.g. 12 mg twice daily.

Dihydroergotoxin may be administered in the form of its methansulfonate to a patient in a total daily dosage of between about 4 mg and 10 mg, e.g. about 8 mg.

Nicergoline may be administered in the form of its tartrate by intramuscular injection to a patient in a total daily dosage of between about 4 mg and 8 mg.

Piracetam may be administered to a patient in a total daily dosage of between about 1200 and 5000 mg, e.g. 4800 mg/day.

Pentifyllin may be administered to a patient in a total daily dosage of between about 400 and 800 mg.

Pyritinol may be administered in the form of its hydrochloride to a patient in a total daily dosage of about 600 mg.

Vinpocetin may be administered to a patient in a total daily dosage of between about 10 and 15 mg.

The following Example serves to illustrate the invention without limiting the invention in its scope.

Object recognition test in rats:

Rats are housed in groups of four in plastic cages with free access to standard food and tap water. Twenty four hours before starting the experiment, rats are individually placed in plastic cages (type III) and transferred in the experiment room. N=12 rats are used per treatment group. Observations are made during the light-phase (0800-1300) in the object recognition test arena. The apparatus is an open box made of black perspex (60 cm L; 60 cm W; 30 cm H). The box is placed on the floor of the experimental room allowing even illumination from indirect ceiling light and is filled to a depth of 2 cm with soiled sawdust (mixture sawdust from all cages of rats involved in the experiment).

Two boxes run in parallel and a camera is mounted approximately 1 m above the boxes and behavior is recorded on videotape.

Test protocol: The experiment is carried out over three days: ^'

Day 1 : Animals are placed singly into the object recognition test apparatus and allowed to explore the arena for a period of 10 minutes. During this session there are no objects present.

Day 2: Two identical objects A (= A1 and A2 black cylinders, H=12 cm, diameter =7cm), are placed randomly in the top left-hand and right hand corners of the arena and randomly turned between each subject in the anti-clockwise The animal is again placed into the arena in the same position as the previous day and allowed to explore for 3 minutes. Drug or vehicle administration is given orally on this day, 1 hour prior to exposure, in order to test for an effect on acquisition of memory.

Day 3: Object A (A1 ) is again placed in the top left hand corner whereas an object B (=B1 , a brick shaped object (6 x 6 x 9cm) in dark grey perspex) is placed in the top right hand corner.

Again similarly to day 2, both objects (A1 and B1) are randomly moved in the anti-clockwise position (see Figure 1, day 3). The animal is placed into the arena again in the same position as the previous day and allowed to explore objects A1 and/or B1 for a period of 3 minutes.

On day 2 and 3 the animals are placed into the box, facing away from the object and on the opposite side to the object to prevent a 'flight-like' reaction and an accidental encounter with the object.

The total exploration time directed towards each object in the arena is calculated for each subject during sessions 2 and 3. The time spent exploring each object (time spent exploring the object A1 and A2, on day 2 and time spent on exploring the object A1 and B2 on day 2 is recorded. Comparing the time spent exploring each object during the second trial assesses recognition memory.

The discrimination index (on day 3) expressed in seconds is calculated as the time spent exploring the novel object (time B1 ) minus the time spent at the familiar object (time A1 ). In addition, a recognition index is calculated for each animal and expressed as a ratio (time B1 x 100)/ (time A1 on day 2 + time B2). The recognition index is around 50% when animals do not remember (thus time A and time B are equivalent) but the recognition index is more than

50% when time B is greater than time A indicating that they have remembered the familiar object. This ratio has the advantage that it takes into account possible changes in the overall levels of exploration between subjects and therefore constitutes a more sensitive index of novelty preference. The object recognition test is suited to detect positive effects on memory; negative effects are not detected by this test. For statistical analysis group comparisons are performed using a one_way analysis of variance (ANOVA) followed post-hoc by the Dunnett's (comparison of different doses versus the respective control group). Values of p<0.05 are considered as statistically significant.

Claims

What is claimed is:

1. The use of an AMPA receptor antagonist for the manufacture of a pharmaceutical composition for the treatment of dementia.

2. The use of an AMPA receptor antagonist for the manufacture of a pharmaceutical composition for the treatment of behavioral disturbances observed with dementia.

3. The use according to claim 1 or 2 wherein the AMPA receptor antagonist is a compound of formula I

wherein

Ri represents hydroxy or an aliphatic, aryl aliphatic or aromatic group,

X represents an aliphatic, cycloaliphatic, cycloaliphatic aliphatic, aryl aliphatic, heteroaryl aliphatic or aromatic group, R₂ represents hydrogen or an aliphatic or aryl aliphatic group, alk stands for C1-C7alkylene, and R₃, R₄ and R₅ represent independently of each other hydrogen, C1-C7alkyl, halogen, trifiuoromethyl, cyano or nitro, or a salt therof.

4. Use according to claim 3, wherein in the formula I R-i is hydroxy, R₂ is hydrogen, alk represents methylene, R₃ and R₅ are both hydrogen, R₄ is nitro and X is methylene.

5. A method for the treatment of dementia or behavioral disturbances observed with dementia in a subject in need of such treatment, which comprises administering to said subject a therapeutically effective amount of an AMPA receptor antagonist or a pharmaceutically acceptable salt thereof.

6. A combination comprising at least one AMPA receptor antagonist and at least one nootropic, in which the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt and optionally at least one pharmaceutically acceptable carrier; for simultaneous, separate or sequential use.

7. Combination according to claim 6 which is a combined preparation or a pharmaceutical composition.

8. Combination according to claim 6 or 7 wherein the AMPA receptor antagonist is a compound of formula I

wherein

R-i represents hydroxy or an aliphatic, aryl aliphatic or aromatic group,

X represents an aliphatic, cycloaliphatic, cycloaliphatic aliphatic, aryl aliphatic, heteroaryl aliphatic or aromatic group, R₂ represents hydrogen or an aliphatic or aryl aliphatic group, alk stands for C1-C7alkylene, and R₃, R₄. and R₅ represent independently of each other hydrogen, C1-C7alkyl, halogen, trifluoromethyl, cyano or nitro, or a salt therof.

9. Combination according to claim 8, wherein in the formula I Ri is hydroxy, R₂ is hydrogen, alk represents methylene, R₃ and R₅ are both hydrogen, R is nitro and X is methylene.

10, Combination according to any one of claims 6 to 9 for simultaneous, separate or sequential use in the treatment of dementia.

11. Combination according to any one of claims 6 to 9 for simultaneous, separate or sequential use in the treatment of behavioral disturbances observed with dementia.

12. Method of treating a warm-blooded animal having dementia or behavioral disturbances observed with dementia comprising administering to the animal a combination according to any one of claims 6 to 9 in a quantity which is jointly therapeutically effective in dementia or behavioral disturbances observed with dementia and in which the compounds can also be present in the form of their pharmaceutically acceptable salts.

13. A pharmaceutical composition comprising a quantity, which is jointly therapeutically effective against dementia or behavioral disturbances observed with dementia of a pharmaceutical combination according to any one of claims 6 to 9 and at least one pharmaceutically acceptable carrier.

14. Use of a combination according to any one of claims 6 to 9 for the preparation of a medicament for the treatment of dementia or behavioral disturbances observed with dementia.

15. A commercial package comprising a combination according to any one of claims 6 to 9 together with instructions for simultaneous, separate or sequential use thereof in the treatment of dementia or behavioral disturbances observed with dementia.