EA044839B1 - METHODS AND COMPOSITIONS FOR IMPROVING COGNITIVE FUNCTION - Google Patents

Description

This application claims priority and benefit to U.S. Provisional Patent Applications 61/105847 (October 16, 2008), 61/152631 (February 13, 2009), and 61/175536 (May 5, 2009). The contents and disclosures of each of these prior applications are incorporated herein by reference in their entirety.

Field of invention

This invention relates to methods and compositions for the treatment of age-related cognitive disorder. In particular, the invention relates to the use of synaptic vesicle glycoprotein 2A (SV2A) inhibitors for the treatment of age-related cognitive disorder in a subject in need of such treatment or at risk of developing such disorder, including but not limited to subjects having or at risk of developing such a disorder. occurrence of mild cognitive impairment (MCI), age-related memory impairment (AAMI) or age-related cognitive decline (ARCD).

BACKGROUND OF THE INVENTION

Cognitive ability may decline, a common consequence of aging. In addition, a significant proportion of older adults experience cognitive decline that exceeds the decline typical of normal aging.

This age-related loss of cognitive function is characterized by clinically progressive loss of memory, cognition, judgment, and decision-making. Disorders associated with this age-related loss of cognitive function include mild cognitive impairment (MCI), age-related memory impairment (AAMI), age-related cognitive decline (ARCD), or similar clinical groups. It is estimated that there are over 16 million people with AAMI in the US alone (Barker et al., 1995), and MCI is estimated to affect 5.5-7 million people in the US over 65 years of age (Plassman et al., 2008) . Therefore, there is a need to effectively treat age-related cognitive impairment and improve cognitive function in patients diagnosed with or at risk of developing MCI, AAMI, ARCD, and similar age-related cognitive disorders.

Summary of the invention

According to a first aspect of the present invention, there is provided a method of treating age-related cognitive disorder in a subject in need of such treatment or at risk of developing such a disorder, said method comprising the step of administering to said subject a therapeutically effective amount of a synaptic vesicle protein 2A (SV2A) inhibitor or a pharmaceutically acceptable amount thereof. salt. In some versions of the SV2A-Inger invention, it was selected from the SV2A-Ingitors group specified in the international patent applications Wo 2001/062726, Wo 2002/094787, Wo 2004/087658, US Patent No. 7244747, International Patent Application Wo 2007/065595, US Patent's patent application 2008/0081832, international patent applications WO 2006/128692, WO 2006/128693, UK patents No. 1039113 and 1309692. In some embodiments of the invention, the SV2A inhibitor is selected from the group consisting of levetiracetam, 140 and seletracetam, or pharmaceutically acceptable salts thereof. In some embodiments, the SV2A inhibitor or a pharmaceutically acceptable salt thereof is administered every 12 or 24 hours at a dose of about 0.1 to 5 mg/kg, or about 1 to 2 mg/kg, or about 0.1 to 0. 2 mg/kg, or about 0.01 to 2.5 mg/kg, or about 0.1 to 2.5 mg/kg, or about 0.4 to 2.5 mg/kg, or about 0.6 -1.8 mg/kg, or about 0.04-2.5 mg/kg, or about 0.06-1.8 mg/kg.

According to a second aspect of the present invention, there is provided a method of treating age-related cognitive disorder in a subject in need of such treatment or at risk of developing such a disorder, said method comprising the step of administering to said subject an SV2A inhibitor or a pharmaceutically acceptable salt thereof in combination with valproate or an analogue thereof. , or a derivative, or a pharmaceutically acceptable salt. In some embodiments, valproate is administered at a daily dosage that maintains the patient's total plasma valproate level of 0.5 to 5 μg/mL, and the SV2A inhibitor is administered at a daily dosage of 0.01 to 1 mg/kg. In some embodiments, valproate is administered at a daily dose that maintains a total plasma valproate level of 0.5 to 5 μg/ml, and the SV2A inhibitor is administered at a daily dose of 0.001 to 1 mg/kg. In some embodiments, the SV2A inhibitor is selected from the group of SV2A inhibitors specified in international patent applications WO 2001/062726, WO 2002/094787, WO 2004/087658, US patent No. 7244747, international patent application WO 2007/065595, US patent application 2008/0081832, international patent applications WO 2006/128692, WO 2006/128693, UK patents No. 1039113 and 1309692. In some embodiments of the invention, the SV2A inhibitor is selected from the group consisting of levetiracetam, brivaracetam and seletracetam or pharmaceutically acceptable salts thereof . In some embodiments, the SV2A inhibitor or a pharmaceutically acceptable salt thereof and valproate or an analogue, derivative or pharmaceutically acceptable salt thereof are administered simultaneously, sequentially or as a single formulation.

According to a third aspect of the present invention, a pharmaceutical composition is provided for improving cognitive function in a subject with or at risk of age-related cognitive impairment.

- 1 044839 occurrence, the composition comprising SV2A-uHru6umop or a pharmaceutically acceptable salt thereof. In some embodiments, the SV2A inhibitor is present in an amount of 5-140 mg. In other embodiments, the SV2A inhibitor is present in an amount of 0.7-180 mg.

According to a fourth aspect of the present invention, there is provided a pharmaceutical composition for improving cognitive function in a subject with or at risk of age-related cognitive impairment, the composition comprising an SV2A inhibitor or a pharmaceutically acceptable salt thereof and valproate or an analogue, derivative or pharmaceutically acceptable salt thereof. In some embodiments, the SV2 inhibitor is present in an amount of 3-50 mg. In other embodiments, the SV2 inhibitor is present in an amount of 0.07-50 mg.

According to a fifth aspect of the present invention, there is provided a method of treating age-related cognitive disorder in a subject in need of such treatment or at risk of developing such a disorder, said method comprising the step of administering to said subject a therapeutically effective amount of levetiracetam or a pharmaceutically acceptable salt thereof. In some embodiments, levetiracetam or a pharmaceutically acceptable salt thereof is administered every 12 or 24 hours at a daily dose of about 1-2 mg/kg. In some embodiments, levetiracetam or a pharmaceutically acceptable salt thereof is administered every 12 or 24 hours at a daily dose of about 70-150 mg. In some embodiments, levetiracetam or a pharmaceutically acceptable salt thereof is administered every 12 or 24 hours at a daily dose of about 0.1 to 2.5 mg/kg. In some embodiments, levetiracetam or a pharmaceutically acceptable salt thereof is administered every 12 or 24 hours at a daily dose of about 7-180 mg. In some embodiments, levetiracetam or a pharmaceutically acceptable salt thereof is administered every 12 or 24 hours at a daily dose of about 0.42.5 mg/kg. In some embodiments, levetiracetam or a pharmaceutically acceptable salt thereof is administered every 12 or 24 hours at a daily dose of about 25-180 mg. In some embodiments, levetiracetam or a pharmaceutically acceptable salt thereof is administered every 12 or 24 hours at a daily dose of about 0.6-1.8 mg/kg. In some embodiments, levetiracetam or a pharmaceutically acceptable salt thereof is administered every 12 or 24 hours at a daily dose of about 40-130 mg.

According to a sixth aspect of the present invention, there is provided a method of treating age-related cognitive disorder in a subject in need of such treatment or at risk of developing such a disorder, said method comprising the step of administering to said subject a therapeutically effective amount of brivaracetam or a pharmaceutically acceptable salt thereof. In some embodiments, brivaracetam or a pharmaceutically acceptable salt thereof is administered every 12 or 24 hours at a daily dose of about 0.1-0.2 mg/kg. In some embodiments, brivaracetam or a pharmaceutically acceptable salt thereof is administered every 12 or 24 hours at a daily dose of about 7-15 mg. In some embodiments, brivaracetam or a pharmaceutically acceptable salt thereof is administered every 12 or 24 hours at a daily dose of about 0.01 to 2.5 mg/kg. In some embodiments, brivaracetam or a pharmaceutically acceptable salt thereof is administered every 12 or 24 hours at a daily dose of about 0.7 to 180 mg. In some embodiments, brivaracetam or a pharmaceutically acceptable salt thereof is administered every 12 or 24 hours at a daily dose of about 0.04 to 2.5 mg/kg. In some embodiments, brivaracetam or a pharmaceutically acceptable salt thereof is administered every 12 or 24 hours at a daily dose of about 2.5 to 180 mg. In some embodiments, brivaracetam or a pharmaceutically acceptable salt thereof is administered every 12 or 24 hours at a daily dose of about 0.06 to 1.8 mg/kg. In some embodiments, brivaracetam or a pharmaceutically acceptable salt thereof is administered every 12 or 24 hours at a daily dose of about 4-130 mg.

According to a seventh aspect of the present invention, there is provided a method of treating age-related cognitive impairment in a subject in need of such treatment or at risk of developing such a disorder, said method comprising the step of administering to said subject a therapeutically effective amount of seletracetam or a pharmaceutically acceptable salt thereof.

Brief description of the drawings

In fig. Figure 1 shows increased mRNA expression of the gene encoding SV2A in the dentate gyrus of the hippocampus of age-related impairment (AI) rats compared to young rats (Y) and aged unimpaired (AU) rats. The normalized signal values of the Affymetrix GeneChip marker set (Y-axis) as a measure of mRNA expression are plotted against the learning scores of various rats as a measure of cognitive impairment.

In fig. Figure 2 depicts the effects of levetiracetam administration on spatial memory retention of six age-impaired (AI) rats in the Morris water maze (MWM) test. Three types of treatment conditions were used: vehicle control, levetiracetam (5 mg/kg/day) and levetiracetam (10 mg/kg/day). Prior to training trials, AI rats are trained for two consecutive days with once-daily treatment. After 24 h, the AI rats are tested. The memory retention test uses as a measure of spatial memory retention the time AI rats swim in a target quadrant or target ring, 24 hours after treatment in different conditions and two days of training. The target quadrant refers to the quadrant of the maze (which is a circular pool) where the rescue platform is located during training tests. The target ring indicates the exact position of the rescue platform during training trials.

In fig. Figure 3 depicts the effects of levetiracetam administration on spatial memory retention of ten age-impaired (AI) rats in the radial arm pool (RAM) test. Six treatment conditions were used: vehicle control, levetiracetam (1.25 mg/kg/day), levetiracetam (2.5 mg/kg/day), levetiracetam (5 mg/kg/day), levetiracetam (10 mg/kg/day). day) and levetiracetam (20 mg/kg/day). The RAM task applies a 1-h delay between the presentation of a subset of arms (five available arms and three blocked arms) and the execution of an eight-arm success-move task (eight arms available). Rats are treated with drug/control 30-40 minutes before daily testing. The number of errors rats made after the delay was used as a measure of spatial memory retention. Errors were defined as instances where, in the pre-delay portion of the trial, rats entered an arm from which food had already been removed, or when rats revisited an arm in the post-delay session that had already been visited. Paired t tests are used to compare error rates between cases with different doses of levetiracetam and vehicle controls.

Detailed Description of the Invention

Unless otherwise defined, scientific and technical terms used herein have meanings that are generally understood by those of ordinary skill in the art. In general, the nomenclature and technology used in relation to the cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics and protein and nucleic acid chemistry described herein are well known and commonly used in this area.

Unless otherwise indicated, the methods and procedures of the present invention are generally performed in accordance with conventional methods that are well known in the art and described in the various general and more specific references that are cited and discussed in this specification. See, for example, Principles of Neural Science, McGraw-Hill Medical, New York, NY (2000); Motulsky, Intuitive Biostatistics, Oxford University Press, Inc. (1995); Lodish et al., Molecular Cell Biology, ^4th ed., W. H. Freeman & Co., New York (2000); Griffiths et al., Introduction to Genetic Analysis, ^7th ed., W. H. Freeman & Co., NY (1999); Gilbert et al., Developmental Biology, ^6th ed., Sinauer Associates, Inc., Sunderland, Mass. (2000).

Chemical terms used herein are used in accordance with common usage in the art, as illustrated in The McGraw-Hill Dictionary of Chemical Terms, Parker S., Ed., McGraw-Hill, San Francisco, C.A. (1985).

All of the above and any other publications, patents and published patent applications referenced in this application are expressly incorporated herein by reference. In the event of any conflict, this specification, including its specific definitions, governs.

It is understood that throughout the specification, the word contain, or its variations such as contains or containing, is intended to include the specified integer (or component) or group of integers (or components), but not to exclude some other integer (or component) or group integers (or components).

Singular forms include the plural unless the context clearly dictates otherwise.

The expression including is used to indicate the expression including, but not limited to. The expressions including and including, but not limited to, are used interchangeably.

The term agent is used herein to mean a chemical compound (e.g., an organic or inorganic compound, a mixture of chemical compounds), a biological macromolecule (e.g., a nucleic acid, an antibody, including parts thereof, as well as humanized, chimeric and human antibodies and monoclonal antibodies, a protein or its part, e.g. peptide, lipid, carbohydrate), or extract prepared from biological materials such as bacteria, plants, fungi, or animal (especially mammalian) cells and tissues. Agents include, for example, agents whose structure is known and agents whose structure is unknown. The SV2A inhibitory activity of such agents may make them suitable as therapeutic agents in the methods and compositions of this invention.

The terms patient, subject or individual are used interchangeably and refer to a human or non-human animal. These terms include mammals, such as humans, primates, cattle (including cows, pigs, etc.), domestic animals (eg, dogs, cats, etc.), and rodents (eg, mice and rats).

The expressions cognitive function or cognitive status refer to some higher order intellectual brain process or brain state, respectively, involved in cognition and/or memory, including, but not limited to, attention, information storage, information processing, working memory, short-term memory, long-term memory, anterograde memory, retrograde memory, memory retrieval, differentiated learning, decision making, control of inhibitory reactions, changes in the set of qualities related to attention, delayed consolidation of learning, remodeling of a skill, temporal integration of voluntary behavior and expression of interest in the environment environment and self-care needs.

In humans, cognitive function can be determined (without limitation), for example, by global clinical presentation of the Change Assessment Scale (CIBIC-plus scale); Mini-Mental State Examination (MMSE); Neuropsychiatric Inventory (NPI); Clinical Dementia Rating (CDR) scale; through the Cambridge Neuropsychological Test with Automated Battery (CANTAB) or the Sandoz Clinical Geriatric Assessment (SCAG). See Folstein et al., J. Psychiatric. Res. 12:189-98, (1975); Robbins et al., Dementia, 5:266-81, (1994); Rey, L'examen clinique en psychologie, (1964); Kluger et al., J. Geriatr. Psychiatry Neurol. 12:168-79, (1999).

In animal model systems, cognitive function can be determined by a variety of conventional methods known in the art, including the use of the Morris water maze (MWM), Barnes circular maze, elevated radial arm maze, T-maze, or any other mazes in which animals use spatial information . Other tests known in the art, such as novel object recognition and odor recognition tasks, can also be used to assess cognitive function.

Cognitive function can also be determined using techniques such as positron emission tomography (PET), functional magnetic resonance imaging (fMRI), single photon emission computed tomography (SPECT), or some other imaging technique that measures brain function. In animals, cognitive function can also be determined using electrophysiological techniques.

The expressions age-related cognitive impairment or cognitive impairment refer to cognitive function in older subjects who are not as healthy as would be expected for a normal subject according to age (i.e., a subject with an average score on a cognitive test for a given age) or as would be expected for a ground person. adult subjects. In some cases, cognitive function is reduced by about 5%, about 10%, about 30%, or more compared to the cognitive function expected for a normal subject based on age. In some cases, cognitive function is expected to be consistent with the age of a normal subject, but reduced by about 5%, about 10%, about 30%, about 50%, or more than the cognitive function expected for a young adult subject. Age-related cognitive decline may be associated with mild cognitive impairment (MCI), age-related memory impairment (AAMI), and age-related cognitive decline (ARCD).

Cognitive stimulation is concerned with influencing age-impaired cognitive function so that it more closely resembles that of an age-matched normal subject without impairment or that of a young adult subject. Cognitive function can be stimulated to some detectable degree, but in humans it is preferably stimulated to a sufficient extent to enable the impaired subject to perform daily activities of normal life with the same level of skill as an age-appropriate normal subject without impairment or a young adult subject.

Preservation of cognitive function refers to the treatment of normal or impaired cognitive function so that it does not deteriorate or fall below the value observed for the subject after first presentation or diagnosis, or slows such deterioration.

The expression improvement of cognitive function includes stimulation of cognitive function and/or preservation of cognitive function in a subject.

The term mild cognitive impairment, or MCI, refers to a condition characterized by isolated memory impairment, unaccompanied by other cognitive impairment, and relatively normal functional abilities. One set of criteria for the clinical description of MCI establishes the following characteristics: (1) memory complaints (as reported by the patient, informant, or clinician), (2) normal activities of daily living (ADL), (3) normal global cognitive function, (4) abnormal memory for age (defined as more than 1.5 times standard deviations below the mean for age) and (5) absence of indicators of dementia (which define DSM-IV guidelines). Petersen et al., Srch. Neurol. 56:303-308 (1999); Petersen, Mild cognitive impairment: Aging to Alzheimer's Disease, Oxford University Press, N.Y. (2003).

Diagnosis of MCI typically involves an objective assessment of cognitive impairment, which is collected through the use of well-established neuropsychological tests including the Mini-Mental State Examination (MMSE), the Cambridge Neuropsychological Test with Automated Battery (CANTAB), and individual tests such as the Rey Auditory and Verbal Test. learning test (AVLT), the Logical Memory subtest of the Wechsler Memory Scale-Revised (WMS-R), and the New York University (NYU) Paragraph Reproduction Test. See Folstein et al., J. Psychiatric. Res. 12:189-98 (1975); Robbins et al., Dementia 5:266-81 (1994); Kluger et al., J. Geriatric. Psychiatry Neurol. 12:168-79 (1999).

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The term age-related memory impairment (AAMI) refers to the deterioration of memory as a result of aging. A patient can be considered to have AAMI if the patient is at least 50 years of age and meets all of the following criteria: a) the patient notices memory impairment, b) the patient performs less well on a standard memory test compared to younger adults, c) all other obvious causes of memory decline other than normal aging have been ruled out (in other words, memory decline cannot be attributed to other causes such as recent heart attack or head injury, depression, adverse reactions to treatment, Alzheimer's disease, etc.).

The term age-related cognitive decline (ARCD) refers to the declines in memory and cognitive abilities that are a common consequence of aging in humans (e.g., Craik & Salthouse, 1992). This is also true for virtually all mammal species. The term age-related memory impairment refers to older people with objective memory decline relative to their younger years, but whose cognitive performance is normal relative to people their age (Crook et al., 1986). Age-appropriate memory decline is a less disruptive feature, highlighting that it is a normal evolutionary change (Crook, 1993; Larrabee, 1996) that is not pathophysiological (Smith et al., 1991) and rarely progresses to overt dementia (Yangjohn & Crook, 1996). 1993). DSM-IV (1994) codifies the diagnostic classification of ARCD.

The expression treating a condition or patient refers to the stages of administration to obtain beneficial or desired results, including clinical results. Beneficial or desirable clinical outcomes include, but are not limited to, alleviation or reduction of one or more symptoms associated with age-related cognitive impairment, delay or retardation of this impairment, reduction, temporary relief or stabilization of this impairment, and other beneficial outcomes such as improvement of cognitive function. function or reduction in the rate of cognitive decline in subjects with or at risk of age-related cognitive impairment.

Supply or administration of a substance, compound or agent to a subject can be accomplished using one of a variety of methods known to those skilled in the art. For example, the compound or agent can be administered intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinal, intracerebral, and transdermally (by absorption, e.g., through cutaneous channels ). The compound or agent may also be suitably administered through rechargeable or biodegradable polymer devices or other devices, such as patches and pumps or formulations, that provide sustained, slow, or controlled release of the compound or agent. Administration can also be carried out, for example, in one or more times and/or over one or more extended periods. In some aspects, the term supply includes direct administration, including self-administration, and indirect administration, including the act of prescribing a drug. For example, as used herein, a patient is provided with a drug by a physician who instructs the patient to self-administer the drug or obtain a drug administered by others, and/or by one who provides the patient with a prescription drug.

Suitable methods of administering a substance, compound, or agent to a subject also depend, for example, on the age of the subject, whether the subject is active or inactive at the time of administration, whether the subject is cognitively impaired at the time of administration, the degree of impairment, and the chemical and biological properties of the compound or agent. (e.g. solubility, digestibility, bioavailability, stability and toxicity). Preferably, the compound or agent is administered to the subject orally, for example by ingestion. In some embodiments, the orally administered compound or agent is a sustained release or slow release formulation, or is administered using a slow or sustained release device.

A therapeutically effective amount of a drug or agent is an amount of a drug or agent that, when administered to a subject, produces an intended therapeutic effect, such as improving the cognitive function of a subject, such as a patient with or at risk for age-related cognitive impairment. The full therapeutic effect does not necessarily occur with a single dose and may only occur after a series of doses. Thus, a therapeutically effective amount can be administered in one or more doses. The exact effective amount required by a subject depends, for example, on the size, health and age of the subject, the nature and extent of the cognitive impairment, the therapeutic agents or combination of therapeutic agents selected for administration, and the route of administration. One skilled in the art can readily determine the effective amount for a given situation through routine experimentation.

Synaptic vesicle protein 2 (SV2) is a family of synaptic vesicle proteins

- 5 044839 zicul, which consists of three members: the indicated SV2A, SV2B and SV2C. SV2A is the most widespread member of the family, expressed throughout the brain. These proteins are integral membrane proteins and have low homology (20-30%) with a family of bacterial and fungal transport proteins with 12 transmembrane segments that transport sugar, citrate and xenobiotics (Bajjalien et al., Science, 257:1271-1273 (1992)). SV2 family proteins are present in the brain and endocrine cells and are also present in all synaptic and endocrine vesicles. SV2 proteins have been reported to play some role in normal synaptic function and act at the stage of seeding vesicle maturation, which converts the vesicles into a Ca(2+)- and synaptotagmin-sensitive state (Sudhof et al., 2009). Functionally, SV2 proteins have been reported to enhance synaptic currents and increase the likelihood of transmitter release while maintaining the size of the readily releasable vesicle pool ( Custer et al., 2006 ).

The expression SV2A inhibitor refers to any agent, substance or compound that binds to SV2A and reduces synaptic function by reducing the release of presynaptic vesicles (see, for example, Noyer et al., 1995; Fuks et al. 2003; Lynch et al. 2004; Gillard et al., 2006; Custer et al., 2006; Smedt et al., 2007; Yang et al., 2007; and Example 8 of WO 2001/62726, which are all specifically incorporated herein by reference). A substance or compound or agent is an SV2A inhibitor (even if it does not itself bind to SV2A) as long as it causes or affects the ability of another compound or agent to bind SV2A or reduce synaptic function by reducing the release of presynaptic vesicles. SV2A inhibitors that are used herein include their pharmaceutically acceptable salts and solvates.

Among the SV2A inhibitors useful in the methods and compositions of this invention are the compounds or agents mentioned in i) international patent application WO 2001/062726; ii) international patent application WO 2002/094787; iii) international patent application WO 2004/087658; iv) US Patent No. 7244747 and v) International Patent Application WO 2007/065595. Applicants also address methods for preparing these compounds found in the documents cited above. Other synthetic methods can also be used. These methods are well known to those skilled in the art.

i) International patent application WO 2001/062726:

a compound having formula (I), or a pharmaceutically acceptable salt thereof

R ^3a R ^4a

where X is -CA1NR5R ⁶ or -CA1OR ⁷ or -CA'-R ⁸ or CN;

A ¹ and A ² independently represent an oxygen, sulfur or -NR ⁹ atom;

R ¹ is hydrogen, alkyl, aryl or -CH ₂ -R ^1a , where R ^la is aryl, heterocycle, halogen, hydroxy, amino, nitro or cyano;

R ² , R ³ and R ⁴ are the same or different and each independently represents a hydrogen atom, a halogen atom, hydroxy, thiol, amino, nitro, nitrooxy, cyano, azido, carboxy, amido, sulfonic acid, sulfonamide, alkyl, alkenyl, alkynyl, ester, ether, aryl, heterocycle or hydroxy derivative, thio derivative, amino derivative, acyl derivative, sulfonyl derivative or sulfinyl derivative;

R ^2a , R ^3a and R ^4a are the same or different and each independently represents a hydrogen atom, a halogen atom, alkyl, alkenyl, alkynyl or aryl;

R ⁵ , R ⁶ , R ⁷ and R ⁹ are the same or different and each independently represents a hydrogen atom, hydroxy, alkyl, aryl, heterocycle or oxy derivative;

R ⁸ represents a hydrogen atom, hydroxy, thiol, halogen atom, alkyl, aryl, heterocycle or thio derivative;

with the proviso that at least one of R ² , R ³ , R ⁴ , R ^2a , R ^3a and R ^4a is different from a hydrogen atom; and if the compound is a mixture of all possible isomers, X is -CONR ⁵ R ⁶ , A ² is an oxygen atom and R ¹ is a hydrogen, methyl, ethyl or propyl atom, then the substitution on the pyrrolidine ring is different from that of the mono-, di- or trimethyl or monoethyl; and if R ¹ , R ² , R ⁴ , R ^2a , R ^3a and R ^4a are each a hydrogen atom, A ² is an oxygen atom and X is CONR ⁵ R ⁶ , then R ³ is other than carboxy, ester, amido , substituted oxopyrrolidine, hydroxy, hydroxy derivative, amino, amino derivatives, methyl, naphthyl, phenyl, optionally substituted with oxy derivatives or a halogen atom in the para position.

In the definitions set forth below, unless otherwise indicated, R ¹¹ and R ¹² are the same or different and, each independently, represent an amido, alkyl, alkenyl, alkynyl, acyl, ester, ether, aryl, aralkyl, heterocycle or hydroxy derivative, a thio derivative, an acyl derivative, an amino derivative, a sulfonyl derivative, or a sulfinyl derivative, each optionally substituted with any suitable group, including, but not limited to, one or more moieties selected from lower alkyl or other groups that are described below as substituents for alkyl

As used herein, the term oxy derivative is defined as a moiety comprising -OR ¹¹ groups in which R ¹¹ is as defined above except for the oxy derivative. Non-limiting examples are alkoxy, alkenyloxy, alkynyloxy, acyloxy, oxyester, oxyamido, alkylsulfonyloxy, alkylsulfinyloxy, arylsulfonyloxy, arylsulfinyloxy, aryloxy, aralkoxy or heterocyclooxy, for example pentyloxy, allyloxy, methoxy, ethoxy, phenoxy, benzyloxy, 2-naphthyloxy, 2- pyridyloxy, methylenedioxy, carbonate.

As used herein, the term thio derivative is defined as a moiety comprising -SR ¹¹ groups in which R ¹¹ is as defined above except for the thio derivative. Non-limiting examples are alkylthio, alkenylthio, alkynylthio and arylthio.

As used herein, the term amino derivative is defined as a moiety comprising -NHR ¹¹ or -NR ¹¹ R ¹² groups, wherein R ¹¹ and R ¹² are as defined above. Non-limiting examples are mono- or dialkyl-, alkenyl-, alkynyl- and arylamino or mixed amino.

As used herein, the term acyl derivative represents a radical derived from a carboxylic acid and is therefore defined as a moiety comprising groups of the formula R ¹¹ -CO-, wherein R ¹¹ is as defined above and may also represent a hydrogen atom. Non-limiting examples include formyl, acetyl, propionyl, isobutyryl, valeryl, lauroyl, heptanedioyl, cyclohexanecarbonyl, crotonoyl, fumaroyl, acryloyl, benzoyl, naphthoyl, furoyl, nicotinoyl, 4-carboxybutanoyl, oxalyl, ethoxalyl, cysteinyl, oxamoyl.

As used herein, the term sulfonyl derivative is defined as a moiety comprising a group of the formula -SO2-R ¹¹ in which R ¹¹ is as defined above except for the sulfonyl derivative. Non-limiting examples include alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl and arylsulfonyl.

As used herein, the term sulfinyl derivative is defined as a moiety comprising a group of the formula -SO-R ¹¹ in which R ¹¹ is as defined above except for the sulfinyl derivative. Non-limiting examples include alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl and arylsulfinyl.

As used herein, the term alkyl is defined as a group comprising saturated, monovalent hydrocarbon radicals having linear, branched or cyclic moieties or combinations thereof and containing 1-20 carbon atoms, preferably 1-6 carbon atoms for acyclic alkyl and 3-6 carbon atoms for cycloalkyl (in these two cases, lower alkyl is preferred unless otherwise noted). The alkyl moieties may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxy, thiol, amino, nitro, cyano, thiocyanato, acyl, acyloxy, sulfonyl derivative, sulfinyl derivative, alkylamino, carboxy, ester, simple ester, amido, azido, cycloalkyl, sulfonic acid, sulfonamide, thio derivative, oxyester, oxyamido, heterocycle, vinyl, C ₁ . ₅ αlkoxy, C ₆ . ₁₀ aryloxy and C6.1oaryl.

Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, iso or tert-butyl and 2,2,2-trimethylethyl, each of which is optionally substituted with at least one substituent selected from the group consisting of halogen, hydroxy, thiol, amino, nitro and cyano, for example trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl.

As used herein, the term alkenyl is defined as a group including branched and unbranched, unsaturated hydrocarbon radicals having at least one double bond, such as ethenyl (=vinyl), 1-methyl-1-ethenyl, 2,2-dimethyl-1 -ethenyl, 1-propenyl, 2-propenyl (=allyl), 1-butenyl, 2-butenyl, 3-butenyl, 4-pentenyl, 1-methyl-4-pentenyl, 3-methyl-1-pentenyl, 1-hexenyl , 2-hexenyl and the like, and are optionally substituted with at least one substituent selected from the group consisting of halogen, hydroxy, thiol, amino, nitro, cyano, aryl and heterocycle, for example mono- and dihalogen, wherein the halogen is fluorine , chlorine or bromine.

As used herein, the term alkynyl is defined as a group comprising a monovalent branched or straight-chain hydrocarbon radical containing at least one carbon-carbon triple bond, for example, ethynyl, 2-propynyl (=propargyl) and the like, and optionally substituted with at least one substituent , selected from the group consisting of halogen, hydroxy, thiol, amino, nitro, cyano, aryl and heterocycle, for example haloethynyl.

If bridged groups are present, alkyl, alkenyl and alkynyl are straight- or branched chain _C1-12 , preferably ^alkylene moieties, or _C2-12 , preferably _{C2.4alkenylene} or -alkynylene moieties _, respectively.

Groups in which branched derivatives are usually qualified by prefixes such as n, sec, iso, and the like (e.g., n-propyl, sec-butyl) are the n-form if

- 7 044839 not otherwise stated.

As used herein, the term aryl is defined as a group containing an organic radical, an aromatic hydrocarbon derivative of 1-3 rings and containing 6-30 carbon atoms, obtained by the removal of one hydrogen atom, for example, phenyl and naphthyl, each of which is optionally substituted with 1-5 substituents independently selected from the following: halogen, hydroxy, thiol, amino, nitro, cyano, acyl, acyloxy, sulfonyl, sulfinyl, alkylamino, carboxy, ester, ether, amido, azido, sulfonic acid, sulfonamide, alkylsulfonyl, alkylsulfinyl , alkylthio, oxyester, oxyamido, aryl, C ₁ . ₆ alkoxy, C ₆ . ₁₀ aryloxy, C ₁ . ₆ alkyl, C ₁ . ₆ haloalkyl. Aryl radicals are preferably monocyclic radicals containing 6-10 carbon atoms. Preferred aryl groups are phenyl and naphthyl, each of which is optionally substituted with 1-5 substituents independently selected from halogen, nitro, amino, azido, C ₁ . ₆ alkoxy, C ₁ . ₆ alkylthio, C ₁ . ₆ alkyl, C ₁ . ₆ haloalkyl and phenyl.

As used herein, the term halogen includes Cl, Br, F, I atom.

As used herein, the term hydroxy refers to a group of the formula -OH.

As used herein, the term thiol refers to a group of the formula -SH.

As used herein, the term cyano refers to a group of the formula -CN.

As used herein, the term nitro refers to a group of the formula -NO2.

As used herein, the term nitrooxy refers to a group of the formula -ONO2.

As used herein, the term amino refers to a group of the formula -NH2.

As used herein, the term azido refers to a group of the formula -N ₃ .

As used herein, the term carboxy refers to a group of the formula -COOH.

As used herein, the expression sulfonic acid refers to a group of the formula -SO3H.

As used herein, the term sulfonamide refers to a group of the formula -SO2NH2.

As used herein, the term ester is defined as a moiety comprising a group of the formula -COO-R ¹¹ in which R ¹¹ is as defined above, excluding the hydroxy derivative, the thio derivative or the amino derivative.

The term ether is defined as a moiety containing a group selected from C ₁ . ₅₀ linear or branched alkyl or C ₂ . ₅₀ straight or branched alkenyl or alkynyl groups or combinations thereof, interrupted by one or more oxygen atoms.

The term amido is defined as a moiety containing a group of the formula -CONH2, or -CONHR ¹¹ , or -CONRHR ¹² , in which R ¹¹ and R ¹² are as defined above.

As used herein, the term heterocycle is defined as a group comprising an aromatic or non-aromatic cyclic alkyl, alkenyl or alkynyl moiety as defined above, including at least one O, S and/or N atom interrupting the carbocyclic ring structure, and optionally one carbon of the carbocyclic ring structure may be substituted with carbonyl. Non-limiting examples of aromatic heterocycles include pyridyl, furyl, pyrrolyl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, quinazolinyl, quinolizinyl, naphthyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, isobenzofuranyl, benzothienyl, pyrazolyl, indole yl, indolizinyl, purinyl, isoindolyl , carbazolyl, thiazolyl, 1,2,4-thiadiazolyl, thieno(2,3-b)furanyl, furopyranyl, benzofuranyl, benzoxepinyl, isooxazolyl, oxazolyl, thianthrenyl, benzothiazolyl or benzoxazolyl, cinnolinyl, phthalazinyl, quinoxalinyl, phenanthridinyl, acridinyl, perimidinyl , phenanthrolinyl, phenothiazinyl, furazanyl, isochromanyl, indolinyl, xanthenyl, hypoxanthinyl, pteridinyl, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl and pyrazolopyrimidinyl, optionally substituted with alkyl or other groups as described above for alkyl groups . Non-limiting examples of non-aromatic heterocycles include tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperidyl, piperazinyl, imidazolidinyl, morpholino, morpholinyl, 1-oxaspiro(4.5)dec-2-yl, pyrrolidinyl, 2-oxopyrrolidinyl, sugar moieties (i.e. glucose, pentose, hexoses, riboses, fructoses, which may also be substituted) or the above compounds, which may optionally be substituted with any suitable group, including, but not limited to, one or more moieties selected from lower alkyl or other groups as described above for alkyl groups.

The term heterocycle also includes bicyclic, tricyclic and tetracyclic spiro groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring or other monocyclic heterocyclic ring, or where the monocyclic heterocyclic group is bridged by an alkylene group, for example, quinuclidinyl, 7-azabicyclo(2.2.1)heptanyl, 7-oxabicyclo(2.2.1)heptanyl, 8-azabicyclo(3.2.1)octanyl.

In the above definitions it should be understood that if a substituent such as ^R2 , ^R3 , ^R4 , R2a, ^R3a , ^{R4a , R5} , ^R6 , ^R7 , ^R8 is attached to the remainder of the molecule through a heteroatom or carbonyl, then between the heteroatom or carbonyl and the point of attachment to the remainder of the molecule may optionally be

- 8 044839 a linear or branched C1-12, preferably alkylene, or C2-12, preferably a C2-4 alkenylene or alkynylene bridge is inserted.

Preferred examples of X are -COOR ⁷ or -CONR5R ⁶ where R ⁵ , R ⁶ and R ⁷ are preferably hydrogen, C _1-4 alkyl, phenyl or alkylphenyl.

Preferred X is carboxy or -CONR5R ⁶ where R ⁵ and R ⁶ are preferably hydrogen, C _1-4 alkyl, phenyl or alkylphenyl, especially -CONH2.

Preferred A ¹ and A ² each represent an oxygen atom.

Preferred R ¹ is a hydrogen atom, alkyl, especially C ₁ . ₁₂ alkyl, in particular lower alkyl or aryl, especially phenyl.

Examples of preferred R ¹ groups are methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethylethyl, each optionally linked via a methylene bridge or substituted with at least one halogen atom, e.g. trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl.

Particularly preferred R ¹ is ethyl.

Preferred R ² and R ^2a are independently hydrogen atom, halogen atom or alkyl, especially lower alkyl.

Examples of preferred R ² and R ^2a groups are independently hydrogen atom, halogen atom or methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethylethyl or these radicals substituted by at least one atom halogen, for example trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl.

It is particularly preferred that at least one of R ² and R ^2a is a hydrogen atom, most preferably both.

Preferred R ^3a , R ⁴ and R ^4a are independently hydrogen, alkyl, especially methyl, or ethyl or aryl, especially phenyl or aralkyl, especially benzyl.

Examples of preferred R ^3a , R ⁴ and R ^4a groups are independently hydrogen, halogen or methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethylethyl or these radicals substituted by at least at least one halogen atom, for example trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl.

It is particularly preferred that at least one of R ⁴ and R ^4a is a hydrogen atom, and most preferably both.

In particular, R ^3a is a hydrogen atom or an alkyl, especially a lower alkyl and most preferably a hydrogen atom.

Preferred R ³ is a hydrogen atom, C ₁ . ₁ 2alkyl, especially C ₁ . ₆ αlkyl, each of which is optionally substituted with one or more substituents selected from hydroxy, halogen, cyano, thiocyanato or alkoxy, and is attached to the ring directly or through a thio-, sulfinyl, sulfonyl, carbonyl or oxycarbonyl group and, optionally, C ₁ . ₄ alkylene bridge, in particular methylene; C2. ₆ alkenyl or -alkynyl, especially C2. ₃ alkenyl or -alkynyl, each of which is optionally substituted by one or more of the following: halogen atoms; azido; cyano; amido; carboxy; triazolyl, tetrazolyl, pyrrolidinyl, pyridyl, 1-oxidopyridyl, thiomorpholinyl, benzodioxolyl, furyl, oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl or piperazinyl, each of which is optionally substituted with one or more substituents selected from a halogen atom, C ₁ . ₆ αlkyl and phenyl, and is attached to the ring directly or through a carbonyl group or C ₁ . ₄ alkylene bridge, in particular methylene; naphthyl; or phenyl, phenylalkyl or phenylalkenyl, each of which is optionally substituted by one or more substituents selected from a halogen atom, C ₁ . ₆ alkyl, C ₁ . ₆ haloalkyl, C ₁ . ₆ αlkoxy, C ₁ . ₆ alkylthio, amino, azido, phenyl and nitro, and each is attached to the ring directly or through an oxy, sulfonyl, sulfonyloxy, carbonyl or carbonyloxy group and optionally an additional C ₁ . ₄ αalkylene bridge, in particular methylene.

Also preferred R ³ is C ₁ . ₆ alkyl, optionally substituted by one or more substituents selected from the following: halogen atom, thiocyanato, azido, alkoxy, alkylthio, phenylsulfonyl; nitrooxy; C2. ₃ alkenyl or alkynyl, each of which is optionally substituted with one or more of the following: halogen atoms or acetyl; tetrazolyl, pyridyl, furyl, pyrrolyl, thiazolyl or thienyl; or phenyl or phenylalkyl, each of which is optionally substituted with one or more substituents selected from a halogen atom, C ₁ . ₆ alkyl, C ₁ . ₆ haloalkyl, C ₁ . ₆ αlkoxy, amino, azido, phenyl and nitro, and each is attached to the ring directly or through sulfonyloxy and optionally additional C ₁ . ₄ alkylene bridge, in particular methylene.

Other examples of preferred R ³ groups are a hydrogen atom, a halogen atom or methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethylethyl or these radicals substituted with at least one halogen atom, for example trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl.

R ³ is mainly C ₁ . ₄ αlkyl, optionally substituted with one or more substituents selected from the following: halogen, thiocyanato or azido;

_C2 . ₅ α-alkenyl or -alkynyl, each of which is optionally substituted by one or more of the following: halogen atoms; thienyl or phenyl, optionally substituted with one or more substituents selected from the halogen atom, C ₁ . ₆ αlkyl, C ₁ . ₆ haloalkyl or azido.

Additional examples _of preferred R ³ groups are C _{1_6} alkyl and C _{2_6} haloalkenyl _.

Preferred R ⁵ and R ⁶ are independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethylethyl, especially hydrogen or methyl.

It is particularly preferred that at least one of R ⁵ and R ⁶ is a hydrogen atom, and most preferably both.

Preferred R ⁷ is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethylethyl, methoxy, ethoxy, phenyl, benzyl or these radicals substituted by at least one halogen atom , for example trifluoromethyl, chlorophenyl.

Preferred R ⁷ is a hydrogen atom, methyl or ethyl, in particular a hydrogen atom.

Preferred R ⁸ is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethylethyl, phenyl, benzyl or these radicals substituted with at least one halogen atom, for example trifluoromethyl , chlorobenzyl.

Preferred R ⁸ is hydrogen or methyl.

Particularly preferred are combinations of one or more of these preferred groups of compounds.

A special group of compounds of formula (I) (compounds IA) includes compounds in which:

A ² represents an oxygen atom;

X is -CONR5R ⁶ or -COOR ⁷ or -CO-R ⁸ or CN;

R ¹ represents a hydrogen atom or alkyl, aryl, halogen, hydroxy, amino, nitro, cyano;

R ² , R ³ , R ⁴ are the same or different and each independently represents a hydrogen or halogen atom, hydroxy, amino, nitro, cyano, acyl, acyloxy, sulfonyl derivative, sulfinyl derivative, amino derivative, carboxy, ester, simple ester, amido, sulfonic acid, sulfonamide, alkoxycarbonyl, thio derivative, alkyl, alkoxy, oxyester, oxyamido, aryl, oxy derivative, heterocycle, vinyl, and R ³ may additionally be C ₂₅ alkenyl, C ₂ . ₅ alkynyl or azido, each of which is optionally substituted with one or more of the following: halogen, cyano, thiocyano, azido, cyclopropyl, acyl and/or phenyl; or phenylsulfonyloxy, whereby any phenyl moiety may be substituted by one or more of the following: halogen, alkyl, haloalkyl, alkoxy, nitro, amino and/or phenyl; most preferred are methyl, ethyl, propyl, isopropyl, butyl or isobutyl;

R ^2a , R ^3a and R ^4a represent a hydrogen atom;

R ⁵ , R ⁶ , R ⁷ are the same or different and each independently represents a hydrogen atom, hydroxy, alkyl, aryl, heterocycle or oxy derivative;

R ⁸ represents a hydrogen atom, hydroxy, thiol, halogen atom, alkyl, aryl, heterocycle, alkylthio or thio derivative.

In these compounds, IA R ¹ is preferably methyl, ethyl, propyl, isopropyl, butyl or isobutyl; most preferably methyl, ethyl or n-propyl.

R ² and R ⁴ preferably independently represent a hydrogen or halogen atom or methyl, ethyl, propyl, isopropyl, butyl, isobutyl; and most preferably, each represents a hydrogen atom.

R ³ is preferably C ₁ . ₅ alkyl, C ₂ . ₅ alkenyl, C ₂ . ₅ alkynyl, cyclopropyl, azido, each of which is optionally substituted with one or more substituents from the following: halogen, cyano, thiocyano, azido, alkylthio, cyclopropyl, acyl and/or phenyl; phenyl; phenylsulfonyl; phenylsulfonyloxy, tetrazole, thiazole, thienyl, furyl, pyrrole, pyridine, whereby any phenyl moiety may be substituted by one or more of the following: halogen, alkyl, haloalkyl, alkoxy, nitro, amino, and/or phenyl; most preferably methyl, ethyl, propyl, isopropyl, butyl or isobutyl;

X is preferably -COOH or -COOMe or -COOEt or -CONH2; most preferably -CONH2.

Another special group of compounds of formula (I) (compounds IB) includes compounds in which:

X is -CA1NH2, -CA1NHCH3 or -CA1N(CH ₃ )2;

R ¹ is alkyl or phenyl;

R ³ is alkyl, alkenyl, alkynyl, cyano, isothiocyanato, ether, carboxyl, amido, aryl, heterocycle or

R ³ is CH2R ¹⁰ where R ¹⁰ is a hydrogen atom, cycloalkyl, hydroxy ester, oxyalkylsulfonyl, oxyarylsulfonyl, aminoalkylsulfonyl, aminoarylsulfonyl, nitrooxy, cyano, isothiocyanato, azido, alkylthio, arylthio, alkylsulfinyl, alkyl sulfonyl, heterocycle, aryloxy , alkoxy or trifluoroethyl;

R ^3a is a hydrogen atom, alkyl or aryl (generally, provided that if R ^3a is a hydrogen atom, then R ³ is other than methyl); or

R ³ R ^3a form cycloalkyl;

R ² , R ^2a , R ⁴ and R ^4a each represent a hydrogen atom.

In compounds of formula (I):

R ¹ is preferably alkyl, especially C _1-12 alkyl, more particularly Cl _-6 αalkyl and most preferably ethyl;

R ² , R ^2a , R ^3a and R ⁴ preferably represent a hydrogen atom;

R ³ is preferably selected from a hydrogen atom; C _1-12 alkyl, in particular C _1-6 αlkyl, each of which is optionally substituted with one or more substituents selected from hydroxy, halogen, cyano, thiocyanato or alkoxy and attached to the ring directly or via thio, sulfinyl, sulfonyl, a carbonyl or oxycarbonyl group and optionally an additional C _1-4 alkylene bridge, in particular methylene; _C2 . ₆ alkenyl or α-alkynyl, especially C _2-3 α-alkenyl or α-alkynyl, each of which is optionally substituted with one or more of the following: halogen atoms; azido; cyano; amido; carboxy; triazolyl, tetrazolyl, pyrrolidinyl, pyridyl, 1-oxidopyridyl, thiomorpholinyl, benzodioxolyl, furyl, oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl or piperazinyl, each of which is optionally substituted with one or more substituents selected from a halogen atom, C ₁ . ₆ alkyl and phenyl and is attached to the ring directly or through a carbonyl group, or C ₁ . ₄ alkylene bridge, in particular methylene; naphthyl; or phenyl, phenylalkyl or phenylalkenyl, each of which is optionally substituted by one or more substituents selected from a halogen atom, C ₁ . ₆ αlkyl, C ₁ . ₆ haloalkyl, C ₁ . ₆ αlkoxy, C ₁ . ₆ alkylthio, amino, azido, phenyl and nitro, and each is attached to the ring directly or through an oxy, sulfonyl, sulfonyloxy, carbonyl or carbonyloxy group and optionally an additional C ₁ . ₄ αalkylene bridge, in particular methylene;

R ^3a preferably represents a hydrogen atom or C ₁ . ₄ alkyl;

R ⁴ and R ^4a preferably independently represent a hydrogen atom, C ₁ . ₄ alkyl, phenyl or benzyl.

Another group of compounds of formula (I) (IC compounds) includes compounds in racemic form in which, if X is -CONR5R ⁶ and R ¹ is hydrogen, methyl, ethyl or propyl, the substitution on the pyrrolidine ring is other than mono-, di- or trimethyl or monoethyl.

Another group of compounds of formula (I) (compounds 1D) includes compounds in racemic form, wherein X is -CONR5R ⁶ and R ¹ is a hydrogen atom or C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl or -alkynyl or cycloalkyl, each of which is unsubstituted, then substitution in the ring is different from substitution with alkyl, alkenyl or alkynyl, each of which is unsubstituted.

Another special group of compounds of formula (I) (IE compounds) includes compounds in which:

X is -CA ^r NH ₂ ;

R ¹ is H;

R ³ denotes azidomethyl, iodomethyl, ethyl, optionally substituted with 1-5 halogen atoms, npropyl, optionally substituted with 1-5 halogen atoms, vinyl, optionally substituted with one or two methyls and/or 1-3 halogen atoms, acetylene, optionally substituted with C ₁ . ₄ αlkyl, phenyl or halogen atom;

R ^3a represents a hydrogen or halogen atom, preferably fluorine;

R ² , R ^2a , R ⁴ and R ^4a each represent a hydrogen atom;

in the form of their racemates or enantiomerically enriched forms, preferably in the form of pure enantiomers.

Another special group of compounds of formula (I) (IF compounds) includes compounds in which:

X is -CA ^r NH ₂ ;

R ¹ is H;

R ³ stands for C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl or C ₂ . ₆ alkynyl, optionally substituted with azido, oxynitro, 1-6 halogen atoms;

R ^3a represents a hydrogen or halogen atom, preferably fluorine;

R ² , R ^2a , R ⁴ and R ^4a each represent a hydrogen atom;

in the form of their racemates or enantiomerically enriched forms, preferably in the form of pure enantiomers.

In all the regions mentioned above: if the carbon atom to which R ¹ is attached is asymmetric, then it is preferably in the S configuration.

In some embodiments, compounds useful in the methods and compositions of this invention are selected from the group consisting of:

- 11 044839 (2S)-2-[4-(bromomethyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-[(4R)-4-(iodomethyl)-2-oxopyrrolidinyl]butanamide;

(2S)-2-(2-oxo-4-phenyl-1-pyrrolidinyl)butanamide;

(2S)-2-[4-(iodomethyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-[4-(chloromethyl)-2-oxo-1-pyrrolidinyl]butanamide;

{1-[(13)-1-(aminocarbonyl)propyl]-5-oxo-Zpyrrolidinyl}methyl 4-methylbenzenesulfonate;

(2S)-2-[(4R)-4-(azidomethyl)-2-oxopyrrolidinyl]butanamide 2-[4-(2,2-dibromovinyl)-2-oxo-1-pyrrolidinyl]butanamide;

{1-[(IS)-1-(aminocarbonyl)propyl]-5-oxo-Zpyrrolidinyl}methyl nitrate;

(2S)-2-[2-OXO-4-(1H-tetraazol-1-ylmethyl)-1pyrrolidinyl]butanamide;

2-(2-oxo-4-vinyl-1-pyrrolidinyl)butanamide;

2-{2-OXO-4-[(phenylsulfonyl)methyl]-1pyrrolidinyl]butanamide;

(2S)—2—[(4R)-4-(2,2-dibromovinyl)-2oxopyrrolidinyl]butanamide;

(2S)—2—[(43)-4-(2,2-dibromovinyl)-2oxopyrrolidinyl]butanamide;

(2S)-2-[4-(isothiocyanatomethyl)-2-oxo-1pyrrolidinyl]butanamide;

2-[2-oxo-4-(1,3-thiazol-2-yl)-1-pyrrolidinyl]butanamide;

(2S)-2-[2-OXO-4-(2-thienyl)-1-pyrrolidinyl]butanamide;

(2S)-2-[4-(2-methoxyphenyl)-2-oxo-1pyrrolidinyl]butanamide;

(2S)-2-[4-(3-methoxyphenyl)-2-oxo-1-12 044839 pyrrolidinyl]butanamide;

(2S)-2-[4-(4-azidophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-[2-OXO-4-(3-thienyl)-1-pyrrolidinyl]butanamide;

(2S)-2-[4-(3-azidophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-[2-OXO-4-(3-thienyl)-1-pyrrolidinyl]butanamide;

(2S)-2-[(4S)-2-oxo-4-vinylpyrrolidinyl]butanamide;

(2S)-2-[(4R)-2-oxo-4-vinylpyrrolidinyl]butanamide;

2-[4-(2-bromophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-[2-OXO-4-(3-pyridinyl)-1-pyrrolidinyl]butanamide;

(2S)—2—(4—[1,1'-biphenyl]-4-yl-2-oxo-1pyrrolidinyl)butanamide;

(2S)-2-{4-[(methylsulfanyl)methyl]-2-oxo-1pyrrolidinyl}butanamide;

2-[4-(iodomethyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-[(4R)-4-(iodomethyl)-2-oxo-1pyrrolidinyl]pentanamide;

(2S)-2-[(4R)-4-(iodomethyl)-2-oxopyrrolidinyl]propanamide;

2-(2-oxo-4-propyl-1-pyrrolidinyl)propanamide;

2-(2-oxo-4-propyl-1-pyrrolidinyl)butanamide;

2-(2-oxo-4-pentyl-1-pyrrolidinyl)butanamide;

(2S)-2-[(4R)-4-(iodomethyl)-2-oxopyrrolidinyl]-Nmethylbutanamide;

(2S)-2-(4-neopentyl-2-oxo-1-pyrrolidinyl)butanamide;

(2S)-2-(4-ethyl-2-oxo-1-pyrrolidinyl)butanamide;

2-[4-(2,2-difluorovinyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-[4-(2,2-difluoroethyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-[(4S)-2-oxo-4-propylpyrrolidinyl]butanamide;

(2S)-2-[(4R)-2-oxo-4-propylpyrrolidinyl]butanamide;

2-{4-[(Z)-2-fluoroethenyl]-2-oxo-1-pyrrolidinyl}butanamide;

2-[4-(2-methyl-1-propenyl)-2-oxo-1-pyrrolidinyl]butanamide 2-(4-butyl-2-oxo-1-pyrrolidinyl)butanamide;

2-[4-(cyclopropylmethyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-(4-isobutyl-2-oxo-1-pyrrolidinyl)butanamide;

2-[4-(4-chlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-[4-(3-chlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-{2-oxo-4-[2-(trifluoromethyl)phenyl]-1-13 044839 pyrrolidinyl]butanamide;

2-[4-(2-fluorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-[4-(3-methylphenyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-[2-OXO-4-(2-phenylethyl)-1-pyrrolidinyl]butanamide;

(2S)-2-[4-(3-bromophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-{4-[3,5-bis(trifluoromethyl)phenyl]-2-oxo-1pyrrolidinyl]butanamide;

2-[4-(3,4-dichlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-[4-(2,4-dichlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-[4-(2-furyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-[2-OXO-4-(3-phenylpropyl)-1-pyrrolidinyl]butanamide;

(2S)-2-[4-(3,5-dibromophenyl)-2-oxo-1pyrrolidinyl]butanamide;

2-[4-(3,4-dichlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-(2-oxo-4-propyl-1-pyrrolidinyl)butanamide;

2-[4-(3-chlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-(4-ethynyl-2-oxo-1-pyrrolidinyl)butanamide;

2-[4-(2-fluorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-[4-(cyclopropylmethyl)-2-oxo-1pyrrolidinyl}butanamide;

(2S)-2-[(4S)-4-(2,2-difluorovinyl)-2oxopyrrolidinyl]butanamide;

(2S)-2-[2-oxo-4-(3,3,3-trifluoropropyl)-1pyrrolidinyl]butanamide;

2-[4-(3-methylphenyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-[4-(cyclopropylmethyl)-2-oxo-1pyrrolidinyl]butanamide;

(2S)-2-[(4R)-4-(2,2-difluorovinyl)-2oxopyrrolidinyl]butanamide;

(2S)-2-[2-oxo-4-(1H-pyrrol-1-yl)-1pyrrolidinyl]butanamide;

(2S)-2-(4-allyl-2-oxo-1-pyrrolidinyl)butanamide;

(2S)-2-[4-(2-iodopropyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-(4-allyl-2-oxo-1-pyrrolidinyl)butanamide;

(2S)-2-[2-OXO-4-(2-oxopropyl)-1-pyrrolidinyl]butanamide;

(2S)-2-[4-(2-bromo-1H-pyrrol-1-yl)-2-oxo-1pyrrolidinyl]butanamide;

(2S)-2-(4-methyl-2-oxo-4-propyl-1-pyrrolidinyl)butanamide;

(2R)-2-[4-(2,2-dichlorovinyl)-2-oxo-1pyrrolidinyl]butanamide;

2-[4-(bromoethynyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-[(4S)-4-(2,2-difluoropropyl)-2-oxopyrrolidinyl]butanamide;

(2S)-2-[4-(bromoethynyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-(2-oxo-4-propyl-1-pyrrolidinyl)pentanamide;

3-cyclopropyl-2-(2-oxo-4-propyl-1pyrrolidinyl)propanamide;

2-(2-oxo-4-propyl-1-pyrrolidinyl)-3-(1,3-thiazol-4yl)propanamide;

2-(2-oxo-4-propyl-1-pyrrolidinyl)-4-pentenamide;

(2S)-2-[(4R)-2-oxo-4-vinylpyrrolidinyl]butanamide;

including all isomeric forms and mixtures thereof or pharmaceutically acceptable salts thereof.

In some embodiments, compounds useful in the methods and compositions of this invention are selected from the group consisting of:

(2S)-2-[(4S)-4-(2,2-difluorovinyl)-2oxopyrrolidinyl]butanamide;

(2S)-2-[(4S)-2-oxo-4-propylpyrrolidinyl]butanamide;

(2S)-2-[(4R)-2-oxo-4-propylpyrrolidinyl]butanamide.

- 14 044839 ii) International patent application WO 2002/094787: compounds of formula (I)

where n is 0 or 1, whereby R ¹ is absent if n=0, and R ¹ is present if n=1;

A ¹ represents an oxygen or sulfur atom;

X is -CONR ⁷ R ⁸ , -COOR ⁹ , -CO-R ¹⁰ or CN;

R ¹ , if present, R ² , R ³ , R ⁴ and R ⁵ are the same or different and each independently represents a hydrogen atom, a halogen atom, hydroxy, thiol, amino, nitro, nitrooxy, cyano, azido, carboxy, amido, sulfonic acid, sulfonamide, alkyl, alkenyl, alkynyl, ester, ether, aryl, heterocycle or hydroxy derivative, thio derivative, amino derivative, acyl derivative, sulfonyl derivative or sulfinyl derivative, provided that at least one of the substituents R, selected from R ¹ , if present, R ² , R ³ , R ⁴ or R ⁵ , is not a hydrogen atom;

R ⁶ is hydrogen, alkyl, aryl or -CH ₂ -R ^6a , where R ^6a is aryl, heterocycle, halogen, hydroxy, amino, nitro or cyano;

R ⁷ , R ⁸ and R ⁹ are the same or different and each independently represents a hydrogen atom, hydroxy, alkyl, aryl, heterocycle or oxy derivative; And

R ¹⁰ represents a hydrogen atom, hydroxy, thiol, halogen atom, alkyl, aryl, heterocycle or thio derivative;

their pharmaceutically acceptable salts, geometric isomers (including cis and trans, Z and E isomers), enantiomers, diastereomers and mixtures thereof (including all possible mixtures of stereoisomers).

In the above formula, at least one substituent from R ¹ to R ⁵ is other than a hydrogen atom. Certain unsubstituted compounds are mentioned in US Pat. No. 5,468,733 and 5,516,759. US Pat. No. 5,468,733 relates to non-cyclic substituted 2-oxo-1-pyrrolidinyl and 2-oxo-1-piperidinyl derivatives as inhibitors of the oncogenic Ras protein. In particular, these compounds block the ability of Ras to transform normal cells into cancer cells and, therefore, can be included in some chemotherapeutic compositions for the treatment of cancer.

US Patent No. 5,516,759 relates to non-cyclic substituted 2-oxo-1-pyrrolidinyl, 2-oxo1-piperidinyl and azepanyl derivatives present at the N-terminus of dodecapeptides having LHRH (luteinizing hormone releasing hormone) antagonistic activity. Such LHRH antagonists are suitable for the treatment of a variety of conditions in which suppression of sex hormones plays a key role, including contraception, delayed puberty, treatment of benign prostatic hyperplasia, etc.

In the definitions below, unless otherwise indicated, R ¹¹ and R ¹² are the same or different and, each independently, represent an amido, alkyl, alkenyl, alkynyl, acyl, ester, ether, aryl, aralkyl, heterocycle or hydroxy derivative, a thio derivative, an acyl derivative, an amino derivative, a sulfonyl derivative, or a sulfinyl derivative, each of which is optionally substituted with any suitable group, including, but not limited to, one or more moieties selected from lower alkyl or other groups as described below for alkyl.

As used herein, the term oxy derivative is defined as a moiety comprising OR ¹¹ groups, where R ¹¹ is as defined above except for the oxy derivative. Non-limiting examples are alkoxy, alkenyloxy, alkynyloxy, acyloxy, oxyester, oxyamido, alkylsulfonyloxy, alkylsulfinyloxy, arylsulfonyloxy, arylsulfinyloxy, aryloxy, aralkoxy or heterocyclooxy, for example pentyloxy, allyloxy, methoxy, ethoxy, phenoxy, benzyloxy, 2-naphthyloxy, 2- pyridyloxy, methylenedioxy, carbonate.

As used herein, the term thio derivative is defined as a moiety comprising -SR ¹¹ groups, where R ¹¹ is as defined above except for the thio derivative. Non-limiting examples are alkylthio, alkenylthio, alkynylthio and arylthio.

As used herein, the term amino derivative is defined as a moiety comprising NHR ¹¹ or -NR11R ¹² groups, where R ¹¹ and R ¹² are as defined above. Non-limiting examples include mono- or di-alkyl, alkenyl, alkynyl and arylamino or mixed amino.

As used herein, the expression acyl derivative represents a radical derived from a carboxylic acid and is therefore defined as a moiety comprising groups of the formula R ¹¹ -CO-, wherein R ¹¹ is as defined above and may also represent a hydrogen atom. Preferred are acyl derivatives of the formula -COR ¹¹ , where R ¹¹ is selected from hydrogen, C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, heterocyclyl and aryl. Non-limiting examples are formyl, acetyl, propionyl, isobutyryl, valeryl, lauroyl, heptanedioyl, cyclohexanecarbonyl, crotonoyl, fumaroyl, acryloyl, benzoyl, naphthoyl, furoyl, nicotinoyl, 4-carboxybutanoyl, oxalyl, ethoxalyl, cysteinyl, oxamoyl.

As used herein, the expression sulfonyl derivative is defined as a moiety comprising a group of the formula -SO2-R ¹¹ wherein R ¹¹ is as defined above except for the sulfonyl derivative. Non-limiting examples include alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl and arylsulfonyl.

As used herein, the expression sulfinyl derivative is defined as a moiety comprising a group of the formula -SO-R ¹¹ wherein R ¹¹ is as defined above except for the sulfinyl derivative. Non-limiting examples include alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl and arylsulfinyl.

As used herein, the term alkyl is defined as a group comprising saturated, monovalent hydrocarbon radicals having linear, branched or cyclic moieties or combinations thereof and typically containing 1-20 carbon atoms, most commonly 1 to 12 carbon atoms, preferably 1-7 carbon atoms for non-cyclic alkyl and 3-7 carbon atoms for cycloalkyl (in these two preferred cases, unless otherwise stated, lower alkyl), each of which is optionally substituted with preferably 1-5 substituents independently selected from the group consisting of halogen, hydroxy, thiol, amino, nitro, cyano, thiocyanato, acyl, acyloxy, sulfonyl derivative, sulfinyl derivative, alkylamino, carboxy, ester, ether, amido, azido, cycloalkyl, sulfonic acid, sulfonamide, thio derivative, alkylthio, oxyester, oxyamido, heterocycle, vinyl, alkoxy (preferably _C1-5 ), aryloxy (preferably _C6-10 ) and aryl (preferably _C6-10 ).

Preferred are alkyl groups containing from 1 to 7 carbon atoms, each of which is optionally substituted by one or more substituents selected from hydroxy, halogen, cyano, thiocyanato, alkoxy, azido, alkylthio, cyclopropyl, acyl and phenyl. Most preferred are C _1-4 alkyl and C _3-7 cycloalkyl, each of which is optionally substituted with one or more of the following: hydroxy, halogen, lower alkyl and/or azido.

The most preferred alkyl groups are hydroxymethyl, propyl, butyl, 2,2,2-trifluoroethyl, 2-bromo-2,2-difluoroethyl, 2-chloro-2,2-difluoroethyl, 3,3,3-trifluoropropyl, cyclopropylmethyl, iodomethyl , azidomethyl, 2,2-difluoropropyl, 2-iodo-2,2-difluoroethyl.

As used herein, the expression lower alkyl, unless otherwise noted, refers to a C1-C7 saturated linear, branched or cyclic hydrocarbon. Non-limiting examples include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, cyclopropyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, 3-methylpentyl, 2,2-dimethylbutyl, optionally substituted with any suitable group including but not limited to, one or more moieties selected from the groups described above for alkyl groups. The preferred lower alkyl is methyl.

As used herein, the term alkenyl is defined as a group including branched and unbranched unsaturated hydrocarbon radicals having at least one double bond and optionally substituted with at least one substituent selected from the group consisting of halogen, hydroxy, thiol, amino, thiocyanato, azido, alkylthio, cycloalkyl, acyl, nitro, cyano, aryl and heterocycle.

Preferred alkenyl groups are C _2-12 alkenyls, especially C _2-6 alkenyls, such as ethenyl (=vinyl), 1-methyl-1-ethenyl, 2,2-dimethyl-1-ethenyl, 1-propenyl, 2- propenyl (=allyl), 1-butenyl, 2-butenyl, 3-butenyl, 4-pentenyl, 1-methyl-4-pentenyl, 3-methyl-1-pentenyl, 1-hexenyl, 2-hexenyl and the like, optionally substituted one or more substituents selected from halogen, cyano, thiocyanato, azido, alkylthio, cycloalkyl, phenyl and acyl. Most preferred is vinyl, optionally substituted with one or more halogen atoms and/or lower alkyl, and in particular 2,2-difluorovinyl, 2,2-dibromovinyl and 2,2-dichlorovinyl.

As used herein, the term alkynyl is defined as a group comprising a monovalent branched or straight-chain hydrocarbon radical containing at least one carbon-carbon triple bond, for example, ethynyl, 2-propynyl (=propargyl) and the like, and optionally substituted with at least , one substituent selected from the group consisting of halogen, hydroxy, thiol, amino, nitro, cyano, aryl, heterocycle, thiocyanato, azido, alkylthio, alkyl and acyl. Preferred alkynyl groups are C _2-12 alkynyl, especially C _2-6 alkynyl, optionally substituted with one or more substituents selected from the following: halogen, cyano, thiocyanato, azido, alkylthio, acyl, aryl such as phenyl, and alkyl, preferably cycloalkyl.

Most preferred are ethynyl, propynyl and butynyl, optionally substituted with lower alkyl and/or halogen, and in particular 1-propynyl, cyclopropylethynyl, 3-methyl-1-butynyl and 3,3,3-trifluoro-1-propynyl.

When alkyl, alkenyl and alkynyl are present as bridging groups, they are C1-12 straight or branched chains, preferably _C1-4 alkylene or C2-12-, preferably _C2 moieties. ₄ -alkenylene or alkynylene, respectively.

Groups where branched derivatives are usually qualified by prefixes such as n, sec, iso, and the like (e.g., n-propyl, sec-butyl) are in the n-form unless otherwise noted.

As used herein, the term aryl is defined as a group comprising an organic radical derived from an aromatic hydrocarbon consisting of at least one ring, most commonly 1-3 rings and typically containing 6-30 carbon atoms, by the removal of one hydrogen atom, e.g. , phenyl and naphthyl, each of which is optionally substituted with one or more substituents independently selected from the following: halogen, hydroxy, thiol, amino, nitro, cyano, acyl, acyloxy, sulfonyl, sulfinyl, alkylamino, carboxy, ester, ether ester, amido, azido, sulfonic acid, sulfonamide, alkylsulfonyl, alkylsulfinyl, C ₁ . ₆ αlkylthio, oxyester, oxyamido, aryl, C ₁ . ₆ alkoxy, C ₆ . ₁₀ aryloxy, C ₁ . ₆ alkyl, C ₁ . ₆ haloalkyl. Aryl radicals are preferably monocyclic or bicyclic containing 6-10 carbon atoms. Preferred aryl groups are phenyl and naphthyl, each of which is optionally substituted with one or more substituents independently selected from the following: halogen, nitro, amino, azido, C ₁ . ₆ alkoxy, C ₁ _ ₆ αlkyl, C ₁ . ₆ haloalkyl, sulfonyl and phenyl.

A preferred aryl is phenyl, optionally substituted with one or more halogen, lower alkyl, azido or nitro atoms, such as 3-chlorophenyl and 3-azidophenyl.

As used herein, the term halogen includes Cl, Br, F, I atom.

As used herein, the term hydroxy refers to a group of the formula -OH.

As used herein, the term thiol refers to a group of the formula -SH.

As used herein, the term cyano refers to a group of the formula -CN.

As used herein, the term nitro refers to a group of the formula -NO2.

As used herein, the term nitrooxy refers to a group of the formula -ONO2.

As used herein, the term amino refers to a group of the formula -NH2.

As used herein, the term azido refers to a group of formula -N3.

As used herein, the term carboxy refers to a group of the formula -COOH.

As used herein, the expression sulfonic acid refers to a group of the formula -SO3H.

As used herein, the term sulfonamide refers to a group of the formula -SO ₂ NH ₂ .

As used herein, the term ester is defined as a moiety comprising a group of the formula -COO-R ¹¹ , wherein R ¹¹ is as defined above, excluding the hydroxy derivative, the thio derivative, or the amino derivative. Preferred are esters of the formula -COOR ¹¹ where R ¹¹ is selected from C ₁ . ₁₂ αlkyl, C ₂ . ₁₂ alkenyl, C ₂ . ₁₂ alkynyl and aryl. Most preferred are esters where R ¹¹ is lower alkyl, especially methyl.

As used herein, the expression ether is defined as a moiety comprising a group selected from C _{1 -50} linear or branched alkyl, or C _{2 -50} linear or branched alkenyl or alkynyl groups, or combinations thereof, interrupted by one or more oxygen atoms.

As used herein, the term amido is defined as a moiety comprising a group of the formula -CONH2, -CONHR ¹¹ or -CONR11R ¹² , where R ¹¹ and R ¹² are as defined above.

As used herein, the term heterocycle is defined as a group comprising an aromatic or non-aromatic cyclic alkyl, alkenyl or alkynyl moiety as defined above, having at least one O, S and/or N atom interrupting the carbocyclic ring structure, and optionally one of the carbocyclic carbon atoms ring structure may be replaced by carbonyl, and optionally substituted by any suitable group, including, but not limited to, one or more moieties selected from lower alkyl or other groups as described above for alkyl groups. Non-limiting examples of heterocycles include pyridyl, furyl, pyrrolyl, thienyl, isothiazolyl, triazolyl, imidazolyl, benzimidazolyl, tetrazolyl, quinazolinyl, quinolisinyl, naphthyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, isobenzofuranyl, benzothienyl, pyrazolyl , indolyl, indolizinyl, purinyl, isoindolyl, carbazolyl, thiazolyl, 1,2,4-thiadiazolyl, thiomorpholinyl, thieno(2,3-b)furanyl, furopyranyl, benzofuranyl, benzoxepinyl, isooxazolyl, oxazolyl, tianthrenyl, benzothiazolyl or benzoxazolyl, cinnolinyl, phthalazinyl, quinoxalinyl, 1- oxidopyridyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenothiazinyl, furazanil, benzodioxolyl, isochromanyl, indolinyl, xanthenyl, hypoxanthinyl, pteridinyl, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyra zolopyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperidyl, piperazinyl, imidazolidinyl, morpholino, morpholinyl, 1-oxaspiro(4.5)dec-2-yl, pyrrolidinyl, 2-oxopyrrolidinyl, sugar moieties (i.e. glucose, pentose, hexose, ribose, fructose, which may also be substituted), optionally substituted with alkyl or other groups as described above for alkyl groups. The term heterocycle also includes bicyclic, tricyclic and tetracyclic spiro groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from the following: an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, or another monocyclic heterocyclic ring, or where the monocyclic heterocyclic group is attached by a bridging alkylene group, for example, quinuclidinyl, 7-azabicyclo(2.2.1)heptanyl, 7-oxabicyclo(2.2.1)heptanyl, 8-azabicyclo(3.2.1)octanyl.

The heterocycle is preferably selected from the following: triazolyl, tetrazolyl, pyrrolidinyl, pyridyl, 1-oxidopyridyl, thiomorpholinyl, benzodioxolyl, furyl, oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl and piperazinyl, each of which is optionally substituted with one or more substituents selected from a halogen atom, alkyl, substituted alkyl, alkoxy, nitro, amino, acyl and phenyl.

More preferably, the heterocycle is selected from tetrazolyl, pyrrolidinyl, pyridyl, furyl, pyrrolyl, thiazolyl and thienyl, each of which is optionally substituted with one or more substituents selected from the following: halogen atom, alkyl, halogenated alkyl, acyl, alkoxy, nitro, amino and phenyl and in particular 2- and 3-thienyl, optionally substituted with one or more halogen atoms, acyl, for example formyl, cyano and/or lower alkyl such as methyl.

In the above definitions, it should be understood that if a substituent such as ^R1 , ^R2 , ^R3 , ^R4 , ^R5 , ^R7 , ^R8 , ^R9 , ^R10 is attached to the remainder of the molecule through a heteroatom or carbonyl, then Between the heteroatom or carbonyl and the point of attachment to the remainder of the molecule there may optionally be a linear or branched Ομ ₁₂ -, preferably a C _1-4 alkylene or C ₂ _ ₁₂ , preferably a C _2-4 alkenylene or -alkynylene bridge.

As used herein, the term substituent R independently refers to R ¹ , R ² , R ³ , R ⁴ or R ⁵ .

In a preferred embodiment, the compound of formula (I) is as defined above, where n is 0. The compound is a 6-membered ring structure (2-thioxo- or 2-oxo-piperidinyl derivative), where R ¹ is absent since n=0, and is represented by the formula (IA)

R ^{4 r6xX} ^ ^X (IA)

According to a further embodiment, the compound of formula (I) is as defined above, where n is 1. The compound is a 7-membered ring structure (2-thioxo- or 2-oxoazepanyl derivative), where R ¹ is present since n= 1, and is represented by formula (IB)

In a more preferred embodiment, said compound is as defined above, wherein n=0, R ³ and/or R ⁴ are other than a hydrogen atom, and R ² and R ⁵ represent a hydrogen atom.

According to another more preferred embodiment, the compound is as defined above, where n=1, R ² , R ³ and/or R ⁴ are other than a hydrogen atom and where R ¹ and R ⁵ represent a hydrogen atom.

According to yet another more preferred embodiment, said compound is as defined above, wherein only one substituent R selected from R ³ or R ⁴ if n=0, or from R ² , R ³ or R ⁴ if n=1 , is different from a hydrogen atom and the remaining substituent(s) R represents a hydrogen atom. Thus, monosubstituted 2-thioxo- or 2-oxopiperidinyl or 2-thioxo or 2-oxoazepanyl derivatives are contemplated.

According to another preferred embodiment, the compounds of formula (I) are as defined above, wherein A ¹ represents an oxygen atom. Thus, 2-oxopiperidinyl or 2-oxoazepanyl derivatives are contemplated.

According to another preferred embodiment, the compounds of formula (I) are as defined above, where X is CONR ⁷ R ⁸ , especially CONH2. Thus, amido derivatives of 2-oxo (or thioxo)piperidinyl or 2-oxo (or thioxo)azepanil are considered.

According to another preferred embodiment, the compounds of formula (I) are as defined above, where R ⁶ represents a hydrogen atom, C1-4 alkyl or a CH2-R ^6a group, where R ^6a represents a heterocycle. The most preferred R ⁶ is C1-4 alkyl, especially ethyl. If R ⁶ is ethyl, then derivatives of 2-(2-oxo (or thioxo)-1piperidinyl)butanamide or 2-(2-oxo(or thioxo)-1-azepanyl)butanamide are contemplated.

According to another preferred embodiment, the compounds of formula (I) are as defined above, wherein the carbon atom to which R ⁶ is attached has the S configuration. In the case where R ⁶ is ethyl, A is an oxygen atom and X is CONR7R ⁸ , derivatives of (2S)-2-(2-oxo-1-piperidinyl)butanamide or (2S)-2-(2-oxo-1) are considered -azepanil)butanamide.

According to a preferred embodiment, the compound is as defined above, wherein R ² if n=1, R ³ and R ⁴ are the same or different and each independently represents a hydrogen atom, a halogen atom, nitro, nitrooxy, cyano, carboxy , amido, sulfonic acid, sulfonamide, alkyl, alkenyl, alkynyl, ester, ether, aryl, heterocycle, acyl derivative, sulfonyl derivative or sulfinyl derivative;

R ¹ if present, R ² if n=0, and R ⁵ represent a hydrogen atom;

R ⁶ is hydrogen, alkyl, aryl or -CH ₂ -R ^6a , where R ^6a is aryl, heterocycle, halogen, hydroxy, amino, nitro or cyano.

According to this preferred embodiment, the compound is typically such if R ⁶ is benzyl, X is -COOCH3 and n=1, R ² is other than methyl if R ³ and R ⁴ are both hydrogen, and R ⁴ is other than methyl if R ² and R ³ both represent a hydrogen atom.

According to another preferred embodiment, the compound is as defined above, wherein R ² if n=1, R ³ and R ⁴ are the same or different and each independently represent a hydrogen atom; cyano; carboxy; amido;

C ₁ . ₁₂ αlkyl, each of which is optionally substituted by one or more substituents selected from hydroxy, halogen, cyano, thiocyanato, alkoxy, azido, alkylthio, cycloalkyl, acyl, aryl and heterocycle;

_C2 . ₁₂ alkenyl, each of which is optionally substituted with one or more substituents selected from halogen, cyano, thiocyanato, azido, alkylthio, alkyl, aryl and acyl;

_C2 . ₁₂ alkynyl, each of which is optionally substituted with one or more substituents selected from halogen, cyano, thiocyanato, azido, alkylthio, alkyl, aryl and acyl;

an acyl derivative of the formula -CO-R ¹¹ , where R ¹¹ is selected from C ₁ . ₁₂ alkyl, C ₂ . ₁₂ αlkenyl, C ₂ . ₁₂ αlkynyl, heterocycle and aryl;

an ester of the formula -CO-OR ¹¹ , where R ¹¹ is selected from C ₁ . ₁₂ αlkulα, C ₂ . ₁₂ alkenyl, C ₂ . ₁₂ alkynyl and aryl;

heterocycle selected from triazolyl, tetrazolyl, pyrrolidinyl, pyridyl, 1-oxidopyridyl, thiomorpholinyl, benzodioxolyl, furyl, oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl and piperazinyl, each of which is optionally substituted with one or more substituents selected from atom halogen, alkyl, substituted alkyl, alkoxy, nitro, amino, acyl and phenyl;

aryl, each of which is optionally substituted with one or more substituents selected from C ₁ . ₆ alkula, C ₁ . ₆ haloalkyl, C ₁ . ₆ alkoxy, C ₁ . ₆ alkylthio, amino, azido, sulfonyl, aryl and nitro.

According to another preferred embodiment, the compound is as defined above, wherein R ² if n=1, R ³ and R ⁴ are the same or different and each independently represent a hydrogen atom;

C ₁ .7alkyl, each of which is optionally substituted with one or more substituents selected from hydroxy, halogen, cyano, thiocyanato, alkoxy, azido, alkylthio, cyclopropyl, acyl and phenyl;

_C2 . ₆ αlkenyl, each of which is optionally substituted by one or more substituents selected from halogen, cyano, thiocyanato, azido, alkylthio, cycloalkyl, phenyl and acyl;

_C2 . ₆ alkynyl, each of which is optionally substituted with one or more substituents selected from halogen, cyano, thiocyanato, azido, alkylthio, cycloalkyl, phenyl and acyl;

a heterocycle selected from tetrazolyl, pyrrolidinyl, pyridyl, furyl, pyrrolyl, thiazolyl and thienyl, each of which is optionally substituted by one or more substituents selected from halogen, alkyl, halogenated alkyl, acyl, alkoxy, nitro, amino and phenyl;

phenyl, each of which is optionally substituted with one or more substituents selected from C ₁ . ₆ alkyl, halogenated alkyl, halogen atom, alkoxy, amino, azido, sulfonyl, phenyl and nitro.

According to another preferred embodiment, the compound is as defined above, wherein at least one of the substituents R selected from the group R ² , R ³ and R ⁴ if n=1, or from the group R ³ and R ⁴ if n =0, independently represents C ₁ . ₄ alkyl or C ₃ . ₇ cycloalkyl, optionally substituted with one or more substituents selected from halogen, hydroxy, lower alkyl and/or azido.

According to another preferred embodiment, the connection is as defined above,

- 19 044839 where at least one of the substituents R selected from the group R ² , R ³ and R ⁴ , if n=1, or from the group

R ³ and R ⁴ , when n=0, are independently vinyl, optionally substituted with one or more halogen atoms and/or lower alkyls.

According to another preferred embodiment, the compound is as defined above, wherein at least one of the substituents R selected from the group R ² , R ³ and R ⁴ if n=1, or from the group R ³ and R ⁴ if n =0, independently represents ethynyl, propynyl or butynyl, optionally substituted with one or more halogen atoms and/or lower alkyls.

According to another preferred embodiment, the compound is as defined above, wherein at least one of the substituents R selected from the group R ² , R ³ and R ⁴ if n=1, or from the group R ³ and R ⁴ if n =0, independently represents phenyl, optionally substituted with one or more halogen, lower alkyl, azido and/or nitro atoms.

According to another preferred embodiment, the compound is as defined above, wherein at least one of the substituents R selected from the group R ² , R ³ and R ⁴ if n=1, or from the group R ³ and R ⁴ if n =0, independently represents 2- or 3-thienyl, optionally substituted with one or more substituents selected from halogen, acyl, cyano and/or lower alkyl.

According to a particular preferred embodiment, the compound is as defined above, wherein at least one of the substituents R selected from the group R ² , R ³ and R ⁴ if n=1, or from the group R ³ and R ⁴ if n =0, represents hydroxymethyl, propyl, butyl, 3,3,3-trifluoropropyl, 2,2,2-trifluoroethyl, cyclopropylmethyl, iodomethyl, azidomethyl, 2-thienyl, 3-thienyl, phenyl, 3-chlorophenyl, 3-azidophenyl , 2,2-difluorovinyl, 2,2-dibromovinyl, 2,2-dichlorovinyl, 2-ethynyl, 5-methyl-2-thienyl, 5-formyl-2-ethynyl, 5-cyano-2-thienyl, 3-bromo -2-thienyl, 4-methyl-2-thienyl, 3,3,3-trifluoro-1-propynyl, 1-propynyl, cyclopropylethynyl, 3-methyl-1-butynyl, 1-butynyl, 2,2-difluoropropyl, 2 -chloro-2,2-difluoroethyl, 2-bromo-2,2-difluoroethyl and 2-iodo-2,2-difluoroethyl.

According to another preferred embodiment, the compound is as defined above, wherein R ¹ , R ² , R ⁴ and R ⁵ represent a hydrogen atom.

According to another preferred embodiment, the compound is as defined above, wherein R ¹ , R ² , R ³ and R ⁵ represent a hydrogen atom.

According to another preferred embodiment, the compound is as defined above, where n=1 and R ¹ , R ³ , R ⁴ and R ⁵ represent a hydrogen atom.

In all the regions mentioned above, if the carbon atom to which R ⁶ is attached is asymmetric, it preferably has the S configuration.

Exemplary compounds useful in the methods and compositions of this invention as defined above are selected from the group consisting of:

- 20 044839

2-[5-(hydroxymethyl)-2-oxo-1-piperidinyl]butanamide,

2-(2-oxo-5-propyl-1-piperidinyl)butanamide,

2-[2-OXO-5-(3,3,3-trifluoropropyl)-1-piperidinyl]butanamide

2-[5-(cyclopropylmethyl)-2-oxo-1-piperidinyl]butanamide,

2-[5-(iodomethyl)-2-oxo-1-piperidinyl]butanamide,

2-[5-(azidomethyl)-2-oxo-1-piperidinyl]butanamide,

2-(2-oxo-5-phenyl-1-piperidinyl)butanamide,

2-[2-OXO-5-(2-thienyl)-1-piperidinyl]butanamide,

2-[2-OXO-5-(3-thienyl)-1-piperidinyl]butanamide,

2-[5-(3-chlorophenyl)-2-oxo-1-piperidinyl]butanamide,

2-[5-(3-azidophenyl)-2-oxo-1-piperidinyl]butanamide,

2-[5-(2,2-difluorovinyl)-2-oxo-1-piperidinyl]butanamide,

2-[5-(2,2-dibromovinyl)-2-oxo-1-piperidinyl]butanamide,

2-[5-(2,2-dichlorovinyl)-2-oxo-1-piperidinyl]butanamide,

2-(5-ethynyl-2-oxo-1-piperidinyl)butanamide,

2[5-(5-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,

2-[5-(5-formyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,

2-[5-(5-cyano-2-thienyl)-2-oxo-1-piperidinyl]butanamide,

2-[5-(3-bromo-2-thienyl)-2-oxo-1-piperidinyl]butanamide,

2-[5-(4-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,

2-[2-OXO-5-(3,3,3-trifluoro-1-propynyl)-1piperidinyl]butanamide,

2-[2-oxo-5-(1-propynyl)-1-piperidinyl]butanamide,

2-[5-(cyclopropylethynyl)-2-oxo-1-piperidinyl]butanamide,

2-[5-(3-methyl-1-butynyl)-2-oxo-1-piperidinyl]butanamide,

2-[5-(1-butynyl)-2-oxo-1-piperidinyl]butanamide,

2-[5-(2,2-difluoropropyl)-2-oxo-1-piperidinyl]butanamide,

2-[5-(2-chloro-2,2-difluoroethyl)-2-oxo-1piperidinyl]butanamide,

- 21 044839

2-[5-(2-bromo-2,2-difluoroethyl)-2-oxo-1piperidinyl]butanamide,

2-[4-(hydroxymethyl)-2-oxo-1-piperidinyl]butanamide,

2-(2-oxo-4-propyl-1-piperidinyl)butanamide,

2-[2-OXO-4-(3,3,3trifluoropropyl)-1-piperidinyl]butanamide,

2-[4-(cyclopropylmethyl)-2-oxo-1-piperidinyl]butanamide,

2-[4-(iodomethyl)-2-oxo-1-piperidinyl]butanamide,

2-[4-(azidomethyl)-2-oxo-1-piperidinyl]butanamide,

2-(2-oxo-4-phenyl-1-piperidinyl)butanamide,

2-[2-OXO-4-(2-thienyl)-1-piperidinyl]butanamide,

2-[2-OXO-4-(3-thienyl)-1-piperidinyl]butanamide,

2-[4-(3-chlorophenyl)-2-oxo-1-piperidinyl]butanamide,

2-[4-(3-azidophenyl)-2-oxo-1-piperidinyl]butanamide,

2-[4-(2,2-difluorovinyl)-2-oxo-1-piperidinyl]butanamide,

2-[4-(2,2-dibromovinyl)-2-oxo-1-piperidinyl]butanamide,

2-[4-(2,2-dichlorovinyl)-2-oxo-1-piperidinyl]butanamide,

2-(4-ethynyl-2-oxo-1-piperidinyl)butanamide,

2-[4-(5-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,

2-[4-(5-formyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,

2-[4-(5-cyano-2-thienyl)-2-oxo-1-piperidinyl]butanamide,

2-[4-(3-bromo-2-thienyl)-2-oxo-1-piperidinyl]butanamide,

2-[4-(4-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,

2-[2-OXO-4-(3,3,3-trifluoro-1-propynyl)-1piperidinyl]butanamide,

2-[2-oxo-4-(1-propynyl)-1-piperidinyl]butanamide,

2-[4-(cyclopropylethynyl)-2-oxo-1-piperidinyl]butanamide,

2-[4-(3-methyl-1-butynyl)-2-oxo-1-piperidinyl]butanamide,

2-[4-(1-butynyl)-2-oxo-1-piperidinyl]butanamide,

2-[4-(2,2-difluoropropyl)-2-oxo-1-piperidinyl]butanamide,

2-[4-(2-chloro-2,2-difluoroethyl)-2-oxo-1piperidinyl]butanamide,

2-[4-(2-bromo-2,2-difluoroethyl)-2-oxo-1piperidinyl]butanamide,

2-(4-(2,2,2-trifluoroethyl)-2-oxo-1-piperidinyl]butanamide,

2-[5-(hydroxymethyl)-2-oxo-1-azepanyl]butanamide,

2-(2-oxo-5-propyl-1-azepanyl)butanamide,

- 22 044839

2-[2-OKCO-5-(3,3,3-trifluoropropyl)-1-azepanyl]butanamide,

2-[5-(cyclopropylmethyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(iodomethyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(azidomethyl)-2-oxo-1-azepanyl]butanamide,

2-(2-oxo-5-phenyl-1-azepanyl)butanamide,

2-[2-OXO-5-(2-thienyl)-1-azepanyl]butanamide,

2-[2-OXO-5-(3-thienyl)-1-azepanyl]butanamide,

2-[5-(3-chlorophenyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(3-azidophenyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(2,2-difluorovinyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(2,2-dibromovinyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(2,2-dichlorovinyl)-2-oxo-1-azepanyl]butanamide,

2-(5-ethynyl-2-oxo-1-azepanyl)butanamide,

2-[5-(5-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(5-formyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(5-cyano-2-thienyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(3-bromo-2-thienyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(4-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,

2-[2-OXO-5-(3,3,3-trifluoro-1-propynyl)-1azepanyl]butanamide,

2-[2-OXO-5-(1-propynyl)-1-azepanyl]butanamide,

2-[5-(cyclopropylethynyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(3-methyl-1-butynyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(1-butynyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(2,2-difluoropropyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(2-chloro-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(2-bromo-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(2,2,2-trifluoroethyl)-2-oxo-1-azepanyl]butanamide,

2-[6-(hydroxymethyl)-2-oxo-1-azepanyl]butanamide,

2-(2-oxo-6-propyl-1-azepanyl)butanamide,

2-[2-oxo-b-(3,3,3-trifluoropropyl)-1-azepanyl]butanamide,

2-[6-(cyclopropylmethyl)-2-oxo-1-azepanyl]butanamide,

2-[6-(iodomethyl)-2-oxo-1-azepanyl]butanamide,

2-[6-(azidomethyl)-2-oxo-1-azepanyl]butanamide,

2-(2-oxo-6-phenyl-1-azepanyl)butanamide,

2-[2-oxo-b-(2-thienyl)-1-azepanyl]butanamide,

- 23 044839

2-[2-oxo-b-(3-thienyl)-1-azepanyl]butanamide,

2-[6-(3-chlorophenyl)-2-oxo-1-azepanyl]butanamide,

2-[6-(3-azidophenyl)-2-oxo-1-azepanyl]butanamide,

2-(6-(2,2-difluorovinyl)-2-oxo-1-azepanyl]butanamide,

2-(6-(2,2-dibromovinyl)-2-oxo-1-azepanyl]butanamide,

2-(6-(2,2-dichlorovinyl)-2-oxo-1-azepanyl]butanamide,

2-(6-ethynyl-2-oxo-1-azepanyl)butanamide,

2-[6-(5-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,

2-[6-(5-formyl-2-thienyl)-2-oxo-1-azepanyl1butanamide,

2-(6-(5-cyano-2-thienyl)-2-oxo-1-azepanyl]butanamide,

2-[6-(3-bromo-2-thienyl)-2-oxo-1-azepanyl]butanamide,

2-[6-(4-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,

2-[2-oxo-b-(3,3,3-trifluoro-1-propynyl)-1|azepanyl]butanamide,

2-[2-oxo-b-(1-propynyl)-1-azepanyl]butanamide,

2-[6-(cyclopropylethynyl)-2-oxo-1-azepanyl]butanamide,

2-[6-(3-methyl-1-butynyl)-2-oxo-1-azepanyl]butanamide,

2-[6-(1-butynyl)-2-oxo-1-azepanyl]butanamide,

2-(6-(2,2-difluoropropyl)-2-oxo-1-azepanyl]butanamide,

2-[6-(2-chloro-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,

2-[6-(2-bromo-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,

2-(6-(2,2,2-trifluoroethyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(hydroxymethyl)-2-oxo-1-azepanyl]butanamide,

2-(2-oxo-4-propyl-1-azepanyl)butanamide,

2-[2-OXO-4-(3,3,3-trifluoropropyl)-1-azepanyl]butanamide,

2-[4-(cyclopropylmethyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(iodomethyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(azidomethyl)-2-oxo-1-azepanyl]butanamide,

2-(2-oxo-4-phenyl-1-azepanyl)butanamide,

2-[2-OXO-4-(2-thienyl)-1-azepanyl]butanamide,

2-[2-OXO-4-(3-thienyl)-1-azepanyl]butanamide,

2-[4-(3-chlorophenyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(3-azidophenyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(2,2-difluorovinyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(2,2-dibromovinyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(2,2-dichlorovinyl)-2-oxo-1-azepanyl]butanamide,

2-(4-ethynyl-2-oxo-1-azepanyl)butanamide,

2-[4-(5-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(5-formyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(5-cyano-2-thienyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(3-bromo-2-thienyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(4-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,

2-[2-OXO-4-(3,3,3-trifluoro-1-propynyl)-1azepanyl]butanamide,

2-[2-OXO-4-(1-propynyl)-1-azepanyl]butanamide,

2-[4-(cyclopropylethynyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(3-methyl-1-butynyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(1-butynyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(2,2-difluoropropyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(2-chloro-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(2-bromo-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,

2-(4-(2,2,2-trifluoroethyl)-2-oxo-1-azepanyl]butanamide.

In some embodiments, compounds useful in the methods and compositions of this invention are selected from the group consisting of:

- 24 044839 (2S)-2-[5-(iodomethyl)-2-oxo-1-piperidinyl]butanamide, (2S)-2-[5-(azidomethyl)-2-oxo-1-piperidinyl]butanamide,

2-(2-oxo-5-phenyl-1-piperidinyl]butanamide, (2S)-2-[4-(iodomethyl)-2-oxo-1-piperidinyl]butanamide,

2-[5-(iodomethyl)-2-oxo-1-azepanyl]butanamide.

w) International patent application WO 2004/087658: compound having formula (I), or pharmaceutically acceptable salts or stereoisomeric forms thereof:

where R ¹ denotes a hydrogen atom;

R ² represents a hydrogen atom or C _1-20 alkyl;

R ³ is a hydrogen atom, C1-20alkyl, C4-8cycloalkyl, C5-8cycloalkenyl, aryl, aromatic or non-aromatic heterocycle, C1-20alkoxy or a group of the formula -WR ⁸ , R ^3a is a hydrogen atom, C1-20alkyl or a group of the formula

or NR ³ R ^3a represents a group of the formula

R ⁴ represents a hydrogen atom;

R ⁵ represents a hydrogen atom; nitro; halogen atom; azido; cyano; -SC _1-4 alkyl; -SO-C _1-4 alkyl; -SO ₂ -C _1-4 alkyl; -SONH _2; C _1-20 alkyl, unsubstituted or substituted with a halogen atom; or C _1-20 alkoxy, unsubstituted or substituted with a halogen atom;

R ⁶ represents a hydrogen atom, a C _1-20 alkyl or a halogen atom;

R ⁷ represents a hydrogen atom, C _1-20 alkyl or a halogen atom;

W is C _1-12 alkylene, -NH- or -NHC(=O)-;

X is O, S or NH;

Y is O, S, -CR ¹² R ¹³ -, -NR ¹⁴ - or -C(=O)-;

R ⁸ is aryl or heterocycle;

R ⁹ , R ¹⁰ , R ^10a and R ¹¹ are independently selected from hydrogen, C _1-4 alkyl, halogen, hydroxy or methoxycarbonyl atoms;

or R ¹⁰ and R ^10a together form a C _3-6 alkylene;

R ¹² represents a hydrogen atom, C _1-4 alkyl, halogen or hydroxy atom;

R ¹³ is a hydrogen atom or CR ¹² R ¹³ is dioxolanyl;

R ¹⁴ is aryl, heterocycle or a group of the formula -VR ¹⁵ ;

V is C _1-12 alkylene;

R ¹⁵ is aryl or heterocycle, m is from 1 to 4;

n is 0 or 1; and at least one of ^R5 , ^R6 or ^R7 is other than a hydrogen atom if ^R2 is a hydrogen atom, ^R3 is H or 2,6-diisopropylphenyl and ^R3a is H.

In another aspect, the compound is a compound of formula (I) or pharmaceutically acceptable salt or stereoisomeric forms thereof:

where R ¹ denotes a hydrogen atom;

R ² represents a hydrogen atom or C _1-20 alkyl;

R ³ represents a hydrogen atom, C _1-20 alkyl, C _4-8 cycloalkyl, C _5-8 cycloalkenyl, aryl, an aromatic or non-aromatic heterocycle, C _1-20 alkoxy or a group of the formula WR ⁸ ;

R ^3a represents a hydrogen atom, C _1-20 alkyl or a group of the formula

or NR ³ R ^3a represents a group of the formula

- 25 044839

R ⁴ represents a hydrogen atom;

R ⁵ represents a hydrogen atom; nitro; halogen atom; C _1-20 alkyl, unsubstituted or substituted by a halogen atom; or C _1-20 alkoxy, unsubstituted or substituted with a halogen atom;

R ⁶ represents a hydrogen atom, C _1-20 alkyl or a halogen atom;

R ⁷ represents a hydrogen atom, a C _1-20 alkyl or a halogen atom,

W is C _1-12 alkylene, -NH- or -NHC(=O)-;

X is O, S or NH;

Y is O, S, -CR12R ¹³ -, -NR ¹⁴ - or -C(=O)-;

R ⁸ is aryl or heterocycle;

R ⁹ , R ¹⁰ , R ^10a and R ¹¹ are independently selected from hydrogen, C _1-4 alkyl, halogen, hydroxy or methoxycarbonyl; or

R ¹⁰ and R ^10a together form C _3-6 alkylene;

R ¹² represents a hydrogen atom, C _1-4 alkyl, halogen or hydroxy atom;

R ¹³ represents a hydrogen atom;

or CR12R ¹³ is dioxolanil;

R ¹⁴ is aryl, heterocycle or a group of the formula -VR ¹⁵ ;

V is C _1-12 alkylene;

R ¹⁵ is aryl or heterocycle;

m is from 1 to 4;

n is 0 or 1; and at least one of ^R5 , ^R6 and ^R7 is other than a hydrogen atom if ^R2 is a hydrogen atom, ^R3 is H or 2,6-diisopropylphenyl and ^R3a is H.

As used herein, the term alkyl is defined as a group comprising saturated, monovalent hydrocarbon radicals having linear, branched or cyclic moieties or combinations thereof and containing 1-20 carbon atoms, preferably 1-6 carbon atoms and more preferably 1-4 carbon atoms for non-cyclic alkyl and 3-8 carbons for cycloalkyl. The allyl moieties may be optionally substituted with 1 to 5 substituents independently selected from halogen, hydroxy, alkoxy, alkoxycarbonyl, ester or alkylamino. Preferred alkyl groups are methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, n-butyl, 2-fluoroethyl, 3-hydroxypropyl, 3-hydroxy-2,2-dimethylpropyl, 1-(hydroxymethyl)propyl, 3,3,3 -trifluoro2-hydroxypropyl, 3-ethoxypropyl, 2-ethoxy-2-oxoethyl and 3-(dimethylamino)propyl.

As used herein, the term cycloalkyl refers to a monovalent group of 3-18 carbon atoms, preferably 4-8 carbon atoms, derived from a saturated cyclic or polycyclic hydrocarbon, which may be substituted by any suitable group, including, but not limited to, one or more moieties selected from groups as described above for alkyl groups. A preferred cycloalkyl group is cycloheptyl.

As used herein, the term alkylene represents a divalent alkyl group having linear or branched moieties containing 1-12 carbon atoms, preferably 1-6 carbon atoms, and optionally substituted with any suitable group, including, but not limited to, one or more moieties selected from groups as described above for alkyl groups. Preferred alkylene groups are methylene, ethylene, hydroxyethylene, trimethylene or propylene.

As used herein, the term cycloalkenyl is defined as a cyclic unsaturated hydrocarbon radical having at least one double bond, containing 4-20 carbon atoms, preferably 5-8 carbon atoms, and optionally substituted by any suitable group, including, but not limited to, one or more moieties selected from the groups described above for alkyl groups. A preferred cycloalkenyl group is 6-(hydroxymethyl)cyclohex-3-en-1-yl.

As used herein, the term aryl is defined as a group comprising an organic radical derived from an aromatic hydrocarbon containing 1-3 rings and containing 6-30 carbon atoms by the removal of one hydrogen atom, for example, phenyl and naphthyl, each of which is optionally substituted with 1-5 substituents , independently selected from halogen, hydroxy, nitro, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylsulfonyl, trifluoromethylthio or pyridinyl alkyl. Aryl radicals are preferably phenyl radicals. Preferred aryl groups are phenyl, 3-hydroxyphenyl, 3-fluorophenyl, 3-methylphenyl, 4-methylphenyl, 4-hydroxyphenyl, 4hydroxy-3-methoxyphenyl, 3-(2-pyridin-2-ylethyl)phenyl, 3,4-dimethylphenyl , 4-tert-butylphenyl, 4methylsulfonylphenyl, 2-nitrophenyl, 2-chloro-6-fluorophenyl, 2-[(trifluoromethyl)thio]phenyl, 2-chlorophenyl, or 4-bromophenyl.

- 26 044839

As used herein, the term halogen includes Cl, Br, F, I atom.

As used herein, the term nitro refers to a group of the formula -NO2.

As used herein, the term hydroxy refers to a group of the formula -OH.

As used herein, the term alkoxy refers to a group of the formula -OR ^b , where R ^b denotes an alkyl group as defined above.

As used herein, the term ester denotes a group of the formula -COORc, where Rc denotes an alkyl group or aryl group as defined above.

As used herein, the term alkoxycarbonyl refers to a group of the formula -COORd, where R ^d denotes an alkyl group as defined above.

As used herein, the term amino refers to a group of the formula -NH2.

As used herein, the term alkylamino refers to a group of the formula -NHR ^e or -NR ^e Rf, where R ^e and R ^f denote alkyl groups as defined above.

As used herein, the term alkylsulfonyl is defined as a typical group of the formula -SO2-R ⁶ where R ^g is C ₁ . ₄ -alkyl.

As used herein, the term heterocycle is defined as a group comprising an aromatic or non-aromatic cycloalkyl or cycloalkenyl moiety as defined above, having at least one O, S and/or N atom interrupting the carbocyclic ring structure, and optionally one of the carbons of the carbocyclic ring structure may be substituted with carbonyl.

Non-limiting examples of aromatic heterocycles include pyrazolyl, furyl, imidazolyl, triazolyl, oxazolyl, pyridinyl, pyrrolyl, thienyl, isothiazolyl, benzimidazolyl, tetrazolyl, isooxazolyl, oxazolyl, thiazolyl, 1,2,4-thiadiazolyl, oxadiazole, pyridazinyl, pyrimidinyl, pyrazinyl , isoindolyl , triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, quinazolinyl, quinolizinyl, naphthyridinyl, quinolyl, isoquinolyl, isobenzofuranyl, benzothienyl, indolyl, indolizinyl, purinyl, carbazolyl, thieno(2,3-b)furanyl, thianthrenyl, benzothiazolyl , benzoxazolyl, cinnolinyl, quinoxalinil , phenothiazinyl, isochromanyl and xanthenyl, optionally substituted with 1-5 substituents independently selected from halogen, hydroxy, thiol, amino, nitro, cyano, azido, C ₁ . ₆ alkoxy, C ₁ . ₆ αlkylthio, C ₁ . ₆ alkyl, C ₁ . ₆ haloalkyl, formyl or ester. More preferred aromatic heterocycles are pyrazolyl, furyl, imidazolyl, triazolyl, oxazolyl and pyridinyl.

Non-limiting examples of non-aromatic heterocycles include tetrahydrofuranyl, piperidinyl, piperidyl, piperazinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, thiazolidinyl, indolinyl, tetrahydrobenzazocinyl, dihydroisochromenyl, tetrahydropyranyl, oxooctahydroquinolinyl, dioxo Lanil, 1-oxaspiro(4.5)dec-2-yl, pyrrolidinyl, 2 -oxo-pyrrolidinyl, 8-thiabicyclo[3.2.1]cyclooctanyl, 1,4-dithiepanyl, tetrahydro-2H-thiopyranyl, azepanyl and azocanyl, optionally substituted with 1-5 substituents independently selected from halogen, hydroxy, thiol, amino, nitro, cyano, azido, C ₁ . ₆ αлkOkсu, C ₁ . ₆ alkylthio, C ₁ .6 alkyl, C ₁ . ₆ haloalkylα, formyl or ester. More preferred non-aromatic heterocycles are tetrahydrofuranyl, piperidinyl, piperidyl, piperazinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, thiazolidinyl, indolinyl, tetrahydro-1-benzazocin-1(2H)-yl, 3,4-dihydro-1H-isochromen-1- yl, tetrahydropyranyl, oxooctahydroquinolinyl and dioxolanil. The term heterocycle also includes bicyclic, tricyclic and tetracyclic spiro groups in which any of the above heterocyclic rings is fused with one or two rings independently selected from an aryl ring, a cycloalkyl ring, a cycloalkenyl ring or other monocyclic heterocyclic ring, or wherein a monocyclic heterocyclic group is attached a bridged alkylene group, for example quinuclidinyl, 7-azabicyclo(2.2.1)heptanyl, 7-oxabicyclo(2.2.1)heptanyl and 8-azabicyclo(3.2.1)octanyl.

As used herein, the term pyridinyl alkyl represents a group of the formula -R ^h -pyridinyl, in which R ^h is C ₁ . ₄ αalkylene.

As used herein, the term azido represents a group of formula -N ₃ .

As used herein, the term cyano represents a group of the formula -CN.

R ² usually represents a hydrogen atom or C ₁ . ₄ alkyl.

Preferred R ² is hydrogen, methyl or ethyl. More preferably, R ² is hydrogen or methyl.

R ³ usually represents a hydrogen atom; C ₁ . ₆ αlkyl, unsubstituted or substituted with 1-5 substituents selected from halogen, hydroxy, alkoxy, alkoxycarbonyl or alkylamino; _C5 . ₇ cycloalkyl; (hydroxymethyl)cyclohexenyl; phenyl, unsubstituted or substituted with 1-5 substituents selected from the halogen atom, C ₁ . ₄ alkyl, hydroxy, methoxy, nitro, methylsulfonyl, trifluoromethylthio or pyridinyl alkyl; pyridinyl, unsubstituted or substituted with methoxy; triazolyl; C ₁ . ₄ αlkoxy or a group of the formula -WR ⁸ , where:

W usually denotes C ₁ . ₄ alkylene, unsubstituted or substituted with a halogen atom, hydroxy, C ₁ . ₄ αlkyl or alkoxy; -NH- or -NHC(=O)-; And

- 27 044839

R ⁸ is phenyl, unsubstituted or substituted with 1 to 5 substituents selected from halogen, C _1-4 alkyl, hydroxy, methoxy, nitro, methylsulfonyl or trifluoromethylthio; furyl, unsubstituted or substituted with methyl; pyrazolyl; pyridinyl; morpholinyl; tetrahydrobenzazocinyl; piperidinyl, unsubstituted or substituted with methyl; dihydroisochromenyl or dihydroimoidazolyl.

Preferred R ³ is hydrogen, n-butyl, cycloheptyl, 2-fluoroethyl, 3-hydroxypropyl, 3-hydroxy-2,2-dimethylpropyl, 1-(hydroxymethyl)propyl, 3,3,3-trifluoro-2-hydroxypropyl, 3-ethoxypropyl, 2-ethoxy-2-oxoethyl, 3-(dimethylamino)propyl, 6-(hydroxymethyl)cyclohex-3-en-1-yl, 3-hydroxyphenyl, 3-fluorophenyl, 3-(2-pyridin-2 -ylethyl)phenyl, 3,4-dimethylphenyl, 4-tert-butylphenyl, benzyl, 4-hydroxy-3-methoxybenzyl, 4-methylsulfonylbenzyl, 2-nitrobenzyl, 2-chloro-6-fluorobenzyl, 2-[(trifluoromethyl)thio ]benzyl, 2-hydroxy-2-phenylethyl, 2-(3,4-dimethoxyphenyl)ethyl, 2-(2-chlorophenyl)ethyl, 2-(4-methylphenyl)ethyl, (4-bromophenyl)amino, pyridine-3 -yl, 6-methoxypyridin-3-yl, 4H-1,2,4triazol-3-yl, pyridin-4-ylmethyl, (5-methyl-2-furyl)methyl, 3-(1H-pyrazol-1-yl )propyl, 2-morpholin-4ylethyl, 2-((3,4,5,6-tetrahydro-1-benzazocin-1 (2Sh-yl)propyl, 2-(2-methylpiperidin-1 -yl)ethyl,

3,4-dihydro-1H-isochromen-1-ylmethyl, methoxy, (4-pyridinylcarbonyl)amino or 4,5-dihydro-1Himidazol-2-ylamino. More preferably, R ³ is a hydrogen atom. R ^a typically represents a hydrogen atom, a C _1-4 alkyl, or a group of the formula

L Jm\ / where m is from 1 to 4.

Preferred R ^3a is hydrogen, methyl or tetrahydrofuran-2-ylmethyl. More preferred R ^3a is a hydrogen atom.

In another embodiment, NR ³ R ^3a is piperidinyl, unsubstituted or substituted with hydroxy; thiomorpholinyl; thiazolidinyl, unsubstituted or substituted with C _1-4 alkoxycarbonyl; 2,5-dihydro-III-pyrrol-1-yl; 1,4-dioxa-8-azaspiro[4.5]dec-8-yl; 4-oxooctahydro-1(2H)-quinolinyl; or a group of the formula -g/ in ¹⁴ where R ¹⁴ denotes pyridinyl; phenyl, unsubstituted or substituted with a halogen atom, hydroxy, C _1-4 alkyl; or a group of formula -VR ¹⁵ where V is unsubstituted C _1-4 alkylene and R ¹⁵ is phenyl or morpholinyl.

In a preferred embodiment, NR ³ R ^3a is 4-pyridin-2-ylpiperazin-1-yl, 4-(3-methylphenyl)piperazin-1-yl, 4-(4-hydroxyphenyl)piperazin-1-yl, 4-( 2-phenylethyl)piperazin-1-yl, 4-(2-morpholin-4-ylethyl)piperazin-1-yl, 3-hydroxypiperidin-1-yl, thiomorpholin-4-yl, 4-methoxycarbonyl-1,3-thiazolidine -3-yl, 2,5-dihydro-1H-pyrrol-1-yl, 1,4-dioxa-8-azaspiro[4.5]dec-8-yl or 4-oxooctahydro-1(2H)-quinolinyl.

Typically, R ⁵ is hydrogen, nitro, halogen, C _1-4 alkyl, unsubstituted or substituted by halogen, or C _1-4 alkoxy, unsubstituted or substituted by halogen.

Preferred R ⁵ is hydrogen, methyl, ethyl, trifluoromethyl, trifluoromethoxy, npropyl, isopropyl, nitro or halogen. More preferably, R ⁵ is a halogen or trifluoromethyl atom.

R ⁶ typically represents a hydrogen atom, a C _1-6 alkyl atom, or a halogen atom.

Preferred R ⁶ is hydrogen, methyl or Cl. More preferably, R ⁶ is a hydrogen atom.

R ⁷ usually represents a hydrogen atom, methyl or a halogen atom.

Preferred R ⁷ is hydrogen, methyl, Br, F or Cl. More preferably, R ⁷ is hydrogen, Br or F.

Particularly preferred are combinations of one or more compounds from these preferred groups.

Preferably, the compound is a compound having formula (I) or pharmaceutically acceptable salt or stereoisomeric forms thereof:

where R ¹ denotes a hydrogen atom;

R ² represents a hydrogen atom or C _1-4 alkyl;

R ³ represents a hydrogen atom; C _1-6 alkyl, unsubstituted or substituted with 1-5 substituents selected from halogen, hydroxy, alkoxy, alkoxycarbonyl or alkylamino; C _5-7 cycloalkyl; (hydroxymethyl)cyclohexenyl; phenyl, unsubstituted or substituted with 1-5 substituents selected from halogen, C _1-4 alkyl, hydroxy, methoxy, nitro, methylsulfonyl, trifluoromethylthio or pyri- 28 044839 dinylalkyl; pyridinyl, unsubstituted or substituted with methoxy; triazolyl; C _1-4 alkoxy or a group of the formula -WR ⁸ ;

R ^3a represents a hydrogen atom, C _1-4 alkyl or a group of the formula

or NR ³ R ^3a is piperidinyl, unsubstituted or substituted with hydroxy; thiomorpholinyl; thiazolidinyl, unsubstituted or substituted with C _1-4 -alkoxycarbonyl; 2,5-dihydroIII-pyrrol-1-yl; 1,4-dioxa-8-azaspiro[4.5]dec-8-yl; 4-oxooctahydro-1(2H)-quinolinyl, or a group of the formula

R ⁴ represents a hydrogen atom;

R ⁵ represents a hydrogen atom; nitro; halogen atom; C _1-4 alkyl, unsubstituted or substituted with a halogen atom; or C _1-4 alkoxy, unsubstituted or substituted with a halogen atom;

R ⁶ represents a hydrogen atom, C _1-6 allyl or a halogen atom;

R ⁷ represents a hydrogen atom, methyl or a halogen atom;

W is C _1-4 alkylene, unsubstituted or substituted by halogen, hydroxy, C _1-4 alkyl or alkoxy; -NH-, or -NHC(=O)-;

R ⁸ is phenyl, unsubstituted or substituted with 1 to 5 substituents selected from halogen, C _1-4 alkyl, hydroxy, methoxy, nitro, methylsulfonyl or trifluoromethylthio; furyl, unsubstituted or substituted with methyl; pyrazolyl; pyridinyl; morpholinyl; tetrahydrobenzazocinyl; piperidinyl, unsubstituted or substituted with methyl; dihydroisochromenyl or dihydroimoidazolyl;

R ¹⁴ is pyridinyl; phenyl, unsubstituted or substituted with a halogen atom, hydroxy, C _1-4 alkyl; or a group of the formula -VR ¹⁵ ;

V is unsubstituted C _1-4 alkylene;

R ¹⁵ is phenyl or morpholinyl;

m is from 1 to 4;

at least one of ^R5 , ^R6 and ^R7 is other than a hydrogen atom if ^R2 is a hydrogen atom, ^R3 is H or 2,6-diisopropylphenyl and ^R3a is H.

More preferably, the compound is a compound having formula (I) or pharmaceutically acceptable salt or stereoisomeric forms thereof:

where R ¹ denotes a hydrogen atom;

R ² is hydrogen, methyl or ethyl;

R ³ is hydrogen, n-butyl, cycloheptyl, 2-fluoroethyl, 3-hydroxypropyl, 3-hydroxy-2,2dimethylpropyl, 1-(hydroxymethyl)propyl, 3,3,3-trifluoro-2-hydroxypropyl, 3-ethoxypropyl , 2-ethoxy2-oxoethyl, 3-(dimethylamino)propyl, 6-(hydroxymethyl)cyclohex-3-en-1-yl, 3-hydroxyphenyl, 3-fluorophenyl, 3-(2-pyridin-2-ylethyl)phenyl, 3,4-dimethylphenyl, 4-tert-butylphenyl, benzyl, 4-hydroxy-3methoxybenzyl, 4-methylsulfonylbenzyl, 2-nitrobenzyl, 2-chloro-6-fluorobenzyl, 2-[(trifluoromethyl)thio]benzyl, 2-hydroxy- 2-phenylethyl, 2-(3,4-dimethoxyphenyl)ethyl, 2-(2-chlorophenyl)ethyl, 2-(4-methylphenyl)ethyl, (4-bromophenyl)amino, pyridin-3-yl, 6-methoxypyridin- 3-yl, 4H-1,2,4-triazol-3-yl, pyridin-4-ylmethyl, (5-methyl-2-furyl)methyl, 3-(1H-pyrazol-1-yl)propyl, 2- morpholin-4-ylethyl, 2-((3,4,5,6tetrahydro-1-benzazocin-1 (2H)-yl)propyl, 2-(2-methylpiperidin-1 -yl)ethyl, 3,4-dihydro- 1 H-isochromen1-ylmethyl, methoxy, (4-pyridinylcarbonyl)amino or 4,5-dihydro-1H-imidazol-2-ylamino;

R ^3a represents a hydrogen atom, methyl or tetrahydrofuran-2-ylmethyl or

NR ³ R ^3a is 4-pyridin-2-ylpiperazin-1-yl, 4-(3-methylphenyl)piperazin-1-yl, 4-(4-hydroxyphenyl)piperazin-1-yl, 4-(2-phenylethyl) )piperazin-1-yl, 4-(2-morpholin-4-ylethyl)piperazin-1-yl, 3-hydroxypiperidin-1-yl, thiomorpholin-4-yl, 4-methoxycarbonyl-1,3-thiazolidin-3yl, 2,5-dihydro-1H-pyrrol-1-yl, 1,4-dioxa-8-azaspiro[4.5]dec-8-yl or 4-oxooctahydro-1(2H)quinolinyl;

R ⁴ represents a hydrogen atom;

R ⁵ represents a hydrogen atom, methyl, ethyl, trifluoromethyl, trifluoromethoxy, n-propyl, isopropyl, nitro or halogen atom;

R ⁶ is hydrogen, methyl or Cl;

R ⁷ is hydrogen, methyl, Br, F or Cl;

at least one of ^R5 , ^R6 and ^R7 is other than a hydrogen atom if ^R2 is a hydrogen atom, ^R3 is H or 2,6-diisopropylphenyl and ^R3a is H.

More preferably, if R ² is a hydrogen atom or methyl, R ³ is a hydrogen atom,

- 29 044839

R ^3a is a hydrogen atom, R ⁵ is a halogen or trifluoromethyl, R ⁶ is a hydrogen atom and

R ⁷ represents a hydrogen atom, Br or F.

In all the regions mentioned above, if R ² is C^alkyl, then the carbon atom to which R ² is attached preferably has the S configuration.

In some embodiments, compounds useful in the methods and compositions of this invention are selected from the group consisting of:

2-(5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide;

2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide;

2-(5,7-dibromo-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide;

2-(5-nitro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide;

2-(5-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide;

2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide;

(2R)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1 -yl)propanamide;

(2S)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide;

2-[2-oxo-5-(trifluoromethoxy)-2,3-dihydro-1H-indol-1-yl]acetamide;

2-(5-isopropyl-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide;

2-(5-ethyl-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide;

2-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide;

2-(5,7-dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide;

2-(5-bromo-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide;

2-(2-oxo-5-propyl-2,3-dihydro-1H-indol-1-yl)acetamide;

2-[2-oxo-5-(trifluoromethyl)-2,3-dihydro-1H-indol-1-yl]acetamide;

2-(5,6-dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide;

2-(7-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide;

2-(6-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide;

2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)butanamide;

(+)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1 -yl)butanamide;

(-)-2-(5-chloro-2-oxo-2,3-dihydro-1 H-indol-1 -yl)butanamide;

2-(5-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide;

(+)-2-(5-methyl-2-oxo-2,3-dihydro-1H-indol-1 -yl)propanamide;

(-)-2-(5-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide;

2-(5-bromo-2-oxo-2,3-dihydro-1 H-indol-1 -yl)propanamide;

(-)-2-(5-bromo-2-oxo-2,3-dihydro-1 H-indol-1 -yl)propanamide;

(+)-2-(5-bromo-2-oxo-2,3-dihydro-1H-indol-1 -yl)propanamide;

2-(5-chloro-7-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide;

2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3-hydroxyphenyl)acetamide;

2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3-fluorophenyl)acetamide;

2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[3-(2-pyridin-2-ylethyl)phenylacetamide;

2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[6-(hydroxymethyl)cyclohex-3-en-1-yl]acetamide;

5-chloro-1-[2-oxo-2-(4-pyridin-2-ylpiperazin-1 -yl)ethyl-1,3-dihydro-2H-indol-2-one;

5-chloro-1-{2-[4-(3-methylphenyl)piperazin-1-yl]-2-oxoethyl}-1,3-dihydro-2H-indol-2-one;

2-(5-chloro-2-oxo-2,3-dihydro-1H-indole-1-πλ)-N-(4-hydroxy-3-methoxybenzyl)acetamide;

2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(pyridin-4-ylmethyl)-N-(tetrahydrofuran-2ylmethyl)acetamide;

5-chloro-1-[2-(3-hydroxypiperidin-1-yl)-2-oxoethyl]-1,3-dihydro-2H-indol-2-one;

2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N'-isonicotinylacetohydrazide;

5-chloro-1-(2-oxo-2-thiomorpholin-4-ylethyl)-1,3-dihydro-2H-indol-2-one;

2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(4H-1,2,4-triazol-3-yl)acetamide;

2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[4-(methylsulfonyl)benzyl]acetamide;

-[(5-chloro-2-oxo-2,3-dihydro-1 H-indol-1 -yl)acetyl]octahydroquinolin-4(1 H)-one;

N'-(4-bromophenyl)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1 -yl)acetohydrazide;

2-(5-chloro-2-oxo-2,3-dihydro-1 H-indol-1 -yl)-N-(6-methoxypyridin-3 -yl)acetamide;

N-butyl-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)αcetamide;

2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3-hydroxypropyl)acetamide;

2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[3-(dimethylamino)propyl]acetamide;

5-chloro-1-{2-oxo-2-[4-(2-phenylethyl)piperazin-1 -yl]ethyl}-1,3-dihydro-2H-indol-2-one;

ethyl {[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetyl]amino}acetate;

2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3-ethoxypropyl)acetamide;

2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(2-fluoroethyl)acetamide;

2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-methoxy-N-methylacetamide;

2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3,4-dimethylphenyl)acetamide;

N-(4-tert-butylphenyl)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide;

- 30 044839

2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3-hydroxy-2,2-dimethylpropyl)acetamide;

2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[1-(hydroxymethyl)propyl]acetamide;

2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3,3,3-trifluoro-2-hydroxypropyl)acetamide;

2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(2-hydroxy-2-phenylethyl)acetamide;

5-chloro-1 - {2-[4-(4-hydroxyphenyl)piperazin-1 -yl]-2-oxoethyl}-1,3-dihydro-2H-indol-2-one;

2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(pyridin-4-ylmethyl)acetamide;

2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[(5-methyl-2-furyl)methyl]acetamide;

2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[3-(1H-pyrazol-1-yl)propyl]acetamide;

methyl 3-[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl]acetyl]-1,3-thiazolidine-4-carboxylate;

5-chloro-1-[2-(2,5-dihydro-1H-pyrrol-1-yl)-2-oxoethyl]-1,3-dihydro-2H-indol-2-one;

2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N'-(4,5-dihydro-1H-imidazol-2-yl)acetohydrazide;

2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[2-(3,4-dimethoxyphenyl)ethyl]acetamide;

2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[2-(2-chlorophenyl)ethylacetamide;

2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[2-(4-methylphenyl)ethyl]acetamide;

2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(2-morpholin-4-ylethyl)acetamide;

2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[2-(3,4,5,6-tetrahydro-1-benzazocin-1 (2H )yl)propyl]acetamide;

2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[2-(2-methylpiperidin-1-yl)ethyl]acetamide;

2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(2-nitrobenzyl)acetamide;

2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-πλ)-N-(3,4-dihydro-1H-isochromen-1-ylmethyl)acetamide;

N-(2-chloro-6-fluorobenzyl)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide;

N-benzyl-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-methylacetamide;

2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-{2-[(trifluoromethyl)thio]benzyl}acetamide;

5-chloro-1-[2-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-2-oxoethyl]-1,3-dihydro-2H-indol-2-one;

2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-cycloheptylacetamide;

5-chloro-1-{2-[4-(2-morpholin-4-ylethyl)piperazin-1-yl]-2-oxoethyl}-1,3-dihydro-2H-indol-2-one and 2-( 5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-pyridin-3-ylacetamide.

In some embodiments, compounds useful in the methods and compositions of this invention are selected from the group consisting of:

2-(5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide;

2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide;

2-(5,7-dibromo-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide;

(2S)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide;

2-[2-oxo-5-(trifluoromethyl)-2,3-dihydro-1H-indol-1-yl]acetamide and

2-(5-chloro-7-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide.

In another embodiment, compounds useful in the methods and compositions of this invention are selected from the group consisting of 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide and (2S)- 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide.

iv) US Patent No. 7244747.

A compound having formula I or a pharmaceutically acceptable salt thereof:

(I)

R ⁴

where R ¹ denotes a hydrogen atom, C ₁ . ₂₀ alkyl, C ₃ . ₈ cycloalkyl, halogen atom, hydroxy, alkoxy, aryloxy, ester, amido, cyano, nitro, amino, guanidine, amino derivative, alkylthio, arylthio, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, arylsulfinyl, aryl or heterocycle;

R ² represents a hydrogen atom, C ₁ . ₂₀ alkyl, alkoxy, amino, halogen, hydroxy, ester, amido, nitro, cyano, carbamate or aryl;

R ³ represents a hydrogen atom, C ₁ . ₂₀ alkyl, alkoxy, amino, halogen, hydroxy, ester, amido, nitro, cyano, carbamate or aryl or

R ² and R ³ can form, together with the imidazole ring, the following 1H-benzimidazole ring

- 31 044839

R ⁴ is a hydrogen atom, C _1-20 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, aryl, azido, alkoxycarbonylamino, arylsulfonyloxy or heterocycle;

R ^4a represents a hydrogen atom or C _1-20 alkyl;

or R ⁴ and R ^4a may together form C _3-8 cycloalkyl;

R ⁵ represents a hydrogen atom or

R ⁴ , R ^4a and R ⁵ can form together with the 2-oxo-1-pyrrolidine ring the following ring 1,3-dihydro-2H-indol-2-one;

R ⁶ represents a hydrogen atom or C _1-20 alkyl;

R ⁷ represents a hydrogen atom;

or R ⁶ and R ⁷ are linked together to form a C _3-6 cycloalkyl;

R ⁸ represents a hydrogen atom, a halogen atom, nitro, cyano, C _1-20 alkyl or alkoxy;

R ⁹ is a hydrogen atom, C _1-20 alkyl, a halogen atom, hydroxy, alkoxy, aryloxy, ester, amido, cyano, nitro, amino, amino derivative, alkylthio, arylthio, alkylsulfonyl, arylsulfonyl, alkylsulfinyl or arylsulfinyl;

R ¹⁰ is a hydrogen atom, C _1-20 alkyl, a halogen atom, hydroxy, alkoxy, aryloxy, ester, amido, cyano, nitro, amino, amino derivative, alkylthio, arylthio, alkylsulfonyl, arylsulfonyl, alkylsulfinyl or arylsulfinyl;

R ¹¹ represents a hydrogen atom, a halogen atom, nitro, cyano, C _1-20 alkyl or alkoxy;

R ¹² represents a hydrogen atom or a halogen atom;

R ¹³ denotes a hydrogen atom, nitro, a halogen atom, heterocycle, amino, aryl, C _1-20 alkyl, unsubstituted or substituted by a halogen atom, or alkoxy, unsubstituted or substituted by a halogen atom;

R ¹⁴ represents a hydrogen atom, C _1-20 alkyl or a halogen atom;

R ¹⁵ represents a hydrogen atom, C _1-20 alkyl or a halogen atom;

provided that ^R4 is other than a hydrogen atom if denotes a group of the formula

An asterisk * indicates the point of substituent addition.

Preferably, the compounds are compounds having formula I, tautomers thereof, geometric isomers (including cis and trans, Z and E isomers), enantiomers, diastereomers and mixtures thereof (including all possible mixtures of stereoisomers) or pharmaceutically acceptable salts thereof:

where R ¹ denotes a hydrogen atom, C _1-20 alkyl, C _3-8 cycloalkyl, a halogen atom, hydroxy, ester, amido, cyano, nitro, amino, guanidine, alkylthio, alkylsulfonyl, alkylsulfinyl, aryl or heterocycle;

R ² is hydrogen, C _1-20 alkyl, halogen, cyano, ester, carbamate or amido;

R ³ represents a hydrogen atom, cyano, C _1-20 alkyl, halogen atom or ester or

R ² and R ³ can form, together with the imidazole ring, the following 1H-benzimidazole ring

R ⁴ represents a hydrogen atom, C _1-20 alkyl, C _2-12 alkenyl or aryl;

- 32 044839

R ^4a represents a hydrogen atom;

R ⁵ represents a hydrogen atom or

R ⁴ , R ^4a and R ⁵ can form together with the 2-oxo-1-pyrrolidine ring the following ring, 3-dihydro-2H-indol-2-one

R ⁶ represents a hydrogen atom or C _1-20 alkyl;

R ⁷ represents a hydrogen atom or

R ⁶ and R ⁷ are linked together to form C _3-6 cycloalkyl;

R ⁸ represents a hydrogen atom;

R ⁹ represents a hydrogen atom, C _1-20 alkyl, halogen or alkoxy;

R ¹⁰ represents a hydrogen atom, C _1-20 alkyl, halogen or cyano atom;

R ¹¹ represents a hydrogen atom;

R ¹² represents a hydrogen atom or a halogen atom;

R ¹³ represents a hydrogen atom, a halogen atom, a heterocycle or a C _1-20 alkyl;

R ¹⁴ represents a hydrogen atom;

R ¹⁵ represents a hydrogen atom;

R ² *N '''A - to ³ provided that R ⁴ is other than a hydrogen atom if ^{Rl N} represents a group of the formula

R ⁸ R ⁹

G Y\J

R ¹¹

As used herein, the term alkyl represents saturated, monovalent hydrocarbon radicals having straight, branched or cyclic chains or combinations thereof and containing 1-20 carbon atoms, preferably 1-10 carbon atoms, more preferably alkyl groups having 1-3 carbon atoms. The alkyl moieties may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxy, cyano, azido, aryloxy, alkoxy, alkylthio, alkanoylamino, arylcarbonylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, or aryl. In the present case, alkyl groups are usually methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 1-ethylpropyl, n-heptyl, 2,4,4-trimethylpentyl, n-decyl, chloromethyl, trifluoromethyl , 2-bromo-2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, hydroxymethyl, cyanomethyl, azidomethyl, (acetylamino)methyl, (propionylamino)methyl, (benzoylamino)methyl, (4 -chlorophenoxy)methyl, benzyl, 2-phenylethyl or 2-(methylthio)ethyl. Preferred alkyl groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, tert-butyl, 1-ethylpropyl, 2,4,4-trimethylpentyl, chloromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxymethyl, cyanomethyl, azidomethyl, (acetylamino)methyl, (propionylamino)methyl, (benzoylamino)methyl or 2-(methylthio)ethyl. More preferred alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, azidomethyl or trifluoromethyl. The most preferred alkyl groups are methyl or n-propyl.

As used herein, the term cycloalkyl represents a monovalent group of 3-8 carbon atoms, typically 3-6 carbon atoms, derived from a saturated cyclic hydrocarbon, which may be substituted by any suitable group, including, but not limited to, one or more moieties selected from the groups, which are described above for alkyl groups. Preferred cycloalkyl groups are cyclopropyl and cyclohexyl.

As used herein, the term alkenyl represents linear, branched or cyclic unsaturated hydrocarbon radicals or combinations thereof having at least one carbon-carbon double bond and containing 2-12 carbon atoms, usually preferably 2-4 carbon atoms. Alkenyl groups are optionally substituted with any suitable group, including, but not limited to, one or more moieties selected from the groups described above for alkyl groups. Typically the alkenyl group is ethenyl (vinyl), optionally substituted with 1-3 halogen atoms. The preferred alkenyl group in the present case is 2,2-difluorovinyl.

As used herein, the term alkynyl represents linear, branched or cyclic hydrocarbon radicals or combinations thereof containing at least one carbon-carbon triple bond containing 2-12 carbon atoms, preferably 2-6 carbon atoms, and optionally

- 33 044839 substituted with any suitable group, including, but not limited to, one or more moieties selected from the groups described above for alkyl groups. A preferred alkynyl group is a haloalkynyl group (haloalkynyl group).

Groups identified by prefixes such as sec, iso, tert and the like (eg, isopropyl, sec-butyl) are branched derivatives.

As used herein, the term aryl is defined as phenyl optionally substituted with 1-4 substituents independently selected from halogen, cyano, alkoxy, alkylthio, C ₁ . ₃ αlkyl or azido, preferably from a halogen or azido atom. In the present case, aryl groups are generally phenyl, 3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3-chloro-4-fluorophenyl, 2,3, 4-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl, 3,4,5-trifluorophenyl, 3-azido-2,4-difluorophenyl or 3-azido-2,4,6-trifluorophenyl. Preferred aryl groups are phenyl, 3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3-chloro-4-fluorophenyl, 2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl, 3,4,5-trifluorophenyl or 3-azido-2,4-difluorophenyl. The most preferred aryl groups are phenyl, 3-chlorophenyl, 3-fluorophenyl, 3,5-difluorophenyl, 2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl, 3,4,5 -trifluorophenyl or 3-azido-2,4-difluorophenyl.

As used herein, the term heterocycle is defined as a group comprising an aromatic or non-aromatic cycloalkyl moiety, as defined above, having at least one O, S and/or N atom interrupting the carbocyclic ring structure. The heterocyclic ring moieties may optionally be substituted with alkyl groups or halogen atoms, and optionally one of the carbons of the carbocyclic ring structure may be substituted with a carbonyl. Typically heterocycles are 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-tetrahydrofuranyl, N-pyrrol-2-yl, 1-methyl-1H- pyrrol-2-yl, 1H-pyrazol-2-yl, 1 H-pyrazol-3-yl, 4-chloro-1-methyl-1 H-pyrazol-3-yl, 5-chloro-1,3-dimethyl- 1 H-pyrazol-4-yl, 1,2,3-thiadiazol-4-yl, 3,5-dimethyl-4-isothiazyl, 1H-imidazol-2-yl, 1-methyl-1H-imidazol-2-yl , 4-methyl-Shimidazol-5-yl or 2-methyl-1,3-thiazol-4-yl. Preferred heterocycles are N-imidazol2-yl, 1,2,3-thiadiazol-4-yl, 1H-pyrazol-3-yl, 2-furyl, 3-furyl, 2-thienyl, 1-methyl-1H-pyrrol-2 -yl, 1 H-pyrrol-2 -yl.

As used herein, the term halogen includes chlorine, bromine, fluorine, iodine. Typically the halogens are chlorine, bromine and fluorine. Preferred halogens are fluorine, bromine and chlorine.

As used herein, the term hydroxy represents a group of the formula -OH.

As used herein, the term alkoxy represents a group of the formula -OR ^a where R ^a denotes an alkyl group as defined above. A preferred alkoxy group is methoxy.

As used herein, the term aryloxy represents a group of the formula -OR ^b , where R ^b denotes an aryl group as defined above. A preferred aryloxy group is phenoxy.

As used herein, the term ester represents a group of the formula -COORc, where Rc denotes an alkyl group or aryl group as defined above. A preferred ester group is methoxycarbonyl.

As used herein, the term amido represents a group of the formula -CONH ₂ .

As used herein, the term amino represents a group of the formula -NH ₂ .

As used herein, the term amino derivative represents an alkylamino or arylamino group, where the terms alkyl and aryl are defined as defined above.

As used herein, the term cyano represents a group of the formula -CN.

As used herein, the term nitro represents a group of the formula -NO2.

As used herein, the term azido represents a group of formula -N ₃ .

As used herein, the term guanidine represents a group of the formula -NHC(=NH)NH ₂ .

As used herein, the term alkylthio represents a group of the formula -SR ^d , where R ^d denotes an alkyl group as defined above. A preferred alkylthio group is methylthio.

As used herein, the term alkylsulfonyl represents a group of the formula -S(=O) ₂ R ^e , where R ^e denotes an alkyl group as defined above. A preferred alkylsulfonyl group is methylsulfonyl.

As used herein, the term alkylsulfinyl represents a group of the formula -S(=O)R ^f , where R ^f denotes an alkyl group as defined above. A preferred alkylsulfinyl group is methylsulfinyl.

As used herein, the term arylthio represents a group of the formula -SR ^g , where R ^g denotes an aryl group as defined above.

As used herein, the term arylsulfonyl represents a group of the formula -S(=O)2R ^h , where R ^h denotes an aryl group as defined above.

As used herein, the term arylsulfinyl represents a group of the formula -S(=O)R', where R ¹ denotes an aryl group as defined above.

As used herein, the term carbamate represents a group of the formula -N(H)C(O)ORj, where Rj is alkyl or aryl, as defined above. Typically carbamate groups are

- 34 044839 (propoxycarbonyl)amino or (benzyloxycarbonyl)amino. A preferred carbamate group is (benzyloxycarbonyl)amino.

As used herein, the term alkanoylamino represents a group of the formula -NHC(=O)R ^k where

R ^k denotes an alkyl group as defined above.

As used herein, the term (arylcarbonyl)amino represents a group of the formula -NHC(=O)R ^m , where R ^m denotes an aryl group as defined above. A preferred (arylcarbonyl)amino group is benzoylamino.

Typically R ¹ is a hydrogen atom; C ₁ . ₁₀ alkyl, unsubstituted or substituted by halogen, hydroxy, cyano, methylthio, phenyl or 4-chlorophenoxy; hydroxy; O _3-6 cycloalkyl; halogen atom; ester; amido; nitro; cyano; amino; phenyl; alkylthio; alkylsulfonyl; alkylsulfinyl; heterocycle, unsubstituted or substituted with alkyl groups; or guanidine. Preferred R ¹ is a hydrogen atom; methyl; ethyl; isopropyl; n-propyl; cyclopropyl; n-butyl; isobutyl; tert-butyl; 1-ethylpropyl; 2,4,4-trimethylpentyl; hydroxymethyl; chloromethyl; trifluoromethyl; 2,2,2-trifluoroethyl; cyanomethyl; 2-(methylthio)ethyl; chlorine atom; bromine atom; nitro; cyano; amino; aminocarbonyl; methoxycarbonyl; methylthio; methylsulfinyl; methylsulfonyl; phenyl; 2-furyl; 3-furyl; Sh-pyrrol-2-yl; 1-methyl-1H-pyrrol-2-yl; 2-thienyl; Sh-pyrazol-3-yl; 1,2,3-thiadiazol-4-yl or 1H-imidazol-2-yl.

More preferably, R ¹ is a hydrogen atom; methyl; ethyl; isopropyl; n-propyl; n-butyl; methylthio; nitro; cyano; amino; chlorine atom or Ш-pyrrol-2-yl. Most preferred R ¹ is a hydrogen atom; methyl; methylthio; nitro; cyano; amino or chlorine atom.

Typically R ² is a hydrogen atom; C _1-4 alkyl, unsubstituted or substituted with hydroxy, alkanoylamino or benzoylamino; halogen atom; ester; cyano; alkyl carbamate; [(N-methoxy-Nmethyl)amino]carbonyl. Preferred R ² is a hydrogen atom; methyl; hydroxymethyl; (acetylamino)methyl; (propionylamino)methyl; (benzoylamino)methyl; [(benzyloxy)carbonyl]amino; chlorine or cyano atom. More preferably, R ² represents a hydrogen atom; chlorine or cyano atom.

Typically R ³ is a hydrogen atom; C _1-4 alkyl, unsubstituted or substituted hydroxy; halogen atom; ester or cyano. Preferred R ³ is a hydrogen atom; hydroxymethyl; chlorine atom; cyano. More preferably, R ³ is hydrogen or cyano. Most preferred R ³ is a hydrogen atom.

Typically R ⁴ is a hydrogen atom; C _1-4 alkyl, unsubstituted or substituted with halogen atoms; C _2-4 alkenyl substituted with halogen atoms or a phenyl group, unsubstituted or substituted with azido and/or halogen atoms. Preferred R ⁴ is a hydrogen atom; n-propyl; 2,2-difluorovinyl; phenyl; 3-chlorophenyl; 3-fluorophenyl; 4-chlorophenyl; 4-fluorophenyl; 3,5-difluorophenyl; 3,4-difluorophenyl; 3-chloro-4-fluorophenyl; 2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl; 3-azido-2,4-difluorophenyl or 3-azido-2,4,6-trifluorophenyl. More preferably, R ⁴ is a hydrogen atom; n-propyl; 2,2-difluorovinyl; phenyl; 3-chlorophenyl; 3-fluorophenyl; 4-chlorophenyl; 4-fluorophenyl; 3,5-difluorophenyl; 3,4-difluorophenyl; 3-chloro-4-fluorophenyl; 2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl or 3-azido-2,4-difluorophenyl. The most preferred R ⁴ is n-propyl; 2,2-difluorovinyl; phenyl; 3-chlorophenyl; 3-fluorophenyl; 3,5-difluorophenyl; 2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl or 3-azido-2,4-difluorophenyl.

Typically R ^4a represents a hydrogen atom.

Typically R ⁵ represents a hydrogen atom.

Typically R ⁶ is hydrogen or C _1-10 alkyl, unsubstituted or substituted hydroxy or azido.

Preferred R ⁶ is hydrogen or azidomethyl. More preferably, R ⁶ is a hydrogen atom.

Typically R ⁷ represents a hydrogen atom.

In other preferred embodiments, R ⁶ and R ⁷ are linked to form cyclopropyl.

In other preferred embodiments, R ² and R ³ can form, together with the imidazole ring, the following III-benzimidazole ring:

Typically R ⁸ represents a hydrogen atom.

Typically R ⁹ is a hydrogen atom; halogen atom; C _1-3 alkyl or alkoxy. Preferred R ⁹ is a hydrogen atom; methyl; chlorine or methoxy atom. More preferably, R ⁹ is a hydrogen atom.

Typically R ¹⁰ is a hydrogen atom; halogen atom; cyano; C _1-3 alkyl, unsubstituted or substituted with halogen atoms; or alkoxy. Preferred R ¹⁰ is methyl; hydrogen atom; trifluoromethyl 35 044839; fluorine; cyano or methoxy. More preferably, R ¹⁰ is a hydrogen atom; trifluoromethyl; fluorine or cyano.

Typically R ¹¹ represents a hydrogen atom.

In other preferred embodiments, R ⁴ , R ^4a and R ⁵ may form together with the 2-oxo-1-pyrrolidine ring the following ring, 1,3-dihydro-2H-indol-2-one.

Typically R ¹² represents a hydrogen atom or a halogen atom. Preferred R ¹² is a hydrogen atom; chlorine atom or fluorine atom. More preferably, R ¹² is a hydrogen atom.

Typically R ¹³ is a hydrogen atom; C _1-3 alkyl; a halogen atom or thiazolyl, unsubstituted or substituted with alkyl groups, for example methylthiazolyl. Preferred R ¹³ is a hydrogen atom; chlorine atom; bromine or methyl atom. Most preferred R ¹³ is a chlorine atom; bromine or methyl atom.

Typically R ¹⁴ represents a hydrogen atom.

Typically R ¹⁵ represents a hydrogen atom.

Particularly preferred are combinations of one or more compounds from these preferred groups.

Typically, among the options are compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein:

R ¹ is selected from a hydrogen atom; C _1-10 αlkyl, unsubstituted or substituted with halogen, hydroxy, cyano, methylthio, phenyl or 4-chlorophenoxy; C _3-6 cycloalkylα; halogen atom; ester; amido; nitro; cyano; amino; phenyl; alkylthio; alkylsulfonyl; alkylsulfinyl; heterocycle, unsubstituted or substituted with an alkyl group; or guanidine;

R ² is selected from a hydrogen atom; C _1-4 alkyl, unsubstituted or substituted with hydroxy, alkanoylamino or benzoylamino; halogen atom; ester; cyano; alkylcarbamate or [(N-methoxy-Nmethyl)amino]carbonyl;

R ³ is selected from a hydrogen atom; C _1-4 alkyl, unsubstituted or substituted hydroxy; halogen atom; ester or cyano;

R ⁴ is selected from a hydrogen atom; C _1-4 αlkyl, unsubstituted or substituted with halogen atoms; C _2-4 alkenyl substituted with halogen atoms, or a phenyl group unsubstituted or substituted with azido and/or halogen atoms;

R ^4a represents a hydrogen atom;

R ⁵ represents a hydrogen atom;

R ⁶ is selected from hydrogen or C _1-10 alkyl, unsubstituted or substituted hydroxy or azido;

R ⁷ represents a hydrogen atom; or

R ⁶ and R ⁷ can be linked to form cyclopropyl; or

R ² and R ³ can form, together with the imidazole ring, the following III-benzimidazole ring

R ⁸ represents a hydrogen atom;

R ⁹ is selected from a hydrogen atom; halogen atom; C _1-3 alkyl; alkoxy;

R ¹⁰ is selected from a hydrogen atom; halogen atom; cyano or C _1-3 alkyl, unsubstituted or substituted with halogen atoms; or alkoxy;

R ¹¹ represents a hydrogen atom; or

R ⁴ , R ^4a and R ⁵ can form together with the 2-oxo-1-pyrrolidine ring the following ring 1,3-dihydro-2H-indol-2-one

R'2

R ¹² is selected from a hydrogen atom or a halogen atom;

R ¹³ is selected from a hydrogen atom; C _1-3 alkyl; halogen atom; thiazolyl, unsubstituted or substituted with alkyl groups, for example, methylthiazolyl;

R ¹⁴ represents a hydrogen atom;

R ¹⁵ represents a hydrogen atom;

R ² 'N A , /-- ^R provided that R ⁴ is other than a hydrogen atom if ^{Rl N} represents a group of the formula

R*

G _R r^N K

In a preferred embodiment, the compounds of formula (I) or pharmaceutically acceptable salts thereof are those where:

R ¹ is selected from a hydrogen atom; methyl; ethyl; isopropyl; n-cut; cyclopropyl; n-butyl; isobutyl; tert-butyl; 1-ethylpropyl; 2,4,4-trimethylpentyl; trifluoromethyl; 2,2,2-trifluoroethyl; hydroxymethyl; chloromethyl; cyanomethyl; 2-(methylthio)ethyl; chlorine atom; bromine atom; nitro; cyano; amino; aminocarbonyl; methoxycarbonyl; methylthio; methylsulfinyl; methylsulfonyl; phenyl; 2-furyl; 3-furyl; 1H-pyrrol-2-yl; 1-methyl-1H-pyrrol-2-yl; 2-thienyl; 1H-pyrazol-3-yl; 1,2,3-thiadiazol-4-yl; or 1H-imidazol-2-yl;

R ² is selected from a hydrogen atom; methyl; hydroxymethyl; (acetylamino)methyl; (propionylamino)methyl; (benzoylamino)methyl; (benzyloxycarbonyl)amino; chlorine or cyano atom;

R ³ is selected from a hydrogen atom; hydroxymethyl; chlorine atom; cyano or

R ² and R ³ can form, together with the imidazole ring, the following III-benzimidazole ring

R ⁸ represents a hydrogen atom;

R ⁹ is selected from a hydrogen atom; methyl; chlorine atom; methoxy; R ¹⁰ is selected from methyl; hydrogen atom; trifluoromethyl; fluorine; cyano or methoxy;

R ¹¹ represents a hydrogen atom;

R ⁴ is selected from a hydrogen atom; n-cut; 2,2-difluorovinyl; phenyl; 3-chlorophenyl; 3-fluorophenyl; 4-chlorophenyl; 4-fluorophenyl; 3,5-difluorophenyl; 3,4-difluorophenyl; 3-chloro-4-fluorophenyl; 2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl; 3-azido-2,4difluorophenyl or 3-azido-2,4,6-trifluorophenyl;

R ^4a represents a hydrogen atom;

R ⁵ represents a hydrogen atom or

R ⁴ , R ^4a and R ⁵ can form together with the 2-oxo-1-pyrrolidine ring the following ring 1,3-dihydro-2H-indol-2-one

R ¹² is selected from a hydrogen atom; chlorine atom; fluorine atom;

R ¹³ is selected from a hydrogen atom; chlorine atom; bromine atom; methyl;

R ¹⁴ represents a hydrogen atom;

R ¹⁵ represents a hydrogen atom;

R ⁶ is selected from a hydrogen atom; azidomethyl;

R ⁷ represents a hydrogen atom or

R ⁶ and R ⁷ are linked together to form cyclopropyl;

provided that ^R4 is other than a hydrogen atom if

denotes a formula group

- 37 044839

More preferably, the compounds of formula (I) or pharmaceutically acceptable salts thereof are those where:

R ¹ is selected from a hydrogen atom; methyl; ethyl; isopropyl; n-cut; n-butyl; methylthio; nitro; cyano; amino; chlorine atom; or 1H-pyrrol-2-yl;

R ² is selected from a hydrogen atom; chlorine atom; cyano;

R ³ is selected from a hydrogen atom; cyano or

R ² and R ³ can form, together with the imidazole ring, the following III-benzimidazole ring:

R ⁸ represents a hydrogen atom;

R ⁹ represents a hydrogen atom;

R ¹⁰ is selected from a hydrogen atom; trifluoromethyl; fluorine atom; cyano;

R ¹¹ represents a hydrogen atom;

R ⁴ is selected from a hydrogen atom; n-cut; 2,2-difluorovinyl; phenyl; 3-chlorophenyl; 3-fluorophenyl; 4-chlorophenyl; 4-fluorophenyl; 3,5-difluorophenyl; 3,4-difluorophenyl; 3-chloro-4-fluorophenyl; 2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl or 3-azido-2,4difluorophenyl;

R ^4a represents a hydrogen atom;

R ⁵ represents a hydrogen atom or

R ⁴ , R ^4a and R ⁵ can form together with the 2-oxo-1-pyrrolidine ring the following ring 1,3-dihydro-2H-indol-2-one:

where R ¹² denotes a hydrogen atom;

R ¹³ is selected from methyl; chlorine atom; bromine atom;

R ¹⁴ represents a hydrogen atom;

R ¹⁵ represents a hydrogen atom;

R ⁶ represents a hydrogen atom;

R ⁷ represents a hydrogen atom;

provided that ^R4 is other than a hydrogen atom if

represents a formula group

In the most preferred embodiment, the compounds of formula (I) or pharmaceutically acceptable salts thereof are those where:

R ¹ is selected from a hydrogen atom; methyl; methylthio; nitro; cyano; amino; chlorine atom;

R ² is selected from a hydrogen atom; chlorine atom; cyano;

R ³ represents a hydrogen atom;

R ⁴ selected from n-propyl; 2,2-difluorovinyl; phenyl; 3-chlorophenyl; 3-fluorophenyl; 3,5-difluorophenyl; 2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl; 3-azido2,4-difluorophenyl;

R ^4a represents a hydrogen atom;

R ⁵ represents a hydrogen atom or

R ⁴ , R ^4a and R ⁵ can form, together with the 2-oxo-1-pyrrolidine ring, the following ring

- 38 044839

1,3-dihydro-2H-indol-2-one:

R ¹² represents a hydrogen atom;

R ¹³ is selected from a chlorine atom; bromine atom; methyl;

R ¹⁴ represents a hydrogen atom;

R ¹⁵ represents a hydrogen atom;

R ⁶ represents a hydrogen atom;

R ⁷ represents a hydrogen atom.

In some embodiments, compounds useful in the methods and compositions of this invention are selected from the group consisting of:

1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;

-(1 H-imidazol-1 -ylmethyl)-4-phenylpyrrolidin-2-one;

4-(3-azido-2,4,6-trifluorophenyl)-1 -(1 H-imidazol-1 -ylmethyl)pyrrolidin-2-one;

-(1 H-imidazol-1 -ylmethyl)-4-propylpyrrolidin-2-one;

(-)-4-(3 -azido-2,4-difluorophenyl)-1-(1 H-imidazol-1 -ylmethyl)pyrrolidin-2-one;

(+)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;

1-[(2-ethyl-1H-umidazol-1-ul)methyl]-4-propylpyrrolidin-2-one;

1-[(2-isopropyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;

-[(2-methyl-1 H-imidazol-1 -yl)methyl]-4-propylpyrrolidin-2-one;

1-[(2-phenyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;

4-propyl-1-[(2-propyl-1H-imidazol-1-yl)methyl]pyrrolidin-2-one;

(+)-1 -(1 H-imidazol-1 -ylmethyl)-4-propylpyrrolidin-2-one;

(-)-1 -(1 H-imidazol-1 -ylmethyl)-4-propylpyrrolidin-2-one;

4-(2,2-difluorovinyl)-1-(1 H-imidazol-1 -ylmethyl)pyrrolidin-2-one;

4-(3-chlorophenyl)-1 -(1 H-imidazol-1 -ylmethyl)pyrrolidin-2-one;

1-{[2-(methylthio)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;

1-{[2-(methylsulfinyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;

1-[(2-tert-butyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;

1-[1-(1H-imidazol-1-yl)cyclopropyl]pyrrolidin-2-one;

1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-phenylpyrrolidin-2-one;

1-{[2-(methylsulfonyl)-1 H-imidazol-1 -yl]methyl}-propylpyrrolidin-2-one;

-[(2-oxo-4-propylpyrrolidin-1 -yl)methyl]-1 H-imidazole-2-carboxamide;

4-(4-fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;

1-(1H-imidazol-1-ylmethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;

4-(3-fluorophenyl)-1 -(1 H-imidazol-1 -ylmethyl)pyrrolidin-2-one;

4-(3,5-difluorophenyl)-1-(1H-umidazol-1-ulmethyl)pyrrolidin-2-one;

4-(3,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;

4-(3-chloro-4-fluorophenyl)-1-(1 H-imidazol-1 -ylmethyl)pyrrolidin-2-one;

4-(4-chlorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;

-(1 H-imidazol-1 -ylmethyl)-4-(2,3,4-trifluorophenyl)pyrrolidin-2-one;

1-(1H-imidazol-1-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;

1-(1H-imidazol-1-ylmethyl)-4-(2,4,5-trifluorophenyl)pyrrolidin-2-one;

1-{[2-(hydroxymethyl)-1 H-imidazol-1 -yl]methyl}-4-propylpyrrolidin-2-one;

methyl 1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-2-carboxylate;

1-[(2-nitro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;

- {[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1 -yl]methyl} -1 H-imidazole-2-carbonitrile;

1-[(2-amino-1H-imidazol-1-ul)methyl]-4-propylpyrrolidin-2-one;

1-[(2,4-dichloro-1H-imudazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;

1-[(5-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;

1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl} -1 H-imidazole-4-carbonitrile;

1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;

(+)-1 -(1 H-imidazol-1 -ylmethyl)-4-phenylpyrrolidin-2-one;

(-)-1 -(1 H-imidazol-1 -ylmethyl)-4-phenylpyrrolidin-2-one;

1-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;

(-)-1 - {[2-oxo-4-(2,3,4-trifluorophenyl)pyrrolidin-1 -yl]methyl} -1 H-imidazole-5-carbonitrile;

(+)-1 -{[2-oxo-4-(2,3,4-trifluorophenyl)pyrrolidin-1 -yl]methyl} -1 H-imidazole-5-carbonitrile;

(-)-1-{[2-oxo-4-(2,3,4-trifluorophenyl)pyrrolidin-1-ul]methyl}-1H-imidazole-4-carbonitrile;

- 39 044839 (+)-1-{[2-oxo-4-(2,3,4-trifluorophenyl)-1-pyrrolidinyl]methyl}-1H-imidazole-4-carbonitrile;

(-)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;

(+)-1-{ [2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1 -yl]methyl} - 1H-imidazole-4-carbonitrile;

(+)-1-{[2-oxo-4-(2,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;

(-)-1-{[2-oxo-4-(2,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-III-imidazole-4-carbonitrile;

(-)-1-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-III-imidazole-4-carbonitrile;

(-)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-III-imidazole-5-carbonitrile;

1-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-III-imidazole-5-carbonitrile;

1-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-III-imidazole-5-carbonitrile;

-[(5-methyl-2-phenyl-1 H-imidazol-1 -yl)methyl]-4-propylpyrrolidin-2-one;

-[(5-methyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;

-[(5-phenyl-1 H-imidazol-1 -yl)methyl]-4-propylpyrrolidin-2-one;

1-[(2-ethyl-5-methyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;

-[(2,5-dimethyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;

-[(2-chloro-1 H-imidazol-1 -yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;

-[2-azido-1 -(III-imidazol-1 -yl)ethyl]-4-propylpyrrolidin-2-one;

-[(4-chloro-1 H-imidazol-1 -yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;

-[(2-bromo-4,5-dichloro-1 H-imidazol-1 -yl)methyl]-4-propylpyrrolidin-2-one;

-[(2-chloro-1 H-imidazol-1 -yl)methyl]-4-propylpyrrolidin-2-one;

(+)-1-{ [2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1 -yl]methyl} - 1H-imidazole-5-carbonitrile;

1-{[5-(hydroxymethyl)-III-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;

1-{[4-(hydroxymethyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;

benzyl 1-[(2-oxo-4-propylpyrrolidin-1 -yl)methyl]-1H-imidazol-5-ylcarbamate;

N-[(1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazol-5-yl)methyl]acetamide;

N-[(1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazol-5-yl)methyl]benzamide;

N-[(1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazol-5-yl)methyl]propanamide;

1-(1H-benzimidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;

-[(2-methyl-1 H-benzimidazol-1 -yl)methyl]-4-propylpyrrolidin-2-one;

4-propyl-1-[(2-propyl-1H-benzimidazol-1-yl)methyl]pyrrolidin-2-one;

-[(2-isopropyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;

4-propyl-1-{[2-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}pyrrolidin-2-one;

1-{[2-(methylthio)-III-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;

-[(2-amino-1 H-benzimidazol-1 -yl)methyl]-4-propylpyrrolidin-2-one;

1-{[2-(chloromethyl)-1 H-benzimidazol-1 -yl]methyl}-4-propylpyrrolidin-2-one;

{1 -[(2-oxo-4-propylpyrrolidin-1 -yl)methyl] - 1H-benzimidazol-2-yl} acetonitrile;

-[(5-methoxy-III-benzimidazol-1 -yl)methyl]-4-propylpyrrolidin-2-one;

-[(5-methyl-1 H-benzimidazol-1 -yl)methyl]-4-propylpyrrolidin-2-one;

-[(5,6-dimethyl-III-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;

1-{[2-isopropyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propyl-pyrrolidin-2-one;

-[(6-chloro-1 H-benzimidazol-1 -yl)methyl]-4-propylpyrrolidin-2-one;

-[(2-oxo-4-propylpyrrolidin-1 -yl)methyl]-2-propyl-1 H-benzimidazole-5-carbonitrile;

1-{[2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;

4-propyl-1-{[2-(1H-pyrrol-2-yl)-1H-benzimidazol-1-yl]methyl}pyrrolidin-2-one;

1-[(5-fluoro-2-propyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;

- {[6-methyl-2-( 1 H-pyrrol-2-yl)-1 H-benzimidazol-1 -yl]methyl} -4-propylpyrrolidin-2-one;

-[(6-methoxy-2-propyl-1 H-benzimidazol-1 -yl)methyl]-4-propylpyrrolidin-2-one;

2-butyl-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazole-5-carbonitrile;

1-{[2-[2-(methylthio)ethyl]-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;

-[(5-fluoro-2-isobutyl-1 H-benzimidazol-1 -yl)methyl]-4-propylpyrrolidin-2-one;

1-{[5-fluoro-2-(2,4,4-trimethylpentyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;

2-cyclopropyl-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1 H-benzimidazole-5-carbonitrile;

-[(2-oxo-4-propylpyrrolidin-1 -yl)methyl]-2-(1 H-pyrazol-3 -yl)-1 H-benzimidazol-5-carbonitrile;

-[(2-cyclopropyl-5-fluoro-1 H-benzimidazol-1 -yl)methyl]-4-propylpyrrolidin-2-one;

1-[(5-fluoro-2-isopropyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;

1-{[2-(3-furyl)-6-methoxy-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;

1-[(2-cyclopropyl-6-methoxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;

-[(2-isopropyl-6-methoxy-1 H-benzimidazol-1 -yl)methyl]-4-propylpyrrolidin-2-one;

-[(2-oxo-4-propylpyrrolidin-1 -yl)methyl]-2-(1,2,3-thiadiazol-4-yl)-1H-benzimidazol-5carbonitrile;

1-{[2-(1H-imidazol-2-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;

1-{[5-fluoro-2-(2,2,2-trifluoroethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;

- 40 044839

1-{[2-(1-ethylpropyl)-6-methoxy-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;

1-{[6-methoxy-2-(1-methyl-1H-pyrrol-2-yl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;

1-{[2-(2-furyl)-5-(trifluoromethyl)-III-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;

4-propyl-1-{[2-thien-2-yl-5-(trifluoromethyl)-1H-benzimidazol-1 -yl]methyl} pyrrolidin-2-one;

1-{[2-(3-furyl)-5-(trifluoromethyl)-1 H-benzimidazol-1 -yl]methyl}-4-propylpyrrolidin-2-one;

-{[2-cyclopropyl-5-(trifluoromethyl)-1H-benzimidazol-1 -yl]methyl}-4-propylpyrrolidin-2-one;

4-propyl-1-{ [2-(1H-pyrrol-2-yl)-5-(trifluoromethyl)-1 H-benzimidazol-1 -yl]methyl} pyrrolidin-2-one;

1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;

5-bromo-1 -(1 H-imidazol-1 -ylmethyl)-1,3-dihydro-2H-indol-2-one;

5-chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;

4-fluoro-1 -(1H-imidazol-1 -ylmethyl)-1,3-dihydro-2H-indol-2-one;

4-chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;

1-(1H-imidazol-1-ylmethyl)-5-methyl-1,3-dihydro-2H-indol-2-one;

1-[(2-oxo-2,3-dihydro-1H-indol-1-yl)methyl]-1H-imidazole-5-carbonitrile and 1-[(5-chloro-2-oxo-2,3dihydro-III -indol-1-yl)methyl]-1 H-imidazole-5-carbonitrile.

In some embodiments, compounds useful in the methods and compositions of this invention are selected from the group consisting of:

1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;

1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;

1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;

(-)-4-(3 -azido-2,4-difluorophenyl)-1 -(1 H-imidazol-1 -ylmethyl)pyrrolidin-2-one;

(+)-4-(3 -azido-2,4-difluorophenyl)-1-(1 H-imidazol-1 -ylmethyl)pyrrolidin-2-one;

-[(2-ethyl-1 H-imidazol-1 -yl)methyl]-4-propylpyrrolidin-2-one;

-[(2-isopropyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;

-[(2-methyl-1 H-imidazol-1 -yl)methyl]-4-propylpyrrolidin-2-one;

4-propyl-1-[(2-propyl-1H-imidazol-1-yl)methyl]pyrrolidin-2-one;

(+)-1 -(1 H-imidazol-1 -ylmethyl)-4-propylpyrrolidin-2-one;

(-)-1 -(1H-imidazol-1 -ylmethyl)-4-propylpyrrolidin-2-one;

4-(2,2-difluorovinyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;

4-(3-chlorophenyl)-1 -(1 H-imidazol-1 -ylmethyl)pyrrolidin-2-one;

1-{[2-(methylthio)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;

-[(2-methyl-1 H-imidazol-1 -yl)methyl]-4-phenylpyrrolidin-2-one;

4-(4-fluorophenyl)-1 -(1 H-imidazol-1 -ylmethyl)pyrrolidin-2-one;

1-(1H-imidazol-1-ylmethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;

4-(3-fluorophenyl)-1 -(1 H-imidazol-1 -ylmethyl)pyrrolidin-2-one;

4-(3,5-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;

4-(3,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;

4-(3-chloro-4-fluorophenyl)-1-(1 H-imidazol-1 -ylmethyl)pyrrolidin-2-one;

4-(4-chlorophenyl)-1 -(1 H-imidazol-1 -ylmethyl)pyrrolidin-2-one;

1-(1H-imidazol-1-ylmethyl)-4-(2,3,4-trifluorophenyl)pyrrolidin-2-one;

1-(1H-imidazol-1-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;

1-(1H-imidazol-1-ylmethyl)-4-(2,4,5-trifluorophenyl)pyrrolidin-2-one;

-[(2-nitro-1 H-imidazol-1 -yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;

- {[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1 -yl]methyl} - 1H-imidazole-2-carbonitrile;

-[(2-amino-1 H-imidazol-1 -yl)methyl]-4-propylpyrrolidin-2-one;

1-[(5-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;

- {[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1 -yl]methyl} - 1H-imidazole-4-carbonitrile;

1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;

(+)-1 -(1 H-imidazol-1 -ylmethyl)-4-phenylpyrrolidin-2-one;

(-)-1 -(1H-imidazol-1 -ylmethyl)-4-phenylpyrrolidin-2-one;

(+)-1-{ [2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1 -yl]methyl} - 1H-imidazole-4-carbonitrile;

-[(2-chloro-1 H-imidazol-1 -yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;

-[2-azido-1 -(III-imidazol-1 -yl)ethyl]-4-propylpyrrolidin-2-one;

-[(2-chloro-1 H-imidazol-1 -yl)methyl]-4-propylpyrrolidin-2-one;

(+)-1-{ [2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1 -yl]methyl} - 1H-imidazole-5-carbonitrile;

-[(2-oxo-4-propylpyrrolidin-1 -yl)methyl]-2-propyl-1 H-benzimidazole-5-carbonitrile;

1-{[2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;

4-propyl-1-{[2-(1H-pyrrol-2-yl)-1H-benzimidazol-1-yl]methyl}pyrrolidin-2-one;

1-[(5-fluoro-2-propyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;

2-butyl-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazole-5-carbonitrile;

1-[(5-fluoro-2-isopropyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;

1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;

- 41 044839

5-bromo-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;

5-chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;

1-(1H-imidazol-1-ylmethyl)-5-methyl-1,3-dihydro-2H-indol-2-one;

-[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)methyl]-1H-imidazole-5-carbonitrile.

In some embodiments, compounds useful in the methods and compositions of this invention are selected from the group consisting of:

1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;

1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;

(-)-4-(3 -azido-2,4-difluorophenyl)-1-(1 H-imidazol-1 -ylmethyl)pyrrolidin-2-one;

(+)-4-(3-azido-2,4-difluorophenyl)-1-(1 H-imidazol-1 -ylmethyl)pyrrolidin-2-one;

4-(2,2-difluorovinyl)-1-(1 H-imidazol-1 -ylmethyl)pyrrolidin-2-one;

4-(3-chlorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;

1-{[2-(methylthio)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;

1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-phenylpyrrolidin-2-one;

1-(1H-imidazol-1-ylmethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;

4-(3-fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;

4-(3,5-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;

1-(1H-imidazol-1-ylmethyl)-4-(2,3,4-trifluorophenyl)pyrrolidin-2-one;

1-(1H-imidazol-1-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;

1-(1H-imidazol-1-ylmethyl)-4-(2,4,5-trifluorophenyl)pyrrolidin-2-one;

1-[(2-nitro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;

1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1 H-imidazole-2-carbonitrile;

1-[(2-amino-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(5-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;

(+)-1 -(1 H-imidazol-1 -ylmethyl)-4-phenylpyrrolidin-2-one;

(-)-1-(1 H-imidazol-1 -ylmethyl)-4-phenylpyrrolidin-2-one;

1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;

1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;

(+)-1 -{[2-oxo-4-(3,4,5-trifluorophenyl)-pyrrolidin-1 -yl]methyl} -1 H-imidazole-5-carbonitrile;

5-bromo-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;

5-chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;

1-(1H-imidazol-1-ylmethyl)-5-methyl-1,3-dihydro-2H-indol-2-one;

-[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)methyl]-1H-imidazole-5-carbonitrile.

In some embodiments, compounds useful in the methods and compositions of this invention are selected from the group consisting of:

(-)-4-(3 -azido-2,4-difluorophenyl)-1-(1 H-imidazol-1 -ylmethyl)pyrrolidin-2-one;

(+)-4-(3-azido-2,4-difluorophenyl)-1-(1 H-imidazol-1 -ylmethyl)pyrrolidin-2-one;

4-(3-azido-2,4-difluorophenyl)-1-(1 H-imidazol-1 -ylmethyl)pyrrolidin-2-one.

v) International patent application WO 2007/065595.

Compounds having formula (I), their enantiomers, diastereomers and mixtures thereof (including all possible mixtures of stereoisomers) or pharmaceutically acceptable salts thereof;

where R ¹ represents a hydrogen atom or C _1-6 alkyl;

R ² represents a hydrogen atom or C _1-4 alkyl;

R ³ represents a group of the formula -CHR ⁵ R ⁶ or a benzyl group;

R ⁴ is C _1-8 alkyl, optionally substituted with alkoxycarbonyl, C _3-6 cycloalkyl, aryl or heterocycle;

R ⁵ is C _2-4 alkyl;

R ⁶ is C _2-4 alkyl, amido or -COOR ⁷ ;

R ⁷ is C _1-4 alkyl.

Typically, if R ³ is a benzyl group, then R ⁴ is C _1-8 alkyl, optionally substituted with alkoxycarbonyl.

Typically, if R ³ is a group of formula -CHR5R ⁶ , then R ⁴ is C _1-8 alkyl, optionally substituted with C _3-6 cycloalkyl, aryl or heterocycle.

As used herein, the term alkyl refers to a group that represents saturated monovalent hydrocarbon radicals having straight-chain or branched moieties or combinations thereof and containing 1-8 carbon atoms, preferably 1-6 carbon atoms; more preferably, alkyl groups have 1 to 4 carbon atoms. The alkyl moieties may be optionally substituted with 1-5 substituents independently selected from the group consisting of

- 42 044839 hydroxy, alkoxy, cyano, ethynyl, alkoxycarbonyl, acyl, aryl or heterocycle. Alkyl moieties may be optionally substituted with cycloalkyl, as defined hereinafter. Preferred alkyl groups are methyl, cyanomethyl, ethyl, 2-ethoxy-2-oxoethyl, 2-methoxyethyl, n-propyl, 2-oxopropyl, 3-hydroxypropyl, 2-propynyl, n-butyl, isobutyl, n-pentyl, 3- pentyl, n-hexyl, cyclohexylmethyl, benzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl, 4-(aminosulfonyl)benzyl, 1-phenylethyl, 2-phenylethyl, ( 3,5-dimethylisoxazol-4-yl)methyl or (5-nitro-2-furyl)methyl. More preferred alkyl groups are methyl, ethyl, cyanomethyl, 2-methoxyethyl, n-propyl, 3-hydroxypropyl, 2-propynyl, n-butyl, 3-pentyl, n-hexyl, benzyl, 3-bromobenzyl, 3-methoxybenzyl, 3 -nitrobenzyl, 3-aminobenzyl, (3,5-dimethylisoxazol-4-yl)methyl or (5-nitro-2-furyl)methyl. The most preferred alkyl groups are methyl, ethyl, 3-methoxybenzyl, 3-nitrobenzyl or (5-nitro-2-furyl)methyl.

As used herein, the term cycloalkyl represents a monovalent group having from 3 to 8 carbon atoms, preferably from 3 to 6 carbon atoms, derived from a saturated cyclic hydrocarbon, which may be substituted by any suitable group, including, but not limited to, one or more moieties selected from the groups described above for alkyl groups. A preferred cycloalkyl group is cyclohexyl.

As used herein, the term aryl is defined as a phenyl group optionally substituted with 1-4 substituents independently selected from halogen, amino, nitro, alkoxy or aminosulfonyl. Preferred aryl groups are phenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 3-methoxyphenyl, 3-nitrophenyl, 3-aminophenyl or 4-(aminosulfonyl)phenyl.

As used herein, the term phenyl represents an aromatic hydrocarbon group of the formula -C ₆ H ₅ .

As used herein, the term benzyl group represents a group of the formula -CH ₂ -aryl. Preferred benzyl groups are benzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl or 4-(aminosulfonyl)benzyl. More preferred benzyl groups are benzyl, 3-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl or 3-aminobenzyl. The most preferred benzyl groups are 3-methoxybenzyl or 3-nitrobenzyl.

As used herein, the term halogen represents a fluorine, chlorine, bromine or iodine atom. The preferred halogen is bromine.

As used herein, the term hydroxy refers to a group of the formula -OH.

As used herein, the term cyano refers to a group of the formula -CN.

As used herein, the term amino refers to a group of the formula -NH2.

As used herein, the term ethynyl refers to a group of the formula -C^CH.

As used herein, the term alkoxy refers to a group of the formula -OR ^a where R ^a represents an alkyl group as defined above. A preferred alkoxy group is a methoxy group.

As used herein, the term nitro refers to a group of the formula -NO2.

As used herein, the term amido refers to a group of the formula -C(=O)NH ₂ .

As used herein, the term acyl denotes a group of the formula -C(=O)R ^b where R ^b denotes an alkyl group as defined herein above. The preferred acyl group is acetyl (-C(=O)Me).

As used herein, the term alkoxycarbonyl (or ester) refers to a group of the formula -COORc, wherein R ^c is an alkyl group; with the proviso that ^Rc is not an alpha-hydroxy-substituted alkyl. A preferred alkoxycarbonyl group is ethoxycarbonyl.

As used herein, the term heterocycle represents a 5-membered ring containing one or two heteroatoms selected from O or N. The heterocycle may be substituted with one or two C ₁ . ₄ alkyls or nitro. Preferred heterocycles are (3,5-dimethylisoxazol-4-yl) or (5-nitro-2-furyl). The most preferred heterocycle is (5-nitro-2-furyl).

Typically, R ¹ represents a hydrogen atom or C1.6αlkyl. Typically R ¹ is a hydrogen atom or C1. ₆ alkyl, optionally substituted with hydroxy, alkoxy, cyano, ethynyl, alkoxycarbonyl or acyl. Preferred R ¹ is hydrogen, methyl, cyanomethyl, 2-ethoxy-2-oxoethyl, 2-methoxyethyl, n-propyl, 2-oxopropyl, 3-hydroxypropyl, 2-propynyl, n-pentyl or n-hexyl. More preferred R ¹ is hydrogen, methyl, cyanomethyl, 2-methoxyethyl, n-propyl, 3-hydroxypropyl or 2-propynyl. Most preferred R ¹ is a hydrogen atom.

Typically, R ² represents a hydrogen atom or C1.4alkyl. Typically ^R2 is a hydrogen atom or an unsubstituted C1. ₄ alkyl. Preferred R ² is hydrogen, methyl or n-butyl. More preferred R ² is methyl.

Typically, R ³ is a group of the formula -CHR5R ⁶ or a benzyl group. Preferred R ³ is 3-pentyl, 1-(aminocarbonyl)propyl, 1-(ethoxycarbonyl)propyl or 3-bromobenzyl. The most preferred R ³ is 1-(ethoxycarbonyl)propyl.

Typically, R ⁴ is C ₁ . ₈ alkyl, optionally substituted with alkoxycarbonyl,

- 43 044839

With _3-6 cycloalkyl, aryl or heterocycle. Typically, R ⁴ is C _1-8 alkyl, optionally substituted with cyclohexyl, phenyl, bromophenyl, aminophenyl, methoxyphenyl, nitrophenyl, aminosulfonylphenyl, 3,5-dimethylisoxazol-4-yl, 5-nitro-2-furyl or ethoxycarbonyl. Preferred R ⁴ is n-butyl, isobutyl, n-pentyl, n-hexyl, cyclohexylmethyl, benzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl, 4-(aminosulfonyl )benzyl, 1-phenylethyl, 2-phenylethyl, (3,5-dimethylisoxazol-4-yl)methyl, (5-nitro-2-furyl)methyl or 1-(ethoxycarbonyl)propyl. More preferred R ⁴ is n-butyl, n-hexyl, benzyl, 3-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl, (3,5-dimethylisoxazol-4-yl)methyl, (5-nitro-2furyl )methyl or 1-(ethoxycarbonyl)propyl. The most preferred R ⁴ is 3-methoxybenzyl, 3-nitrobenzyl or (5-nitro-2-furyl)methyl.

Typically, R ⁵ is C2-4alkyl. Typically R ⁵ is unsubstituted C2-4alkyl. A preferred R ⁵ is ethyl.

Typically, R6 is C _2-4 alkyl, amido or -COOR ⁷ . Typically, R6 is unsubstituted C _2-4 alkyl, amido or -COOR ⁷ . Preferred R6 is ethyl, amido or ethoxycarbonyl. The most preferred R ⁶ is ethoxycarbonyl.

Typically, R ⁷ is C1-4alkyl. Typically R ⁷ is unsubstituted C1-4alkyl. A preferred R ⁷ is ethyl.

In some embodiments, the compounds are compounds having formula (I), enantiomers, diastereomers and mixtures thereof (including all possible mixtures of stereoisomers) or pharmaceutically acceptable salts thereof:

R ² where R ¹ represents a hydrogen atom, C _1-6 alkyl, optionally substituted with hydroxy, alkoxy, cyano, ethynyl, alkoxycarbonyl or acyl;

R ² represents a hydrogen atom or unsubstituted C _1-4 alkyl;

R ³ represents a group of the formula -CHR5R ⁶ or a benzyl group;

R ⁴ is C _1-8 alkyl, optionally substituted with cyclohexyl, phenyl, bromophenyl, aminophenyl, methoxyphenyl, nitrophenyl, aminosulfonylphenyl, 3,5-dimethylisoxazol-4-yl, 5-nitro-2-furyl or ethoxycarbonyl;

R ⁵ is unsubstituted C _2-4 alkyl;

R ⁶ is unsubstituted C _2-4 alkyl, amido or -COOR ⁷ ;

R ⁷ is unsubstituted C _1-4 alkyl;

provided that if R ¹ is hydrogen, R ² is methyl, R ³ is -CHR ⁵ R ⁶ , R ⁶ is ethoxycarbonyl and R ⁵ is ethyl, then R ⁴ is other than n-propyl, isopropyl, n-pentyl, n-heptyl, 3-bromobenzyl, 4-chlorobenzyl, 4-methylbenzyl or 2-phenylethyl.

In the embodiment described above, preferably, if R ³ denotes a benzyl group, then R ⁴ denotes C _1-8 alkyl, optionally substituted with alkoxycarbonyl.

In the embodiment described above, preferably, if R ³ is a group of the formula -CHR5R ⁶ , then R ⁴ is C _1-8 alkyl, optionally substituted with C _3-6 cycloalkyl, aryl or heterocycle.

Preferably, R ¹ is hydrogen, methyl, cyanomethyl, 2-ethoxy-2oxoethyl, 2-methoxyethyl, n-propyl, 2-oxopropyl, 3-hydroxypropyl, 2-propynyl, n-pentyl or n-hexyl;

R ² is hydrogen, methyl or n-butyl;

R ³ is 3-pentyl, 1-(aminocarbonyl)propyl, 1-(ethoxycarbonyl)propyl or 3-bromobenzyl;

R ⁴ is n-butyl, isobutyl, n-pentyl, n-hexyl, cyclohexylmethyl, benzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl, 4-(aminosulfonyl) benzyl, 1-phenylethyl, 2-phenylethyl, (3,5-dimethylisoxazol-4-yl)methyl, (5-nitro-2-furyl)methyl or 1-(ethoxycarbonyl)propyl;

with the proviso that if R ¹ is hydrogen, R ² is methyl and R ³ is 1-(ethoxycarbonyl)propyl, then R ⁴ is other than n-pentyl, 3-bromobenzyl or 2-phenylethyl.

In the embodiment described above, preferably, if R ³ is 3-bromobenzyl, then R ⁴ is C _1-8 alkyl, optionally substituted with alkoxycarbonyl.

In the embodiment described above, preferably, if R ³ is 3-pentyl, 1-(aminocarbonyl)propyl or 1-(ethoxycarbonyl)propyl, then R ⁴ is other than 1-(ethoxycarbonyl)propyl.

More preferably, R ¹ is hydrogen, methyl, cyanomethyl, 2-methoxyethyl, n-propyl, 3-hydroxypropyl or 2-propynyl;

R ² is methyl;

R ³ is 3-pentyl, 1-(aminocarbonyl)propyl, 1-(ethoxycarbonyl)propyl or 3-bromobenzyl;

R ⁴ is n-butyl, n-hexyl, benzyl, 3-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl, (3,5-dimethylisoxazol-4-yl)methyl, (5-nitro-2-furyl )methyl or 1-(ethoxycarbonyl)propyl;

- 44 044839 provided that if R ¹ represents a hydrogen atom, R ² represents methyl and R ³ represents

1-(ethoxycarbonyl)propyl, then R ⁴ is different from 3-bromobenzyl.

In the embodiment described above, preferably, if R ³ is 3-bromobenzyl, then R ⁴ is

1-(ethoxycarbonyl)propyl.

In the embodiment described above, preferably, if R ³ is 3-pentyl, 1-(aminocarbonyl)propyl or 1-(ethoxycarbonyl)propyl, then R ⁴ is other than 1-(ethoxycarbonyl)propyl.

Most preferably, R ¹ is a hydrogen atom; R ² is methyl; R ³ is 1-(ethoxycarbonyl)propyl, and R ⁴ is 3-methoxybenzyl, 3-nitrobenzyl or (5-nitro-2furyl)methyl.

Another embodiment includes compounds wherein R ² is methyl, R ³ is a group of the formula CHR5R ⁶ and R ⁵ is C ₂ . ₄ alkyl, R ⁶ is amido or -COOR ⁷ and R ⁷ is methyl or ethyl.

In some embodiments, compounds useful in the methods and compositions of this invention are selected from the group consisting of:

ethyl 2-[(7-benzyl-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;

ethyl 2-{[7-(3-bromobenzyl)-1-(2-ethoxy-2-oxoethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1Hpurin-8-yl ]thio}butanoate;

ethyl 2-{[7-(3-bromobenzyl)-1-(2-methoxyethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8yl]thio} butanoate ;

ethyl 2-{[7-(3-bromobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio} butanoate;

ethyl 2-{[7-(3-bromobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio} butanoate;

ethyl 2-{[7-(2-bromobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;

ethyl 2-{[7-(3-bromobenzyl)-1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio} butanoate;

ethyl 2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;

ethyl 2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio }butanoate;

ethyl 2-{[7-(3-bromobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin8-yl]thio}butanoate ;

ethyl 2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-(2-propynyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio }butanoate;

ethyl 2-{[7-(3-methoxybenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;

ethyl 2-{[3-methyl-7-(3-nitrobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;

ethyl 2-{[7-(3-aminobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;

ethyl 2-({7-[4-(aminosulfonyl)benzyl]-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate;

ethyl 2-{[7-(4-bromobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;

ethyl 2-{[7-(cyclohexylmethyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-nurun-8-ul]thio}butanoate;

ethyl 2-{[1,3-dimethyl-2,6-dioxo-7-(1-phenylethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;

ethyl 2-{[1,3-dimethyl-2,6-dioxo-7-(2-phenylethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;

ethyl 2-({7-[(3,5-dimethylisoxazol-4-yl)methyl]-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8yl}thio) butanoate;

ethyl 2-({3-methyl-7-[(5-nitro-2-furyl)methyl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio) butanoate;

ethyl 2-[(7-butyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;

ethyl 2-{[7-(3-bromobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio} butanoate;

ethyl 2-[(1,7-dihexyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;

ethyl 2-[(7-hexyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;

ethyl 2-[(3-methyl-2,6-dioxo-1,7-dipentyl-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;

2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio } butanamide;

2-[(7-butyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanamide;

7-(3-bromobenzyl)-8-[(1-ethylpropyl)thio]-3-methyl-3,7-dihydro-1H-purine-2,6-dione;

ethyl 2-{8-[(3-bromobenzyl)thio]-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl}butanoate and ethyl 2- [(7-isobutyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate.

In some embodiments, compounds useful in the methods and compositions of this invention are selected from the group consisting of:

ethyl 2-[(7-benzyl-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;

ethyl 2-{[7-(3-bromobenzyl)-1-(2-methoxyethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8yl]thio} butanoate ;

ethyl 2-{[7-(3-bromobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio} butanoate;

- 45 044839 ethyl 2-{[7-(3-bromobenzyl)-1 -(cyanomethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1 H-purin-8yl]thio } butanoate;

ethyl 2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-propyl-2,3,6,7-tetrahydro-III-purin-8-yl]thio}butanoate;

ethyl 2-{[7-(3-bromobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-III-purin8-yl]thio}butanoate ;

ethyl 2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-(2-propynyl)-2,3,6,7-tetrahydro-1H-purin-8yl]thio} butanoate ;

ethyl 2-{[7-(3-methoxybenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;

ethyl 2-{[3-methyl-7-(3-nitrobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;

ethyl 2-{[7-(3-aminobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;

ethyl 2-({7-[(3,5-dimethylisoxazol-4-yl)methyl]-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8yl}thio) butanoate;

ethyl 2-({3-methyl-7-[(5-nitro-2-furyl)methyl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio) butanoate;

ethyl 2-[(7-butyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;

ethyl 2-[(7-hexyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;

2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio } butanamide;

7-(3-bromobenzyl)-8-[(1-ethylpropyl)thio]-3-methyl-3,7-dihydro-III-purine-2,6-dione and ethyl 2-{8-[(3bromobenzyl)thio ]-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl}butanoate.

In some embodiments, compounds useful in the methods and compositions of this invention are selected from the group consisting of:

ethyl 2-{[7-(3-methoxybenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;

ethyl 2-{[3-methyl-7-(3-nitrobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate and ethyl 2-({ 3-methyl-7-[(5-nitro-2-furyl)methyl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate.

Compounds or agents or pharmaceutically acceptable salts thereof useful in the methods and compositions of this invention also include those mentioned in i) US patent application 2008/0081832; ii) international patent application WO 2006/128692; iii) international patent application WO 2006/128693; iv) UK Patent No. 1039113 and v) UK Patent No. 1309692.

In one aspect of the present invention, the SV2A inhibitor is levetiracetam. Levetiracetam is the International Union of Pure and Applied Chemistry (IUPAC) nomenclature name for the compound (2S)-2-(2-oxopyrrolidin-1-yl)butanamide). Levetiracetam is a widely used antiepileptic drug. Levetiracetam binds to a specific site in the CNS: synaptic vesicle protein 2A (SV2A) (see, for example, Noyer et al., 1995; Fuks et al., 2003; Lynch et al., 2004; Gillard et al., 2006) and is further shown to directly inhibit synaptic activity and neurotransmission through inhibition of presynaptic neurotransmitter release (Yang et al., 2007).

As used herein, the term prodrug is accepted in the art and is intended to encompass compounds or agents that are converted to an SV2A inhibitor under physiological conditions. A general method for preparing a prodrug involves selecting moieties that are hydrolyzed or metabolized under physiological conditions to produce the desired compound or agent. In other embodiments, the prodrug is converted by the enzymatic activity of a host animal into an SV2A inhibitor.

The term analogue is used here to mean a compound that is functionally similar to another chemical entity, but does not have an identical chemical structure. For example, an analogue is sufficiently similar to the parent or parent compound that it can replace the parent compound in therapeutic applications despite minor structural differences, i.e. be an SV2A inhibitor.

The term derivative is used here to denote a chemical modification of a compound. Chemical modifications of a compound may include, for example, replacement of hydrogen with an alkyl, acyl, or amino group. Many other modifications are also possible. The SV2A inhibitor derivative used in the methods and compositions of this invention binds SV2A and reduces synaptic function by reducing presynaptic vesicle release, i.e. is an SV2A inhibitor.

The expression pharmaceutically acceptable salts is used herein to refer to the agents or compounds of the invention that are therapeutically active, non-toxic salt forms of the compounds with bases and acids. The acid addition salt form of a compound which occurs in its free form as a base can be prepared by treating said free base form with a suitable acid, for example an inorganic acid such as hydrochloric or hydrobromic, sulfuric, nitric, phosphoric and the like; or organic acid, for example acetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, para-toluenesulfonic, cyclic, salicylic, para-aminosalicylic , pamoeva and the like. See, for example, WO 01/062726.

Compounds containing acidic protons can be converted into their therapeutically active, non-toxic base addition salt forms, such as metal and amine salts, by treatment with suitable organic and inorganic bases. Suitable forms of base salts include, for example, ammonium salts, alkali and alkaline earth metal salts, for example, lithium, sodium, potassium, magnesium, calcium and the like salts, salts with organic bases, for example, N-methyl-D-glucamine, hydrabamine and salts with amino acids such as, for example, arginine, lysine and the like. Conversely, said salt forms can be converted into free forms by treatment with a suitable base or acid. The compounds and their salts may be in the form of solvates, which are included within the scope of the present invention. Such solvates include, for example, hydrates, alcoholates and the like. See, for example, WO 01/062726.

Many compounds useful in the methods and compositions of this invention have at least one stereogenic center in their structure. This stereogenic center may be present in the R- or S-configuration, the specified R and S designation being used in accordance with the rules described in Pure Appl. Chem. (1976), 45, 11-30. The invention also concerns all stereoisomeric forms of the compounds, for example enantiomeric and diastereomeric forms or mixtures thereof (including all possible mixtures of stereoisomers). See, for example, WO 01/062726.

Additionally, some compounds that contain alkenyl groups can exist as Z (zusammen = together) or E (entgegen = towards) isomers. In each case, the invention includes both the mixture and the individual individual isomers. Various substituents on the piperidinyl or azepanyl ring may also be in cis or trans relative positions to each other relative to the plane of the piperidinyl or azepanyl ring. Some compounds can also exist in tautomeric forms. Such forms are intended to be included within the scope of the present invention, although they are not expressly indicated in the above claims. With respect to the methods and compositions of the present invention, reference to a compound or compounds is intended to include that compound in each of its possible isomeric forms and mixtures thereof, unless a particular isomeric form is specifically indicated. See, for example, WO 01/062726.

This invention relates to methods and compositions for treating age-related cognitive impairment or the risk of its occurrence using an SV2A inhibitor and its analogs, derivatives and pharmaceutically acceptable salts and solvates. The methods and compositions can be used in human patients in clinical applications for the treatment of age-related cognitive impairment in conditions such as MCI, ARCD and AAMI or at risk for them. As described herein, the dosage of the composition and the dosage range for this method are safe and effective in such applications.

In some embodiments, the SV2A inhibitor activity is levetiracetam, or a pharmaceutically acceptable salt or solvate thereof, or a composition containing such levetiracetam, and the invention relates to such levetiracetam or levetiracetam-containing compositions and a method of using such levetiracetam or such composition for the purpose of improving cognitive function in patients suffering from or at risk of age-related cognitive impairment, the method comprising the step of administering to the subject a therapeutically effective amount of levetiracetam or a composition containing the same. In other embodiments, analogs or derivatives of levetiracetam and its pharmaceutically acceptable salt or solvate are used.

In some embodiments, the SV2A inhibitor activity is brivaracetam, or a pharmaceutically acceptable salt or solvate thereof, or a composition containing such brivaracetam, and the invention relates to such brivaracetam or brivaracetam-containing compositions and a method of using such brivaracetam or such composition to improve cognitive function in patients suffering from or at risk of age-related cognitive impairment, the method comprising the step of administering to the subject a therapeutically effective amount of brivaracetam or a composition containing the same. In other embodiments, analogs or derivatives of brivaracetam and a pharmaceutically acceptable salt or solvate thereof are used.

The subject to be treated with the methods and compositions of this invention exhibits or is at risk of developing age-related cognitive impairment. In some embodiments, age-related cognitive impairment includes, but is not limited to, MCI, ARCD, and AAMI.

It will be appreciated that the compounds and agents used in the compositions and methods of the present invention should preferably readily cross the blood-brain barrier when administered peripherally. However, compounds that cannot penetrate the blood-brain barrier can nevertheless be effectively administered directly into the central nervous system, for example, by the intraventricular route.

In some embodiments of this invention, the SV2A inhibitor is formulated in a pharmaceutically acceptable carrier. In other embodiments, no carrier is used. For example, the SV2A inhibitor can be administered by itself or as a component of a pharmaceutical preparation (therapeutic composition). SV2A-uHru6uTop can be prepared in the form of a drug for administration in any convenient way for use in human treatment.

In some embodiments, the therapeutic methods of the invention include administering the compound or agent composition topically, systemically, or locally. For example, therapeutic compositions of compounds or agents of the invention may be formulated for administration, for example, by injection (eg, intravenously, subcutaneously or intramuscularly), inhalation or insufflation (oral or nasal), or by oral, buccal, sublingual, transdermal , nasal or parenteral administration. The compositions of the compounds or agents described herein can be formulated as part of an implant or device or formulated for slow or sustained release. When administered, the therapeutic composition of compounds or agents for use in this invention is in a physiologically acceptable form that does not contain pyrogens. Techniques and preparations can generally be found in Remington's Pharmaceutical Sciences, Meade Publishing Co., Easton, PA.

In some embodiments, pharmaceutical compositions suitable for parenteral administration may contain an SV2A inhibitor in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted to sterile conditions immediately prior to use. solutions or dispersions for injection, which may contain antioxidants, buffers, bacteriostatic factors, solutes that make the drug isotonic with the blood of the intended recipient, or suspending or thickening agents. Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerin, propylene glycol, polyethylene glycol and the like) and suitable mixtures thereof, vegetable oils such as olive oil, and organic esters for injection, for example ethyl oleate. Proper fluidity can be maintained, for example, by using coating materials such as lecithin, maintaining the required particle size in the case of dispersions and using surfactants.

The SV2A inhibitor-containing composition may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by including various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol, sorbic acid and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride and the like in the compositions. In addition, prolonged absorption of the injectable pharmaceutical form can be achieved, including agents that delay absorption such as aluminum monostearate and gelatin.

In some embodiments, compositions containing an SV2A inhibitor can be administered orally, for example, in the form of capsules, wafers, pills, tablets, lozenges (using a flavored base, typically sucrose and gum arabic or tragacanth), powders, granules, or in the form of a solution or a suspension in an aqueous or non-aqueous liquid, or in the form of a liquid emulsion of oil in water or water in oil, or in the form of an elixir or syrup, or in the form of lozenges (using an inert base such as gelatin and glycerin, or sucrose and gum arabic) and the like, each form containing a predetermined amount of an SV2A inhibitor as an active ingredient.

In solid oral dosage forms (capsules, tablets, pills, dragees, powders, granules and the like), one or more compositions containing an SV2A inhibitor may be admixed with one or more pharmaceutically acceptable carriers, such as sodium citrate, or dicalcium phosphate, and/or any of the following agents: (1) fillers or diluents such as starches, lactose, sucrose, glucose, mannitol and/or silicic acid; (2) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or gum arabic; (3) humectants such as glycerin; (4) leavening agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, some silicates and sodium carbonate; (5) dissolution retarding agents such as paraffin; (6) absorption accelerators such as quaternary ammonium compounds; (7) wetting agents such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents such as kaolin and bentonite clay; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also contain buffering agents. Solid compositions of a similar type can also be used as fillers in soft and hard filled gelatin capsules, using fillers such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

Oral liquid dosage forms include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the SV2A inhibitor, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers such

- 48 044839 as ethyl alcohol (ethanol), isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular cottonseed, peanut, corn, wheat germ, olive, castor and sesame oil), glycerin, tetrahydrofuryl alcohol, polyethylene glycols and sorbitan fatty acid esters and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, coloring agents, fragrances and preservatives.

Suspensions may contain, in addition to the active compound, suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.

As described above, compounds, agents and compositions thereof can be administered to provide slow, controlled or sustained release. As used herein, the expression sustained release is widely recognized in the pharmaceutical sciences and is used herein to mean the controlled release of an active compound or agent from a dosage form into the environment over an extended period of time, such as a period greater than or equal to 1 hour. A sustained release dosage form releases the drug is released at a substantially constant rate over an extended period of time, or a substantially constant amount of drug is released in steps over an extended period of time. As used herein, the expression sustained release includes the expressions controlled release, sustained release, continuous release, or slow release, as these terms are used in the pharmaceutical sciences. In some embodiments, a sustained release dosage form is used in the form of a patch or pump.

One skilled in the art, such as a physician, can readily determine the amount of SV2A inhibitor(s) needed to treat a subject using the composition and methods of this invention. It is understood that the dosage regimen is determined individually, taking into account, for example, various factors that modify the action of SV2A inhibitors: severity or stage of the disease, route of administration, and characteristics unique to the individual, such as age, weight, size, and degree of cognitive impairment.

In addition, although the invention is illustrated using levetiracetam, the results and method of the present invention are also applicable to other SV2A inhibitors. Accordingly, the present invention also provides compositions and methods of using other such SV2A inhibitors to improve cognitive function in patients suffering from or at risk of age-related cognitive impairment.

It is well known in the art that normalization to body surface area is a suitable way to extrapolate doses between species. To calculate the human equivalent dose (HED) from the dose used to treat age-related cognitive impairment in rats, the formula can be used: HED (mg/kg) = rat dose (mg/kg) χ 0.16 (see Determination of safe starting dose in clinical trials for therapy in adult healthy volunteers, December 2002, Center for Biologies Evaluation and Research). For example, application of this formula shows that a dose of 10 mg/kg in rats is equivalent to 1.6 mg/kg in humans. This conversion is based on a more general formula: HED = animal dose in mg/kg χ (animal weight in kg/human weight in kg) ^0.3 3.

In some embodiments, the dose of the SV2A inhibitor is from 0.1 to 5 mg/kg/day (which for a typical 70 kg human patient is from 7 to 350 mg/day). Doses that may be used include, but are not limited to, 0.1, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5 mg/kg/day. In embodiments, the dose is 1-2 mg/kg/day (which for a typical 70 kg human patient is 70-140 mg/day). In other embodiments, the dose of the SV2A inhibitor is from 0.1 to 0.2 mg/kg/day. Other doses higher, intermediate, or lower than these doses may also be used, and doses can be determined by one skilled in the art by following the methods of this invention.

In some embodiments, the dose of the SV2A inhibitor is from 0.01 to 2.5 mg/kg/day (which is about 0.7 to 180 mg/day for a typical 70 kg human patient). Dosages that may be used include (but are not limited to) 0.01, 0.02, 0.03, 0.04, 0.06, 0.08, 0.12, 0.14, 0.16, 0. 18, 0.2, 0.4, 0.6, 0.8, 1.0, 1.2, 1.4, 1.6, 1.8, 2.0, 2.2, 2.4, 2.5 mg/kg/day. In some embodiments, the dose is 0.1-2.5 mg/kg/day (which for a typical 70 kg human patient is approximately 7-180 mg/day). In some embodiments, the dose is 0.4-2.5 mg/kg/day (which for a typical 70 kg human patient is approximately 25-180 mg/day). In some embodiments, the dose of the SV2A inhibitor is from 0.6 to 1.8 mg/kg/day. In some embodiments, the dose of the SV2A inhibitor is from 0.04 to 2.5 mg/kg/day. In some embodiments, the dose of the SV2A inhibitor is from 0.06 to 1.8 mg/kg/day. Other doses higher, intermediate or lower than these doses may also be used, and one skilled in the art can determine

- 49 044839 dose, following the methods of this invention.

In some embodiments, the dosing interval is 12 or 24 hours. Dosing may also be done at shorter intervals, such as once every 6 hours. In some embodiments, the SV2A inhibitor is administered every 12 or 24 hours for a total daily dose of 0.1 to 5 mg. /kg (for example, if a daily dose of 2 mg/kg is taken every 12 hours, each dose is 1 mg/kg). In some embodiments, the SV2A inhibitor is administered every 24 hours at a daily dose of 1 to 2 mg/kg. In another embodiment, a selective SV2A inhibitor is administered every 24 hours at a daily dose of 0.1-0.2 mg/kg. In some embodiments, the SV2A inhibitor is administered every 12 or 24 hours at a daily dose of 0.01 to 2.5 mg/kg (e.g., if a daily dose of 0.8 mg/kg is administered every 12 hours, each dose is 0.4 mg/kg). In some embodiments, the SV2A inhibitor is administered every 12 or 24 hours at a daily dose of 0.1 to 2.5 mg/kg. In some embodiments, the SV2A inhibitor is administered every 12 or 24 hours at a daily dose of 0.4 to 2.5 mg/kg. In some embodiments, the SV2A inhibitor is administered every 12 or 24 hours at a daily dose of 0.6 to 1.8 mg/kg. In some embodiments, the selective SV2A inhibitor is administered every 12 or 24 hours at a daily dose of 0.04-2.5 mg/kg. In some embodiments, the selective SV2A inhibitor is administered every 12 or 24 hours at a daily dose of 0.06-1.8 mg/kg.

If the SV2A inhibitor is administered by means of an implant, device or slow or sustained release formulation, it may be administered once or more times periodically throughout the life of the patient as needed. For clinical applications, other dosing intervals intermediate or shorter than these dosing intervals may also be used, as may be determined by one skilled in the art following the methods of this invention.

One skilled in the art can determine the desired dosing time by performing routine experiments. For example, the SV2A inhibitor can be administered over a period of 1-4 weeks, 1-3 months, 3-6 months, 6-12 months, 1-2 years, or more, up to a lifetime of the patient.

In addition to SV2A inhibitors, the compositions and methods of this invention may also include other therapeutically useful agents. These other therapeutically beneficial agents can be administered as a single formulation, concomitantly or sequentially with SV2A inhibitors, according to the methods of the invention.

In some embodiments, the present invention provides methods and compositions for treating age-related cognitive disorder, the method comprising administering to a subject in need thereof or at risk of developing such a disorder an SV2A inhibitor as described above in combination with valproic acid (or salts thereof). , solvates, analogues or derivatives).

Valproic acid (VPA) analogs and derivatives useful in the methods and compositions of this invention include compounds of the formula

1^0^ R X where, independently for each case:

X is -OH, C ₁ . ₁₀ alkoxy, -O-alkali metal, -N(R1) ₂ , -SH, or -SC ₁ . ₁₀ alkyl;

R denotes linear or branched C ₁ . ₃₀ alkyl;

R ¹ stands for H, C ₁ . ₁₀ alkyl, C2. ₁₀ alkenyl, C2. ₁₀ alkynyl, aryl or aralkyl;

with the proviso that R may be unsubstituted or substituted with one or more -OH, C ₁ . ₁₀ αlkoxy, -N(R1) ₂ , -SH, -SC ₁ . ₁₀ alkyls or aryls.

Methods for preparing compounds of the formula can be found, for example, in US patents No. 4558070; 4595695; 4654370; 4895873; 4913906; 5017613; 5019398; 5049586; 5162573; 5440023; 5856569; 6131106 and 6610326.

VPA refers to 2-propyl pentanoate, an anticonvulsant drug that has been reported to modify excitatory-inhibitory functions by increasing glutamate reuptake and γ-aminobutyric acid (GABA) concentrations (Hassel et al., 2001; Loscher, 1999; Owens and Nemeroff , 2003). Other names and descriptions of VPAs are also provided here, such as Depakote, Valrelease, valproate, and sodium valproate. In addition to epilepsy, VPA is prescribed to treat bipolar disorder, migraine, and post-traumatic stress disorder.

In addition to the above indications, valproate has been reported to be effective in the treatment of age-related cognitive impairment (Koh et al., ^36th annual meeting of the Society for Neuroscience, Oct. 15, 2006, No. 273.14, D,3). Chronic subcutaneous administration of 100 mg/kg/day sodium valproate to aged memory-impaired rats treats their age-related cognitive impairment and their performance in memory studies is significantly improved. This dosage results in a total plasma valproate level of 10 mcg/mL (10 mcg/mL total VPA). However, treatment with chronic subcutaneous administration of 50 mg/kg/day VPA is not effective.

In some embodiments, where the SV2A inhibitor is administered in combination with VPA or its analogs, derivatives, pharmaceutically acceptable salts or solvates, the dose of VPA or its analogs is

- 50 044839 aqueous, pharmaceutically acceptable salts or solvates and SV2A-uHru6umopa are each subtherapeutic for the treatment of age-related cognitive impairment when administered alone. In some embodiments, the daily dose of the SV2A inhibitor administered in combination with VPA or its analogs, derivatives, pharmaceutically acceptable salts or solvates is from 0.01 to 1 mg/kg. In some embodiments, the daily dose of the SV2A inhibitor administered in combination with VPA or its analogs, derivatives, pharmaceutically acceptable salts or solvates is from 0.001 to 1.0 mg/kg. In some embodiments, the dose of valproate administered in combination with the SV2A inhibitor is 0.5 to 5 μg/ml total VPA. One skilled in the art will readily determine dosages suitable for VPA analogues or derivatives, pharmaceutically acceptable salts or solvates thereof, using the methods of this invention.

One of ordinary skill in the art will appreciate that the compositions and methods described herein can be adapted and modified as appropriate for targeted use, and that the compositions and methods described herein can be used in other suitable applications, and that such other additives and modifications are within the scope of the art. this invention.

The present invention can be better understood from the experimental details that follow. However, one skilled in the art will readily appreciate that the specific methods and results discussed are only illustrative of the invention, which is described more fully in the embodiments that follow.

Examples

Introduction and models of age-related cognitive impairment.

Aging is thought to include a variety of conditions characterized by cognitive impairment (eg, age-related memory impairment [AAMI], mild cognitive impairment [MCI], and age-related cognitive decline [ARCD]). Animal models serve as an important means of developing and evaluating treatments for such age-related cognitive disorders. The features that characterize age-related cognitive impairment in animal models generally extend to age-related cognitive impairment in humans. Thus, effectiveness in such animal models predicts effectiveness in humans.

Of the available models, the Long-Evans rat model of cognitive impairment is particularly well suited for distinguishing between disease-related cognitive impairment and aging-related cognitive impairment. Indeed, comprehensive behavioral characterization identifies a naturally occurring form of cognitive impairment in an outbred strain of aged Long-Evans rats (Charles River Laboratories; Gallagher et al., Behav. Neurosci. 107:618-626, (1993)). In a behavioral assessment using the Morris water maze (MWM), rats learn and remember the location of an escape platform based on the configuration of spatial cues surrounding the maze. The cognitive basis of action is examined in test trials, using determinations of the spatial displacement of animals in search of the location of the rescue platform. Aged rats in the study population have no difficulty swimming to a visible platform, but age-dependent impairment is detected when the platform is camouflaged, requiring the use of spatial information. The actions of individual old rats in the Long-Evans outbred strain vary greatly. For example, some of these rats act on par with young adult animals. However, approximately 40-50% are outside the range of effectiveness in young animals. This variability among aged rats reflects plausible individual differences. Thus, in a population of aged animals, some animals are cognitively impaired and are designated as age-impaired (AI), and other animals are not impaired and are designated as unimpaired aged animals (AU). See, for example, Colombo et al., Proc. Natl. Acad. Sci. 94:14195-14199, (1997); Gallagher and Burwell, Neurobiol. Aging, 10:691708, (1989); Rapp and Gallagher, Proc. Natl. Acad. Sci. 93:9926-9930, (1996); Nicolle et al., Neuroscience, 74:741-756, (1996) and Nicolle et al., J. Neurosci. 19:9604-9610, (1999).

The authors use this rat model to identify genes involved in age-related changes in cognitive function.

Example 1. Enhanced expression of SV2A genes in rats with age-related disorders.

Behavioral characterization of young, age-deficient and aged unimpaired rats in the Morris water maze (MWM)

Behavioral tests are performed on young (4-month-old) and aged (24-month-old) pathogen-free male Long-Evans rats.

The MWM device consists of a large circular basin (diameter 1.83 m; height 0.58 m) filled with water (27°C), which is opaque due to the addition of a non-toxic pigment or some other substance. In a typical version of the hidden platform test, rats are trained to find a camouflaged white rescue platform (34.5 cm high) that is located in the center of one quadrant of the maze approximately 1.0 cm below the surface of the water. This platform can be returned back to the bottom of the tank or raised to its normal position on the outside of the maze during behavioral testing. Platform location remains constant from trial to trial

- 51 044839 niyu. Because there are no local cues that mark the position of the platform, the ability of rats to efficiently locate it from any starting position along the perimeter of the pool depends on the use of information surrounding the maze. The labyrinth is surrounded by black curtains, to which white drawings are attached, providing the outlines of spatial markers. A second platform (37.5 cm high) with a surface painted black was raised 2 cm above the surface of the water during cue training to control for factors unrelated to recognition. The behavior of the rat in the pool is recorded using a camera suspended at a height of 2.5 m above the center of the pool. The camera is connected to a video tracking system (HVS Image Advanced Tracker VP200) and a personal computer using HVS software developed by Richard Baker of HVS Image, Hampton, UK.

The MWM protocol has been optimized for sensitivity to the effects of aging on cognition and for detecting significant individual differences in a population of aged outbred Long-Evans rats (Gallagher et al. Behav. Neurosci. 107:618-626, (1993)). Rats are subjected to three trials per day for 8 consecutive days with an interval of 60 sec between trials. On each training trial, the rat is released into the maze from one of four equally spaced starting positions around the perimeter of the pool. The starting position changes from trial to trial, thus preventing the use of a response strategy (e.g., always turning left from the starting position to locate the rescue platform). If the rat does not locate the escape platform within 90 s on any trial, the experimenter directs the rat to the platform where it remains for 30 s. Every sixth trial is a practice trial to assess the improvement of spatial displacements in the maze. During these trials, the rat swims for 30 s with the platform retracted to the bottom of the pool, during which time the platform is raised to its normal position to complete the escape trial. Upon completion of the hidden platform protocol, rats are assessed for cue acquisition using the visible platform. The location of this platform varies from trial to trial in one session of six training trials.

The proximity of the animal's position relative to the target is used to analyze performance in the training and test trials. A measure of proximity is obtained by determining the position of the animal in the maze (10 times/s), ensuring that the distance from the rescue platform is recorded on average in 1 s. For test trials and training trials, the correlation procedure is performed in such a way that the test performance is relatively objective for differences in the distance to the target from different starting positions on the perimeter of the pool. When performing this correlation, the average swimming speed for each trial (path length/latency state) is calculated. The time required to swim to the target at that speed from the starting position used for the test is then removed from the recorded result prior to computer calculation of test performance, i.e. cumulative distance in training trials and average distance from the target in practice trials. Thus, estimates obtained using the proximity measure are assumed to reflect search error, representing deviations from the optimal search, i.e. direct path to the target, and search in the immediate vicinity of this position during the trial trials.

Computer video recordings are compiled to produce performance data for each rat in the maze. Measurements in the training trials and probe trials were analyzed by analysis of variance (ANOVA).

In one set of tests, performance during training with a hidden camouflaged platform differed between groups consisting of young and old rats [F(1,23)=12.69, p<0.002]. In this series of tests, no differences were observed between groups for training trials on visible platform cues. In this series of tests, escape latencies during cue training averaged 9.36 s for young and 10.60 s for aged rats.

The average proximity measure of the interpolated trial trials is used to calculate the spatial orientation learning coefficient for each individual subject, as described in detail in Gallagher et al., Behav. Neurosci. 107:618-26, (1993). If a rat quickly learns to search for a platform close to its location, its spatial learning rate is low. Old rats always differ from young rats in the same series of tests [F(1,23)=15.18, p<0.001]. Aged rats are classified as normal or impaired relative to the learning index profile of a population of young experimental rats. Old rats that fall within the normative range for young rats (index values <241) are designated old unimpaired (AU). The remaining aged subjects, which have index values outside the performance range for young animals, are designated aged impaired (AI).

Obtaining RNA from behaviorally characterized rats.

outbred Long-Evans rats, behaviorally characterized as described above, were sacrificed by live decapitation to obtain fresh brain tissue. The brains of 24 characterized rats are removed and microdissection of the dentate gyrus of the hippocampal region is performed from 500 micron sections obtained through the transverse axis of a single hippocampal formation (both hippocampi, left and right). There are 8 animals in each group (AI, AU and Y).

Total RNA was isolated using TRIzol reagent (Invitrogen, Carlsbad, Calif.) according to a standard protocol (homogenization in TRIzol reagent followed by chloroform extraction and isopropanol precipitation). Total RNA was then purified using the RNeasy mini kit (Qiagen, Valencia, Calif.). cRNA probes are then generated from the RNA samples on the Johns Hopkins Microarray Core Facility, typically according to Affymetrix specifications.

Briefly, 5 μg of total RNA was used to synthesize first-strand cDNA using oligonucleotide probes with the 24 oligo-dT plus T7 promoter primer (Proligo LLC, Boulder, Calif.) and the Superscript Choice System (Invitrogen). After double-stranded cDNA synthesis, the product is purified by phenol-chloroform extraction and biotinylated antisense cRNA is generated by in vitro transcription using the BioArray RNA High Yield Transcript Labeling kit (ENZO Life Sciences Inc., Farmingdale, N.Y.). Fragmentation of 15 μg of biotinylated cRNA is carried out at 94°C for 35 minutes. (100 mM Trix-acetate, pH 8.2, 500 mM KOAC, 150 mM MgOAC. 10 μg of total fragmented cRNA was hybridized in the RAT genome 230-2 Affymetrix GeneChip array assay for 16 h at 45°C and constant rotation (60 rpm /min).

An Affymetrix Fluidics Station 450 is then used to wash and stain the chips, removing unhybridized target and incubating with streptavidin-phycoerythrin conjugate to stain the biotinylated cRNA. The staining is then enhanced using goat immunoglobulin-G (IgG) as a blocking reagent and biotinylated anti-streptavidin antibody (goat), followed by a second staining step with streptavidin-phycoerythrin conjugate.

To control the quality of total RNA from samples, Agilent Bioanalyzer, Lab on a Chip technology is used to ensure that all samples have optimal rRNA ratios (1:2 for 18S and 28S, respectively) and clean working systems.

To control the quality of hybridization of the chip image and comparison between chips, the following parameters are considered: conversion factor - refers to the overall intensity of the chip, to confirm the same signal intensity and coloring of the samples; basis - assessment of nonspecific or cross-hybridization; percentage of existing signals: percentage of transcripts that are considered to be significantly hybridized to the chip (available) by the algorithm; glyceraldehyde-3phosphate dehydrogenase (GAPDH) (3'/5'): RNA integrity representation as determined by the ratio of 3' to 5' regions for the housekeeping gene GAPDH, its presence on the chip and a ratio close to 1 supports good target integrity (sample); peaks (BioB/BioC) to confirm detection level and sensitivity after hybridization.

Microarray data analysis.

Fluorescence is detected using the Affymetrix G3000 GeneArray Scanner and image analysis of each gene chip is performed using GeneChip Operating System 1.1.1 (GCOS) software from Affymetrix and standard settings. All gene chip sets use short oligonucleotides for genes in an RNA sample.

For comparison between different chips, global scaling is used, scaling all sample sets to a target intensity (TGT) of 150. The total number of existing signals and scaling factors are the same for all chips. Additional presence/absence and statistical difference analyzes are performed area by area as follows. Sample sets are determined to be present in an area if they have an existing signal in four of the eight animals in one group.

Probe sets are annotated using the June 20, 2005 Affymetrix annotation, and all probe sets representing a specific gene are identified.

Perform an ANOVA on the sample set signal values for all available sample sets, combining the two groups of animals and comparing them with a third group. An AI ANOVA was performed with the AU group combined with the young group compared to the AI group.

Pearson correlations are calculated, comparing the signal values of a set of trials with the indicators of learning for old animals (excluding young ones) for all available sets of trials. As shown in FIG. 1, the expression of genes encoding SV2A is significantly increased in old impaired individuals (AI) relative to young individuals (Y) and old unimpaired individuals (AU) in the series of experiments performed above. These results indicate that increased SV2A expression correlates with the development of age-related cognitive impairment.

Example 2. Effect of levetiracetam in rats with age-related disorders.

Results of research in the Morris water maze.

Six age-impaired (AI) Long-Evans rats (as characterized above) are tested on their memory of novel spatial information in the MWM, under different drug/control treatment conditions (vehicle control and two different levetiracetam dose levels). The MWM protocol is essentially the same as that described in Example 1. Specifically for this study, a post-training memory retention test is conducted as described below.

- 53 044839

AI rats are given six training trials per training day with a 60-second interval each time between training trials for two consecutive days. On each training trial, the rat is released into the maze from one of four starting positions located at equal distances around the perimeter of the pool. If the rat does not locate the escape platform within 90 s on any trial, the experimenter directs the rat to the platform where it remains for 30 s. On each training day, 30 minutes - 1 hour before all training tests, AI rats are pre-treated into conditions according to one of three options: 1) control vehicle (0.9% saline solution); 2) levetiracetam (5 mg/kg/day) and 3) levetiracetam (10 mg/kg/day); via intraperitoneal (i.p.) injection. The same six AI rats are used for all tests, so that each treatment condition is tested on all six rats. Therefore, in contrast to any possible biases, the location of the rescue platform and the spatial cues surrounding the water maze are different for the three treatment conditions. Therefore, using one set of locations and spatial cues, two rats were treated with saline control, two with levetiracetam (5 mg/kg/day), and two with levetiracetam (10 mg/kg/day). Using the second set of locations and spatial cues, two rats treated with saline control in the first test were treated with either levetiracetam (5 mg/kg/day) or levetiracetam (10 mg/kg/day) and two rats pretreated with levetiracetam (5 mg/kg/day) treated with either control saline or levetiracetam (10 mg/kg/day) and two rats pretreated with levetiracetam (10 mg/kg/day) treated with either control saline or levetiracetam (5 mg /kg/day). Using the last set of locations and spatial cues, the grouping of rats is again changed so that each group is treated under conditions different from those of the previous treatments.

After the second training day and completion of 12 training trials (over two days), the rat is returned to its home cage and placed in the living room. After a 24-h delay after the last training trial, the rat is subjected to one test trial (memory retention trial), which is a similar MWM task as the training trials, but with the rescue platform removed.

For the memory retention test, the MWM circle pool is divided into 4 quadrants. The specific quadrant where the rescue platform is located in the training trials is designated the target quadrant. The specific area where the platform is located in the training trials is designated the target ring. In the memory retention test, the time AI rats spend swimming in a target quadrant is measured and then plotted as a percentage of total swimming time. In fig. Figure 2 shows the results of one such set of memory retention tests. The time that the AI rats spend in the target ring is also determined. In fig. Figure 2 shows the results of one such set of memory retention tests. Temporal data are collected for all three drug treatment conditions.

In the memory storage test, the results of which are shown in FIG. 2, the time that AI rats spend in the target quadrant is approximately 25%, which corresponds to an efficiency equivalent to results in the absence of memory information about the location of the platform. This efficacy was not significantly improved in the group treated with levetiracetam at 5 mg/kg/day. However, the group treated with levetiracetam at 10 mg/kg/day showed significantly improved memory compared to vehicle-treated controls, as indicated by a significant increase in time spent in the target quadrant, up to approximately 35% of total swimming time (see Fig. 2). This level of efficacy is equivalent in young and old unimpaired rats, indicating that treatment with levetiracetam 10 mg/kg/day produces a significant restoration of the ability of AI rats to find the optimal route in this MWM. The effectiveness of treatment with levetiracetam 10 mg/kg/day is also seen by the time spent in the target ring (see Fig. 2).

Results of studies in a maze with radial arms.

The effects of levetiracetam on spatial memory retention in aged AI rats were assessed by performing a behavioral radial arm maze (RAM) task using a vehicle control and five different levetiracetam dosage levels (1.25, 2.5, 5. 10 and 20 mg/kg/day). RAM behavioral tests are performed on ten AI rats. All six treatment conditions were tested on all ten rats as described above for the MWM study.

The RAM setup used consists of eight equally spaced arms. From each face of the octagonal central platform (diameter 30 cm, height 51.5 cm) protrudes the arm of a raised labyrinth (width 7 cm x length 75 cm). The transparent side walls on the sleeves are 10 cm high and are located at an angle of 65°, forming a groove. A cuvette with food (diameter 4 cm, depth 2 cm) is placed at the far end of each sleeve. The reward is Froot Loops™ (Kellogg Company). Blocks constructed from Plexiglas™ (height 30 cm x width 12 cm) can be positioned so that they

- 54 044839 prevented entry into any sleeve. There are also numerous additional markers around the labyrinth installation.

AI rats are first subjected to pre-training testing (Chappell et al. Neuropharmacology, 37:481-487, 1998). The pre-training test consists of a habituation phase (4 days), a training phase with a standard success-move task (18 days), another training phase (14 days) in which a short delay is administered between the presentation of a subset of arms assigned by the experimenter (e.g., five arms available and three arms are blocked), and completion involving a success-move task with eight arms (i.e., all eight arms are accessible).

During the habituation phase, rats are introduced to the maze in an 8-min session over four consecutive days. In each of these sessions, food rewards are scattered across the RAM, first on the central platform and in the arms, and then gradually limited to the arms. After this habituation phase, a standard training protocol is used in which a food pellet is placed at the end of each arm. Rats are subjected to one test every day for 18 days. The daily test ends when all eight pellets have been received, or 16 attempts have been made, or 15 minutes have elapsed. Following completion of this training phase, a second training phase is conducted in which the memory demand is increased by introducing a brief delay during the test. At the beginning of each trial, three arms of an eight-arm maze are blocked. Rats are allowed to feed in five arms that are allowed access during this initial 'information phase' of the trial. The rats are then removed from the maze for 60 s, during which the barriers are removed from the maze, thus allowing access to all eight arms. The rats are then placed back in the center of the platform and allowed to receive the remaining food rewards during this 'delay test' phase of the trial. The identity and configuration of the hoses varied throughout the tests.

The number of errors the AI rats make during the delay phase of the test is monitored. An error occurs on a trial if rats enter an arm from which food has already been collected in the pre-delay portion of the trial, or if they revisit an arm that they have already visited in the post-delay session.

After completing the pre-training test, rats are tested at longer delay intervals, i.e. with a delay of 1 hour between the information phase (presentation with several blocked arms) and the test for storing information in memory (presentation with all arms). During the delay interval, rats are left outside the maze in the research room on carts in their individual home cages. AI rats are pretreated 30-40 minutes before daily testing with a single dose of one of the following conditions: 1) vehicle control (0.9% saline); 2) levetiracetam (1.25 mg/kg/day); 3) levetiracetam (2.5 mg/kg/day); 4) levetiracetam (5 mg/kg/day); 5) levetiracetam (10 mg/kg/day); 6) levetiracetam (20 mg/kg/day), by intraperitoneal (i.p.) injection. Injections are given every other day, alternating with flushing days. Over the course of 23 days of testing, each AI rat is exposed to all six treatment conditions. To counter any possible bias, the effect of the drug is assessed using a series of increasing-decreasing doses, i.e. series of doses are given first in ascending order and then repeated in descending order. Therefore, there are two definitions for each dose.

In the context of varying doses of levetiracetam and vehicle control, parametric statistics (paired t-tests) were used to compare AI rats' retention test performance on the 1-hour delay version of the RAM task (see FIG. 3). The average number of errors that occur in trials is also significantly lower when treated with levetiracetam 5 mg/kg/day (mean number of errors ± standard deviation of the mean (SEM) = 0.75 ± 0.32) and 10 mg/kg/day ( mean number of errors ± SEM = 0.80 ± 0.27) than when using control media (mean number of errors ± SEM = 2.00 ± 0.42). Relative to vehicle control treatment, levetiracetam significantly improved memory performance at 5 mg/kg/day (t(9)=2.18, p=0.057) and 10 mg/kg/day (t(9)=2.37, p= 0.042).

To calculate the human equivalent dose (HED), the authors use the formula: HED (mg/kg) = rat dose (mg/kg) x 0.16 (see Determining a safe starting dose in clinical trials of therapy in healthy adult volunteers, December 2002 , Center for Biologies Evaluation and Research) for the dosage of levetiracetam for the treatment of age-related cognitive impairment in humans. Therefore, a dose of 5 mg/kg/day in rats is equivalent to 0.8 mg/kg/day in humans and a dose of 10 mg/kg/day in rats is equivalent to 1.6 mg/kg/day in humans.

Claims (3)

CLAIM 1. The use of a pharmaceutical composition containing levetiracetam or a pharmaceutically acceptable salt thereof in an amount of 7-350 mg to improve cognitive function in a subject with or at risk of age-related cognitive impairment. 2. A method of treating age-related cognitive impairment in a subject in need of such treatment or at risk of developing such a disorder, comprising administering to said subject a therapeutically effective amount of levetiracetam or a pharmaceutically acceptable salt thereof, wherein levetiracetam is administered at a dose of 7-350 mg. 3. The method according to claim 2, where levetiracetam is administered every 12 or 24 hours.