WO2005049041A1 - Combinations comprising ampa receptor antagonists for the treatment of anxiety disorders - Google Patents

Combinations comprising ampa receptor antagonists for the treatment of anxiety disorders Download PDF

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Publication number
WO2005049041A1
WO2005049041A1 PCT/EP2004/012151 EP2004012151W WO2005049041A1 WO 2005049041 A1 WO2005049041 A1 WO 2005049041A1 EP 2004012151 W EP2004012151 W EP 2004012151W WO 2005049041 A1 WO2005049041 A1 WO 2005049041A1
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Prior art keywords
anxiety
aliphatic
disorders
combination according
treatment
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PCT/EP2004/012151
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French (fr)
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Kurt LINGENHÖHL
Ferenc Martenyi
Silvio Ofner
Mary Ann Karolchyk
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Novartis Ag
Novartis Pharma Gmbh
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Publication of WO2005049041A1 publication Critical patent/WO2005049041A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61P25/22—Anxiolytics

Definitions

  • the present invention relates to combinations suitable for the treatment of neurological / psychiatric disorders, in particular anxiety disorders or other psychiatric disorders with underlying anxiety symptomatologies.
  • the effect of a combination which comprises at least one AMPA receptor antagonist and at least one compound selected from the group consisting of benzodiazepines, selective serotonin reuptake inhibitors (SSRIs), selective serotonin and norepinephrine reuptake inhibitors (SNRIs), buspirone and pregabalin is greater than the additive effect of the combined drugs.
  • the combinations disclosed herein can be used to treat anxiety disorders or other psychiatric disorders with underlying anxiety symptomatologies which are refractory to monotherapy employing one of the combination partners alone.
  • 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 benzodiazepines, SSRIs, SNRIs, buspirone and pregabalin, 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.
  • 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 benzodiazepines, SSRIs, SNRIs, buspirone and pregabalin, 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.
  • anxiety or other psychiatric disorders with underlying anxiety symptomatologies includes, but is not restricted to disorders, such as general anxiety disorder, social anxiety disorder, post traumatic stress disorder, obsessive compulsive disorder, panic and anxiety occurring following cessation of psychostimulants or intake of other psychotropics with abuse potential.
  • AMPA receptor antagonists as used herein includes, but is not limited to the quinoxaline-dione aminoalkylphosphonates of formula I
  • 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
  • R 2 represents hydrogen or an aliphatic or aryl aliphatic group, alk stands for C1-C7alkylene, and
  • R 3 , R 4 and R 5 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, EG IS 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[fJazuIen-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
  • 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-imidazoI-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-4
  • An SSRI suitable for the present invention is especially selected from fluoxetine, fuvoxamine, sertraline, paroxetine, citalopram and escitalopram.
  • An SNRI suitable for the present invention is especially selected from venlafaxine and duloxetine.
  • benzodiazepines as used herein includes, but is not limited to clonazepam, diazepam and lorazepam.
  • Buspirone can be administered in free form or as a salt, e.g. as its hydrochloride, e.g., in the form as marketed, e.g. under the trademark AnxutTM, BusparTM or BesparTM. It can be prepared and administered, e.g., as described in US 3,717,634. Topiramate can be administered, e.g., in the form as marketed, e.g. under the trademark TopamaxTM. The compounds of formula I as well as their production process and pharmaceutical compositions thereof are known e.g. from WO 98/17672. Fluoxetine can be administered, e.g., in the form of its hydrochloride as marketed, e.g.
  • ProzacTM Prozac
  • Paroxetine ((3S,4R)-3- [(1 ,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine) can be administered, e.g., in the form as marketed, e.g. under the trademark PaxilTM.
  • PaxilTM a trademark of the trademark of the trademark of the trademark of the form as marketed
  • Sertraline can be administered, e.g., in the form as marketed, e.g. under the trademark ZoloftTM. It can be prepared and administered, e.g., as described in US 4,536,518.
  • Clonazepam can be administered, e.g., in the form as marketed, e.g. under the trademark AntelepsinTM.
  • Diazepam can be administered, e.g., in the form as marketed, e.g. under the trademark Diazepam DesitinTM.
  • Lorazepam can be administered, e.g., in the form as marketed, e.g. under the trademark TavorTM.
  • Citalopram can be administered in free form or as a salt, e.g. as its hydrobromide, e.g., in the form as marketed, e.g. under the trademark CipramilTM.
  • Escitalopram can be administered, e.g., in the form as marketed, e.g.
  • CipralexTM under the trademark CipralexTM. It can be prepared and administered, e.g., as described in AU623144. Venlafaxine can be administered, e.g., in the form as marketed, e.g. under the trademark TrevilorTM. Duloxetine can be administered, e.g., in the form as marketed, e.g. under the trademark CymbaltaTM. It may be prepared and administered, e.g., as described in CA 1302421.
  • a combined preparation 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.
  • 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.
  • 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 therapeutical 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.
  • 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 benzodiazepines, SSRIs, SNRIs, buspirone and pregabalin 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.
  • mice Male mice are used. Treated animals were placed in their home cage for 1 h. This time interval may depend on the combination partner and may therefore be longer or shorter. After this pretreatment time, the core body temperature is measured using a rectal probe. Subsequently, the animal is placed back in the cage and the measurement is repeated after 15 min. The first rectal measurement including handling is a stressful situation for the animal which causes the body temperature to rise. Anxiolytic compounds are known to prevent the increase in core body temperature in response to the first measurement. In principle 4 treatment groups are formed: 1 ) Solvent followed by solvent. 2) Solvent pretreatment followed by the combination partner.
  • Drugs are administered subcutaneous (s.c.) or orally (p.o.) at doses close to threshold when administered alone.
  • the pharmacological activity of 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 anxiety or other psychiatric disorders with underlying anxiety symptomatologies.
  • Such studies demonstrate, in particular, the synergism of the active ingredients of the COMBINATIONS OF THE INVENTION.
  • the beneficial effects on anxiety or other psychiatric disorders with underlying anxiety symptomatologies 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 anxiety or other psychiatric disorders with underlying anxiety symptomatologies which is refractory to monotherapy.
  • the AMPA receptor antagonists used in the present invention are competitive AMPA receptor antagonists.
  • 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
  • X represents an aliphatic, cycloaliphatic, cycloaliphatic aliphatic, aryl aliphatic, heteroaryl aliphatic or aromatic group
  • R 2 represents hydrogen or an aliphatic or aryl aliphatic group, alk stands for C1-C7alkylene, and
  • R 3 , R 4 and R 5 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 COMBINATION OF THE INVENTION comprises an AMPA receptor antagonist which is a compound of formula I, wherein R-j represents hydroxyl, X represents methylene, R 2 represents hydrogen, alk stands for methylene, R 3 and R 5 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 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-
  • 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[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
  • It is one objective of this invention to provide a pharmaceutical composition comprising a quantity, which is jointly therapeutically effective against anxiety and other psychiatric disorders with underlying anxiety symptomatologies, comprising at least one AMPA receptor antagonist, at least one compound selected from the group consisting of benzodiazepines, selective serotonin reuptake inhibitors (SSRIs), selective serotonin and norepinephrine reuptake inhibitors (SNRIs), buspirone and pregabalin and at least one pharmaceutically acceptable carrier.
  • 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.
  • 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 humans, 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.
  • enteral such as oral or rectal
  • parenteral administration to mammals (warm-blooded animals), including humans, 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.
  • 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.
  • the present invention relates to the use of a COMBINATION OF THE INVENTION for the preparation of a medicament for the treatment of anxiety or other psychiatric disorders with underlying anxiety symptomatologies.
  • the present invention provides a method of treating a warm-blooded animal having anxiety modelled in a particular paradigm comprising administering to the animal a COMBINATION OF THE INVENTION in a quantity which is jointly therapeutically effective against anxiety or other psychiatric disorders with underlying anxiety symptomatologies and in which the compounds can also be present in the form of their pharmaceutically acceptable salts.
  • 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 anxiety or other psychiatric disorders with underlying anxiety symptomatologies.
  • 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.
  • the method of treatment of anxiety or other psychiatric disorders with underlying anxiety symptomatologies 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.
  • 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 COMBINATION OF THE INVENTION is used for the treatment of anxiety or other psychiatric disorders with underlying anxiety symptomatologies which are 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.
  • 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.
  • Topiramate may be administered to an adult patient in a total daily dosage of between about 250 to about 500 mg.
  • Buspirone may be administered in a total daily dosage of between about 15 to about 60 mg.
  • Clonazepam may be administered to an adult patient in a total daily dosage between about 3 to about 8 mg and to a paediatric patient in a total daily dosage between about 0.5 to about 3 mg, split into three of four separate units.
  • Diazepam may be administered to an adult patient in a total daily dosage between about 5 to about 10 mg and to a paediatric patient in a total daily dosage between about 5 to about 10 mg.
  • Lorazepam may be administered to an adult patient in a total daily dosage between about . 0.044 mg/kg body weight to about 0.05 mg/kg body weight.
  • Citalopram may be administered in a total daily dosage of between about 20 to about 60 mg.
  • Paroxetine may be administered in a total daily dosage of between about 20 to about 50 mg.
  • Venlafaxine may be administered in a total daily dosage of between about 70 to about 150 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.

Abstract

The present invention relates to combinations suitable for the treatment of neurological psychiatric disorders, in particular anxiety disorders or other psychiatric disorders with underlying anxiety symptornatologies. The combinations comprise at least one AMPA receptor antagonist and at least one compound selected from the group consisting of benzodiazepines, selective serotonin reuptake inhibitors (SSRls), selective serotonin and norepinephrine reuptake inhibitors (SNRls), buspirone and pregabalin.

Description

COMBINATIONS COMPRISING AMPA RECEPTOR ANTAGONISTS FOR THE TREATMENT OF ANXIETY DISORDERS
The present invention relates to combinations suitable for the treatment of neurological / psychiatric disorders, in particular anxiety disorders or other psychiatric disorders with underlying anxiety symptomatologies.
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 benzodiazepines, selective serotonin reuptake inhibitors (SSRIs), selective serotonin and norepinephrine reuptake inhibitors (SNRIs), buspirone and pregabalin is greater than the additive effect of the combined drugs. Furthermore, the combinations disclosed herein can be used to treat anxiety disorders or other psychiatric disorders with underlying anxiety symptomatologies which are 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 benzodiazepines, SSRIs, SNRIs, buspirone and pregabalin, 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 "anxiety or other psychiatric disorders with underlying anxiety symptomatologies" as used herein includes, but is not restricted to
Figure imgf000002_0001
disorders, such as general anxiety disorder, social anxiety disorder, post traumatic stress disorder, obsessive compulsive disorder, panic and anxiety occurring following cessation of psychostimulants or intake of other psychotropics with abuse potential.
The term "AMPA receptor antagonists" as used herein includes, but is not limited to the quinoxaline-dione aminoalkylphosphonates of formula I
Figure imgf000003_0001
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, EG IS 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[fJazuIen-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-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-imidazoI-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), Y-293558 (6-[2-(1 H-tetrazol-5-yl)- ethyl]-decahydro-isoquinoline-3-carboxylic acid).
An SSRI suitable for the present invention is especially selected from fluoxetine, fuvoxamine, sertraline, paroxetine, citalopram and escitalopram.
An SNRI suitable for the present invention is especially selected from venlafaxine and duloxetine.
The term "benzodiazepines" as used herein includes, but is not limited to clonazepam, diazepam and lorazepam.
Buspirone can be administered in free form or as a salt, e.g. as its hydrochloride, e.g., in the form as marketed, e.g. under the trademark Anxut™, Buspar™ or Bespar™. It can be prepared and administered, e.g., as described in US 3,717,634. 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. Fluoxetine can be administered, e.g., in the form of its hydrochloride as marketed, e.g. under the trademark Prozac™. It can be prepared and administered, e.g., as described in CA 2002182. Paroxetine ((3S,4R)-3- [(1 ,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine) can be administered, e.g., in the form as marketed, e.g. under the trademark Paxil™. It can be prepared and administered, e.g., as described in US 3,912,743. Sertraline can be administered, e.g., in the form as marketed, e.g. under the trademark Zoloft™. It can be prepared and administered, e.g., as described in US 4,536,518. Clonazepam can be administered, e.g., in the form as marketed, e.g. under the trademark Antelepsin™. Diazepam can be administered, e.g., in the form as marketed, e.g. under the trademark Diazepam Desitin™. Lorazepam can be administered, e.g., in the form as marketed, e.g. under the trademark Tavor™. Citalopram can be administered in free form or as a salt, e.g. as its hydrobromide, e.g., in the form as marketed, e.g. under the trademark Cipramil™. Escitalopram can be administered, e.g., in the form as marketed, e.g. under the trademark Cipralex™. It can be prepared and administered, e.g., as described in AU623144. Venlafaxine can be administered, e.g., in the form as marketed, e.g. under the trademark Trevilor™. Duloxetine can be administered, e.g., in the form as marketed, e.g. under the trademark Cymbalta™. It may be prepared and administered, e.g., as described in CA 1302421.
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 therapeutical 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 benzodiazepines, SSRIs, SNRIs, buspirone and pregabalin 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 the COMBINATION OF THE INVENTION in the treatment of anxiety symptomatologies is evidenced, for example, in preclinical studies known as such, e.g. the stress induced hyperthermia model.
The following Example serves to illustrate the invention without limiting the invention in its scope.
Male mice are used. Treated animals were placed in their home cage for 1 h. This time interval may depend on the combination partner and may therefore be longer or shorter. After this pretreatment time, the core body temperature is measured using a rectal probe. Subsequently, the animal is placed back in the cage and the measurement is repeated after 15 min. The first rectal measurement including handling is a stressful situation for the animal which causes the body temperature to rise. Anxiolytic compounds are known to prevent the increase in core body temperature in response to the first measurement. In principle 4 treatment groups are formed: 1 ) Solvent followed by solvent. 2) Solvent pretreatment followed by the combination partner.
3) AMPA receptor antagonist followed by solvent.
4) The COMBINATION OF THE INVENTION (low doses of each active ingredients)
Mice are randomly allocated to these pretreatment groups (n=10 / dose group). Drugs are administered subcutaneous (s.c.) or orally (p.o.) at doses close to threshold when administered alone.
The pharmacological activity of 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 anxiety or other psychiatric disorders with underlying anxiety symptomatologies. Such studies demonstrate, in particular, the synergism of the active ingredients of the COMBINATIONS OF THE INVENTION. The beneficial effects on anxiety or other psychiatric disorders with underlying anxiety symptomatologies 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 anxiety or other psychiatric disorders with underlying anxiety symptomatologies 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
Figure imgf000008_0001
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.
Most preferably, the COMBINATION OF THE INVENTION comprises an AMPA receptor antagonist which is a compound of formula I, wherein R-j 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-methyI-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[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-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 anxiety and other psychiatric disorders with underlying anxiety symptomatologies, comprising at least one AMPA receptor antagonist, at least one compound selected from the group consisting of benzodiazepines, selective serotonin reuptake inhibitors (SSRIs), selective serotonin and norepinephrine reuptake inhibitors (SNRIs), buspirone and pregabalin 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 humans, 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 anxiety or other psychiatric disorders with underlying anxiety symptomatologies.
Additionally, the present invention provides a method of treating a warm-blooded animal having anxiety modelled in a particular paradigm comprising administering to the animal a COMBINATION OF THE INVENTION in a quantity which is jointly therapeutically effective against anxiety or other psychiatric disorders with underlying anxiety symptomatologies 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 anxiety or other psychiatric disorders with underlying anxiety symptomatologies.
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 anxiety or other psychiatric disorders with underlying anxiety symptomatologies 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 anxiety or other psychiatric disorders with underlying anxiety symptomatologies which are 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.
Buspirone may be administered in a total daily dosage of between about 15 to about 60 mg.
Clonazepam may be administered to an adult patient in a total daily dosage between about 3 to about 8 mg and to a paediatric patient in a total daily dosage between about 0.5 to about 3 mg, split into three of four separate units.
Diazepam may be administered to an adult patient in a total daily dosage between about 5 to about 10 mg and to a paediatric patient in a total daily dosage between about 5 to about 10 mg.
Lorazepam may be administered to an adult patient in a total daily dosage between about . 0.044 mg/kg body weight to about 0.05 mg/kg body weight.
Citalopram may be administered in a total daily dosage of between about 20 to about 60 mg.
Paroxetine may be administered in a total daily dosage of between about 20 to about 50 mg.
Venlafaxine may be administered in a total daily dosage of between about 70 to about 150 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 benzodiazepines, selective serotonin reuptake inhibitors (SSRIs), selective serotonin and norepinephrine reuptake inhibitors (SNRIs), buspirone and pregabalin, 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
Figure imgf000014_0001
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 Ri 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 anxiety disorders or other psychiatric disorders with underlying anxiety symptomatologies.
6. Method of treating a warm-blooded animal having anxiety modeled in a particular paradigm comprising administering to the animal a combination according to any one of claims 1 to 4 in a quantity which is jointly therapeutically effective in the anxiety model 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 anxiety disorders or other psychiatric disorders with underlying anxiety symptomatologies, 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 anxiety disorders or other psychiatric disorders with underlying anxiety symptomatologies.
9. Use according to claim 5 or 8 wherein the anxiety disorders or other psychiatric disorders with underlying anxiety symptomatologies are 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 anxiety disorders or other psychiatric disorders with underlying anxiety symptomatologies.
PCT/EP2004/012151 2003-10-28 2004-10-27 Combinations comprising ampa receptor antagonists for the treatment of anxiety disorders WO2005049041A1 (en)

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