KR100831545B1 - 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 treating central nervous system disorders and related syndromes, such as Parkinson's disease, Alzheimer's disease, mild cognitive impairment, Huntington's disease, amyotrophic lateral sclerosis, depression and long-term memory deficits are disclosed. Certain methods include administering a selected 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 or suitable for use in the methods of the invention are disclosed.

CNS disorders, cytokine inhibitory drugs

Description

METHODS OF USING AND COMPOSITIONS COMPRISING SELECTIVE CYTOKINE INHIBITORY DRUGS FOR THE TREATMENT AND MANAGEMENT OF DISORDERS OF THE CENTRAL NERVOUS SYSTEM}

One. Field of invention

The present invention relates in part to central nervous system disorders (Parkinson's disease, Alzheimer's disease) comprising administration of selective cytokine inhibitory drugs, or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates or prodrugs thereof. , Mild cognitive impairment, Huntington's disease, amyotrophic lateral sclerosis, depression, long-term memory impairment, and related diseases).

2. Background of the Invention

Central nervous system disorders affect a wide range of people with varying severity. In general, one important feature of this disease group includes significant impairment of cognition or memory, which shows a marked drop from previous levels of function. For example, dementia is characterized by various cognitive impairments (e.g. significant memory loss) and is itself a disease, or even a few of the underlying causes of various diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease and multiple sclerosis. Can be a feature. Other central nervous system disorders include short-term delirium or disturbances in consciousness, and memory loss in the absence of other central nervous system damage, or discrete memory impairment.

2.1 Parkinson's disease

Parkinson's disease (PD) is the second most common degenerative neurological disease, affecting about 1% of the population over 50 years old. Polymeropoulos et. al., 1996, Science 274: 1197-1198. About one million Americans suffer from PD, and 50,000 are diagnosed with the disease each year. Olson, L., 2000, Science 290: 721-724. Since the initial symptoms of PD may not be recognized, 5-10% of the population over 60 may have the disease. Olson, L., 2000, Science 290: 721-724.

Since the 1960s, the loss of dopamine neurons in the brain's neurotransmitter system has been known to lead to PD dyskinesia. Typical onset of PD appears in middle to old age with progressive clinical features. Some physical signs of PD include resting tremor, muscle stiffness, postural instability and dementia. Pathological features of PD include loss of dopamine-based neurons in substantia nigra (SN) as well as the presence of intracellular inclusions or Lewy Bodies in neurons that survive in various regions of the brain. Nussbaum, R. L. and Polymeropoulos, M. H., 1997, Hum. Molec. Genet. 6: 1687-1691. Interestingly, many other diseases have the motor characteristics of Parkinson's disease. The motor symptoms of PD are generally thought to be due to the lack or impairment of dopamine or dopamine-based neurons in the medulla. Nussbaum, R. L., Polymeropoulos, M. H., 1997, Hum. Molec. Genet. 6: 1687-1691. There is evidence suggesting that molecular chaperones, particularly the heat shock proteins HSP70 and HSP40, may play a role in PD progression. Auluck et. al., 2002, Science 295: 865-868.

There is much debate regarding the pathogenesis of PD, and there is evidence that both genetic and environmental factors can contribute to the disease. Studies of the nuclear family of 948 PD patients have concluded that there are rare major Mendelian genetic factors that affect the age at onset. Maher et. al., 2002, Am. J. Med. Genet. 109: 191-197. The study also hinted at the presence of genetic factors that influence susceptibility. Other evidence also suggests that environmental factors may be more important in contributing to PD than genetic factors. Calne et. al., 1987, Canad. J. Neurol. Sci. 14: 303-305]. The researchers concluded that most PD patients are affected by environmental factors in addition to the background of gradual neuronal loss due to aging. Calne, D. B. and Langston, J. W., 1993, Lancet II: 1457-1459. Although the etiology is not clear, it is likely that genetic and environmental factors contribute to PD and that environmental factors also act on the genetic susceptibility that causes the disease. Recent evidence in animal models of PD suggests that anti-inflammatory agents inhibit dopaminergic cell death. McGeer et. al., 2001, B. C. Med. J. 43: 138-141.

While there are no treatments currently available for Parkinson's disease, traditional therapies focus on countering the effects of dopamine loss in the brain. Therapies using levodopa, the dopamine precursor, have been the best treatment when it has been found that it can alleviate PD symptoms and thus improve the quality of life of patients. Unfortunately, it has been found that prolonged levodopa administration can have side effects. Caraceni et. al., 1994 Neurology, 41: 380. Several treatment strategies have been developed for the treatment of PD. In particular, MPTP, a neurotoxin known to damage dopamine neurons, is commonly used as a model for the effects of PD. In certain experiments, investigators used lentiviral transporters to identify SN and Rhesus monkeys who had been previously treated with MPTP for a weekly glial cell line derived neurotrophic factor (GDNF) with MPTP. Delivered to the striated body. Kordower et. al., 2000, Science 290: 767-773]. GDNF is known to have a nutritional effect on degenerative nigrostriatal neurons in non-human primate models of Parkinson's disease. The results showed that dopaminergic function was increased in aged monkeys, reversed functional deficits and prevented regression of black ancestors in monkeys treated with MPTP. GDNF treatment was also found to reverse the lack of exercise in MPTP-treated monkeys. The study also came to the conclusion that in primate models of PD, it could prevent the degeneration of melanoma progenitors and induce neuronal regeneration. Kordower et. al., 2000, Science 290: 767-773].

Other studies using electrical suppression and pharmacological silencing of the hypothalamus nucleus (STN) suggest that changes in basal ganglia network activity may preclude the firing activity of nerve cells, perhaps in SN. It has been shown that it can improve motor network activity in PD. Luo et. al., 2002, Science 298: 425-429. Investigators transformed the excitable glutamine-based neurons of the rat STN to glutamic acid decarboxylase (GAD) to show that such changes provide neuroprotection to dopamine-based cells from toxic insults. Virus was used. Interestingly, rats with the transformed gene also showed significant improvement from the Parkinson's disease phenotype.

Selective PDE4 inhibitors Ro-20 1724 and SDZ-MNS 949 have been shown to stimulate the dopamine uptake by rat messenphalonic neurons in vitro in the presence of adenylate cyclase activator forskolin ( Huley et al., J Neural Transm Suppl, 46: 217-228, 1995). In these studies, an increase in cAMP by the addition of dibutyryl cAMP or forskolin protected dopamine-based neurons from the neurotoxic effects of MPP '(1-methyl-4-phenyl pyridinium ion). These PDE4 inhibitors have been shown to reduce dopamine depletion in striated bodies and to reduce the loss of tyrosine hydroxylase-immunopositive neurons in the black matter of C57BL / 6 mice subjected to MPTP injection (Hulley et al. al., Eur J Neurosci, 7: 2431-2440, 1995]. Thus, PDE4 inhibitors have shown efficacy in the MPTP mouse model of PD, and based on in vitro studies it is believed that the mechanism of action includes at least partially direct neuroprotective effects.

Recently, two groups studied the role of TNF-α receptors in the MPTP mouse model of PD. In one study, mice lacking both forms of TNF-α receptor forms (TNFR1 and TNFR2) were found to have reduced striated dopamine levels and increased dopamine turnover (Rousselet et al., Exp Neurol, 177: 183-192, 2002]. In a separate study, double knockout mice of TNFR1 and TNFR2 were completely protected from dopamine-based neurotoxicity of MPTP (Sriram et al., Faseh J 16: 1474-1476, 2002). Thus, TNF-α has been shown to mediate neurotoxicity in this animal model of PD.

Furthermore, JD Parkes et al. Investigated the anti-Parkinson's action of the PDE4 inhibitor Rolipram in PD patients (JD Parkes et al., 1984, Advances in Neurology, Vol. 40, 563-564]. The effect of rolipram was also assessed as a double blind test versus placebo in PD patients already on treatment. Casacchia et al., Pharmacological Research Communications, Vol. 15, No. 3, 1983, 329-330. Unlike other findings related to certain phosphodiesterase inhibitors, no degradation of the therapeutic effect of dopamine on lisuride was found when rolipram was used at a dose of 3 mg / day. [From the past]. Nausea, a dose-limiting side effect of the PDE4 inhibitor rolipram in the phase 2 trial of PD, significantly reduced its potential use.

2.2 Alzheimer's disease

Alzheimer's disease (AD) is the leading form of increasing neurodegeneration, accounting for approximately 50% to 60% of the overall case of dementia among people 65 years or older. This currently affects an estimated population of 15 million people around the world, and the prevalence is likely to increase over the next twenty years due to the relative increase of the elderly in population distribution. Alzheimer's disease is a progressive disease with an average duration of about 8.5 years between onset of clinical symptoms and death. The death of pyramidal neurons and loss of neuronal synapses in the brain regions associated with higher mental function leads to typical symptoms characterized by a general 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 in both senile and elderly dementia worldwide and is recognized as a progressively progressive dementia clinically manifested with increased memory, intellectual impairment and speech impairment (Merritt, 1979, A). Textbook of Neurology , 6 ^th edition, pp. 484-489 Lea & Febiger, Philadelphia]. In general, the disease itself has a slow and insidious progression that equally affects benign worldwide. It begins with mild inadequate behavior, uncritical speech, anger, aggravating exaggeration, good fortune and poor work; Progressing through reduced computational judgment, impaired insight, recent memory degradation and impairment; Severe disorientation and delirium, inability to walk, general stiffness and incontinence (Gilroy & Meyer, 1979, Medical Neurology , pp. 175-179 MacMillan Publishing Co.).

The etiology of Alzheimer's disease is unknown. The evidence for genetic factors, familial incidence, came from several important observations, such as the relevance of the pedigree analysis, monozygotic and dizygotic twin studies and Down syndrome (document for review [Baraitser, 1990, The Genetics of Neurological Disorders, 2 nd edition, pp. 85-88). Nevertheless, it is clear that this evidence is not conclusive and that one or more other factors are also required. Increased levels of aluminum have been found in the brains of some patients who have died from Alzheimer's disease (Crapper et al., 1976, Brain , 99: 67-80), and one case reports a patient with Alzheimer's disease. Reported significantly increased levels of manganese in tissues (Banta & Markesberg, 1977, Neurology , 27: 213-216), indicating that high levels of these metals can be neurotoxic and go into the development of Alzheimer's disease. It is to suggest. It is interesting that aluminum ions have been found to be primarily associated with nuclear chromatin in areas of the brain that are likely to show neurofibrillary tangles in Alzheimer's disease. However, from a statistical point of view, the absolute differences found for aluminum concentrations between normal and Alzheimer's brains were not convincing. Recently, defects have occurred in the transcriptional splicing of mRNA encoding tau complexes of microtubules associated with proteins and / or (for review see Kosik, 1990, Curr. Opinion Cell Biol ., 2: 101- 104), it has been suggested that there is an inappropriate phosphorylation of these proteins (Grundke-Igbak et al., 1986, Proc. Natl. Acad. Sci. USA, 83: 4913-4917; Wolozin & Davies, 1987, Ann. Neurol . 22: 521-526; Hyman et al., 1988, Ann, Neurol. , 23: 371-379; Bancher et al., 1989, Brain Res ., 477: 90-99). Moreover, the reduction of the enzymes involved in the synthesis of acetylcholine led to the failure of the cholinergic system in terms of Alzheimer's disease (Danes & Moloney, 1976, Lancet , ii: 1403-14). However, although cholinergic neurons are most dangerous in Alzheimer's disease, these decreases in enzyme activity appear secondary rather than causally related to the degenerative process itself.

At present, no agents are consistently effective in inhibiting the progression of the disease. Acetylcholinesterase inhibitors are the center of therapy. Many current therapeutic agents focus on the management of symptoms of AD. This strategy has used the use of antipsychotics as well as neuroleptics and acetylcholinesterase inhibitors. However, due to the side effects and poor dose conditions of these drugs, there is a great need for new methods and compounds that can treat AD and its symptoms.

2.3 Mild cognitive impairment

Mild cognitive impairment or minimal cognitive impairment (MCI) refers to a stage of cognitive impairment, particularly in subtypes with memory impairment before achieving clinical criteria for dementia in Alzheimer's disease (AD). However, to distinguish between MCI patients with latent AD and MCI patients with less frequently occurring symptoms, there is no completely reliable means other than long-term follow-up and final necropsy (Petersen et. al., Arch Neurol , 2001, 58 (12): 1985-92]. As used herein, MCI is regarded as a high risk condition that precedes AD in most cases. A relatively recent formulation of MCI follows prior attempts to characterize aging-related cognitive decline, including benign aging forgetfulness, age-related memory impairment, and age-related cognitive decline (Crook et al., Dev Neuropsychol. , 1986, 2: 261-276; Kral, CMAJ 1962, 86: 257-260; Levy et al., Int Psychogeriatr 1994, 6 (10: 63-8) .In contrast to many previous terms, individuals with MCI However, long-term follow-up has different conditions from normal aging in that they show that they progress as a group for AD at accelerated rates Other terms that have similar connotation to MCI include isolated memory impairment, early Dementia and dementia precursor symptoms, but these latter terms are not as common as MCI.

The pathophysiology of MCI is unknown. One hypothesis is that this often results from the gradual build-up of senile plaques and neurofibrillary tangles in the area of the cerebral cortex targeted by AD before the density of these disorders reaches the threshold required to diagnose the history of AD. will be. Similarly, the progression of certain neurotransmitter deficiencies, and in particular of the cortical cholinergic deficiency, has been assumed in the most common form of forgetfulness of MCI. In some studies so far, most patients with MCI have neuropathic changes close to AD, but some clinically similar individuals have not shown a significant number of AD-like disorders (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]) .

MCI is a complex symptom due to a number of different causes that can overlap in individual patients. In one attempt to distinguish between groups of patients, it was often emphasized whether memory was included or single nonmemory domains were included instead. The most common form of MCI is amortized as forgetful MCI, where a single infected region is a memory region. Many of these patients progress to AD. Perhaps the less common form of MCI is that multiple cognitive regions are infected. This is at least theoretically related to dementia and atypical modification of AD associated with cerebrovascular disease. The third hypothetical form is that a single non-memory region is infected. Such conditions are thought to develop with anterior temporal dementia, Lewy body dementia, primary progressive aphasia, Parkinson's disease dementia and other atypical modifications of AD.

There is currently no cure for MCI. Several attempts are currently underway to test whether cholinesterase inhibitors, anti-inflammatory drugs and antioxidants may be beneficial for MCI. Smaller studies suggest that at least cholinesterase inhibitors can improve memory impairment, but larger studies are needed to confirm this more accurately. (Freo et al., Soc Neurosci Abstr , 677, 2001)

2.4 depression

Depression is characterized by feelings of intense sadness or pessimistic anxiety, anger, self-degradation, mental delay, insomnia, loss of appetite, loss of desire, passion and libido. The effect of long-term antidepressant administration on the expression of the three main phosphodiesterase (PDE) 4 subtypes (PDE4A, PDE4B and PDE4C) found in the brain was examined (Takahashi et al., The Journal of Neuroscience , 1999, 19 (2): 610-618]. The treatments are samples of four major classes of antidepressants, such as selective reuptake inhibitors of serotonin (sertraline and fluoxetine), or norepinephrine (decpramine), monoamine oxidase inhibitor (tranilcypromine) and Electroconvulsive seizures; The results of this study show that long-term antidepressant administration increased PDE4A and PDE4B expression in the cerebral cortex and PDE4B expression in the lateral septal nucleus. Increased regulation of PDE4A and PDE4B may indicate 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, have been studied in animal models and clinical trials (Zhu et al., CNS Drug Reviews , Vol. 7, No. 4, 387-398, 2001). ). It has been reported that PDE4 is responsible for the hydrolysis of cyclic nucleotides cAMP and cGMP, especially in neuronal and immune cells. Rolipram induces an increase in intracellular cAMP and increases the synthesis and release of norepinephrine, which enhances central noradrenergic delivery and the like. Rolipram weakens inflammation in endogenous depression and the central nervous system. However, there are some inconsistencies between the ex vivo and in vivo effects of rolipram, and also between the results obtained from animal models and clinical studies. In addition, the clinical use of rolipram was limited due to its behavior and other side effects. Thus, there is a significant need for selective PDE4 inhibitors with higher potency and lower toxicity.

2.5 Long-term memory damage

Rubinstein Tei syndrome (RTS) is a genetic disorder of humans characterized by mental retardation and physical malformations including wide thumb, large wide toe, small stature and maxillofacial malformations. Bourtchouladze et al., PNAS, 2003, vol. 100, no. 18]. RTS occurs in about 1 in 125,000 births and in 1 in 300 patients with mental retardation. In many patients, RTS is mapped to chromosome 16p13.3, a genomic region containing cAMP-reactive element binding protein (CREB) -binding protein (CBP). Many RTS patients are heterologous to CBP mutations that produce cleavage of the CBP C terminus, suggesting that dominant negative mechanisms may contribute to clinical signs of long-term memory impairment.

A study by Bourtchouladze et al. Demonstrated that CREB and CBP together would act as molecular switches during long-term memory formation. They demonstrated that the PDE4 inhibitors roliram and HT0712 eliminate long-term memory damage in CBP ^+/- mutant mice. It has been reported that inhibitors of PDE4 increase the expression of CREB-dependent genes and ameliorate long term memory damage in CBP ^+/− mutant mice in a dose dependent manner.

2.6 Selective Cytokine Inhibitory Drugs

Compounds called SelCIDs ™ (Celgene Corporation) or selective cytokine inhibitors were synthesized and tested. These compounds strongly inhibited TNF-α production, but showed moderate inhibitory effects on LPS-induced IL1β and IL12 and did not inhibit IL6 even at high drug concentrations. SelCIDs ™ also tend to produce moderate IL10 stimuli. L.G. Corral, et al., Ann. Rheum. Dis. 58: (Suppl I) 1107-1113 (1999).

Further analysis of selective cytokine inhibitory drugs indicates that they are potent PDE4 inhibitors. PDE4 is one of the major phosphodiesterase isoenzymes found in human bone marrow and lymphoid cells. Enzymes degrade the ubiquitous secondary messenger cAMP and maintain it at a low concentration, which plays an important role in regulating intracellular activity. In the central nervous system (CNS), PDE4 is an inflammation of nerves and brains in many locations in the brain, including dopamine-based nerves of the black matter (Cherry and Davis, J Comp Nurol 407: 287-301 1999), which are the major target sites for Parkinson's disorder damage. It is expressed in astrocytes, the cell type involved in. In addition, the elevation of cAMP in neural progenitors may result in the release of norepinephrine and acetylcholine (Rabe et al. J Cyclic Nucleotide Res 8: 371-384, 1982), swelling of neurites (Traynor and Schubert, Brain Res 316: 197-204 , 1984; Westlund et al., Int J Dev Neurosci 10: 361-373,1992) and serotonin signal transduction (Akaike et al., Brain Res 620: 58-6, 1993) and dopamine-based from embryonic stem cells Induce differentiation of nerves (Iacovitti et al., Brain Res 912: 99-104,2001). Inhibition of PDE4 results in increased cAMP levels leading to the regulation of LPS-induced cytokines, including inhibition of TNF-α production in monocytes as well as lymphocytes.

3. Summary of the Invention

The present invention provides a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, for the treatment or prevention of central nervous system disorders and related disorders. A method of treating or preventing a central nervous system disorder and related disorders, comprising administering to a patient in need thereof. Central nervous system disorders include Alzheimer's disease, mild cognitive impairment (MCI), Parkinson's disease, depression, long-term memory impairment, Huntington's disease, multiple sclerosis, delirium, or perceptual anxiety and forgetfulness that occur over a short time, or perceptual memory that occurs without other central nervous system damage Including, but not limited to, damage. In addition, the present invention encompasses administering to a patient in need thereof a prophylactically effective amount of a selective cytokine inhibitory drug or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. Includes methods for treating neurological disorders (eg, increasing the time to alleviate the symptoms). Each of these methods includes specific administration or dosing regimens, including cyclical therapy.

In addition, the present invention provides for the treatment, prevention and / or management of central nervous system disorders, including one or more selective cytokine inhibitory drugs, or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates or prodrugs thereof. Pharmaceutical compositions, single dosage unit forms and kits.

Selective cytokine inhibitory drugs or compounds of the invention described in detail below are those having small organic molecules, ie, molecular weights of less than 1,000 g / mol. The compound preferably inhibits PDE4 activity and TNF-α.

In specific embodiments of the invention, the selective cytokine inhibitory drug is used, administered or formulated with one or more second active ingredients to treat, prevent or manage a central nervous system disorder. Examples of second active ingredients are compounds used to enhance levodopa therapy, such as dopamine antagonists, levodopa, monoamine oxidase inhibitors (MAO) and catechol-O-methyltransferase inhibitors (COMT), amantadine, Anticholinergic agents, vomiting inhibitors and other standard drugs for central nervous system disorders. In another embodiment, the second active ingredient is an anti-inflammatory agent, including but not limited to nonsteroidal anti-inflammatory agents (NSAIDs), methoxetate, leflunomide, antimalarial drugs and sulfasalazine, gold salts, glucocorticoids, immunosuppressants And other standard drugs for central nervous system disorders.

4. Detailed description of the invention

A first embodiment of the present invention is directed to treating a central nervous system disorder with a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof. Or a method of treating or preventing a central nervous system disorder, comprising administering to a patient in need thereof. Central nervous system disorders include Parkinson's disease; Exercise relaxation; Dystonia; Parkinson's disease tremors; Parkinson's disease walking; Activity stiffness; depression; Long term memory appearance; Rubinstein Taby Syndrome (RTS); dementia; Sleep disorders; Postural anxiety; Dyskinesia; Inflammation; Synuclein disorders; Multiple cranial nervous system atrophy; Striatum-black degenerative; Olive bridge cerebellar atrophy; Shire-Dragger syndrome; Motor neuron disorder with Parkinson's disease characteristics; Lewy body dementia; Disorders with tau pathology; Advanced nuclear palsy; Cortex-basal nucleus degeneration; Anterior temporal dementia; Amyloid pathological disorders; Mild cognitive impairment; Alzheimer's disease; Alzheimer's disease with Parkinson's disease; Genetic diseases that may have Parkinson's disease characteristics; Wilson's disease; Halleborden-Spartz disease; Sediak-haga's disease; SCA-3 spinal cord ataxia; X-linked dystonia Parkinson's disease; Huntington's disease; Prion disease; Hyperactivity disorder; chorea; Balimus; Myotonic progression; Amyotrophic lateral sclerosis (ALS); CNS trauma and myoclonus.

Another embodiment of the invention is a patient requiring a prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, for the management of a central nervous system disorder. It includes a method of managing a central nervous system disorder, comprising administering to a.

Another embodiment of the invention provides a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, Methods of treating, preventing and / or managing a central nervous system disorder comprising administering an effective amount of a second active drug to a patient in need of treatment, prevention and / or management of the central nervous system disorder. Without being bound by theory, it is believed that certain selective cytokine inhibitory drugs and agents commonly used in central nervous system disorders can act in a complementary or synergistic manner in the treatment or management of the disorder. In addition, the use of such drugs may reduce or eliminate the side effects associated with some selective cytokine inhibitory drugs, thereby allowing the administration of a larger amount of selective cytokine inhibitory drug to the patient and / or improving patient compliance. It is thought to be able to increase. In addition, some selective cytokine inhibitory drugs may reduce or eliminate the side effects associated with some conventional drugs, thereby allowing the administration of a larger amount of selective cytokine inhibitory drug to the patient and / or increasing patient compliance. It seems to be possible.

Another embodiment of the invention provides a therapeutically or prophylactically effective amount of selective cytokine to a patient in need of reversal, reduction or prevention of side effects associated with the administration of conventional therapeutics for a central nervous system disorder or related disorder. Common to central nervous system disorders or related disorders in patients with central nervous system disorders or related disorders, including administering an inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof Methods for reversing, reducing or preventing side effects associated with administration of a phosphorus therapeutic.

Another embodiment of the present invention comprises a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient thereof. A pharmaceutical composition is included, wherein the composition is suitable for parenteral, oral or transdermal administration, and the amount is sufficient to treat or prevent a central nervous system disorder, or ameliorate the progression of a symptom or disorder.

The invention also encompasses a single dosage form comprising a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.

The second active agent may be a macromolecule (eg a protein) or a small molecule (eg a synthetic inorganic, organometallic or organic molecule). Examples of the second active agent include, but are not limited to, cytokines, hematopoietic growth factors, anticancer agents such as isomerase inhibitors, antiangiogenic agents, microtubule stabilizers, alkylating agents; Acetylcholinesterase inhibitors, antiviral agents; Antifungal agents; Antibiotic; Anti-inflammatory agents; Immunomodulators; Immunosuppressants such as cyclosporin; And other known or conventional agents used in patients with central nervous system disorders. Specific second active agents include, but are not limited to, dopamine agonists or antagonists for Parkinson's disease, or acetylcholinesterase inhibitors for Alzheimer's disease.

The present invention also encompasses kits comprising a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, and a second active ingredient thereof.

4.1. Selective Cytokine Inhibitory Drugs

The compounds used in the present invention are racemates, stereoisomerically pure stereoisomerically enriched selective cytokine inhibitory drugs, stereoisomeric and enantiomerically pure compounds having selective cytokine inhibitory activity and Pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates or precursors thereof. Preferred compounds used in the present invention are known as Selective Cytokine Inhibitory Drugs (SelCIDs ™) from Celgene Corporation, NJ.

As used herein, unless otherwise indicated, the terms "selective cytokine inhibitory drug" and "SelCIDs ™" refer to small organic drugs that are not small molecule drugs, such as peptides, proteins, nucleic acids, oligosaccharides or other macromolecules. It includes molecules. Preferred compounds inhibit TNF-α production. The compounds may also have a modest inhibitory effect on LPS induced IL1β and IL12. More preferably, the compounds of the present invention are latent PDE4 inhibitors.

Specific examples of selective cytokine inhibitory drugs include cyclic imides disclosed in US Pat. Nos. 5,605,914 and 5,463,063, US Pat. Nos. 5,728,844, 5,728,845, 5,968,945, 6,180,644 and The aryl amides of 6,518,281 cycloalkyl amides and cycloalkyl nitriles, US Pat. Nos. 5,801,195, 5,736,570, 6,046,221 and 6,284,780 (e.g., N-benzoyl-3-amino-3- (3 '). Embodiments of, 4'-dimethoxyphenyl) -propanamide), imide / amide ethers and alcohols disclosed in US Pat. No. 5,703,098 (eg, 3-phthalimido-3- (3 ', 4'-) Dimethoxyphenyl) propan-1-ol), succinimide and maleimide (eg, methyl 3- (3 ', 4', 5 ', 6'-tetrahydrophthalimido) disclosed in US Pat. No. 5,658,940 ) -3- (3 ", 4" -dimethoxyphenyl) propionate), imidos and aminos disclosed in US Pat. No. 6,214,857 and WO 99/06041 Substituted alkanohydroxysamic acid, substituted phenethylsulfones disclosed in US Pat. Nos. 6,011,050 and 6,020,358, substituted imides disclosed in US Pat. No. 6,429,221 (eg, 2-phthalimido-3- (3 ', 4'-dimethoxyphenyl) propane), substituted 1,3,4-oxadiazoles disclosed in US Pat. No. 6,326,388 (eg, 2- [1- (3-cyclopentyloxy-4 -Methoxyphenyl) -2- (1,3,4-oxadiazol-2-yl) ethyl] -5-methylisoindolin-1,3-dione, US Pat. No. 5,929,117, 6,130,226 , Cyano and carboxy derivatives of substituted styrenes disclosed in US Pat. Nos. 6,262,101 and 6,479,554 (eg, 3,3-bis- (3,4-dimethoxyphenyl) acrylonitrile), WO 01/34606 Isoindolin-1-one and isoindolin-1,3-dione (2-positions are substituted with an α- (3,4-disubstituted phenyl) alkyl group, and 4- and / or 5-positions Substituted by a nitrogen containing group), and the imido and amido substituents disclosed in WO 01/45702 Acyl hydroxamic acid (e.g., (3- (1,3-dioxoisoindolin-2-yl) -3- (3-ethoxy-4-methoxyphenyl) propanoylamino) propanoate Including but not limited to. All patents and patent applications mentioned herein are incorporated by reference herein.

Additional selective cytokine inhibitory drugs belong to the group of synthetic compounds, representative examples of which 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 specific selective cytokine inhibitory drugs belong to the non-polypeptide cyclic amide classes disclosed in US Pat. Nos. 5,698,579, 5,877,200, 6,075,041, and 6,200,987, respectively, incorporated herein. Representative cyclic amides include compounds of the formula

Where

n has a value of 1, 2 or 3;

R ⁵ is unsubstituted or is respectively nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino O-phenylene substituted with 1 to 4 substituents independently selected from the group consisting of dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms, alkoxy and halo of 1 to 10 carbon atoms;

R ⁷ is (i) phenyl or nitro, cyano, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, Phenyl substituted by one or more substituents independently selected from the group consisting of alkyl of 1 to 10 carbon atoms, alkoxy and halo of 1 to 10 carbon atoms, (ii) unsubstituted or respectively nitro, cyano, trifluoro Methyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy and halo of 1 to 10 carbon atoms Benzyl, (iii) naphthyl or (iv) benzyloxy substituted with one to three substituents selected from the group consisting of:

이고;R ¹² is —OH, alkoxy of 1 to 12 carbon atoms or

ego;

R ⁸ is hydrogen or alkyl of 1 to 10 carbon atoms;

R ⁹ is hydrogen, alkyl of 1 to 10 carbon atoms, —COR ¹⁰ or —SO ₂ R ¹⁰ , wherein R ¹⁰ is hydrogen, alkyl or phenyl of 1 to 10 carbon atoms.

Specific compounds of this class are

3-phenyl-2- (1-oxoisoindolin-2-yl) propionic acid,

3-phenyl-2- (1-oxoisoindolin-2-yl) propionamide,

3-phenyl-3- (1-oxoisoindolin-2-yl) propionic acid,

3-phenyl-3- (1-oxoisoindolin-2-yl) propionamide,

3- (4-methoxyphenyl) -3- (1-oxysoindolin-yl) propionic acid,

3- (4-methoxyphenyl) -3- (1-oxysoindolin-yl) propionamide,

3- (3,4-dimethoxyphenyl) -3- (1-oxysoindolin-2-yl) propionic acid,

3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydroisoindol-2-yl) propionamide,

3- (3,4-dimethoxyphenyl) -3- (1-oxysoindolin-2-yl) propionamide,

3- (3,4-diethoxyphenyl) -3- (1-oxoisoindolin-yl) propionic acid,

Methyl 3- (1-oxoisoindolin-2-yl) -3- (3-ethoxy-4-methoxyphenyl) propionate,

3- (1-oxoisoindolin-2-yl) -3- (3-ethoxy-4-methoxyphenyl) propionic acid,

3- (1-oxoisoindolin-2-yl) -3- (3-propoxy-4-methoxyphenyl) propionic acid,

3- (1-oxoisoindolin-2-yl) -3- (3-butoxy-4-methoxyphenyl) propionic acid,

3- (1-oxoisoindolin-2-yl) -3- (3-propoxy-4-methoxyphenyl) propionamide,

3- (1-oxoisoindolin-2-yl) -3- (3-butoxy-4-methoxyphenyl) propionamide,

Methyl 3- (1-oxoisoindolin-2-yl) -3- (3-butoxy-4-methoxyphenyl) propionate, and

Methyl 3- (1-oxoisoindolin-2-yl) -3- (3-propoxy-4-methoxyphenyl) propionate, including but not limited to. Other representative cyclic amides include compounds of the formula:

Where Z is

to be.

here,

R ¹ is (i) 3,4-pyridine, (ii) pyrrolidine, (iii) imidazole, (iv) naphthalene, (v) thiophene, or (vi) phenyl, or nitro, cyano, tri Fluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or A divalent residue of a straight or branched alkane of 2 to 6 carbon atoms, substituted or unsubstituted with phenyl substituted with halo, wherein the divalent bond of said residue is on an adjacent ring carbon atom;

R ² is -CO- or -S0 _2- ;

R ³ represents (i) nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, carbon atoms 1 to Phenyl substituted with one to three substituents each independently selected from alkyl of 10, alkoxy of 1 to 10 carbon atoms, (ii) pyridyl, (iii) pyrrolyl, (iv) imidazolyl, (iv ) Naphthyl, (vi) thienyl, (vii) quinolyl, (viii) furyl, or (ix) indolyl;

R ⁴ is alanyl, arginyl, glycyl, phenylglycyl, histidyl, rusil, isoleucyl, lysyl, methionyl, prolyl, sarcosyl, seryl, homoceryl, threonyl, tyronyl, tyrosyl, valeryl , Benzimidol-2-yl, benzoxazol-2-yl, phenylsulfonyl, methylphenylsulfonyl, or phenylcarbamoyl;

n has a value of 1, 2 or 3. Other representative cyclic amides include compounds of the formula:

Wherein R ⁵ is (i) nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino O-phenylene unsubstituted or substituted with 1 to 4 substituents each independently selected from dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo, or (ii ) Is a divalent residue of a pyridine, pyrrolidine, imidazole, naphthalene, or thiophene, wherein the divalent bond is on an adjacent ring carbon atom;

R ⁶ is —CO—, —CH ₂ —, or —SO ₂ —;

R ⁷ is (i) hydrogen when R ⁶ is —S0 ₂ —, (ii) straight, branched or cyclic alkyl of 1 to 12 carbon atoms, (iii) pyridyl, (iv) phenyl, or nitro , Cyano, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, carbon atom 1 Phenyl substituted by one or more substituents each independently selected from alkoxy of 10 to 10, or halo, (v) alkyl of 1 to 10 carbon atoms, (vi) nitro, cyano, trifluoromethyl, carethoxy, 1 to 1 selected from the group consisting of carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo Benzyl, unsubstituted or substituted with three substituents, (vii) b. Naphthyl, (viii) benzyloxy, or (ix) imnida-4-yl methyl;

R ¹² is —OH, alkoxy of 1 to 12 carbon atoms, or

이고,

ego,

Wherein n has a value of 0, 1, 2, or 3;

R ^{8 '} is hydrogen or alkyl of 1 to 10 carbon atoms;

R ^{9 '} is hydrogen, alkyl of 1 to 10 carbon atoms, -COR ¹⁰ , or -S0 ₂ R ¹⁰ , wherein R ¹⁰ is hydrogen, alkyl of 1 to 10 carbon atoms, or phenyl.

Other specific selective cytokine inhibitory drugs include the imido and amido substituted alkanohydroxamic acids disclosed in WO 99/06041, which is incorporated herein by reference. Examples of such compounds include, but are not limited to, compounds having a structure of the formula: and acid addition salts of those compounds containing protonable nitrogen atoms.

Where

R ¹ and R ² are unsubstituted or are each independently of the other hydrogen or lower alkyl, or R ¹ and R ² together with the carbon atom to which they are attached, are each nitro, cyano, trifluoromethyl, carboethoxy, 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 o-phenylene, o-naphthylene or cyclohexene-1,2-diyl substituted with 1 to 4 substituents independently selected from the group consisting of halo;

R ³ is nitro, cyano, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms , Alkoxy of 1 to 10 carbon atoms, alkylthio, benzyloxy of 1 to 10 carbon atoms, cycloalkoxy of 3 to 6 carbon atoms, C ₄ -C ₆ -cycloalkylidenemethyl, C ₃ -C ₁₀ -alkylidenemethyl Phenyl substituted with 1 to 4 substituents selected from the group consisting of, indanyloxy and halo;

R ⁴ is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl or benzyl;

R ^{4 '} is hydrogen or alkyl of 1 to 6 carbon atoms;

R ⁵ is —CH ₂ —, —CH ₂ —CO—, —SO ₂ —, —S— or —NHCO—;

n has a value of 0, 1 or 2.

Specific selective cytokine inhibitory drugs for use in the present invention further include, but are not limited to, the following compounds:

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- (3,4-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-1H-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-dimethoxyphenyl) -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.

Further selective cytokine inhibitory drugs for use in the present invention further include substituted phenethylsulfones substituted with oxoisoindine groups on the phenyl group. Examples of such compounds include, but are not limited to, those disclosed in US Pat. No. 6,020,358, incorporated herein, including the following compounds.

Where

Carbon atoms denoted by * represent chiral centers;

Y is C═O, CH ₂ , SO ₂ or CH ₂ C═O; R ¹ , R ² , R ³ and R ⁴ are each independently of each other hydrogen, halo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, nitro, cyano, hydroxy or —NR ⁸ R ⁹ ; Or any ^two of R ¹ , R ² , R ³ and R ⁴ on adjacent carbon atoms together with the phenylene ring form naphthylidene;

R ⁵ and R ⁶ are each independently of each other hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cyano, or cycloalkoxy of up to 18 carbon atoms;

R ⁷ is hydroxy, alkyl of 1 to 8 carbon atoms, phenyl, benzyl or NR ^{8 ′} R ^{9 ′} ;

R ⁸ and R ⁹ are each independently of each other hydrogen, alkyl of 1 to 8 carbon atoms, phenyl or benzyl, or one of R ⁸ and R ⁹ is hydrogen and the other is —COR ¹⁰ or —SO ₂ R ^10, or Or R ⁸ and R ⁹ together form tetramethylene, pentamethylene, hexamethylene or -CH ₂ CH ₂ X ¹ CH ₂ CH _2- , wherein X ¹ is -O-, -S- or -NH-;

R ^{8 '} and R ^9' are each, independently of one another, hydrogen, alkyl of 1 to 8 carbon atoms, phenyl or benzyl, or one of R ^{8 '} and R ^9' is hydrogen and the other is -COR ^{10 '} or -SO ₂ R ^{10 '} , or R ^8' and R ^{9 '} together form tetramethylene, pentamethylene, hexamethylene or -CH ₂ CH ₂ X ² CH ₂ CH _2- , wherein X ² is -O-,- S- or -NH-;
R ¹⁰ is hydrogen, alkyl of 1 to 8 carbon atoms or phenyl; R ^{10 '} is hydrogen, alkyl of 1 to 8 carbon atoms or phenyl.

For convenience the compound is treated as phenethylsulfone, but it will be understood that sulfonamides are included when R ⁷ is NR ^{8 ′} R ^{9 ′} .

A specific group of such compounds are those in which Y is C═O or CH ₂ .

A further specific group of such compounds is that R ¹ , R ² , R ³ and R ⁴ are each independently of each other hydrogen, halo, methyl, ethyl, methoxy, ethoxy, nitro, cyano, hydroxy or -NR ⁸ R ⁹ Wherein R ⁸ and R ⁹ are each, independently of one another, hydrogen or methyl, or one of R ⁸ and R ⁹ is hydrogen and the other is —COCH ₃ .

Specific compounds are those in which ^one of R ¹ , R ² , R ³ and R ⁴ is —NH ₂ and the other of R ¹ , R ² , R ³ and R ⁴ is hydrogen.

Specific compounds are those in which ^one of R ¹ , R ² , R ³ and R ⁴ is —NHCOCH ₃ and the other of R ¹ , R ² , R ³ and R ⁴ is hydrogen.

Specific compounds are those in which ^one of R ¹ , R ² , R ³ and R ⁴ is —N (CH ₃ ) ₂ and the other of R ¹ , R ² , R ³ and R ⁴ is hydrogen.

More preferred groups of these compounds are those in which ^one of R ¹ , R ² , R ³ and R ⁴ is methyl and the other of R ¹ , R ² , R ³ and R ⁴ is hydrogen.

Specific compounds are those in which ^one of R ¹ , R ² , R ³ and R ⁴ is fluoro and the remaining of R ¹ , R ² , R ³ and R ⁴ are hydrogen.

Specific compounds are those in which R ⁵ and R ⁶ are each, independently of one another, hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopentoxy or cyclohexoxy.

Specific compounds are those in which R ⁵ is methoxy and R ⁶ is monocycloalkoxy, polycycloalkoxy and benzocycloalkoxy.

Specific compounds are those in which R ⁵ is methoxy and R ⁶ is ethoxy.

Specific compounds are those wherein R ⁷ is hydroxy, methyl, ethyl, phenyl, benzyl or NR ^{8 '} R ^9' , wherein R ^{8 '} and R ^9' are each independently hydrogen or methyl.

Specific compounds are those wherein R ⁷ is methyl, ethyl, phenyl, benzyl or NR ^{8 '} R ^9' , wherein R ^{8 '} and R ^9' are each independently hydrogen or methyl.

Specific compounds are those in which R ⁷ is methyl.

Specific compounds are those wherein R ⁷ is NR ^{8 '} R ^9' , wherein each of R ^{8 '} and R ^9' is independently hydrogen or methyl.

Additional selective cytokine inhibitory drugs are described in US patent application Ser. No. 10 / 392,195, filed March 19, 2003; International Patent Applications Nos. PCT / US03 / 08737 and PCT / US03 / 08738, filed March 20, 2003; Filed January 7, 2003. Including enantiomerically pure compounds disclosed in US Provisional Application Nos. 60 / 438,450 and 60 / 438,448 to G. Muller et al., All of which are incorporated herein by reference. Preferred compounds include enantiomers of 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-1,3-dione and 3- (3, Enantiomers of 4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide are included.

Preferred selective cytokine inhibitory drugs for use in the present invention include 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide and Cyclopropanecarboxylic acid {2- [1- (3-ethoxy-4-methoxy-phenyl) -2-methanesulfonyl-ethyl] -3-oxo-2,3-dihydro-1 H-isoindole -4-yl} -amides, which are available from Selgin Corporation, Warren, NJ. 3- (3,4-Dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide has the following chemical structure:

Other specific selective cytokine inhibitory drugs include, but are not limited to, cycloalkyl amides and cycloalkyl nitriles of U.S. Pat. Inserted herein. Representative compounds have the formula:

Wherein one of R ¹ and R ² is R ³ -X- and the other is hydrogen, nitro, cyano, trifluoromethyl, carbo (lower) alkoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxide Hydroxy, amino, lower alkyl, lower alkoxy, halo, or R ³ -X-;

R ³ is monocycloalkyl, bicycloalkyl, benzocycloalkyl with up to 18 carbon atoms;

X is a carbon-carbon bond, -CH _2- , or -0-;

R ⁵ is (i) nitro, cyano, halo, trifluoromethyl, optionally substituted with lower alkyl, acetoxy, carboxy, hydroxy, amino, lower alkylamino, lower acylamino, or lower alkoxy; O-phenylene unsubstituted or substituted with 1 to 3 substituents each independently selected from carbo (lower) alkoxy, acetyl, or carbamoyl; (ii) a divalent residue of a pyridine, pyrrolidine, imidazole, naphthalene, or thiophene, wherein the divalent bond is on an adjacent ring carbon atom; (iii) nitro, cyano, halo, trifluoromethyl, carbo (lower) alkoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, lower alkylamino, lower alkyl, lower alkoxy or phenyl Adjacent divalent cycloalkyl or cycloalkenyl of 4 to 10 carbon atoms, unsubstituted or substituted with 1 to 3 substituents each independently selected from the group consisting of; (iv) vinylene di-substituted with lower alkyl; Or (v) ethylene unsubstituted or monosubstituted or substituted with lower alkyl;

R ⁶ is —CO—, —CH _{2 —} , or —CH ₂ CO—;

Y is -COZ, -C≡N, -OR ⁸ , lower alkyl, or aryl;

Z is -NH ₂ , -OH, -NHR, -R ⁹ , or -OR ⁹ ;

R ⁸ is hydrogen or lower alkyl;

R ⁹ is lower alkyl or benzyl;

n has a value of 0, 1, 2, or 3.

Other representative compounds have the formula:

here,

Y is —C≡N or CO (CH ₂ ) _m CH ₃ ;

m is 0, 1, 2, or 3;

R ⁵ represents (i) nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, carbamoyl substituted with alkyl of 1 to 3 carbon atoms, 1-3 substituents each independently selected from 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 O-phenylene substituted or unsubstituted with; (ii) divalent residues of pyridine, pyrrolidine, imidazole, naphthalene, or thiophene, wherein the divalent bond is on an adjacent ring carbon atom; (iii) nitro, cyano, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, carbon atom 1 Divalent cycloalkyl of 4 to 10 carbon atoms unsubstituted or substituted with one or more substituents each independently selected from the group consisting of alkyl of 10 to 10, alkoxy, phenyl or halo of 1 to 10 carbon atoms; (iv) nitro, cyano, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, carbamoyl substituted with alkyl of 1 to 3 carbon atoms, acetoxy, Di-substituted vinylene substituted with carboxy, hydroxy, amino, amino substituted with alkyl of 1 to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy or halo of 1 to 4 carbon atoms; Or (v) nitro, cyano, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, carbamoyl substituted with alkyl of 1 to 3 carbon atoms, acetoxy Or substituted with 1 to 2 substituents each independently selected from carboxy, hydroxy, amino, amino substituted with alkyl of 1 to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy or halo of 1 to 4 carbon atoms, or Or unsubstituted ethylene;

R ⁶ is —CO—, —CH ₂ —, —CH ₂ CO—, or —SO ₂ —;

R ⁷ is (i) straight or branched chain alkyl of 1 to 12 carbon atoms; (ii) cyclic or bicyclicalkyl of up to 12 carbon atoms; (iii) pyridyl; (iv) nitro, cyano, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, straight chain of 1 to 10 carbon atoms , Branched chain, cyclic or bicyclic alkyl, straight chain, branched chain, cyclic, or bicyclic alkoxy of 1 to 10 carbon atoms, CH ₂ R wherein R is cyclic or bi of carbon atoms 1 to 10 Cyclic alkyl), or phenyl substituted with one or more substituents each independently selected from halo; (v) nitro, cyano, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 4 carbon atoms Benzyl substituted with 1 to 3 substituents each independently selected from the group consisting of alkoxy or halo of 1 to 10 carbon atoms; (vi) naphthyl; Or (vii) benzyloxy;

n has a value of 0, 1, 2, or 3.

Other specific selective cytokine inhibitory drugs include the aryl amides of US Pat. Nos. 5,801,195, 5,736,570, 6,046,221 and 6,284,780 (e.g., N-benzoyl-3-amino-3- (3 ', 4) '-Dimethoxyphenyl) -propanamide), each of which is incorporated herein by reference. Representative compounds have the formula:

here:

Ar is (i) unsubstituted straight, branched or cyclic alkyl of 1 to 12 carbon atoms; (ii) straight, branched or cyclic alkyl of substituted carbon atoms 1-12; (iii) phenyl; (iv) nitro, cyano, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, carbon atom 1 Phenyl substituted with one or more substituents each independently selected from the group consisting of alkyl of 10 to 10, alkoxy of 1 to 10 carbon atoms, or halo; (v) heterocycles; Or (vi) nitro, cyano, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, of 1 to 10 carbon atoms Heterocycle substituted with one or more substituents each independently selected from alkyl, 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, wherein Z is alkoxy, benzyloxy, or NHR ¹ of carbon atoms 1 to 10, wherein R ¹ is H or alkyl of 1 to 10 carbon atoms;

Y is i) nitro, cyano, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, of 1 to 10 carbon atoms Phenyl or heterocycle rings optionally substituted with one or more substituents each independently selected from alkyl, alkoxy of 1 to 10 carbon atoms, or halo; Or ii) naphthyl. Specific examples of the compound have the formula:

here:

Ar is substituted with each substituent nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, carbon atoms 1-10 3,4-disubstituted phenyl independently selected from the group consisting of alkyl of, alkoxy of 1 to 10 carbon atoms, and halo;

Z is alkoxy, benzyloxy, amino, or alkylamino of 1 to 10 carbon atoms;

Y is (i) nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, carbon atoms 1-10 Phenyl unsubstituted or substituted with one or more substituents each independently selected from the group consisting of alkyl, alkoxy of 1 to 10 carbon atoms, and halo, or (ii) naphthyl.

Other specific selective cytokine inhibitory drugs include imide / amide ethers and alcohols disclosed in US Pat. No. 5,703,098 (eg, 3-phthalimido-3- (3 ', 4'-dimethoxyphenyl) propane-1- O), which is incorporated herein by reference. Representative compounds have the general formula:

here:

R ¹ is (i) straight, branched, or cyclic, alkyl of 1 to 12 unsubstituted carbon atoms; (ii) straight chain, branched, or cyclic alkyl of substituted carbon atoms 1-12; (iii) phenyl; Or (iv) nitro, cyano, trifluoromethyl, carboethoxy, 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 having 5 to 12 carbon atoms, and phenyl substituted with one or more substituents each independently selected from the group consisting of halo;

R ² is hydrogen, alkyl of 1 to 8 carbon atoms, benzyl pyridylmethyl, or alkoxymethyl;

R ³ represents (i) ethylene, (ii) vinylene, (iii) branched alkylene of 3 to 10 carbon atoms, (iv) branched alkenylene of 3 to 10 carbon atoms, (v) nitro, cyano, Trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, amino substituted with alkyl of 1 to 6 carbon atoms, carbon atom 1 4 to 9 carbon atoms, unsubstituted or substituted with one or more substituents each independently selected from the group consisting of amino substituted with acyl of 6 to 6, alkyl of 1 to 10 carbon atoms, alkoxy and halo of 1 to 12 carbon atoms Cycloalkylene, (vi) nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, carbon atoms Amino, carbon substituted with 1 to 6 alkyl Carbon atoms, unsubstituted or substituted with one or more substituents each independently selected from the group consisting of amino substituted by acyl of 1 to 6 atoms, alkyl of 1 to 10 carbon atoms, alkoxy and halo of 1 to 12 carbon atoms Cycloalkenylene of 4 to 9, (vii) nitro, cyano, trifluoromethyl, carbuethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino Each independently selected from the group consisting of 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 and halo of 1 to 12 carbon atoms O-phenylene, unsubstituted or substituted with one or more substituents, (viii) naphthyl, or (ix) pyridyl;

R ⁴ is -CX -, - CH ₂ - or -CH ₂ CX- gt;

X is O or S;

n is 0, 1, 2, or 3.

Other specific selective cytokine inhibitory drugs include succinimides and maleimides disclosed in US Pat. No. 5,658,940, incorporated herein by reference (eg, methyl 3- (3 ', 4', 5 ', 6'-tetra). Hydrophthalimido) -3- (3 ", 4" -dimethoxyphenyl) propionate). Representative compounds have the general formula:

here:

R ¹ is —CH ₂ —, —CH ₂ CO—, or —CO—;

R ² and R ³ are each independently selected from each other from the group consisting of (i) phenyl unsubstituted or substituted with alkyl of 1 to 10 carbon atoms, (ii) phenyl and alkyl of 1 to 10 carbon atoms. Or substituted with vinylene substituted with four substituents, or (iii) nitro, cyano, trifluoromethyl, carbrothoxy, carbomethoxy, carbopropoxy, acetyl, alkyl of 1 to 3 carbon atoms Unsubstituted carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy, norbornyl, phenyl or halo of 1 to 10 carbon atoms Divalent cycloalkyl of 5 to 10 carbon atoms, each substituted or unsubstituted with one or more substituents selected;

R ⁴ is (i) straight or branched alkyl of 4 to 8 unsubstituted carbon atoms, (ii) nitro, cyano, trifluoromethyl, carbuethoxy, carbomethoxy, carbopropoxy, acetyl, carbo Independently from each other from the group consisting of barmoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, branched from 1 to 10 carbon atoms, straight or cyclic alkyl, alkoxy, phenyl or halo of 1 to 10 carbon atoms Cycloalkyl or bicycloalkyl of 5 to 10 carbon atoms, optionally substituted by one or more substituents selected, (iii) nitro, cyano, trifluoromethyl, carboethoxy, carbomethoxy, carbo Propoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, or Is bicycloalkyl, cycloalkoxy having 3 to 10 carbon atoms or biphenyl, substituted by one or more substituents each independently selected from the group consisting of phenyl or halo, (iv) nitro, cyano, trifluoro Methyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, of 1 to 10 carbon atoms Pyridine or pyrrolidine, unsubstituted or substituted with one or more substituents each independently selected from the group consisting of alkoxy, phenyl or halo;

R ⁵ is —COX, —CN, —CH ₂ COX, alkyl of 1 to 5 carbon atoms, aryl, —CH ₂ OR, —CH ₂ aryl, or —CH ₂ OH,

Wherein X is NH ₂ , OH, NHR, or OR ⁶ ,

Wherein R is lower alkyl;

Wherein R ⁶ is alkyl or benzyl.

Other specific selective cytokine inhibitory drugs include substituted imides (e.g., 2-phthalimido-3- (3 ', 4'-dimethoxyphenyl) disclosed in US Pat. No. 6,429,221, which is incorporated herein by reference. Propane).

Representative compounds have the formula:

here:

R ¹ is (i) straight, branched or cyclic alkyl of 1 to 12 carbon atoms, (ii) phenyl or nitro, cyano, trifluoromethyl, carboethoxy, carbomethoxy, carbopro Substituted with one or more substituents each independently selected from foxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, straight or branched alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo Phenyl, (iii) benzyl, or nitro, cyano, trifluoromethyl, carbuethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, Benzyl substituted with one or more substituents each independently selected from alkyl of carbon atoms 1-10, alkoxy of carbon atoms 1-10, or halo, or (iv) -Y-Ph, wherein Y is carbon atoms of 1 to 12 straight chain, branch Or cyclic alkyl, Ph is phenyl or nitro, cyano, trifluoromethyl, carbuethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino , Alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or phenyl substituted with one or more substituents each independently selected from halo;

R ² is —H, branched or unbranched alkyl of 1 to 10 carbon atoms, phenyl, pyridyl, heterocycle, —CH ₂ -aryl, or —CH ₂ -heterocycle;

R ³ is i) ethylene, ii) vinylene, iii) branched alkylene of 3 to 10 carbon atoms, iv) branched alkenylene of 3 to 10 carbon atoms, v) nitro, cyano, trifluoromethyl, Carbuethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or Cycloalkylene with 4 to 9 carbon atoms, unsubstituted or substituted with 1 to 2 substituents each independently selected from halo, vi) nitro, cyano, trifluoromethyl, carboethoxy, carbomethoxy, 1 to 2 each independently selected from carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 4 carbon atoms, alkoxy or halo of 1 to 4 carbon atoms With four substituents Or unsubstituted cycloalkenylene of 4 to 9 carbon atoms, or vii) nitro, cyano, trifluoromethyl, carbuethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, ace O-phenyl unsubstituted or substituted with 1 to 2 substituents each independently selected from oxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halo Ren;

R ⁴ is -CX, or -CH _2- ;

X is O or S.

Other specific selective cytokine inhibitory drugs include substituted 1,3,4-oxadiazoles disclosed in US Pat. No. 6,326,388, which is incorporated herein by reference (eg, 2- [1- (3-cyclopentyloxy-). 4-methoxyphenyl) -2- (1,3,4-oxadiazol-2-yl) ethyl] -5-methylisoindolin-1,3-dione). Representative compounds are compounds of the formula below and acid addition salts of these compounds containing protonable nitrogen atoms.

Where

Carbon atoms represented by * constitute a chiral center;

Y is C═O, CH ₂ , SO ₂ or CH ₂ C═O;

X is hydrogen or alkyl of 1 to 4 carbon atoms;

R ¹ , R ² , R ³ and R ⁴ are each independently of the other hydrogen, halo, trifluoromethyl, acetyl, alkyl of 1 to 8 carbon atoms, alkoxy of 1 to 4 carbon atoms, nitro, cyano, hydroxy , -CH ₂ NR ⁸ R ⁹ ,-(CH ₂ ) ₂ NR ⁸ R ⁹ or -NR ⁸ R ⁹ , or

Any ^two of R ¹ , R ² , R ³ and R ⁴ on adjacent carbon atoms together with the benzene ring shown may be naphthylidene, quinoline, quinoxaline, benzimidazole, benzodioxol or 2-hydroxybenzimi Dazole;

R ⁵ and R ⁶ are each independently of each other hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 6 carbon atoms, cyano, benzocycloalkoxy, cycloalkoxy of up to 18 carbon atoms, up to 18 carbon atoms Bicycloalkoxy, tricycloalkoxy of up to 18 carbon atoms or cycloalkylalkoxy of up to 18 carbon atoms;

R ⁸ and R ⁹ are each independently of each other hydrogen, straight or branched chain alkyl of 1 to 8 carbon atoms, phenyl, benzyl, pyridyl, pyridylmethyl, or one of R ⁸ and R ⁹ is hydrogen, the other Is -COR ¹⁰ or -SO ₂ R ¹⁰ , or R ⁸ and R ⁹ together are tetramethylene, pentamethylene, hexamethylene, -CH = NCH = CH- or -CH ₂ CH ₂ X ¹ CH ₂ CH _2- ( Wherein X ¹ is -O-, -S- or -NH-;

R ¹⁰ is hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl, cycloalkylmethyl of up to 6 carbon atoms, phenyl, pyridyl, benzyl, imidazolylmethyl, pyridylmethyl, NR ¹¹ R ¹² , CH ₂ R ¹⁴ R ¹⁵ or NR ¹¹ R ¹² ,

Wherein R ¹⁴ and R ¹⁵ are independently of each other hydrogen, methyl, ethyl or propyl,

Wherein R ¹¹ and R ¹² independently of one another are hydrogen, alkyl of 1 to 8 carbon atoms, phenyl or benzyl.

Specific examples of the compound are compounds of the formula

Where

Carbon atoms represented by * constitute a chiral center;

Y is C═O, CH ₂ , SO ₂ or CH ₂ C═O;

X is hydrogen or alkyl of 1 to 4 carbon atoms;

(i) R ¹ , R ² , R ³ and R ⁴ are each independently of each other hydrogen, halo, trifluoromethyl, acetyl, alkyl of 1 to 8 carbon atoms, alkoxy of 1 to 4 carbon atoms, nitro, cyano , Hydroxy, -CH ₂ NR ⁸ R ⁹ ,-(CH ₂ ) ₂ NR ⁸ R ⁹ or -NR ⁸ R ⁹ , or

(ii) any ^two of R ¹ , R ² , R ³ and R ⁴ on adjacent carbon atoms together with the illustrated benzene ring to which they are attached are naphthylidene, quinoline, quinoxaline, benzimidazole, benzodioxol Or 2-hydroxybenzimidazole;

R ⁵ and R ⁶ are each independently of each other hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 6 carbon atoms, cyano, benzocycloalkoxy, cycloalkoxy of up to 18 carbon atoms, up to 18 carbon atoms Bicycloalkoxy, tricycloalkoxy of up to 18 carbon atoms or cycloalkylalkoxy of up to 18 carbon atoms;

(i) R ⁸ and R ⁹ are each, independently of one another, hydrogen, alkyl of 1 to 8 carbon atoms, phenyl, benzyl, pyridyl, pyridylmethyl, or

(ii) one of R ⁸ and R ⁹ is hydrogen, the other is —COR ¹⁰ or —SO ₂ R ¹⁰ , wherein R ¹⁰ is hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl, 6 carbon atoms Cycloalkylmethyl, phenyl, pyridyl, benzyl, imidazolylmethyl, pyridylmethyl, NR ¹¹ R ¹² or CH ₂ R ¹⁴ R ¹⁵ , wherein R ¹¹ and R ¹² independently of one another are hydrogen, carbon atom 1 To 8 alkyl, phenyl or benzyl, R ¹⁴ and R ¹⁵ are independently of each other hydrogen, methyl, ethyl or propyl, or

(iii) R ⁸ and R ⁹ together are tetramethylene, pentamethylene, hexamethylene, -CH = NCH = CH- or -CH ₂ CH ₂ X ¹ CH ₂ CH _2- , wherein X ¹ is -O-,- S- or -NH-.

Other specific selective cytokine inhibitory drugs are substituted with an α- (3,4-disubstituted phenyl) alkyl group at position 2 as disclosed in WO 01/34606, incorporated herein by reference, and position 4 and / or 5 Isoindolin-1-one and isoindolin-1,3-dione substituted with a nitrogen-containing group at, but are not limited thereto. Representative compounds include compounds of the formula

Where

Carbon atoms represented by * constitute a chiral center;

R ¹ and R ² are each independently of one another alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cyano, cycloalkoxy of 3 to 18 carbon atoms, cycloalkyl of 3 to 18 carbon atoms, or cycloalkyl Cycloalkylmethoxy having 3 to 18 carbon atoms;

One of X and X 'is = C = O or = SO ₂ and the other of X and X' is a divalent group selected from = C = O, = CH ₂ , = SO ₂ or = CH ₂ C = O ;

n has a value of 1, 2 or 3;

R ³ is —SO ₂ —Y, —COZ, —CN, or hydroxyalkyl of 1 to 6 carbon atoms, wherein

Y is alkyl of 1 to 6 carbon atoms, phenyl or benzyl;

Z is —NR ^{6 ″} R ^{7 ″} , alkyl of 1 to 6 carbon atoms, phenyl or benzyl;

R ^{6 ″} is hydrogen, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 18 carbon atoms, phenyl, benzyl or alkanoyl of 2 to 5 carbon atoms, each of which is halo, amino or 1 to 4 carbon atoms Substituted or unsubstituted with alkylamino;

R ^{7 ″} is hydrogen or alkyl of 1 to 4 carbon atoms;

R ⁴ and R ⁵ together are (i) -NH-CH ₂ -R ^8- , -NH-CO-R ⁸ -or -N = CH-R ^8- , wherein -R ⁸ -is -CH _2- Or -O-, -NH-, -CH = CH-, -CH = N- or -N = CH-, or

이고,(ii) independently, R ⁴ and R ⁵ is one of hydrogen, R ⁴ and R ⁵ of the other is imidazolyl, pyrrolyl each other; Oxadiazolyl, triazolyl, or chemical formula

ego,

Where z is 0 or 1;

R ⁶ is, independently of R ⁷ , hydrogen; Alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 18 carbon atoms, alkanoyl of 2 to 5 carbon atoms, or cycloalkanoyl of 2 to 6 carbon atoms [each of which is halo, amino, monoalkylamino or dialkyl Amino (with each alkyl group containing 1-4 carbon atoms) or unsubstituted; Phenyl; benzyl; Benzoyl; Alkoxycarbonyl having 2 to 5 carbon atoms; Alkoxyalkylcarbonyl having 2 to 5 carbon atoms; N-morpholinocarbonyl; Carbamoyl; N-substituted carbamoyl [wherein the substituents are 1 to 4 carbon atoms of alkyl, 3 to 18 cycloalkyl of carbon atoms, or 2 to 5 alkanoyl of carbon atoms, each of which is halo, amino, monoalkylamino Or unsubstituted or substituted with dialkylamino, wherein each alkyl group contains 1 to 4 carbon atoms; Phenyl; benzyl; Or methylsulfonyl;

이고,R ⁷ is hydrogen, alkyl of 1 to 4 carbon atoms, methylsulfonyl; Or alkoxyalkylcarbonyl having 2 to 5 carbon atoms. Preferably, (i) when R ³ is -SO ₂ -Y, -COZ or -CN, and (ii) R ⁴ or R ⁵ is hydrogen, z is not zero. R ⁶ and R ⁷ together with each other —CH═CH—CH═CH—, —CH═CH—N═CH—, or amino, alkylamino or dialkylamino, wherein each alkyl group has from 1 to 4 carbon atoms May have 1 or 2 alkylidene carbon atoms, and one of R ⁴ and R ⁵ is

ego,

이고,Wherein R ⁶ , R ⁷ and z are as defined above; The other of R ⁴ and R ⁵ is

ego,

Where z 'is 0 or 1;

R ^{6 '} has the same meaning as R ⁶ , but is selected independently from it;

R ^{7 ′} has the same meaning as R ⁷ but is selected independently.

Specific examples of the compound are compounds of the formula

Where

R ¹ and R ² are each independently of one another alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cyano, cycloalkoxy of 3 to 18 carbon atoms, cycloalkyl of 3 to 18 carbon atoms, or cycloalkyl Methoxy, wherein cycloalkyl has 3 to 18 carbon atoms;

One of X and X 'is = C = O or = SO ₂ and the other of X and X' is a divalent group selected from = C = O, = CH ₂ , = SO ₂ or CH ₂ CO;

R ³ is —SO ₂ —Y, —COZ, —CN, or hydroxyalkyl of 1 to 6 carbon atoms, wherein

Y is alkyl of 1 to 6 carbon atoms, phenyl or benzyl;

Z is —NR ^{6 ″} R ^{7 ″} , alkyl of 1 to 6 carbon atoms, phenyl or benzyl;

R ^{6 ″} is hydrogen, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 18 carbon atoms, phenyl, benzyl or alkanoyl of 2 to 5 carbon atoms, each of which is halo, amino or 1 to 4 carbon atoms Substituted or unsubstituted with alkylamino;

R ^{7 ″} is hydrogen or alkyl of 1 to 4 carbon atoms;

n has a value of 1, 2 or 3;

(i) R ⁴ and R ⁵ together are —NH—CH ₂ —R ⁸ —, —NH—CO—R ⁸ — or —N═CH—R ⁸ —, where —R ⁸ — is —CH ₂ — Or -O-, -NH-, -CH = CH-, -CH = N- or -N = CH-, or

(ii) independent of each other,

이고,(1) one of R ⁴ and R ⁵ is hydrogen and the other of R ⁴ and R ⁵ is imidazolyl, pyrrolyl; Oxadiazolyl, triazolyl, or chemical formula

ego,

Wherein z is 0 or 1, provided that (i) R ³ is —SO ₂ Y, —COZ or —CN, and (ii) when R ⁴ or R ⁵ is hydrogen, z is not zero;

R ⁶ is, independently of R ⁷ , hydrogen; Alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 18 carbon atoms, alkanoyl of 2 to 5 carbon atoms, or cycloalkanoyl of 2 to 6 carbon atoms [each of which is halo, amino, monoalkylamino or dialkyl Amino (with each alkyl group containing 1-4 carbon atoms) or unsubstituted; Phenyl; benzyl; Benzoyl; Alkoxycarbonyl having 2 to 5 carbon atoms; Alkoxyalkylcarbonyl having 2 to 5 carbon atoms; N-morpholinocarbonyl; Carbamoyl; N-substituted carbamoyl [wherein the substituents are 1 to 4 carbon atoms of alkyl, 3 to 18 cycloalkyl of carbon atoms, or 2 to 5 alkanoyl of carbon atoms, each of which is halo, amino, monoalkylamino Or substituted or unsubstituted with dialkylamino, wherein each alkyl group contains 1 to 4 carbon atoms; Phenyl; benzyl; Or methylsulfonyl;

R ⁷ is hydrogen, alkyl of 1 to 4 carbon atoms, methylsulfonyl; Or alkoxyalkylcarbonyl having 2 to 5 carbon atoms;

R ⁶ and R ⁷ together represent —CH═CH—CH═CH—, —CH═CH—N═CH—, or amino, alkylamino or dialkylamino, wherein each alkyl group has from 1 to 4 carbon atoms Or alkylidene of 1 or 2 carbon atoms substituted with; or

이고,(2) one of R ⁴ and R ⁵ is

ego,

이고,Wherein R ⁶ , R ⁷ and z each have the meaning defined above; The other of R ⁴ and R ⁵ is

ego,

Where z 'is 0 or 1;

R ^{6 '} has the same meaning as R ⁶ , but is selected independently from it;

R ^{7 ′} has the same meaning as R ⁷ , but is selected independently and the carbon atoms indicated constitute a chiral center. Specific compounds are compounds of the formula and enantiomers thereof.

Another specific selective cytokine inhibitory drug is an imido and amido substituted acylhydroxysamic acid (e.g., (3- (1,3-dioxoisoindolin) disclosed in WO 01/45702, which is incorporated herein by reference. -2-yl) -3- (3-ethoxy-4-methoxyphenyl) propanoylamino) propanoate Representative compounds are compounds of the formula:

Where

Carbon atoms represented by * constitute a chiral center;

R ⁴ is hydrogen or — (C═O) —R ¹² ,

R ¹ and R ¹² are each independently of each other alkyl, phenyl, benzyl, pyridyl methyl, pyridyl, imidazolyl, imidazolyl methyl, or 1 to 6 carbon atoms, or

CHR ^* (CH ₂ ) _n NR ^* R ⁰ ,

Wherein R ^* and R ⁰ are, independently from each other, hydrogen, alkyl of 1 to 6 carbon atoms, phenyl, benzyl, pyridyl methyl, pyridyl, imidazolyl or imidazolylmethyl, n = 0, 1 or 2 ego;

R ⁵ is C═O, CH ₂ , CH ₂ —CO—, or SO ₂ ;

R ⁶ and R ⁷ are each independently of each other nitro, cyano, trifluoromethyl, carethoxy, 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- Nyloxy, 2-indanyloxy, C ₄ -C ₈ -cycloalkylidenemethyl or C ₃ -C ₁₀ -alkylidenemethyl;

R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently of one another,

(i) hydrogen, nitro, cyano, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino, dialkyl Amino, acylamino, alkyl of 1 to 10 carbon atoms, alkoxy, halo, or 1 to 10 carbon atoms

(ii) one of R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ is acylamino including lower alkyl and the other of R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ is hydrogen, or

(iii) hydrogen (when R ⁸ and R ⁹ together are benzo, quinoline, quinoxaline, benzimidazole, benzodioxole, 2-hydroxybenzimidazole, methylenedioxy, dialkoxy or dialkyl), or

(iv) hydrogen (when R ¹⁰ and R ¹¹ together are benzo, quinoline, quinoxaline, benzimidazole, benzodioxole, 2-hydroxybenzimidazole, methylenedioxy, dialkoxy or dialkyl), or

(v) hydrogen (when R ⁹ and R ¹⁰ together are benzo).

In addition, certain selective cytokine inhibitory drugs include, but are not limited to, the 7-amido-isoindoleyl compounds disclosed in US Provisional Application No. 60 / 454,155, filed March 12, 2003, which is incorporated herein by reference. Include. Representative compounds are compounds of the formula: or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates or prodrugs thereof.

Where

Y is -C (O) -, - CH 2, -CH 2 C (O) - or SO _2, and;

X is H,

Z is (C _0-4 -alkyl) -C (O) R ³ , C _1-4 -alkyl, (C _0-4 -alkyl) -OH, (C _1-4 -alkyl) -O (C _{1- 4} -alkyl), (C _1-4 -alkyl) -SO ₂ (C _1-4 -alkyl), (C _0-4 -alkyl) -SO (C _1-4 -alkyl), (C _0-4- Alkyl) -NH ₂ , (C _0-4 -alkyl) -N (C _1-8 alkyl) ₂ , (C _0-4 -alkyl) -N (H) (OH), CH ₂ NS0 ₂ (C _{1- 4} -alkyl);

R ₁ and R ₂ are independently C _1-8 -alkyl, cycloalkyl or (C _1-4 -alkyl) cycloalkyl;

R ³ is NR ⁴ R ⁵ , OH or O— (C _1-8 -alkyl);

R ⁴ is H;

R ⁵ is —OH or —OC (O) R ⁶ ;

R ⁶ is C _1-8 -alkyl, amino- (C _1-8 -alkyl), (C _1-8 -alkyl)-(C _3-6 -cycloalkyl), C _3-6 -cycloalkyl, phenyl, Benzyl or aryl.

Or a compound of the formula: or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof.

Where

Y is —C (O) —, —CH ₂ , —CH ₂ C (O) — or SO ₂ ;

X is halogen, -CN, -NR ₇ R ₈ , -N0 ₂ or -CF ₃ ,

W is

이고;

ego;

Z is (C _0-4 -alkyl) -SO ₂ (C _1-4 -alkyl),-(C _0-4 -alkyl) -CN, (C _0-4 -alkyl) -C (O) R ³ , C _1-4 -alkyl, (C _0-4 -alkyl) OH, (C _0-4 -alkyl) O (C _1-4 -alkyl), (C _0-4 -alkyl) SO (C _1-4- Alkyl), (C _0-4 -alkyl) NH ₂ , (C _0-4 -alkyl) N (C _1-8 -alkyl) ₂ , (C _0-4 -alkyl) N (H) (OH) or ( C _0-4 -alkyl) NSO ₂ (C _1-4 -alkyl);

W is -C _3-6 -cycloalkyl,-(C _1-8 -alkyl)-(C _3-6 -cycloalkyl),-(C _0-8 -alkyl)-(C _3-6 -cycloalkyl) NR ₇ R ₈ , (C _0-8 -alkyl) -NR ₇ R ₈ , (C _0-4 -alkyl) -CHR _9- (C _0-4 -alkyl) -NR ₇ R ₈ ,

R ₁ and R ₂ are independently C _1-8 -alkyl, cycloalkyl or (C _1-4 -alkyl) cycloalkyl;

R ³ is C _1-8 -alkyl, NR ⁴ R ⁵ , OH or O- (C _1-8 -alkyl);

R ⁴ and R ⁵ are independently H, C _1-8 -alkyl, (C _0-8 -alkyl)-(C _3-6 -cycloalkyl), OH or -OC (O) R ⁶ ;

R ⁶ is C _1-8 -alkyl, (C _0-8 -alkyl)-(C _3-6 -cycloalkyl), amino- (C _1-8 -alkyl), phenyl, benzyl or aryl;

R ₇ and R ₈ are each independently H, C _1-8 -alkyl, (C _0-8 -alkyl)-(C _3-6 -cycloalkyl), phenyl, benzyl, aryl or together with the atoms connecting them May represent a 3-7 membered heterocycloalkyl or heteroaryl ring with one another;

R ₉ is C _1-4 -alkyl, (C _0-4 -alkyl) aryl, (C _0-4 -alkyl)-(C _3-6 -cycloalkyl), (C _0-4 -alkyl) _-heterocycle to be.

In addition, certain selective cytokine inhibitory drugs include, but are not limited to, N-alkyl-hydroxysamic acid-isoin disclosed in US Provisional Application No. 60 / 454,149, filed March 12, 2003, which is incorporated herein by reference. It includes a compound to be turned. Representative compounds are compounds of the formula: or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates or prodrugs thereof.

Where

Y is —C (O) —, —CH ₂ , —CH ₂ C (O) — or S0 ₂ ;

R ₁ and R ₂ are independently C _1-8 -alkyl, CF ₂ H, CF ₃ , CH ₂ CHF ₂ , cycloalkyl or (C _1-8 -alkyl) cycloalkyl;

Z ₁ is H, C _1-6 -alkyl, -NH ₂ , -NR ₃ R ₄ or OR ₅ ;

Z ₂ is H or C (O) R ₅ ;

X ₁ , X ₂ , X ₃ and X ₄ are each independently H, halogen, N0 ₂ , OR ₃ , CF ₃ , C _1-6 -alkyl, (C _0-4 -alkyl)-(C _3-6- Cycloalkyl), (C _0-4 -alkyl) -N- (R ₈ R ₉ ), (C _0-4 -alkyl) -NHC (O)-(R ₈ ), (C _0-4 -alkyl)- NHC (O) CH (R ₈ ) (R ₉ ), (C _0-4 -alkyl) -NHC (O) N (R ₈ R ₉ ), (C _0-4 -alkyl) -NHC (O) O ( R ₈ ), (C _0-4 -alkyl) -OR ₈ , (C _0-4 -alkyl) -imidazolyl, (C _0-4 -alkyl) -pyrrolyl, (C _0-4 -alkyl) oxa Diazolyl, (C _0-4 -alkyl) -triazolyl or (C _0-4 -alkyl) _-heterocycle ;

R ₃ , R ₄ and R ₅ are each independently H, C _1-6 -alkyl, OC _1-6 -alkyl, phenyl, benzyl or aryl;

R ₆ and R ₇ are independently H or C _1-6 -alkyl;

R ₈ and R ₉ are each independently H, C _1-9 -alkyl, C _3-6 -cycloalkyl, (C _1-6 -alkyl)-(C _3-6 -cycloalkyl), (C _0-6 -Alkyl) -N (R ₄ R ₅ ), (C _1-6 -alkyl) -OR ₅ , phenyl, benzyl, aryl, piperidinyl, piperidinyl, pyrrolidinyl, morpholino or C _3-7 Heterocycloalkyl.

Compounds of the invention are commercially available or may be prepared according to the methods described in the patents or patent publications disclosed herein. In addition, optically pure compositions can be asymmetrically synthesized or separated using other standard synthetic organic chemistry techniques as well as known disintegrating agents or chiral columns.

As used herein, unless otherwise specified, the term "pharmaceutically acceptable salts" includes addition salts of non-toxic acids and bases of the compound to which the term refers. Acceptable nontoxic acid addition salts include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, tartaric acid, lactic acid, succinic acid, citric acid, malic acid, maleic acid, sorbic acid, aconitic acid, salicylic acid, phthalic acid, emvolic acid and enan Those derived from organic and inorganic acids or salts known in the art, including formic acid, and the like.

Inherently acidic compounds may form salts with various pharmaceutically acceptable bases. Bases that can be used in the preparation of pharmaceutically acceptable base addition salts of such acidic compounds are non-toxic base addition salts, ie salts containing pharmacologically acceptable cations, for example alkali metal or alkaline earth metal salts, and especially calcium salts, magnesium Salts, sodium salts or potassium salts, but are not limited to these. Suitable organic bases include, but are not limited to, N, N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), lysine and procaine, and the like. It is not.

As used herein, unless otherwise specified, the term “prodrug” means a derivative of a compound that can be hydrolyzed, oxidized or otherwise reacted to provide a compound under biological conditions (in vitro or in vivo). Examples of prodrugs include, but are not limited to, biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides and biohydrolyzable phosphate homologs. Derivatives of cytokine inhibitory drugs include, but are not limited to. Other examples of prodrugs include derivatives of selective cytokine inhibitory drugs that include -NO, -NO ₂ , -ONO or -ONO ₂ residues. Prodrugs are commonly known methods, for example Burger's Medicinal Chemistry and Drug Discovery, 172-178, 949-982 (Manfred E. Wolff ed., 5th ed. 1995) and Design of Prodrugs (H. Bundgaard ed., Elselvier, New York 1985).

As used herein, unless otherwise specified, the terms "biohydrolyzable amide", "biohydrolyzable ester", "biohydrolyzable carbamate", "biohydrolyzable carbonate", "biohydrolyzable woo" Laid "," biohydrolyzable phosphate "may 1) impart beneficial properties to the compound in vivo, such as absorption, duration of action or onset of action without interfering with the biological activity of the compound; Or 2) amide, ester, carbamate, carbonate, ureate or phosphate, respectively, of a compound that is biologically inert but converted to a biologically active compound in vivo. Examples of biohydrolyzable esters include lower alkyl esters, lower acyloxyalkyl esters (eg, acetosylmethyl, acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl and pivaloyloxyethyl esters), lactonyl esters (E.g. phthalidyl and thiophthalidyl esters), lower alkoxyacyloxyalkyl esters (e.g. methoxycarbonyloxymethyl, ethoxycarbonyloxyethyl and isopropoxycarbonyloxyethyl esters), alkoxyalkyl esters , Choline esters and acylamino alkyl esters (eg, acetamidomethyl esters). Examples of biohydrolyzable amides include, but are not limited to, lower alkyl amides, α-amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides. Examples of biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, amino acids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines.

Various selective cytokine inhibitory drugs contain one or more chiral centers and may exist in racemic mixtures of enantiomers or mixtures of diastereomers. The present invention includes the use of pure stereoisomeric forms of such compounds and the use of mixtures of these forms. For example, mixtures comprising the same or non-equivalent amounts of enantiomers of selective cytokine inhibitory drugs can be used in the methods and compositions of the present invention. Purified (R) or (S) enantiomers of the specific compounds disclosed herein can be used in the substantial absence of another enantiomer thereof.

As used herein, unless stated otherwise, the term "stereoisomerically pure" means a composition that includes one stereoisomer of a compound but is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure composition of a compound having one chiral center will be substantially free of the relative enantiomers of that compound. Stereoisomeric pure compositions of a compound having two chiral centers will be substantially free of other diastereomers of that compound. Typical stereoisomerically pure compounds comprise greater than about 80 weight percent of one stereoisomer of the compound and less than about 20 weight percent of the other stereoisomer of the compound, more preferably greater than about 90 weight percent of one stereoisomer of the compound and other stereoisomers of the compound. Less than about 10 weight percent, even more preferably greater than about 95 weight percent of one stereoisomer of the compound and less than about 5 weight percent of the other stereoisomer of the compound, most preferably greater than about 97 weight percent of one stereoisomer of the compound and Less than about 3 weight percent of other stereoisomers.

As used herein, unless otherwise specified, the term "stereoenhanced" means more than about 60 weight percent of one stereoisomer of the compound, preferably more than about 70 weight percent of one stereoisomer of the compound, more preferably Means a composition comprising greater than about 80% by weight.

As used herein, unless otherwise specified, the term "enantiomerically pure" means a stereoisomerically pure composition of a compound having one chiral center. Similarly, the term “stereoisotropically enhanced” means a stereoisomerically enhanced composition of a compound having one chiral center.

It should be noted that if the described structure is inconsistent with the name given to the structure, more emphasis should be placed on the described structure. In addition, when a stereochemistry of a structure or part of a structure is not indicated by a thick line or dotted line, the structure or part of the structure should be interpreted as including all stereoisomers thereof.

4.2 Second active ingredient

As discussed above, the second active ingredient or agent may be used in the methods and compositions of the present invention in combination with selective cytokine inhibitory drugs, in particular conventional or therapeutic agents used to treat or manage central nervous system disorders. In addition, certain second active agents promote the division and differentiation of committed erythrocyte precursors in cells in vivo or in vitro.

In one embodiment, the second active ingredient can be administered with a selective cytokine inhibitory drug. In one embodiment, the second active ingredient is a dopamine agonist or antagonist, such as, but not limited to, levodopa, L-DOPA / carbidopa combination, cocaine, α-methyl-tyrosine, reserpin, tetrabenazine , Parglin, phenodolpam, mesylate, cabergoline, pramipexole dihydrochloride, ropinolol, amantadine hydrochloride, selegiline hydrochloride, carbidopa, pergolide mesylate, cinemet CR or cimet It's Lel.

In another embodiment, the second active ingredient administered with the selective cytokine inhibitory drug is MAO, such as, but not limited to, iproniazide, chlorgiline, phenelgin and isocarboxazide.

In another embodiment, the second active ingredient administered with the selective cytokine inhibitory drug is COMT, such as, but not limited to, tolcapone and entacapone.

In another embodiment, the second active ingredient administered with a selective cytokine inhibitory drug is an acetylcholinesterase inhibitor, such as, but not limited to, tacrine, donepezil, rivastigmine, physstigmine sally Crate, physostigmine sulphate, physostigmine bromide, meostigmine bromide, neostigmine methylsulfate, trimedoxime bromide, diacetyl monoxime, endrophonium, pyridostigmine and demecarium.

In another embodiment, the second active ingredient administered with a selective cytokine inhibitory drug is, but is not limited to, naproxen sodium, diclofenac sodium, diclofenac potassium, celecoxib, sulindac, oxaprozin, diflunisal, Etodolak, Meloxycham, Ibuprofen, Ketoprofen, Nabumethone, Lefecoxib, Methotrexate, Etodolac, Meloxycham, Ibuprofen, Ketoprofen, Nabuprofen, Nabumetone, Lefecoxib, Methotrexate, Lefluflux Nomid, sulfasalazine, gold salt, RHo-D Immune Globulin, mycophenylate mofetil, cyclosporine, azathioprine, tacrolimus, basilicimab, daclizumab, salicylic acid, acetylsalicylic acid , Methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazine, acetaminophen, indomethacin, sulindac, mefenamic acid, metlofenamate sodium, tolmethine, ketorolac, Diclofenac, Flurbinpropene, Oxaprozin, Pyroxycham, Meloxycham, Ampiroxycam, Doxycham, Cocsicam, Tenoxycam, Phenylbutazone, Oxyfenbutazone, Antipyrine, Aminopyrin, Apazone , Anti-inflammatory agents including, zileuton, aurothioglucose, gold sodium thiomalate, auranopine, methotrexate, colchicine, allopurinol, probenside, sulfinpyrazone and benzbromarone or betamethasone and other glucocorticoids.

In another embodiment, the second active ingredient administered with a selective cytokine inhibitory drug is an antiemetic agent, such as, but not limited to, metoclopromid, domperidone, prochlorperazine, promethazine, chlor Promazine, Trimethobenzamide, Ondansetron, Granistron, Hydroxyzine, Acetylleucine Monoethanolamine, Alizaprid, Azasetron, Benzquinamide, Bietaunatin, Bromoprid, Buclizin , Clevoprid, Cyclizin, Dimenhydrinate, Diphenidol, Dolasetron, Meclizin, Metallatal, Metopimarine, Nabilone, Oxyperdil, Piperazine, Scopolamine, Sulpyrid, Tetra Hydrocannabinol, thiethylperazine, thioproprazine, trocetolone and mixtures thereof.

4.3 Treatment and Care Methods

The methods of the present invention include methods for the prevention, treatment and / or management of central nervous system disorders. Unless otherwise specified, the term "prevention" as used herein includes, but is not limited to, suppression or avoidance of symptoms associated with central nervous system disorders. Central nervous system disorders include Parkinson's disease; Alzheimer's disease, mild cognitive impairment; depression; Organ memory damage; Amyotrophic lateral sclerosis (ALS); CNS trauma; Dyskinesia; Motor laxity; Slowing of operation; Lack of motion; Weakening of agility; Erectile dysfunction; Monotonous speaking; Muscle stiffness; Facial expression reduction; Reduced blinking; Squat posture; Reduction of arm shaking when walking; Melancholy; Development of Parkinson's disease; Walking in Parkinson's disease; Postural instability; Walking faster; Motion freezing; Cognitive, mood, sensory, sleep or autonomic dysfunction; dementia; And sleep disorders. Unless otherwise specified, the term "treatment" as used herein refers to administration of a composition after the onset of symptoms of a central nervous system disorder or related disorder, while "prevention" especially refers to a patient at risk of a central nervous system disorder or related disorder. Means administration before the onset of symptoms. Unless stated otherwise, the term “managing” as used herein refers to preventing recurrence of CNS symptoms in patients suffering from CNS disorders, alleviating symptoms for patients suffering from CNS disorders. Increasing the time that is left unattended, and / or preventing the occurrence of a central nervous system disorder in a patient at risk of suffering from a central nervous system disorder.

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

The present invention includes methods of treating or preventing central nervous system disorders, preferably Parkinson's disease or Alzheimer's disease. In one embodiment, the methods of the present invention are slow performance or ataxia, lack of movement or ataxia, movement disorders in which micromotor control and finger agility are weakened, and other signs of ataxia, such as dysphonia And monotonous speech and the like, but is not limited thereto. In another embodiment, the methods of the present invention are directed to the treatment or prevention of muscle stiffness-related disorders, including but not limited to a uniform increase in resistance to passive movement, discontinuation of passive movement, and a combination of stiffness and dystonia. Used. In certain embodiments, the methods of the invention are used to treat inflammation associated with Parkinson's or related diseases. In another embodiment of the present invention, disorders similar to the progression of Parkinson's disease, including, but not limited to, the progression of the face, jaw, tongue, posture, and other progression that are present during relaxation and are alleviated during movement, the method of the present invention. It is treated or prevented by. In another embodiment, the methods of the present invention treat or prevent walking disorders, including, but not limited to, walking, shuffling, short steps, turn en bloc tendencies, and rapid walking in Parkinson's disease. Used to. In another embodiment of the present invention, non-motor symptoms, including but not limited to mood, cognition, long-term memory impairment, sensory, sleep, dementia and depressive disorders, can be treated or prevented using the methods of the present invention. have. In another embodiment of the invention, drug-induced Parkinson's disease, Vascular Parkinson's disease, multiple systemic atrophy, progressive nuclear palsy, disorders with primary tau pathology, basal ganglia coronary degeneration, Parkinson's disease with dementia, hyperactivity A second form of Parkinson's disease, including, but not limited to, disorders, chorea, Huntington's disease, dystonia, Wilson's disease, Tourette's syndrome, essential tremor, myoclonus, and dyskinesia, is treated by the methods of the present invention. Or is prevented. In another embodiment of the present invention, other central nervous system disorders, including but not limited to Alzheimer's disease, mild cognitive impairment, atrophic lateral sclerosis (ALS) and CNS trauma, are treated or prevented by the methods of the present invention.

The methods encompassed by the present invention include those in which one or more selective cytokine inhibitory drugs, or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates, or prodrugs thereof, appear to suffer or suffer from central nervous system disorders. Administering to a patient (eg, a human).

Another method comprises the steps of: 1) at least one selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and 2) a second active agent or active ingredient. Administering. Examples of selective cytokine inhibitory drugs are disclosed herein (see, eg, Section 4.1); Examples of second active agents are also disclosed herein (see, eg, Section 4.2).

Administration of the selective cytokine inhibitory drug and the second active agent to the patient may occur simultaneously or sequentially, by the same or different routes of administration. The suitability of a particular route of administration used for a particular active agent will depend on the active agent itself (eg, whether it can be administered orally without degradation prior to entering the bloodstream) and the condition being treated. The preferred route of administration of the selective cytokine inhibitory drug is oral. Preferred routes of administration of the second active agents or components of the invention are known to those skilled in the art.

In one embodiment of the invention, the recommended daily dosage range of the selective cytokine inhibitory drug for the conditions described herein is a single dose once daily, or preferably as a divided dose throughout the day. , About 1 mg to about 10,000 mg per day. More specifically, the daily dose is administered twice daily in equally divided doses. Specifically, the daily dosage range is between about 1 mg and about 5,000 mg per day, more specifically between about 10 mg and about 2,500 mg per day, between 100 mg and about 800 mg per day, and between about 100 mg and per day Between about 1,200 mg, or between about 25 mg and about 2500 mg per day. In the management of the patient, the therapy can be started at lower dosages, possibly from about 1 mg to about 2,500 mg, and if necessary, increased from about 200 mg to about 5,000 mg per day, depending on the patient's comprehensive response, in single or divided doses. Should be administered. In certain embodiments, 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide is preferably about about per day It may be administered in divided doses in amounts of 400, 800, 1,200, 2,500, 5,000 or 10,000 mg.

In another embodiment, the selective cytokine inhibitory drug is administered in combination with a second active agent. The second active agent is administered orally, intravenously or subcutaneously, once or twice daily, in an amount of about 1 to about 1,000 mg, about 5 to about 500 mg, about 10 to about 350 mg, or about 50 to about 200 mg. . The specific amount of the second active agent will depend on the particular agent used, the disease being treated or managed, the severity and progression of the central nervous system disorder, and the amount of the selective cytokine inhibitory drug and any additional active agent administered simultaneously to the patient. will be.

In certain embodiments, the prophylactic or therapeutic agent of the invention is administered to a patient periodically. Cycling therapy requires administration of the first agent for a period of time, followed by administration of the agent and / or second agent for a period of time, and this sequential administration. Circulation therapy can reduce the development of resistance to one or more therapies, avoid or reduce the side effects of one of the therapies, and / or improve the therapeutic effect.

In a preferred embodiment, the prophylactic or therapeutic agent is administered about once or twice daily, about every 24 weeks. One cycle may include administration of a therapeutic or prophylactic agent and a rest period for at least one or three weeks. The number of cycles administered is about 1 to about 12 cycles, more typically about 2 to about 10 cycles, more typically about 2 to about 8 cycles.

4.4 Pharmaceutical Compositions and Single Unit Dosage Forms

Pharmaceutical compositions can be used in the manufacture of individual, single unit dosage forms. Pharmaceutical compositions and dosage forms of the invention include selective cytokine inhibitory drugs, or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates or prodrugs thereof. Pharmaceutical compositions and dosage forms of the invention may also include one or more excipients.

Pharmaceutical compositions and dosage forms of the invention may comprise one or more additional active agents. As a result, the pharmaceutical compositions and dosage forms of the present invention may comprise active agents disclosed herein (eg, selective cytokine inhibitory drugs, or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates or prodrugs thereof, and Second active agent). Examples of optional additional active agents are disclosed herein (see, eg, Section 4.2).

Single unit dosage forms of the invention may be administered orally, mucosa (eg, nasal, sublingual, intravaginal, buccal or rectal), parenteral (eg, subcutaneous, intravenous, bolus injection, intramuscular or intraarterial), dermal or skin to a patient. Suitable for transdermal administration. Examples of dosage forms include tablets, caplets, capsules (e.g. soft elastic gelatin capsules), cachets, troches, lozenges, dispersants, suppositories, powders, aerosols (e.g. nasal sprays or inhalants), Liquid dosage forms, solvents and elixirs, suitable for oral or mucosal administration, including gels, suspensions (e.g. aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), parenteral administration to patients And sterile solids (eg, crystalline or amorphous solids) that can be reconstituted to provide a liquid dosage form suitable for parenteral administration, and a liquid dosage form suitable for parenteral administration to a patient.

The composition, shape and type of dosage forms of the invention will generally vary depending on their use. For example, a dosage form used for the acute treatment of a disease may contain more of one or more active agents it contains than a dosage form used for chronic treatment of the same disease. Likewise, parenteral dosage forms may contain smaller amounts of one or more active agents it contains than oral dosage forms used to treat the same disease. Such and other ways in which certain dosage forms encompassed by the present invention may differ from one another will be readily understood by those skilled in the art (eg, Remington's Pharmaceutical Sciences , 18th ed., Mack Publishing, Easton PA (1990)) Reference).

Typical pharmaceutical compositions and dosage forms comprise one or more excipients. Suitable excipients are known to those skilled in the pharmaceutical arts, and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for introduction into a pharmaceutical composition or dosage form depends on a variety of factors known in the art, including but not limited to the manner in which the dosage form is administered to a patient. For example, oral dosage forms such as tablets may contain excipients that are not suitable for use in parenteral dosage forms. The suitability of particular excipients may also vary depending on the specific active agents in the dosage form. For example, degradation of some active agents may be accelerated by some excipients, such as lactose, or upon exposure to water. Active agents comprising primary or secondary amines are particularly susceptible to such accelerated degradation. As a result, the present invention includes pharmaceutical compositions and dosage forms which, if any, contain very small amounts of lactose, other monosaccharides or disaccharides. The term "lactose-free" as used herein means that the amount of lactose present is present in an amount insufficient to substantially increase the degradation rate of the active agent.

The lactose-free compositions of the present invention may include excipients known in the art and are listed, for example, in USP 25-NF20 (2002). Generally, the lactose-free composition comprises the active agent, the binder / filler and the lubricant in a pharmaceutically compatible and pharmaceutically acceptable amount. Preferred lactose-free dosage forms include active agents, microcrystalline cellulose, pregelatinized starch and magnesium stearate.

The present invention also encompasses anhydrous pharmaceutical compositions and dosage forms comprising the active agent as water may facilitate the degradation of some compounds. For example, the addition of water (eg 5%) as a means of stimulating long term storage to determine properties such as shelf life or stability over time of the formulation is widely accepted in the pharmaceutical arts (eg Jens T Carstensen, Drug Stablility: Principles & Practice , 2d.Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80). In short, water and heat accelerate the decomposition of some compounds. Thus, the effects of water on the formulation can be very important, as moisture and / or humidity are typically encountered during the manufacture, handling, packaging, storage, shipping and use of the formulation.

Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. If substantial contact with moisture and / or humidity is to be expected during the manufacturing, packaging and / or storage process, it is preferred that the pharmaceutical composition and dosage form comprising at least one active agent comprising lactose and a primary or secondary amine are anhydrous. .

Anhydrous pharmaceutical compositions should be prepared and stored so that their anhydrous properties are maintained. Thus, anhydrous compositions are preferably packaged with materials known to prevent exposure to water so that they can be included in the kit in a suitable manner. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (eg, vials), blister packs, and strip packs.

The invention also includes pharmaceutical compositions and dosage forms comprising one or more compounds that reduce the rate at which the active agent degrades. Such compounds referred to as “stabilizers” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers or salt buffers.

As with the amount and form of the excipient, the amount and specific form of the active ingredients in the dosage form can vary depending on factors such as, but not limited to, the route by which it is administered to the patient. However, typical dosage forms of the invention include selective cytokine inhibitory drugs, or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates or prodrugs thereof in an amount of about 1 to about 1200 mg. Typical dosage forms comprise a selective cytokine inhibitory drug of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, of about 1, 2, 5, 10, 25, 50, 100, In amounts of 200, 400, 800, 1,200, 2,500, 5,000 or 10,000 mg. In certain embodiments, a preferred dosage form comprises 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide at about 400, In amounts of 800 or 1,200 mg. Typical dosage forms comprise the second active ingredient in an amount of 1 to about 1000 mg, about 5 to about 500 mg, about 10 to about 350 mg, or about 50 to about 200 mg. Of course, the specific amount of the second active ingredient will vary depending on the particular agent used, the type of disease to be treated or managed, and the amount of the optional cytokine inhibitory drug of the invention and any optional additional active agents administered simultaneously to the patients. .

4.4.1 Oral dosage form

Pharmaceutical compositions of the invention suitable for oral administration may exist as separate dosage forms such as, but not limited to, tablets (e.g. chewable tablets), caplets, capsules and liquids (e.g. flavored syrups). have. Such dosage forms contain a predetermined amount of active agent and can be prepared by methods of pharmacy known to those skilled in the art (see generally Remigton's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990)). .

Typical oral dosage forms of the present invention are prepared by combining the active ingredients in a well mixed mixture with one or more excipients according to conventional pharmaceutical formulation techniques. Excipients can take a wide variety of forms depending on the form of preparation desired for administration. For example, excipients suitable for oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavorings, preservatives and coloring agents. Examples of excipients suitable for use in solid oral dosage forms (eg, powders, tablets, capsules and caplets) include starch, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders and disintegrants, It is not limited to this.

Tablets and capsules represent the most advantageous oral dosage unit forms when solid excipients are used because of their ease of administration. If desired, tablets may be coated by standard aqueous or non-aqueous techniques. Such dosage forms can be prepared by any of the methods of preparation. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and well mixing the active ingredient with the liquid carrier, finely divided solid carrier or both, and then, if necessary, shaping the product to the desired appearance.

For example, tablets can be made by compression or molding. Compressed tablets may be prepared by compressing the active ingredient in a suitable machine in a free-flowing form (optionally mixed with excipients) such as a powder or granules. Molded tablets may be prepared by molding in a suitable machine a mixture of the powdered compound soaked with an inert liquid diluent.

Examples of excipients that can be used in the oral dosage form of the invention include, but are not limited to, binders, fillers, disintegrants and lubricants. Suitable binders for use in pharmaceutical compositions and dosage forms include 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 its derivatives (e.g. ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, gelatinized starch, hydroxypropyl methyl cellulose (e.g. 2208, 2906, 2910), but not limited to microcrystalline cellulose and mixtures thereof.

Suitable forms of microcrystalline cellulose include those sold as Avicel-PH-101, Avicel-PH-103, Avicel RC-581, Avicel-PH-105 (FMC, American Viscose Division, Avicel Series, Marcus) Hooks (available from FMC Corporation, American Viscose Division, AVICEL Sales, Marcus Hook, Pennsylvania, USA) and mixtures thereof, but are not limited thereto. Particular binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as Avicel RC-581. Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103 ™ and Starch 1500 LM.

Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include talc, calcium carbonate (eg, granules or powders), microcrystalline cellulose, powdered cellulose, dexrate, kaolin, mannitol, silicic acid, sorbitol, starch, Gelatinized starch and mixtures thereof, but is not limited thereto. The binder or filler in the pharmaceutical composition of the present invention is typically present in about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.

Disintegrants are used in the compositions of the present invention to provide tablets that disintegrate upon exposure to an aqueous environment. Tablets containing excessive disintegrants may disintegrate during storage, but containing too little may not disintegrate under the desired conditions or at the desired rate. Therefore, neither too much nor too little of a sufficient amount of disintegrant that adversely alters the release of the active ingredient should be used to form the solid oral dosage form of the present invention. The amount of disintegrants used varies depending on the type of formulation and is readily apparent to those skilled in the art. Typical pharmaceutical compositions comprise about 0.5 to about 15 weight percent of disintegrant, preferably about 1 to about 5 weight percent.

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

Lubricants that can be used in the pharmaceutical compositions and dosage forms of the present invention are calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc Hydrogenated vegetable oils (eg, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar and mixtures thereof, but are not limited to these. . Additional lubricants include, for example, siloid silica gel (AEROSIL 200 (double oil, WR Grace Co., Baltimore, MD)), solidified aerosols of synthetic silica (Degussa) (Degussa Co., Plano, Tex.), CAB-O-SIL (pyrogenic silicon dioxide sold by Cabot Co., Boston, Mass.) And mixtures thereof have. If used as such, lubricants are typically used in amounts of less than about 1% by weight of the pharmaceutical composition or dosage form in which they are contained.

Preferred solid oral dosage forms of the invention include selective cytokine inhibitory drugs, lactose anhydrous, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica and gelatin.

4.4.2 Sustained release dosage forms

The active agents of the present invention may be administered by delivery devices known to those skilled in the art or by controlled release means. Examples include U.S. Patents 3,845,770, 3,916,899, 3,536,809, 3,598,123, 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, but is not limited thereto. Such dosage forms can be delayed or delayed in one or more active ingredients, for example using hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, particulates, liposomes, microspheres, or combinations thereof. It can be used to provide a desired release profile while varying the ratio by providing a controlled release. Suitable controlled-release formulations known to those skilled in the art, including those described herein, can be readily selected for use with the active ingredients of the present invention. Accordingly, the present invention encompasses single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps and caplets suitable for controlled release.

All controlled-release pharmaceutical products have a common purpose of improving drug treatment over that achieved by their uncontrolled counterparts. Ideally, the use of controlled-release preparations that are optimally designed for medical treatment are characterized by the least amount of drug used for the treatment or control of symptoms in the shortest time. Advantages of controlled-release formulations include prolonging drug activity, decreasing dosing frequency, and increasing patient compliance. In addition, controlled-release formulations may be used to influence other characteristics, such as blood levels of the drug, or the time of onset of action, and thus may affect the occurrence of side effects (eg, adverse effects).

Most controlled-release formulations initially release the amount of drug (active ingredient) that immediately produces the desired therapeutic effect, and gradually and continuously to maintain this level of therapeutic or prophylactic effect over an extended period of time. It is designed to release the remaining amount of drug. To keep these levels of drug constant in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug metabolized and secreted from the body. Controlled-release of the active ingredient can be stimulated by a variety of conditions, including but not limited to pH, temperature, enzymes, water, or other physiological conditions or compounds.

4.4.3 Parenteral Dosage Forms

Parenteral dosage forms can be administered to a patient by a variety of routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular and intraarterial administration. Since these administrations typically bypass the patient's natural defenses against contaminants, parenteral dosage forms are preferably aseptic or can be sterilized prior to administration to the patient. Examples of parenteral dosage forms include, but are not limited to, injectable solutions, dry products that can be dissolved or suspended in pharmaceutically acceptable injectable vehicles.

Suitable vehicles that can be used to provide the parenteral dosage forms of the invention are known to those skilled in the art. Examples include aqueous vehicles such as, but not limited to, water for injection USP, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; Water miscible vehicles 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 active ingredients disclosed herein can also be included in the parenteral dosage forms of the invention. For example, cyclodextrins and derivatives thereof can be used to increase the solubility of selective cytokine inhibitory drugs and derivatives thereof (see, eg, US Pat. No. 5,134,127, incorporated herein by reference).

4.4.4 Topical and mucosal dosage forms

Topical and mucosal dosage forms of the present invention include, but are not limited to, sprays, aerosols, solutions, emulsions, suspensions, or other forms known to those of skill in the art (eg, Remington's Pharmaceutical Sciences , 16 ^th and 18 ^th eds., Mack Publishing, Easton PA (1980 & 1990) and Introduction to Pharmaceutical Dosage Forms , 4th ed., Lea & Febiger, Philadelphia (1985). Dosage forms suitable for treating mucosal tissue in the oral cavity may be formulated as mouthwashes or oral gels.

Suitable excipients (eg, carriers or diluents) and other materials that can be used to provide the topical and mucosal dosage forms encompassed by the present invention are known to those skilled in the art of pharmacy, and are given to particular tissues to which a given pharmaceutical composition or dosage form is to be applied. Depends. Given this fact, typical excipients include water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate, which form non-toxic and pharmaceutically acceptable solvents, emulsions or gels. Isopropyl palmitate, mineral oil and mixtures thereof, but is not limited thereto. Humidifiers or wetting agents can also be added to pharmaceutical compositions and dosage forms if desired. Examples of such additional ingredients are known in the art (see, eg, Remington's Pharmaceutical Sciences , 16 ^th and 18 ^th eds., Mack Publishing, Easton PA (1980 & 1990)).

The pH of the pharmaceutical composition or dosage form can also be adjusted to improve delivery of one or more active ingredients. Likewise, the polarity of the solvent carrier, its ionic strength, or isotonicity can be adjusted to improve delivery. Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously change the hydrophilicity or lipophilic properties of one or more active ingredients to improve delivery. In this regard, stearate can act as a lipid vehicle for the formulation, as an emulsifier or surfactant, and as a delivery or penetration enhancer. Different salts, hydrates or solvates of the active ingredients can be used to further control the properties of the resulting composition.

4.4.5 Kit

Typically, the active ingredients of the present invention are preferably not administered to the patient at the same time or by the same route of administration. Accordingly, the present invention includes kits that can simplify the administration of a suitable amount of active ingredient to a patient when used in a clinical practitioner.

Conventional kits of the present invention include a selective cytokine inhibitory drug of the dosage form or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug or clathrate thereof. Kits encompassed by the present invention may also include additional active ingredients. Examples of additional active ingredients include, but are not limited to, those disclosed herein (see, eg, section 4.2.).

Kits of the invention may also include a device used to administer the active ingredient. Such devices include, but are not limited to, syringes, drip bags, patches, and inhalers.

Kits of the present invention may also include pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients. For example, if the active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit may contain a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a sterile, sterile solution suitable for parenteral administration. It may include. Examples of pharmaceutically acceptable vehicles include 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 lactated Ringer's injection; Water miscible vehicles 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.

5. Example

The following examples are intended to further illustrate the invention without limiting its scope.

5.1 Pharmacological and toxicological studies

A series of nonclinical pharmacological and toxicological studies were conducted to support the clinical evaluation of selective cytokine inhibitory drugs in humans. These studies were conducted in accordance with internationally recognized guidelines for study design, unless otherwise indicated, to meet the requirements of Good Laboratory Practice (GLP).

Pharmacological of 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide, including a comparison of activity with thalidomide Properties were characterized by in vitro studies. The study examined the effect of 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide on various cytokine productions . In addition, safety pharmacological studies of 3- (3-, 4-dimethoxy-phenyl) -3- (1-oxo-1,3-dioxo-isoindol-2-yl) -propionamide were also conducted in dogs, The effect on the ECG parameters of the compounds was further examined as part of three replicate dose toxicity studies in primates.

5.2 Regulation of Cytokine Production

LPS-stimulation of human PBMCs and human whole blood by 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide It was tested in vitro for inhibition of TNF-α production (Muller et al., Bloorg. Med. Chem. Lett. 9: 1625-1630, 1999). 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindole-2- on inhibition of LPS-stimulation of PBMC and human whole blood followed by TNF-α production IC _{50 of} I) -propionamide was measured.

In vitro studies are similar to thalidomide but are 5-50 times more potent 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl The pharmacological activity profile of) -propionamide was suggested. The pharmacological effect of 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide is a nutritional signal initiated by the receptor Cell response to (eg, IGF-1, VEGF, cyclooxygenase-2) and their action as inhibitors of other activities. As a result, 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide inhibits the development of inflammatory cytokines, Downregulate adhesion molecules and apoptosis inhibitory proteins (eg cFLIP, cIAP), promote sensitivity to programmed cell death initiated by kill-receptors, and inhibit angiogenic responses.

5.3 Toxicological Research

Effect of 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide on cardiovascular and respiratory function in anesthetized dogs Tested. Two groups of Beagle dogs (2 / sex / group) were used. Group 1 received only three doses of vehicle and the other group received three increased doses of 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindole -2-yl) -propionamide (400, 800 and 1200 mg / kg / day) was administered. In all cases, the dosage of 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide or vehicle is at least 30 Administration was continued by infusion through the jugular vein at intervals of minutes.

Cardiovascular and respiratory changes induced by 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide compared to vehicle control At all doses were minimal.

5.4 Research in Parkinson's Disease

The effects of selective cytokine inhibitory drugs in the Parkinson's disease model were studied in mice. Male C57 / BL6 mice were injected with MPTP (30 mg / kg, i.p.) once a day for 7 days. Selective cytokine inhibitory drugs were administered once daily or twice daily for 14 days. On day 28, striata was removed, homogenized in perchloric acid and centrifuged. The supernatant was removed and analyzed for other monoamines such as dopamine and serotonin by reverse phase HPLC and electrochemical detection. The anti-Parkinson activity of selective cytokine inhibitory drugs was evaluated in comparison to the control compound selegiline.

5.5 Research in Alzheimer's Disease

The effects of selective cytokine inhibitory drugs in the Alzheimer's disease model were studied in rat PC12 pheochromocytoma cells. PC12 cells were cultured in the presence of dopamine, D1 dopamine receptor agonist, adenosine, adenosine A2a receptor agonist, nicotine or alpha 7 nicotine acetylcholine receptor agonist and selective cytokine inhibitory drug. After 24 hours, cell supernatants were collected and tested for acetylcholinesterase activity by Elman method (Hawkins and Knittle, Anal Chem 44: 416-417, 1972). Inhibition of acetylcholinesterase activity levels by selective cytokine inhibitory drugs was evaluated in comparison to the control compound tacrine.

5.6 Cycling therapy in central nervous system disorders

In certain embodiments, selective cytokine inhibitory drugs are administered cyclically to patients with central nervous system disorders. Cycling therapy involves administering a first agent for a period of time, then administering the same agent for a period of time, and / or administering a second agent, and repeating the circulation administration. Circulation therapy can reduce the development of resistance to one or more therapies, prevent or reduce the side effects of one therapy and / or improve the efficacy of the treatment.

In certain embodiments, a dose of about 400, 800, or 1200 mg of prophylactic or therapeutic agent is administered about once daily or twice daily for a cycle of about 25 weeks. One cycle may comprise the administration of a therapeutic or prophylactic agent and at least one, two or three weeks of rest. The number of administration cycles is about 1 to about 12 cycles, more typically about 2 to about 10 cycles, and more typically about 2 to about 8 cycles.

For example, on day 1 of a 24 week cycle, blood product fluid is administered to a patient with Parkinson's disease. On day 10, administration of 800 mg / d of 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide was started do. On day 30, blood product sap is administered. At day 34, the administration of 800 mg / d 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide was terminated do. On day 59, administration of 400 mg / d of 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide was started do.

Embodiments of the invention described herein are merely illustrative of the scope of the invention. The full scope of the invention will be better understood with reference to the appended claims.

Claims (27)

Selective cytokine inhibitory drug that is a therapeutically or prophylactically effective amount of 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) propionamide Or Parkinson's disease, including pharmaceutically acceptable salts or stereoisomers thereof; Alzheimer's disease; Mild cognitive impairment; Amyotrophic lateral sclerosis; Central nervous system (CNS) trauma; Alzheimer's disease with Parkinson's disease; Exercise relaxation; Impotence; Movement disorders impairing fine motor control and finger utilization; Erectile dysfunction; Monotonic speech; cirrhosis; Dystonia; Inflammation associated with Parkinson's disease; Tremor of the face, jaw, tongue or posture; Parkinson's disease walking; Shuffling; Short steps; Rapid walking; Disorders of mood, cognition, sensation or sleep; dementia; depression; Organ memory damage; Drug-induced Parkinson's disease; Vascular Parkinson's disease; Multiple systemic atrophy; Advanced nuclear palsy; Disorders involving primary tau pathology; Basal ganglia cortical degeneration; Parkinson's disease with dementia; Hyperactivity disorder; chorea; Huntington's disease; Dystonia; Wilson's disease; Tourette's syndrome; Essential progression; Myoclonus; Or a pharmaceutical composition for treating or preventing a central nervous system disorder which is a movement delay disorder. Selective cytokine inhibitory drug or a pharmaceutical thereof that is a prophylactically effective amount of 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) propionamide Parkinson's disease, including pharmaceutically acceptable salts or stereoisomers; Alzheimer's disease; Mild cognitive impairment; Amyotrophic lateral sclerosis; Central nervous system (CNS) trauma; Alzheimer's disease with Parkinson's disease; Exercise relaxation; Impotence; Movement disorders impairing fine motor control and finger utilization; Erectile dysfunction; Monotonic speech; cirrhosis; Dystonia; Inflammation associated with Parkinson's disease; Tremor of the face, jaw, tongue or posture; Parkinson's disease walking; Shuffling; Short steps; Rapid walking; Disorders of mood, cognition, sensation or sleep; dementia; depression; Organ memory damage; Drug-induced Parkinson's disease; Vascular Parkinson's disease; Multiple systemic atrophy; Advanced nuclear palsy; Disorders involving primary tau pathology; Basal ganglia cortical degeneration; Parkinson's disease with dementia; Hyperactivity disorder; chorea; Huntington's disease; Dystonia; Wilson's disease; Tourette's syndrome; Essential progression; Myoclonus; Or a pharmaceutical composition for managing a central nervous system disorder impaired by movement. delete delete The pharmaceutical composition of claim 1, wherein the central nervous system disorder is Parkinson's disease. The pharmaceutical composition of claim 2, wherein the central nervous system disorder is Parkinson's disease. Selective cytokine inhibitory drug that is a therapeutically or prophylactically effective amount of 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) propionamide Or a pharmaceutically acceptable salt or stereoisomer thereof; And At least one therapeutically or prophylactically effective amount of levodopa (L-DPOA), L-DOPA / carbidopa combination, cocaine, α-methyl-tyrosine, reserpin, tetrabenazine, arglin, phenodolpam mesylate, Cabergoline, pramipexole dihydrochloride, ropinolol, amantadine hydrochloride, selegiline hydrochloride, carbidopa, pergolide mesylate, iproniazide, chlorgiline, phenelzin, isocarboxide, toll Carpones, entacapones, amantadines, tacrine, donepezil, rivastigmine, physostigmine sallylate, physostigmine sulphate, physostigmine bromide, neostigmine methylsulfate, trimmedok Shim bromide, diacetyl monoxime, endrophonium, pyridostigmine, demecarium, metoclopromid, domperidone, prochlorperazine, promethazine, chlorpromazine, trimme Benzamide, ondansetron, granisetron, hydroxyzine, acetylleucine monoethanolamine, alizaprid, azasetron, benzquinamide, bietaunatin, bromoprid, buclizin, clevoprid, Cyclizin, Dimenhydrinate, Diphenidol, Dolacetron, Meclizin, Metallatal, Metopimarine, Nabilon, Oxyperdil, Piperazine, Scopolamine, Sulpyrid, Tetrahydrocannabinol, Thiethylperazine, thioproprazine, trophetrone, naproxen sodium, diclofenac sodium, diclofenac potassium, celecoxib, sulindac, oxaprozin, diflunisal, etodolak, meloxycamp, ibuprofen, ketoprofen , Nabumethone, repecoxib, methotrexate, leflunomide, sulfasalazine, gold salt, RHo-D Immune Globulin, mycophenylate mofetil, cyclosporine, azathioprine, tacrolimus, basilic Shimab, Darkly Zumab, Salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazine, acetaminophen, indomethacin, sulindac, mefenamic acid, meclofenamate sodium, tolmethine, ketorolac , Diclofenac, flurbinpropene, oxaprozin, phyroxam, meloxycham, ampyroxamc, doxycam, caffecicam, tenoxycam, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrin, apa Zone, zileuton, aurothioglucose, gold sodium thiomaleate, auranopine, methotrexate, colchicine, allopurinol, probenside, sulfinpyrazone, benzbromarone, betamethasone or other glucocorticoids Including, Parkinson's disease; Alzheimer's disease; Mild cognitive impairment; Amyotrophic lateral sclerosis; Central nervous system (CNS) trauma; Alzheimer's disease with Parkinson's disease; Exercise relaxation; Impotence; Movement disorders impairing fine motor control and finger utilization; Erectile dysfunction; Monotonic speech; cirrhosis; Dystonia; Inflammation associated with Parkinson's disease; Tremor of the face, jaw, tongue or posture; Parkinson's disease walking; Shuffling; Short steps; Rapid walking; Disorders of mood, cognition, sensation or sleep; dementia; depression; Organ memory damage; Drug-induced Parkinson's disease; Vascular Parkinson's disease; Multiple systemic atrophy; Advanced nuclear palsy; Disorders involving primary tau pathology; Basal ganglia cortical degeneration; Parkinson's disease with dementia; Hyperactivity disorder; chorea; Huntington's disease; Dystonia; Wilson's disease; Tourette's syndrome; Essential progression; Myoclonus; Or a pharmaceutical composition for treating or preventing a central nervous system disorder which is a movement delay disorder. Selective cytokine inhibitory drug or a pharmaceutical thereof that is a prophylactically effective amount of 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) propionamide Academically acceptable salts or stereoisomers, and At least one therapeutically or prophylactically effective amount of levodopa (L-DPOA), L-DOPA / carbidopa combination, cocaine, α-methyl-tyrosine, reserpin, tetrabenazine, arglin, phenodolpam mesylate, Cabergoline, pramipexole dihydrochloride, ropinolol, amantadine hydrochloride, selegiline hydrochloride, carbidopa, pergolide mesylate, iproniazide, chlorgiline, phenelzin, isocarboxide, toll Carpones, entacapones, amantadines, tacrine, donepezil, rivastigmine, physostigmine sallylate, physostigmine sulphate, physostigmine bromide, neostigmine methylsulfate, trimmedok Shim bromide, diacetyl monoxime, endrophonium, pyridostigmine, demecarium, metoclopromid, domperidone, prochlorperazine, promethazine, chlorpromazine, trimme Benzamide, ondansetron, granisetron, hydroxyzine, acetylleucine monoethanolamine, alizaprid, azasetron, benzquinamide, bietaunatin, bromoprid, buclizin, clevoprid, Cyclizin, Dimenhydrinate, Diphenidol, Dolacetron, Meclizin, Metallatal, Metopimarine, Nabilon, Oxyperdil, Piperazine, Scopolamine, Sulpyrid, Tetrahydrocannabinol, Thiethylperazine, thioproprazine, trophetrone, naproxen sodium, diclofenac sodium, diclofenac potassium, celecoxib, sulindac, oxaprozin, diflunisal, etodolak, meloxycamp, ibuprofen, ketoprofen , Nabumethone, repecoxib, methotrexate, leflunomide, sulfasalazine, gold salt, RHo-D Immune Globulin, mycophenylate mofetil, cyclosporine, azathioprine, tacrolimus, basilic Shimab, Darkly Zumab, Salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazine, acetaminophen, indomethacin, sulindac, mefenamic acid, meclofenamate sodium, tolmethine, ketorolac , Diclofenac, flurbinpropene, oxaprozin, phyroxam, meloxycham, ampyroxamc, doxycam, caffecicam, tenoxycam, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrin, apa Zone, zileuton, aurothioglucose, gold sodium thiomaleate, auranopine, methotrexate, colchicine, allopurinol, probenside, sulfinpyrazone, benzbromarone, betamethasone or other glucocorticoids Including, Parkinson's disease; Alzheimer's disease; Mild cognitive impairment; Amyotrophic lateral sclerosis; Central nervous system (CNS) trauma; Alzheimer's disease with Parkinson's disease; Exercise relaxation; Impotence; Movement disorders impairing fine motor control and finger utilization; Erectile dysfunction; Monotonic speech; cirrhosis; Dystonia; Inflammation associated with Parkinson's disease; Tremor of the face, jaw, tongue or posture; Parkinson's disease walking; Shuffling; Short steps; Rapid walking; Disorders of mood, cognition, sensation or sleep; dementia; depression; Organ memory damage; Drug-induced Parkinson's disease; Vascular Parkinson's disease; Multiple systemic atrophy; Advanced nuclear palsy; Disorders involving primary tau pathology; Basal ganglia cortical degeneration; Parkinson's disease with dementia; Hyperactivity disorder; chorea; Huntington's disease; Dystonia; Wilson's disease; Tourette's syndrome; Essential progression; Myoclonus; Or a pharmaceutical composition for managing a central nervous system disorder impaired by movement. 8. The pharmaceutical composition of claim 7, wherein the central nervous system disorder is Parkinson's disease. The pharmaceutical composition of claim 8, wherein the central nervous system disorder is Parkinson's disease. delete delete delete delete The method according to any one of claims 1, 2 and 5 to 10, wherein the selective cytokine inhibitory drug is 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1, Pharmaceutical composition which is the R or S enantiomer of 3-dihydro-isoindol-2-yl) propionamide. delete delete delete delete delete delete delete delete delete delete delete delete