WO2005049039A1

WO2005049039A1 - Combinations comprising ampa receptors antagonists for the treatment of affective and attention deficit disorders

Info

Publication number: WO2005049039A1
Application number: PCT/EP2004/012145
Authority: WO
Inventors: Kurt LINGENHÖHL; Ferenc Martenyi; Silvio Ofner; Mary Ann Karolchyk; Hans O. Kalkman; David Aitken
Original assignee: Novartis Pharma GmbH Austria; Novartis AG
Current assignee: Novartis Pharma GmbH Austria; Novartis AG
Priority date: 2003-10-28
Filing date: 2004-10-27
Publication date: 2005-06-02
Anticipated expiration: 2006-04-28
Also published as: GB0325172D0

Abstract

The present invention relates to combinations suitable for the treatment of neurological/psychiatric disorders, in particular affective and attention disorders. The combination comprise at least one AMPA receptor antagonist and at least one compound selected from the group consisting of lithium, valproic acid sodium salt, conventional antipsychotics, atypical antipsychotics, lamotrigine, methylphenidate, antidepressants and antiepileptics.

Description

COMBINATIONS COMPRISING AMPA RECEPTORS ANTAGONISTS FOR THE TREATMENT OF AFFECTIVE AND ATTENTION DEFICIT DISORDERS

The present invention relates to combinations suitable for the treatment of neurological / psychiatric disorders, in particular affective and attention disorders.

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 lithium, valproic acid sodium salt, conventional antipsychotics, atypical antipsychotics, lamotrigine, methylphenidate, antidepressants and antiepileptics is greater than the additive effect of the combined drugs. Furthermore, the combinations disclosed herein can be used to treat affective and attention disorders 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 lithium, valproic acid sodium salt, conventional antipsychotics, atypical antipsychotics, lamotrigine, methylphenidate, antidepressants and antiepileptics, 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 "affective and attention disorders" as used herein includes, but is not limited to bipolar disorder, e.g. manic-depressive psychoses, mania with or without psychotic feature, attention deficit hyperactivity disorder (ADHD), and other attention disorders, e.g. autism, as well as those behavioural states characterized by social withdrawal, e.g., negative symptoms.

The term "lithium" as used herein includes, but is not limited to lithium acetate, lithium carbonate, lithium chloride, lithium citrate and lithium sulfate. The term "conventional antipsychotics" as used herein includes, but is not limited to haloperidol and fluphenazine. The term "atypical antipsychotics" as used herein includes, but is not limited to olanzapine, quetiapine and risperidone. The term "antidepressants" as used herein includes, but is not limited to tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRI's), or selective serotonin and norepinephrine reuptake inhibitors (SNRI-s). A tricyclic antidepressant suitable for the present invention is especially selected from amitriptyline, butriptyline, clomipramine, desipramine, dibenzepin, dothiepin, doxepin, imipramine, nortriptyline, opipramol, protriptyline, trimipramine, maprotiline, mianserin, and mirtazepine. An SSRI suitable for the present invention is especially selected from fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram and escitalopram, and an SNRI selected from venlafaxine and duloxetine.

The term "anti-epileptics" as used herein includes, but is not limited to barbiturates and derivatives thereof, benzodiazepines, carboxamides, hydantoins, succinimides, valproic acid and other fatty acid derivates, AMPA antagonists and other anti-epileptic drugs, 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 "barbiturates and derivatives thereof as used herein includes, but is not limited to phenobarbital, pentobarbital, mepobarbital and primidon. The term "benzodiazepines" as used herein includes, but is not limited to clonazepam, diazepam and lorazepam. The term "carboxamides" as used herein includes, but is not limited to carbamazepine, oxcarbazepine, 10-hydroxy-10,11-dihydrocarbamazepine and the compounds of formula II

wherein Ri' represents C C₃alkyl carbonyl. The term "hydantoins" as used herein includes, but is not limited to phenytoin. The term "succinimides" as used herein includes, but is not limited to ethosuximide, phensuximide and mesuximide. The term "valproic acid and other fatty acid derivates" as used herein includes, but is not limited to valproic acid sodium salt, tiagabine hydrochloride monohydrate and vigrabatrine. The term "other anti-epileptic drugs" as used herein includes, but is not limited to levetiracetam, lamotrigine, gabapentin, sultiam, felbamate, the 1 ,2,3-1 H-triazoles disclosed in EP 114 347, esp. rufinamide [1-(2,6-difluoro- benzyl)-1H-[1,2,3]triazole-4-carboxylic acid amide] and the 2-aryl-8-oxodihydropurines disclosed in WO99/28320.

Lithium acetate can be administered, e.g., in the form as marketed, e.g. under the trademark Quilonorm™. Lithium carbonate can be administered, e.g., in the form as marketed, e.g. under the trademark Eskalith™. Lithium citrate can be administered, e.g., in the form as marketed, e.g. under the trademark Litarex™. Lithium sulfate can be administered, e.g., in the form as marketed, e.g. under the trademark Lithium-Duriles™, or, e.g., by transdermal release (US 6,375,990). Valproic acid sodium salt can be administered, e.g., in the form as marketed, e.g. under the trademark Divalproex Sodium™. Haloperidol can be administered, e.g., in the form as marketed, e.g. under the trademark Haloperidol STADA™. Olanzapine can be administered, e.g., in the form as marketed, e.g. under the trademark Zyprexa™. Risperidone can be administered, e.g., in the form as marketed, e.g. under the trademark Risperdal™. Quetiapine can be administered, e.g., in the form as marketed, e.g. under the trademark Seroquel™. Fluphenazine can be administered, e.g., in the form of its dihydro- chloride as marketed, e.g. under the trademark Prolixin™. Lamotrigine can be administered, e.g., in the form as marketed, e.g. under the trademark Lamictal™. Fluoxetine can be administered, e.g., in the form of its hydrochloride as marketed, e.g. under the trademark Prozac™. Paroxetine can be administered, e.g., in the form as marketed, e.g. under the trademark Paxil™. Methylphenidate can be administered, e.g., in the form as marketed, e.g. under the trademark Ritalin™.

Methylphenidate is the most commonly prescribed psychotropic medication for children in the United States, primarily for the treatment of children diagnosed with attention deficit disorder (ADD) and Attention Deficit Hyperactivity Disorder (ADHD), and thus, is widely available. Methylphenidate is described in U.S. Patent Nos. 2,838,519 and 2,957,880. U.S. Patent Nos. 5,922,736; 5,908,850; 5,773,478; 6,113,879 describe administering d-threo methylphenidate to treat nervous system disorders. U.S. Patent Nos. 6,100,401; 6,121,453; and 6,162,919 describe processes for preparing substantially the single enantiomer d-threo methylphenidate. U.S. Patent Nos. 5,874,090 and 5,837,284 describe sustained release formulations of methylphenidate. All these citations are included herein by reference.

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, 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, 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-methyI-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-carboxyphenyI)-amino]carbonyl]oxy]methyl]-1H-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]isoquinoIin-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- 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-chIoro-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[fjinden-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-yI)-vinyl]-6-fluoro-3H-quinazolin-4- one), SYM-2189 (4-(4-amino-phenyl)-6-methoxy-1-methyl-1H-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).

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.

The structure of the active ingredients identified by code nos., generic or trade names and their preparation may be taken from the actual edition of the standard compendium "The Merck Index" (e.g.M. J. O'Neil et al., ed., The Merck Index', 13^th ed., Merck Research Laboratories, 2001) 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 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 compound selected from the group consisting of lithium, valproic acid sodium salt, conventional antipsychotics, atypical antipsychotics, lamotrigine, methylphenidate and antidepressants, 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 activity of the COMBINATION OF THE INVENTION in the treatment of affective disorders is evidenced, for example, in the preclinical tests suitable for detecting drugs reversing psycho-motor stimulatory effects.

Test 1 : NMDA-antagonist induced locomotion:

Male rats are used. In principle 8 treatment groups are formed:

1 ) AMPA receptor antagonist followed by solvent 2 and solvent 3 to study the effects of the

AMPA receptor antagonist on locomotor activity. 2) Solvent 1 , combination partner and solvent 3 to study the effects of the combination partner on locomotor activity.

3) Solvent 1 , solvent 2, followed by the competitive NMDA receptor antagonist (S)-2-amino- 3-(2'-chloro-5-phosphonomethyl-biphenyl-3-yl)-propionic acid, hereinafter SDZ 220-581 (10 mg/kg) to study the induction of hyperlocomotor activity.

4) AMPA receptor antagonist followed by solvent 2 and SDZ 220-581.

5) Solvent 1 followed by combination partner and SDZ 220-581.

6) The COMBINATION OF THE INVENTION (doses of each active ingredients at doses close to threshold) followed by solvent 3.

7) The COMBINATION OF THE INVENTION (doses of each active ingredients at doses close to threshold) followed by SDZ 220-581 (10 mg/kg).

8) Solvent 1 - solvent 2 - solvent 3.

Rats are randomly allocated to these pretreatment groups (n=10 / dose group). Drugs are administered subcutaneous (s.c), 15 min prior to SDZ 220-581. Immediately after the animals received SDZ 220-581 , they are placed into the activity monitor for a period of 60 min. Locomotor activity is analysed over the initial 30 minutes.

Locomotion is recorded with a videotracking system. Animals are on a normal 12/12 h day- night cycle, with light on at 06:00 H. Experiments are performed in a dimly lit room between 07:00 H and 15:00 H. Animals are placed in a round arena (diameter 42 cm, height 32 cm) made of grey polyvinylchloride plastic.

In this test, the COMBINATION OF THE INVENTION (1-10 mg/kg, s.c.) do not significantly alter locomotor activity as compared to vehicle-treated animals at any time during a period of 30 min. However, the competitive NMDA receptor antagonist SDZ 220-581 (10 mg/kg, s.c.) induces a strong locomotor response. Thus, whereas control animals walk approximately 8- 10 m during 30 min, SDZ 220-581 -treated animals walked approximately 30 m. This locomotor response is reduced in a dose dependent synergistic manner by the COMBINATION OF THE INVENTION.

Test 2: NMDA-channel blocker induced head swaying and circling:

Adult male rats are used. The animals are randomized to the following treatment groups (n=

10 per group): 1) AMPA receptor antagonist (t= -15 min) followed by solvent 2 (t = -15 min) and solvent 3 (t = 0 min) to study whether head swaying and circling is induced by the AMPA receptor antagonist given alone.

2) Solvent 1 (t = -15 min), combination partner (t = -15 min) and solvent 3 (t = 0 min) to study whether head swaying and circling is induced by the combination partner given alone.

3) Solvent 1 (t = -15 min), solvent 2 (t = -15 min), followed by phencyclidine (PCP; an NMDA channel blocker, dosed 3 and 10 mg/kg, t = 0 min) to induce circling and head swaying.

4) AMPA receptor antagonist (t = -15 min) followed by solvent 2 (t = -15 min) and PCP (t = 0 min).

5) Solvent 1 (t = -15 min) followed by combination partner (t = -15 min) and PCP (t = 0 min).

6) The COMBINATION OF THE INVENTION (doses of each active ingredients at doses close to threshold (t = -15 min)) followed by solvent 3 (t = 0 min).

7) The COMBINATION OF THE INVENTION (doses of each active ingredients at doses close to threshold (t = -15 min)) followed by PCP (3 and 10 mg/kg, t = 0 min).

8) Solvent 1 (t = -15 min), solvent 2 (t = -15 min), solvent 3 (t = 0 min).

COMBINATION OF THE INVENTION (at t = -15 min) and PCP (at t = 0 min) are administered s.c. in a volume of 1 ml/kg. Video-recordings of the animals behavior over the period 0 - 30 min following PCP are scored by an observer who is unaware about the animals pretreatment. Head-swaying (rocking the head repeatedly by at least 2 cm left and right) and circling (turning around by using the forepaws, whereas the hindpaws remain more or less on the original position) are scored as present (1) or absent (0), every five minutes for the duration of 1 min. The scores for individual animals is summed and group scores used for statistical analysis (t-test with Bonferroni correction).

In this test, PCP (10 mg/kg, s.c.) induces weak head-swaying and circling. Pretreatment with the COMBINATION OF THE INVENTION (3 and 10 mg/kg, s.c.) significantly enhances these behavioral responses to PCP (P<0.05) in a synergistic manner.

NMDA-antagonist induced locomotor responses reflect a psychosis / mania-like state. Blockade of this activity indicates an anti-psychotic, anti-manic activity. Furthermore, enhancement of head-swaying and circling suggest a behavioral disinhibition (= anxiolytic- /antidepressant- like) and sociotropic activity. Therefore, the compounds are useful in the treatment of affective disorders including bipolar disorders, e.g. manic-depressive psychoses, extreme psychotic states e.g. mania with psychotic feature and excessive mood swings where behavioral stabilization is desired. In addition, the COMBINATION OF THE INVENTION are indicated in ADHD (attention deficit hyperactivity disorders) and other attention disorders, e.g. autism, and as well as those behavioral states characterized by social withdrawal e.g. negative symptoms.

The pharmacological activity of a COMBINATION OF THE INVENTION may also be demonstrated in a clinical study. Such clinical studies are preferably randomized, double- blind, clinical studies in patients with affective and attention disorders. Such studies demonstrate, in particular, the synergism of the active ingredients of the COMBINATIONS OF THE INVENTION. The beneficial effects on affective and attention disorders 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 affective and attention disorders 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 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,

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.

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 R₄ 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]-1H-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-(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]phthaIazine-6- carboxylic acid propylamide, RPR-117824 ((4-oxo-2-phosphono-5,10-dihydro-4H- imidazo[1 ,2-a]indeno[1 ,2-e]pyrazin-9-yI)-acetic acid) and LY-293558 (6-[2-(1 H-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 affective and attention disorders, comprises at least one AMPA receptor antagonist, at least one compound selected from the group consisting of lithium, valproic acid sodium salt, conventional antipsychotics, atypical antipsychotics, lamotrigine, methylphenidate and antidepressants 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.

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.

Furthermore, the present invention relates to the use of a COMBINATION OF THE INVENTION for the preparation of a medicament for the treatment of affective and attention disorders.

Additionally, the present invention provides a method of treating a warm-blooded animal having affective and attention disorders comprising administering to the animal a COMBINATION OF THE INVENTION in a quantity which is jointly therapeutically effective against affective and attention disorders 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 affective and attention disorders. 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 affective and attention disorders 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 affective and attention disorders 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.

Haloperidol may be administered to a patient in a total daily dosage of between about 2.5 to about 30 mg.

Lithium can be administered to a patient in a total daily dosage of between about 0.5 to about 2 g.

Olanzapine can be administered to a patient in a total daily dosage of between about 2.5 to about 20 mg.

Quetiapine can be administered to a patient in a total daily dosage of between about 500 to about 600 mg.

Risperidone may be administered to a patient in a total daily dosage of between about 2 to about 6 mg.

Valproic acid sodium salt may be administered to a patient in a total daily dosage of between about 2000 to about 3000 mg.

Amitriptyline may be administered to a patient in a total daily dosage of between about 30 to about 300 mg.

Clomipramine may be administered to a patient in a total daily dosage of between about 30 to about 150 mg. Desipramine may be administered to a patient in a total daily dosage of between about 25 to about 200 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 lithium, valproic acid sodium salt, conventional antipsychotics, atypical antipsychotics, lamotrigine, methylphenidate, antidepressants and antiepileptics, 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

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, trifluoromethyl, cyano or nitro, or a salt therof.

4. Combination 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. Combination according to any one of claims 1 to 4 for simultaneous, separate or sequential use in the treatment of affective and attention disorders.

6. Method of treating a warm-blooded animal having affective and attention disorders 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 affective and attention disorders 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 affective and attention disorders, 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 affective and attention disorders.

9. Use according to claim 5 or 8 wherein the affective and attention disorders 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 affective and attention disorders.