ZA200507322B - Selective cytokine inhibitory drugs for treating disorders of the central nervous system - Google Patents

Description

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METHODS OF USING AND COMPOSITIONS COMPRISING SELECTIVE

CYTOKINE INHIBITORY DRUGS FOR THE TREATMENT AND

MANAGEMENT OF DISORDERS OF THE CENTRAL NERVOUS SYSTEM

1. FIELD OF THE INVENTION

This invention relates, in part, to methods of treating, preventing and/or managing central nervous system disorders, including but not limited to, Parkinson disease, Alzheimer disease, mild cognitive impairment, Huntington disease, Amytophic Lateral Sclerosis, depression and defective long-term memory, and related disorders which comprise the administration of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. 2. BACKGROUND OF THE INVENTION

Central nervous system disorders affect a wide range of the population with differing severity. Generally, one major feature of this class of disorders includes the significant impairment of cognition or memory that represents a marked deterioration from a previous level of functioning. Dementia, for example, is characterized by several cognitive impairments including significant memory deficit and can stand alone or be an underlying characteristic feature of a variety of diseases, including Alzheimer disease,

Parkinson disease, Huntington disease, and Multiple Sclerosis to name but a few. Other central nervous system disorders include delerium, or disturbances in consciousness that occur-over a short period of time, and amnestic disorder, or discreet memory impairments that occur in the absence of other central nervous system impairments. 2.1 PARKINSON DISEASE

Parkinson disease (PD) is the second most common neurodegenerative disease and affects approximately 1% of the population over 50 years of age. Polymeropoulos et. al., 1996, Science 274: 1197-1198. Approximately one million Americans suffer from PD, and each year 50,000 individuals are diagnosed with the disorder. Olson, L., 2000, Science 290:721-724. Because early symptoms of PD may go unrecognized, perhaps as many as § to 10% of individuals over 60 years of age may have the illness. Olson, L., 2000, Science 290:721-724.

It has been known since the 1960s that loss of dopamine neurons in the nigrostriatal pathway of the brain results in the motor abnormalities characteristic of PD. Typical onset of PD occurs in mid to late adulthood with progressive clinical features. Some of the

Vv physical manifestations of PD include resting tremors, muscular rigidity, postural instability, and dementia. Pathologic characteristics of PD include a loss of dopaminergic neurons in the substantia nigra (SN) as well as the presence of intracellular inclusions or

Lewy Bodies in surviving neurons in various areas of the brain, Nussbaum, R. L. and Polymeropoulos, M. H., 1997, Hum. Molec. Genet. 6: 1637-1691. Interestingly, many other diseases have parkisonian motor features. The motor symptoms in PD are generally thought to result from the deficiency or dysfunction of dopamine or dopaminergic neurons in the substantia nigra. Nussbaum, R. L., Polymeropoulos, M. H., 1997, Hum. Molec.

Genet. 6: 1687-1691. Evidence has also suggested that molecular chaperones, specifically heat shock proteins, HSP70 and HSP40, may play a role in PD progression. Auluck et. al, : 2002, Science 295: 865-868.

Much controversy exists regarding the etiology of PD, and there is evidence that both genetic and environmental factors may contribute to the disease. A study of the nuclear families of 948 PD cases concluded that a rare major mendelian inheritance gene, that influences age of onset, exists. Maher et. al., 2002, Am. J. Med. Genet. 109: 191-197.

This study also suggested the existence of a gene that influences susceptibility. Other evidence also suggests that environmental factors may be more significant than genetic factors in contributing to PD. Calne et. al., 1987, Canad. J. Neurol. Sci. 14: 303-305.

Researchers have concluded that most cases of PD are caused by environmental factors superimposed on a background of slow and sustained neuronal loss due to aging. Calne, D.

B. and Langston, J. W., 1993, Lancet II: 1457-1459. While the etiology remains unclear, it is likely that both genetic and environmental factors contribute to PD, and that environmental factors act upon genetic susceptibility to cause the disease. Recent evidence in animal models of Parkinson disease, suggests that anti-inflammatory agents inhibit dopaminergic cell death. McGeer et. al., 2001, B.C. Med. J. 43:138-141.

While a cure is not currently available for Parkinson disease, traditional treatment has focused on responding to the effect of dopamine loss in the brain. Therapy using dopamine precursor, levodopa, became the treatment of choice when it was discovered that : the compound could alleviate PD symptoms, thereby improving the quality of life for affected individuals. Unfortunately, it has become clear that long-term levodopa administration can have side affects. Caraceni et. al., 1994 Neurology, 41:380. A variety of therapeutic strategies have been developed for the treatment of PD. MPTP, a neurotoxin known to specifically damage dopamine neurons, is commonly used as a model for the effects of PD. In one study, investigators used lentiviral vectors to deliver glial cell line derived neurotrophic factor (GDNF) to the striatum and SN of rhesus monkeys that had been treated one week prior with MPTP. Kordower et. al., 2000, Science 290: 767-773.

GDNF is known to have trophic effects upon degenerating nigrostriatal neurons in nonhuman primate models of Parkinson disease. Results of the study showed that GDNF augmented dopaminergic function in aged monkeys and reversed functional deficits and prevented nigrostriatal degeneration in monkeys that had been treated with MPTP. It was also noted that GDNF treatment reversed motor deficits in MPTP treated monkeys. This study also concluded that GDNF delivery could prevent nigrostriatal degeneration and induce regeneration of neurons in primate models of PD. Kordower et. al., 2000, Science 290: 767-773.

Another study, using electrical inhibition and pharmacologic silencing of the subthalmic nucleus (STN), demonstrated that the alteration of basal ganglia network activity could improve motor network activity in PD, presumably by suppressing the firing activity of neurons in the SN. Luo et. al., 2002, Science 298: 425-429. Investigators used an adeno-associated virus to transduce excitatory glutaminergic neurons in the rat STN with glutamic acid decarboxylase (GAD) to demonstrate that the change provided neuroprotection to the dopaminergic cells from toxic insults. Interestingly, rats with the transduced gene also showed significant improvement from parkinsonian phenotypes.

The selective PDE4 inhibitors Ro-20 1724 and SDZ-MNS 949, in the presence of the adenylate cyclase activator forskolin, have been shown to stimulate uptake of dopamine by rat mesencephalonic neurons in vitro (Hulley et al., J Neural Transm Suppl, 46:217-228, 1995). In these studies, elevation of cAMP by the addition of dibutyryl cAMP or forskolin protected dopaminergic neurons from the neurotoxic effects of MPP' (1-methyl-4-phenyl pyridinium ion). These PDE4 inhibitors were shown to reduce dopamine depletion in the striatum and reduce loss of tyrosine hydroxylase-immunopositive neurons in the substantia nigra of C57BL/6 mice injected with MPTP (Hulley et al., Eur J Neurosci, 7:2431-2440, 1995). Therefore, PDE4 inhibitors have shown efficacy in the MPTP mouse model of PD, and based on in vitro studies, the mechanism of action is believed to at least partially involve a direct neuroprotective effect.

Recently, two groups have studied the role of TNF-a receptors in the MPTP mouse model of PD. In one study, mice deficient in both forms of the TNF- a receptor (TNFR1 and TNFR2) were found to have decreased striatal dopamine levels and increased dopamine turnover (Rousselet et al., Exp Neurol, 177:183-192, 2002). In a separate study, TNFR1 and TNFR2 double knockout mice were completely protected against dopaminergic neurotoxicity of MPTP (Sriram et al., Faseh J 16:1474-1476, 2002). Therefore, it appears that TNF-a mediates neurotoxicity in this animal model of PD.

Further, J.D. Parkes et al. have investigated the anti-parkinsonian action of PDE4 inhibitor Rolipram in patients with PD. 1.D. Parkes et al., 1984, Advances in Neurology,

Vol. 40, 563-564. The effects of Rolipram were also assessed in a double-blind trial versus placebo in patients with PD already under treatment. Casacchia ez al., Pharmacological

Research Communications, Vol. 15, No. 3, 1983, 329-330. Contrary to other findings with specific phosphodiesterase inhibitors, no significant deterioration of the therapeutic action of dopamine against Lisuride was noted with Rolipram at the dose of 3 mg per day. Id.

The dose-limiting side effect of nausea encountered with the PDE4 inhibitor Rolipram in

Phase II trials of PD has significantly reduced its potential use. 2.2 ALZHEIMER DISEASE

Alzheimer disease (AD) is an increasingly prevalent form of neurodegeneration that accounts for approximately 50 % - 60 % of the overall cases of dementia among people over 65 years of age. It currently affects an estimated 15 million people worldwide and owing to the relative increase of elderly people in the population its prevalence is likely to increase over the next 2 to 3 decades. Alzheimer disease is a progressive disorder with a mean duration of around 8.5 years between onset of clinical symptoms and death. Death of pyramidal neurons and loss of neuronal synapses in brains regions associated with higher mental functions results in the typical symptoms, characterized by gross and progressive impairment of cognitive function (Francis ef al., 1999, J. Neurol. Neurosurg. Psychiatry 66:137-47). Alzheimer disease is the most common form of both senile and presenile dementia in the world and is recognized clinically as relentlessly progressive dementia that presents with increasing loss of memory, intellectual function and disturbances in speech (Merritt, 1979, A Textbook of Neurology, 6 edition, pp. 484-489 Lea & Febiger,

Philadelphia). The disease itself usually has a slow and insidious progress that affects both sexes equally, worldwide. It begins with mildly inappropriate behavior, uncritical statements, irritability, a tendency towards grandiosity, euphoria and deteriorating performance at work; it progresses through deterioration in operational judgment, loss of insight, depression and loss of recent memory; it ends in severe disorientation and confusion, apraxia of gait, generalized rigidity and incontinence (Gilroy & Meyer, 1979,

Medical Neurology, pp. 175-179 MacMillan Publishing Co.).

The etiology of Alzheimer disease is unknown. Evidence for a genetic contribution comes from several important observations such as the familial incidence, pedigree analysis, monozygotic and dizygotic twin studies and the association of the disease with

Down’s syndrome (for review see Baraitser, 1990, The Genetics of Neurological Disorders, 2™ edition, pp. 85-88). Nevertheless, this evidence is far from definitive and it is clear that one or more other factors are also required. Elevated concentrations of aluminum have been found in the brains of some patients dying with Alzheimer disease (Crapper et al, 1976, Brain, 99:67-80) and one case report has documented markedly elevated levels of manganese in the tissues of a patient with Alzheimer disease (Banta & Markesberg, 1977,

Neurology, 27:213-216), which has led to the suggestion that high levels of these metals may be neurotoxic and lead to the development of Alzheimer disease. It was interesting that the aluminum ions were found to be associated mainly with the nuclear chromatin in brain regions most likely to display neurofibrillary tangles in Alzheimer disease. However, from a statistical point of view the absolute differences found for the aluminum levels between normal and Alzheimer brains were far from convincing. It has recently been suggested that defects in the transcriptional splicing of mRNA coding for the tau complex of microtubule associated proteins occur (for review see Kosik, 1990, Curr. Opinion Cell

Biol., 2:101-104) and/or that inappropriate phosphorylation of these proteins exists (Grundke-Igbak et al., 1986, Proc. Natl. Acad. Sci. USA, 83:4913-4917; Wolozin &

Davies, 1987, Ann. Neurol. 22:521-526; Hyman et al., 1988, Ann. Neurol., 23:371-379,

Bancher et al., 1989, Brain Res., 477:90-99). Furthermore, reduction in the enzymes involved in the synthesis of acetylcholine has led to the view of Alzheimer disease as a cholinergic system failure (Danes & Moloney, 1976, Lancet, ii:1403-14). However, even if cholinergic neurons are most at risk in Alzheimer disease, it appears likely that these reductions in enzyme activity are secondary to the degenerative process itself rather than causally related.

At present, there are no agents that are consistently effective in preventing the progression of the disease. Acetylcholinesterase inhibitors are the mainstay of therapy. The majority of therapeutics that are in current use focus on the management of the symptoms of

AD. These strategies have employed the use of anti-psychiatric drugs as well as neuroleptic agents and acetylcholinesterase inhibitors. However, due to the side effects and unattractive dosing requirements of these drugs, new methods and compounds that are able to treat AD and its symptoms are highly desirable. 23 MILD COGNITIVE IMPAIRMENT

Mild cognitive impairment or minimal cognitive impairment (MCI) refers to a stage of cognitive impairment and specifically a subtype with memory loss prior to attaining clinical criteria for dementia in Alzheimer disease (AD). However, no completely reliable means, other than long-term follow-up and eventual autopsy, exist to distinguish between patients experiencing MCI due to preclinical AD and patients experiencing MCI due to less frequently occurring conditions (Petersen et al., Arch Neurol, 2001, 58(12): 1985-92). In this context, MCI is regarded as a high-risk condition that precedes AD in a large proportion of cases. The relatively recent formulation of MCI follows previous attempts to characterize cognitive decline associated with aging, including benign senescent forgetfulness, age-associated memory impairment, and age-associated cognitive decline (Crook et al., Dev Neuropsychol., 1986, 2: 261-276; Kral, CMAJ 1962, 86: 257-260; Levy et al., Int Psychogeriatr 1994, 6(1): 63-8). In contrast with many previous terms, individuals with MCI have a condition that is different from normal aging in that long-term follow-up indicates that they progress as a group to AD at an accelerated rate (Petersen et al., JAMA, 1995, 273(16): 1274-8; Petersen et al., Arch Neurol, 1999, 56(3): 303-8). Other terms with connotations similar to MCI include isolated memory impairment, incipient dementia, and dementia prodrome, although these latter terms are not nearly as widely accepted as MCL

The pathophysiology of MCI is unknown. One hypothesis is that it often results from a gradual build-up of senile plaques and neurofibrillary tangles in areas of the cerebral cortex targeted by AD before the density of these lesions reaches the threshold necessary for the histopathologic diagnosis of AD. Similarly, the development of certain neurotransmitter deficiencies, and especially a cortical cholinergic deficiency, in the most common amnestic form of MCI is hypothesized. In the few studies undertaken to date, most patients with MCI have neuropathologic changes akin to AD, while a few clinically similar individuals do not have significant numbers of AD-like lesions (Mufson et al., Exp

Neurol, 1999, 158(2): 469-90; Price et al., Ann Neurol, 1999, 45(3): 358-68; Troncoso ef al., Neurobiol Aging, 1996, 17(3): 365-71).

MCI is a heterogeneous condition due to numerous different causes, which may overlap in individual patients. In an attempt to distinguish among patient groups, emphasis is often placed on whether memory is involved or single nonmemory domains are involved instead. The most common form of MCI is thought to be amnesic MCI, in which the single domain affected is memory. A large percentage of these patients progress to AD. A presumably less common form of MCI is one in which multiple cognitive domains are affected. This is at least theoretically associated with atypical variants of AD and dementia associated with cerebrovascular disease. A third postulated type is one in which a single j WO 2004/080393 PCT/US2004/006782 nonmemory domain is affected. Such a condition is believed to evolve into frontotemporal dementia, Lewy body dementia, primary pro gressive aphasia, dementia in Parkinson disease, and other atypical variants of AD.

There is no treatment for MCI at present. Several trials are currently underway to determine whether cholinesterase inhibitors, anti-inflammatory agents, and antioxidants may be beneficial in MCI. Smaller scale studies suggest that at least cholinesterase inhibitors may improve the memory loss, although larger scale studies are necessary to ascertain this more rigorously. Freo et al., Soc Neurosci Abstr, 677, 2001. 24 DEPRESSION

Depression is characterized by feelings of intense sadness or pessimistic worry, agitation, self-deprecation, mental slowing, insomnia, anorexia, loss of drive, enthusiasm and libido. The influence of chronic antidepressant administration on expression of the three major phosphodiesterase (PDE) 4 subtypes found in brain (PDE4A, PDE4B, and

PDEA4C) was examined. Takahashi et al., The Journal of Neuroscience, 1999, 19(2):610- 618. The treatments included representatives of four major classes of antidepressants such as selective reuptake inhibitors of serotonin (sertraline and fluoxetine), or norepinephrine (desipramine), a monoamine oxidase inhibitor (tranylcypromine), and electroconvulsive seizure. Jd. The results of this study demonstrate that chronic antidepressant administration increased expression of PDE4A and PDE4B on cerebral cortex and expression of PDE4B in nucleus accumbens. Upregulation of PDE4A and PDE4B may represent a compensatory response to antidepressant treatment and activation of the cAMP system.

The antidepressant effects of Rolipram, a selective inhibitor of PDE4, in the central nervous system were studied in animal models and clinical trials. Zhu et al., CNS Drug

Reviews, Vol. 7, No. 4, 387-398, 2001. It has been reported that PDEA4 is responsible for hydrolysis of the cyclic nucleotide cAMP and cGMP, particularly in nerve and immune cells. Id. Rolipram induces elevation of intracellular cAMP, and increases synthesis and release of norepinephrine, which enhance central noradrenergic transmission. /d. Rolipram attenuates endogenous depression and inflammation in the central nervous system. Id.

However, there are some discrepancies between in vitro and in vivo effects of Rolipram, as well as between results obtained in animal models and clinical studies. /d. In addition, the clinical use of Rolipram is limited due to its behavioral and other side effects. Therefore, there is a significant need for a selective PDE4 inhibitor with higher potency and lower toxicity.

25 DEFECTIVE LONG-TERM MEMORY

Rubinstein-Taybi syalrome (RTS) is a human genetic disorder characterized by mental retardation and physical abnormalities including broad thumbs, big and broad toes, short stature, and craniofacial anomalies. Bourtchouladze et al., PNAS, 2003, vol. 100, no. 18. RTS occurs in about 1 in 125,000 births and accounts for as many as 1 in 300 cases of institutionalized mentally retarded people. Jd. In many patients, RTS has been mapped to chromosome 16p13.3, 2 genomic region containing cAMP-responsive element binding protein (CREB)-binding protein (CBP). Id. Many RTS patients are heterozygous for CBP mutations that yield truncations of the CBP C terminus, suggesting that a dominant- negative mechanism may contribute to the clinical symptoms of defective long-term memory. Id.

The studies by Bourtchouladze et al. demonstrated that CREB and CBP likely function together as a molecular switch during long-term memory formation. Id. They demonstrated that PDE4 inhibitors Rolipram and HT0712 abolished the long-term memory defects of CBP" mutant mice. Jd. It was reported that the inhibitors of PDE4 enhanced

CREB-dependent gene expression and ameliorated the long-term memory defects of CBP* mutant mice in a dose-dependent manner. Id. 2.6 SELECTIVE CYTOKINE INHIBITORY DRUGS

Compounds referred to as SelCIDs™ (Celgene Corporation) or Selective Cytokine

Inhibitory Drugs have been synthesized and tested. These compounds potently inhibit

TNF-a production, but exhibit modest inhibitory effects on LPS induced IL18 and IL12, and do not inhibit IL6 even at high drug concentrations. In addition, SeICIDs™ tend to produce a modest IL10 stimulation. L.G. Corral, ef al., Ann. Rheum. Dis. 58:(Suppl I) 1107-1113 (1999).

Further characterization of the selective cytokine inhibitory drugs shows that they are potent PDE4 inhibitors. PDE4 is one of the major phosphodiesterase isoenzymes found in human myeloid and lymphoid lineage cells. The enzyme plays a crucial part in regulating cellular activity by degrading the ubiquitous second messenger cAMP and maintaining it at low intracellular levels. 1d. In the central nervous system (CNS), PDE4 is expressed in neurons of many portions of the brain, including dopaminergic neurons of the substantia nigra (Cherry and Davis, J Comp Neurol 407:287-301 1999), a key target area of damage in Parkinson disease, and in astrocytes, a cell type associated with inflammation in the brain. Elevation of cAMP in neuronal precursors also promotes secretion of norepinephrine and acetylcholine (Rabe et al. J Cyclic Nucleotide Res 8:371-384, 1982),

neurite extension (Traynor and Schubert, Brain Res 316:197-204, 1984; Westlund et al. Int

J Dev Neurosci 10:361-373, 1992), and serotonin signaling (Akaike et al. Brain Res 620:58-6, 1993), and drives differentiation of dopaminergic neurons from embryonic stem cells (Tacovitti et al. Brain Res 912:99-104, 2001). Inhibition of PDE4 activity results in increased cAMP levels leading to the modulation of LPS induced cytokines including inhibition of TNF-« production in monocytes as well as in lymphocytes. 3. SUMMARY OF THE INVENTION

This invention encompasses methods of treating or preventing central nervous system disorders and related disorders which comprise administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. Central nervous system disorders include, but are not limited to, Alzheimer disease, mild cognitive impairment (MCI), Parkinson disease, depression, defective long-term memory, Huntington disease, Multiple Sclerosis, delerium, or disturbances in consciousness that occur over a short period of time, and amnestic disorder, or discreet memory impairments that occur in the absence of other central nervous system impairments. The invention also encompasses methods of managing central nervous system disorders (e.g., lengthening the time of remission of their symptoms) which comprise administering to a patient in need of such management a prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. Each of these methods includes specific dosing or dosing regimens including cycling therapy.

The invention further encompasses pharmaceutical compositions, single unit dosage forms, and kits suitable for use in treating, preventing and/or managing central nervous system disorders, which comprise one or more selective cytokine inhibitory drugs, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.

The selective cytokine inhibitory drugs, or compounds of the invention, which are described in detail below, are small organic molecules, i.e., having a molecule weight less than 1,000 g/mol. The compounds preferably inhibit PDE4 activity and TNF-o.

In particular embodiments of the invention, a selective cytokine inhibitory drug is used, administered, or formulated with one or more second active ingredients to treat, prevent or manage central nervous system disorders. Examples of the second active ingredients include but are not limited to dopamine agonists, Levodopa, compounds used to augment Levodopa therapy such as monoamine oxidase inhibitors (MAO) and catechol-O-methyltransferase inhibitors (COMT), amantadine, anticholinergics, antiemetics, and other standard therapies for central nervous system disorders. In another example, the second active ingredients are anti-inflammatory agents, including, but not limited to, nonsteroidal anti-inflammatory drugs (NSAIDs), Methotrexate, Leflunomide, antimalarial drugs and sulfasalazine, gold salts, glucocorticoids, immunosuppresive agents, and other standard therapies for central nervous system disorders. 4. DETAILED DESCRIPTION OF THE INVENTION

A first embodiment of the invention encompasses methods of treating or preventing a central nervous system disorder, which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. Central nervous system disorders, include, but are not limited to, Parkinson disease; bradykinesia; muscle rigidity; parkinsonian tremor; parkinsonian gait; motion freezing; depression; defective long-term memory, Rubinstein-

Taybi syndrome (RTS); dementia; sleep disorders; postural instability; hypokinetic disorders; inflammation; synuclein disorders; multiple system artrophies; striatonigral degeneration; olivopontocerebellar atrophy; Shy-Drager syndrome; motor neuron disease with parkinsonian features; Lewy body dementia; Tau pathology disorders; progressive supranculear palsy; corticobasal degeneration; frontotemporal dementia; amyloid pathology disorders; mild cognitive impairment; Alzheimer disease; Alzheimer disease with parkinsonism, genetic disorders that can have parkinsonian features; Wilson disease;

Hallervorden-Spatz disease; Chediak-Hagashi disease; SCA-3 spinocerebellar ataxia;

X-linked dystonia parkinsonism; Huntington disease; prion disease; hyperkinetic disorders; chorea; ballismus; dystonia tremors; Amyotrophic Lateral Sclerosis (ALS); CNS trauma and myoclonus.

Another embodiment of the invention encompasses methods of managing a central nervous system disorder, which comprises administering to a patient in need of such management a prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.

Another embodiment of the invention encompasses a method of treating, preventing and/or managing a central nervous system disorder, which comprises administering to a patient in need of such treatment, prevention and/or management a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and a therapeutically or prophylactically effective amount of a second active agent.

Without being limited by theory, it is believed that certain selective cytokine inhibitory drugs and agents conventionally used in central nervous system disorders can act in complementary or synergistic ways in the treatment or management of the disorders. It is also believed that the combined use of such agents may reduce or eliminate adverse effects associated with some selective cytokine inhibitory drugs, thereby allowing the administration of larger amounts of selective cytokine inhibitory drugs to patients and/or increasing patient compliance. It is further believed that some selective cytokine inhibitory drugs may reduce or eliminate adverse effects associated with some conventional agents, thereby allowing the administration of larger amounts of the agents to patients and/or increasing patient compliance.

Another embodiment of the invention encompasses a method of reversing, reducing or avoiding an adverse effect associated with the administration of conventional therapy for central nervous system disorders to a patient suffering from central nervous system disorders or a related disorder, which comprises administering to a patient in need of such reversion, reduction or avoidance a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. ‘Yet another embodiment of the invention encompasses a pharmaceutical composition comprising a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient wherein the composition is adapted for parenteral, oral or transdermal administration and the amount is sufficient to treat or prevent a central nervous system disorder, or to ameliorate the symptoms or progress of the disorder.

Also encompassed by the invention are single unit dosage forms comprising a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.

Second active agents can be large molecules (e.g., proteins) or small molecules (e.g., synthetic inorganic, organometallic, or organic molecules). The examples of the second active agent include, but are not limited to, cytokines, hematopoietic growth factors, anti- cancer agents such as topoisomerase inhibitors, anti-angiogenic agents, microtubule i WO 2004/080393 PCT/US2004/006782 stabilizing agents, alkylating agents; acetylcholinesterase inhibitors; antivirals; antifungals; antibiotics; anti-inflammatories; immunomodulatory agents; immunosuppressive agents such as cyclosporins; and other known or conventional agents used in patients with central nervous system disorders. Specific second active agents include but are not limited to a dopamine agonist or antagonist for Parkinson disease or an acetylcholinesterate inhibitor for

Alzheimer disease.

The invention also encompasses kits which comprise a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, a second active ingredient. 41 SELECTIVE CYTOKINE INHIBITORY DRUGS

Compounds used in the invention include racemic, stereomerically pure and stereomerically enriched selective cytokine inhibitory drugs, stereomerically and enantiomerically pure compounds that have selective cytokine inhibitory activities, and pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates, and prodrugs thereof. Preferred compounds used in the invention are known Selective Cytokine

Inhibitory Drugs (SelCIDs™) of Celgene Corporation, NJ.

As used herein and unless otherwise indicated, the terms “selective cytokine inhibitory drugs” and “SelCIDs™” encompass small molecule drugs, e.g., small organic molecules which are not peptides, proteins, nucleic acids, oligosaccharides or other macromolecules. Preferred compounds inhibit TNF-a production. Compounds may also have a modest inhibitory effect on LPS induced IL18 and [L12. More preferably, the compounds of the invention are potent PDE4 inhibitors.

Specific examples of selective cytokine inhibitory drugs include, but are not limited to, the cyclic imides disclosed in U.S. patent nos. 5,605,914 and 5,463,063; the cycloalkyl amides and cycloalkyl nitriles of U.S. patent nos. 5,728,844, 5,728,845, 5,968,945, 6,180,644 and 6,518,281; the aryl amides (for example, an embodiment being N-benzoyl-3- amino-3-(3’,4’-dimethoxyphenyl)-propanamide) of U.S. patent nos. 5,801,195, 5,736,570, 6,046,221 and 6,284,780; the imide/amide ethers and alcohols (for example, 3-phthalimido- } 3-(3’,4’-dimethoxyphenyl)propan-1-ol) disclosed in U.S. patent no. 5,703,098; the succinimides and maleimides (for example methyl 3-(3°,4°,5°6’-petrahydrophthalimdo)-3- (3”,4”-dimethoxyphenyl)propionate) disclosed in U.S. patent no. 5,658,940; imido and amido substituted alkanohydroxamic acids disclosed in U.S. patent no. 6,214,857 and WO 99/06041; substituted phenethylsulfones disclosed in U.S. patent nos. 6,011,050 and 6,020,358; substituted imides (for example, 2-phthalimido-3-(3’,4’-dimethoxyphenyl)

Claims (51)

CLAIMS What is claimed is:

1. A selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for use in a method of treating or preventing a central nervous system disorder, which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of the selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

2. A selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for use in a method of managing a central nervous system disorder, which comprises administering to a patient in need of such management a prophylactically effective amount of the selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

3. The selective cytokine inhibitory drug, pharmaceutically acceptable salt, solvate or stereoisomer of claim 1, wherein the central nervous system disorder is Parkinson disease; Alzheimer disease; mild cognitive impairment; Amyotrophic Lateral Sclerosis; CNS trauma; Alzheimer disease with parkinsonism; bradykinesia; alkinesia; movement disorder that impairs fine motor control and finger dexterity; hypophonia; monotonic speech; rigidity; dystonia; inflammation associated with Parkinson disease; tremor of the face, jaw, tongue or posture; parkinsonian gait; shuffling; short step; festinating gait; disorder of mood, cognition, sensation, or sleep; dementia; depression; defective long-term memory; drug induced parkinsonism; vascular parkinsonism; multiple system atrophy; progressive supranuclear palsy; disorder with primary tau pathology; cortical basal ganglia degeneration; parkinsonism with dementia; hyperkinetic disorder; chorea; Huntington disease; dystonia; Wilson disease; Tourette syndrome; essential tremor; myoclonus; or a tardive movement disorder. 4, The selective cytokine inhibitory drug, pharmaceutically acceptable salt, solvate or stereoisomer of claim 2, wherein the central nervous system disorder is Parkinson disease; Alzheimer disease; mild cognitive impairment; Amyotrophic Lateral -56- AMENDED SHEET: 31 OCTOBER 200&

! Sclerosis; CNS trauma; Alzheimer disease with parkinsonism; bradykinesia; alkinesia; movement disorder that impairs fine motor control and finger dexterity; hypophonia; monotonic speech; rigidity; dystonia; inflammation associated with Parkinson disease; tremor of the face, jaw, tongue or posture; parkinsonian gait; shuffling; short step; festinating gait; disorder of mood, cognition, sensation, or sleep; dementia; depression; defective long-term memory; drug induced parkinsonism; vascular parkinsonism; multiple system atrophy; progressive supranuclear palsy; disorder with primary tau pathology; cortical basal ganglia degeneration; parkinsonism with dementia; hyperkinetic disorder; chorea; Huntington disease; dystonia; Wilson disease; Tourette syndrome; essential tremor; myoclonus; or a tardive movement disorder.

5. The selective cytokine inhibitory drug, pharmaceutically acceptable salt, solvate or stereoisomer of claim 3, wherein the central nervous system disorder is Parkinson disease.

6. The selective cytokine inhibitory drug, pharmaceutically acceptable salt, solvate or stereoisomer of claim 4, wherein the central nervous system disorder is Parkinson disease.

7. A selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for use in a method of treating or preventing a central nervous system disorder, which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of the selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a therapeutically or prophylactically effective amount of at least one second active ingredient.

8. A selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for use in a method of managing a central nervous system disorder, which comprises administering to a patient in need of such management a prophylactically effective amount of the selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a therapeutically or prophylactically effective amount of at least one second active ingredient. -57- AMENDED SHEET: 31 OCTOBER 2006

9. The selective cytokine inhibitory drug, pharmaceutically acceptable salt, solvate or stereoisomer of claim 7, wherein the central nervous system disorder is Parkinson disease.

10. The selective cytokine inhibitory drug, pharmaceutically acceptable salt, solvate or stereoisomer of claim 8, wherein the central nervous system disorder is Parkinson disease.

11. The selective cytokine inhibitory drug, pharmaceutically acceptable salt, solvate or stereoisomer of claim 7, wherein the second active ingredient is a dopamine agonist, a monoamine oxidase inhibitor (MAO), a catechol-O-methyltransferase inhibitor (COMT), amantadine, an acetylcholinesterase inhibitor, an antiemetic, or an anti- inflammatory agent.

12. The selective cytokine inhibitory drug, pharmaceutically acceptable salt, solvate or stereoisomer of claim 8, wherein the second active ingredient is a dopamine agonist, a monoamine oxidase inhibitor (MAO), a catechol-O-methyltransferase inhibitor (COMT), amantadine, an acctylcholinesterase inhibitor, an antiemetic, or an anti- inflammatory agent.

13. The selective cytokine inhibitory drug, pharmaceutically acceptable salt, solvate or stereoisomer of any one of claims 1, 2, 7, or 8, wherein the stereoisomer of the selective cytokine inhibitory drug is an enantiomer.

14. The selective cytokine inhibitory drug, pharmaceutically acceptable salt, solvate or stereoisomer of any one of claims 1, 2, 7, or 8, wherein the selective cytokine inhibitory drug is 3-(3,4-dimethoxy-phenyl)-3-(1-ox0-1,3-dihydro-isoindol-2-yl) propionamide.

15. The selective cytokine inhibitory drug, pharmaceutically acceptable salt, solvate or stereoisomer of claim 14, wherein the selective cytokine inhibitory drug is the R or S enantiomer of 3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl) propionamide. -58- AMENDED SHEET: 31 OCTOBER 2006

16. The selective cytokine inhibitory drug, pharmaceutically acceptable salt, solvate or stereoisomer of any one of claims 1, 2, 7 or 8, wherein the selective cytokine inhibitory drug is cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-2- methanesulfonyl-ethyl]-3-ox0-2,3-dihydro-1 H-isoindol-4-yl}-amide.

17. The selective cytokine inhibitory drug, pharmaceutically acceptable salt, solvate or stereoisomer of claim 16, wherein the selective cytokine inhibitory drug is the R or S enantiomer of cyclopropanecarboxylic acid {2-[1-(3 -ethoxy-4-methoxy-phenyl)-2- methanesulfonyl-ethyl]-3-0x0-2,3-dihydro-1 H-isoindol-4-yl}-amide. ’ 10

18. The selective cytokine inhibitory drug, pharmaceutically acceptable salt, solvate or stereoisomer of any one of claims 1,2, 7 or 8, wherein the selective cytokine inhibitory drug has formula (I):

[0] A Q RY MN CH (C Hp — R12 Jb H “H M : wherein n has a value of 1, 2, or 3; R’is o-phenylene, unsubstituted or substituted with 1 to 4 substituents each selected independently from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino, dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, and halo; R’ is (i) phenyl or phenyl substituted with one or more substituents each selected independently of the other from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, and halo, (ii) benzyl unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of nitro, cyano, trifluoromethyl, carbothoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, AMENDED SHEET: 31 OCTOBER 2006 Corrected sheet: 1 November 2006 acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, and halo, (iii) naphthyl, and (iv) benzyloxy; R'? is -OH, alkoxy of 1 to 12 carbon atoms, or & BEAN R® Ris hydrogen or alkyl of 1 to 10 carbon atoms; and R’ is hydrogen, alkyl of 1 to 10 carbonatoms, -COR'?, or -SO,R'?, wherein R'’ is hydrogen, alkyl of 1 to 10 carbon atoms, or phenyl.

19. The selective cytokine inhibitory drug, pharmaceutically acceptable salt, solvate or stereoisomer of claim 18, wherein the selective cytokine inhibitory drug is an enantiomer of the compound having formula (1).

20. The selective cytokine inhibitory drug, pharmaceutically acceptable salt, solvate or stereoisomer of any one of claims 1, 2, 7 or 8, wherein the selective cytokine inhibitory drug has formula (II): Oo AT R Cc R3 \ / N= CH! 2 R2 RS (CrHzn— CPO Re R¥ am wherein each of R' and R?, when taken independently of each other, is hydrogen, lower alkyl, or R! and R?, when taken together with the depicted carbon atoms to which each is bound, is o-phenylene, o-naphthylene, or cyclohexene-1,2-diyl, unsubstituted or substituted with 1 to 4 substituents each selected independently from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino, dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, and halo; -60 - AMENDED SHEET: 31 OCTOBER 2006

R?is phenyl substituted with from one to four substituents selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, alkylthio of 1 to 10 carbon atoms, benzyloxy, cycloalkoxy of 3 to 6 carbon atoms, C4-Ce-cycloalkylidenemethyl, C3-Co-alkylidenemethyl, indanyloxy, and halo; Ris hydrogen, alkyl of 1 to 6 carbon atoms, phenyl, or benzyl; RY is hydrogen or alkyl of 1 to 6 carbon atoms; R’ is -CHy-, -CH,-CO-,-SO,-,-S-, or -NHCO-; and n has a value of 0, 1, or 2.

21. The selective cytokine inhibitory drug, pharmaceutically acceptable salt, solvate or stereoisomer of claim 20, wherein the selective cytokine inhibitory drug is an enantiomer of the compound having formula (II).

22. The selective cytokine inhibitory drug, pharmaceutically acceptable salt, solvate or stereoisomer of any one of claims 1, 2, 7 or 8, wherein the selective cytokine inhibitory drug has formula (111): RS 3 Or

R?. - orf RS Y CHy—S0~R7 R4 (Im) wherein the carbon atom designated * constitutes a center of chirality; Y is C=0, CH2, SO, or CH,C=0; each of R}, R% R? and R®, independently of the others, is hydrogen, halo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, nitro, cyano, hydroxy, or -NR®R; of any -61- AMENDED SHEET: 31 OCTOBER 2006

.. WO2004030353 PCT/US2004/006782 two of R! R?, R?, and R* on adjacent carbon atoms, together with the depicted phenylene ring are naphthylidene; each of R® and R®, independently of the other, is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cyano, or cycloalkoxy of up to 18 carbon atoms; R'is hydroxy, alkyl of 1 to 8 carbon atoms, phenyl, benzyl, or NR¥R®"; each of R® and R® taken independently of the other is hydrogen, alkyl of 1 to 8 carbon atoms, phenyl, or benzyl, or one of R® and R® is hydrogen and the other is -COR"® or -SO;R" in which R" is hydrogen, alkyl of 1 to 8 carbon atoms, or phenyl, or R¥and R’ taken together are tetramethylene, pentamethylene, hexamethylene, or -CH,CH,X'CH,CH,- in which X' is -O-, -S- or -NH-; and each of R® and R® taken independently of the other is hydrogen, alkyl of 1 to 8 carbon atoms, phenyl, or benzyl, or one of R® and R? is hydrogen and the other is -COR'” or -SO,R'” in which R'is hydrogen, alkyl of 1 to 8 carbon atoms, or phenyl, or R® and R”’ taken together are tetramethylene, pentamethylene, hexamethylene, or -CH,CH,X*CH,CH,- in which X? is -O-, -S-, or -NH-.

23. The selective cytokine inhibitory drug, pharmaceutically acceptable salt, solvate or stereoisomer of claim 22, wherein the selective cytokine inhibitory drug is an enantiomer of said compound.

24. A selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for use in a method of reducing or avoiding an adverse effect associated with the administration of a second active ingredient in a patient suffering from a central nervous system disorder, which comprises administering to a patient in need of such reduction or avoidance an amount of the second active ingredient and a therapeutically or prophylactically effective amount of the selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

25. A pharmaceutical composition comprising a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, or stereoisomer, thereof in an amount effective to treat, prevent or manage a central nervous system disorder, and a carrier.

26. A pharmaceutical composition comprising a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in an amount effective to treat, prevent or manage a central nervous system disorder, and a second active ingredient. 6. AMENDED SHEET: 31 OCTOBER 2006 Corrected sheet: 1 November 2006

27. The pharmaceutical composition of claim 26, wherein the second active ingredient is a dopamine agonist, a monoamine oxidase inhibitor (MAO), a catechol-O- methyltransferase inhibitor (COMT), amantadine, an anticholinergic, an antiemetic, or an anti-inflammatory agent.

28. The use of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, in the manufacture of a medicament for use in a method of treating or preventing a central nervous system disorder, which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of the medicament.

29. The use of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, in the manufacture of a medicament for use in a method of managing a central nervous system disorder, which comprises administering to a patient in need of such management a prophylactically effective amount of the medicament.

30. The use of claim 28, wherein the central nervous system disorder is Parkinson disease; Alzheimer disease; mild cognitive impairment; Amyotrophic Lateral Sclerosis; CNS trauma; Alzheimer disease with parkinsonism; bradykinesia; alkinesia; movement disorder that impairs fine motor control and finger dexterity; hypophonia; monotonic speech; rigidity; dystonia; inflammation associated with Parkinson disease; tremor of the face, jaw, tongue or posture; parkinsonian gait; shuffling; short step; festinating gait; disorder of mood, cognition, sensation, or sleep; dementia; depression; defective long-term memory; drug induced parkinsonism; vascular parkinsonism; multiple system atrophy; progressive supranuclear palsy; disorder with primary tau pathology; cortical basal ganglia degeneration; parkinsonism with dementia; hyperkinetic disorder; chorea; Huntington disease; dystonia; Wilson disease; Tourette syndrome; essential tremor; myoclonus; or a tardive movement disorder.

31. The use of claim 29, wherein the central nervous system disorder is Parkinson disease; Alzheimer disease; mild cognitive impairment; Amyotrophic Lateral Sclerosis; CNS trauma; Alzheimer disease with parkinsonism; bradykinesia; alkinesia; -63- AMENDED SHEET: 31 OCTOBER 2006 movement disorder that impairs fine motor control and finger dexterity; hypophonia; monotonic speech; rigidity; dystonia; inflammation associated with Parkinson disease; tremor of the face, jaw, tongue or posture; parkinsonian gait; shuffling; short step; festinating gait; disorder of mood, cognition, sensation, or sleep; dementia; depression; defective long-term memory; drug induced parkinsonism; vascular parkinsonism; multiple system atrophy; progressive supranuclear palsy; disorder with primary tau pathology; cortical basal ganglia degeneration; parkinsonism with dementia; hyperkinetic disorder; chorea; Huntington disease; dystonia; Wilson disease; Tourette syndrome; essential tremor; myoclonus; or a tardive movement disorder.

32. The use of claim 30, wherein the central nervous system disorder is Parkinson disease.

33. The use of claim 31, wherein the central nervous system disorder is Parkinson disease.

34. The use of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, in the manufacture of a medicament for use in a method of treating or preventing a central nervous system disorder, which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of the medicament, and a therapeutically or prophylactically effective amount of at least one second active ingredient.

35. The use of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, in the manufacture of a medicament for use in a method of managing a central nervous system disorder, which comprises administering to a patient in need of such management a prophylactically effective amount of the medicament, and a therapeutically or prophylactically effective amount of at least one second active ingredient.

36. The use of claim 34, wherein the central nervous system disorder is Parkinson disease. -64- AMENDED SHEET: 31 OCTOBER 2006

37. The use of claim 35, wherein the central nervous system disorder is Parkinson disease.

38. The use of claim 34, wherein the second active ingredient is a dopamine agonist, a monoamine oxidase inhibitor (MAO), a catechol-O-methyltransferase inhibitor (COMT), amantadine, an acetylcholinesterase inhibitor, an antiemetic, or an anti- inflammatory agent.

39. The use of claim 35, wherein the second active ingredient is a dopamine agonist, a monoamine oxidase inhibitor (MAO), a catechol-O-methyltransferase inhibitor (COMT), amantadine, an acetylcholinesterase inhibitor, an antiemetic, or an anti- inflammatory agent.

40. The use of any one of claims 28, 29, 34, or 35, wherein the stereoisomer of the selective cytokine inhibitory drug is an enantiomer.

41. The use of any one of claims 28, 29, 34, or 35, wherein the selective cytokine inhibitory drug is 3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl) propionamide.

42. The use of claim 41, wherein the selective cytokine inhibitory drug is the R or S enantiomer of 3-(3,4-dimethoxy-pheny!)-3-(1-oxo0-1,3-dihydro-isoindol-2-yl) propionamide.

43. The use of any one of claims 28, 29, 34 or 35, wherein the selective cytokine inhibitory drug is cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-2- methanesulfonyl-ethyl]-3-0x0-2,3-dihydro-1 H-isoindol-4-yl}-amide.

44. The use of claim 43, wherein the selective cytokine inhibitory drug is the R or S enantiomer of cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-2- methanesulfonyl-ethyl}-3-0x0-2,3-dihydro-1 H-isoindol-4-yl}-amide.

45. The use of any one of claims 28, 29, 34 or 35, wherein the selective cytokine inhibitory drug has formula (I): -65 - AMENDED SHEET: 31 OCTOBER 2006

Io) I 0 RY “N— CH—(C Hom be Riz \N/

c. Fr HH wherein n has a value of 1, 2, or 3; Ris o-phenylene, unsubstituted or substituted with 1 to 4 substituents each selected independently from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino, dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, and halo; Ris (i) phenyl or phenyl substituted with one or more substituents each selected independently of the other from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, and halo, (ii) benzyl unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of nitro, cyano, trifluoromethyl, carbothoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, and halo, (iii) naphthyl, and (iv) benzyloxy; RZ is -OH, alkoxy of 1 to 12 carbon atoms, or RS —N R® is hydrogen or alkyl of 1 to 10 carbon atoms; and Ris hydrogen, alkyl of 1 to 10 carbonatoms, -COR'?, or -SO,R!®, wherein R'is hydrogen, alkyl of 1 to 10 carbon atoms, or phenyl. AMENDED SHEET: 31 OCTOBER 2006 oe Corrected sheet: 1 November 2006

46. The use of claim 45, wherein the selective cytokine inhibitory drug is an enantiomer of the compound having formula (I).

47. The use of any one of claims 28, 29, 34 or 35, wherein the selective cytokine inhibitory drug has formula (II): O R1 I R3 I “Ne CH- 7 R2 RS h (CHzp—C—~N—0O—R4 Re am wherein each of R' and R?, when taken independently of each other, is hydrogen, lower alkyl, or R' and R?, when taken together with the depicted carbon atoms to which each is bound, is o-phenylene, o-naphthylene, or cyclohexene-1,2-diyl, unsubstituted or substituted with 1 to 4 substituents each selected independently from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino, dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, and halo; R}is phenyl substituted with from one to four substituents selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, alkylthio of 1 to 10 carbon atoms, benzyloxy, cycloalkoxy of 3 to 6 carbon atoms, C4-Ce-cycloalkylidenemethyl, C3-Cjp-alkylidenemethyl, indanyloxy, and halo; R* is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl, or benzyl; RY is hydrogen or alkyl of 1 to 6 carbon atoms; R’ is -CH,-, -CHz-CO-,-SO2-,-S-, or -NHCO-; and n has a value of 0, 1, or 2.

48. The use of claim 47, wherein the selective cytokine inhibitory drug is an -67- AMENDED SHEET: 31 OCTOBER 2006 enantiomer of the compound having formula an.

49. The useof any one of claims 28, 29, 34 or 35, wherein the selective cytokine - inhibitory drug has formula 10): RS R2 MN CH! RS Y CHo—S0—R7 R4 wherein the carbon atom designated * constitutes a center of chirality; Y is C=0, CH2, SO,, or CH,C=0; each of R! R%, rR, and RY, independently of the others, is hydrogen, halo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, nitro, cyano, hydroxy, or NR®R’; or any two of R!, I: R? ,and R* on adjacent carbon atoms, together with the depicted phenylene ring are naphthylidene; each of R® and R®, independently of the other, is hydrogen, alkyl of 1 to 4 carbon atorns, alkoxy of 1 to 4 carbon atoms, cyano, or cycloalkoxy of up to 18 carbon atoms; Ris hydroxy, alkyl of 1 to 8 carbon atoms, phenyl, benzyl, or NR¥*R%; each of R® and R’ taken independently of the other is hydrogen, alkyl of 1 to 8 carbon atoms, phenyl, or benzyl, or one of R® and R® is hydrogen and the other is ~COR!? or-SO,R" in which R'is hydrogen, alkyl of 1 to 8 carbon atoms, or phenyl, or R® and R® taken together are tetramethylene, pentamethylene, hexamethylene, or -CH;CH;X'CH,CH;- in which X' is -O-, -S- or -NH-; and : each of R® and R” taken independently of the other is hydrogen, alkyl of 1 to 8 carbon atoms, phenyl, or benzyl, or one of R* and RY is hydrogen and the other is -COR'”’ or-SO,R' in which R'" is hydrogen, alkyl of 1 to 8 carbon atoms, or phenyl, or R® and R” taken together are tetramethylene, pentamethylene, hexamethylene, or -CH,CH,X*CH,CH,- . . 2. in which X" is -O-, -S-, or -NH-. AMENDED SHEET: 31 OCTOBER 2006 -68 - Corrected sheet: 1 November 2006

50. The use of claim 49, wherein the selective cytokine inhibitory drug is an enantiomer of said compound.

51. The use of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, in the manufacture of a medicament for use in a method of reducing or avoiding an adverse effect associated with the administration of a second active ingredient in a patient suffering from a central nervous system disorder, which comprises administering to a patient in need of such reduction or avoidance an amount of the second active ingredient and a therapeutically or prophylactically effective amount of the medicament. -69 - AMENDED SHEET: 31 OCTOBER 2006 -