WO2005049042A1

WO2005049042A1 - Combinations comprising ampa receptor antagonists for the treatment of tinnitus

Info

Publication number: WO2005049042A1
Application number: PCT/EP2004/012263
Authority: WO
Inventors: Kurt LINGENHÖHL; Silvio Ofner; Mary Ann Karolchyk
Original assignee: Novartis Ag; Novartis Pharma Gmbh
Priority date: 2003-10-30
Filing date: 2004-10-29
Publication date: 2005-06-02
Also published as: GB0325390D0

Abstract

The present invention relates to combinations suitable for the treatment of neurological disorders, in particular tinnitus. The combinations comprise at least one AMPA receptor antagonist and at least one compound selected from the group consisting of ant-anxiety drugs, antidepressants, antihistamines, anticonvulsants, vasodilators, zinc salts and anesthetics.

Description

COMBINATIONS COMPRISING AMPA RECEPTOR ANTAGONISTS FOR THE TREATMENT O_F TINNITUS

The present invention relates to combinations suitable for the treatment of neurological disorders, in particular tinnitus.

Tinnitus is the medical term for roaring, buzzing, clicking, whistling, hissing, or high pitched ringing in the ears or inside the head. Tinnitus may be constant or occur intermittently in one or both ears. Although there are many theories about how tinnitus occurs, there is no scientific consensus to its origin. Some causes of tinnitus result from a blow to the head, large doses of aspirin, anemia, noise exposure, stress, impacted wax, hypertension and certain types of medications and tumors.

Surprisingly, it has been found that the effect of a combination which comprises at least one AMPA receptor antagonist and at least one compound selected from the group consisting of anti-anxiety drugs, antidepressants, antihistamines, anticonvulsants, vasodilators, zinc salts and anesthetics is greater than the additive effect of the combined drugs. Furthermore, the combinations disclosed herein can be used to treat tinnitus which is refractory to monotherapy employing one of the combination partners alone.

Hence, 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 compound selected from the group consisting of anti-anxiety drugs, antidepressants, antihistamines, anticonvulsants, vasodilators, zinc salts and anesthetics, 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 "AMPA receptor antagonists" as used herein includes, but is not limited to the quinoxaline-dione aminoalkylphosphonates 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, 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.

AMPA receptor antagonists include also, 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-3,1O,10a-triaza-benzo[f]azulen-9-yl)-phenylamine), irampanel (BUR 561; N,N-dimethyl-2-[2-(3-phenyl-1 ,2,4-oxadiazol-5-yl)phenoxy]ethanamine), KRP 199 (7-[4- [[[[(4-carboxyphenyl)-amino]carbonyl]oxy]methyl]-1H-imidazoI-1-yl]-3,4-dihydro-3-oxo-6- (trifluoromethyl)-2-quinoxalinecarboxylic 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-methylethylidene)-beta-D-fructo- pyranose sulfamate, preparation, e.g. as described in US 535475), 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-(1 H)-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-(1 H-tetrazol-5-yl)- ethyl]-decahydro-isoquinoline-3-carboxylic acid).

The term "anti-anxiety drug" as used herein includes, but is not limited to alprazolam.

The term "antidepressants" as used herein includes, but is not limited to nortriptyline (N- methyl-3-(10, 11 -dihydro-5H-dibenzo[a,d]cyclohepten-5-yliden)propylamine).

The term "anticonvulsants" as used herein includes, but is not limited to oxcarbazepine.

The term "anesthetics" as used herein includes, but is not limited to lidocaine.

The term "vasodilators" as used herein includes, but is not limited to pentoxifylline.

The term "zinc salts" as used herein includes, but is not limited to zinc sulfate.

Topiramate can be administered, e.g., in the form as marketed, e.g. under the trademark Topamax™. The compounds of formula I as well as their production process and pharmaceutical compositions thereof are known, e.g., from WO 98/17672. Alprazolam can be administered, e.g., in the form as marketed, e.g. under the trademark Xanax™. Nortriptyline can be administered, e.g., in the form as marketed, e.g. under the trademark Nortrilen™. Oxcarbazepine can be administered, e.g., in the form as marketed, e.g. under the trademark Trileptal™. Lidocaine can be administered in the form of its hydrochloride, e.g., in the form as marketed as injection solution, e.g. under the trademark Heweneural™. zinc sulfate can be administered, e.g., in the form as marketed, e.g. under the trademark Zink-Sandoz™. Pentoxifyllin can be administered, e.g., in the form as marketed, e.g. under the trademark Trental™.

The structure of the active ingredients identified by code nos., generic or trade names 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.

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 therapeutically 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 compound selected from the group consisting of anti-anxiety drugs, antidepressants, antihistamines, anticonvulsants, vasodilators, zinc salts and anesthetics, 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.

Surprisingly it was found that the administration of a COMBINATION OF THE INVENTION results in a beneficial, especially a synergistic, therapeutic effect or in other surprising beneficial effects, e.g. less side effects, compared to a monotherapy applying only one of the pharmaceutically active ingredients used in the COMBINATION OF THE INVENTION.

The pharmacological activity of a COMBINATION OF THE INVENTION may, for example, be evidenced in preclinical studies known as such, e.g., the methods described herein.

The activity in tinnitus of the COMBINATION OF THE INVENTION can be shown in standard tests, e.g. in the salicylate-induced tinnitus model.

It has been demonstrated [C.A. Bauer et al., Hearing Research 147 (2000) 175-182] that chronic salicylate exposure causes upregulation of glutamic acid decarboxylase (GAD) expression in the rat inferior colliculus (IC), associated with the development of tinnitus. Furthermore, electrophysiological recordings from auditory neurons using patch clamp recording techniques [D. Peruzzi et al. Neuroscience 101 (2000) 403-416, X. Lin et al., Journal of Neurophysiology 79 (1998) 2503-2512} and single neuron recordings [J.J. Eggermont and M. Kenmochi, Hearing Research 117 (1998) 149-160] showed that the excitability of neurons is changed following salicylate and quinine treatment.

Administration of salicylate or quinine caused an increase in the firing rate auditory neurons measured by extracellular electrophysiological recording techniques. Using in vitro electrophysiological recording techniques superfusion with salicylate increases the excitability of the recorded neurons. On administration of the COMBINATIONS OF THE INVENTION at concentrations of about 1nM to 100 μM, the effects of salicylate were reversed.

Furthermore, the pharmacological activity of a COMBINATION OF THE INVENTION may, for example, be demonstrated in a clinical study. Such clinical studies are preferably randomized, double-blind, clinical studies in patients with tinnitus. Such studies demonstrate, in particular, the synergism of the active ingredients of the COMBINATIONS OF THE INVENTION. The beneficial effects on tinnitus_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 tinnitus 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

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

Most preferably, the COMBINATION OF THE INVENTION comprises an AMPA receptor antagonist which is a compound of formula I, wherein R-i represents hydroxyl, X represents methylene, R₂ represents hydrogen, alk stands for methylene, R₃ and R₅ represent hydrogen, and R-t represents nitro or a salt thereof, i.e. is {[(7-Nitro-2,3-dioxo-1 ,2,3,4- tetrahydro-quinoxalin-5-ylmethyl)-amino]-methyl}-phosphonic acid or a salt thereof (cf. WO 97/08155, Example 57, 1st entry, and WO 98/17672, Example 12, 4th entry).

The disclosures of WO 97/08155 and WO 98/17672 are incorporated by reference.

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- dimethyl-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-quinoxalinecarboxylic 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), 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-fIuoro-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-(1 H-tetrazoI-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 tinnitus, comprising at least one AMPA antagonist and at least one compound selected from the group consisting of anti- anxiety drugs, antidepressants, antihistamines, anticonvulsants, vasodilators, zinc salts and anesthetics, 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. 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 or local application into the ear showing the tinnitus. 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.

In 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 example, 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.

Unit dosage forms may contain, for example, from about 2.5 mg to about 500 mg of the active ingredients.

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

Additionally, the present invention provides a method of treating a warm-blooded animal having tinnitus_comprising administering to the animal a COMBINATION OF THE INVENTION in a quantity which is jointly therapeutically effective against tinnitus_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 tinnitus.

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 tinnitus 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.

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

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,

Topiramate may be administered to an adult patient in a total daily dosage of between about 250 to about 500 mg.

{[(7-Nitro-2,3-dioxo-1 ,2,3,4-tetrahydro-quinoxalin-5-ylmethyl)-amino]-methyl}-phosphonic acid may be administered to a patient in a total daily dosage of about 60 to about 400 mg.

Claims

What is claimed is:

1. A combination comprising at least one AMPA receptor antagonist and at least one compound selected from the group consisting of anti-anxiety drugs, antidepressants, antihistamines, anticonvulsants, vasodilators, zinc salts and anesthetics, 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.

2. Combination according to claim 1 which is a combined preparation or a pharmaceutical composition.

3. Combination according to claim 1 or 2 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.

4. Combination according to claim 3, 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.

5. Combination according to any one of claims 1 to 4 for simultaneous, separate or sequential use in the treatment of tinnitus.

6. Method of treating a warm-blooded animal having tinnitus comprising administering to the animal a combination according to any one of claims 1 to 4 in a quantity which is jointly therapeutically effective against tinnitus and in which the compounds can also be present in the form of their pharmaceutically acceptable salts.

7. A pharmaceutical composition comprising a quantity, which is jointly therapeutically effective against tinnitus, of a pharmaceutical combination according to any one of claims 1 to 4 and at least one pharmaceutically acceptable carrier.

8. Use of a combination according to any one of claims 1 to 4 for the preparation of a medicament for the treatment of tinnitus.

9. Use according to claim 5 or 8 wherein the tinnitus is refractory to monotherapy.

10. A commercial package comprising a combination according to any one of claim 1 to 4 together with instructions for simultaneous, separate or sequential use thereof in the treatment of tinnitus.