US 2010O28O124A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0280124 A1 Bialer et al. (43) Pub. Date: Nov. 4, 2010

(54) ACYL-UREADERVATIVES AND USES Related U.S. Application Data THEREOF (60) Provisional application No. 60/929,387, filed on Jun. 25, 2007, provisional application No. 61/006,317, (75) Inventors: Meir Bialer, Jerusalem (IL); Boris filed on Jan. 7, 2008. Yagen, Jerusalem (IL); Jakob Avi Publication Classification Shimshoni. Rechovot (IL) (51) Int. Cl. A6II 3/17 (2006.01) Correspondence Address: C07C 275/50 (2006.01) MARTIN D. MOYNIHAN d/b/a PRTSI, INC. C07C 273/18 (2006.01) P.O. BOX16446 A6IP 25/00 (2006.01) ARLINGTON, VA 22215 (US) A6IP 25/08 (2006.01) A6IP3/00 (2006.01) (73) Assignee: Yissum Research Development A6IP 25/28 (2006.01) Company of the Hebrew A6IP 25/06 (2006.01) University of Jerusalem Ltd., (52) U.S. Cl...... 514/594; 564/44 Jerusalem (IL) (57) ABSTRACT Novel acyl-urea containing compounds, processes of prepar (21) Appl. No.: 12/666,703 ing same, compositions containing same and uses thereof in the treatment of neurological diseases and disorders such as epilepsy, neuropathic pain, bipolar disorder, status epilepti (22) PCT Fled: Jun. 25, 2008 cus, chemically-induced convulsions and/or disor ders, febrile convulsions conditions, metabolic disturbances (86) PCT NO.: PCT/IL08/0O870 and a Sustenance withdrawal conditions, are provided. Also provided are uses of these and other acyl-urea containing S371 (c)(1), compounds in the treatment of neurological diseases and (2), (4) Date: Jul. 7, 2010 disorders. US 2010/02801 24 A1 Nov. 4, 2010

ACYL-UREADERVATIVES AND USES lished AEDs are associated with some rare but severe side THEREOF effect such as teratogenicity and other adverse effects that limit their use. FIELD AND BACKGROUND OF THE 0006 Status epilepticus is typically treated with benzodi INVENTION azepines such as diazepam, clonazepam, lorazepam phe nobarbital, phenyloin andlorazepam. Phenyloin and it's pro 0001. The present invention, in some embodiments drug fosphenyloin as well as other hydantoin derivatives are thereof, relates to novel acyl-urea containing compounds, and also used to treat SE, and are typically co-administered with to uses of acyl-urea containing compounds in a variety of a benzodiazepine phenobarbital or barbiturate. Barbiturates therapeutic applications, including, for example, neurologi such as phenobarbital, secobarbital, thiopental or pentobar cal diseases and disorders such as epilepsy, neuropathic pain bital, are still used today to treat SE if benzodiazepines or the and bipolar disorders. hydantoins are not an option, primarily by induction of a 0002 Epilepsy, also referred to in the art as a seizure barbituric coma. In that respect of coma-causing agents, gen disorder, is a chronic disorder of the eral anesthetics Such as propofol and lidocaine are used where (CNS), characterized either by recurrent and unprovoked epi barbiturates are ineffective or cannot be used for some other sodic loss of attention or sleepiness or by severe convulsions CaSO. with loss of consciousness called or fits. The seizures 0007 Valproic acid is a broad-spectrum antiepileptic and are considered as transient symptoms which are attributed to CNS active agent, which is still in use as an anticonvulsant irregular immoderate or coincident neuronal activity in the and mood-stabilizing drug in the treatment of epilepsy and brain. This incurable yet typically therapeutically controlled bipolar disorder. It has also been used in the treatment of medical condition affects about 0.5% of the population, neuropathic pain, myoclonus, Schizophrenia and formigraine whereas about 1.5-5.0% of the population may have a seizure prophylaxis. VPA is believed to act through a combination of in their lifetime at any age. mechanisms, namely as a membrane stabilizer, as a GABA 0003 Prolonged seizures may lead to the development of transaminase inhibitor, thereby enhancing GABA signaling; Status epilepticus (SE), which is a life threatening cerebral and as a serotonergic inhibitor which reduces NMDA-recep state of a persistent seizure. SE can be defined broadly as one tor mediated glutamate excitation. In principle, such multi continuous seizure or a series of recurrent seizures wherein level action is highly advantageous, promising improved effi the Subject does not regain consciousness between seizures cacy with reduced side effects. However, the clinical use of for longer than 30 minutes. It is believed that 5 minutes are VPA is limited by two rare, but potentially life-threatening Sufficient to cause irreparable damage to the neurons, and in side effects, teratogenicity and hepatotoxicity that restrict its SE cases seizures are unlikely to terminate spontaneously by utilization in women of child bearing age and in children. that time. In a subject known to suffer from epilepsy, SE can While VPA's teratogenicity is associated with the parent com be brought about or be aggravated by poor compliance to pound 1, its hepatotoxicity results from biotransformation treatment (adherence to medication regimen), with into hepatotoxic metabolites with a terminal double bond, drawal and/or metabolic disturbances. As a primary presen specifically 4-ene-VPA 2-4. tation it may indicate a brain tumor or abscess. SE was also 0008 Extensive efforts have therefore been directed reported to be caused by various nerve agents (organophos towards therapeutically active derivatives of VPA which phates) Such as , VX and . exhibit improved activity and/or reduced side effects. 0004 Current treatment of epilepsy typically consists of 0009. Therapeutically active derivatives of VPA include oral administration of anti-convulsants or antiepileptic drugs the Salt sodium valproate which is used in anticonvulsant (AEDs). This symptomatic treatment is aimed at reducing the formulations, and valproate semisodium, which is used as an number and severity of future seizures. The efficacy of AEDs anticonvulsant and a mood stabilizer. A homologue of VPA depends on the patient's response to a particular AED, which wherein one of the alkyl chains is three carbons longer, arun in turn is selected according to the type and severity of the dic acid ((R)-(–)-2-propyloctanoic acid, also known as ONO seizure. Some epileptic patients are known to respond well to 2506), is currently under clinical development for the poten one AED and may respond poorly or even worsen the condi tial treatment of stroke, as well as of other neurodegenerative tion by others. When the epileptic condition seems not to diseases including amytrophic lateral sclerosis (ALS), Alzhe respond to the use of AEDs, it is referred to as “refractory imer's disease and Parkinson's disease 5. epilepsy, which is typically treated by brain surgery to 0010. A series of VPA-amide analogue and derivatives remove the abnormal brain cells that are causing the seizures, thereof was developed via a series of structure (pharmacoki or by a vagal nervestimulator, which is implanted in the chest, netic/pharmacodynamic) activity relationship studies, and which helps reducing the number of seizures. were found to exhibit improved anticonvulsant activity while 0005 Four major antiepileptic drugs (AEDs) are currently avoiding teratogenicity and hepatotoxicity 6-9. Some of used for the treatment of epilepsy (epileptic seizures and these VPA amide derivatives were also active in animal mod convulsions), which include phenyloin (marketed as Dilan els of neuropathic pain 10, 11 and bipolar disorder 12, 13. tin R) in the USA and as Epanutin R) in the UK), carbamazepine 0011 Urea is an integral part of the heterocyclic chemical (sold under the brand-names Biston, Calepsin, Carbatrol, structures of three leading AEDs, namely phenobarbital, phe Epitol, Equetro, Finlepsin, Sirtal, Stazepine, Tegretol, nyloin and carbamazepine. These drugs consist of a lipophilic Telesmin, Timonil), phenobarbital (also known as phenobar moiety delineated by phenyl-alkyl in phenobarbital, diphenyl bitone or Luminal(R) and valproic acid (VPA). However, in phenyloin and dibenzazepine in carbamazepine, and a about 25% of the patients do not respond to the current medi hydrophilic moiety, containing a ring fused urea molecule. cations. Furthermore, AEDs are administered repetitively as The presence of urea in all of these drugs implies that it plays chronic treatment and the adverse effects associated with an important role in the anticonvulsant pharmacophore 6, antiepileptic therapy are of a major concern. The major estab 14. US 2010/02801 24 A1 Nov. 4, 2010

0012 Acyl-urea containing compounds are known for 0019. Thus, according to one aspect of the present inven many decades 15-18. These compounds have been consid tion there is provided a compound having the general For ered promising anticonvulsants 19 and as sedative or hyp mula I: notic agents 20. Spielman and coworkers 19 synthesized a series of acyl-urea derivatives using a variety of branched aliphatic and aromatic residues, and evaluated as potential Formula 1 anticonvulsant agents using maximal electroshock seizure Rb O O test (MES) and subcutaneous metrazol test (scMet) in mice. 2 ls R3 In this series, Spielman reports that several derivatives of acyl-urea demonstrated potent anticonvulsant activity, Ra11. including 2-ethyl-3-methylvalerylurea, 2-ethylcaproylurea R R2 R4 and 2-isopropyl-A-pentenoylurea, whereby other deriva tives were found non-active. The anticonvulsant profile of wherein: valproylurea was also evaluated by Tantisira et al. 21 on 0020 R-R are each independently hydrogen or an alkyl mice MES and scMET models, who showed an excellent having from 1 to 10 carbon atoms; and protection in both models with a favorable protective index 0021 Ra and Rb are each methyl, compared to Valproic acid. 0022 with the proviso that when each of R-Ra is hydro 0013. Other acyl-urea containing compounds have been gen, R is an alkyl having from 3 to 10 carbon atoms. previously reported and studied as drugs for the treatment of 0023. According to further features in some embodiments psychiatric and neurological conditions. An example is the of the invention described below, each of R-R is hydrogen. drug Sedormid (allyl-isopropyl-acetyl urea) which was used 0024. According to still further features in the described as a mild anxiolytic and sedative agent until it was found toxic embodiments R is propyl. and therefore is no longer marketed. 0025. According to further features in some embodiments 0014 U.S. Pat. No. 3,282,998 teaches the synthesis of of the invention described below, each of R-R is hydrogen, (2-ethyl-3-methyl-pentanoyl)-urea, and Goldstein et al. 22 and R is propyl. reported studies relating to this compound, known as the drug 0026. According to further features in some embodiments Capuride (PacinoxR) which was indicated for sleep disor of the invention described below, each of R-R is hydrogen, ders, as a minor tranquilizer and anti-anxiety agent. None of R is propyl, and the stereo-configuration at position 2 is these publications relates to the stereochemistry of the com selected from the group consisting of an R-configuration, an pound. S-configuration and a mixture thereof. 0027. According to further features in some embodiments 0.015. One of the observations which stem from these of the invention described below, each of R-R is hydrogen, seminal Studies is the effect of seemingly minor structural and R is isopropyl. changes in the acyl group. Such as the location, addition or 0028. According to another aspect of the present invention elimination of even a single methyl group or more, on the there is provided a pharmaceutical composition which activity of the resulting compound. includes, as an active ingredient, the compound defined by 0016. A new and highly effective AED, 2.2.3,3-tetrameth Formula I, and a pharmaceutically acceptable carrier. ylcyclopropylcarbonylurea, has recently been synthesized 0029. According to further features in some embodiments and tested 6. This acyl-urea derivative of cyclopropane of the invention described below, the pharmaceutical compo showed anticonvulsant activity in both the scMet and the sition is being packaged in a packaging material and identi MES model tests in mice and rats 23, with a protective fied in print, in or on the packaging material, for use in the index, e.g. median neurological toxic dose to median effec treatment of a neurological disease or disorder. tive dose ratio (TDs-to-EDs ratio) of 18.5 in the MES test, 0030. According to still another aspect of the present compared to 1.6 which was measured and calculated for invention there is provided a pharmaceutical composition, valproic acid. being packaged in a packaging material and identified in 0017 U.S. Pat. No. 6,417,399 by two of the present inven print, in or on the packaging material, for use in the treatment tors relates to the individual stereoisomers of the drug val of a neurological disease or disorder, the composition com noctamide (a mixture of four stereoisomer kinds of 2-ethyl prising a compound having a general formula selected from 3-methyl-pentanamide, VCD) which are shown to be more the group consisting of Formula II and III: potent than any mixture thereof in the treatment of neurologi cal and psychotic disorders such as epilepsy, pain and affec tive disorders, and useful as tranquilizers. This disclosure Formula II further teaches a method for stereoselective separation and Rb O O quantification of each of the four stereoisomers from a race mic mixture of VCD or from plasma of patients treated with the racemic drug, and to a unique method for the synthesis of --- the individual stereoisomers. R R2 R4 Formula III O O SUMMARY OF THE INVENTION ls R 0018. The present inventors have now prepared and suc A-1, 3 cessfully practiced various acyl-urea containing compounds R2 R4 as agents for the treatment of neurological diseases and dis orders. US 2010/02801 24 A1 Nov. 4, 2010

wherein: 0046 According to still further features in the described 0031) R-Ra, Ra and Rb are each independently hydrogen embodiments, the compound of the composition, method or or an alkyl having from 1 to 10 carbon atoms. use presented above is having the general Formula III, and 0032. According to yet another aspect of the present each of R-R is independently hydrogen. invention there is provided a method of treating a medical 0047 According to still further features in the described condition associated with a neurological disorder, the method embodiments, the compounds of the composition, method or is effected by administering to a subject in need thereof a use presented above are selected from the group consisting of therapeutically effective amount of a compound having a 0048 1-(2-isopropylpentanoyl)urea (Compound 1, PIU), general formula selected from the group consisting of For having the formula: mula II and III as defined herein. 0033 According to further features in some embodiments of the invention described below, the therapeutically effective amount ranges from about 0.1 mg/kg body to about 100 O l mg/kg body. Alternatively, the therapeutically effective N NH2: amount ranges from about 5 mg/kg body to about 70 mg/kg body, and in other embodiments the therapeutically effective s 2 amount ranges from about 10 mg/kg body to about 40 mg/kg body. 0049 R-1-(2-isopropylpentanoyl)urea (Compound 1R, 0034. According to an additional aspect of the present R-PIU), having the formula: invention there is provided a use of a compound having a O O general formula selected from the group consisting of For mula II and III as defined herein, in the manufacture of a medicament for the treatment of a neurological disease or s disorder. s 2 0035. According to further features in some embodiments of the invention described below, the compound has the gen 0050 S-1-(2-isopropylpentanoyl)urea (Compound 1S, eral Formula II. S-PIU), having the formula: 0036. According to still further features in the described O O embodiments, each of R-R is hydrogen in the compound having the general Formula II. 0037 According to still further features in the described s embodiments, each of R-R is hydrogen and R is propyl in the compound having the general Formula II. 0038 According to still further features in the described 0051 1-(2-isopropyl-3-methylbutanoyl)urea (Compound embodiments, each of R-R is hydrogen, R is propyl, and 2, DIU), having the formula: the Stereo-configuration at position 2 is selected from the group consisting of an R-configuration, an S-configuration and a mixture thereof in the compound having the general Formula II. O l 0039. According to still further features in the described N NH2: embodiments, each of R-R is hydrogen and R is isopropyl in the compound having the general Formula II. 2. 2 0040. According to still further features in the described embodiments, each of R-R is hydrogen and Rb is methyl in 0052 1-(3,3-dimethyl-butyryl)urea (Compound 3, TBU), the compound having the general Formula II. having the formula: 0041 According to still further features in the described embodiments, each of R-R and Rb is hydrogen in the com pound having the general Formula II. O O 0042. According to still further features in the described embodiments, each of R-R and Rb is hydrogen, Rais propyl and R is ethyl in the compound having the general Formula 4- 1s.2 II. 0043. According to still further features in the described 0053 1-(2-ethyl-hexanoyl)-urea (Compound 5, EBU), embodiments, each of R-R and Rb is hydrogen, Ra is ethyl having the formula: and R is propyl in the compound having the general Formula II. 0044 According to still further features in the described embodiments, each of R-R is hydrogen, and Ra and Rb is O l methyl in the compound having the general Formula II. N NH2: 0045. According to still further features in the described embodiments, each of R-R and Ra is hydrogen, and each of Rb and R is methyl in the compound having the general r’s 2 Formula II. US 2010/02801 24 A1 Nov. 4, 2010

0054 1-(2-propyl-pentanoyl)-ureaorvalproate la 0061 wherein R is hydrogen oran alkyl having from 1 to (Compound 6, VPU), having the formula: 10 carbon atoms, 0062 with a compound having the general Formula V:

O O s Formula V c's 2 0055 2-methylbutanoylurea (Compound 8), having the formula: 0063 wherein R-R are each independently hydrogen or an alkyl having from 1 to 10 carbon atoms, 0064 with the proviso that when each of R-Ra is hydro gen, R is an alkyl having from 3 to 10 carbon atoms. 0065 According to further features in some embodiments O l of the invention described below, prior to reacting, the com pound having the general Formula IV is converted into a l, NH2: reactive carboxylic derivative thereof. Alternatively the reac tive carboxylic derivative is an acyl-halide. and 0066. According to further features in some embodiments 0056 2.2-dimethylpropanoylureaor 1-(pivaloyl)urea of the invention described below, the compound having gen (Compound 9), having the formula: eral Formula IV is obtained by reacting isovaleric acid with an alkylating agent having the general Formula VI: R—X Formula VI. 0067. According to another aspect of the present invention O l there is provided a pure (isolated) stereoisomer of (2-ethyl N NH. 3-methyl-pentanoyl)-urea. x 2 0068 According to further features in some embodiments of the invention described below, the stereoisomer of 0057 According to further features in some embodiments (2-ethyl-3-methyl-pentanoyl)-urea is selected from the group of the invention described below, the neurological disorder treatable using compound having general Formulae II and III, consisting of ((2S)-2-ethyl-(3S)-3-methyl-pentanoyl)-urea, is selected from the group consisting of epilepsy, convulsions, ((2S)-2-ethyl-(3R)-3-methyl-pentanoyl)-urea, ((2R)-2- seizure disorder, complex partial seizures, status epilepticus, ethyl-(3S)-3-methyl-pentanoyl)-urea and ((2R)-2-ethyl a chemically-induced convulsion and/or seizure disorder, a (3R)-3-methyl-pentanoyl)-urea. febrile convulsion condition, a metabolic disturbance and a 0069. According to another aspect of the present invention Sustenance withdrawal condition, spasticity, there is provided a pharmaceutical composition packaged in spasms, restless leg syndrome, anxiety, stress, multiple scle a packaging material and identified in print, in or on the rosis, stroke, head trauma, spinal cord injury, amytrophic packaging material, for use in the treatment of a neurological lateral sclerosis (ALS), Parkinson's Disease, Huntington's disease or disorder, the composition comprising at least one Disease, Alzheimer's Disease, amyotrophic lateral Sclerosis, of pure (isolated) stereoisomer of (2-ethyl-3-methyl-pen neuropathic pain, deafferentation pain, myoclonus, Schizo tanoyl)-urea, as described herein. phrenia migraine, headaches and a bipolar disorder, with the 0070 According to yet another aspect of the present proviso that when each of R-R is hydrogen, Ra is methyl or invention there is provided a method of treating a medical ethyl and Rb is methyl, R is an alkyl having from 3 to 10 condition associated with a neurological disorder, the method carbon atoms. comprising administering to a Subject in need thereofathera 0058 According to some embodiments of the present peutically effective amount of at least one pure Stereoisomer invention the neurological disorder treatable using com of (2-ethyl-3-methyl-pentanoyl)-urea. pounds having general Formulae II and III, is selected from the group consisting of status epilepticus, a chemically-in 0071. According to yet another aspect of the present duced convulsion and/or seizure disorder, a febrile convul invention there is provided a use of at least one pure Stereoi sion condition, a metabolic disturbance and a Sustenance Somer of (2-ethyl-3-methyl-pentanoyl)-urea, in the manufac withdrawal condition. ture of a medicament for the treatment of a neurological 0059. According to an additional aspect of the present disease or disorder. invention there is provided a process of preparing the novel 0072 According to further features in some embodiments compounds described herein, the process comprising: of the invention described below, the neurological disorder is 0060 reacting a compound having the general Formula selected from the group consisting of epilepsy, convulsions, IV: seizure disorder, complex partial seizures, status epilepticus, a chemically-induced convulsion and/or seizure disorder, a febrile convulsion condition, a metabolic disturbance and a Formula IV Sustenance withdrawal condition, spasticity, skeletal muscle spasms, restless leg syndrome, anxiety, stress, sleep disorder, multiple Sclerosis, stroke, head trauma, spinal cord injury, amytrophic lateral sclerosis (ALS), Parkinson's Disease, OH Huntington's Disease, Alzheimer's Disease, amyotrophic lat eral Sclerosis, neuropathic pain, deafferentation pain, myo clonus, Schizophrenia migraine, headaches and a bipolar dis US 2010/02801 24 A1 Nov. 4, 2010 order. Alternatively the neurological disorder is selected from subject in need thereofatherapeutically effective amount of a the group consisting of epilepsy, status epilepticus, a chemi compound having a general formula selected from the group cally-induced convulsion and/or seizure disorder, a febrile consisting of Formula II and III: convulsion condition, a metabolic disturbance and a Suste nance withdrawal condition, complex partial seizures, neuro pathic pain and bipolar disorder. Formula II 0073. According to another aspect of the present invention Rb O O there is provided a pharmaceutical composition packaged in 2 ls R3 a packaging material and identified in print, in or on the 11. Y packaging material, for use in the treatment of a neurological R R R4 disease or disorder selected from the group consisting of Formula III epilepsy, convulsions, seizure disorder, complex partial Sei O O Zures, status epilepticus, a chemically-induced convulsion and/or seizure disorder, a febrile convulsion condition, a ls R3 metabolic disturbance and a Sustenance withdrawal condi A-1, tion, spasticity, skeletal muscle spasms, restless leg Syn R R4 drome, multiple Sclerosis, stroke, head trauma, spinal cord injury, amytrophic lateral sclerosis (ALS), Parkinson's Dis ease, Huntington's Disease, Alzheimer's Disease, amyo 0081 an enantiomer, a diastereomer, a prodrug, a hydrate, trophic lateral Sclerosis, neuropathic pain, deafferentation a Solvate or a pharmaceutically acceptable salt thereof, pain, myoclonus, Schizophrenia migraine, headaches and a 0082 wherein: bipolar disorder, the composition comprising a compound I0083) R-Ra, Ra and Rb are each independently hydrogen having a general formula selected from the group consisting or an alkyl having from 1 to 10 carbon atoms; of Formula II and III: I0084 with the provisos that: I0085 when each of R-R is hydrogen and each of Ra and Rb is methyl, R is an alkyl having from 3 to 10 carbonatoms; Formula II and Rb O O I0086 when each of R-R is hydrogen, Ra is ethyl and Rb is methyl, R is an alkyl having from 2 to 10 carbon atoms. 2 l R3 0087. According to still another aspect of the present -> invention there is provided a use of a compound having a R R2 R4 general formula selected from the group consisting of For Formula III mula II and III: O O

ls R3 Formula II A-l Rb O O R2 R4

0.074 an enantiomer, a diastereomer, a prodrug, a hydrate, ----- R R R4 a solvate or a pharmaceutically acceptable salt thereof, Formula III 0075 wherein: O O 0076 R-Ra, Ra and Rb are each independently hydrogen or an alkyl having from 1 to 10 carbon atoms; ls R 0077 with the provisos that: A-l 3 0078 when each of R-R is hydrogen and each of Ra and R R4 Rb is methyl, R is an alkyl having from 3 to 10 carbonatoms: and 0088 an enantiomer, a diastereomer, a prodrug, a hydrate, 0079 when each of R-R is hydrogen, Ra is ethyl and Rb a Solvate or a pharmaceutically acceptable salt thereof, is methyl, R is an alkyl having from 2 to 10 carbon atoms. 0089 wherein: 0080 According to yet another aspect of the present 0090 R-Ra, Ra and Rb are each independently hydrogen invention there is provided a method of treating a neurologi or an alkyl having from 1 to 10 carbon atoms; cal disease or disorder selected from the group consisting of (0091 with the provisos that: epilepsy, convulsions, seizure disorder, complex partial Sei 0092 when each of R-R is hydrogen and each of Ra and Zures, status epilepticus, a chemically-induced convulsion Rb is methyl, R is an alkyl having from 3 to 10 carbonatoms; and/or seizure disorder, a febrile convulsion condition, a and metabolic disturbance and a Sustenance withdrawal condi 0093 when each of R-R is hydrogen, Ra is ethyl and Rb tion, spasticity, skeletal muscle spasms, restless leg Syn is methyl, R is an alkyl having from 2 to 10 carbon atoms, drome, multiple Sclerosis, stroke, head trauma, spinal cord 0094 in the manufacture of a medicament for the treat injury, amytrophic lateral sclerosis (ALS), Parkinson's Dis ment of a neurological disease or disorder selected from the ease, Huntington's Disease, Alzheimer's Disease, amyo group consisting of epilepsy, convulsions, seizure disorder, trophic lateral Sclerosis, neuropathic pain, deafferentation complex partial seizures, status epilepticus, chemically-in pain, myoclonus, Schizophrenia migraine, headaches and a duced convulsions and/or seizure disorders, febrile convul bipolar disorder, the method comprising administering to a sion conditions, metabolic disturbances, Sustenance with US 2010/02801 24 A1 Nov. 4, 2010

drawal conditions, spasticity, skeletal muscle spasms, restless processes of preparing same. The present invention, in some leg syndrome, multiple Sclerosis, stroke, head trauma, spinal embodiments thereof, is further of uses of acyl-urea contain cord injury, amytrophic lateral Sclerosis (ALS), Parkinson's ing compounds in the treatment of neurological diseases and Disease, Huntington's Disease, Alzheimer's Disease, amyo disorders such as epilepsy, status epilepticus, chemically trophic lateral Sclerosis, neuropathic pain, deafferentation induced convulsions and seizures and other non-epileptic pain, myoclonus, Schizophrenia migraine, headaches and a convulsions, neuropathic pain and bipolar disorders. bipolar disorder. 0103) The acyl-urea containing compounds described 0095 According to exemplary embodiments, the neuro herein are characterized by improved efficacy and reduced logical disease or disorder is epilepsy, status epilepticus, a side effects and hence present a novel family of potent agents chemically-induced convulsion and/or seizure disorder, a for treating a variety of medical conditions. febrile convulsion condition, a metabolic disturbance, a sus 0104. The acyl-urea containing compounds described tenance withdrawal condition, neuropathic pain or a bipolar herein possess unique and novel therapeutic features that disorder. render these compounds Superior to other acyl-urea contain 0096. Unless otherwise defined, all technical and scien ing compounds known in the art in the treatment of neuro tific terms used herein have the same meaning as commonly logical diseases and disorders such as epilepsy. understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or 0105. The principles and operation of the present inven equivalent to those described herein can be used in the prac tion may be better understood with reference to the figures tice or testing of the present invention, Suitable methods and and accompanying descriptions. materials are described below. In case of conflict, the patent 0106 Before explaining at least one embodiment of the specification, including definitions, will control. In addition, invention in detail, it is to be understood that the invention is the materials, methods, and examples are illustrative only and not limited in its application to the details set forth in the not intended to be limiting. following description or exemplified by the Examples. The 0097. The term “comprising means that other steps and invention is capable of other embodiments or of being prac ingredients that do not affect the final result can be added. ticed or carried out in various ways. Also, it is to be under This term encompasses the terms "consisting of and “con stood that the phraseology and terminology employed herein sisting essentially of. is for the purpose of description and should not be regarded as 0098. The phrase “consisting essentially of means that limiting. the composition or method may include additional ingredi 0107 As discussed hereinabove, acyl-urea containing ents and/or steps, but only if the additional ingredients and/or compounds are well known in the art, and some where con steps do not materially alter the basic and novel characteris sidered as promising therapeutic agents in the treatment of tics of the claimed composition or method. epilepsy and other neurological diseases and disorders. For 0099. As used herein, the singular form “a,” “an and many decades researchers have manipulated valproic acid “the include plural references unless the context clearly and acyl-urea containing compounds in an attempt to strike a dictates otherwise. For example, the term “a compound” or new path to a more potent antiepileptic drug (AED) and thus “at least one compound may include a plurality of com created a vast repository of these compounds. pounds, including mixtures thereof. 0108. While conceiving the present invention, the present 0100 Throughout this disclosure, various aspects of this inventors hypothesized that combining some basic structural invention can be presented in a range format. It should be features of valproic acid with urea may produce effective understood that the description in range format is merely for AEDs. While reducing the present invention to practice it was convenience and brevity and should not be construed as an found that the acyl-urea containing compounds are much inflexible limitation on the scope of the invention. Accord more potent as anticonvulsants and possess a higher protec ingly, the description of a range should be considered to have tive index, than their corresponding acids, and more particu specifically disclosed all the possible Subranges as well as larly it was found that urea derivatives of valproic acid are individual numerical values within that range. For example, very promising anticonvulsants, possessing the potential in description of a range such as from 1 to 6 should be consid the treatment of several neurological diseases and disorders. ered to have specifically disclosed Subranges Such as from 1 0.109 As mentioned hereinabove, one of the observations to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 which stemmed from early studies such as that of Spielman et to 6 etc., as well as individual numbers within that range, for al. was the effect of seemingly minor structural changes in the example, 1, 2, 3, 4, 5, and 6. This applies regardless of the acyl group. Such as the location, addition or elimination of breadth of the range. even a single methyl group or more, on the pharmacologic 0101. Whenever a numerical range is indicated herein, it is profile of the resulting compound. meant to include any cited numeral (fractional or integral) within the indicated range. The phrases “ranging/ranges 0110. As demonstrated in the Examples section that fol between a first indicate number and a second indicate num lows, while reducing the present invention to practice, several ber and “ranging/ranges from a first indicate number “to a acyl-urea containing compounds were prepared and Success second indicate number are used herein interchangeably and fully tested for their anticonvulsant activity in animal models. are meant to include the first and second indicated numbers As mentioned hereinabove, it was indeed shown that by selecting the location, addition or elimination of even a single and all the fractional and integral numerals therebetween. methyl group or more, improved activity is obtained. It was DESCRIPTION OF SPECIFIC EMBODIMENTS further shown that several acyl-urea containing compounds OF THE INVENTION that were previously prepared and previously tested for anti convulsant activity in the art, have now been found to exhibit 0102 The present invention, in some embodiments completely different activity levels as compared to the activi thereof, is of novel acyl-urea containing compounds, and of ties reported in the art. US 2010/02801 24 A1 Nov. 4, 2010

0111. Thus, according to one aspect of the present inven embodiments encompass the racemate, Compound 1, as well tion, there is provided a compound having the general For as both optically active enantiomers thereof, namely, when mula I: the stereo-configuration at position 2 is an R-configuration, resulting in 1-((R)-2-isopropylpentanoyl)urea (Compound 1R, see Table 1 hereinbelow), an S-configuration, resulting in Formula I 1-((S)-2-isopropyl-pentanoyl)urea (Compound 1S, see Table Rb O O 1 hereinbelow), and a mixture of any ratio thereof. Alterna 2 ls R3 tively, the racemate of Compound 1 has a 1:1 enantiomeric ratio. 0126. According to other embodiments, R. R. and Rare R R2 R4 each hydrogen, and R is isopropyl, resulting in the com pound 1-(2-isopropyl-3-methylbutanoyl)urea which is 0112 wherein R-R are each independently hydrogen or referred to hereinbelow as Compound 2, as demonstrated in an alkyl having from 1 to 10 carbon atoms; and the Examples section that follows. 0113 Ra and Rb are each independently methyl. I0127. The present embodiments further encompass any 0114 with the proviso that when each of R-R is hydro enantiomers, diastereomers, prodrugs, Solvates, hydrates gen, R is an alkyl having from 3 to 10 carbon atoms. and/or pharmaceutically acceptable salts of the compounds 0115. As used herein, the term “alkyl describes an ali described herein. phatic hydrocarbon including straight chain and branched 0128. As used herein, the term “enantiomer' refers to a chain groups. Preferably, the alkyl group has 1 to 10 carbon Stereoisomer of a compound that is Superposable with respect atoms, and more preferably 1 to 4 carbonatoms. Whenever a to its counterpart only by a complete inversion/reflection numerical range; e.g., "1-10”, is stated herein, it implies that (mirror image) of each other. Enantiomers are said to have the group, in this case the alkyl group, may contain 1 carbon “handedness' since they refer to each other like the right and atom, 2 carbonatoms, 3 carbonatoms, etc., up to and includ left hand. Enantiomers have identical chemical and physical ing 10 carbon atoms. The alkyl can be substituted or unsub properties except when present in an environment which by stituted. itself has handedness, such as all living systems. 0116. The term “alkyl, as used herein, also encompasses 0129. The terms “diastereomers' or “diastereoisomers', saturated or unsaturated hydrocarbon, hence this term further as used herein, refer to stereoisomers that are not enantiomers encompasses alkenyl and alkynyl, however, the term “alkyl with respect to one another. Diastereomers have more than does not encompass allyl (—CH2—CH=CH-). one chiral center, and can have different physical properties 0117 The term “alkenyl' describes an unsaturated alkyl, and different reactivity. Diastereoisomers are not mirror as defined herein, having at least two carbon atoms and at images of each other but rather have one or more chiral least one carbon-carbon double bond. The alkenyl may be centers inverted between the two stereoisomers. If a molecule substituted or unsubstituted by one or more substituents, as exhibits two chiral centers (two asymmetric carbons), there described herein. are up to four possible stereo-configurations and hence up to 0118. The term “alkynyl', as defined herein, is an unsat four possible diastereomers. In the context of the present urated alkyl having at least two carbonatoms and at least one embodiments, diastereomers include compounds having dif carbon-carbon triple bond. The alkynyl may be substituted or ferent chirality in at least one of the two chiral centers at unsubstituted by one or more substituents, as described positions 2 and 3 of the compound (see, Formula I). herein. 0.130. The term “prodrug” refers to an agent, which is 0119 The term “urea' as used herein, refers to a NRC converted into the active compound (the active parent drug) in (=O) NR"R", where R', R" and R" are each selected from vivo. Prodrugs are typically useful for facilitating the admin the group consisting of hydrogen, alkyl, cycloalkyl, heteroali istration of the parent drug. They may, for instance, be bio cyclic, aryl or heteroaryl, as these terms are defined herein. available by oral administration whereas the parent drug is 0120. The term “acyl, as used herein, refers to an R' not. A prodrug may also have improved solubility as com (C=O)—, where R' is as defined herein. pared with the parent drug in pharmaceutical compositions. 0121 Therefore, the phrase “acyl-urea containing', as Prodrugs are also often used to achieve a Sustained release of used herein, refers to a compound which includes an R the active compound in vivo. An example, without limitation, (C=O) NR"C(=O) NR"R" group, where R', R" and of a prodrug would be a compound of the present invention, R" are as defined herein, and R" is as defined for R'. having one or more carboxylic acid moieties, which is admin 0122) According to some embodiments of the present istered as an ester (the “prodrug'). Such a prodrug is hydro invention, each of R. R. and R is hydrogen. Alternatively, lyzed in vivo, to thereby provide the free compound (the one or more of R-R is an N-alkyl, which is a low alkyl parent drug). The selected ester may affect both the solubility having 1 to 4 carbon atoms. characteristics and the hydrolysis rate of the prodrug. 0123. According to other embodiments of the present I0131 The term “solvate” refers to a complex of variable invention, R is propyl. Stoichiometry (e.g., di-, tri-, tetra-, penta-, hexa-, and so on), 0124. In some embodiments, R. R. and R are each which is formed by a solute (the compound of the present hydrogen, and R is propyl, resulting in the compound 1-(2- invention) and a solvent, whereby the solvent does not inter isopropylpentanoyl)urea which is referred to hereinbelow as fere with the biological activity of the solute. Suitable sol Compound 1, as demonstrated in the Examples section that vents include, for example, ethanol, acetic acid and the like. follows. 0.132. The term “hydrate” refers to a solvate, as defined 0.125. The compound 1-(2-isopropylpentanoyl)urea hereinabove, where the solvent is water. (Compound 1, see Table 1 hereinbelow) has a chiral center at I0133. The phrase “pharmaceutically acceptable salt position 2, as denoted in Formula I. Hence, the present refers to a charged species of the parent compound and its US 2010/02801 24 A1 Nov. 4, 2010 counter ion, which is typically used to modify the solubility nounced anticonvulsant and anti-bipolar activities, namely characteristics of the parent compound and/or to reduce any the ability to reduce the effect of chemically and electrically significant irritation to an organism by the parent compound, induced seizures and bipolar behavior in rats and mice. Such while not abrogating the biological activity and properties of a therapeutic activity renders these compounds suitable for the administered compound. An example, without limitation, use as therapeutically active agents for the treatment of neu of a pharmaceutically acceptable salt would be a carboxylate rological diseases and disorders, and particularly conditions anion and a cation Such as, but not limited to, ammonium, which involve seizures and other involuntary convulsions and Sodium, potassium and the like. other mental conditions, as defined and discussed hereinbe 0134. According to the present embodiments, compounds low. according to general Formula I wherein R-R is hydrogen 0141 Based on the therapeutic activity exhibited by these and R is an alkyl having less than 3 carbon atoms (e.g., compounds, according to another aspect of the present inven methyl or ethyl), have been previously described and are tion there is provided a use of the acyl-urea containing com therefore excluded from the scope of this aspect of the present pounds, represented in the general Formulae II and III: invention. 0135. As discussed hereinabove, certain acyl-urea com pounds, among which is (2-ethyl-3-methyl-pentanoyl)-urea Formula II (VCU, Compound 4) have been prepared and studied as anti Rb O O convulsants for many decades 19 and some have also been 2 ls R3 used as drugs for use in human for treating anxiety and sleep disorders 22. However, VCU was studied and used as a --- R R R4 racemic mixture, and none of the previous disclosures refers Formula III to pure isolates of any particular stereoisomer thereof. As O O discussed hereinabove, other derivatives of valproic acid, and particularly diastereomers of 2-ethyl-3-methyl-pentanoic ls R3 acid amide, disclosed in U.S. Pat. No. 6,417.399, have been shown to exhibit stereoconfiguration-sensitive activity, or in A-1, R R4 other words, the Stereoconfiguration of these compounds have been shown to have significant impact on their activity, such that purified diastereoisomers have Superior activity 0.142 wherein: over that of the racemate. I0143 R-Ra, Ra and Rb are each independently hydrogen 0.136 Hence, according to another aspect of the present or an alkyl having from 1 to 10 carbon atoms, as well enan invention, there is provided a pure (isolated) Stereoisomer of tiomers, diastereomers, hydrates, Solvates or pharmaceuti (2-ethyl-3-methyl-pentanoyl)-urea. cally acceptable salts thereof, as defined hereinabove, in the 0.137 More specifically, the stereoisomer of (2-ethyl-3- preparation of a medicament. Alternatively, the medicament methyl-pentanoyl)-urea include (2S)-2-ethyl-(3S)-3-methyl is for treating a neurological disease or disorder. pentanoyl)-urea, (2S)-2-ethyl-(3R)-3-methyl-pentanoyl)- 0144. According to the present embodiments, compounds urea, (2R)-2-ethyl-(3S)-3-methyl-pentanoyl)-urea and (2R)- according to general Formula II and III wherein each of R-R- 2-ethyl-(3R)-3-methyl-pentanoyl)-urea. is hydrogen, Ra is methyl or ethyl, Rb is methyl and R is an 0.138. As discussed hereinabove, acyl-urea containing alkyl having less than 3 carbon atoms, have been previously compounds have been known and studied for decades, yet described in the context of Some particular neurological few have been considered as drug candidates, particularly for therapeutic uses, as presented hereinabove, and are therefore the treatment of neurological diseases or disorders, and none excluded from the scope of this aspect of the present invention were shown to possess the qualities which are necessary for a for those specific indications they were Suggested for. compound to be considered as a drug candidate. 0145 Accordingly, according to another aspect of the 0.139. As discussed hereinabove, the present inventors present invention, there is provided a method of treating a have envisioned that particular acyl-urea containing com neurological disease or disorder. The method is effected by pounds according to Some embodiments presented herein administering to a subject in need thereof a therapeutically would exhibit highly effective therapeutic activity as com effective amount of acyl-urea containing compounds as rep pared to valproic acid and other acyl-urea containing com resented in general Formulae II and III above. pounds, and hence these compounds were developed as, for 0146. As used herein, the terms “treating and “treatment' example, potential antiepileptic drugs. While reducing the includes abrogating, Substantially inhibiting, slowing or present invention to practice, as is demonstrated in the reversing the progression of a condition, Substantially ame Examples section that follows, it was indeed shown that liorating clinical or aesthetical symptoms of a condition or exemplary acyl-urea containing compounds as presented Substantially preventing the appearance of clinical or aes herein are highly effective therapeutic agents. In particular, it thetical symptoms of a condition. is shown in the Examples section that follows, that this family 0147 As used herein, the phrase “neurological disease or of compounds displays in vivo therapeutic activity levels disorder” refers to a genetic or acquired dysfunction in one of which are highly sensitive to Small and even minute structural the component of the brain and spinal cord, namely the cen changes in their structure, even at the level of the addition, tral nervous system (CNS), peripheral and cranial nerves removal and/or displacement of a single carbon atom in the (PNS), namely the peripheral nervous system or the auto acyl part of the molecule. nomic nervous system and the musculoskeletal system. These 0140. As demonstrated in the Examples section that fol diseases and disorders express themselves in a variety of lows the compounds presented herein were designed and behavioral symptoms, motorial symptoms, form disfigure selected so as to, and were indeed shown to, possess a pro ments (deformity, abnormality), neuropathic pain and cogni US 2010/02801 24 A1 Nov. 4, 2010 tive disturbances and other physiological symptoms. In the 0153. Examples of neurodegenerative diseases and disor context of the present invention, neurological diseases and ders include, without limitation, Alexander disease, Alper's disorders include psychiatric diseases and disorders and neu disease, Alzheimer's disease, Amyotrophic lateral Sclerosis, rodegenerative diseases and disorders. Ataxiatelangiectasia, Batten disease (also known as Spielm eyer-Vogt-Sjogren-Batten disease), Bovine Spongiform 0148. According to an exemplary embodiment of the encephalopathy (BSE), Canavan disease, Cockayne Syn present invention, the neurological disorder comprises sei drome, Corticobasal degeneration, Creutzfeldt-Jakob dis Zures, relating to any abnormal electrical discharge in the ease, Huntington disease, HIV-associated dementia, brain resulting in abnormal synchronization of electrical neu Kennedy's disease, Krabbe disease, Lewy body dementia, ronal activity. Seizures may be due to epilepsy and non epi Machado-Joseph disease (Spinocerebellar ataxia type 3), lepsy associated. Multiple sclerosis, Multiple System Atrophy (MSA), Parkin 0149 For example non epileptic seizures can be caused by son's disease, Pelizaeus-Merzbacher Disease, Pick's disease, chemical agents. As used herein, the phrase “chemically Primary lateral sclerosis, Refsum’s disease, Sandhoff dis induced convulsions and/or seizure disorder” refers to a sei ease, Schilder's disease, Schizophrenia, Spielmeyer-Vogt Zure caused by temporary or chronic exposure to an exogenic Sjogren-Batten disease (also known as Batten disease), Substance or chemical Such as, for example, a (such as, Spinocerebellar ataxia (multiple types with varying charac for example, toxin (tetanospasmin), botulin, tetrodot teristics), Spinal muscular atrophy, and Steele-Richardson oxin, , , , , Olszewski disease. , , , hefutoxin, , 0154 The neurological disease or disorder, according to and ), an alkaloid (such as ephedrine Some embodiments of the present invention, is selected from alkaloids, phenethylamines, amphetamines, tryptamines, the group consisting of epilepsy, convulsions, and seizure mescaline, psilocybin and pilocarpine), a , an and disorders, spasticity, skeletal muscle spasms, restless leg Syn an organophosphate (such as, for example, (GA), Sarin drome, anxiety, stress, multiple Sclerosis, stroke, head (GB), soman (GD), (GF), GV, VE, VG, VM, VX, trauma, spinal cord injury, (ALS), Parkinson's Disease, Hun Novichokagents, pulmonary agents, (PS), phos tington's Disease, Alzheimer's Disease, amyotrophic lateral gene (CG) and (DP)) and a drug (such as, for Sclerosis, neuropathic pain, myoclonus, Schizophrenia, example, aminophylline or local anaesthetics as well as anti migraine, headaches and bipolar disorders. According to depressants). Some embodiments of the present invention, the compounds 0150. Other seizures without epilepsy include but are not described herein are utilized for treating epilepsy. limited to those induced by fever leading to febrile convul 0155 According to other embodiments of the present sions, metabolic disturbances such as hypoglycemia invention, the compounds described herein are utilized for hyponatremia or hypoxia, Sustenance withdrawal (e.g., GHB treating epilepsy, other types of seizures, neuropathic pain and derivatives thereof, benzos, ethanol and baclofen), and a bipolar disorder. eclampsia, binaural beat brainwave entertainment. Others are 0156. As discussed hereinabove, (2-ethyl-3-methyl-pen listed hereinbelow. tanoyl)-urea, which is referred to herein as Compound 4 or 0151. Thus, examples of neurological diseases and disor VCU (see, Table 1 hereinbelow), has been previously ders include, without limitation, altered mental status, described as a minor tranquilizer and anti-anxiety agent, and encephalopathy, stupor and coma, fever (febrile convulsions), was further studied by Goldstein et al. 22 as an aid for sleep cerebral palsy, cerebrovascular disease Such as transient disorders. Hence, the use of (2-ethyl-3-methyl-pentanoyl)- ischemic attack and stroke, demyelinating diseases such as urea (Compound 4 or VCU, as a racemate) as a compound multiple sclerosis, Guillain-Barré syndrome and chronic which can be used to treat anxiety and sleep disorders is inflammatory demyelinating polyneuropathy (CIDP), epi excluded from the scope of the present embodiments. lepsy and seizure disorders, headache disorders such as 0157. Nonetheless, the advantageous use of purified ste migraine, cluster headache and tension headache, infections reoisomers of VCU, purified diastereoisomers in particular, of the brain (encephalitis), brain meninges (meningitis), Spi has never been suggested. nal cord (myelitis), movement disorders such as in Parkin 0158 Thus, according to another aspect of the present son's disease, Huntington's disease, hemibalismus, tic dis invention, there is provided a pharmaceutical composition order, and Gilles de la Tourette syndrome, CNS neoplasms packaged in a packaging material and identified in print, in or (brain tumors), spinal cord tumors, PNS tumors, sleep disor on the packaging material, for use in the treatment of a neu ders, speech and language disorders, spinal cord disorders rological disease or disorder, the composition includes at Such as tumors, infections, trauma, malformations (e.g., least one pure (isolated) stereoisomer of (2-ethyl-3-methyl myelocele, meningomyeloceletethered cord), traumatic inju pentanoyl)-urea as presented herein. ries to the brain, spinal cord and PNS, disorders of peripheral 0159. According to yet another aspect of the present nerves, muscle (myopathy) and neuromuscular junctions, invention there is provided a method of treating a medical deafferentation pain (also called phantom pain, anesthesia condition associated with a neurological disorder, the method dolorosa or denervation pain), various infections of the PNS is effected by administering to a subject in need thereof a Such as botulism. therapeutically effective amount of at least one pure (isolated) 0152 Examples of psychiatric diseases and disorders Stereoisomer of (2-ethyl-3-methyl-pentanoyl)-urea as pre include, without limitation, psychotic disorders or diseases sented herein. Such as Schizophrenia, anxiety disorders, dissociative disor 0160 According to still another aspect of the present ders, personality disorders, mood disorders such as depres invention there is provided a use of at least one pure (isolated) Sion, affective disorders including unipolar and bipolar dis Stereoisomer of (2-ethyl-3-methyl-pentanoyl)-urea, in the orders, boarder line disorders and mental diseases or manufacture of a medicament for the treatment of a neuro disorders. logical disease or disorder. US 2010/02801 24 A1 Nov. 4, 2010

0161. As used herein, the phrase “therapeutically effective 0173 Pharmaceutical compositions for use in accordance amount describes an amount of the compound being admin with the present invention thus may beformulated in conven istered which will relieve to some extent one or more of the tional manner using one or more pharmaceutically acceptable symptoms of the condition being treated. carriers comprising excipients and auxiliaries, which facili 0162. As demonstrated in the examples section that fol tate processing of the compounds into preparations which can lows, an exemplary therapeutically effective amount of the be used pharmaceutically. Proper formulation is dependent compounds presented herein ranges between about 0.1 mg/kg upon the route of administration chosen. The dosage may body and about 100 mg/kg body. Alternatively, the therapeu vary depending upon the dosage form employed and the route tically effective amount ranges from about 5 mg/kg body to of administration utilized. The exact formulation, route of about 70 mg/kg body, and according to other embodiments of administration and dosage can be chosen by the individual the present invention the therapeutically effective amount physician in view of the patient's condition (see e.g., Finglet ranges from about 10 mg/kg body to about 40 mg/kg body. al., 1975, in “The Pharmacological Basis of Therapeutics'. 0163 As used herein throughout the term “about refers to Ch. 1 p. 1). 10%. 0.174. The pharmaceutical composition may be formu 0164. In any of the methods and uses described herein, the lated for administration in either one or more of routes acyl-urea containing compounds of the present embodiments depending on whether local or systemic treatment or admin can be utilized either perse or as a part of a pharmaceutical istration is of choice, and on the area to be treated. Adminis composition that further comprises a pharmaceutically tration may be done orally, by inhalation, or parenterally, for acceptable carrier. example by intravenous drip or intraperitoneal, Subcutane 0.165. The compounds described hereinabove under For ous, intramuscular or intravenous injection, or topically (in mula I, as defined hereinabove, can be utilized either perse or cluding ophtalmically, vaginally, rectally, intranasally). form a part of a pharmaceutical composition, which further 0.175 Formulations for topical administration may comprises a pharmaceutically acceptable carrier. include but are not limited to lotions, ointments, gels, creams, 0166 Thus, according to another aspect of the present Suppositories, drops, liquids, sprays and powders. Conven invention, there is provided a pharmaceutical composition tional pharmaceutical carriers, aqueous, powder or oily bases, which comprises, as an active ingredient, any of the com thickeners and the like may be necessary or desirable. pounds described hereinabove under Formula I and a phar maceutically acceptable carrier. Some compounds according 0176 Compositions for oral administration include pow to this aspect of the present invention are Compound 1 and ders or granules, Suspensions or Solutions in water or non Compound 2, as presented in the Examples section that fol aqueous media, Sachets, pills, caplets, capsules or tablets. lows. Thickeners, diluents, flavorings, dispersing aids, emulsifiers 0167 Correspondingly, according to additional aspects of or binders may be desirable. the present invention, there is provided pharmaceutical com 0177. Formulations for parenteral administration may position, which comprises one or more compounds having include, but are not limited to, sterile solutions which may the general Formulae II and III, as defined hereinabove, and a also contain buffers, diluents and other suitable additives. pharmaceutically acceptable carrier. Slow release compositions are envisaged for treatment. 0168 Additionally, there is provided a pharmaceutical 0.178 The amount of a composition to be administered composition which comprises one or more of the pure (iso will, of course, be dependent on the subject being treated, the lated) Stereoisomer of (2-ethyl-3-methyl-pentanoyl)-urea as severity of the affliction, the manner of administration, the presented herein and a pharmaceutically acceptable carrier. judgment of the prescribing physician, etc. 0169. As used herein a “pharmaceutical composition' 0179. As mentioned hereinabove, the present inventors refers to a preparation of the compounds presented herein, have shown in vivo therapeutic activity in animal models for with other chemical components such as pharmaceutically Status Epilepticus (SE), other chemically-induced convul acceptable and Suitable carriers and excipients. The purpose sion and/or seizure disorders, fever related and other febrile of a pharmaceutical composition is to facilitate administra convulsion conditions, a metabolic disturbance and a Suste tion of a compound to an organism. nance withdrawal condition, as presented in the Examples 0170 Hereinafter, the term “pharmaceutically acceptable section that follows. Such a therapeutic activity renders these carrier” refers to a carrier or a diluent that does not cause compounds Suitable for use as therapeutically active agents significant irritation to an organism and does not abrogate the for the treatment of neurological diseases and disorders biological activity and properties of the administered com which involve chemically-induced seizures and other invol pound. Examples, without limitations, of carriers are: propy untary convulsions and other chronic conditions such as SE, lene glycol, Saline, emulsions and mixtures of organic Sol as defined and discussed herein. vents with water, as well as Solid (e.g., powdered) and 0180 Based on the therapeutic activity exhibited by these gaseous carriers. compounds, according to another aspect of the present inven 0171 Herein the term “excipient” refers to an inert sub tion there is provided a use of the acyl-urea containing com stance added to a pharmaceutical composition to further pounds, represented in the general Formulae II and III as facilitate administration of a compound. Examples, without presented hereinabove, as well enantiomers, diastereomers, limitation, of excipients include calcium carbonate, calcium hydrates, Solvates or pharmaceutically acceptable salts phosphate, various Sugars and types of starch, cellulose thereof, as defined hereinabove, in the preparation of a medi derivatives, gelatin, vegetable oils and polyethylene glycols. cament for the treatment of a neurological disease or disorder 0172 Techniques for formulation and administration of selected from the group consisting of status epilepticus (SE), drugs may be found in “Remington's Pharmaceutical Sci a chemically-induced convulsions and/or seizure disorder, a ences’ Mack Publishing Co., Easton, Pa., latest edition, febrile convulsion condition, a metabolic disturbance and a which is incorporated herein by reference. Sustenance withdrawal condition. US 2010/02801 24 A1 Nov. 4, 2010

0181. As demonstrated in the examples section that fol prepared, placed in an appropriate container, and labeled for lows, an exemplary therapeutically effective amount of the treatment of a neurological disease or disorder, as is detailed compounds presented herein ranges between about 0.1 mg/kg hereinabove. body and about 100 mg/kg body. According to some embodi 0187 Thus, according to an embodiment of the present ments, the therapeutically effective amount ranges from about 5 mg/kg body to about 70 mg/kg body, and according to invention, the pharmaceutical composition of the present other embodiments the therapeutically effective amount invention is being packaged in a packaging material and ranges from about 10 mg/kg body to about 40 mg/kg body. identified in print, in or on the packaging material, for use in 0182 An exemplary compound according to the present the treatment of a neurological disease or disorder, as is embodiments, namely (2-ethyl-3-methyl-pentanoyl)-urea defined hereinabove. (VCU. Compound 4), belonging to the family of compounds 0188 According to some embodiments of the present falling under Formula II, has been shown to have a protective invention, in any of the methods, uses and compositions pre effect against chemically-induced convulsions, as demon sented herein pertaining to the compounds falling under the strated in the Examples section that follows. Hence, accord general Formula II, Some compounds are those wherein each ing to Some embodiments of the present invention, the com of R-R is hydrogen, and other are compounds wherein each positions, methods or uses presented herein which are of R-Ra is hydrogen and Rb is methyl. directed at treating status epilepticus (SE), a chemically-in (0189 In one embodiment each of R-R is hydrogen, Rb is duced convulsions and/or seizure disorder, a febrile convul methyl, and each of Ra and R is ethyl, resulting in the com sion condition, a metabolic disturbance and a Sustenance pound 1-(2-ethyl-3-methylpentanoyl)urea which is referred withdrawal condition, utilize compounds having the general to hereinbelow as VCU or Compound 4, as discussed herein Formula II. above demonstrated in the Examples section that follows. 0183. According to some embodiments of the present 0190. Another one of the compounds wherein each of invention, each of R-R is hydrogen. Further according to R-R and Rb is hydrogen, Ra is propyl and R is ethyl, Some embodiments of the present invention, R is ethyl, and resulting in the compound 1-(2-ethylhexanoyl)urea which is according to other embodiments, Rb is ethyl and Ra is methyl referred to hereinbelow as Compound 5, as demonstrated in or Rb is methyl and Ra is ethyl. the Examples section that follows. 0184 Such compounds defined in the above embodiments 0191 Another compound wherein each of R-R and Rb is result in (2-ethyl-3-methyl-pentanoyl)-urea (VCU, Com hydrogen, Ra is ethyl and R propyl is, resulting in the com pound 4, see Table 1 hereinbelow) which possesses two chiral pound 1-(2-propylpentanoyl)urea which is referred to here CenterS. inbelow as Compound 6, as demonstrated in the Examples 0185. The advantageous use of a racemate of VCU or section that follows. purified stereoisomers of VCU, purified diastereoisomers in particular, against status epilepticus and/or other chemically 0.192 Another one of the compounds wherein each of induced seizures has never been Suggested. Thus, according R-R and R is hydrogen, and each of Ra and Rb is methyl, to Some embodiments of the present invention, the prepara resulting in the compound 1-(3-methylbutanoyl)urea which tions of a medicament, methods and/or compositions pre is referred to hereinbelow as Compound 7, as demonstrated in sented herein utilize a racemic mixture or a pure (isolated) the Examples section that follows. stereoisomer of (2-ethyl-3-methyl-pentanoyl)-urea wherein 0193 Another one of the compounds wherein each of the Stereo-configuration at positions 2 and/or 3 is selected R-R and Ra is hydrogen, and each of Rb and R is methyl, from the group consisting of an R-configuration, an S-con resulting in the compound 1-(3-methylbutanoyl)urea which figuration or a combination thereof. More specifically, the is referred to hereinbelow as Compound 8, as demonstrated in stereoisomer of (2-ethyl-3-methyl-pentanoyl)-urea include the Examples section that follows. ((2S)-2-ethyl-(3S)-3-methyl-pentanoyl)-urea, (2S)-2-ethyl 0194 Similarly, according to some embodiments of the (3R)-3-methyl-pentanoyl-urea, ((2R)-2-ethyl-(3S)-3-me present invention, in any of the methods, uses and composi thyl-pentanoyl-urea and ((2R)-2-ethyl-(3R)-3-methyl-pen tions presented herein pertaining to the compounds falling tanoyl-urea. under the general Formula III, R-R independently hydro 0186 Compositions of the present invention may, if gen. desired, be presented in a pack or dispenser device, such as an 0.195 According to further embodiments of the present FDA (the U.S. Food and Drug Administration) approved kit, invention, in any of the methods, uses and compositions pre which may contain one or more unit dosage forms containing sented herein, the compounds can be combined with other the active ingredient. The pack may, for example, comprise active ingredients which are commonly used to treat neuro metal or plastic foil. Such as, but not limited to ablister pack logical diseases and disorders. Examples include, without or a pressurized container (for inhalation). The pack or dis limitation, carbamazepine (Tegretol), clobazam (Frisium), penser device may be accompanied by instructions for admin clonazepam (Klonopin), diazepam (Valium), ethoSuximide istration. The pack or dispenser may also be accompanied by (Zarontin), felbamate (Felbatol), fosphenyloin (Cerebyx), a notice associated with the container in a form prescribed by flurazepam (Dalmane), gabapentin (Neurontin), lamotrigine a governmental agency regulating the manufacture, use or (Lamictal), levetiracetam (Keppra), lorazepam (Ativan), sale of pharmaceuticals, which notice is reflective of approval oXcarbazepine (Trileptal), mephenyloin (Mesantoin), phe by the agency of the form of the compositions for human or nobarbital (Luminal), phenyloin (Dilantin), pregabalin Veterinary administration. Such notice, for example, may be (Lyrica), paraldehyde (Paral), pentobarbital (Nembutal), of labeling approved by the U.S. Food and Drug Administra primidone (MySoline), Valproic acid (Depakene, ConVulex), tion for prescription drugs or of an approved product insert. Sodium valproate (Epilim), tiagabine (Gabitril), topiramate Compositions comprising a compound of the invention for (Topamax), Valproate semisodium (Depakote, Epival) and mulated in a compatible pharmaceutical carrier may also be vigabatrin (Sabril). US 2010/02801 24 A1 Nov. 4, 2010

0196. According to yet another aspect of the present 0208. The phrase “alkylating agent', as used herein, refers invention there is provided a process of preparing the novel to a chemical reagent which use thereof can place an alkyl, as compounds presented herein, falling under Formula I, the this is define herein, at a designated position on a given process is effected by: reactant compound. 0.197 reacting a compound having the general Formula 0209 Examples of known alkylating agents include, with IV: out limitation, an alkylsulfonate, an alkyleneimine, phos gene, alkyl tosylates Such as methyl tosylate, alkyl triflates Formula IV such as methyl triflate, alkyl halides such as methyl bromide O and methyl iodide, trimethyloxonium tetrafluoroborate, dialkyl Sulfate, alumoxanes, trialkylaluminum and tris(tri OH alkylyl)aluminum. 0210. According to further aspects of the present invention R there is provided a process of preparing isolated Stereoiso mers of (2-ethyl-3-methyl-pentanoyl)-urea (VCU), essen 0198 wherein R is hydrogen oran alkyl having from 1 to tially as described in the Example section that follows below. 10 carbon atoms, 0211. In essence, (2R)-ethyl-(3R)-methyl-valnoctic acid, 0199 with a compound having the general Formula V: (2S)-ethyl-(3S)-methyl-valnoctic acid, (2R)-ethyl-(3S)-me thyl-valnoctic acid and (2S)-ethyl-(3R)-methyl-valnoctic acid are prepared as described in U.S. Pat. No. 6,417.399, Formula V using the corresponding starting materials, L-isoleucine or D-isoleucine, and are thereafter reacted with thionylchloride to thereby obtain the acyl-chloride of each of the four diaste reomers, the acyl-chloride is thereafter reacted with urea to afford the enantiomerically pure (isolated) stereoisomers of (2-ethyl-3-methyl-pentanoyl)-urea. 0212. Additional objects, advantages, and novel features (0200 wherein R-R are each independently hydrogen or of the present invention will become apparent to one ordi an alkyl having from 1 to 10 carbon atoms, thereby obtaining narily skilled in the art upon examination of the following the compounds. examples, which are not intended to be limiting. Additionally, 0201 It is note that since there is an option to have com each of the various embodiments and aspects of the present pounds having the general Formula IV with at least one chiral invention as delineated hereinabove and as claimed in the center at position-2, the scope of the present embodiments claims section below finds experimental Support in the fol encompasses all stereoisomers of the compound having the lowing examples. general Formula IV, including isolated forms or any racemic mixtures thereof. EXAMPLES 0202 Excluded from the scope of this aspect of the present invention are compounds having the general Formula I, 0213 Reference is now made to the following examples, which result from reacting compounds having the general which together with the above descriptions; illustrate the Formula V wherein each of R-R is hydrogen, with com invention in a non limiting fashion. pounds having the general Formula IV wherein R is an alkyl having from 3 to 10 carbon atoms. Example 1 0203. According to some embodiments, compound hav ing the general Formula IV is converted into a reactive car boxylic derivative thereof. Alternatively the reactive carboxy Chemical Syntheses lic derivative is an acyl-halide. 0214. Materials and Methods: 0204 The phrase “reactive carboxylic derivative', as used 0215 Lithium diisopropylamine, n-butyl lithium, isova herein, refers to a derivative of a carboxylic acid or a carboxy leric acid, hexamethylphosphoramide, urea, 1-iodopropane, late group which more reactive than the parent carboxylic 2-iodopropane and t-butylacetylchloride were obtained from acid group. Such as, for example, a an acyl-halide an anhy Sigma-Aldrich Israel Ltd. dride, a carboxylic ester oran amide, which are more reactive 0216 Melting point was measured using Buchi 530 Cap than their corresponding carboxylic acid. illary melting point apparatus. 0205 The term “carboxylic acid', as used herein, refers to 0217 NMR measurements were performed using Varian an R' C(=O)—OH group, where R' is as defined herein. mercury series NMR 300 spectrometer. 0206. The term “carboxylate', as used herein, refers to an 0218. GC-MS measurements were performed using HP R' C(=O) OR" group, where R and R" are as defined 5890 series II GC equipped with a Hewlett-Packard ms herein. engine (HP5989A) single quadropole, MS spectrometer, 0207. According to some embodiments, the process is fur HP7673 auto-sampler, HP MS-DOS Chemistation and ther effected by obtaining the compound having general For HP-5MS capillary column (0.25 umx15 mx0.25 mm). mula IV by reacting isovaleric acid with an alkylating agent Elemental analysis was performed using a 2400-2 Perkin having the general Formula VI: Elmer C, H, N analyzer, and an acceptance threshold of +0.4 R—X Formula VI. of theoretical values. US 2010/02801 24 A1 Nov. 4, 2010 13

Preparation of N-(2-isopropyl-2-substituted-acetyl) organic solvent is evaporated under reduced pressure and the urea (Formula I) product is dissolved in ethyl acetate (100 ml) and washed three times with 10 ml of distilled water. The organic fraction General Procedure is dried over MgSO, filtered and evaporated under reduced 0219) pressure. The product is purified by crystallization using an ethyl acetate:petroleum ether mixture (1:3), typically afford ing white crystals at a typical yield of 85%. Formula I O O 0225. The general procedure for obtaining a compound having the general Formula I from 2-isopropyl-2-substituted 1. ls R 3 acetic acid is illustrated in Scheme 2 below. R R2 R4 Scheme 2 0220. A solution of lithium diisopropylamine (0.126 moles) in anhydrous THF (70 ml) is added to a dry flask and Thionylchloride -e- maintained under nitrogen atmosphere. After cooling the OH in dichloromethane mixture to -15°C., n-butyl lithium (0.126 moles) in hexane solution is added slowly to the reaction mixture. Isovaleric R acid (0.06 moles) is added dropwise while maintaining the 2-isopropyl-2-substituted temperature below 0°C. and the reaction mixture is stirred for acetic acid 15 minutes. Thereafter, hexamethylphosphoramide (HMPA, O 0.06 moles) is added rapidly and the reaction is completed by stirring at room temp for 30 minutes. l R4 0221) An alkyl halide (0.12 moles) is added rapidly at 0° s C. and the reaction is completed by Stirring for 1 hour at room R2 R3 temperature. C in acetonitrile at 80°C. 0222. The product is isolated by acidification to pH 1-2 R with ice-cold 10% HCl (150ml), followed by extractions with 2-isopropyl-2-substituted petroleum ether. The combined organic layers are washed acetylchloride three times with 10% HCl, water and brine, dried over sodium Sulfate and the Solvent is evaporated under reduced pressure O O after filtration to obtain the crude product at a typical yield of l R4 98%. 0223) The general procedure for obtaining 2-isopropyl-2- 1. R R2 R3 substituted-acetic acid is illustrated in Scheme 1 below. Formula I

Scheme 1 Preparation of N-(2-isopropyl-2-propyl-acetyl)urea Lithium diisopropylamide (LDA) -e- (Compound 1, PIU) in THF at -15° C. lu. OH Isovaleric acid 0226 OLi Hexamethylphosphoramide R-X

e- e Compound 1 (PIU) --- (HMPA) (alkylin THF halide) at 4So Oo C. O l 1.O R 2-isopropyl-2-substituted-acetic acid 0227 N-(2-Isopropyl-2-propyl-acetyl)urea (Compound 1) was prepared according to the general procedure presented hereinabove for obtaining compounds having the general 0224. An acyl halide of 2-isopropyl-2-substituted-acetic Formula I, using 1-iodopropane for an alkyl halide and urea. acid, namely 2-isopropyl-2-substituted-acetyl chloride, is obtained by using thionyl chloride (SOCl) according to Fur 0228 Pure 2-isopropyl-2-propyl-acetic acid was obtained niss et al. 24. 2-Isopropyl-2-substituted-acetyl chloride after distillation at a boiling point of 125° C. under reduced (0.03 moles) dissolved in dry acetonitrile (50 ml) is added pressure (30 mm Hg). slowly to a stirred and boiling Solution of urea or an urea 0229 Compound 1 was obtained at an overall yield of derivative (0.08 mole) in dry acetonitrile (150 ml) and the 71% as white crystals which exhibited a melting point of 213 reaction mixture is refluxed for two hours. Thereafter the C., the chemical structure thereof was confirmed by spectro US 2010/02801 24 A1 Nov. 4, 2010

scopic methods (NMR and GC-MS), and its purity was estab inabove for obtaining compounds having the general Formula lished by elemental analysis. I, using 2-iodopropane for an alkyl halide and urea. 0230 MS-EI, m/z.: 144, 129, 115,72, 61. 0238 Compound 2 was obtained at an overall yield of 0231. HNMR (300 MHz, DMSO-d): 0.78-0.88 (m,9H), 51% as white crystals which exhibited a melting point of 1.06-1.22 (m, 2H), 1.28-1.54 (m, 2H), 1.62-1.74 (m. 1H), 199-200°C., the chemical structure thereof was confirmed by 2.1-2.2 (m. 1H), 7.21 (s, 1H), 7.86 (s, 1H), 10.14 (s, 1H). spectroscopic methods (NMR and GC-MS), and its purity 0232 Elemental analysis (C, H, N): CHNO. established by elemental analysis. 0239. MS-EI: m/z =144, 129, 86, 69, 61. Preparation of optically active N-(2-isopropyl-2- 0240 "H NMR (300 MHz, CDC1 & TMS): 0.91-0.98 (t, propyl-acetyl)urea (R-PIU and S-PIU) J=0.02, 12H), 1.78-1.84 (t, J=0.02, 1H), 1.98-2.1 (m, 2H), 5.49 (s, 1H), 8.41 (s, 1H), 8.9 (s, 1H). 0233 0241 Elemental analysis (C, H, N): CHNO. Preparation of N-(t-butyl-acetyl)urea (Formula II) General Procedure 0242

Formula II O O /-, ls R 3 N R R4 R-PIU 0243 Urea or a urea derivative (0.045 moles) is dissolved in dry acetonitrile (40 ml) and refluxed for one hour, followed 0234. The optically active, or enantiomerically pure (R)- by the addition of tert-butylacetylchloride (0.018 moles, 2-isopropyl-2-propyl-acetic acid (R-PIA) and (S)-2-isopro Sigma-Aldrich Israel Ltd.) dissolved in acetonitrile (7 ml). pyl-2-propyl-acetic acid (S-PIA) were prepared according to The reaction mixture is stirred for additional two hours, the published procedures 25. Briefly, the enantioselective syn organic solvent is thereafter evaporated under reduced pres thesis of 2-isopropyl-2-propyl-acetic acid (PIA) enantiomers sure and the residue is dissolved in ethyl acetate (20 ml), was achieved by conversion of Valeric acid to acylchloride washed three times with distilled water, 1N NaOH solution followed by coupling of Valeroylchloride with optically pure and brine, and adjusted to a neutral pH. The organic fraction (4S)- and (4R)-benzyl-2-oxazolidinones chiral auxiliary in is dried over MgSO, filtered and evaporated under reduced order to prepare (4S)- and (4R)-3-(1'-oxopentyl)-4-benzyl-2- pressure. oxazolidinones respectively. The two oxazolidinone enolates were alkylated using isopropyltriflate to obtain (4S,2R)- and 0244. The product is purified by crystallization using an (4R,2S)-3-(2-isopropyl-1'-oxopentyl)-4-benzyl-2-oxazoli ethyl acetate:petroleum ether mixture (1:3), typically afford dinones respectively, which were further hydrolyzed using ing white crystals at a typical yield of 89%. lithium hydroperoxide to yield R-PIA and S-PIA enantiomers 0245. The general procedure for obtaining a compound respectively with optical purity (enantiomeric excess) above having the general Formula II from tert-butylacetylchloride is 99.4%. illustrated in Scheme 3 below. 0235. The successive conversions of R-PIA and S-PIA to the respective amides and urea derivatives were accom plished as described in the previous example for racemic PIU. Scheme 3 O Preparation of N-(2,2-Diisopropyl-acetyl)urea (Compound 2, DIU) HN - N1-, O 0236 R2 R3 in acetonitrile at 80°C. C Compound 2 (DIU) t-butylacetylchloride O O

NH2 ls R3 r R2 R4 Formula II 0237 N-(2,2-Diisopropyl-acetyl)urea (Compound 2) was prepared according to the general procedure presented here US 2010/02801 24 A1 Nov. 4, 2010 15

Preparation of N-(t-butyl acetyl)urea (Compound 3, method 24, and dissolved in dry acetonitrile (50 ml). The TBU) 2-ethyl-3-methyl-pentanoylchloride solution was slowly 0246 added to a boiling solution of urea (0.14 moles) in dry aceto nitrile (100 ml) and was allowed to reflux for 2 hours. There after the organic solvent was evaporated under reduced pres Compound 3 (TBU) sure and the product was dissolved in 100 ml ethyl acetate and washed three times with 20 ml of distilled water. The organic O l fraction was dried over MgSO, filtered and evaporated under reduced pressure. The product was purified by crystallization from ethyl acetate. 0247 N-(t-Butyl acetyl)urea (Compound 3) was prepared 0257 Compound 4 was obtained in an overall yield of according to the general procedure presented hereinabove for 61% as white crystals which exhibited a melting point of obtaining compounds having the general Formula II, using 147-148°C., the chemical structure thereof was confirmed by lea. spectroscopic methods (NMR and GC-MS), and its purity 0248 Compound 3 was obtained in an overall yield of established by elemental analysis. 51% as white crystals which exhibited a melting point of 174-175°C., the chemical structure thereof was confirmed by 0258 MS-EI, m/z.: 130, 115, 87, 72, 61. spectroscopic methods (NMR, GC-MS and IR), and its purity (0259 'H NMR (300 MHz, CDC1, 8 TMS): 0.86-0.96 (m, established by elemental analysis. 9H), 1.08-1.24 (m, 1H), 1.38-1.74 (m, 4H), 1.96-2.06 (m, 0249 MS-EI, m/z.: 143, 102, 83, 59, 1H), 5.35 (s, 1H), 8.37 (s, 1H), 8.7 (s, 1H) (0250 "H NMR (300 MHz, CDC1, STMS): 1,044 (s.9H), 0260 Elemental analysis (C, H, N): CHNO. 2.191 (s. 2H), 5.67 (s, 1H), 8.371 (s, 1H), 9.532 (s, 1H). 0251 Elemental analysis (C, H, N): C.H.N.O. Preparation of pure diastereomers of Preparation of 1-(2-ethyl-3-methyl-pentanoyl)-urea 1-(2-ethyl-3-methyl-pentanoyl)-urea (Compound 4, VCU) 0261 0252)

(2R, 3S)-VCU Compound 4 (VCU) O

NH2

(2R,3R)-VCU O

0253) A solution of 0.126 mole of lithiumdiisopropy NH2 lamine (LDA) prepared by dissolving diisopropylamine in dry tetrahydrofuran under nitrogen. Thereafter the mixture cooled to -20°C. and butyl lithium (Buli, 0.126 moles) was added slowly. After completing the addition of Buli, the reaction mixture was stirred at 0°C. for 30 minutes. 0254 The LDA solution was cooled again to -20° C. (2S,3S)-VCU followed by addition of 3-methylpentanoic acid (0.06 moles). After completing the addition of the carboxylic acid, the mixture was stirred for 15 minutes and a solution of HMPA (0.06 mole) was added rapidly to the reaction mixture and stirred for 5 minutes at 4° C. to form the corresponding enolate. 0255 Following the enolate formation, ethyliodide (0.12 moles) was added drop wise to the reaction mixture at 0°C. and stirred for 1 hour at room temperature. After the reaction (2S,3R)-VCU was completed, the reaction mixture was acidified to pH 1-2 using 10% HCl and the product was extracted three times O l with 300 ml of petroleum ether. The combined petroleum N NH2 ether fractions was washed with HCl (1N), water and brine, Et dried over sodium sulfate and filtered. The solvent evaporated under reduced pressure to yield pure branched carboxylic acids. 0262 The synthesis of pure diastereomers of VCU is 0256 2-Ethyl-3-methyl-pentanoylchloride (0.057 mol), executed substantially as described in U.S. Pat. No. 6,417. was prepared using thionylchloride according to a published 399, as illustrated in Schemes 4, 5 and 6 below.

US 2010/02801 24 A1 Nov. 4, 2010

0264 Scheme 5 presents the synthetic paths starting from 0269 2-Ethyl-hexanoylchloride (0.057 mol, Sigma-Ald (3S)-3-methyl Valeric acid and diverging into two of the pos rich Israel Ltd.), dissolved in dry acetonitrile (50 ml), was sible diastereomers of VCU, namely (2S)ethyl(3S)methyl slowly added to a dry, boiling solution of urea (0.14 mole) in and (2R)ethyl(3S)methyl forms. acetonitrile (100 ml) and allowed to reflux for 2 hours. There after the organic solvent was evaporated under reduced pres sure and the product was dissolved in ethyl acetate (100 ml) and washed three times with 20 ml of distilled water. The organic fraction was dried over MgSO4, filtered and evapo rated under reduced pressure. The product was purified by crystallization from ethyl acetate. 0270 Compound 5 was obtained in an overall yield of 61% as white crystals which exhibited a melting point of Et 158-159°C., the chemical structure thereof was confirmed by PS spectroscopic methods (NMR and GC-MS), and its purity 3-((2S)2-ethyl-(3S)3-methyl (2S)2-ethyl-(3S)3- pentanoyl)-(4S)4-phenyl methyl established by elemental analysis. oxazolidin-2-one pentanoic acid 0271 MS-EI, m/z.: 158, 130, 115, 87, 72, 61,57. (0272) H NMR (300 MHz, CDC1, 8 TMS): 0.848-0.929 (m, 6H), 1.209-1.69 (m, 8H), 2.133-2.209 (m. 1H), 5.543 (s, 1H), 8.392 (s, 1H), 9.255 (s, 1H). LiOH -e- 0273 Elemental analysis (C, H, N): CHNO. H2O2 Preparation of 1-(2-propyl-pentanoyl)-urea (Compound 6, VPU) (2R)2-ethyl-(3S)3- methyl 0274 pentanoic acid Compound 6 (VPU) 0265 Scheme 6 presents the parallel synthetic paths O l which afford two diastereomers of valnoctic acid, (2S)-ethyl N NH (3S)-methyl-valnoctic acid and (2R)-ethyl-(3S)-methyl-val noctic acid. 0266 (2R)-Ethyl-(3R)-methyl-valnoctic acid and (2S)- c 2 ethyl-(3R)-methyl-valnoctic acid are prepared in a similar process, using the corresponding starting materials, D-isoleu 0275 Valproyl chloride (0.057 mol), prepared by coupling cine, (4R)-benzyl-2-oxazolidinone and (4R,3R)-3-(3'-me of thionylchloride and valproic acid according to a published thyl-1'-oxopentyl)-4-benzyl-2-oxazolidinone. method 24), was dissolved in dry acetonitrile (50 ml), and the 0267. The acyl-chloride of each of the four diastereomers resulting Solution was slowly added to a boiling Solution of of valnoctic acid, namely (2S)-ethyl-(3S)-methyl-valnoctic urea (0.14 mole) in dry acetonitrile (100 ml) and allowed to acid, (2R)-ethyl-(3S)-methyl-valnoctic acid, (2R)-ethyl reflux for 2 hours. Thereafter the organic solvent was evapo (3R)-methyl-valnoctic acid and (2S)-ethyl-(3R)-methyl-val rated under reduced pressure and the product was dissolved in noctic acid (0.057 mol), are prepared by coupling of thionyl ethyl acetate (100 ml) and washed three times with 20 ml of chloride and the corresponding valnoctic acid diastereomer distilled water. The organic fraction was dried over MgSO, according to a published method 24. The valnoctyl-chloride filtered and evaporated under reduced pressure. The products is dissolved in dry acetonitrile (50 ml), and the resulting were purified by crystallization from ethyl acetate. solution is slowly added to a boiling solution of urea (0.14 mole) in dry acetonitrile (100 ml) and allowed to reflux for 2 0276 Compound 6 was obtained in an overall yield of hours. Thereafter the organic solvent is evaporated under 83% as white crystals which exhibited a melting point of reduced pressure and the product is dissolved in ethyl acetate 217-220°C., the chemical structure thereof was confirmed by (100 ml) and washed three times with 20 ml of distilled water. spectroscopic methods (NMR and GC-MS), and its purity The organic fraction is dried over MgSO4, filtered and evapo established by elemental analysis. rated under reduced pressure. The products are purified by (0277. MS-EI, m/z.: 144, 129, 115,72, 61. crystallization from ethyl acetate. (0278 H NMR (300 MHz, CDC1, 8 TMS): 0.86-0.94 (t, J=0.05, 6H), 1.2-1.74 (m,8H), 2.24-2.4 (m. 1H), 5.62 (s, 1H), Preparation of 1-(2-ethyl-hexanoyl)-urea (Compound 8.4 (s, 1H), 9.42 (s, 1H). 5, EBU) 0279 Elemental analysis (C, H, N): CHNO. 0268 Preparation of 3-methylbutanoylurea (Compound 7) 0280 Compound 5 (EBU) O O Compound 7 N ls NH H 2 lu. N l NH2 US 2010/02801 24 A1 Nov. 4, 2010

0281) Isovaleryl chloride (0.057 mol, Sigma-Aldrich 0293 Tert-butyryl chloride (0.057 mol, Sigma-Aldrich Israel Ltd.), dissolved in dry acetonitrile (50 ml), was slowly Israel Ltd.), dissolved in dry acetonitrile (50 ml), was slowly added to a boiling solution of urea (0.14 mole) in dry aceto added to a boiling solution of urea (0.14 mole) in dry aceto nitrile (100 ml) and allowed to reflux for 2 hours. Thereafter the organic solvent was evaporated under reduced pressure nitrile (100 ml) and allowed to reflux for 2 hours. Thereafter and the product was dissolved in ethyl acetate (100 ml) and the organic solvent was evaporated under reduced pressure washed three times with 20 ml of distilled water. The organic and the product was dissolved in ethyl acetate (100 ml) and fraction was dried over MgSO filtered and evaporated under washed three times with 20 ml of distilled water. The organic reduced pressure. The product was purified by crystallization fraction was dried over MgSO, filtered and evaporated under from ethyl acetate. reduced pressure. The products were purified by crystalliza 0282 Compound 7 was obtained at an overall yield of tion from ethyl acetate. 71% as white needles which exhibited a melting point of 0294 Compound 9 was obtained at an overall yield of 206-208°C., the chemical structure thereof was confirmed by spectroscopic methods (NMR and GC-MS), and its purity 75% as white needles which exhibited a melting point of established by elemental analysis. 148-149°C., the chemical structure thereof was confirmed by 0283 MS-EI, m/z.: 129, 102,85, 61, 59. spectroscopic methods (NMR and GC-MS), and its purity 0284 H NMR (300 MHz, CDC1, 8 TMS): 0.977-0.999 established by elemental analysis. (d. J=0.022, 6H), 2.09-2.209 (m,3H), 5.237 (s, 1H), 8.252 (s, 0295 MS-EI, m/z.: 144, 129, 89, 57. 1H), 8.392 (s, 1H). 0296) "H NMR (300 MHz, CDC1, 8 TMS): 1,246 (s.9H), 0285) Elemental analysis (C, H, N): C.H.N.O. 5.234 (s, 1H), 7.794 (s, 1H), 8.269 (s, 1H). Preparation of 2-methylbutanoylurea (Compound 8) 0297 Elemental analysis (C, H, N): CHNO. 0286 0298 Table 1 below summarizes the compounds that were synthesized according to the above procedures. Compound 8 TABLE 1 ---N NH Structure Chemical Name Abbreviation O O 1-(2- Compound 1 isopropyl- PIU (0287 2-Methylbutyryl chloride (0.057 mol, Sigma-Ald pentanoyl)urea rich Israel Ltd.), dissolved in dry acetonitrile (50 ml), was N NH2 slowly added to a boiling solution of urea (0.14 mole) in dry H acetonitrile (100 ml) and allowed to reflux for 2 hours. There after the organic solvent was evaporated under reduced pres sure and the product was dissolved in ethyl acetate (100 ml) and washed three times with 20 ml of distilled water. The O O R-1-(2- Compound 1R isopropyl- R-PIU organic fraction was dried over MgSO4, filtered and evapo pentanoyl)urea rated under reduced pressure. The products were purified by N NH2 crystallization from ethyl acetate. H 0288 Compound 8 was obtained at an overall yield of 68% as white needles which exhibited a melting point of 178-180°C., the chemical structure thereof was confirmed by S-1-(2- Compound 1S spectroscopic methods (NMR and GC-MS), and its purity isopropyl- S-PIU established by elemental analysis. pentanoyl)urea 0289 MS-EI, m/z.: 129, 116,73, 57, 61,57. 0290 "H NMR (300 MHz, CDC18 TMS): 0.905-0.954 (t, J=0.025, 3H), 1.165-1.188 (d. J=0.023,3H), 1.441-1.748 (m, N-1 2H), 2.269-2.339 (m. 1H), 5.391 (s, 1H), 8.33 (s, 1H), 8.959 (s, 1H). O O 1-(2-isopropyl-3- Compound 2 0291 Elemental analysis (C, H, N): CHNO. methyl- DIU Preparation of 2,2-dimethylpropanoylurea butanoyl)urea N NH2 (Compound 9) H 0292

Compound 9 1-(3,3-dimethyl- (Compound 3) O O butyryl)urea TBU

N ls NH H 2 US 2010/02801 24 A1 Nov. 4, 2010 19

limb extension. Animals not displayingtonic hind limb exten TABLE 1-continued sion were considered affected positively by the tested com pound. Structure Chemical Name Abbreviation 0302. Subcutaneous Metrazole Seizure Threshold Test 1-(2-ethyl-3- Compound 4 (ScMet) assay measures the ability of an agent to elevate methyl- VCU seizure threshold and is considered to model generalized pentanoyl)-urea absence seizures. The assay was performed by Subcutaneous injection of 85 mg/kg of the convulsant agent metrazole that induces clonic seizures in at least 97% of all animal models (rats and mice). 0303. In a third model, the compounds were tested for O O 1-(2-ethyl- Compound 5 their ability to block 6 Hz (32 mA) seizures following intra l hexanoyl)- EBU peritoneal administration thereof to male mice. This test is N NH 8 aimed at identifying new drug candidates for the treatment of H 2 therapy-resistant partial seizures. 0304 Briefly, psychomotor seizure (6-HZ) assay measures O O 1-(2-propyl- Compound 6 the resistance of a subject to induced psychomotor seizures. pentanoyl)- VPU The assay was conducted in mice which were pretreated with 8 N NH2 O the test compound. At varying times after treatment, indi H valproate urea vidual subjects were challenged with sufficient current of 32 mA at 6 Hz for 3 seconds, or 44 mA at 6 Hz for 3 seconds, delivered through corneal electrodes to elicit a psychomotor O O 3-methyl- Compound 7 seizure. Animals which were not affected by the current were butanoylurea considered affected positively by the tested compound, thus O compounds which were found active in this test are consid N NH2 isovaleroyl urea ered promising novel drug candidates for the treatment of therapy-resistant seizures. O O 2-methyl- Compound 8 0305 Compounds were also tested in two other models: ls butanoylurea the (BIC) and (PIC) assay and the N NH2 hippocampal kindling screening assay, as described herein H below. 0306 Thus, in a fourth model, Bicuculline (BIC) and O O 2.2- Compound 9 Picrotoxin (PIC) were used to further investigate the anticon dimethyl propanoylurea Vulsant activity of the compounds presented herein. Bicu N NH2 O culline is a competitive antagonist of GABAA receptors, and H 1-(pivaloyl)urea thus induces an effect that mimics epilepsy. It is therefore widely utilized in the in vitro study of epilepsy, generally in cortical neurons in prepared brain slices from rodents. Picro toxin, also known as cocculin, is a alkaloid which exhib Example 2 its a strong non-competitive antagonist activity of GABAA In-Vivo Studies receptors, and thus picrotoxin has a seizure simulative effect. Hence, BIC and PIC are chemoconvulsants that act by 0299 Anticonvulsant Activity Assays: antagonizing GABA receptors and blocking chloride chan 0300 Exemplary compounds according to the present nels respectively, thereby inducing clonic seizures. embodiments were tested for their ability to protect against (0307 Briefly, the Bicuculline (BIC) and Picrotoxin (PIC) chemically and electrically induced convulsions, in two mod assay was conducted by administering the agents Subcutane els of epilepsy in mice and rats. In the first model, the maxi ously at a dosage of 2.7 mg/kg for BIC and 3.15 mg/kg for PIC mal electroshock seizure test (MES) was used to show effi at the previously determined time to peak effect for the test cacy for antiepileptic agents against partial and generalized compound. Absence of a clonic seizure in the Subject indi seizure type epilepsy, the common epilepsy among therapy cated that the test compound has the ability to protect against resistant epileptic patients. In the second model, the Subcuta seizure threshold. neous metrazol test (ScMet) was used to measure seizure 0308. In a fifth model, the hippocampal kindling assay threshold and was used as a standard Screening procedure to 23, 26 was used to identify new drug candidates effective for show efficacy for agents against seizure threshold and the treatment of difficult-to-control seizure types and com absence seizures. The models and the biological activity pro plex partial seizures, as well as compounds that may be effec tocols followed in the examples presented herein have been tive as mood stabilizer for treating bipolar disorder 26, and described in the art 23. was conducted according to the protocol described therein. 0301 Briefly, Maximal Electroshock Seizure (MES) 0309 Briefly, this test was conducted by using a bipolar assay measures drug capacity to prevent seizure spread and is stimulating electrode which was implanted in the hippocam thus considered to model generalized tonic-clonic seizures. pus of rats, and the rats were kindled according to a described The assay was conducted using a Supra-maximal current of 50 method 27. One week after implantation of the electrodes, mA and 60 Hz for 0.2 seconds in mice, and 150 mA and 60Hz the rats were stimulated with supra-threshold trains of 200LA for 0.2 seconds in rats. The current was delivered to the and 50 Hz for 10 seconds every 30 minutes for 6 hours on Subjects by means of corneal electrodes to produce tonic hind alternate days until the animals were fully kindled. Animals US 2010/02801 24 A1 Nov. 4, 2010 20 were considered fully kindled when they displayed stable rent seizures. The characteristic of the seizure resembles stage 5 seizures. The behavioral seizures were scored accord human partial epilepsy. In rats, a behavior (akinesia, facial ing to the following criteria ('seizure score): stage automatisms, limbic seizures consisting of forelimb clonus 1—mouth and facial clonus; stage 2-stage 1 plus head nod with rearing, salivation, masticatory jaw movements, and ding; stage 3-stage 2 plus forelimb clonus; stage 4-stage 3 falling) and EEG changes (significant theta rhythm and iso plus rearing; and stage 5-stage 4 plus repeated rearing and lated spikes in hippocampus, Synchronization of the activity falling. in hippocampus and cortex, EEG seizures, status epilepticus) 0310. For these studies, each of the compounds was evalu can be observed and recorded. ated for its ability to block the kindled motor seizure (seizure 0315. The application of this model in rodents causes the scores 4 and 5) and limbic behavioral seizures (seizure score induction of both fetal arid interictal activity in hippocampal between 1 and 3). Additionally the new drug candidate was and cortical regions of the brain. Clinical manifestations evaluated for their ability to reduce after discharge duration. include ataxia, akinesia and facial automatisms where symp The term “after-discharge-duration' is the duration (mea toms quickly progress to full SE lasting up to twelve hours. Sured in seconds) of the stages defined above, which are This protective activity can be correlated closely with elec elicited by the electrical currents delivered to the rats. A trographic changes, depending of the level of protection promising drug candidate is one that can reduce the seizure observed in the initial qualitative screen a series of evalua score and the after-discharge-duration to a minimum, there tions using this chemoconvulsant may be employed to assess fore the more potent the drug is, the lower is the seizure score certain pharmacological characteristics of candidate com and the shorter the after-discharge-duration are after drug pounds. Specifically, the effects of systematic administration administration. of pilocarpine in rats promotes sequential behavioral and 0311. At least one week after the fully kindled state was electrographic changes that can be divided in three distinct reached, a dose of the test compound was administered intra periods: (a) an acute period that built up progressively into a peritoneally and its effect on behavioral seizure score and limbic status epilepticus and that lasts 24 hours, (b) a silent after-discharge-duration following 200 LA stimulation was period with a progressive normalization of EEG and behav assessed at various time intervals before drug administration iour which varies from 4 to 44 days, and (c) a chronic period and after drug administration. Animals not displaying stage 4 with spontaneous recurrent seizures (SRSs). The main fea or 5 were considered affected positively from seizure gener tures of the SRSs observed during the long-term period alization. resemble those of human complex partial seizures and recurs 0312 Status Epilepricus (SE) Protection Assays: 2-3 times per week per animal. Therefore, this experimental 0313 Exemplary compounds according to the present approach serves as a model of epilepsy mimicking the human embodiments were tested for their ability to protect against condition. chemically induced convulsions, using a model of epilepsy in 0316 Acute toxicity was determined by recording acute rats. The pilocarpine (see, chemical structure below) model of motor impairment after three doses of 30, 100 and 300 mg/kg epilepsy was used to measure seizure threshold and was used of the tested compounds. The compounds were administered as a standard Screening procedure to show efficacy of the by the intraperitoneal (i.p.) route to three groups of 4 Sprague compounds presented herein against Status Epilepricus (SE) Dawley rats. The behavior of the animals was observed seizures. The models and the biological activity protocols closely and recorded over a time period of two hours. followed in the examples presented herein have been 0317. The ability to prevent the development of SE was described in the art 28. This model shares many character determined by the administration of a minimally toxic dose of istics with nerve agent induced seizures since both initiation the tested compounds, given to male albino Sprague Dawley and early expression of nerve agent induced seizures are rats via the i.p. route of administration. Thereafter a challeng cholinergic followed by the recruitment of other neurotrans ing dose of pilocarpine (380 mg/kg) was administered after mitter systems that serve to reinforce recurring seizure activ 0.25, 0.5, 1, 2, and 4 hours of treatment with the tested ity progressing to Status Epilepricus. compounds. The results were used as an indication of the capacity to provide protection or lack thereof against chemi cally induced SE. The seizure severity was determined using Pilocarpine the Racine scale 29. 0318. The Racine scale was used to classify and quantify the effects according to the following stages: 0319 Stage 1—mouth and facial tonus: 0320 Stage 2 stage 1 plus head nodding: 0321 Stage 3 stage 2 plus fore limb clonus: 0322 Stage 4-stage 3 plus rearing; and 0323 Stage 5-stage 4 plus repeated rearing and falling. (3-ethyl-dihydro-4-(1-methyl-1H-imidazol-5-yl) 0324. This capacity of a test compound to arrest pilo methyl)furan-2(3H)-one) carpine-induced status was quantified by the dose of the tested compound which was calculated by Statistical tech 0314. The pilocarpine model is one of the most recognized niques to produce a characteristic effect in 97 percent of the animal models of SE. Briefly, the Pilocarpine Induced Epi Subjects to whom the dose was given (ED7). In addition, the lepsy model (PIE) consists of systemic administration of the 24 hours morbidity was also be determined after each test was cholinergic agent and muscarinic agonist pilocarpine which completed. induces spontaneous seizures in Subjects after a latency of 0325 Quantitative determination of the protective effects 14-15 days. Experiments presented in the art demonstrated was measured for compounds which had significant qualita that structural damage of the brain leads to spontaneous recur tive protection. These tests included calculations of the peak US 2010/02801 24 A1 Nov. 4, 2010

time-response as well as determination of the effective dose ence Compound 2 below) as well as for valproic acid, are (EDso) and the toxic dose (TDs). At least 10 potential doses brought herein for comparison. with a minimum of 8 rats per dose were utilized in these calculations. Confidence limits and standard errors were pro vided for each candidate undergoing quantitative assessment. Reference Compound 1 0326 Results of Anticonvulsant Activity Assays: 0327 Table 2 presents the experimental results of the tests conducted in the scMet and MES rat models, according to N NH2 which the median effective dose (EDs) of Compound 1 was evaluated: Reference Compound 2 TABLE 2

Fraction of rats which Dose responded to Test model (mg/kg) the treatment O ScMet 25 1.8 ScMet 40 2.8 ScMet 50 5.8 0334. In the rat-scMet model, Reference Compound 1 ScMet 1OO 8.8 exhibited an EDs of 92 mg/kg with a 95% confidence inter MES 6 Of8 val of 50-151 mg/kg (6), while Reference Compound 2 was MES 12 3.8 MES 25 6.8 inactive at a dose of 250 mg/kg (EDso higher than 250 mg/kg) MES 50 8.8 30, and valproic acid showed an EDso of 646 mg/kg with a 95% confidence interval of 466 to 869 mg/kg in the rat-scMet model 23. 0328. As can be seen in Table 2, Compound 1 clearly 0335) In the rat-MES model, Reference Compound 1 exhibited dose dependent anticonvulsant activity in rat-scMet exhibited an EDs of 29 mg/kg with a 95% confidence inter model. The EDs (median effective dose) in the scMet model val of 18 to 47 mg/kg (6), while Reference Compound 2 following oral administration to rats was 45 mg/kg with a exhibited an EDso of 73 mg/kg 30. Valproic acid was sig 95% confidence interval of 35 to 61 mg/kg. nificantly less active than the compounds presented herein, 0329. As can further be seen in Table 2, Compound 1 was exhibiting an EDs of 485 mg/kg with a 95% confidence also active in the rat-MES model, exhibiting an EDs of 16 interval of 324 to 677 mg/kg. 23. mg/kg with a 95% confidence interval of 11 to 23 mg/kg. 0336 Compound 3 was tested in the psychomotor 6 Hz 0330 Table 3 presents the experimental results of the tests model at 32 mA and exhibited significant activity with an conducted in the scMet and MES rat models, according to EDs of 80 mg/kg having a 95% confidence interval of 54.9- which the EDs of Compound 2 was evaluated: 103.7. 0337. In addition Compound 3 was evaluated quantita TABLE 3 tively in the hippocampal kindling screen-rats model and Fraction of exhibited high anticonvulsant activity with an EDs value of rats which 35 mg/kg having a 95% confidence interval of 22.8-52.5. Dose responded to 0338 Table 4 presents the experimental results of the tests Test model (mg/kg) the treatment conducted in the hippocampal Kindling screen-rats model, ScMet 6 1.8 according to which the anticonvulsant profile of Compound 3 ScMet 12 2.8 was evaluated. ScMet 25 6.8 ScMet 50 8.8 TABLE 4 MES 15 1.8 MES 30 5.8 Seizure Score MES 60 5.8 After Discharge Duration (see MES 120 8.8 Rat Before After Before After ID administration administration administration administration 0331. As can be seen in Table 3, Compound 2 demon 1 5 O 93-103 4 strated excellent efficacy and dose dependent anticonvulsant 2 5 O 28-75 14 activity in rat-scMet model, and exhibited an EDs of 16 mg/kg with a 95% confidence interval of 10 to 23 mg/kg. 0339. As can be seen in Table 4, 15 minutes after intrap 0332. As can further be seen in Table 3, Compound 2 also eritoneal drug administration, Compound 3 demonstrated demonstrated efficacy in the rat-MES model, exhibiting an complete reduction of the seizure score from 5 to 0 and EDs of 33 mg/kg with a 95% confidence interval of 18 to 51 significantly decreased the after discharge duration. mg/kg. 0340. The results also demonstrate that Compound 3 is a 0333 Results disclosed in the art, which were measured in promising candidate as an effective mood stabilizer, based on both the rat-scMet and the rat-MED models for the reference its excellent ability to completely prevent seizures and sig compounds N-(2,2,3,3-tetramethylcyclopropanecarbonyl) nificantly reduce “after discharge duration' in the hippocam urea (see, Reference Compound 1 below) and N-(2,2,3,3- pal kindling test, which a widely accepted animal model for tetramethylcyclopropyl carbonyl)glycinamide (see, Refer bipolar disorder 26. US 2010/02801 24 A1 Nov. 4, 2010 22

0341 Table 5 below presents the results obtained for Com 0347 Assays: pound 3 in the Bicucullin and Picrotoxin assay in mice, show 0348. The neurotoxicity of the compounds of the present ing the EDso values in mg/kg as measured in mice. embodiments was tested using rats which were treated by oral administration, and evaluated according to the 'gait and TABLE 5 stance' test, which assesses minimal neurotoxicity. The neu VPAEDso Compound 3 EDso rotoxicity assays were design to assess the effect of putative Assay (mg/kg) 31 (mg/kg) neurotoxicants on the normal activity of the nervous system, Bicucullin 589 2O4.6 which can adversely disrupt or cause neuronal death, and Picrotoxin 270 166.6 damage other parts of the nervous system. The median neu rological toxic dose (TDs) was used for quantization of 0342. It should be noted that the bicucullin and picrotoxin neurotoxicity. In some of the species the TDso was deter tests were performed in mice and not in rats, therefore no mined to be above a certain level, indicating a lower neuro comparison can be made between the MES and scMet EDso's toxicity than specified 23. evaluated in rats on the one hand and the bicucullin and picrotoxin EDso's determined in mice on the other hand. 0349 The protective index (PI), or margin of safety, is 0343. The bicucullin and picrotoxin tests measure the abil defined as the ratio of TDs and EDs (PI-TDs/EDs). The ity of new drugs to provide complete protection against clonic PI is used to show an effective differentiation between toxic threshold seizures induced by these two convulsant agents. ity and activity, whereas the larger the PI value, the safer and The convulsant agents were administered only after the mice more efficacious the antiepileptic drug is 23. received the tested compounds, and the mice were observed 0350 Results of Neurotoxicity Assays: for the presence or absence of a clonic seizure. Absence of clonic seizure is indicative of the ability of the tested com 0351. The protective index (PI) of exemplary acyl-urea pound to elevate the seizure threshold. derivative compounds, according to some embodiments of 0344 As can be seen in Table 5, Compound 3 exhibited the invention, namely Compounds 1, 2 and 3, was compared significant protective activity against clonic threshold sei to the protective index obtained for valproic acid, and the Zures, being 2.8 and 1.6 times more potent than Valproic acid results are presented in Table 7 herein below. in the bicucullin and picrotoxin test respectively. (0345 2-ethyl-3-methylvaleroylurea (Compound 4) was TABLE 7 also found to exhibit promising anticonvulsant activity and low toxicity, having EDso in the MES assay in rats of 24 Tested compound PI in the MES test PI in the ScMettest mg/kg, 14 mg/kg in the ScMet assay in rats, and TDso of 97 Valproic acid 1.6 1.2 Compound 1 6 2 mg/kg in rats. According to these results, Compound 4 exhib Compound 2 1.7 3.5 its a protective index (scMet) of 6.9 and a protective index Compound 3 2.2 5.5 (MES) of 4. This compound was first tested by Spielman et al. Compound 4 4 6.9 19 and was reported to be inactive in the MES assay and only active at toxic doses in the scMet assay. The results presented herein clearly show the efficacy in the MES and 0352. As can be seen in Table 7, a wide range of PI values ScMet assay at non toxic levels. was observed for the acyl-urea derivative compounds pre 0346 Table 6 below summarizes the results of all assays sented herein, all of which were higher than the PI observed conducted for Some of the exemplary compounds according for valproic acid. These results clearly demonstrate that a to the present embodiments. significant improvement interms of pharmacological efficacy

TABLE 6 EDso (mg/kg Hippocamp 6 Hz, 44 mA al TDso MES scMet in in 6 Hz, 32 mA kindling in (mg/kg) Compound in Rats Rats Mice in Mice Rats in Rats

Compound 1 16 45.4 71 42.2 94> 94.5 Compound 1R ND ND 56 43 ND ND Compound 1S ND ND 75 46 ND ND Compound 2 32.7 15.7 48.6 43.3 200 55.6 Compound 3 63.9 26 ND 8O 35.1 143 Compound 4 24 14 48 21 ND 97 Compound 5 ND ND ND ND ND ND Compound 6 53.8 76.8 1054 57.8 18O 232.2 Compound 7 >250 83 ND ND ND <500 Compound 8 ND ND ND ND ND ND Compound 9 69.4 29.8 ND ND ND 228.3 US 2010/02801 24 A1 Nov. 4, 2010

and safety is achieved with the acyl-urea derivative com 0362 Table 9 presents quantitative anticonvulsant data pounds presented herein as compared to valproic acid. obtained in rats which were treated i.p. with VCU. 0353. The TDs of Compounds 1 and 2 was 95 mg/kg and 56 mg/kg respectively following oral administration to rats. TABLE 9 For comparison, the TDs of Reference Compound 1 was determined at 538 mg/kg following oral administration to rats (ED50 Values) 6, VPA exhibits a TDs value of 784 mg/kg (23), and Ref erence Compound 2 exhibits a TDs above 500 mg/kg (30. TPE 0354. The results for other exemplary compounds accord (hours) Dose (mg/kg) 95% C.I. Slope S.E.M. ing to some embodiments are presented in Table 5 herein above. O 22.73 4.O2-33.17 3.82 1.64 0355 Particular attention is drawn to compounds such as Compounds 4, 5, 6, 7 and 8, which were tested for anti 0363 As can be seen in Table 9, the calculated EDso at convulsant activity by Spielman and co-workers and were time of peak effect (TPE), which equals time 0, is 22.73 found to lack beneficial activity, but were found quite active mg/kg. by the present inventors, as presented hereinabove. 0356 Altogether, the experimental results presented here 0364 Tables 10 and 11 present the response data pertain inabove clearly demonstrate that the acyl-urea derivative ing to the anticonvulsant profile of VCU 30 minutes after i.p. compounds presented herein and exemplified with Com administration of various doses (75, 112.5 and 150 mg/kg) to pounds 1, 2 and 3, have an unexpected potential as highly rats, and thus provide information regarding VCU's protec efficacious drugs for the treatment of epilepsy and other neu tion against pilocarpine-induced seizures. rological and psychiatric diseases and disorders. TABLE 10 0357 Results of Status Epilepricus (SE) Protection Assays: Duration after Average weight Dose first stage III change Prot, 0358. As detailed hereinabove, the animal model used (mg/kg) seizure (hours) (grams S.E.M.) tested Died Comment (i.e., pilocarpine) is characterized by a large number of spon 75 0.5 -14.2 it 1.3 48 2 Sedated taneous recurrent seizures as well as development of mossy 112.5 O.S -23.1 +3.2 6.8 O Sedated fiber sprouting. The model features both acute induced SE 150 O.S -21.4 + 2.4 6.8 1 Sedated and chronic spontaneous seizures. An important feature of the model is the occurrence of spontaneous seizures post admin istration of the chemoconvulsant. TABLE 11 0359 The tests were conducted using an exemplary com pound according to some embodiments of the present inven Duration after first Average weight tion, (a racemate of 2-ethyl-3-methyl-pentanoyl)-urea (VCU, Dose stage III seizure change Prot, Compound 4, Valnoctyl urea), which is an urea amide of (mg/kg) (hours) (grams it S.E.M.) tested Died Comment valnoctic acid having two chiral centers one in each of posi 75 O.S -14.2 + 1.3 4.8 2 Sedated tions 2 and 3 (see, Table 1 hereinabove). 112.5 O.S -23.1 +3.2 6.8 O Sedated 0360 Table 8 presents the results of the basic anticonvul 150 O.S -21.4 + 2.4 6.8 1 Sedated sant profile of VCU after i.p. administration to rats. 0365. As can be seen in Tables 10 and 11, at doses above TABLE 8 112.5 mg/kg, 6/8 animals were protected 30 minutes post Duration after drug administration. first stage III Average weight Dose seizure Prot, change 0366 Tables 12 and 13 present the response data pertain (mg/kg) (hours) Tested Died (grams it S.E.M.) Comments ing to the anticonvulsant profile of VCU after i.p. administra 18.75 O 3/7 O -7.9 6.5 tion to rats, and provide additional information about the 37.5 O 6.8 O +8.85.4 Sedated number of protected animals per tested animals at various 75 O 8.8 O +15.6+ 2.2 Sedated 37.5 O.25 9.15 O -13.3 + 3.4 VCU doses at time 0, 15 minutes and 30 hours after the 75 O.25 8.8 O -3.1 + 6.2 Sedated administration of the tested compounds according to some embodiments of the present invention.

0361. As can be seen on Table 8, at time of pilocarpine TABLE 12 administration (at a dose causing at least Stage III seizures, referred to herein as “Time 0) and immediately after admin Duration after Average weight istration of VCU, the number of protected animals per tested Dose first stage III change increased gradually with increasing dose until full protection (mg/kg) seizure (hours) Prot. Tested Died (grams it S.E.M.) 1OO O 8.8 O +9.4 + 1.1 was achieved at a dose of 75 mg/kg of VCU (see, Table 8 50 O 4.8 1 -36 6.5 below). As can further be seen in Table 8, full protection was 1OO O.25 1,8 O -17.5 - 2.5 achieved even 15 minutes post VCU administration of 75 mg/kg. US 2010/02801 24 A1 Nov. 4, 2010 24

Drugs, ed. R. H. M. R. H. Levy, B. S. Meldrum and E. TABLE 13 Perucca. 1995, Raven Press: New York. 589-603. 0374 4. Rettie, A. E., et al., Cytochrome P-450-catalyzed Duration after first Average weight Dose stage III seizure change formation of delta 4- VPA, a toxic metabolite of valproic (mg/kg) (hours) Prot. Tested Died (grams it S.E.M.) acid. Science, 1987. 235(4791): p. 890-3. 0375 5.de Paulis, T., ONO-2506. Ono. Curr Opin Investig 2OO 30 2.6 1 -18.0 + 1.6 Drugs, 2003. 4(7): p. 863-7. 0376 6. Sobol, E., M. Bialer, and B. Yagen, Tetramethyl 0367 Table 14 presents the toxicity profile of VCU as cyclopropyl analogue of a leading antiepileptic drug, val determined after its i.p. administration to rats. proic acid. Synthesis and evaluation of anticonvulsant activity of its amide derivatives. J Med Chem, 2004. TABLE 1.4 47(17): p. 43.16-26. 0377 7. Isoherranen, N., et al., Anticonvulsant profile and Time (hours teratogenicity of N-methyl-tetramethylcyclopropyl car boxamide: a new antiepileptic drug. Epilepsia, 2002. Dose (mg/kg) O.25 O.S 1 2 4 43(2): p. 115-26. 300 2.2 2.2 2.2 2.2 2.2 0378 8. Isoherranen, N., B. Yagen, and M. Bialer, New 100 O2 1.2 1.2 O2 O2 CNS-active drugs which are second-generation valproic acid can they lead to the development of a magic bullet? 0368. As can be concluded from the results presented Curr Opin Neurol, 2003. 16(2): p. 203-11. hereinabove, Compound 4 displayed a remarkable capacity to 0379 9. Isoherranen, N., et al., Metabolism of a new anti halt the progression of SE, at a behaviorally toxic dose, when epileptic drug, N-methyl-tetramethylcyclopropanecar administered immediately after the first appearance of a Stage boxamide, and anticonvulsant activity of its metabolites. III seizure. Compound 4 was also very effective when admin Epilepsy Res, 2004. 58(1): p. 1-12. istered 15 minutes after the first Stage III seizure (“Time 15'). 0380 10. Winkler, I., et al., Eficacy of antiepileptic tet Although less effective, it also decreased seizure activity 30 ramethylcyclopropyl analogues of valproic acid amides in minutes after the first Stage III seizure, an effect which a rat model of neuropathic pain. Neuropharmacology, appears to be dose dependent. 2005. 49(8): p. 1110-20. 0369. It is appreciated that certain features of the inven (0381) 11. Winkler, I., et al., Eficacy of antiepileptic iso tion, which are, for clarity, described in the context of separate mers of valproic acid and valpromide in a rat model of embodiments, may also be provided in combination in a neuropathic pain. Br J Pharmacol, 2005. 146(2): p. 198 single embodiment. Conversely, various features of the 2O8. invention, which are, for brevity, described in the context of a 0382 12. Shimshoni, J., Dalton, E. C. Jenkins, A., Eyal, single embodiment, may also be provided separately or in any S. Ewen, K., Williams, R. S. B. Yagen, B., Harwood, J.A., suitable subcombination. Bialer, M., Probing CNS-active analogues and amide 0370 Although the invention has been described in con derivatives of valproic acid for mood stabilizer properties. junction with specific embodiments thereof, it is evident that Neuropsychopharmacology, TBP. many alternatives, modifications and variations will be appar 0383 13. Shaltiel, G., et al., Valproate decreases inositol ent to those skilled in the art. Accordingly, it is intended to biosynthesis. Biol Psychiatry, 2004. 56(11): p.868-74. embrace all Such alternatives, modifications and variations 0384 14. Swinyard, E. A. and J. E. Toman. A comparison that fall within the spirit and broad scope of the appended of the anticonvulsant actions of some phenylhydantoins claims. All publications, patents and patent applications men and their corresponding phenylacetylureas. J Pharmacol tioned in this specification are herein incorporated in their Exp Ther, 1950. 100(2): p. 151-7. entirety by reference into the specification, to the same extent 0385 15. Moldenhauser, A., J. Chem. Soc., 1855. 102 as if each individual publication, patent or patent application (94). was specifically and individually indicated to be incorporated (0386 16. Dilthey, F.a., J. Chem. Soc., 1904.335: p. 366-7. herein by reference. In addition, citation or identification of (0387 17. Newberry, J. Chem. Soc., 1925(125): p. 295 any reference in this application shall not be construed as an 0388. 18. Stoughton, R. W., Diacylureas. II. Preparation admission that such reference is available as prior art to the and properties of diacylureas derived from branched ali present invention. phatic acids. J. Am. Chem. Soc., 1939. 61(2): p. 408-410. (0389 19. Spielman, M. A., Geiszler, A. O., Close, W.J., REFERENCES CITED BY NUMERALS Anticonvulsant Drugs. II. Some acetylureas. J. Am. Chem. Other References are Cited in the Text Soc., 1948.70: p. 4189-4191. 0390 20. Mrongovius, R. I., Structure-activity correla 0371 1. Nau, H., Valproic acid teratogenesis in mice after tions for central depressant Acylureas and alkylureas. Eur. various administration and phenobarbital-pretreatment J. Med. Chem., 1975. 10: p. 474-479. regimens. The parent drug and not one of the metabolites 0391) 21. Tantisira, B., et al., Preliminary evaluation of the assayed is implicated as teratogen. Fund. Appl. Toxicol., anticonvulsant activity of a valproic acid analog: N-(2- 1986. 6: p. 662-668 propylpentanoyl)urea. Res Commun Mol Pathol Pharma 0372 2. Baillie, T. A., Metabolism of valproate to hepa col, 1997.97(2): p. 151-64. totoxic intermediates. Pharm WeekblSci, 1992. 14(3A): p. 0392) 22. Goldstein, L. and C. C. Pfeiffer, Ouantitative 122-5. EEG analysis of single-dose effect relationships in normal 0373) 3. Baillie, T. A., Scheffels, P. R., ed. Valproic acid, volunteers of Pacinox (capuride), a new antianxiety drug. chemistry and biotransformation. 4 ed. Antiepileptic Biol Psychiatry, 1971.3(2): p. 165-72. US 2010/02801 24 A1 Nov. 4, 2010 25

0393 23. White, H. S., ed. General principles. Discovery 53. A pharmaceutical composition packaged in a packag and preclinical development of antiepileptic drugs. 5 ed. ing material and identified in print, in or on said packaging Antiepileptic drugs, ed. M. R. Levy R H, Meldrum B S. material, for use in the treatment of a neurological disease or Perucca E. 2002, Lippincott-Raven: Philadelphia. 36-48. disorder, the composition comprising a compound having a 0394. 24. Furniss, B. S. H., A.J.; Smith, P.W. G.; Tatchell, A. R., Vogel's Textbook of Practical Organic Chemistry, in general formula selected from the group consisting of For New York. 1989, Prentice Hall. p. 720-723. mula II and III: 0395. 25. Spiegelstein, O., et al., Enantioselective synthe sis and teratogenicity of propylisopropyl acetamide, a CNS-active chiral amide analogue of valproic acid. Chiral- Ri O O Formula II ity, 1999. 11 (8): p. 645-50. 0396 26. Weiss, S. R. and R. M. Post, Kindling: separate 2 ls - R3 . shared mechanisms in affective disorders and epilepsy. R1 3 1 NN N Neuropsychobiology, 1998. 38(3): p. 167-80. R l k 0397 27. Lothman, E. W., et al., Screening and charac- 2 terization of antiepileptic drugs with rapidly recurring hip- O O Formula III pocampal seizures in rats. Epilepsy Res, 1988. 2(6): p. 0398.367-79. 28. Cavalheiro, E. A., The pilocarpine model of \ul N ls N - R3 epilepsy. The Italian Journal of Neurological Sciences, l 1995. 16(1-2): p. 33-37. 2 R4 0399. 29. Racine, R. J., Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencepha- wherein: logr. Clin Neurophysiol. 1972. 32(3): p. 281-94. ?olo 3O. E R E. analysis and a stereo-configuration at position 2 is selected from the antiepileptic activity of tetra-methylcyclopropane ana- group consisting of an R-configuration, an S-configura logues of valpromide. Pharm Res, 1996. 13(2): p. 284-9. tion and a mixture thereof; 04.01 31. White, H. S., Woodhead, J. H., Wilcox, K. S., R-Ra, Ra and Rb are each independently hydrogen O a Stables, J. P. Kupferberg, H. J.; Wolf, H. H., Discovery and alkyl having from 1 to 10 carbon atoms, Preclinical Development of Antiepileptic Drugs, in Anti epileptic Drugs, R. H. Levy, Mattson, R. H., Meldrum, B. with the proviso that when each of R-R is hydrogen, and S., Perucca, E., Editor. 2002, Lippincott Williams & Ra is methyl or ethyl and Rb is methyl, R is an alkyl Wilkins: New York. p. 36-48. having from 3 to 10 carbon atoms. 1-45. (canceled) 54. The composition of claim 53, wherein said compound 46. A compound having the general Formula I: has said general Formula II. 55. The composition of claim 54, wherein each of R-R is hydrogen. Formula I Ri O O 56. The composition of claim 55, wherein R is propyl. 2 ls R3 57. The composition of claim 53, wherein said compound R1 3 is selected from the group consisting of R R2 R4 1-(2-isopropylpentanoyl)urea (Compound 1, PIU), having the formula: wherein: R-R are each independently hydrogen oran alkyl having O O from 1 to 10 carbon atoms; and ls Ra and Rb are each methyl, with the proviso that when each of R-R is hydrogen, R is N NH2: an alkyl having from 3 to 10 carbon atoms. 47. The compound of claim 46, wherein each of R-R is hydrogen. 48. The compound of claim 47, wherein R is propyl. R-1-(2-isopropylpentanoyl)urea (Compound 1 R, R-PIU), 49. The compound of claim 48, wherein a stereo-configu having the formula: ration at position2 is selected from the group consisting of an R-configuration, an S-configuration and a mixture thereof. 50. The compound of claim 46, wherein R is isopropyl. O O 51. A pharmaceutical composition comprising, as an active l ingredient, the compound of claim 1 and a pharmaceutically acceptable carrier. N NH2: 52. The pharmaceutical composition of claim 51, being packaged in a packaging material and identified in print, in or on said packaging material, for use in the treatment of a neurological disease or disorder. US 2010/02801 24 A1 Nov. 4, 2010 26

S-1-(2-isopropylpentanoyl)urea (Compound 1S, S-PIU), and having the formula: 2,2-dimethylpropanoylureaor 1-(pivaloyl)urea (Com pound 9), having the formula:

O ls O O NH2: N ls NH. H 2

58. A method of treating a medical condition associated 1-(2-isopropyl-3-methylbutanoyl)urea (Compound 2. with a neurological disorder, the method comprising admin istering to a subject in need thereofatherapeutically effective DIU), having the formula: amount of a compound having a general formula selected from the group consisting of Formula II and III: O O Formula II s Rb O O 2. 2 --> ls R3 R R2 R4 1-(3.3-dimethyl-butyryl)urea (Compound 3, TBU), having Formula III O O the formula: A-1, ls R3 O l R2 R4 N NH2: 4- 2 wherein: a stereo-configuration at position 2 is selected from the group consisting of an R-configuration, an S-configura 1-(2-ethyl-hexanoyl)-urea (Compound 5, EBU), having tion and a mixture thereof; the formula: R-Ra, Ra and Rb are each independently hydrogen or an alkyl having from 1 to 10 carbon atoms, with the proviso that when each of R-R is hydrogen, Ra is methyl or ethyl and Rb is methyl, R is an alkyl having from 3 to 10 carbon atoms. O l 59. The method of claim 58, wherein said compound has N NH2: said general Formula II. 60. The method of claim 59, wherein each of R-R is hydrogen. r's 2 61. The method of claim 60, wherein R is propyl. 62. The method of claim 58, wherein said compound is selected from the group consisting of: 1-(2-propyl-pentanoyl)-ureaorvalproate urea (Compound 1-(2-isopropylpentanoyl)urea (Compound 1, PIU), having 6, VPU), having the formula: the formula:

O l O l c N NH2:2 sN NH2:2 2-methylbutanoylurea (Compound 8), having the formula: R-1-(2-isopropylpentanoyl)urea (Compound 1 R, R-PIU), having the formula: O l N NH2: O l ... sN NH2:2 US 2010/02801 24 A1 Nov. 4, 2010 27

S-1-(2-isopropylpentanoyl)urea (Compound 1S, S-PIU), and having the formula: 2,2-dimethylpropanoylureaor 1-(pivaloyl)urea (Com pound 9), having the formula:

O O O ls NH2: N ls NH. H 2

1-(2-isopropyl-3-methylbutanoyl)urea (Compound 2. 63. The method of claim 58, wherein said neurological DIU), having the formula: disorder is selected from the group consisting of epilepsy, complex partial seizures, neuropathic pain and bipolar disor der. 64. A pharmaceutical composition packaged in a packag O l ing material and identified in print, in or on said packaging N NH2: material, for use in the treatment of a neurological disease or disorder selected from the group consisting of status epilep 2. 2 ticus, a chemically-induced convulsion and/or seizure disor der, a febrile convulsion condition, a metabolic disturbance 1-(3.3-dimethyl-butyryl)urea (Compound 3, TBU), having and a Sustenance withdrawal condition, the composition com the formula: prising a compound having a general formula selected from the group consisting of Formula II and III:

Formula II O l Rb O O 4- N NH2:2 1-(2-ethyl-hexanoyl)-urea (Compound 5, EBU), having --- R R2 R4 the formula: Formula III O O ls R3 O l /-, N NH2: R2 R4

r's 2 wherein: a stereo-configuration at position 2 is selected from the 1-(2-propyl-pentanoyl)-ureaorvalproate urea (Compound group consisting of an R-configuration, an S-configura 6, VPU), having the formula: tion and a mixture thereof; R-Ra, Ra and Rb are each independently hydrogen or an alkyl having from 1 to 10 carbon atoms. 65. The composition of claim 64, wherein said compound O l has said general Formula II. N NH2: 66. The composition of claim 65, wherein each of R-R is c's 2 hydrogen. 67. The composition of claim 66, wherein R is ethyl. 68. The composition of claim 67, wherein Rb is ethyl and 2-methylbutanoylurea (Compound 8), having the formula: Ra is methyl or Rb is methyl and Ra is ethyl. 69. A method of treating a neurological disease or disorder O O selected from the group consisting of status epilepticus, a chemically-induced convulsion and/or seizure disorder, a febrile convulsion condition, a metabolic disturbance and a s Sustenance withdrawal condition, the method comprising l, 2 administering to a subject in need thereof a therapeutically effective amount of a compound having a general formula selected from the group consisting of Formula II and III: US 2010/02801 24 A1 Nov. 4, 2010 28

77. A pharmaceutical composition packaged in a packag ing material and identified in print, in or on said packaging Formula II material, for use in the treatment of a neurological disease or Rb O O disorder, the composition comprising the pure stereoisomer of (2-ethyl-3-methyl-pentanoyl)-urea of claim 76. 78. A method of treating a medical condition associated R R2 R4 with a neurological disorder, the method comprising admin Formula III istering to a subject in need thereofatherapeutically effective O O amount of the pure stereoisomer of (2-ethyl-3-methyl-pen tanoyl)-urea of claim 76. ls R3 79. A pharmaceutical composition packaged in a packag /-, ing material and identified in print, in or on said packaging R2 R4 material, for use in the treatment of a neurological disease or disorder selected from the group consisting of epilepsy, con Vulsions, seizure disorder, complex partial seizures, status wherein: epilepticus, a chemically-induced convulsion and/or seizure a stereo-configuration at position 2 is selected from the disorder, a febrile convulsion condition, a metabolic distur group consisting of an R-configuration, an S-configura bance, a Sustenance withdrawal condition, spasticity, skeletal tion and a mixture thereof; muscle spasms, restless leg syndrome, multiple Sclerosis, R-Ra, Ra and Rb are each independently hydrogen or an stroke, head trauma, spinal cord injury, amytrophic lateral alkyl having from 1 to 10 carbon atoms. sclerosis (ALS), Parkinson's Disease, Huntington's Disease, 70. The method of claim 69, wherein said compound has Alzheimer's Disease, amyotrophic lateral sclerosis, neuro said general Formula II. pathic pain, deafferentation pain, myoclonus, Schizophrenia 71. The method of claim 70, wherein each of R-R is migraine, headaches and a bipolar disorder, the composition hydrogen. comprising a compound having a general formula selected 72. The method of claim 71, wherein R is ethyl. from the group consisting of Formula II and III: 73. The method of claim 72, wherein Rb is ethyl and Ra is methyl or Rb is methyl and Ra is ethyl. 74. A process of preparing the compound of claim 1, the Formula II process comprising: Rb O O reacting a compound having the general Formula IV: --> 2 ls R3 Formula IV R R2 R4 Formula III O O OH \ul ls R 3 R R R4 wherein R is hydrogen or an alkyl having from 1 to 10 carbon atoms, wherein: with a compound having the general Formula V: a stereo-configuration at position 2 is selected from the group consisting of an R-configuration, an S-configura tion and a mixture thereof; Formula V R-Ra, Ra and Rb are each independently hydrogen or an O alkyl having from 1 to 10 carbon atoms: with the provisos that: l R4 when each of R-R is hydrogen and each of Ra and Rb is ins methyl, R is an alkyl having from 3 to 10 carbonatoms; R R3 and when each of R-R is hydrogen, Ra is ethyl and Rb is wherein R-R are each independently hydrogen or an methyl, R is an alkyl having from 2 to 10 carbonatoms. alkyl having from 1 to 10 carbon atoms, 80. The composition of claim 79, wherein said compound with the proviso that when each of R-Ra is hydrogen, R is has said general Formula II. an alkyl having from 3 to 10 carbon atoms, 81. The composition of claim 80, wherein each of R-R is thereby obtaining the compound of claim 1. hydrogen. 75. A pure stereoisomer of (2-ethyl-3-methyl-pentanoyl)- 82. The composition of claim 81, wherein R is propyl. lea. 83. A method of treating a neurological disease or disorder 76. The stereoisomer of claim 75, selected from the group selected from the group consisting of epilepsy, convulsions, consisting of ((2S)-2-ethyl-(3S)-3-methyl-pentanoyl)-urea, seizure disorder, complex partial seizures, status epilepticus, ((2S)-2-ethyl-(3R)-3-methyl-pentanoyl)-urea, ((2R)-2- a chemically-induced convulsion and/or seizure disorder, a ethyl-(3S)-3-methyl-pentanoyl)-urea and ((2R)-2-ethyl febrile convulsion condition, a metabolic disturbance, a Sus (3R)-3-methyl-pentanoyl)-urea. tenance withdrawal condition, spasticity, skeletal muscle US 2010/02801 24 A1 Nov. 4, 2010 29 spasms, restless leg syndrome, multiple Sclerosis, stroke, S-1-(2-isopropylpentanoyl)urea (Compound 1S, S-PIU), head trauma, spinal cord injury, amytrophic lateral Sclerosis having the formula: (ALS), Parkinson's Disease, Huntington's Disease, Alzhe imer's Disease, amyotrophic lateral sclerosis, neuropathic pain, deafferentation pain, myoclonus, Schizophrenia migraine, headaches and a bipolar disorder, the method com prising administering to a subject in need thereofatherapeu tically effective amount of a compound having a general . formula selected from the group consisting of Formula II and III:

Formula II 1-(2-isopropyl-3-methylbutanoyl)urea (Compound 2. Rb O O DIU), having the formula: R Ra1 21 3 O O R R R4 ls Formula III N NH2: O O H

R

A-1,R R4 3 1-(3.3-dimethyl-butyryl)urea (Compound 3, TBU), having the formula: wherein: a stereo-configuration at position 2 is selected from the O O group consisting of an R-configuration, an S-configura tion and a mixture thereof; ls R-Ra, Ra and Rb are each independently hydrogen or an N NH2: alkyl having from 1 to 10 carbon atoms: with the provisos that: when each of R-R is hydrogen and each of Ra and Rb is 1-(2-ethyl-3-methyl-pentanoyl)-urea (Compound 4. methyl, R is an alkyl having from 3 to 10 carbonatoms; VCU), having the formula: and when each of R-R is hydrogen, Ra is ethyl and Rb is methyl, R is an alkyl having from 2 to 10 carbon atoms. 84. The method of claim 83, wherein said compound has said general Formula II. 85. The method of claim 84, wherein each of R-R is hydrogen. 86. The method of claim 85, wherein R is propyl. 87. The method o of claim 83, wherein said compound is selected from the group consisting of: 1-(2-isopropylpentanoyl)urea (Compound 1, PIU), having 1-(2-ethyl-hexanoyl)-urea (Compound 5, EBU), having the formula: the formula:

O O O l N ls NH2: r N NH2:

R-1-(2-isopropylpentanoyl)urea (Compound 1R, R-PIU), 1-(2-propyl-pentanoyl)-ureaorvalproate urea (Compound having the formula: 6, VPU), having the formula:

O l O l N NH2: N NH2: H H US 2010/02801 24 A1 Nov. 4, 2010 30

2-methylbutanoylurea (Compound 8), having the formula: and 2,2-dimethylpropanoylureaor 1-(pivaloyl)urea (Com pound 9), having the formula: ls