Patent Abstract:
the present invention relates to the use of 1 -- 4 -- 2 . 5 - dihydro - 1h - imidazol - 2 - one or a physiologically acceptable salt thereof in a method for treatment and / or prevention of one or more epileptic disorders in a feline animal , preferably a cat .

Detailed Description:
before the embodiments of the present invention are described in further details it shall be noted that as used herein and in the appended claims , the singular forms “ a ”, “ an ”, and “ the ” include plural reference unless the context clearly dictates otherwise . unless defined otherwise , all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs . all given ranges and values may vary by 1 to 5 % unless indicated otherwise or known otherwise by the person skilled in the art , therefore , the term “ about ” was usually omitted from the description and claims . although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention , the preferred methods , devices , and materials are now described . all publications mentioned herein are incorporated herein by reference for the purpose of describing and disclosing the substances , excipients , carriers , and methodologies as reported in the publications which might be used in connection with the invention . nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention . in the following , 1 -( 4 - chlorophenyl )- 4 -( 4 - morpholinyl )- 2 , 5 - dihydro - 1h - imidazol - 2 - one ( imepitoin ) is also referred to as compound of the ( present ) invention . the compound of the invention can , if it has a sufficiently basic group such as , for example , a secondary or tertiary amine , be converted with inorganic and organic acids into salts . the pharmaceutically acceptable salts of the compound of the invention are preferably formed with hydrochloric acid , hydrobromic acid , iodic acid , sulfuric acid , phosphoric acid , methanesulfonic acid , p - toluenesulfonic acid , carbonic acid , formic acid , acetic acid , sulfoacetic acid , trifluoroacetic acid , oxalic acid , malonic acid , maleic acid , succinic acid , tartaric acid , racemic acid , malic acid , embonic acid , mandelic acid , fumaric acid , lactic acid , citric acid , taurocholic acid , glutaric acid , stearic acid , glutamic acid or aspartic acid . the salts which are formed are , inter alia , hydrochlorides , chlorides , hydrobromides , bromides , iodides , sulfates , phosphates , methanesulfonates , tosylates , carbonates , bicarbonates , formates , acetates , sulfoacetates , triflates , oxalates , malonates , maleates , succinates , tartrates , malates , embonates , mandelates , fumarates , lactates , citrates , glutarates , stearates , aspartates and glutamates . the stoichiometry of the salts formed from the compound of the invention may moreover be an integral or non - integral multiple of one . the compound of the invention can , if it contains a sufficiently acidic group such as , for example , the carboxy , sulfonic acid , phosphoric acid or a phenolic group , be converted with inorganic and organic bases into its physiologically tolerated salts . examples of suitable inorganic bases are ammonium , sodium hydroxide , potassium hydroxide , calcium hydroxide , and of organic bases are ethanolamine , diethanolamine , triethanolamine , ethylenediamine , t - butylamine , t - octylamine , dehydroabietylamine , cyclohexylamine , dibenzylethylene - diamine and lysine . the stoichiometry of the salts formed from the compound of the invention can moreover be an integral or non - integral multiple of one . it is likewise possible for the compound of the invention to be in the form of its solvates and , in particular , hydrates which can be obtained for example by crystallization from a solvent or from aqueous solution . it is moreover possible for one , two , three or any number of solvate or water molecules to combine with the compound of the invention to give solvates and hydrates . by the term “ solvate ” is meant a hydrate , an alcoholate , or other solvate of crystallization . in the course of the present invention , ( antiepileptic ) drug resistant or - refractory epileptic disorders , preferably phenobarbital - resistant or - refractory epileptic disorders , refers to failure of adequate trials of one or two tolerated and appropriately chosen and used anti - epileptic drug ( aed ) schedules ( whether as monotherapies or in combination ) to achieve sustained therapeutic success ( e . g . seizure freedom or significant reduction in seizure frequency ). herein , a feline animal is a member of the felidae family ( i . e . a felid ). it may thus belong either to the subfamily felinae or the subfamily pantherinae . the term feline animal encompasses the term cat , e . g ., a domestic cat . the term domestic cat encompasses the terms felis catus and felis silvestris catus . the dosage regimen for the compound of the present invention according to the present invention will , of course , vary depending upon known factors , such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration ; the species , age , sex , health , medical condition , and weight of the recipient ; the nature and extent of the symptoms ; the kind of concurrent treatment ; the frequency of treatment ; the route of administration , the renal and hepatic function of the patient , and the effect desired . a physician or veterinarian can determine and prescribe the effective amount of the drug required to prevent , counter , or arrest the progress of the disorder . in addition , radioisotope labeled compound of the invention ( e . g . 99m tc ) can be used to examine the distribution of the compound of the invention and their potential metabolites in the body . based on the currently available scientific data , the dose of the compounds of the invention , when used for the indicated effects , will be in the range of from 0 . 5 or 1 to 150 mg / kg bodyweight , preferably from 5 to 100 mg / kg bodyweight , more preferably from 5 to 50 mg / kg bodyweight , even more preferably from 20 to 100 mg / kg bodyweight , even more preferably from 20 to 60 mg / kg bodyweight , most preferably 25 to 40 mg / kg bodyweight . examples of individual doses are 1 mg / kg , 2 mg / kg , 5 mg / kg , 8 mg / kg , 10 mg / kg , 12 . 5 mg / kg , 15 mg / kg , 18 mg / kg , 20 mg / kg , 22 mg / kg , 25 mg / kg , 30 mg / kg , 35 mg / kg , 40 mg / kg , 45 mg / kg , 50 mg / kg , 55 mg / kg , 60 mg / kg , 65 mg / kg , 70 mg / kg , 75 mg / kg , 80 mg / kg , 85 mg / kg , 90 mg / kg , 95 mg / kg , 100 mg / kg bodyweight , preferably 10 mg / kg , 15 mg / kg , 20 mg / kg , 25 mg / kg , 30 mg / kg , 35 mg / kg , 40 mg / kg , 45 mg / kg , 50 mg / kg , 55 mg / kg or 60 mg / kg bodyweight , more preferably 20 mg / kg , 25 mg / kg , 30 mg / kg , 35 mg / kg , 40 mg / kg , 45 mg / kg , 50 mg / kg , 55 mg / kg or 60 mg / kg bodyweight , most preferably 25 mg / kg , 30 mg / kg , 35 mg / kg or 40 mg / kg bodyweight . these doses are preferably to be administered once , twice or three - times per day , preferably once or twice daily / once or twice per day , more preferably twice per day . also , if treated two or three times a day , equal or different doses can be administered . alternatively , the dosage can be split into / reduced to anywhere in between one dose once in two days up to one dose once in a week . the treatment is advisable in clinically apparent cases , both in acute as well as in chronic settings . suitable forms for administration are for example parenteral or oral administration of the compound of the invention , preferably oral administration . the compound of the invention can be formulated for instance in a solid , preferably a tablet formulation , or a liquid formulation . efficacy is based on the proportion of animals that achieve seizure freedom ( complete prevention of seizures ) over a given observation period , for example , 1 week , 2 weeks , 3 weeks , 4 weeks , 1 months , 2 months , 3 months , 4 months , 5 months , 6 months , 7 months , 8 months , 9 months , 10 months , 11 months , 12 months , 13 months , 14 months , 15 months , 16 months , 17 months , 18 months , 19 months , 20 months , 21 months , 22 months , 23 months , 24 months , 1 year , 2 years , 3 years , 4 years , 5 years , 6 years , 7 years , 8 years , 9 years , 10 years or even longer . such seizure freedom can be achieved , preferably without considerable adverse events , at doses of for example 15 mg / kg bodyweight or higher , such as doses of 20 to 60 mg / kg bodyweight or doses of 25 to 40 mg / kg bodyweight , for instance 15 mg / kg , 20 mg / kg , 25 mg / kg , 30 mg / kg , 35 mg / kg , 40 mg / kg , 45 mg / kg , 50 mg / kg , 55 mg / kg or 60 mg / kg bodyweight , preferably 20 mg / kg , 25 mg / kg , 30 mg / kg , 35 mg / kg , 40 mg / kg , 45 mg / kg , 50 mg / kg , 55 mg / kg or 60 mg / kg bodyweight , more preferably 25 mg / kg , 30 mg / kg , 35 mg / kg or 40 mg / kg bodyweight of the compound of the invention . during the course of treatment , the initial / starting dose can be reduced to lower maintenance doses to achieve the indicated herein described effects . these lower maintenance doses are preferably in the range of from 0 . 5 to 60 mg / kg bodyweight , more preferably from 1 to 30 mg / kg bodyweight , even more preferably from 5 to 20 mg / kg bodyweight . examples of individual doses are 1 mg / kg , 2 mg / kg , 5 mg / kg , 8 mg / kg , 10 mg / kg , 12 . 5 mg / kg , 15 mg / kg , 18 mg / kg , 20 mg / kg , 22 mg / kg , 25 mg / kg , 30 mg / kg bodyweight , most preferably 5 mg / kg , 10 mg / kg , 15 mg / kg , 20 mg / kg or 25 mg / kg bodyweight . these doses are also preferably to be administered once , twice or three - times per day , preferably once or twice daily / once or twice per day , more preferably twice per day . in this context and in the context of the present invention “ seizure freedom ” ( complete prevention of seizures ) or “ seizure - free ” means that a given animal does not show one or more seizures in the respective observation period , preferably in a year . in the context of the present invention “ good seizure control ” or “ good control of seizures ” means that a given animal does only show 1 to 5 seizures in the respective observation period , preferably in a year . in the context of the present invention “ moderate seizure control ” or “ moderate control of seizures ” means that a given animal does only show 6 to 10 seizures in the respective observation period , preferably in a year . in the context of the present invention “ poor seizure control ” or “ poor control of seizures ” means that a given animal does only show more than 10 seizures in the respective observation period , preferably in a year . the compound of the invention upon administration of the herein described doses and dosage regimens to a feline animal advantageously and preferably does not cause / elicit considerable adverse events . in this context and in the context of the present invention “ considerable adverse events ” refers to severe sedation , severe and long lasting somnolence ( i . e . longer than 3 hours ), hepatotoxicosis , hepatic necrosis , liver failure , kidney damage , kidney failure , drug addiction , leukopenia , thrombocytopenia , lymphadenopathies , coagulopathies and / or death . fig1 mean plasma concentration - time curves of imepitoin after the first oral dose of 30 mg / kg imepitoin in male ( m ) and female cats ( f ) at day 0 , day 14 and day 29 ( semi - logarithmic scale ). fig2 a and 2b results of clinical chemistry for enzymes in blood , routinely used to judge liver function and diagnose liver pathologies ( fig2 a = untreated / control ; fig2 b = imepitoin at 30 mg / kg bodyweight twice daily ). fig3 measurement of alkaline phosphatase ( ap ) in serum following administration of imepitoin in doses of 40 or 80 mg / kg bodyweight twice daily , or placebo . ap is routinely used to judge liver function and diagnose liver pathologies , and an elevated ap is indicative for a variety of diseases . all values measured here are in the physiological range with normal variance . day 0 reflects measurement before treatment start . the following examples serve to further illustrate the present invention ; but the same should not be construed as a limitation of the scope of the invention disclosed herein . when administered orally at a preferred dose of e . g . 30 mg / kg bodyweight twice daily ( 60 mg / kg bodyweight daily dose ) imepitoin the highest plasma concentration ( t max ) is reached in median 1 hour ( range 0 . 5 to 3 hours ) after administration , in most cases 1 hour . this plasma concentration rapidly declines over the next 24 hours , with a half - life time t 1 / 2 of 1 . 5 hours . the highest c max - values of imepitoin is observed at the first day of dosing ( day 0 ), 1 to 3 hours after the first dose is given . mean c max values are 7050 ng / ml for males ( n = 3 ) and 6643 ng / ml for females ( n = 3 ). corresponding auc 0 - 6h - values are 28001 ng · h / ml and 24467 ng · h / ml , respectively . after 14 and 29 days of twice daily dosing , a slightly lower exposure of imepitoin is observed compared to the first dosing day , indicating that no accumulation occurs upon long - term bid dosing . the last measurable concentration is found after more than 18 hours indicating that a dosing interval of 12 hours ( twice daily ) is adequate to assure permanent plasma levels throughout a chronic treatment . the imepitoin serum plasma concentration over time is shown in fig1 . in conclusion , the pharmacokinetic data show a favorable profile for administration in a feline animal . in a randomized , controlled , blinded study the tolerance of imepitoin is investigated in clinically healthy male and female cats after repeated oral administration for 30 days . twelve 1 - 3 years old , male and female domestic short hair cats with a body weight range of 2 . 8 - 4 . 4 kg are assigned to this study . the animals are randomly allocated to two groups , three male and three female animals per group . the test article ( imepitoin ) is orally administered to the animals of group ii at a target dose of 30 mg imepitoin / kg bodyweight twice daily at an interval of 8 - 12 h on days 0 - 29 . group i is left untreated serving as controls . mortality is not observed . no evidence of a clear effect of the repeated administration of imepitoin to cats on body weight development , food and water consumption , heart rate , respiratory rate and on parameters of laboratory investigations ( i . e . hematology , clinical chemistry and urinalysis ) is found . no sedation is observed in any animal . with respect to the liver there is no difference between imepitoin - treated and untreated ( control ) animals as shown by liver enzyme measurements ( fig2 a + 2 b ). temporary vomitus or choking is noted in 3 of 6 animals of the treated group from the second week of treatment onwards . two males of the untreated control group also show a vomitus at one occasion . it is noteworthy that vomitus is observed in cats from time to time after oral administration irrespective of the administered substance . in conclusion , imepitoin shows a favorable safety profile in feline animals at preferred high doses . eighteen 9 months old , male and female domestic short hair cats with a body weight range of 2 . 3 - 4 . 9 kg are assigned to this study . the animals are allocated to three test groups employing a pseudo - random body weight stratification procedure that yielded groups with approximately equal mean body weight , with three male and three female animals per group . the test article ( imepitoin ) is orally administered to the animals at a target dose of 40 mg imepitoin / kg bodyweight and 80 mg imepitoin / kg bodyweight twice daily at an interval of 8 - 12 h on days 0 - 30 . the third group receives visually identical placebo tablets , to avoid identification of the placebo group . physical examination a day before treatment start and on study days 7 , 14 and 30 includes body temperature ( rectal ), ocular system , musculoskeletal system , cardiovascular system , reproductive system , lymphatic system , behavior , nervous system , integumentary system , respiratory system , urinary system and gastro - intestinal system . in addition , blood and urine samples are analyzed before treatment and after 30 days . repeated oral administration of imepitoin to clinically healthy male and female cats at high doses of 40 and 80 mg imepitoin / kg body weight twice daily for 30 days is well tolerated by all cats , as none of the animals died prematurely and no considerable adverse events are observed . behavioral changes or sedation is not noted during the course of the study . in this randomized , controlled , blinded study emesis is intermittently observed in the second and third week of treatment , indicating a transient effect at high doses . no hematological or biochemical abnormalities are noted in the blood examination ( see e . g . fig3 ), and urine analysis shows physiological results . unexpectedly , imepitoin shows a favorable safety profile in feline animals even at very high doses . in contrast to other antiepileptic drugs , no severe sedation , severe and long lasting somnolence ( i . e . longer than 3 hours ), hepatotoxicosis , hepatic necrosis , liver failure , kidney damage , kidney failure , drug addiction , leukopenia , thrombocytopenia , lymphadenopathies , coagulopathies and / or death was observed . most other known antiepileptics cause sedation in cats , which is especially with phenobarbital quite pronounced . this is a severe challenge for the human - animal - interaction ( pet owner / animal ). two cats are diagnosed with epilepsy , having severe generalized seizures . both are treated with imepitoin at a starting dose of 30 mg / kg bodyweight twice daily . the first cat , a 14 year old european short - hair cat , had two severe generalized seizures . both lasted around two minutes , the cat lost consciousness and was disoriented after the seizure . in addition , a fibrosarcoma and hyperthyroidism was diagnosed . the cat was treated twice a day with 100 mg imepitoin , being a dose of 25 mg / kg bodyweight . it responded immediately to treatment , showing no further seizures . no considerable adverse events were observed . initially , the cat showed tiredness 1 - 1 . 5 hours after application of the drug , which lasted for about two hours . this resolved spontaneously after 10 days of treatment . after three months , the tiredness returned as described above , and consequently the dose was reduced to 20 mg / kg bodyweight , and the tiredness disappeared . until the end of the observation period of 6 months , the cat did not show any seizures , demonstrating complete seizure freedom for 6 months . the second cat , 7 years old , experienced two generalized seizures on two consecutive days , and the diagnosis was epilepsy of unknown cause . the cat appeared to be sleepier in the time before occurrence of first seizure . it also responded immediately to treatment with 30 mg / kg bodyweight imepitoin twice a day , but showed the tiredness observed in the first cat already after treatment start . a reduction of the dose to 10 mg / kg bodyweight twice daily resolved the tiredness , but with this dose the cat experienced again a seizure . the dose was increased to 20 mg / kg bodyweight imepitoin twice daily , and the cat showed complete seizure freedom for an observation period of 2 . 5 months . no tiredness or other adverse events were observed with this last dose . surprisingly and in contrast to dogs , a high dose of imepitoin leads to seizure freedom in cats with epilepsy , which is not achieved with low doses . unexpectedly , no considerable adverse events were observed . compared to untreated status at diagnosis , seizure frequency and severity are significantly reduced — at least 40 % of the cats even achieve seizure freedom when administering to feline patients a target dose of e . g . 30 mg imepitoin / kg bodyweight twice daily at an interval of 8 - 14 hours . such cats do also not experience considerable adverse events . in most of the other cats , seizure frequency and severity are significantly reduced . in some animals , treatment with current standard of care , phenobarbital , is not effective and results in frequent severe seizures despite high - dose treatment . administration of imepitoin in preferred doses , such as 20 to 60 mg / kg bodyweight , preferably such as 25 mg / kg bodyweight to 50 mg / kg bodyweight , more preferably such as 25 mg / kg bodyweight to 40 mg / kg bodyweight , two - or three - times daily reduces seizure frequency and / or severity significantly , in best case until complete seizure freedom . two groups of cats with epileptic disorders are treated with either imepitoin at a preferred dose of 30 mg / kg bodyweight twice daily or with phenobarbital at a common dose of 3 . 5 mg / kg bodyweight twice daily . in the phenobarbital group , 65 % of treated cats experience at least one adverse event , and approximately 40 % of all treated cats experience sedation as side effect . in contrast , the occurrence of adverse events is greatly and significantly reduced in the imepitoin treated groups , where about 30 % of all cats experience at least on adverse event . in the phenobarbital group , 30 % of treated cats are considered poorly controlled and in 70 % epilepsy was well controlled . for imepitoin , in about 15 % of cats treatment is not able to control the disease adequately . in 85 % of cats seizures are well controlled , and the majority of them reach seizure freedom . cats with epileptic disorders are treated with increasing doses of phenobarbital , starting from 3 mg / kg bodyweight twice daily up to the maximum tolerated dose . with this treatment protocol , sustained and significant reduction in seizure frequency cannot be obtained , and seizures remain poorly controlled . according to this treatment failure this represents drug - resistant epileptic disorders . the treatment of these cats with drug resistant epilepsy is now changed to imepitoin , provided at high doses as for example 30 mg / kg bodyweight twice daily . the seizure frequency of these cats reduced significantly by at least 50 % in most cases . 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