MXPA06010091A - Methods of using and compositions comprising selective cytokine inhibitory drugs for the treatment and management of disorders of the central nervous system - Google Patents

Abstract

Methods of treating, preventing and/or managing central nervous system disorders, such as Parkinson disease, Alzheimer disease, mild cognitive impairment, Huntington disease, Amytophic Lateral Sclerosis, depression and defective long-term memory, and related syndromes are disclosed. Specific methods encompass the administration of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, alone or in combination with a second active ingredient. Pharmaceutical compositions, single unit dosage forms, and kits suitable for use in methods of the invention are also disclosed.

Description

METHODS OF USE AND COMPOSITIONS CONTAINING SUBSTANCES CYCLOIN INHIBITOR ACTIVES, SELECTIVE, FOR THE TREATMENT AND MANAGEMENT OF DISORDERS OF THE NERVOUS SYSTEM CENTRAL 1. FIELD OF THE INVENTION This invention relates, in part, to the methods of treatment, prevention and / or management of disorders of the central nervous system, including, but not limited to, Parkinson's disease, Alzheimer's disease, mild cognitive impairment, Huntington's disease, Amyotrophic lateral sclerosis depression and long-term memory defects, and related disorders, methods consist of the administration of an active substance or selective inhibitory drug of cytokines or a salt, solvate, hydrate, stereoisomer, clathrate, accepted for pharmaceutical use or prodrug thereof. 2. BACKGROUND OF THE INVENTION The alterations of the central nervous system affect a wide range of the population with different severity. In general, the primordial particularity of this class of disorders includes the significant deterioration of cognition or memory that represents a notable deterioration with respect to the previous level of functioning. Dementia, for example, is characterized by various cognitive impairments that include significant memory deficiency, and may be independent or as an underlying feature of various diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and Sclerosis. multiple, to mention just a few. Other disorders of the central nervous system may be delirium, or alterations of consciousness that occur for a short time, and amnestic alterations or small impairments of memory that occur in the absence of other central nervous system impairments. 2. 1 PARKINSON DISEASE Parkinson's 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 .21 A: 1197-1198. Approximately one million Americans suffer from PD, and every year 50,000 people are diagnosed with the disease. Olson, L., 2000, Science 290: 721-724. Because the first symptoms of PD may not be recognized, perhaps as many as 5 to 10% of people over 60 years of age may have the disease. Olson, L., 2000, Science 290: 721-724.

Since 1960 it has been known that the loss of dopamine from neurons in the nigrostriatal pathway of the brain leads to motor abnormalities characteristic of PD. The common onset of PD occurs in middle to late adulthood with progressive clinical peculiarities. Some of the physical manifestations of PD may be rest tremors, muscle rigidity, postural instability, and dementia. The pathological characteristics of PD can be loss of dopaminergic neurons in the substantia nigra (SN) as well as the presence of intracellular inclusions or Lewy bodies in the surviving neurons in different areas of the brain. Nussbaum, R. L. and Polymeropoulos, M. H., 1997, Hum. Molec. Genet 6: 1687-1691. It is interesting to note that many other diseases have parkinsonian motor characteristics. The motor symptoms in PD are, in general, considered as a result of the deficiency or dysfunction of the dopamine or dopaminergic neurons in the substantia nigra. Nussbaum, R. L. and Polymeropoulos, M. H., 1997, Hum. Molec. Genet 6: 1687-1691. Some evidence has also suggested that molecular chaperones, specifically heat shock proteins, HSP70 and HSP40, may play a role in PD advancement. Auluck et al., 2002, Science 295: 865-868.

Much controversy has arisen regarding the origin of PD, and there is evidence that genetic and environmental factors can contribute to the disease. A study of the nuclear families of 948 PD cases concluded that there is a hereditary, Mendelian, primary and uncommon gene that influences the age of onset. Maher et al., 2002, Am. J. Med. Genet. 109: 191-197. This study also suggests 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, Cañad. J. Neurol. Sci. 14: 303-305. Researchers have concluded that most cases of PD are caused by environmental factors imposed in a history of slow and prolonged neuronal loss due to aging. Calne, D. B and Langston, J. W., 1993, Lancet II 1457-1459. Although the origin is still unknown, it is very likely that genetic and environmental factors contribute to PD, and that environmental factors act on the genetic susceptibility to cause the disease. Recent evidence in animal models of Parkinson's disease suggests that anti-inflammatory agents inhibit the death of dopaminergic cells. McGeer et al., 2001, B. C. Med. J. 43: 138-141.

Although a cure for Parkinson's disease is not available, traditional treatment has focused on responding to the effect of the loss of dopamine in the brain. The treatment used by the dopamine precursor, levodopa, has become the treatment of choice when it was discovered that the compound could alleviate PD symptoms, thereby improving the quality of life of the affected persons. Unfortunately, it has been found that long-term administration of levodopa can have side effects. 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, researchers used lentiviral vectors to deliver the neurotrophic factor derived from the cell line (GDNF) to the striatum and SN from rhesus monkeys that had been treated a week earlier with MPTP. Kordower et al., 2000, Science 290: 767-773. It is known that GDNF has trophic effects on the degeneration of nigrostriatal neurons in non-human primate models of Parkinson's disease. The results of the study showed that GDNF increased dopaminergic function in old monkeys and reversed functional deficiencies and prevented nigrostriatal degeneration in monkeys that had been treated with MPTP. It was also observed that treatment with GDNF reversed the motor deficiencies in monkeys treated with MPTP. This study also concluded that GDNF delivery could prevent nigrostriatal degeneration and induce regeneration of neurons in primate PD models. Kordower et al., 2000, If Cence 290: 767-773.

Another study that used electrical inhibition and pharmacological concealment of the symptoms of the subthalmic nucleus (STN), showed that the alteration of the activity of the basal ganglia network would improve the activity of the motor network in PD, supposedly suppressing the discharge activity of the cells. neurons in the SN. Lou et al., 2002, Science 298: 425-429. The researchers used an adeno-associated virus to transduce the excitatory glutaminergic neurons in the rat STN with glutamic acid decarboxylase (GAD) to show that the change provided neuroprotection to the dopaminergic cells against toxic insults. It is interesting to note that the rats with the transduced gene also showed significant improvement of parkinsonian phenotypes.

Selective PDE4 inhibitors, Ro-20-1724 and SDZ-MNS 949, in the presence of the adenylate cyclase activator, forskolin, have been shown to stimulate dopamine uptake by rat mesencephalon neurons in vitro (Hulley et al., J. Neural Transm Suppl, 46: 217-228, 1995). In these studies, the elevation of cAMP by the addition of dibutyryl cAMP or forskolin protected the dopaminergic neurons against the neurotoxic effects of MPP '(the l-methyl-4-phenylpyridinium ion). These PDE4 inhibitors were shown to reduce the depletion of dopamine in the striatum and reduce the loss of immunopositive neurons for tyrosine hydroxylase 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, it is considered that the mechanism of action involves at least in part a direct neuroprotective effect.

Recently, two groups have studied the function 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 with decreased levels of striatal dopamine and increased dopamine turnover (Rousselet et al., Exp Neurol, 177: 183-192, 2002) . In another study, double knockout mice of TNFR1 and TNFR2 were fully protected against dopaminergic neurotoxicity of MPTP (Sriram et al., Faseh J 16: 14741476, 2002). Therefore, it seems that TNF-a is an intermediary of neurotoxicity in this model of PD animals.

In addition, J. D. Parkes et al., Have investigated the antiparkinsonian action of the PDE4 inhibitor, Rolipram, in patients with PD. J. D. Parkes et al., 1984, Advances in Neurology, vol 40, 563-564. The effects of Rolipram were also evaluated in a double-blind study against placebo in patients with PD already in treatment. Casacchia et al., Pharmacological Research Communications, Vol. 15, No. 3, 1983, 329-330. Contrary to other findings with specific phosphodiesterase inhibitors, with Rolipram at the dose of 3 mg per day, no significant deterioration of the therapeutic action of dopamine against Lisuride Id was observed. The side effect, nausea, dose limiter that was found with the PDE4 inhibitor, Rolipram, in PD phase II studies has significantly reduced its potential use. 2. 2 ALZHEIMER'S DISEASE Alzheimer's disease (AD) is a form of neurodegeneration that increasingly prevails representing approximately 50-60% of the total cases of dementia among people over 65 years of age. It currently affects approximately 15 million people worldwide, and due to the relative increase of people in advanced ages of the population it is very likely that its frequency increases during the next 2 to 3 decades. Alzheimer's disease is a progressive disease with an average duration of approximately 8.5 years between the onset of clinical symptoms and death. The death of pyramidal neurons and the loss of neuronal synapses in the brain regions associated with higher mental functions results in typical symptoms, characterized by evident and progressive impairment of cognitive function (Francis et al, 1999, J. Neurol. Neurosurg, Psychiatry 66: 137-47). Alzheimer's disease is the most common form of senile and presenile dementia in the world, and is clinically recognized as the relentlessly progressive dementia that presents with increasing memory loss, intellectual function and speech disturbances (Merritt, 1979, A Texbook of Neurology, 6th edition pp. 484-489 Read &Febiger, Philadelphia). The disease itself usually has a slow and steady progress that affects both sexes worldwide equally. It begins with moderately inappropriate behavior, noncritical statements, irritability, tendency toward grandiosity, euphoria, and decreased work performance; advances through deterioration in operative judgment, loss of perception, depression and loss of recent memory; it results in severe disorientation and confusion, apraxia of gait, generalized stiffness, and incontinence (Gilroy &Meyer, 1979, Medical Neurology, pp. 175-179, MacMillan Publishing Co.).

The origin of Alzheimer's disease is unknown. Evidence of genetic contribution emerges from some important observations such as family incidence, genealogical tree analysis, monozygotic and zygotic twin studies and the association of disease with Down syndrome (for review see Baraitser, 1990, The Genetics of Neurological Disorders , 2nd edition, pp. 85-88). However, this evidence is far from definitive and it is clear that one or more other factors are also needed. Elevated concentrations of aluminum have been found in the brains of some patients who died with Alzheimer's disease (Crapper et al, 1976, Brain, 99: 67-80) and one case documented markedly elevated magnesium concentrations in the tissues of a patient with Alzheimer's disease (Banta &Markesberg, 1977, Neurology, 27: 213-216), which gave rise to the suggestion that high concentrations of these metals can be neurotoxic and lead to the development of Alzheimer's disease. It was interesting to find that aluminum ions associated mainly with nuclear chromatin in regions of the brain were more likely to have neurofibrillary tangles in Alzheimer's disease. HoweverFrom the statistical point of view, the absolute differences found in the levels of aluminum between normal and Alzheimer brains were far from convincing. Recently, it has been suggested that there are effects on the transcriptional splicing of the mRNA that codes for the tau complex of the microtubules associated with the proteins (for review see Kosik, 1990, Curr, Opinion Cell Biol. 2: 101-104) and / or that there is inappropriate phosphorylation of these proteins (Grundke-Igbak et al., 1986, Proc. Nati. 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, the reduction in the enzymes involved in the synthesis of acetylcholine has allowed Alzheimer's disease to be seen as a failure of the cholinergic system (Danish &Moloney, 1976, Lancet, ii: 1403-14). However, even if cholinergic neurons are more at risk in Alzheimer's disease, it seems very likely that these reductions in enzyme activity are secondary to the degenerative process itself rather than related to the cause.

At present there are no compounds that are consistently effective to prevent the progression of the disease. Acetylcholinesterase inhibitors are the main therapy. Most of the therapy currently used focuses on the management of AD symptoms. These strategies have used anti-psychiatric drugs, as well as neuroleptic agents and acetylcholinesterase inhibitors. However, due to the side effects and the unattractive dosage requirements of these drugs, new methods and compounds that can treat AD and its symptoms are needed. 2. 3. MILD COGNITIVE DETERIORATION Mild cognitive impairment (MCI) refers to a stage of cognitive decline and specifically to a subtype of memory loss before reaching the clinical criteria for dementia in Alzheimer's disease (AD). . However, there is no completely reliable means, in addition to long-term follow-up and final autopsy, to distinguish between patients who experience MCI due to preclinical AD and patients who experience MCI due to conditions that occur less frequently (Petersen et al., Arch Neurol, 2001, 58 (12): 1985-92). In this context, MCI is considered a high-risk state that precedes AD in a large proportion of cases. The relatively recent formulation of MCI follows previous attempts to characterize cognitive decline associated with age, such as senescent, benign memory, memory impairment associated with age, and cognitive decline associated with age (Crook et al. ., Dev Neuropsychol., 1986, 2: 261-276, Oral, CMAJ 1962, 86: 257-260, Levy et al., Int Psychogeria tr 1994, 6 (1): 63-8). Contrary to many previous terms, people with MCI have a different state of normal aging in that long-term follow-up indicates that they advance as a group toward AD at an accelerated rate (Petersen et al., JAMA, 1995, 273 ( 16): 1274-8, Petersen et al., Arch Neurol, 1999, 56 (3): 308-8). Other terms with connotations similar to MCI can be the deterioration of isolated memory, insentient dementia and prodigal dementia, although the latter terms are almost not widely accepted as MCI.

The pathophysiology of MCI is unknown. One hypothesis is that it often results from a progressive accumulation of senile plaques and neurofibrillary tangles in areas of the cerebral cortex chosen by AD before the density of these lesions reaches the threshold necessary for the histopathological diagnosis of AD. Similarly, there is a hypothesis that deficiencies of some neurotransmitters, and especially a cortical cholinergic deficiency, occur in the most common amnestic form of MCI. In some studies undertaken to date, the majority of patients with MCI have neuropathological changes due to AD, while few individuals with similar clinical symptoms do not have significant amounts of type AD lesions (Mufson et al., Exp Neurol, 1999, 158 (2): 469-90; Price et al., Ann Neurol, 1999, 45 (3): 358-68; Troncoso et al., Neurobiol Aging, 1996, 17 (3): 365-71).

The MCI is a heterogeneous state due to different causes, which may overlap in some patients. In an attempt to differentiate between groups of patients, emphasis is often placed on whether memory is involved or whether individual domains that do not correspond to memory are involved. The most common form of MCI, it is thought, would be amnestic MCI, in which the only affected domain is memory. A large percentage of these patients progress to AD. A perhaps less common form of MCI is one in which multiple cognitive domains are affected. This is associated, at least in theory, with atypical variants of AD and dementia associated with cerebrovascular disease. A third proposed type is one in which a single non-memory domain is affected. It is believed that a state like this evolves into fronto-temporal dementia, dementia of Lewy bodies, progressive primary acacia, dementia in Parkinson's disease and other atypical variants of AD.

There is no treatment for MCI today. Currently, some tests are being conducted to determine if cholinesterase inhibitors, anti-inflammatory agents and antioxidants can benefit ICM. Smaller scale studies suggest that at least cholinesterase inhibitors can improve memory loss, although larger-scale studies are needed to evaluate this finding more rigorously. Freo et al., Soc Neurosci Abstr, 677, 2001. 2. 4. DEPRESSION Depression is characterized by feelings of intense sadness or pessimistic worry, agitation, disability, mental encouragement, insomnia, anorexia, loss of impulse, enthusiasm and livid. The effect of chronic antidepressant administration on the expression of three major subtypes of phosphodiesterase (PDE) 4 found in the brain (PDE4A, PDE4B and PDE4C) was examined. Takahashi et al., The Journal of Neuroscience, 1999, 19 (2): 610-618. The treatments included representatives of the four main classes of antidepressants such as selective serotonin reuptake inhibitors (Sertraline and fluoxetine), or norepinephrine (desipramine), an inhibitor of monoamine oxidase (tranylcypromine), and electroconvulsive spasm. Id. The results of this study demonstrate that the chronic administration of antidepressants increased the expression of PDE4A and PDE4B in the cerebral cortex and the expression of PDE4B in the nucleus accumbens. The 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 studies. Zhu et al., CNS Drug Reviews, Vol. 7, No. 4, 387-398, 2001. It has been documented that PDE4 is responsible for the hydrolysis of the cyclic nucleotide cAMP and cGMP, particularly in nerve and immune cells. Jd. Rolipram induces the elevation of intracellular cAMP and increases the synthesis and release of norepinephrine, which improves central noradrenergic transmission. Id. Rolipram mitigates endogenous depression and inflammation in the central nervous system. Id. However, there are some differences between the in vitro and in vivo effects of Rolipram, as well as between the results obtained in animal models and clinical studies. Id. In addition, the clinical use of Rolipram is limited due to its behavior and other side effects. Therefore, there is a huge need for a selective PDE4 inhibitor with higher potency and lower toxicity. 2. 5 LOSS OF LONG-TERM MEMORY Rubinstein-Taybi syndrome (RTS) is a human genetic disorder characterized by mental retardation and physical abnormalities such as wide thumbs, large and broad toes, short stature and craniofacial anomalies. Bourtchouladze et al., PNAS, 2003, vol. 100, No. 18. The RTS presents approximately 1 of 125 thousand births and represents as much as 1 in 300 cases of people with mental retardation seen in health facilities. Jd. In many patients, RTS has been determined on chromosome 16pl3.3, a genomic region that contains the binding protein (CBP) of the cAMP-sensitive element binding protein (CREB). Jd. Many patients with RTS are heterozygous for CBP mutations that produce truncations of C-terminal CBP, suggesting that a dominant negative mechanism may contribute to the clinical symptoms of long-term memory loss. Jd.

The studies of Bourtchouladze et al., Showed that CREB and CBP probably work together as a molecular switch during the formation of long-term memory. Jd. They demonstrated that PDE4 inhibitors, Rolipram and HT0712, suppressed long-term memory defects of CBP + mutant mice. Jd. It was reported that PDE4 inhibitors potentiated CREB-dependent gene expression and lessened long-term memory defects of CBP mutant mice in a dose-dependent manner. Jd. 2. 6 ACTIVE CYCLOIN INHIBITOR SUBSTANCES SELECTIVE Compounds known as SelCIDs ™ (Celgene Corporation) or Selective Cytokine Inhibitory Drugs (Selective cytokine inhibitory active substances) have been synthesized and analyzed. These compounds potently inhibit the production of TNF-α, but show moderate inhibitory effects on IL1β and IL12 induced LPS and do not inhibit IL6 even at high concentrations of the active substance. In addition, SelCIDs ™ tend to produce a mild stimulation of IL10, L. G. Corral, et al., Ann. Rheum. Dis. 58: (Suppl I) 1107-1113 (1999).

Another characterization of selective cytokine inhibitory active substances shows that they are potent PDE4 inhibitors. PDE4 is one of the major phosphodiesterase isozymes found in cells of the human lymphoid myeloid lineage. The enzyme plays an important role in the regulation of cellular activity by degrading the second ubiquitous cAMP messenger and maintaining it at low intracellular concentrations. Jd. In the central nervous system (CNS), PDE4 is expressed in neurons from multiple parts of the brain, including the dopaminergic neurons of the substantia nigra (Cherry and Davis, J Comp Neurol 407: 287-301 1999), a key target area of the brain. damage in Parkinson's disease, and in astrocytes, a type of cells associated with inflammation in the brain. The elevation of cAMP in neuronal precursors also favors the secretion of norepinephrine and acetylcholine (Rabe et al., J Cyclic Nucleotide Res 8: 371-384, 1982), the extension of neurites (Traynor and Schubert, Brain Res 316: 197 -204, 1984; Estlund et al., Int J Dev Neurosci 10: 361-373, 1992), and serotonin signaling (Akaike et al., Brain Res 620: 58-6, 1993), and makes the Differentiation of dopaminergic neurons from embryonic stem cells (Iacovitti et al., Brain Res 912: 99-104, 2001). The inhibition of PDE4 activity gives rise to increased levels of cAMP causing the modulation of cytokines induced by LPS including the inhibition of TNF-α production in monocytes as well as in lymphocytes. 3. COMPENDIUM OF THE INVENTION This invention comprises the methods of treatment or prevention of central nervous system disorders and related disorders, which consist of administering to a patient in need of such treatment or prevention an effective therapeutic or prophylactic amount of an active substance inhibitor of cytokines, selective, or a salt, solvate, hydrate, stereoisomer, clathrate accepted for pharmaceutical use or prodrug thereof. Central nervous system disorders may be, but are not limited to, Alzheimer's disease, mild cognitive impairment (MCI), Parkinson's disease, long-term memory impairment, Huntington's disease, multiple sclerosis, delirium or conscious disorders. that occur for a short time, and amnestic disorders or small memory impairments that occur in the absence of other central nervous system impairments. The invention also comprises the methods of managing disorders of the central nervous system (for example the lengthening of the time of remission of its symptoms) consisting of administering to a patient in need of such management an effective prophylactic amount of an active substance inhibiting the cytokine, selective, or a salt, solvate, hydrate, stereoisomer, clathrate accepted for pharmaceutical use or prodrug thereof. Each of these methods includes specific dosing or dosing schedules such as cyclic therapy.

The invention further comprises the pharmaceutical compositions. The individual unit dosage forms and the equipment for use in the treatment, prevention and / or management of central nervous system disorders, which contain one or more selective cytokine inhibitory active substances, or a salt, solvate, hydrate, stereoisomer, clathrate accepted for pharmaceutical use or prodrug thereof.

The selective cytokine inhibitory active substances, or the compounds of the invention, which are described in more detail below, are small organic molecules, ie they have a molecular weight less than 1000 g / mol. The compounds preferably inhibit the activity of PDE4 and TNF-a.

In specific embodiments of the invention, a selective cytokine inhibitory substance is used, administered or formulated with one or more second active ingredients to treat, prevent or manage disorders of the central nervous system. Examples of the second active ingredients may be, but are not limited to, dopamine agonists, levodopa, compounds that are used to increase the therapeutics of levodopa, such as monoamine oxidase (MAO) inhibitors and catechol inhibitors. O-methyltransferase (COMT), amantadine, anticholinergics, antiemetics, and other normal therapies for central nervous system disorders. In another example, the second active ingredients are anti-inflammatory compounds such as, but not limited to, nonsteroidal anti-inflammatory active substances (NSAIDs), methotrexate, leflunomide, antimalarial and sulfasalizine active substances, gold salts, glucocorticoids , immunosuppressive compounds and other normal therapies for disorders of the central nervous system. 4. DETAILED DESCRIPTION OF THE INVENTION A first embodiment comprises the methods for the treatment or prevention of disorders of the central nervous system, which comprise administering to a patient in need of treatment or prevention such as this an effective therapeutic or prophylactic amount of an active substance or selective cytokine inhibitory drug, or a salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, accepted for pharmaceutical use. Central nervous system disorders may be, but are not limited to, Parkinson's disease; bradykinesia; muscular stiffness; Parkinsonian tremors; parkinsonian gait; rigidity of movement; depression; deterioration of long-term memory; Rubinstein-Taybi syndrome; dementia; sleep disturbances; postural instability; hypokinetic disorders; inflammation; alterations of synuclein; atrophies of multiple systems; degeneration of the striatonigra connection, olivopontocerebellar atrophy; Shy-Draguer syndrome; motor neuron disease with parkinsonian characteristics; dementia of the Lewy bodies; alterations due to tau pathology; progressive supranuclear palsy; corticobasal degeneration; frontotemporal dementia; alterations in amyloid pathology; light cognitive impairment; Alzheimer disease; Alzheimer's disease with Parkinsonism; genetic alterations that may have parkinsonian characteristics; Wilson's disease; Hallervorden-Spatz disease; Chediak-Hagashi disease; SCA-3 spinocerebellar ataxia; parkinsonism with dystonia linked to the X chromosome; Huntington's disease; disease caused by prions; hyperkinetic alterations; Korea; ballism; dystonic tremors; Amyotrophic lateral sclerosis (ALS); CNS trauma and myoclonus.

Another embodiment of the invention comprises methods for the management of a disorder of the central nervous system, which consists of administering to a patient in need of management such as this an effective prophylactic amount of a selective cytokine inhibitor drug, or a salt , solvate, hydrate, stereoisomer, clathrate, accepted for pharmaceutical use or prodrug thereof.

Another embodiment of the invention comprises a method of treatment, prevention and / or management of a disorder of the central nervous system, which consists of administering to a patient in need of treatment, prevention and / or management such as this, a therapeutic or therapeutic amount. effective prophylactic of a selective cytokine inhibitory drug, or a salt, solvate, hydrate, stereoisomer, clathrate, accepted for pharmaceutical use or prodrug thereof, and an effective therapeutic or prophylactic amount of a second active agent. Without theoretical limitation, it is considered that some selective cytokine inhibitor drugs and the compounds normally used in central nervous system disorders can act in complementary or synergistic ways in the treatment or management of the disorders. It is considered that the combined use of these agents can reduce or eliminate the adverse effects associated with some selective cytokine inhibitor drugs, allowing the administration of larger amounts of conventional ALS agents, thereby allowing the administration of larger amounts of the drugs. Selective cytokine inhibitory drugs, to patients and / or increasing patient compliance. It is further thought that some selective cytokine inhibitory drugs can reduce or eliminate the adverse effects associated with some conventional agents thereby allowing the administration of larger amounts of agents to patients and / or increasing patient compliance.

Another embodiment of the invention comprises a method for reversing, reducing or avoiding an adverse effect associated with the administration of traditional treatment of central nervous system disorders to a patient suffering from central nervous system disorders or a related disorder, which consists of in administering to a patient in need of such reversion, reduction or avoidance an effective therapeutic or prophylactic amount of a selective cytokine inhibitor drug, or a salt, solvate, hydrate, stereoisomer, clathrate, accepted for pharmaceutical use, or prodrug thereof .

Yet another embodiment of the invention comprises a pharmaceutical composition containing a selective cytokine inhibitory drug, or a salt, solvate, hydrate, stereoisomer, clathrate, accepted for pharmaceutical use, or prodrug thereof, and an acceptable carrier, diluent or excipient. for pharmaceutical use, 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, preferably ALS or to lessen the symptoms or the progression of the disease.

Also encompassed by the invention are individual unit dosage forms containing a selective cytokine inhibitory drug, or a salt, solvate, hydrate, stereoisomer, clathrate, accepted for pharmaceutical use or prodrug thereof.

The second active agents can be large molecules (for example proteins) or small molecules (for example inorganic, organometallic or synthetic organic molecules). Examples of the second active agent may be, but are not limited to, cytokines, hematopoietic growth factors, anti-cancer agents such as topoisomerase inhibitors, anti-angiogenic agents, microtubule stabilizing agents, acetylcholinesterase inhibiting alkylating agents.; antivirals; antifungals; antibiotics; anti-inflammatory; immunomodulatory agents; immunosuppressive agents such as cyclosporins; and other known or usual agents that are used in patients with central nervous system disorders. The second active agents include, but are not limited to, a dopamine agonist or antagonist for Parkinson's disease or an acetylcholinesterase inhibitor for Alzheimer's disease.

The invention also comprises the equipment containing a selective cytokine inhibitory drug, or a salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, accepted for pharmaceutical use, a second active ingredient. 4. 1. CYTOKINE INHIBITORS, SELECTIVE The compounds that are used in the invention include selective, racemic, stereomeric and stereomerically enriched cytokine inhibitory drugs, stereomeric and enantiomerically pure compounds having selective cytokine inhibitory activity, and the salts, solvates, stereoisomers, clathrates accepted for pharmaceutical use and prodrive of these. The preferred compounds used in the invention are Selective Citokine Inhibitory Drugs (SelCIDs ™, Cytokine Inhibitory Drugs, Selective) known from Celegene Corporation, NJ.

When used herein, and unless otherwise indicated, the terms "selective cytokine inhibitory drugs" and "SelCIDs ™" encompass small molecule drugs, eg, small organic molecules other than peptides, proteins, nucleic acids. , oligosaccharides or other macromolecules. Preferred compounds inhibit the production of TNF-α. The compounds may also have a moderate inhibitory effect on IL1β and IL12 induced by LPS. More preferably, the compounds of the invention are potent PDE4 inhibitors.

Specific examples of selective cytokine inhibitor drugs may be, but are not limited to, cyclic imides described in US Patent Nos. 5,605,914 and 5,463,063; the cycloalkylamides and cycloalkyl nitriles of US Patents Nos. 5,728,844, 5,728,845, 5,968,945, 6,180,644 and 5,518,281; the arylamides (for example, one embodiment is N-benzoyl-3-amino-3- (3 ', 4'-dimethoxyphenyl) -propanamide) of US 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) described in US Patent No. 5,703,098; succinimides and maleimides (for example methyl 3- (3 ', 4', 5 ', 6' -tetrahydrophthalimido) -3- (3", 4" -dimethoxyphenyl) propionate) described in US Patent No. 5,658,940; imido and amido substituted hydroxamic alkane acids described in US Pat. No. 6,214,857 and WO 99/06041; substituted phenethylsulfones described in U.S. Patent Nos. 6,011,050 and 6,020,058; 1,3-dihydro-isoindolyl compounds substituted with fluoroalkoxy described in the application of US Patent No. 10 / 748,085 filed on December 29, 2003; substituted imides (for example 2-phthalimido-3- (3 ', 4'-dimethoxyphenyl) propane) described in US Patent No. 6,429,221; 1, 3, 4-substituted oxadiazoles (for example 2- [1- (3-cyclopentyloxy-4-methoxyphenyl) -2- (1,3,4-oxadiazol-2-yl) ethyl] -5-methylisoindoline-1, 3-dione) described in US Patent No. 6,326,388; cyano and carboxy derivatives of substituted styrenes (for example 3,3-bis- (3, 4-dimethoxyphenyl) acrylonitrile) described in US Patent Nos. 5,929,117, 6,130,226, 6,262,101 and 6,479,554; isoindolin-1-one and isoindoline-1,3-dione substituted at the 2-position with an a- group (disubstituted phenyl at the 3,4-position) alkyl and at the 4-position and / or 5 with a nitrogen-containing group described in WO 01/34606 and US Patent No. 5,667,316; acidohydroxamic acids substituted with imido and amido (for example (3- (1, 3-dioxoindolin-2-yl) -3- (3-ethoxy-4-methoxyphenyl) -propanoylamino) propanoate described in WO 01/45702 and US Patent No. 6,699,899. Other selective cytokine inhibitory drugs may be the diphenyl ethylene compounds described in US Provisional Application No. 60 / 452,460, filed March 5, 2003, the content of which is incorporated herein by reference in its entirety. . Other selective cytokine inhibitory drugs may be the isoindoline compounds described in US Patent Applications Nos. 10 / 900,332 and 10 / 900,270, both filed July 28, 2004. The totality of each of the patents and patent applications in the present identified is incorporated for reference.

Other selective cytokine inhibitory drugs belonging to a family of synthesized chemical compounds of which the common modalities include 3- (1,3-dioxobenzo- [f] isoindol-2-yl) -3- (3-cyclopentyloxy-4) -methoxyphenyl) propionamide and 3- (1, 3-dioxo-4-azaisoindol-2-yl) -3- (3,4-dimethoxyphenyl) -propionamide.

Other selective, specific cytokine inhibitory drugs belong to a class of non-polypeptide cyclic amides described in US Patent Nos. 5,698,579, 5,877, 200, 6,075,041, and 6,200,987, and WO 95/01348, each of which is incorporated in the present by reference. Representative cyclic amides include the compounds of the formula: where n has a value of 1, 2 or 3; R is o-phenylene, unsubstituted or substituted by 1 to 4 substituents, each independently selected 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, alkyl of 1 to 10 carbon atoms and halo; R is: (i) phenyl or phenyl substituted with one or more substituents, each selected independently 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, carbetoxy , 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; R 12 is -OH, alkoxy of 1 to 12 carbon atoms, or R is hydrogen or alkyl of 1 to 10 carbon atoms; and R9 is hydrogen, alkyl of 1 to 10 carbon atoms, -COR10 or -S02R10, wherein R10 is hydrogen, alkyl of 1 to 10 carbon atoms or phenyl.

Specific compounds of this class can be, but are not limited to: 3-phenyl-2- (l-oxoisoindolin-2-yl) propionic acid; 3-phenyl-2- (l-oxoisoindolin-2-yl) propionamide; 3-phenyl-3- (l-oxoisoindolin-2-yl) propionic acid; 3-phenyl-3- (l-oxoisoindolin-2-yl) propionamide; 3- (4-methoxyphenyl) -3- (1-oxisoindolin-yl) propionic acid; 3- (4-methoxyphenyl) -3- (1-oxisoindolin-yl) propionamide; 3- (3, 4-dimethoxyphenyl) -3- (1-oxisoindolin-2-yl) propionic acid; 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-l, 3-dihydroisoindol-2-yl) propionamide; 3- (3, 4-dimethoxyphenyl) -3- (1-oxisoindolin-2-yl) propionamide; 3- (3,4-diethoxyphenyl) -3- (1-oxoisoindolin-yl) propionic acid; methyl 3- (l-oxoisoindolin-2-yl) -3- (3-ethoxy-4-methoxyphenyl) propionate; 3- (l-Oxoisoindolin-2-yl) -3- (3-ethoxy-4-methoxyphenyl) propionic acid; 3- (l-Oxoisoindolin-2-yl) -3- (3-propoxy-4-ethoxyphenyl) propionic acid; 3- (l-Oxoisoindolin-2-yl) -3- (3-butoxy-4-methoxy-phenyl) -propionic acid; 3- (l-Oxoisoindolin-2-yl) -3- (3-propoxy-4-methoxyphenyl) propionamide; 3- (1-oxoisoindolin-2-yl) -3- (3-butoxy-4-methoxyphenyl) propionamide; methyl 3- (l-oxoisoindolin-2-yl) -3- (3-butoxy-4-methoxyphenyl) propionate; and methyl 3- (l-oxoisoindolin-2-yl) -3- (3-propoxy-4-methoxyphenol) propionate.

Other representative cyclic amides include the compounds of the formula: in which Z is: wherein: R is the divalent residue of: (i) 3,4-pyridine, (ii) pyrrolidine, (iii) imidazole, (iv) naphthalene, (v) thiophene or (vi) a linear or branched alkane of 2 to 6 carbon atoms, unsubstituted or substituted by phenyl or phenyl substituted with 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 or halo, wherein the divalent bonds of the residue are in the carbon atoms of the near ring; R2 is -CO- or -S02-; 3 R is; (i) phenyl substituted with 1 to 3 substituents, each independently selected from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy from 1 to 10 carbon atoms or halo; (ii) pyridyl, (iii) pyrrolyl, (iv) imidazolyl, (v) naphthyl, (vi) thienyl, (vii) quinolyl, (viii) furyl or (ix) indolyl; R is alanyl, arginyl, glycyl, phenylglycyl, histidyl, leucyl, isoleucyl, lysyl, methionyl, prolyl, sarcosyl, seryl, homoseryl, threonyl, thironyl, tyrosyl, valyl, benzimidol-2-yl, benzoxazol-2-yl, phenylsulfonyl, methylphenylsulfonyl or phenylcarbamoyl; and n has a value of 1, 2 or 3. Other representative cyclic amides include the compounds having the formula: wherein R is: (i) o-phenylene, unsubstituted or substituted with 1 to 4 substituents, each independently selected from: 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, (ii) the divalent residue of pyridine, pyrrolidine, imidazole, naphthalene or thiophene, where the bonds divalents are in the carbon atoms of the near ring; R6 is -CO-, -CH2- or S02-; R is: (i) hydrogen if R is -S02-, (ii) linear, branched or cyclic alkyl having 1 to 2 carbon atoms, (iii) pyridyl, (iv) phenyl or phenyl substituted with one or more substituents each independently selected from the other 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 or halo, (v) alkyl of 1 to 10 carbon atoms, (vi) benzyl unsubstituted or substituted with 1 to 3 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 or halo, (vii) naphthyl, (viii) benzyloxy or (ix) imidazol-4-yl methyl; R 12 is -OH, alkoxy of 1 to 13 carbon atoms, or n has a value of 0, 1, 2 or 3; R is hydrogen or alkyl of 1 to 10 carbon atoms; and R 9 'is hydrogen, alkyl of 1 to 10 carbon atoms, -COR "or -S02R wherein R is hydrogen, alkyl of 1 to 10 carbon atoms or phenyl Other representative imides may be the compounds having the formula: Wherein R is: (i) linear, branched or cyclic alkyl of 1 to 12 carbon atoms, (ii) pyridyl, (iii) phenyl or phenyl substituted with one or more substituents, each independently selected from the other 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 or halo, (iv) unsubstituted benzyl or substituted with 1 to 3 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 or halo, (v) naphthyl, (vi) benzyloxy or (vii) imidazol-4-yl methyl; R 12 is -OH, alkoxy of 1 to 12 carbon atoms, -0-CH 2 -pyridyl, -0-benzyl or; where n has a value of 0, 1, 2 or 3; R is hydrogen or alkyl of 1 to 10 carbon atoms; R 9 'is hydrogen, alkyl of 1 to carbon atoms, -CH 2 -pyridyl, benzyl, -COR or -S0 2 R, wherein R is hydrogen, alkyl of 1 to 4 carbon atoms or phenyl.

Other selective, specific, cytokine inhibitory drugs may be the substituted ix or amido substituted hydroxamic acids described in WO 99/06041 and US Patent No. 6,214,857, each of which is incorporated herein by reference. Examples of these compounds may be, but are not limited to: wherein each of R 1 and R 2, when taken independently of each other, is hydrogen, lower alkyl, or R 1 and R 2, when taken together with the carbon atoms represented to which each is attached, is o- phenylene, o-naphthylene or cyclohexe? -1, 2-diyl, unsubstituted or substituted by 1 to 4 substituents, each independently selected 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, alkyl of 1 to 10 carbon atoms and halo; 3 R is phenyl substituted with from 1 to 4 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, cycloalkylidene methyl of C4-C6, alkylidene methyl of C3-C10, indanyloxy and halo; R is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl or benzyl; R is hydrogen, or alkyl of 1 to 6 carbon atoms; R5 is -CH2-, -CH2-CO-, ~ S02-, -S- or -NHCO-; and n has a value of 0, 1 or 2; and the acid addition salts of the compounds containing a nitrogen atom that can be protonated; Other specific selective cytokine inhibitory drugs that are used in the invention may be, but are not limited to: 3- (3-ethoxy-4-methoxyphenyl) -N-hydroxy-3- (1-oxoisoindolinyl) propionamide; 3- (3-ethoxy-4-methoxyphenyl) -N-methoxy-3- (1-oxoisoindolinyl) propionamide; N-benzyloxy-3- (3-ethoxy-4-methoxyphenyl) -3-phthalimidopropionamide; N-benzyloxy-3- (3-ethoxy-4-methoxyphenyl) -3- (3-nitrophthalimido) propionamide; N-benzyloxy-3- (3-ethoxy-4-methoxyphenyl) -3- (1-oxoisoindolinyl) propionamide; 3- (3-ethoxy-4-methoxyphenyl) -N-hydroxy-3-phthalimidopropionamide; N-hydroxy-3- (3,4-dimethoxyphenyl) -3-phthalimidopropionamide; 3- (3-ethoxy-4-methoxyphenyl) -N-hydroxy-3- (3-nitrophthalimido) propionamide; N-hydroxy-3- (3, -dimethoxyphenyl) -3- (1-oxoisoindolinyl) propionamide; 3- (3-ethoxy-4-methoxyphenyl) -N-hydroxy-3- (4-methyl-phthalimido) propionamide; 3- (3-cyclopentyloxy-4-methoxyphenyl) -N-hydroxy-3-phthalimidopropionamide; 3- (3-ethoxy-4-methoxyphenyl) -N-hydroxy-3- (1,3-dioxo-2,3-dihydro-lH-benzo [f] isoindol-2-yl) propionamide; N-hydroxy-3-. { 3- (2-propoxy) -4-methoxyphenyl} -3-phthalimidopropionamide; 3- (3-ethoxy-4-methoxyphenyl) -3- (3,6-difluorophthalimido) -N-hydroxypropionamide; 3- (4-aminophthalimido) -3- (3-ethoxy-4-methoxyphenyl) -N-hydroxypropionamide; 3- (3-aminophthalimido) -3- (3-ethoxy-4-methoxyphenyl) -N-hydroxypropionamide; N-hydroxy-3- (3,4-dimethoxy-phenyl) -3- (1-oxoisoindolinyl) propionamide; 3- (3-cyclopentyloxy-4-methoxyphenyl) -N-hydroxy-3- (1-oxoisoindolinyl) propionamide; and N-benzyloxy-3- (3-ethoxy-4-methoxyphenyl) -3- (3-nitrophthalimido) propionamide.

The additional, selective, cytokine inhibiting drugs which are used in the invention may be phenethylsulfones substituted in the phenyl group with an oxoisoindin group [sic]. Examples of these compounds may be, but are not limited to those described in US Patent No. 5,020,358, which is incorporated herein by reference, which may be the following: where the carbon atom designated with the * constitutes a center of chirality; Y is C = 0, CH2, S02 or CH2C = 0; each variable R1, R2, R3 and R, independent of each other, is hydrogen, halo, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, nitro, cyano, hydroxy or -NR R, or any other of R, R, R and R in contiguous carbon atoms, together with the represented phenylene ring are naphthylidene; R and R, independent of each other, is hydrogen, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, cyano, or cycloalkoxy constituted by up to 18 carbon atoms; R is hydroxy, alkyl of 1 to 8 carbon atoms, phenyl, benzyl or NR 8 'R9'; each of R 8 and R 9 taken independently from one another is hydrogen, alkyl of 1 to 8 carbon atoms, phenyl or benzyl, or one of R 8, R 9 is hydrogen and the other is -COR 10 or -S0 2 R 10 or R 8 and R9 taken together with tetramethylene, pentamethylene, hexamethylene or -CH2CH2X1CH2CH2-wherein X1 is -O-, -S- or -NH-; and each of R 8 'and R 9' taken independently from each other is hydrogen, alkyl of 1 to 8 carbon atoms, phenyl or benzyl, or one of R 8 'R 9' is hydrogen and the other is '10' 8 '9' -COR or -S02R or R and R taken together with tetramethylene, pentamethylene, hexamethylene or -CH2CH2X1CH2CH2- wherein X2 is -O-, -S- or -NH-.

It will be noted that while for convenience the above compounds are identified as 7 phenethylsulfones, these include sulfonamides when R is 8 '9' NR R.

The specific groups of these compounds are those in which Y is C = 0 or CH2.

Another specific group of these compounds are those in which each of R 1, each of R1, R2, R3 and R, independent of each other, is hydrogen, halo, methyl, ethyl, methoxy, ethoxy, nitro, cyano, hydroxy or QQQ -NR R in which each of R and R, taken independently from each other, is hydrogen or methyl, or one of R 8 and R9 is hydrogen and the other is -COCH.

The particular compounds are those in which one of R, each of R ~, R, R and R4 is -NH2 and the remaining of R1, R2, R3 and R4 are hydrogen.

Particular compounds are those in which one of R, R, R and R4 is -NHCOCH3 and the remainder of R, R, R and R are hydrogen.

The specific compounds are those in which one of R 1, R 2, R 3 and R 4 is -N (CH 3) 2 and the remainder 1 2 3 4 of R, R, R and R are hydrogen.

Another preferred group of these compounds are those in which one of R 1, R 2, R 3 and R 4 is methyl and the remaining groups of R 1, R 2, R 3 and R 4 are hydrogen.

The specific compounds are those in which one of R 1, R 2, R 3 and R 4 is fluorine and the remainder of R 1, R 2, R 3 and R 4 are hydrogen.

The particular compounds are those in which one of R 5 and R 6, independent of each other, is hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopentoxy or cyclohexoxi.

The particular compounds are those in which the 5-mmeettooxxii RR and the R6 is monocycloalkoxy, polycycloalkoxy and benzocycloalkoxy.

The specific compounds are those in which R is methoxy and R is ethoxy.

The particular compounds are those in which R is hydroxy, methyl, ethyl, phenyl, benzyl, or NR 8 'R9' in which each of R8 'and R9' taken independently from each other is hydrogen or methyl.

The particular compounds are those in the 7 3 'g' which R is methyl, ethyl, phenyl, benzyl or NR R in which each of R 8 'and R 9' taken independently from each other is hydrogen or methyl.

Particular compounds are those in which R is methyl, The particular compounds are those in which R 7 is NR 8 'R 9' in which each of R 8 'and R' taken independently from each other is hydrogen or methyl.

Other selective cytokine inhibitory drugs may be the fluoroalkoxy-substituted 1,3-dihydroisoindolyl compounds described in US Patent Application No. 10 / 748,085 filed on December 29, 2003, which is incorporated herein by reference. . The representative compounds have the formula: wherein: Y is -C (O) -, -CH2, -CH2C (0) -, -C (0) CH2- or S02; Z is -H, -C (O) R3, - (C0-? Alkyl) -S02- (alkyl of L-4), alkyl of C? _8, -CH2OH, CH2 (O) (alkyl of C ^ s ) or CN; R 1 and R 2 are each independently of one another, -CHF 2, -C 1-8 alkyl, -C 3 -18 cycloalkyl or - (C 1-10 alkyl) (C 3 -18 cycloalkyl), and at least R and R 2 , is CHF2; R3 is -NR4R5, -alkyl, -OH, -O-alkyl, phenyl, benzyl, substituted phenyl or substituted benzyl; R 5 and R are each, independent of each other, -H, -alkyl of C; L_8, -OH, -0C (0) R6; R is-C1-3 cycloalkyl, amino (C? ~ 8 cycloalkyl), -phenyl, -benzyl or -aryl; X, L, X2, X3 and X4 are, independently of each other, -H, -halogen, -nitro, -NH2, -CF3, -alkyl of C? _6, - (C0-4 alkyl) - (C3_6 cycloalkyl) ), (C0-4 alkyl) -NR7R8, - (C0-4 alkyl) -N (H) C (0) - (R8), (C04 alkyl) -N (H) C (0) N ( R7R8), (C0-4 alkyl) -N (H) C (0) N (R7R8), p (Co-4 alkyl) -OR, (C0-4 alkyl) -imidazolyl, (C0-4 alkyl) -pyrrolyl, (C0-4 alkyl) -oxadiazolyl or (C0-4 alkyl) -triazolyl, or two of Xi r 2A X3 and X4 may be linked together to form a cycloalkyl or heterocycloalkyl ring, (e.g. and X2, X2 and X3, X3 and X4, Xx and X3, X2 and X4, Xi and X4, can form a 3, 4, 5, 6 or 7 membered ring which can be aromatic, thereby forming a bicyclic system with the isoindolyl ring); and R 7 and R 8 are each, independently from each other, H, Cx-g alkyl, C3_6 cycloalkyl, (C6_6 alkyl) - (C3_6 cycloalkyl), (C6_6) alkyl- (cycloalkyl) from C3_6), (C6_6 alkyl) -N (R7R8), (C6_6) -0R8 alkyl, phenyl, benzyl or aryl; or a salt, solvate, hydrate stereoisomer, clathrate accepted for pharmaceutical use or prodrug thereof.

Other selective cytokine inhibitory drugs may be the enantiomerically pure compounds described in US Patent Application No. 10 / 392,195 filed March 19, 2003; International Patent Applications Nos. PCT / US 03/08737 and PCT / US 03/08738, filed on March 20, 2003; US Provisional Patent Applications Nos. 60 / 438,450 and 60 / 438,448 for G. Muller et al., both were filed on January 7, 2003; US Provisional Patent Application No. 60 / 452,460 for G. Muller et al, filed March 5, 2003 and US Patent Application No. 10 / 715,184 filed on November 17, 2003, all of which are incorporated in the present for reference. Preferred compounds can be an enantiomer of 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindoline-1,3-dione and one enantiomer of 3- (3,4-dimethoxy) phenyl) -3- (1-oxo-l, 3-dihydroisoindol-2-yl) -propionamide.

Preferred selective cytokine inhibitor drugs used in the invention are 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide and . { 2- [l- (3-Ethoxy-4-methoxyphenyl) -2-methanesulfonyl-ethyl] -3-oxo-2,3-dihydro-lH-isoindol-4-yl} - Cyclopropanecarboxylic acid amide, which are available from Celgene Corp., Warren NJ. The compound 3- (3,4-dimethoxyphenyl) -3- (1-oxo-l, 3-dihydro-isoindol-2-yl) -propionamide has the following chemical structure: Other selective and specific cytokine inhibitor drugs may be, but are not limited to, the cycloalkylamides and cycloalkyl nitriles of US Patent Nos. 5,728,844, 5,728,845, 5,968,945, 6,180,644 and 6,518,281 and WO 97/08143 and WO 97/23457, each of which is incorporated herein by reference. The representative compounds have the formula: wherein: one of the radicals R1 and R2 is R3-X- and the other is hydrogen, nitro, cyano, trifluoromethyl, carboalkoxy (lower), acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, lower alkyl, lower alkoxy, halo or R3-X-; 3 R is monocycloalkyl, bicycloalkyl or benzocycloalkyl of up to 18 carbon atoms; X is a carbon-carbon bond, -CH- or -0-; R is: (i) 0-phenylene, unsubstituted or substituted with 1 to 3 substituents, each independently selected from: nitro, cyano, halo, trifluoromethyl, carboalkoxy (lower), acetyl or carbamoyl, unsubstituted or substituted with lower alkyl , acetoxy, carboxy, hydroxy, amino, lower alkylamino, lower acylamino or lower alkoxy; (ii) a divalent vicinal residue of pyridine, pyrrolidine, imidazole, naphthalene or thiophene, wherein the divalent bonds are on the carbon atoms of the vicinal ring; (iii) a divalent vicinal cycloalkyl or cycloalkenyl of 4-10 carbon atoms, unsubstituted or substituted with 1 to 3 substituents, each independently selected from the group consisting of nitrogen, cyano, halo, trifluoromethyl, carboalkoxy (lower), acetyl , carbamoyl, acetoxy, carboxy, hydroxy, amino, lower alkylamino, lower alkyl, lower alkoxy or phenyl; (iv) vinylidene disubstituted with lower alkyl; or (v) ethylene, unsubstituted or monosubstituted or disubstituted with lower alkyl; R6 is -CO-, -CH2- or -CH2C0-; Y is -COZ, -C = N, -OR, lower alkyl or aryl; Z is -NH 2 -, -OH-, -NHR-, -R 9 or -OR 9; p R is hydrogen or lower alkyl; R is lower alkyl or benzyl; and n has a value of 0, 1, 2 or 3.

In another embodiment, one of the radicals R1 and R2 is 3 -X- and the other is hydrogen, nitro, cyano trifluoromethyl, carboalkoxy (lower), acetyl, carbamoyl, acetoxy, carboxy hydroxy, amino, lower alkyl, lower alkoxy, halo or R -X-; R is monocycloalkyl of up to 10 carbon atoms, polycycloalkyl of up to 10 carbon atoms or benzocyclic alkyl of up to 10 carbon atoms; X is -CH2- or -O-; R is: the vicinal divalent residue of pyridine, pyrrolidine, imidazole, naphthalene or thiophene, wherein the two bonds of the divalent residue are on the carbon atoms of the vicinal ring; (ii) a divalent vicinal cycloalkyl of 4-10 carbon atoms, unsubstituted or substituted with 1 to 3 substituents, each selected independently of the group consisting of: nitro, cyano, halo, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms or phenyl; (iii) disubstituted vinylene, substituted with nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, carbamoyl substituted with [lacuna] and alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, substituted amino with an alkyl of 1 to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halo; (iv) ethylene, unsubstituted or substituted with 1 to 2 substituents, each independently selected from: nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, carbamoyl substituted with an alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, amino substituted with alkyl of 1 to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halo; R6 is -CO-, -CH2- or -CH2C0; Y is -COX, -C = N, -OR, alkyl of 1 to 5 carbon atoms; or aryl; X is -NH2-, -OH-, -NHR-, -R9 or -OR9 or alkyl of 1 to 5 carbon atoms; or R is hydrogen or lower alkyl; R is lower alkyl or benzyl; and n has a value of 0, 1, 2 or 3.

In another embodiment, one of the radicals R and R2 is ^ 3 and -X- and the other is hydrogen, nitro, cyano, trifluoromethyl, carboalkoxy (lower), acetyl, carbamoyl, acetoxy, carboxy hydroxy, amino, lower alkyl, lower alkoxy, halo, HF2CO, F3CO or R -X-; 3 R is monocycloalkyl, bicycloalkyl, benzocycloalkyl of up to 18 carbon atoms, tetrahydropyran or tetrahydrofuran; X is a carbon-carbon bond -CH2-, -O- or -N =; R is: (i) o-phenylene, unsubstituted or substituted with 1 to 3 substituents, each independently selected from nitro, cyano, halo, trifluoromethyl, carboalkoxy (lower) acetyl or carbamoyl, unsubstituted or substituted by lower alkyl, acetoxy , carboxy, hydroxy, amino, lower alkylamino, lower acylamino or lower alkoxy; (ii) a divalent vicinal residue of pyridine, pyrrolidine, imidazole, naphthalene or thiophene, wherein the divalent bonds are on the carbon atoms of the vicinal ring; (iii) a divalent vicinal cycloalkyl or cycloalkenyl of 4-10 carbon atoms, unsubstituted or substituted by one or more substituents, each independently selected from the group consisting of nitro, cyano, halo, trifluoromethyl carboalkoxy (lower), acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, lower alkylamino, lower alkyl, lower alkoxy or phenyl; (iv) vinylene disubstituted with lower alkyl; or (v) ethylene, unsubstituted or monosubstituted or disubstituted with lower alkyl; R6 is -CO-, -CH2- or -CH2C0; Y is -COX, -C = N, -OR, alkyl of 1 to 5 carbon atoms; or aryl; X is -NH2-, -OH-, -NHR-, -R9 or -OR9 or alkyl of 1 to 5 carbon atoms; R is hydrogen or lower alkyl; R is lower alkyl or benzyl; and n has a value of 0, 1, 2 or 3.

Other representative compounds have the formula: where: Y is C = N or CO (CH2) mCH3; m is 0, 1, 2 or 3; R is: (i) o-phenylene, unsubstituted or substituted with 1 to 3 substituents, each selected from nitro, cyano, halo, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, carbamoyl substituted with an alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1 to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halo; (ii) the divalent residue of pyridine, pyrrolidine, imidazole, naphthalene or thiophene, wherein the divalent bonds are on the carbon atoms of the vicinal ring; (iii) a divalent cycloalkyl of 4-10 carbon atoms, unsubstituted or substituted by one or more substituents, each independently selected from the others of the group consisting of: nitro, cyano, trifluoromethyl carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, phenyl or halo; (iv) disubstituted vinylene, substituted with nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, carbamoyl substituted with an alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino substituted with alkyl of 1 to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halo; or (v) ethylene, unsubstituted or substituted with 1 to 2 substituents, each independently selected from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, carbamoyl substituted with an alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1 to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halo; R6 is -CO-, -CH2-, -CH2CO- or -S02-; R is: (i) linear or branched alkyl of 1 to 12 carbon atoms; (ii) cyclic or bicyclic alkyl of 1 to 12 carbon atoms; (iii) pyridyl; (iv) phenyl substituted with one or more substituents, each independently selected from the others of the group of: nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, linear alkyl, branched , cyclic or bicyclic of 1 to 10 carbon atoms, linear, branched, cyclic or bicyclic alkoxy of 1 to 10 carbon atoms, CH2R, where R is a cyclic or bicyclic alkyl of 1 to 10 carbon atoms, or halo; (v) benzyl substituted with 1 to 3 substituents, each independently selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl from 1 to 4 carbon atoms, alkoxy of 1 to 10 carbon atoms or halo; (vi) naphthyl; or (vii) benzyloxy; and n has a value of 0, 1, 2 or 3.

In another embodiment, the selective, specific cytokine inhibitor drugs have the formula: wherein R is: (i) the divalent residue of pyridine, pyrrolidine, imidazole, naphthalene or thiophene, wherein the divalent bonds are on the carbon atoms of the vicinal ring; (ii) a divalent cycloalkyl of 4-10 carbon atoms, unsubstituted or substituted by one or more substituents, each independently selected from the group consisting of: nitro, cyano, trifluoromethyl carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, phenyl or halo; (iii) disubstituted vinylene, substituted with nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, carbamoyl substituted with an alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino substituted with alkyl of 1 to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halo; or (iv) ethylene, unsubstituted or substituted with 1 to 2 substituents, each independently selected from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, carbamoyl substituted with an alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1 to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halo; R6 is -CO-, -CH2-, -CH2CO- or -S02-; R is: (i) cyclic or bicyclic alkyl of 1 to 12 carbon atoms; (ii) pyridyl; (iii) phenyl substituted with one or more substituents, each independently selected from the others of the group of: nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, linear alkyl, branched , cyclic or bicyclic of 1 to 10 carbon atoms, linear, branched, cyclic or bicyclic alkoxy of 1 to 10 carbon atoms, CH2R, where R is a cyclic or bicyclic alkyl of 1 to 10 carbon atoms, or halo; (iv) benzyl substituted with 1 to 3 substituents, each independently selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl from 1 to 4 carbon atoms, alkoxy of 1 to 10 carbon atoms or halo; (v) naphthyl; or (vi) benzyloxy; and p Y is -COX, -C = N, -OR, alkyl of 1 to 5 carbon atoms, or aryl; X is -NH2-, -OH-, -NHR-, -R9 or -OR9 or alkyl of 1 to 5 carbon atoms; or R is hydrogen or lower alkyl; R is lower alkyl or benzyl; and n has a value of 0, 1, 2 or 3.

Other selective, specific, cytokine inhibitory drugs include, but are not limited to, the arylamides (e.g., one embodiment is N-benzoyl-3-amino-3- (3 ', 4'-dimethoxyphenyl) -propanamide), US Patent Nos. 5,801,195, 5,7736,570, 6,046,221 and 6,284,780, each of which is incorporated herein by reference. The representative compounds have the formula: wherein: Ar is (i) linear, branched or cyclic alkyl, unsubstituted, of 1 to 12 carbon atoms; (ii) linear, branched or cyclic alkyl, substituted, of 1 to 12 carbon atoms; (iii) phenyl; (iv) phenyl substituted with one or more substituents each independently selected from the others of the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl from 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms or halo; (v) heterocycle; or (vi) heterocycle substituted with one or more substituents, each independently selected from the others of the group nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl from 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms or halo; R is -H, alkyl of 1 to 10 carbon atoms, CH 2 OH, CH 2 CH 2 OH, or CH 2 COZ where Z is alkoxy of 1 to 10 carbon atoms, benzyloxy or RHR 1, where R 1 is H or alkyl of 1 to 10 carbon atoms; and Y is i) a phenyl or heterocyclic ring, not substituted with one or more substituents each independently selected from the others of 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 or halo or ii) naphthyl. Specific examples of the compounds have the formula: wherein Ar is disubstituted phenyl at 3.4, of each substituent is independently selected from the others of 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 or halo; Z is alkoxy of 1 to 10 carbon atoms, benzyloxy, amino or alkylamino of 1 to 10 carbon atoms; and Y is: (i) phenyl, unsubstituted or substituted, with one or more substituents each independently selected from the others of 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 or halo; or (ii) naphthyl.

Other selective, specific, cytokine inhibitory drugs can be, but are not limited to, the amide / amide, ethers and alcohols (for example 3-phthalimido-3- (3 ',' -dimethoxyphenyl) propan-1-ol) described in U.S. Patent No. 5,703,098, which is incorporated herein by reference. The representative compounds have the formula: wherein: R1 is (i) alkyl of 1 to 12 carbon atoms, linear, branched or cyclic, unsubstituted; (ii) alkyl of 1 to 12 carbon atoms, linear, branched or cyclic, substituted; (iii) phenyl; or (iv) phenyl substituted with one or more substituents, each independently selected from the group consisting of: nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, acylamino , alkylamino, di (alkyl) amino, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, bicycloalkyl of 5 to 12 carbon atoms, alkoxy of 1 to 10 carbon atoms, cycloalkoxy of 3 to 10 carbon atoms, bicycloalkoxy of 5 to 12 carbon atoms and halo; 2 R is hydrogen, alkyl of 1 to 8 carbon atoms, benzyl, pyridylmethyl or alkoxymethyl; 3 R is: (i) ethylene, (ii) vinylene, (ii) an alkylene of 3 to 10 carbon atoms, branched, (iv) an alkenylene of 3 to 10 carbon atoms, branched, (v) cycloalkylene of 4 to 9 carbon atoms unsubstituted or substituted by one or more substituents, each independently selected from the group consisting of: nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy , amino, amino substituted with alkyl of 1 to 6 carbon atoms, amino substituted with acyl of 1 to 6 carbon atoms, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 12 carbon atoms and halo, (vi) cycloalkenylene of 4 to 9 carbon atoms unsubstituted or substituted by one or more substituents, each independently selected from the group consisting of: nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, amine substituted with alkyl of 1 to 6 carbon atoms, amino substituted by acyl of 1 to 6 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 12 carbon atoms and halo, (vii) o-phenylene unsubstituted or substituted by one or more substituents each independently selected from the group consisting of: nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, amino substituted with alkyl of 1 to 6 carbon atoms, amino substituted with acyl having 1 to 6 carbon atoms, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 12 carbon atoms and halo, (viii) naphthyl, or (ix) pyridyl; R4 is -CX-, -CH2- or -CH2CX-; X is O or S; and n is 0, 1, 2 or 3.

Other selective, specific, cytokine inhibitory drugs can be, but are not limited to, succinimides and maleimides (for example 3- (3 ', 4', 5 ', 6' -pentahydrophthalimido) -3- (3", 4 methyl-dimethoxyphenyl) ropionate described in US Patent No. 5,658,940 which is incorporated herein by reference. The representative compounds have the formula: wherein: R 1 is -CH 2 -, -CH 2 CO- or -CO-, 2 3 R and R taken together are: (i) ethylene unsubstituted or substituted by alkyl of 1 to 10 carbon atoms or phenyl, (ii) vinylene substituted with two substituents, each selected, independent of each other, from the group consisting of alkyl of 1-10 carbon atoms and phenyl, or (iii) a divalent cycloalkyl of 5-10 carbon atoms, unsubstituted or substituted by one or more substituents, each independently selected from the others of the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl unsubstituted or substituted by alkyl of 1-3 carbon atoms, acetoxy, carboxy, hydroxy , amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, norbornyl, phenyl or halo; R is (i) alkyl of 4 to 8 carbon atoms, linear or branched, unsubstituted, (ii) cycloalkyl or bicycloalkyl of 5-10 carbon atoms, unsubstituted or substituted with one or more substituents, each independently selected of the others from the group consisting of: nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 branched carbon atoms, linear or cyclic, C 1-10 alkoxy, phenyl or halo, (iii) phenyl substituted with one or more substituents, each independently selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl , acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, cycloalkyl or bicycloalkyl of 3 to 10 carbon atoms, cycloalkoxy or bicycloalkoxy of 3 to 10 a carbon atoms, phenyl or halo, (iv) pyridine or pyrrolidine, unsubstituted or substituted by one or more substituents each independently selected from the others, from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl , carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, phenyl or halo; and R5 is -COX, -CN, -CH2COX, alkyl of 1 to 5 carbon atoms, aryl, -CH2OR, -CH2 aryl or -CH2OH, where X is NH2, OH, NHR or OR6, where R is lower alkyl; and where R is alkyl or benzyl.

Other selective, specific, cytokine inhibitory drugs may be, but are not limited to, substituted imides (e.g., 2-phthalimido-3- (3 ', 4'-dimethoxyphenyl) propane) described in US Patent No. 6,429,221 which is incorporated herein by reference.

The representative compounds have the formula: wherein: R1 is: (i) straight, branched or cyclic alkyl of 1 to 12 carbon atoms; (ii) phenyl substituted with one or more substituents, each independently selected from the others of: nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl, to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, phenyl or halo; (iii) benzyl or benzyl substituted with one or more substituents, each independently 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 or halo, or (iv) -Y-Ph where Y is an alkyl of 1 to 12 carbon atoms, branched or cyclic linear, and Ph is phenyl or phenyl substituted with one or more substituents, each independently selected from the group consisting of: nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl, to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms or halo; R is -H, alkyl of 1 to 10 carbon atoms, branched or unbranched, phenyl, pyridyl, heterocycle, -CH0-aryl or -CH2-heterocycle; R3 is i) ethylene, ii) vinylene, iii) an alkylene of 3 to 10 carbon atoms, branched, iv) an alkenylene of 3 to 10 carbon atoms, branched, v) cycloalkylene of 4 to 9 carbon atoms unsubstituted or substituted with 1 to 2 substituents, each selected independently of the others from the group consisting of: nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, phenyl or halo; vi) cycloalkenylene of 4 to 9 carbon atoms, unsubstituted or substituted by 1 to 2 substituents, each selected independently of the others from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy , carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, phenyl or halo, or vii) o-phenylene unsubstituted or substituted with 1 to 2 substituents, each independently selected from the others of the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, phenyl or halo; and R 4 is -CX or -CH 2 -; X is 0 or S.

Other selective, specific, cytokine inhibitory drugs include, but are not limited to, substituted 1,3,4-oxadiazoles (e.g. 2- [1- (3-cyclopentyloxy-4-methoxyphenyl) -2- (1,3, 4-oxadiazol-2-yl) ethyl] -5-methylisoindoline-1,3-dione) described in US Patent No. 6,326,388, which is incorporated herein by reference. The representative compounds have the formula: wherein: the carbon atom designated with a * constitutes a center of chirality; Y is C = 0, CH2, S02 or CH2C = 0; X is hydrogen, or alkyl of 1 to 4 carbon atoms; 1 2 3 4 each of the radicals R, R, R and R, independent of each other, is hydrogen, halo, trifluoromethyl, acetyl, alkyl of 1 to 8 carbon atoms, alkoxy of 1 to 4 carbon atoms, nitro, cyano, hydroxy, -CH2NR8R9, - (CH2) 2NR8R9 or -NR8R9 or any pair of the radicals R, R, R3 and R4 in adjacent carbon atoms, together with the benzene ring represented are naphthylidene, quinoline, quinoxaline, benzimidazole, benzodioxole or 2-hydroxybenzimidazole; each of the radicals R 5 and R 6, independent of each other, is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 6 carbon atoms, cyano, benzocycloalkoxy, cycloalkoxy of up to 18 carbon atoms, bicycloalkoxy of up to 18 carbon atoms. carbon atoms, tricycloalkoxy of up to 18 carbon atoms or cycloalkylalkoxy of up to 18 carbon atoms; each of the radicals R 8 and R 9, taken independently of the others is hydrogen, linear or branched alkyl of 1 to 8 carbon atoms, phenyl, benzyl, pyridyl, pyridylmethyl, or one of R and R is hydrogen and the other is -COR or -S02R or R and R taken together are tetramethylene, pentamethylene, hexamethylene, -CH = NCH = CH- or -CH2CH2X1CH2CH2-, wherein X1 is -O-, -S- or -NH-, R is hydrogen , alkyl of 1 to 8 carbon atoms, cycloalkyl, cycloalkylmethyl of up to 6 carbon atoms, phenyl, pyridyl, benzyl, imidazolylmethyl, pyridylmethyl, NRX1R12, CH2R14R15 or NRX1R12, wherein R and R, independent of each other, are hydrogen, methyl , ethyl or propyl, and wherein R 11 and R 12, independent of each other, are hydrogen, alkyl of 1 to 8 carbon atoms, phenyl or benzyl; and the acid addition salts of the compounds containing a nitrogen atom that can be protonated.

Specific examples of the compounds have the formula: wherein: the carbon atom designated with the * constitutes a center of chirality; Y is C = 0, CH2, S02 or CH2C = 0; X is hydrogen, or alkyl of 1 to 4 carbon atoms; 1 2 3 4 (i) each of the radicals R, R, R and R, independent of each other, is hydrogen, halo, trifluoromethyl, acetyl, alkyl of 1 to 8 carbon atoms, alkoxy of 1 to 4 carbon atoms, nitro, cyano , hydroxy, -CH2NR8R9, - (CH2) 2NR8R9 or -NR8R9 or (ii) any pair of the radicals R1, R2, R3 and R4 in adjacent carbon atoms, together with the represented benzene ring to which they are attached are naphthylidene, quinoline , quinoxaline, benzimidazole, benzodioxole or 2-hydroxybenzimidazole; each of the radicals R 5 and R 6, independently of the others, is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 6 carbon atoms, cyano, benzocycloalkoxy, cycloalkoxy of up to 18 carbon atoms, bicycloalkoxy of up to 18 carbon atoms, tricycloalkoxy of up to 18 carbon atoms or cycloalkylalkoxy of up to 18 carbon atoms; 8 9 (i) each of the radicals R and R, independently of the other, is hydrogen, alkyl of 1 to 8 carbon atoms, phenyl, benzyl, pyridyl, pyridylmethyl, or (ii) one of the radicals R 8 and R 9 is hydrogen and the other is -COR or -S02R, in which R is hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl, cycloalkylmethyl of up to 6 carbon atoms, phenyl, pyridyl, benzyl, imidazolylmethyl, pyridylmethyl, NR11R12 or CH2NR14R15, wherein R11 and R12, independent of each other, are hydrogen, alkyl, of 1 to 8 carbon atoms, phenyl or benzyl, and R and R, independent of each other, are hydrogen, methyl, ethyl or propyl; or 8 (111) R and R taken together are tetramethylene, pentamethylene, hexamethylene, -CH = NCH = CH-, or -CH2CH2X1CH2CH2-, wherein X1 is -0-, -S- or -NH-.

Other selective, specific, cytokine inhibitory drugs may be, but are not limited to, cyano and carboxy derivatives of substituted styrenes (eg, 3, 3-bis- (3,4-dimethoxyphenyl) acrylonitrile) described in US Pat. 5,929,117, 6,130,226, 5,262,101, and 6,479,554, each of which is incorporated herein by reference. The representative compounds have the formula: wherein: (a) X is -0- or - (CnH2n) - wherein n has a value of O, 1, 2 or 3, and R is alkyl of 1 to 10 carbon atoms, monocycloalkyl of up to 10 atoms of carbon, polycycloalkyl of up to 10 carbon atoms or benzocyclic alkyl of up to 10 carbon atoms, or 1 (b) X is -CH = and R is alkylidene of up to 10 carbon atoms, monocycloalkylidene of up to 10 carbon atoms or bicycloalkylidene of up to 10 carbon atoms; 2 R is hydrogen, nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, lower alkyl, lower alkylidene, lower alkoxy or halo; 3 R is (i) phenyl, unsubstituted or substituted by one or more substituents, each independently selected from the group consisting of: nitro, cyano, halo, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, alkyl substituted carbamoyl from 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, amino substituted with alkyl of 1 to 5 carbon atoms, alkyl of up to 10 carbon atoms, cycloalkyl of up to 10 carbon atoms, alkoxy of up to 10 carbon atoms carbon, cycloalkoxy of up to 10 carbon atoms, alkylidene methyl of up to 10 carbon atoms, cycloalkylidenemethyl of up to 10 carbon atoms, phenyl or methylenedioxy; (ii) pyridine, substituted pyridine, pyrrolidine, imidazole, naphthalene or thiophene; (iii) cycloalkyl of 4-10 carbon atoms, unsubstituted or substituted by one or more substituents each independently selected from the group consisting of nitro, cyano, halo, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or phenyl; each of the radicals R and R, taken individually is hydrogen or R and R taken together are a carbon-carbon bond; Y is -COZ, C = N, or lower alkyl of 1 to 5 carbon atoms; Z is -OH, -NR R, -R or R; R is hydrogen or lower alkyl; and R is alkyl or benzyl. Specific examples of the compounds have the formula: wherein: (a) X is -O- or (CnH2n) - wherein n has a value of 0, 1, 2 or 3, and R1 is alkyl of 1 to 10 carbon atoms, monocycloalkyl of up to 10 carbon atoms carbon, polycycloalkyl of up to 10 carbon atoms, or benzocyclic alkyl of up to 10 carbon atoms, or (b) X is -CH = and R is alkylidene of up to 10 carbon atoms, monocycloalkylidene of up to 10 carbon atoms or bicycloalkylidene of up to 10 carbon atoms; 2 R is hydrogen, nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, lower alkyl, lower alkylidenemethyl, lower alkoxy or halo; R is pyrrolidine, imidazole or thiophene unsubstituted or substituted with one or more substituents each independently selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, amino substituted, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms or phenyl; Each of the radicals R 4 and R 5 taken individually is hydrogen, or R 4 and R 5, taken together are a carbon-carbon bond; Y is -COZ, C = N, or lower alkyl of 1 to 5 carbon atoms; Z is -OH, -NR6Rd, -R7, or R7; R6 is hydrogen or lower alkyl; and R is alkyl or benzyl.

Particularly preferred nitriles are compounds of the formula: wherein: (a) X is -O- or ~ (CnH2n) - wherein n has a value of 0, 1, 2 or 3, and R is alkyl of up to 10 carbon atoms, monocycloalkyl of up to 10 carbon atoms carbon, polycycloalkyl of up to 10 carbon atoms, or benzocyclic alkyl of up to 10 carbon atoms, or (b) X is -CH = and R is alkylidene of up to 10 carbon atoms, monocycloalkylidene of up to 10 carbon atoms; R is hydrogen, nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, lower alkyl, lower alkoxy or halo; and R3 is (i) phenyl or naphthyl, unsubstituted or substituted with one or more substituents, each independently selected from the group consisting of: nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, or carbamoyl substituted with alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1 to 5 carbon atoms, alkoxy or cycloalkoxy of 1 to 10 carbon atoms; or (ii) cycloalkyl of 4 to 10 carbon atoms, unsubstituted or substituted by one or more substituents each independently selected from the group consisting of: nitro, cyano, halo, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms or phenyl.

The particularly preferred nitrile compound has the formula: Other selective, specific, cytokine inhibitory drugs can be, but are not limited to, isoindolin-1-one and isoindoline-1,3-dione substituted at the 2-position with an a- (disubstituted phenyl at 3-position, 4) and in position 4 and / or 5 with a nitrogen containing group described in WO 01/34606 and US Patent No. 6,667,316, which are incorporated herein by reference. The representative compounds have the formula: and include the salts and stereoisomers accepted for pharmaceutical use thereof, wherein: one of X and X 'is = C = 0 or = S02, and the other of X and X' is = C = 0, = CH2, = S02 ó = CH2C = 0; n is 1, 2 or 3; Ri and R2 are each independently of one another, (C1-C4) alkyl, (C! -C) alkoxy, cyano, (C3-C13) cycloalkyl, (C3-C? 8) cycloalkoxy or cycloalkyl (from C3-C13) -methoxy; R3 is S02-Y, COZ, CN or hydroxyalkyl (from C? -C6), wherein: Y is alkyl (of C? ~ C6), benzyl or phenyl; Z is -R6R7, (Cx-Cg) alkyl, benzyl or phenyl; R ?, is H, alkyl (of Cx-Cg), cycloalkyl (of C3-C18), alkanoyl (of C2-Cs), benzyl or phenyl, each of which may be optionally substituted with halo, amino or alkyl ( of C1-C4) -amino; R7 is H or (C1-C4) alkyl; R4 and R5 are taken together to obtain -NH-CH2-CH2-R8-, -NH-CO-R8- or -NH = CH-R8-, wherein: R8 is CH2, O, NH, CH = CH = CH = N or N = CH; or one of the radicals R4 and R5 is H, and the other of R4 and R5 is imidazolyl, pyrrolyl, oxadiazolyl, thiazolyl or a structure of formula (A): (A) where: Z is 0 or 1; Rg is H; alkyl (from C? -C4), cycloalkyl (from C3-C18), alkanoyl (from C2-C5), or cycloalkanoyl (from C4-Cg), optionally substituted with halo, amino, alkyl (from C1-C4), amino or dialkyl (of C 1 -C 4) -amino; phenyl, benzyl, benzoyl; alkoxycarbonyl (from C2-C5); C3-C5 alkoxyalkylcarbonyl; N-morpholino carbonyl, carbamoyl; carbamoyl with N-substitution with alkyl (from C? -C); or methyl sulfonyl; and Rio is H, alkyl (from C? -C4), methyl sulfonyl or alkoxy alkyl carbonyl (from C3-C5); or Rg and R10 are taken together to obtain -CH = CH-CH = CH-, -CH = CH-N = CH-, or alkylidene (of C? -C2), optionally substituted with amino, alkylamino (of C? - C4), or dialkylamino (of C1-C4); or R and R5 are both structures of the formula (A). 3 In one mode, z is not 0 when (i) R is -S02-Y, -COZ or -CN and (ii) one of R4 or R5 is hydrogen. In another embodiment, R 9 and R 10, taken together is -CH = CH-CH = CH-, -CH = CH-N = CH- or alkylidene (from C? -C) substituted by amino, alkylamino (from C 1 -C 4) ) or dialkylamino (C1-C4). In another embodiment, of R4 or R5 both are structures of formula (A).

The specific compounds have the formula: and the enantiomers of these. Other specific compounds have the formulas: and Other examples include, but are not limited to: 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4,5-dinitroisoindoline-1,3-dione; 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4,5-diaminoisoindoline-1,3-dione; 7- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -3-pyrrolino [3,4-e] benzimidazole-6,8-dione; 7- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] idro-3-pyrrolino [3,4-e] benzimidazole-2,6,6-trione; 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -3-pyrrolino [3, -f] quinoxalin-1,3-dione; cyclopropyl-N-. { 2- [1- (3-ethoxy-4-methoxyphenyl) -2-ethylsulfonylethyl] -1,3-dioxoisoindolin-4-yl} carboxamide; 2-chloro-N-. { 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -1,3-dioxoisoindolin-4-yl} acetamide; 2-amino-N-. { 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -1,3-dioxoisoindolin-4-yl} acetamide; 2-N, N-dimethylamino-N-. { 2- [- (3-ethoxy-4-methoxyphenyl) -2-ethylsulfonylethyl] -1,3-dioxoisoindolin-4-yl} acetamide; N-. { 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -1,3-dioxoisoindolin-4-yl} -2, 2, 2-trifluoroacetamide; N-. { 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -1,3-dioxoisoindolin-4-yl} methoxycarboxamide; 4- [1-aza-2- (dimethylamino) prop-1-enyl] -2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4- (5-methyl-1,3, 4-oxadiazol-2-yl) isoindoline-1,3-dione; 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulphonylethyl] -4-pyrrolyl-isoindolin-1,3-dione; 4- (aminomethyl) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -isoindolin-1,3-dione; 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4- (pyrrolylmethyl) isoindoline-1,3-dione; N ~. { 2- [1- (3-ethoxy-4-methoxyphenyl) ~ 3-hydroxybutyl] -1,3-dioxoisoindolin-4-yl} acetamide; N-. { 2- [1- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -1,3-dioxoisoindolin-4-yl} acetamide; N-. { 2- [1R- (3-ethoxy-4-methoxyphenyl) -3-hydroxybutyl] -1,3-dioxoisoindolin-4-yl} acetamide; N-. { 2- [IR- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -1,3-dioxoisoindolin-4-yl} acetamide; N-. { 2- [1 S- (3-ethoxy-4-methoxyphenyl) -3-hydroxybutyl] -1,3-dioxoisoindolin-4-yl} acetamide; N-. { 2- [1S- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -1,3-dioxoisoindolin-4-yl} acetamide; 4-amino-2- [1- (3-ethoxy-4-methoxyphenyl) -3-hydroxybutyl isoindoline-1,3-dione; 4-amino-2- [1- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -isoindoline-1,3-dione; 2- [1- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -4-pyrrolyl-isoindoline-1,3-dione; 2-Chloro-N-. { 2- [1- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -1,3-dioxoisoindol-4-ylkaketa ida; 2- (dimethylamino) -N-. { 2- [1- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -1,3-dioxoisoindolin-4-yl} acetamide; 4-amino-2- [IR- (3-ethoxy-4-methoxyphenyl) -3-hydroxybutyl] -isoindoline-1,3-dione; 4-amino-2- [IR- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -isoindolin-1,3-dione; 2- [IR- (3-ethoxy-4-methoxyphenyl) -3-oxo-butyl] -4-pyrrolyl-isoindoline-1,3-dione; 2- (dimethylamino) -N-. { 2- [1R- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -1,3-dioxoisoindolin-4-yl} acetamide; cyclopentyl-N-. { 2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl} carboxamide; 3- (cimethylamino) -N-. { 2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl} propanamide; 2- (dimethylamino) -N-. { 2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl} propanamide; N-. { 2- [(IR) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl} -2- (dimethylamino) acetamide; N-. { 2- [(SS) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl} -2- (dimethylamino) acetamide; 4-. { 3- [(dimethylamino) methyl] pyrrolyl} -2- [1- (3-ethoxy-4-ethoxyphenyl) -2- (methylsulfonyl) ethyl] isoindoline-1,3-dione; cyclopropyl-N-. { 2- [(1S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl} carboxamide; 2- [1- (3, 4-dimethoxyphenyl) -2- (methylsulfonyl) ethyl] -4-pyrrolylisoindoline-1,3-dione; N-. { 2- [1- (3, 4-dimethoxyphenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl} -2- (dimethylamino) acetamide; cyclopropyl-N-. { 2- [1- (3, 4-dimethoxyphenyl) -2- (methylsulfonyl) ethyl-1,3-dioxoisoindolin-4-yl} carboxamide; cyclopropyl-N-. { 2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -3-oxoisoindolin-4-yl} carboxamide; 2- (dimethylamino) -N-. { 2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -3-oxoisoindolin-4-yl} acetamide; cyclopropyl-N-. { 2- [(1S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -3-oxoisoindolin-4-yl} carboxamide; cyclopropyl-N-. { 2- [(IR) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -3-oxoisoindolin-4-yl} carboxamide; (3R) -3- [7- (acetylamino) -l-oxoisoindolin-2-yl] -3- (3-ethoxy-4-methoxyphenyl) -N, N-dimethylpropanamide; (3R) -3- [7- (Cyclopropylcarbonylamino) -l-oxoisoindolin-2-yl] -3- (3-ethoxy-4-methoxyphenyl) -N, N-dimethylpropanamide; 3-. { - [2- (dimethylamino) acetylamino] -1,3-dioxoisoindolin-2-yl} -3- (3-ethoxy-4-methoxyphenyl) -N, N-dimethylpropanamide; (3R) -3- [7- (2-Chloroacetylamino) -l-oxoisoindolin-2-yl] -3- (3-ethoxy-4-methoxy-phenyl) -N, -dimethylpropanamide; (3R) -3-. { 4- [2- (dimethylamino) acetylamino] -1,3-dioxoisoindolin-2-yl} -3- (3-ethoxy-4-methoxyphenyl) -N, N-dimethylpropanamide; 3- (1, 3-dioxo-4-pyrrolylisoindolin-2-yl) -3- (3-ethoxy-4-methoxyphenyl) -N, N-dimethylpropanamide; 2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -4- (imidazolyl-methyl) isoindoline-1,3-dione; N- ( { 2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl} methyl) acetamide; 2-chloro-N- (. {2- [1- (3-ethoxy-4-ethoxyphenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl} methyl) acetamide; 2- (dimethylamino) -N- (. {2- 2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl} methyl) acetamide; 4- [bis (methylsulfonyl) amino] -2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] isoindoline-1,3-dione; 2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -4- [(methylsulfonyl) amino] isoindoline-1,3-dione; N-. { 2- [1- (3-ethoxy-4-methoxyphenyl) -3-hydroxypentyl] -1,3-dioxoisoindolin-4-yl} acetamide; N-. { 2- [1- (3-ethoxy-4-methoxyphenyl) -3-oxopentyl] -1,3-dioxoisoindolin-4-yl} acetamide; 2- [(IR) -1- (3-ethoxy-4-methoxyphenyl) -3-hydroxybutyl] -4- (pyrrolylmethyl) -isoi-dolin-1,3-dione; 2- [(IR) -1- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -4- (pyrrolyl ethyl) isoindoline-1,3-dione; N-. { 2- [1- (3-cyclopentyloxy-4-methoxyphenyl) -3-hydroxybutyl] -1,3-dioxoisoindolin-4-yl} acetamide; N-. { 2- [1- (3-Cyclopentyloxy-4-methoxyphenyl) -3-oxobutyl] -1,3-dioxoisoindolin-4-yl} acetamide; 2- [1- (3-Cyclopentyloxy-4-methoxy-phenyl) -3-oxo-butyl] -4-pyrrolyl-isoindolin-1,3-dione; 2- [1- (3, 4-Dimethoxyphenyl) -3-oxobutyl] -4- [bis (methylsulfonyl) amino] isoindoline-1,3-dione; and salts salts, solvates and stereoisomers accepted for pharmaceutical use thereof.

Still other selective, specific, cytokine inhibitory drugs can be, but are not limited to, imido and amido-substituted acylhydroxamic acids (for example (3- (1,3-dioxoisoindolin-2-yl) -3- (3-ethoxy) 4-methoxyphenyl) propanoylamino) propionate described in WO 01/45702 and US Patent No. 6,699,899, which are incorporated herein by reference, Representative compounds have the formula: wherein: the carbon atom designated with a * constitutes a center of chirality; R is hydrogen or - (C = 0) -R, each of the radicals R 1 and R 2, independent of each other, is alkyl of 1 to 6 carbon atoms, phenyl, benzyl, methylpyridyl, pyrimidyl, imidazolyl, methylimidazolyl, or CHR * (CH2) nNR * R °, wherein R * and R, independent of each other, are hydrogen, alkyl of 1 to 6 carbon atoms, phenyl, benzyl, methylpyridyl, pyridyl, imidazolyl or methylimidazolyl, and n = 0.1 or 2; R5 is C = 0, CH2, CH2-CO- or S02; each of the radicals R and R, independent of each other, is nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, cycloalkoxy of 3 to 8 carbon atoms, halo, bicycloalkyl of up to 18 carbon atoms, tricycloalkoxy of up to 18 carbon atoms, 1-indanyloxy, 2-indanyloxy, cycloalkylidene methyl of C4-C3 or alkylidene methyl C3-C? o; p Q 1 Q 11 each of R, R, R and R, independent of each other, is: (i) hydrogen, 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, halo op Q 1 11 (ii) one of the radicals R, R, R and R, is acylamino containing a lower alkyl , and the res 4t-an4t-es nR8, pR9, R-, 10 and yR i are vh, i • djro -geno, op Q (iii) hydrogen if R and R taken together are benzo, quinoline, quinoxaline, benzimidazole, benzodioxol, 2-hydroxybenzimidazole, methylenedioxy, dialkoxy or dialkyl, (iv) hydrogen if R10 and R11, taken together are benzo, quinoline, quinoxaline, benzimidazole, benzodioxole, 2-hydroxybenzimidazole, methylenedioxy, dialkoxy or dialkyl, or (v) hydrogen if R and R, taken together are benzo.

Still selective, specific cytokine inhibitory drugs can be, but are not limited to, the 7-amido-isoindolyl compounds described in the application of US Patent No. 10 / 798,317 filed March 12, 2004, which is incorporated in the present for reference. The representative compounds have the formula: wherein: Y is -C (O) -, -CH2, -CH2C (0) - or S02; X is H; Z is (C 0-4 alkyl) -C (O) R 3, C 4 alkyl, 4 C 4 alkyl) -OH, (C 4 alkyl) 4) -O (C 2 -4 alkyl), (alkyl) of C? _) -S0 (C4 alkyl), (C0_4 alkyl) -SO (C4_4 alkyl), (C0-4 alkyl) -NH2, (C0-4 alkyl) -N ( C? _8) 2, (C0-4 alkyl) -N (H) (OH) or CH2NS02 (C? _4 alkyl); Ri and R2 are independently alkyl (from C? _8), cycloalkyl or (C? _4 alkyl) cycloalkyl; R3 is NR4R5, OH, or 0- (C? _8 alkyl); R4 is H; R5 is -OH or -0C (0) R6; R is C? _8 alkyl, amino (C? _8 alkyl), (C_8 alkyl) - (C3_g cycloalkyl), C3_6 cycloalkyl, phenyl, benzyl or aryl; or a salt, solvate, hydrate, stereoisomer, clathrate accepted for pharmaceutical use or prodrug thereof; or the formula: Y is -C (0) -, CH2, -CH2C (0) - or S02; X is halogen, -CN, -NR7R8, -N02 or CF3; Z is (C0-4 alkyl) -S02 (Cx_ alkyl), - (C0_4 alkyl) -CN, - (C0-4 alkyl) -C (0) R3, C? _ Alkyl, (alkyl) of C0-4) -OH, (C0_4 alkyl) 0 (C? _ alkyl), (C0_4 alkyl) SO (C? _4 alkyl), (C0_4 alkyl) NH2, C0-4) N (C? _8 alkyl) / (C0_4 alkyl) N (H) (OH), (C0_4 alkyl) -dichloropyridine or (C0-4 alkyl) NSO2 (C? _ Alkyl); W is - C3_6 cycloalkyl, - (C? -8 alkyl) (C3_ cycloalkyl), - (C0-8 alkyl) - (C3_6 cycloalkyl) -NR7R8, (Co-8 alkyl) -NR7R8, - (C0_ alkyl) -CHR9- (Co-4 alkyl) -NR7R8; R x and R 2 are independently C 1 8 alkyl, cycloalkyl or C 4 alkyl cycloalkyl; R3 is C? _8 alkyl, NR4R5, OH or O- (C? _8 alkyl); R 4 and R 5 are, independently of each other, H, C 1-8 alkyl, C 1 -C 6 alkyl, C 0 6 cycloalkyl, OH or -OC (0) R 6; R is C? _8 alkyl, (Co-s alkyl) ~ (C3_6 cycloalkyl), amino (C_8 alkyl), phenyl, benzyl or aryl; R7 and R8 are each, independently of each other, H, C? _8 alkyl, (Cys-alkyl) - (C3-6 cycloalkyl), phenyl, benzyl, aryl or can be taken together with the atom that connects to form a 3 to 7 membered heterocycloalkyl or heteroaryl ring; R g is C 4 alkyl, aryl (C 4 alkyl), (C 4 alkyl) - (C 3 6 cycloalkyl), (C 4 alkyl) -heterocycle; or a salt, hydrate solvate, stereoisomer, clathrate accepted for pharmaceutical use or prodrug thereof. In another modality, W is: In another embodiment, the representative compounds have the formula: wherein: Rx, R and R3 are, independently of each other, H or alkyl of C? "8, with the proviso that at least one of the radicals Rx, R2 and R3 is not H; and the salts, solvates, hydrates, stereoisomers, clathrates accepted for pharmaceutical use or prodrugs thereof.

Still, selective, specific, cytokine inhibitory drugs can be, but are not limited to, isoindoline compounds described in US Patent Application No. 10 / 900,332 filed July 28, 2004, which is incorporated herein by reference. . Representative compounds are listed in Table 1 below, and the salts, solvates and stereoisomers accepted for pharmaceutical use of "these: Table 1 In another embodiment, this invention also comprises 2- [l- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl)] - 4,5-dinitroisoindoline-1,3-dione and its acid addition salts, in a Specific, this invention comprises a hydrochloride salt of 2- [l- (3-ethoxy-4-methoxyphenyl) -2-methylsulphonylethyl)] - 4,5-dinitroisoindoline-1,3-dione.

Still, selective, specific, cytokine inhibitory drugs can be, but are not limited to, isoindoline compounds described in US Patent Application No. 10 / 900,270 filed July 28, 2004, which is incorporated herein by reference. for reference. The representative compounds are. { 2- [l- (3-ethoxy-4-methoxyphenyl) -2-methylsufonylethyl) -2- [1, 3, 4] oxadiazol-2-yl-ethyl] -3, oxo-2,3-dihydro-lH- isoindol-4-yl} cyclopropane carboxylic acid amide, which has the following chemical structure, and the salts, solvates, prodrugs and stereoisomers accepted for pharmaceutical use of these: Still the selective, specific cytokine inhibitor drugs may be, but are not limited to, the isoindolyl compounds of N-alkyl-hydroxamic acid described in the Provisional Application No. 60 / 454,149 filed on March 12, 2003, and its application non-provisional US entitled isoindolyl compounds of "N-alkylhydroxamic acid and its pharmaceutical uses" which was filed on March 12, 2004 by Man et al., with US series No. 10 / 798,372, each of which is incorporated in the present for reference. The representative compounds have the formula: Y is -C (O) -, CH2, -CH2C (0) - or S02; R 1 and R 2 are independent from each other, C 1 8 alkyl, CF 2 H, CF 3, CH 2, cycloalkyl or (C 8 alkyl), cycloalkyl; Zi is H, alkyl of C? _6, -NH2, NR3R4 or 0R5; Z2 is H or C (0) R5; Xi, X2, X3 and 4 are each independently H, halogen, N02, OR3, CF3, C? _6 alkyl, CQ-4) - (C3_g cycloalkyl), (C0-4 alkyl) -N- (R8Rg), (C04 alkyl) -NHC (O) (R8), (C0-4 alkyl) -NHC (0) CH (R8) (Rg), (C0-4 alkyl) "NHC (O) N (R8Rg) , (C0_4 alkyl) -NHC (O) or (R8), (C0-4 alkyl) ~ O-R8, (C0-4 alkyl) -imidazolyl, (C0-4 alkyl) -pyrrolyl, (alkyl) of C0-4) -oxadiazolyl, (C0-4 alkyl) -triazolyl or (C0-4 alkyl) -heterocycle; R3, R4 and R5 are each, independently of each other, H, C? -alkyl of C? _6, phenyl, benzyl, or aryl; Rg and R7 are independently H or alkyl of C? _g; R8 and R9 are each, independently of each other, H, Ci_g alkyl, C3_g cycloalkyl, (alkyl) of C? _ g) -C3_6 cycloalkyl, (C? _6 alkyl) -N (R4R5), (C? _6 alkyl) -OR5, phenyl, benzyl, aryl, piperidinyl, piperizinyl, pyrrolinyl, morpholino or C3_7 heterocycloalkyl , - I a salt, solvate, hydrate, stereoisomer, clathrate accepted for pharmaceutical use or prodrug thereof.

Still, selective, specific, cytokine inhibitory drugs can be, but are not limited to, the diphenylethylene compounds described in US Patent Application No. 10 / 794,931, filed March 5, 2004, which is incorporated herein by reference. for reference. The representative compounds have the formula: and the salts, solvates or hydrates accepted for pharmaceutical use thereof, wherein: Ri is -CN, lower alkyl, -COOH, -C (O) - (R9) 2, -C (O) -lower alkyl, -C (O) -benzyl, -C (O) -lower alkyl, -C (O) -O-benzyl; R4 is -H, -N02, cyano, substituted or unsubstituted lower alkyl, substituted or unsubstituted alkoxy, halogen, -OH, -C (O) (R10) 2, -COOH, -NH2, -OC (O) - N (R10) 2; R5 is substituted or unsubstituted lower alkyl, substituted or unsubstituted alkoxy or substituted or unsubstituted alkenyl; X is substituted or unsubstituted phenyl, substituted or unsubstituted pyridine, substituted or unsubstituted pyrrolidine, substituted or unsubstituted imidazole, substituted or unsubstituted naphthalene, substituted or unsubstituted thiophene, or substituted or unsubstituted cycloalkyl; each time Rg appears, independently -H or substituted or unsubstituted lower alkyl; and each time Rio is listed is, independently -H or substituted or unsubstituted lower alkyl. In another embodiment, the representative compounds have the formula: and the salts, solvates, or hydrates accepted for pharmaceutical use thereof, wherein: R1 and R2 are independent from each other, -H, -CN, substituted or unsubstituted lower alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl , -COOH, -C (O) -lower alkyl, -C (O) -lower alkyl, C (0) -N (R9) 2, substituted or unsubstituted aryl, or heterocycle; each time one of the radicals Ra appears, R ^ ,, Rc and Rd is, independently of the others, -H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl , substituted or unsubstituted alkoxy, halogen, cyano, -N02, -OH, -OPO (OH) 2, -N (R9) 2, -OC (0) -R? o, -OC (O) -R10-N (Ri0) 2, -C (0) N (R? O) 2, -NHC (O) -Rio, -NHS (O) 2 -R? 0, -S (O) 2 -R10, -NHC (0 ) NH-R? O, -NHC (O) N (Rio) 2, -NHC (O) NHSO2-R? 0, -NHC (O) -Ri0-N (R10) 2, -NHC (O) CH ( R10) (N (R9) 2) or -NHC (O) -R? 0 ~ NH2; R3 is -H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, -N02, -OH, -OPO (OH) 2, -N (Rg) 2, -OC (O) -Rio, -OC (OJR? ON (R? 0) 2, -C (O) N (R? 0) 2, -NHC (O) -Rio , -NHS (O) 2-R10, -S (O) 2 -R10, -NHC (0) NH-R? O, -NHC (O) N (Rio) 2, -NHC (O) NHSO2-R? 0, -NHC (O) -R10-N (R10) 2, -NHC (O) CH (Rio) (N (R9) 2) or -NHC (O) -R10-NH2; or R3 with Ra or R4, together they form -OC (R? 6R? 7) -O- or -0 ~ (C (R? 5R? 7)) 2-0-; R4 is -H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, -N02, -OH, -0P0 (0H) 2, -N (R9) 2, -OC (O) -R10, -OC (O) -R? ON (R? 0) 2 -C (0) N (R? O) 2, -NHC (O) -Rio, -NHS (O) 2 -R10 / -S (O) 2-R? 0, -NHC (0) NH-R? O, -NHC (O) N (R10) 2, -NHC (O) NHSO2-R? 0, -NHC (0) -R? ON (R10 ) 2, -NHC (O) CH (Rio) (N (R9) 2) or -N HC (O) -R? 0-NH2; R5 is -H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, -N02, -OH, ~OPO (OH) 2, -N (R9) 2, -OC (O) -Rio, -OC (O) -RlO-N (R? O) 2 / -C (O) N (R10) 2, -NHC (O) - Rio, -NHS (O) 2-R? O, -S (0) 2-R? O, -NHC (0) NH-R? O, -NHC (O) N (Rio) 2, -NHC (O NHSO2-R? 0, -NHC (0) -R? Or N (R? O) 2 / -NHC (O) CH (R10) (N (R9) 2) or -NHC. { O) -R10-NH2; Re is -H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, -N02, -OH, -OPO (OH) 2, -N (Rg) 2, -OC (O) -Rio, -OC (O) -RlO-N (R? O) 2, -C (0) N (R? O) 2, -NHC (O ) -Rio, -NHS (O) 2-R? 0, -S (0) 2-R? O / -NHC (0) NH-R? O, -NHC (O) N (R? O) 2 / -NHC (O) NHS02-Rio, -NHC (0) -R? ON (R? O) 2 / -NHC (O) CH (Rio) (N (R9) 2) or -NHC (O) -R? 0-NH2; R7 is -H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, -N02, -OH, -OPO (OH) 2, -N (R9) 2, -OC (O) -Rio, -OC (O) -Rlo-N (R? O) / -C (O) N (R10) 2, -NHC (O) -Rio , -NHS (O) 2-R? O, -S (0) 2-R? O, -NHC (0) NH-R? O, -NHC (O) N (Rio) 2, -NHC (O) NHS02-R? O, -NHC (0) -R? ON (R? O), -NHC (O) CH (Rio) (N (R9) 2) OR -NHC (O) -R10-NH2; R8 is -H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, -N02, -OH, -OPO (OH) 2, -N (Rg) 2, -OC (O) -Rio, -OC (O) -RlO-N (R? O) 2, -C (0) N (R? O) 2, -NHC (O ) -Rio, -NHS (O) 2-R? 0, -S (0) 2-R? O, -NHC (0) NH-R? O, -NHC (O) N (Rio) 2, -NHC (O) NHS02-R? O, -NHC (0) -R? ON (R? 0) 2, -NHC (O) CH (Rio) (N (R9) 2) or -NHC (O) -R? 0-NH2; or R3 with Ra or R4, together form -OC (R16 17) "O- or -0- (C (R? 6Ri7)) 2-0-; each time R9 appears, it is, independently of the others, -H , substituted or unsubstituted lower alkyl or substituted or unsubstituted cycloalkyl, each time Rio appears is, independently of the other substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted lower hydroxyalkyl or Rio and a nitrogen to which it is attached forms a substituted or unsubstituted heterocycle, or Rio is -H where appropriate, and each time a radical Rig and R? 7 appear, independent of each other, -H or halogen.

The compounds of the invention can be purchased commercially or prepared according to the methods described in the patents or patent publications described herein. Moreover, the optically pure compounds can be synthesized asymmetrically or can be resolved using the known resolving agents or chiral columns as well as other normal synthetic organic chemistry techniques.

As used herein, and unless otherwise indicated, the term "salt accepted for pharmaceutical use" includes non-toxic acid and basic addition salts of the compound to which the term refers. toxic, acceptable may be those obtained from organic and inorganic acids or bases known in the art, including, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, tartaric acid, lactic acid, acid succinic acid, citric acid, malic acid, maleic acid, sorbic acid, aconitic acid, salicylic acid, phthalic acid, embolic acid, enanthic acid and the like.

The acidic compounds can form salts with different bases accepted for pharmaceutical use. The bases that can be used to prepare accepted basic addition salts for pharmaceutical use of such acidic compounds are those which form non-toxic base addition salts, ie, the salts containing cations accepted for pharmaceutical use as they can be, but are not they limit to, salts of alkaline metals or alkaline earth metals and the salts of calcium, magnesium, sodium, or potassium in particular. Suitable organic bases can be, but are not limited to, N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine (N-methylglucamine), lysine and procaine.

When used herein, and unless otherwise indicated, the term "prodrug" means a derivative of a compound that can be hydrolyzed, oxidized or otherwise reacted under biological conditions (in vi tro or in vivo) to provide the compound. Examples of the prodrugs may be, but are not limited to, those derived from selective cytokine inhibitor drugs, which contain biohydrolyzable portions such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides and biohydrolyzable phosphate analogues. Other examples of prodrugs may be those derived from a selective cytokine inhibitor drug containing portions -NO, -NO2, -ONO or -ONO2. Prodrugs can usually be prepared using well-known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery, 172-178, 949-982 (Manfred E. Wolff ed., 5th edition 1995), and Design of Produgs ( H. Bundgaard ed., Elselvier, New York 1985).

When used herein, and unless otherwise indicated, the terms "biohydrolyzable amide", "biohydrolyzable ester", "biohydrolyzable carbamate", "biohydrolyzable carbonate", "biohydrolyzable ureide", "biohydrolyzable phosphate" means an amide , ester, carbamate, carbonate, ureide or phosphate, respectively, of a compound that: 1) does not interfere with the biological activity of the compound, but can provide that compound with advantageous in vivo properties, such as uptake, duration of action or initiation Of action; or 2) is biologically inactive but is converted in vivo into the biologically active compound. Examples of the biohydrolyzable esters include, but are not limited to, lower alkyl esters, lower acyloxyalkyl esters (such as esters of acetoxy ethyl, acetoxyethyl, aminocarbonyloxy ethyl, pivaloyloxymethyl and pivaloyloxyethyl), lactonyl esters (as may be phthalidyl and thiophthalidyl esters), lower alkoxyacyloxyalkyl esters (such as esters of methoxycarbonyloxy ethyl, ethoxycarbonyloxyethyl, and isopropoxycarbonyloxyethyl), alkoxyalkyl esters, choline esters, and acylamino alkyl esters (such as acetarabid methyl esters). Examples of the biohydrolyzable amides may be, but are not limited to, lower alkyl amides, alpha-amino acid amides, alkoxyacyl amides and alkylaminocarbonyl amides. Examples of the biohydrolyzable carbamates may be, but are not limited to, lower alkylamides, substituted ethylenediamines, amino acids, hydroxyalkylamines, heterocyclic and heteroaromatic amines and polyether amines.

Some selective cytokine inhibitory drugs contain one or more chiral centers, and may exist as racemic mixtures of enantiomers or mixtures of diastereomers. This invention comprises the use of the stereomerically pure forms of these compounds, as well as the use of mixtures of these forms. For example, mixtures containing equal or equivalent amounts of the enantiomers of the selective cytokine inhibitory drugs can be used in the methods and compositions of the invention. The purified (R) or (S) enantiomers of the specific compounds described herein can be used practically free of their other enantiomer.

When used herein, and unless otherwise indicated, the term "stereo-purely pure" means a composition that contains a stereoisomer of one compound and is substantially free of the other stereoisomer of that compound. For example, a stereomerically pure composition of a compound having a chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure, common compound contains more than about 80% by weight of a stereoisomer of the compound and less than about 20% by weight of the other stereoisomer of the compound. More preferably, more than about 90% by weight of a stereoisomer of the compound and less than about 10% by weight of the other stereoisomer of the compound, even more preferably more than about 95% by weight of a stereoisomer of the compound and less than about 5% by weight of the other stereoisomer of the compound and more preferably, more than about 97% by weight of a stereoisomer of the compound and less than about 3% by weight of the other stereoisomer of the compound.

When used herein, and unless otherwise indicated, the term "stereomerically enriched" means a composition that contains more than about 60% by weight of a stereoisomer of a compound, preferably more than about 70% by weight, more preferably 80% by weight of a stereoisomer of a compound.

When used herein, and unless otherwise mentioned, the term "enantiomerically pure" means a stereomerically pure composition of a compound having a chiral center. Likewise, the term "enantiomerically enriched" means a stereomerically pure composition of a compound having a chiral center.

It should be noted that if there is a difference between a structure represented and a name given to this structure, the structure represented must be taken more into account. Furthermore, if the stoichiometry of a structure or a part of a structure is not indicated with, for example, bold or dashed lines, the structure or part of the structure must be construed as comprising all stereoisomers thereof. 4. 2 SECONDS ACTIVE INGREDIENTS As already mentioned, it is possible to use a second ingredient or active agent in the methods and compositions of the invention together with selective cytokine inhibitory drugs, particularly the traditional agents or therapeutics that are used to treat or manage disorders of the cytokine. Central Nervous System. The second specific active agents also stimulate the division and differentiation of erythroid progenitors committed in cells in vitro or in vivo.

In one embodiment, it is possible to administer a second active ingredient with selective cytokine inhibitory drugs. In one embodiment, the second active ingredient is a dopamine agonist or antagonist, for example, but not limited to, Levodopa, L-DOPA, combinations of carbidopa cocaine, a-methyltyrosine, reserpine, tetrabenazine, benzotropin, pargyline, mesylate, fenodolpam, cabergoline, pramipexole dihydrochloride, ropinorol, amantadine hydrochloride, selegiline hydrochloride, carbidopa, pergolide mesylate, Sinemet CR or Symetrel.

In another embodiment, the second active ingredient that is administered with a selective cytokine inhibitor drug is an MAO inhibitor, for example, but not limited to, iproniazid, clorgyline, phenelzine and isocarboxazide.

In another embodiment, a second active ingredient that is administered with a selective cytokine inhibitory drug is a COMT inhibitor, for example, but is not limited to tolcapone and entacapone.

In another embodiment, the second active ingredient that is administered with a selective cytokine inhibitor drug is an acetylcholinesterase inhibitor, for example, but not limited to, tacrine, donepezil, rivastigmine, physystigmine [sic] salicylate, sulfate physostigmine, physostigmine bromide, meostigmine bromide, neostigmine methylsulfate, ambenonim chloride, edrophonium chloride pralidoxime chloride, obidoxime chloride, triiaedoxirane bromide, diacetyl monoxime, endophonium, pyridostigmine and ecarium.

In still another embodiment, the second active ingredient that is administered with a selective cytokine inhibitory drug is an anti-inflammatory agent including, but not limited to, naproxen sodium, diclofenac sodium, potas diclofenac, celecoxib, sulindac, oxaprozin, diflunisal, etodolaco, eloxicam, ibuprofen, ketoprofen, nabumetone, refecoxib, methotrexate, leflunomide, sulfasalazine, gold salts, immunoglobulin RHQ-D, mycophenolate mofetil, cyclosporine, azathioprine, tacrolide, basilixi ab, daclizumab, salicylic acid, acid acetylsalicylic, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazine, acetaminophen, indomethacin, sulindac, mefenamic acid, meclofenamate sodium, tolmetin, ketorolac, diclofenac, flurbinprofen, oxaprozin, piroxicam, meloxicam, ampiroxicam, droxica, pivoxicam, tenoxicam, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, apazone, zileuton, aurothioglucose, gold sodium thiomalate, auranofin, meto trexate colchicine, allopurinol, probenecid, sulfinpyrazone and benzbromarone or betamethasone and other glucocorticoids.

In yet another embodiment, the second active ingredient that is administered with a selective cytokine inhibitory drug is an antiemetic agent, for example, but not limited to, etoclopromide, domperidone, prochlorperazine, promethazine, chlorpromazine, trimethobenzamide, ondansetron, granisetron. , hydroxyzine, acetyleucine monoethanolamine, alizapride, azasetron, benzquinamide, bietanautin, bromopride, bluclizine, clebopride, cyclizine, dihydrinate, diphenidol, dolasetron, meclizine, metalatal, etopimazine, nabilon, oxyperdyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinol, thiethylperazine, thioproperazine , tropisetron and mixtures of these. 4. 3. METHODS OF TREATMENT AND HANDLING The methods of this invention comprise methods for the prevention, treatment and / or management of central nervous system disorders. When used herein, unless otherwise indicated, the term "prevention" includes, but is not limited to, the inhibition or avoidance of symptoms associated with central nervous system disorders. Central nervous system disorders may be, but are not limited to, Parkinson's disease; Alzheimer's disease, mild cognitive impairment, depression, long-term memory loss, amyotrophic lateral sclerosis (ALS), CNS trauma; hypokinetic disorders, bradykinesia, movement promotion; difficulty of movement; deteriorate of dexterity; hypophony; monotonic voice; muscle stiffness, facial expression inexpressive; decreased flicker; stooped posture; decreased swing of the arms when walking; micrography; Parkinsonian tremor; parkinsonian gait; postural instability; hurried march; rigidity of movement; cognitive disorders, mood, sensation, sleep or autonomic function; dementia and sleep disturbances. When used herein, unless otherwise indicated, the term "treatment" refers to the administration of a composition after the onset of the symptoms of central nervous system disorders, while "prevention" refers to to administration before the onset of symptoms, particularly in patients at risk for central nervous system disorders or a related disorder. When used herein, and unless otherwise indicated, the term "management" includes the prevention of the reappearance of the symptoms of central nervous system disorders in a patient who has suffered disorders of the central nervous system, the prolongation of the time in which the symptoms remain in remission in a patient who has suffered central nervous system disorders and / or the prevention of the incidence of central nervous system disorders in patients at risk of suffering central nervous system disorders.

In a specific modality, the central nervous system disorder that could be prevented, treated and / or managed is Parkinson's disease, Alzheimer's disease, mild cognitive impairment, dementia, depression, long-term memory loss, amyotrophic lateral sclerosis. (ALS) or CNS trauma.

The invention comprises methods for the treatment or prevention of disorders of the central nervous system, preferably Parkinson's disease or Alzheimer's disease. In one embodiment, the methods of the invention are used to treat or prevent disorders related to movement, including but not limited to, slow performance or bradykinesia, lack of movement or akinesia, movement disorders that impair fine motor control and finger skills, and other manifestations of bradykinesia such as, but not limited to, hypophonia and monotonic speech. In another embodiment, the methods of the invention are used to treat or prevent disorders related to muscle rigidity, including but not limited to, uniform increase in resistance to passive movement, interruptions to passive movement, and combinations of stiffness and dystonia. In a specific embodiment, the methods of the invention are used to treat inflammation associated with Parkinson's disease or related. In still another embodiment of the invention, disorders resembling parkinsonian tremors are treated or prevented by the methods of the invention, including, but not limited to, tremors of the face, jaw, tongue, posture and other tremors. that are present at rest and that decrease during movement. In another embodiment, the methods of the invention are used to treat or prevent gait disorders that include, but it is not limited to, those that resemble the Parkinsonian gait, shuffle walking, short steps, tendency to turn en bloc and hurried gait. In another embodiment of the invention, non-motor symptoms are treated or prevented using the methods of the invention which include, but are not limited to, alterations in mood, cognition, sensation, sleep, dementia and depression. In another embodiment of the invention, secondary forms of parkinsonism are treated or prevented by the methods of the invention including, but not limited to, drug-induced parkinsonism, vascular parkinsonism, multiple system atrophy, progressive supranuclear palsy, disorders with primary tau pathology, degeneration of cortical basal ganglia, parkinsonism with dementia, hyperkinetic disorders, chorea, Huntington's disease, dystonia, Wilson's disease, Tourette's syndrome, essential tremor, myoclonus and slow-moving disorders. In another embodiment of the invention, other disorders of the central nervous system are treated or prevented by the methods of the invention including, but not limited to, Alzheimer's disease, mild cognitive impairment, amyotrophic lateral sclerosis (ALS) and trauma of the SNC.

The methods encompassed by this invention consist of administering one or more selective cytokine inhibitory drugs, or a salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, accepted for pharmaceutical use, to a patient (may be a human) suffer, or probably suffer, disorders of the central nervous system.

Another method is to administer: 1) a selective cytokine inhibitory drug, or a salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof accepted for pharmaceutical use, and 2). a second active agent or active ingredient. Examples of selective cytokine inhibitor drugs are described herein (see section 4.1); and the second active agents are also described herein (see section 4.2).

The administration of selective cytokine inhibitory drugs and the second active agent to a patient can occur at the same time or in succession by the same or different administration route. The suitability of a specific route of administration employed for a particular active agent will depend on the active agent itself (for example, if it can be administered orally without decomposing before entering the circulation) and the disease being treated. A preferred route of administration for a selective cytokine inhibitor drug is the oral route. Preferred routes of administration for the second active agents or active ingredients of the invention are known to those skilled in the art.

In one embodiment of the invention, the range of the recommended daily dose of a selective cytokine inhibitor drug for the conditions described herein is within the range of from about 1 mg to about 10,000 mg per day, administered as a single dose once a day or preferably in divided doses throughout the day.

More specifically, the daily dose is administered twice a day in evenly divided doses. Specifically, a daily dose range should be from about 1 mg to about 5,000 mg per day, more specifically, between about 10 mg and about 2500 mg per day, between about 100 mg and about 800 mg per day, between about 100 mg and approximately 1200 mg per day or between around 25 mg and around 2500 mg per day. To manage a patient, treatment should be started at a lower dose, perhaps around 1 mg to about 2500 mg, and should be increased if necessary to approximately 200 mg to about 5000 mg per day as a single dose or in divided doses. , depending on the patient's general response. In a particular embodiment, 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide can preferably be administered in an amount of about 400, 800 , 1200, 2500, 5000 or 10,000 mg per day in two divided doses.

In another embodiment, a selective cytokine inhibitory drug is administered together with a second active agent. The second active agent is administered orally, intravenously or subcutaneously and once or twice a day in an amount of from about 1 to about 1000 mg, from about 5 to about 500 mg, from about 10 to about of 350 mg or from about 50 to about 200 mg. The specific amount of the second active agent will depend on the specific agent being used, the disorder being treated or handled, the severity and stage of the central nervous system disorder and the amount or amounts of a cytokine inhibitory drug, selective agents and additional, optional assets that are administered concomitantly to the patient.

In some embodiments, the prophylactic or therapeutic agents of the invention are administered in a cyclic fashion to a patient. The cyclic treatment consists in the administration of a first agent for a time, followed by the administration of the agent and / or the second agent for a time and repeating this successive administration. Cyclic treatment can reduce the development of resistance to one or more of the therapies, avoid or reduce side effects of one of the therapies and / or improve the efficacy of the treatment.

In a preferred embodiment, the prophylactic or therapeutic agents are administered in a cycle of approximately 24 weeks, approximately once or twice a day. A cycle may consist of the administration of a therapeutic or prophylactic agent and at least one (1) or three (3) weeks of rest. The number of cycles that are administered will be from about 1 to about 12 cycles, most commonly from about 2 to about 10 cycles and more commonly from about 2 to about 8 cycles. 4. 4. PHARMACEUTICAL COMPOSITIONS AND INDIVIDUAL UNITARY DOSAGE FORMS Pharmaceutical compositions can be used in the preparation of individual unit dosage forms. The pharmaceutical compositions and dosage forms of the invention contain a selective cytokine inhibitory drug, or a salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, accepted for pharmaceutical use. The pharmaceutical compositions and dosage forms of the invention may also contain one or more excipients.

The pharmaceutical compositions and dosage forms of the invention may also contain one or more additional active ingredients. Accordingly, the pharmaceutical compositions and dosage forms of the invention contain the active ingredients described herein (e.g., a selective cytokine inhibitory drug, or a salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, accepted for pharmaceutical use, and a second active ingredient). Examples of additional, optional active ingredients are described herein (see for example section 4.2).

The individual unit dosage forms of the invention are suitable for oral, mucosal (eg nasal, sublingual, vaginal, buccal or rectal), or parenteral (eg, subcutaneous, intravenous, bolus, intramuscular or intraarterial), transdermal or transcutaneous to a patient. Examples of the dosage forms may be, but are not limited to: tablets, caplets, capsules such as soft gelatin capsules; cachets, troches, pills, dispersions, suppositories, powders, aerosols (for example nasal sprays or inhalers); gels, liquid dosage forms suitable for oral or mucosal administration to a patient such as suspensions (for example, aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs; liquid dosage forms suitable for parenteral administration to a patient and sterile solids (eg, crystalline or amorphous solids) that can be resuspended or reconstituted to obtain liquid dosage forms suitable for parenteral administration to a patient.

The composition, configuration and type of dosage forms of the invention will vary depending on the use. For example, a dosage form that is used in the acute treatment of a disease may contain larger amounts of one or more of the active ingredients contained therein compared to a dosage form used in the chronic treatment thereof. disease. Likewise, a parenteral dosage form may contain smaller amounts of one or more active ingredients that it contains compared to an oral dosage form that is used to treat the same disease. These and other forms in which the specific dosage forms encompassed by this invention will vary will be apparent to those skilled in the art. See for example Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing, Easton PA (1990).

The pharmaceutical compositions and the common dosage forms contain one or more excipients. Suitable excipients are well known to those skilled in the art and non-limiting examples of suitable excipients are provided herein. Whether a specific excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on various factors well known in the art including, but are not limited to, the way in which the dosage form is administered to the patient. For example, oral dosage forms as tablets may contain excipients not suitable for use in parenteral dosage forms. The suitability of a specific excipient will also depend on the specific active ingredients in the dosage form. For example, the decomposition of some active ingredients can be accelerated by some excipients such as lactose, or when exposed to water. Active ingredients containing primary or secondary amines are particularly susceptible to this accelerated decomposition. Accordingly, this invention comprises pharmaceutical compositions and dosage forms that contain little, if any, lactose other mono- or disaccharides [sic]. When used herein, the term "lactose free" means that the amount of lactose present, if any, is insufficient to significantly increase the rate of degradation of an active ingredient.

The lactose-free compositions of the invention may contain excipients well known in the art and are listed, for example, in the US Pharma Copeia (USP) 25-NF20 (2002). In general, the lactose-free compositions contain active ingredients, a binder / diluent, and a lubricant in compatible and accepted amounts for pharmaceutical use. Preferred lactose-free dosage forms contain active ingredients, microcrystalline cellulose, pregelatinized starch and magnesium stearate.

This invention also comprises anhydrous pharmaceutical compositions and dosage forms containing active ingredients, since water can facilitate the degradation of some compounds. For example, the addition of water (for example 5%) is widely accepted in pharmaceutical techniques as a means to simulate long-term storage to determine the characteristics of a shelf life or the stability of the formulations over time. See, for example, Jens T. Carstensen, Drug Stability: Principies & Practice, 2nd edition, Marcel Dekker, NY, NY, 1995, pp. 379-80. In effect, water and heat accelerate the decomposition of some compounds. Thus, the effect of water in a formulation can be of great importance since moisture is commonly encountered during the manufacture, handling, packaging, storage, shipping and use of the formulations.

The anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture content ingredients and low humidity conditions. Pharmaceutical compositions and dosage forms containing lactose and at least one active ingredient containing a primary or secondary amine are preferably anhydrous if considerable contact with moisture is expected during manufacture, packaging and storage.

An anhydrous pharmaceutical composition must be prepared and stored so that its anhydrous nature is maintained. Accordingly, the anhydrous compositions are preferably packaged using known materials to avoid exposure to water so that they can be included in convenient kits or formulation equipment. Examples of suitable packaging can be, but are not limited to, hermetically sealed aluminum sheets, plastics, unit dose packs (eg vials), blister packs and strip packs.

The invention further comprises pharmaceutical compositions and dosage forms containing one or more compounds that reduce the rate at which the active ingredient decomposes. These compounds, which are known herein as "stabilizers", include, but are not limited to, antioxidants such as ascorbic acid, pH buffers or saline buffers [sic].

Like the amounts and types of excipients, the specific amounts and types of active ingredients in a dosage form may differ depending on factors such as, but not limited to, the route by which they are administered to patients. However, the common dosage forms of the invention contain a selective cytokine inhibitory drug, or a salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, accepted for pharmaceutical use, in an amount from about 1 to about 1200. mg. Common dosage forms contain a selective cytokine inhibitory drug, a salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, accepted for pharmaceutical use, in an amount of about 1, 2, 5, 10, 25, 50 , 100, 200, 400, 800, 1,200, 2,500, 5,000 or 10,000 mg. In a particular embodiment, a preferred dosage form contains a 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide in a quantity of about of 400, 800 or 1,200 mg. The common dosage forms contain the second active ingredient in an amount of 1 to about 1000 mg, from about 5 to about 500 mg, from about 10 to about 350 mg or from about 50 to about 200 mg. Of course, the specific amount of the second active ingredient will depend on the specific agent being used, the disorder being treated or handled and the amount and amounts of a selective cytokine inhibitory drug and any additional, optional active agents that are administer concomitantly to the patient. 4. 4.1 ORAL DOSAGE FORMS The pharmaceutical compositions of the invention which are suitable for oral administration may be presented as small dosage forms, such as, but not limited to, tablets (eg chewable tablets), caplets, capsules, and liquids. (like syrups flavored). These dosage forms contain predetermined amounts of active ingredients and can be prepared by pharmacy methods well known to those skilled in the art. See, in general, Remington's, Pharmaceuticals Sciences, 18th edition Mack Publishing, Easton PA (1990).

The common oral dosage forms of the invention are prepared by combining the active ingredients in an intimate mixture with at least one excipient according to the traditional pharmaceutical composition techniques. The excipients can take a wide variety of forms depending on the form of preparation desired for administration. For example, suitable excipients for use in the liquid dosage form or oral aerosol include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives and coloring agents. Examples of excipients suitable for use in solid oral dosage forms (eg powders, tablets, capsules or caplets) can be, but are not limited to, starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders. and disintegrating agents.

Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid excipients are employed. If desired, the tablets can be coated by the normal aqueous or non-aqueous techniques. These dosage forms can be prepared by any pharmacy method. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then molding the product into the desired presentation, if necessary.

For example, a tablet can be prepared by compression or molding. Compressed tablets can be prepared by compressing in a convenient machine the active ingredients in a free-flowing form such as powders or granules, optionally mixed with an excipient. The molded tablets can be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

Examples of the excipients that may be used in the oral dosage forms of the invention may be, but are not limited to, binders, diluents, disintegrants and lubricants. Suitable binders for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and their derivatives (for example ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropyl methyl cellulose (for example the numbers 2208, 2906 , 2910), microcrystalline cellulose and mixtures thereof.

Suitable forms of microcrystalline cellulose include, but are not limited to, materials marketed as AVICEL-PH-101, AVICEL-PH-103, AVICEL-RC-581, AVICEL-PH-105, (available from FMC Corporation), American Viseóse Division, sales Avicel, Marcus Hook, PA), and mixtures of these. A specific binder is a mixture of microcrystalline cellulose and sodium carboxymethylcellulose marketed as AVICEL-RC-581. The suitable and low moisture anhydrous additives or additives can be AVICEL-PH-103 ™ and Starch 1500 LM.

Examples of suitable diluents for use in the pharmaceutical compositions and dosage forms described herein include, but are not limited to, talc, calcium carbonate (eg, granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch and mixtures thereof. The binder or diluent in the pharmaceutical compositions of the invention will usually be present in amounts of from about 50 to about 99% by weight of the pharmaceutical composition or dosage form.

The disintegrants are used in the compositions of the invention to allow the tablets to disintegrate if exposed to an aqueous environment. Tablets that contain too much disintegrant can disintegrate in storage, while those that contain too little can not disintegrate at the desired rate or in the desired conditions. Thus, a sufficient amount of disintegrant that is not too much or too little to detrimentally alter the release of the active ingredients should be used to form the solid oral dosage forms of the invention. The amount of disintegrant used varies based on the type of formulation, and can be readily ascertained by those skilled in the art. Common pharmaceutical compositions contain from about 0.5 to about 15% by weight of disintegrant, preferably from about 1 to about 5% by weight of the disintegrant.

Disintegrants that can be used in the pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, glycolate starch sodium, potato starch or tapioca, other starches, pregelatinized starch, other starches, clays, other algin, other celluloses gums and mixtures thereof.

Lubricants that can be used in the pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (such as peanut oil, cottonseed oil, sunflower oil, cessation oil, olive oil, corn oil and soybean oil), stearate of zinc, ethyl oleate, ethyl laureate agar and mixtures thereof. Other lubricants may be, for example, a siloid silica gel (AEROSIL200, manufactured by WR Grace Co. of Baltimore, MD), a synthetic silica coagulated aerosol (marketed by Degusta Co. of Plano, TX), CAB-O- SIL (a pyrogenic silicon dioxide product marketed by Cabot Co. of Boston, MA) and mixtures thereof. If used, lubricants are normally used in an amount of less than about 1% by weight of the pharmaceutical compositions or dosage forms in which they are incorporated.

A preferred oral solid dosage form of the invention contains a selective cytokine inhibitory drug, anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica and gelatin. 4. 4.2 DOSAGE FORMS FOR DELAYED DELIVERY The active ingredients of the invention can be administered by controlled release means or by delivery devices that are well known to those skilled in the art. Examples may be, but are not limited to, those described in US Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719; 5,674,533; 5,059,595, 5,591,767; 5,120,548; 5,073,543; 5,639,476;, 5,354,556 and 5,733,566, each of which is incorporated herein by reference. These dosage forms can be used to offer the slow or controlled release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymeric matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres or a combination of these to obtain the desired release profile in different proportions. Suitable controlled release formulations, known to those skilled in the art include those described herein, and can be readily selected for use with the active ingredients of the invention. The invention thus comprises individual unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps and caplets that are adapted for controlled release.

All controlled release pharmaceutical products have a common goal of improving medicinal therapy over that obtained by their non-controlled counterparts. In theory, the use of a controlled release preparation optimally designed in medical treatments is characterized by a minimum of the active substance used to cure or control the condition in a minimum amount of time. The advantages of controlled release formulations include prolonged drug activity, reduced dosing frequency and increased compliance or patient compliance. In addition, controlled release formulations can be used to affect the time of onset of action or other characteristics such as concentrations of the drug in blood, and thus can modify the incidence of side effects (eg adverse).

Most controlled-release formulations are designed to initially release a quantity of drug (active ingredient) that soon produces the desired therapeutic effect, and little by little and continuously release the other amounts of medication to maintain this level of effect therapeutic or prophylactic for a long time. To maintain this constant level of medication in the body, the drug must be released from the dosage form at a rate that replaces the amount of drug that is being metabolized and excreted from the body. The controlled release of the active ingredient can be stimulated by some states such as, but not limited to, pH, temperature, enzymes, water or other conditions or physiological compounds. 4. 4.3 PARENTERAL DOSAGE FORMS Parenteral dosage forms can be administered to patients by different routes including, but not limited to, subcutaneous, intravenous (including plunger injection), intramuscular, or intraarterial. Because their administration normally derives the patients' natural defenses against contaminants, the parenteral dosage forms are preferably sterile or can be sterilized before being administered to a patient. Examples of parenteral dosage forms can be, but are not limited to, ready-to-inject solutions, anhydrous powders ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, ready-for-injection suspensions and emulsions.

Suitable vehicles that can be used to obtain the parenteral dosage forms of the invention are well known to those skilled in the art. Examples may be, but are not limited to: water for injection USP; aqueous vehicles such as, but not limited to, sodium chloride injection, Ringer's injection, dextrose injection, dextrose and sodium chloride injection, lactose-free Ringer's injection; miscible vehicles in water such as, but not limited to, ethyl alcohol, polyethylene glycol and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate and benzyl benzoate.

Compounds that increase the solubility of one or more of the active ingredients described herein may also be incorporated into the parenteral dosage forms of the invention. For example, it is possible to use cyclodextrin and its derivatives to increase the solubility of a selective cytokine inhibitor drug and its derivatives. See, for example, US Patent No. 5,134,127, which is incorporated herein by reference. 4. 4.4. TYPICAL AND MUCOUS DOSING FORMS The topical and mucosal dosage forms of. The invention may be, but is not limited to, sprays, aerosols, solutions, emulsions, suspensions or other forms known to those skilled in the art. See, for example, Remington's Pharmaceuticals Sciences, 16th and 18th edition, Mack Publishing, Easton PA (1980 &1990); and Introduction to Pharmaceuticals Dosage Forms, 4th Edition, Lea & Febiger, Philadelphia (1985). Suitable dosage forms for treating mucosal tissues within the oral cavity can be formulated as mouth rinses or as oral gels.

Suitable excipients (e.g. carriers and diluents) and other materials that can be used to provide topical and mucosal dosage forms comprised by this invention are well known to those skilled in the pharmaceutical art and depend on the specific tissue to which a a certain composition or pharmaceutical dosage form. Taking this into account, common excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butan-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil and mixtures of these to form solutions, emulsions or gels, which are non-toxic and accepted for pharmaceutical use. Moisturizers may also be added to pharmaceutical compositions and dosage forms if desired. Examples of these additional ingredients are well known in the art. See, for example, Remington's Pharmaceuticals Sciences, 16th and 18th edition, Mack Publishing, Easton PA (1980 &1990).

The pH of a pharmaceutical composition or dosage form can also be adjusted to improve the delivery of one or more active ingredients. In the same way, the polarity of a solvent carrier, its ionic concentration or tonicity can be adjusted to improve the supply. Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously modify the hydrophilicity or lipophilicity of one or more active ingredients to improve delivery. In this regard, stearates can contribute as a lipid vehicle for the formulation, as an emulsifying or surfactant agent and as a feed improver or penetration enhancing agent. It is possible to use different salts, hydrates or solvates of the active solvents to further adjust the properties of the resulting composition. 4. 4.5 EQUIPMENT In general, the active ingredients of the invention are preferably not administered to a patient at the same time and by the same route of administration. This invention, therefore, comprises the equipment that, when used by the physician, can simplify the administration of adequate amounts of active ingredients to a patient.

A common kit of the invention comprises a dosage form of a selective cytokine inhibitory drug, or a salt, solvate, hydrate, stereoisomer, prodrug or clathrate, accepted for pharmaceutical use or the like. The equipment comprised by this invention may also contain other active ingredients. Examples of the other active ingredients may be, but are not limited to, those described herein (see for example section 4.2).

The equipment of the invention may further comprise devices that are used to administer the active ingredients. Examples of these devices may be, but are not limited to, syringes, drip bags, patches and inhalers.

The kits of the invention may further contain vehicles accepted for pharmaceutical use which may be used to administer one or more active ingredients. For example, if an active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the equipment may contain a sealed container with a convenient vehicle in which the active ingredient can be dissolved to form a sterile, particle-free solution. , which is suitable for parenteral administration. Examples of vehicles accepted for pharmaceutical use may be, but are not limited to: water for injection USP; aqueous vehicles such as, but not limited to, sodium chloride injection, Ringer's injection, dextrose injection, dextrose and sodium chloride injection, and lactose-free Ringer's injection; miscible vehicles in water such as, but not limited to, ethyl alcohol, polyethylene glycol and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate and benzyl benzoate.

. EXAMPLES The following studies are intended to further illustrate the invention without limiting its scope. . 1 PHARMACOLOGICAL AND TOXICOLOGICAL STUDIES A series of non-clinical pharmacological and toxicological studies was carried out to support the clinical evaluation of selective cytokine inhibitor drugs in humans. These studies are conducted in accordance with internationally recognized guidelines for the design of the study and in compliance with the Good Laboratory Practice (GLP) requirement, unless otherwise indicated.

The pharmaceutical properties of the compound 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-l, 3-dihydro-isoindol-2-yl) -propionamide, including comparisons of its activity with thalidomide, were characterized in the in vitro studies. The studies examine the effects of the compound 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-l, 3-dihydro-isoindol-2-yl) -propionamide on the production of various cytokines.

In addition, a pharmacological safety study of the compound 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-l, 3-dihydro-isoindol-2-yl) -propionamide was conducted in dogs and the effects of the compound on ECG parameters as part of three repeated dose toxicity studies in primates. . 2 MODULATION OF CYTOKINE PRODUCTION The inhibition of TNF-a production was investigated in vitro after stimulation with LPS of human PBMC and human whole blood with 3- (3, -dimethoxy-phenyl) -3- ( 1-oxo-l, 3-dihydro-isoindol-2-yl) -propionamide (Muller et al., Bioorg, Med. Chem. Lett 9: 1625-1630, 1999). The IC50's of the compound 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-l, 3-dihydro-isoindol-2-yl) -propionamide were measured to inhibit the production of TNF-a after the LPS stimulation of PBMC (peripheral blood mononuclear cells) and human whole blood.

In vitro studies suggest a profile of pharmacological activity for the compound 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-l, 3-dihydro-isoindol-2-yl) -propionamide which is similar to , but 5 to 50 times more potent than thalidomide. The pharmacological effects of the compound 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-l, 3-dihydro-isoindol-2-yl) -propionamide derived from its action as an inhibitor of the cellular response to trophic signals initiated at the receptor (eg, IGF-1, VEGF, cyclo-oxygenase-2) and other activities. As a result, the compound 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-l, 3-dihydro-isoindol-2-yl) -propionamide suppresses the production of inflammatory cytokines, effects a down-regulation of Adhesion molecules and apoptosis inhibitory proteins (eg cFLIP, cIAP), favors the sensitivity to programmed cell death initiated by the death receptor and suppresses the angiogenic response. . 3 STUDIES OF TOXICOLOGY The effects of the compound 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-l, 3-dihydro-isoindol-2-yl) -propionamide on cardiovascular function were investigated in anesthetized dogs. respiratory Two groups of beagle dogs (2 / sex / group) were used for the study. One group receives three vehicle doses only and the other receives three ascending doses of the compound 3- (3, -dimethoxy-phenyl) -3- (1-oxo-l, 3-dihydro-isoindol-2-yl) -propionamide ( 400,800 and 1200 mg / kg / day). In all cases, the doses of the compound 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-l, 3-dihydro-isoindol-2-yl) -propionamide or the vehicle are administered successively by infusion through the jugular vein at intervals of at least 30 minutes.

The cardiovascular and respiratory changes induced by the compound 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide are minimal at all doses if compare with the vehicle witness group. . 4 STUDIES ON PARKINSON DISEASE The effects of the selective cytokine inhibitor drug in a model of Parkinson's disease were investigated in mice. Male C57 / BL6 mice were injected once a day for 7 days with MPTP (30 mg / kg, i.p.). The selective cytokine inhibitor drug was administered once or twice a day for 14 days. On day 28, the striatum was removed, homogenized in perchloric acid and centrifuged. The supernatant was separated and analyzed for dopamine and other monoamines such as serotonin by reverse phase HPLC and electrochemical detection. The antiparkinson activity of the selective cytokine inhibitor drug was evaluated in comparison to the reference compound, selegiline. . 5 STUDIES ON ALZHEIMER'S DISEASE The effects of the selective cytokine inhibitor drug were investigated in a model of Alzheimer's disease in rat PC12 pheochromocytoma cells. PC12 cells were cultured in the presence of dopamine, dopamine receptor agonist DI, adenosine, the adenosine A2a receptor, nicotine or acetic acid agonist alpha 7 nicotinic receptor and the selective cytokine inhibitor drug. After 24 hours, the cell supernatants were harvested and analyzed for the activity of acetylcholinesterase by the Ellman method (Hawkins and Knittle, Anal Chem. 44: 416-417, 1972). The suppression of acetylcholinesterase activity levels by the selective cytokine inhibitor drug was evaluated in comparison to the tacrine reference compound. . 6 CYCLICAL THERAPEUTICS IN CENTRAL NERVOUS SYSTEM DISORDERS In a specific modality, selective cytokine inhibitor drugs are administered cyclically to patients with central nervous system disorders. The cyclic therapy consists in the administration of a first compound for a time, followed by the administration of the compound and / or the second compound for a time and repeating this successive administration. Cyclic therapy can reduce resistance to one or more of the therapeutic ones, avoid or reduce the side effects of one of the therapies and / or improve the efficacy of the treatment.

In a specific embodiment, the prophylactic or therapeutic compounds are administered in an amount of about 400, 800 or 1200 mg in a cycle of about 24 weeks, about once or twice per day. A cycle may consist of the administration of a therapeutic or prophylactic compound and at least one (1), two (2) or three (3) weeks of rest. The number of cycles administered is from about 1 to about 12 cycles, most commonly from about 2 to about 10 cycles and more commonly from about 2 to about 8 cycles.

For example, on day 1 of a 24-week cycle, the transfusion of a blood product was administered to patients with Parkinson's disease. On day 10, administration of 800 mg / d of 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-l, 3-dihydro-isoindol-2-yl) -propionamide was started.

During day 30, transfusion of a blood product was administered. On day 34, the administration of 800 mg / d of 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-l, 3-dihydro-isoindol-2-yl) -propionamide was interrupted. On day 59 the administration of 400 mg / d of 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-l, 3-dihydro-isoindol-2-yl) -propionamide was started.

The embodiments of the invention described herein are only a sampling of the scope of the invention. The full scope of the invention is better understood with reference to the appended claims.

Claims (27)

1. A method for the treatment or prevention of a central nervous system disorder, which consists of administering to a patient in need of such treatment or prevention an effective therapeutic or prophylactic amount of a selective cytokine inhibitor drug, or a solvate or salt thereof. stereoisomer accepted for pharmaceutical use of this.

2. A method for the management of a central nervous system disorder, which consists in administering to a patient in need of such management an effective prophylactic amount of a selective cytokine inhibitory drug, or a salt, solvate or stereoisomer accepted for pharmaceutical use. of this.

3. The method of claim 1, characterized in that the central nervous system disorder is Parkinson's disease, Alzheimer's disease, light cognitive impairment, amyotrophic lateral sclerosis; CNS trauma; Alzheimer's disease with Parkinsonism; bradykinesia; alkinesia; movement disorder that impairs fine motor control and finger dexterity; hypophonia; speak onotonic; rigidity, dystonia, inflammation associated with Parkinson's disease; tremor of the face, jaw, tongue, or posture; parkinsonian gait, shuffling, short steps, hurried gait; disorders of mood, cognition, sensation or sleep; dementia; depression; loss of long-term memory, drug-induced parkinsonism; vascular parkinsonism; atrophy of multiple systems; progressive supranuclear palsy; disorders with primary tau pathology; degeneration of cortical basal ganglia; parkinsonism with dementia; hyperkinetic disorder; Korea; Huntington's disease; dystonia; Wilson's disease; Tourette syndrome; essential tremor; myoclonus; or a slow-moving disorder.

4. The method of claim 2, characterized in that the central nervous system disorder is Parkinson's disease, Alzheimer's disease; light cognitive impairment; Amyotrophic Lateral Sclerosis; CNS trauma; Alzheimer's disease with Parkinsonism; bradykinesia; alkinesia; movement disorder that impairs fine motor control and finger dexterity; hypophonia; He speaks monotonously; rigidity, dystonia, inflammation associated with Parkinson's disease; tremor of the face, jaw, tongue, or posture; parkinsonian gait, shuffling, short steps, hurried gait; disorders of mood, cognition, sensation or dream-dementia; depression; loss of long-term memory, drug-induced parkinsonism; vascular parkinsonism; atrophy of multiple systems; progressive supranuclear palsy; disorders with primary tau pathology; degeneration of cortical basal ganglia; parkinsonism with dementia; hyperkinetic disorder; Korea; Huntington's disease; dystonia; Wilson's disease; Tourette syndrome; essential tremor; myoclonus; or a slow-moving disorder.

5. The method of claim 3, characterized in that the disorder of the central nervous system is Parkinson's disease.

6. The method of claim 4 characterized in that the disorder of the central nervous system is Parkinson's disease.

7. A method of treating or preventing a central nervous system disorder, which is to administer to a patient in need of such treatment or prevention an effective therapeutic or prophylactic amount of a selective cytokine inhibitor drug, or a solvate salt, or stereoisomer accepted for pharmaceutical use thereof, and an effective therapeutic or prophylactic amount of at least one second active ingredient.

8. A method for managing a central nervous system disorder, which is to administer to a patient in need of such management an effective prophylactic amount of a selective cytokine inhibitor drug, or a solvate or stereoisomer salt accepted for pharmaceutical use thereof, and an effective therapeutic or prophylactic amount of at least one second active ingredient.

9. The method of claim 3, characterized in that the disorder of the central nervous system is Parkinson's disease.

10. The method of claim 12, characterized in that the disorder of the central nervous system is Parkinson's disease.

11. The method of claim 7, characterized in that the second active ingredient is a dopamine agonist, an inhibitor of monoamine oxidase (MAO), a catechol-O-methyltransferase (COMT) inhibitor, amantadine, an anticholinergic, an antiemetic or a anti-inflammatory agent.

12. The method of claim 7, characterized in that the second active ingredient is a dopamine agonist, an inhibitor of monoamine oxidase (MAO), a catechol-O-methyltransferase (COMT) inhibitor, amantadine, an anticholinergic, an antiemetic or a anti-inflammatory agent.

13. The method of any of claims 1, 2, 7 or 8, characterized in that the stereoisomer of a selective cytokine inhibitor drug is an enantiomer.

14. The method of any of claims 1, 2, 7 or 8, characterized in that the selective cytokine inhibitor drug is 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro) -isoindol-2-yl) -propionamide.

15. The method of claim 14, characterized in that the selective cytokine inhibitor drug is the R or S enantiomer of 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-l, 3-dihydro- isoindol-2-yl) -propionamide.

16. The method of any of claims 1, 2, 7 or 8, characterized in that the selective cytokine inhibitory drug is cyclopropanecarboxylic acid. { 2- [1- (3-ethoxy-4-methoxy-phenyl) -2-methanesulfonyl-ethyl] -3-oxo-2,3-dihydro-lH-isoindol-4-yl} -amide.

17. The method of claim 16, characterized in that the selective cytokine inhibitor drug is the R or S enantiomer of cyclopropanecarboxylic acid. { 2- [1- (3-ethoxy-4-methoxy-phenyl) -2-methanesulfonyl-ethyl] -3-oxo-2,3-dihydro-lH-isoindol-4-yl} -amide.

18. The method of any of claims 1, 2, 7 or 8, characterized in that the selective cytokine inhibitory drug has the formula (I): (I) where n has a value of 1, 2 or 3; R is o-phenylene, unsubstituted or substituted by 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, alkyl of 1 to 10 carbon atoms and halo; R is: (i) phenyl or phenyl substituted with one or more substituents, each selected independently 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, 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, (iii) naphthyl and (iv) benzyloxy; R1 is -OH, alkoxy of 1 to 12 carbon atoms, or R is hydrogen or alkyl of 1 to 10 carbon atoms; and R- is hydrogen, alkyl of 1 to 10 carbon atoms, -COR, or wherein R 10u is hydrogen, alkyl of 1 to 10 carbon atoms or phenyl.

19. The method of claim 18, characterized in that the selective cytokine inhibitory drug is an enantiomer of the compound having the formula (I).

20. The method of any of claims 1, 2, 7 or 8 characterized in that the selective cytokine inhibitory drug has the formula (II): (II) wherein each of R 1 and R 2, when taken independently from each other, is hydrogen, lower alkyl, or R 1 and R 2, when taken together with the carbon atoms represented to which each is attached, is o-phenylene, o-naphthylene or cyclohexen-1,2-diyl, unsubstituted or substituted with 1 to 4 substituents, each independently selected 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, alkyl of 1 to 10 carbon atoms and halo; 3 R is phenyl substituted with from 1 to 4 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, cycloalkylidene methyl of C4-Cg, alkylidene methyl of C3-C10, indanyloxy and halo; R is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl or benzyl; R is hydrogen, or alkyl of 1 to 6 carbon atoms; R5 is -CH2-, -CH2-CO-, -S02-, -S- or -NHCO-; and n has a value of 0, 1 or 2.

21. The method of claim 20, characterized in that the selective cytokine inhibitory drug is an enantiomer of the compound having the formula (II).

22. The method of any of claims 1, 2, 7 or 8, characterized in that the selective cytokine inhibitory drug has the formula (III): (III) wherein the carbon atom designated with the * constitutes a center of chirality; Y is C = 0, CH2, S02 or CH2C = 0; each variable R, R, R and R, independent of each other, is hydrogen, halo, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, nitro, pq 1 3 cyano, hydroxy or -NR R, or any pair of R, R, R and R in contiguous carbon atoms, together with the represented phenylene ring are naphthylidene; each of R and R, independent of each other, is hydrogen, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, cyano, or cycloalkoxy constituted by up to 18 carbon atoms; R is hydroxy, alkyl of 1 to 8 carbon atoms, phenyl, benzyl or NR8'R9 '; each of R 8 and R 9 taken independently of one another is hydrogen, alkyl of 1 to 8 carbon atoms, phenyl or benzyl, or one of R, R is hydrogen and the other is -COR 10 or 1 O R Q -S02R or R and R taken together with tetramethylene, 1 pentamethylene, hexamethylene or -CH CH 2 X CH CH 2 - wherein X is -O-, -S- or -NH-; and each of R 8 'and R 9' taken independently from each other is hydrogen, alkyl of 1 to 8 carbon atoms, phenyl or benzyl, or one of R 8 'R 9' is hydrogen and the other is -COR10 ' or -S02R 10 'or R8' and R9 'taken together with tetramethyl, pentamethylene, hexamethylene or -CH2CH2X 1CH2CH2- wherein X2 is -O-, -S- or -NH-.

23. The method of claim 22, characterized in that the selective cytokine inhibitory drug is an enantiomer of the compound.

24. A method for reducing or avoiding an adverse effect associated with the administration of a second active ingredient in a patient suffering from a disorder of the central nervous system, which consists of administration to a patient in need of such reduction or avoidance, a quantity of the second active ingredient and an effective therapeutic or prophylactic amount of a selective cytokine inhibitory drug, or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof.

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

26. A pharmaceutical composition containing a selective cytokine inhibitory drug, or a solvate or stereoisomer salt accepted for pharmaceutical use thereof, in an amount effective to treat, prevent or manage a central nervous system disorder, and a second active ingredient.

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