HK1103990A - Method of using and compositions comprising selective cytokine inhibitory drugs for the treatment and management of myelodysplastic syndromes - Google Patents

Abstract

Methods of treating, preventing and/or managing a myelodysplastic syndrome are disclosed. Specific methods encompass the administration of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, alone or in combination with a second active ingredient, and/or blood or cells for transplantation therapy. Specific second active ingredients are capable of affecting or improving blood cell production. Pharmaceutical compositions, single unit dosage forms, and kits suitable for use in methods of the invention are also disclosed.

Description

Use of selective cytokine inhibitory drugs in myelodysplastic syndromes

1. Field of the invention

The present invention relates, in part, to methods of treating, preventing and/or managing myelodysplasia and related syndromes, which comprise administering a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. The use of such agents, alone or in combination with conventional treatment of myelodysplastic syndromes and/or transplantation therapy, is also described.

2. Background of the invention

2.1 Pathology of MDS

Myelodysplastic syndrome (MDS) refers to various types of hematopoietic stem cell disorders. MDS is characterized by impairment of the morphology and maturation of the cell marrow (myelodysplasia), peripheral blood cytopenia and a variable risk of developing acute leukemia due to failure of hematopoiesis. The merck manual953 (17 th edition, 1999) and List et al, 1990, j. clin. oncol.8: 1424.

initial hematopoietic stem cell damage may result from, for example but not limited to: cytotoxic chemotherapy, radiation, viruses, chemical exposure, and genetic preferences. The cloning mutation controls bone marrow and inhibits healthy stem cells. In the early stages of MDS, the main cause of cytopenia is increased programmed cell death (apoptosis). When the disease progresses and is converted into leukemia, gene mutation rarely occurs, and proliferation of leukemia cells controls healthy bone marrow. The course of the disease is different, with some cases presenting as chronic disease and others presenting invasively as a clinical course in a very short term that will turn into the form of acute leukemia.

The actual incidence of MDS in the united states is unknown. MDS was initially considered a different disease in 1976, with an estimated incidence of 1500 new cases per year. At that time, only patients with less than five percent of blasts were considered to have this disease. According to the 1999 statistics, an estimated 13,000 new cases per year, approximately 1000 cases per year in children, over chronic lymphocytic leukemia becomes the most common form of leukemia in the western hemisphere. It is recognized that increased morbidity may be due to improved recognition and diagnostic criteria. The disease is found worldwide.

The international hematologist group, france-usa-uk (FAB) cooperative group, divided MDS diseases into five subgroups, distinguishing them from acute myeloid leukemia. The Merck Manual954 (17 th edition, 1999); bennett j.m. et al, ann.lnn.med.1985 month 10, 103 (4); and besae.c., med.clin.northam.1992, month 5, 76 (3): 599-617. Potential myelodysplastic trilineage changes were found in patients of all subtypes.

There are two refractory anemia subgroups, characterized by bone marrow containing five percent or less of myeloblasts, these two being: (1) refractory Anemia (RA); and (2) ra (rars) with cyclic ferrierythroblasts, morphologically defined as 15% of erythroid lines with abnormal cyclic ferrierythroblasts, which reflect abnormal iron accumulation in mitochondria. Both have a prolonged clinical course and a low incidence of developing acute leukemia. Besae.c., med.clin.north am.1992, month 5, 76 (3): 599-617.

There are two refractory anemia subgroups with more than five percent myeloblasts: (1) ra (raeb) with hyperpolyblasts, defined as 6-20% myeloblasts; and (2) RAEB (RAEB-T) in transit, with 21-30% myeloblasts. The higher the percentage of myeloblasts, the shorter the clinical course and the closer the disease is to acute myeloid leukemia. The transition from early to higher stages in patients suggests that these subgroups are merely stages of the disease and not distinct entities. Elderly MDS patients with trilineage dysplasia and greater than 30% myeloblasts will develop acute leukemia and are generally considered to have a poor prognosis because their response rate to chemotherapy is lower than in new acute myelocytic leukemia patients. The World Health Organization (WHO) classification (1999) recently proposed the inclusion of all RAEB-T cases, or patients with more than 20% myeloblasts, into the acute leukemia category as these patients had similar prognostic outcomes. However, they respond poorly to treatment than patients with new or more typical acute myeloid leukemia or acute non-lymphocytic leukemia (ANLL). The same goes out as above.

The fifth MDS, which is the most difficult to classify, is called chronic myelomonocytic leukemia (CMML). This subset may have any percentage of myeloblasts, but a mononucleosis of 1000/dL or greater. It may be accompanied by splenomegaly. This subset overlaps with myeloproliferative diseases and may have intermediate clinical course. It is distinct from the classic Chronic Myelogenous Leukemia (CML), which is characterized by a negative Ph chromosome. Recent WHO classification (1999) proposed the separate listing of promyelocytic and proliferative CMMLs from FAB to MDS/myeloproliferative disease (MPD), with splenomegaly and total WBCs greater than 13,000. CMML is limited to mononucleosis with total leukocytes less than 13,000/mm³Three-line dysplasia is required. Harris n.l. et al, j.clin.oncol.1999 month 12, 17 (12): 3835-49. Finally, some other international organizations, including WHO, proposeA sixth category of MDS patients is characterized by a del (5q) abnormality.

MDS is initially a disease in the elderly, with the median point of occurrence being the seventh decade of life. The median age of these patients was 65 years with the age range being 30 to 80 years or older early in life. This syndrome may occur in any age group, including the pediatric population. Patients who survive treatment of malignancies with alkylating agents, with or without radiation therapy, have a high incidence of developing MDS or secondary acute leukemia. About 60-70% of patients who do not have a significant cause of exposure to, or cause of, MDS are classified as primary MDS patients.

The most common cases of MDS are primary or paroxysmal. However, 10-15 years before the onset of disease, about 50% of patients have a nonspecific history of exposure to indeterminate chemicals or radiation. This relationship to pathogenesis has not been demonstrated. Compounds such as, but not limited to, benzene, pesticides, herbicides, and fungicides are possible causes of MDS. Goldberg h. et al, Cancer res.1990, 11/1/month; 50(21): 6876-81. Secondary MDS manifests in the development of MDS or acute leukemia following known exposures to chemotherapeutic agents that cause bone marrow damage. These drugs are associated with a high incidence of chromosomal abnormalities upon diagnosis of MDS or acute leukemia after exposure.

In addition, MDS is associated with complications associated with severe cytopenia. Other complications are myelofibrosis, which can accelerate the decrease in blood counts and increase the need for blood transfusion. Conversion to acute leukemia accelerates development of complications such as anemia, bleeding, and infection.

Recently, the world MDS risk analysis (IMRA) working group proposed that the International Prognostic Scoring System (IPSS) reduces inaccuracies in predicting survival and AML risk in MDS patients. IPSS is based on the number of cytopenias, the percentage of BM blasts, and the type of cytogenetic abnormality (table 1). Greenberg P, Cox C, Le Beau MM et al, Blood 1997, 89: 2079-88. The latter are divided into good subgroups (normal, -Y, del (5q), del (20q)), medium subgroups, and bad subgroups (complex or chromosome 7 abnormalities).

TABLE 1 International prognostic scoring system for MDS
							Score value
Sign change	0	0.5	1.0	1.5	2.0
						Marrow cell (%)	＜5	5-10	-	11-20	21-30
Karyotype*	Good effect	Medium and high grade	Difference (D)
						Cytopenia	0/1	2/3

*Good, normal, del (5q), del (20q), -Y; poor, complex (> 3) or chromosomal > 7 abnormalities; middle, +8, and other single or two anomalies.

2.2 MDS treatment

Current treatments for MDS are based on the stage of the disease and the mechanisms that control the specific stage of the disease process. Bone marrow transplantation is used in patients with poor prognosis or patients with advanced MDS. Epstein and slide, 1985, surg. ann.17: 125. however, because of the invasive procedure used, this type of treatment is painful to both the donor and recipient and can cause serious and even fatal complications to the recipient, especially allogeneic transplants and related graft-versus-host disease (GVHD). Thus, the risk of GVHD limits the use of bone transplants in patients with other fatal diseases. Furthermore, because most patients are elderly and only a few young MDS patients have matched donors, the use of bone marrow transplantation is limited.

An alternative method of treating MDS is to use hematopoietic growth factors or cytokines to stimulate blood cell growth in a recipient. Dexter, 1987, j.cell sci.88: 1; moore, 1991, annu, rev, immunol.9: 159; and Besa e.c., med.clin.north am.1992, month 5, 76 (3): 599-617. It has been shown that the process of blood cell formation, by which a small number of self-renewing stem cells produce lineage specific progenitor cells that subsequently undergo proliferation and differentiation to produce mature circulating blood cells, is at least partially regulated by specific hormones. These hormones are collectively referred to as hematopoietic growth factors. Metcalf, 1985, Science 229: 16; dexter, 1987, j.cell sci.88: 1; golde and Gasson, 1988, Scientific American, month 7: 62, a first step of mixing; tabbara and Robinson, 1991, Anti-Cancer Res.11: 81; ogawa, 1989, environ. health presp.80: 199; and Dexter, 1989, br.med.ball.45: 337. the best characterized growth factors include Erythropoietin (EPO), granulocyte-macrophage colony stimulating factor (GM-CSF), and granulocyte colony stimulating factor (G-CSF). In addition to inducing proliferation and differentiation of hematopoietic progenitor cells, these cytokines have also been shown to activate many functions of mature blood cells, including affecting the migration of mature hematopoietic cells. Stanley et al, 1976, j.exp.med.143: 631; schrader et al, 1981, proc.natl.acad.sci.u.s.a.78: 323; moore et al, 1980, j. immunol.125: 1302; kurland et al, 1979, proc.natl.acad.sci.us.a.76: 2326; handman and BuRgess, 1979, j.immunol.122: 1134, carrying out microwave irradiation; vadas et al, 1983, Blood 61: 1232, and; vadas et al, 1983, j. immunol.130: 795; and Weibart et al, 1986, j. immunol.137: 3584.

unfortunately, hematopoietic growth factors have not proven effective in many clinical settings. Clinical trials of treatment of patients with MDS with recombinant human GM-CSF and G-CSF have shown that although these cytokines restore granulocyte production in treated patients, their effects are limited to the granulocyte or monocyte lineage with little or no improvement in hemoglobin or platelet counts. Schuster et al, 1990, Blood 76 (suppl.1): 318 a. When these patients were treated with recombinant human EPO, sustained improved hemoglobin or reduced transfusion requirements were obtained in only less than 25% of the patients. Besa et al, 1990, 76 (suppl.1): 133 a; hellstrom et al, 1990, 76 (suppl.1): 279 a; bowen et al, 1991, br.j. haematol.77: 419. thus, there remains a need for safe and effective methods for the treatment and management of MDS.

2.3 Selective cytokine inhibitory drugs

Have been synthesized and tested to be called SelCIDs^TM(Celgene corporation) or a selective cytokine inhibitory drug. These compounds strongly inhibited TNF- α production, but showed moderate inhibition of LPS-induced IL1 β and IL12, but no inhibition of IL6, even at high drug concentrations. L.g.corral et al, ann.rheum.dis.58: (supplement I) 1107-.

Other characteristics of selective cytokine inhibitory drugs suggest that they are potent PDE4 inhibitors. PDE4 is one of the major phosphodiesterase isozymes found in human bone marrow and lymphoid lineage cells. This enzyme plays a crucial role in regulating cellular activity by degrading the ubiquitous second messenger cAMP and maintaining it at low intracellular levels. The same goes out as above. Inhibition of PDE4 activity increases cAMP levels, thereby modulating LPS-induced cytokines, including inhibition of TNF- α production in monocytes and lymphocytes.

3. Summary of the invention

The invention encompasses methods of treating or preventing MDS, which comprise administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. The selective cytokine inhibitory drugs or compounds of the invention as described below are small organic molecules, i.e., they have a molecular weight of less than 1,000 g/mol. The compounds preferably have PDE4 activity and inhibit TNF- α. The invention also encompasses methods of managing MDS (e.g., prolonging time in remission) comprising administering to a patient in need of such management a prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. Each of these methods includes a specific dose or dosage regimen, including cycling therapy.

The invention also encompasses pharmaceutical compositions, single unit dosage forms, and kits for the treatment, prevention, and/or management of MDS, which comprise one or more selective cytokine inhibitory drugs, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.

In particular embodiments of the invention, selective cytokine inhibitory drugs are used, administered or formulated with one or more second active ingredients to treat, prevent or manage MDS. Examples of the second active ingredient include, but are not limited to: cytokines, hematopoietic growth factors, cancer chemotherapeutics, immunosuppressants, anti-inflammatory agents, antibiotics, antifungals, and other standard treatments for MDS. In addition, the invention encompasses the use of a compound of the invention in combination with transplantation therapy to treat, prevent or manage MDS.

4. Detailed description of the invention

A first embodiment of the invention encompasses methods of treating or preventing MDS, which comprise administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.

The term "myelodysplastic syndrome" or "MDS" as used herein refers to a disease of hematopoietic stem cells characterized by one or more of the following: ineffective hematopoiesis, progressive cytopenia, risk of developing acute leukemia or risk of damage to the morphology and maturation of the cell marrow (myelodysplasia). Unless otherwise indicated, the term "myelodysplastic syndrome" or "MDS" includes: refractory anemia, refractory anemia with cricoid ferrierythroid, refractory anemia with excess blasts in transit, and chronic myelomonocytic leukemia.

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

Yet another embodiment of the invention encompasses pharmaceutical compositions comprising a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and a pharmaceutically acceptable carrier, diluent, or excipient, wherein the composition is suitable for parenteral, oral, or transdermal administration and in an amount sufficient to treat or prevent MDS, or ameliorate the symptoms or progression of a disease.

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

One embodiment of the invention encompasses methods of treating, preventing and/or managing MDS, which comprises administering to a patient in need of such treatment, prevention and/or management a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and a therapeutically or prophylactically effective amount of a second active agent. Without being limited by theory, it is believed that certain selective cytokine inhibitory drugs and common agents for subjects with MDS may act in a complementary or synergistic manner in the treatment or management of MDS. It is also believed that the combined use of these agents may reduce or eliminate the adverse side effects associated with some selective cytokine inhibitory drugs, thereby allowing a greater amount of the selective cytokine inhibitory drug to be administered to the patient and/or improving patient compliance. It is also believed that some selective cytokine inhibitory drugs can reduce or eliminate the adverse side effects associated with some conventional MDS agents, thereby allowing a greater amount of the agent to be administered to a patient and/or improving patient compliance.

Preferably, the second active agent is capable of affecting or improving hematopoiesis. The second active agent can be a macromolecule (e.g., a protein) or a small molecule (e.g., a synthetic inorganic metal, organometallic, or organic molecule). Examples of such second active agents include, but are not limited to: cytokines, hematopoietic growth factors, anti-cancer agents such as topoisomerase inhibitors, anti-angiogenic agents, microtubule stabilizing agents, apoptosis inducing agents, alkylating agents, and other conventional chemotherapeutic agents described in the Physician's Desk Reference 2002; an antiviral agent; an antifungal agent; (ii) an antibiotic; anti-inflammatory agents; an immunomodulator; IMiDsTM; immunosuppressants such as cyclosporine; and other known or conventional agents for use in MDS patients. Specific second active agents include, but are not limited to: etanercept (Enbrel ®), imatinib (Glevec ®), anti-TNF- α antibodies, infliximab (Remicade ®), G-CSF, GM-CSF, EPO, topotecan, irinotecan, pentoxifylline, doxorubicin, ciprofloxacin, dexamethasone, IL2, IL8, IL18, Ara-C, vinorelbine, isotretinoin, and 13-cis-retinoic acid. The invention also includes the use of native, natural, and recombinant proteins. The invention also includes variants and derivatives (e.g., modified forms) of the native protein that have at least some of the pharmacological activity of the protein on which it is based in vivo. Examples of variants include, but are not limited to, proteins having one or more amino acid residues that differ from the corresponding residues in the native form of the protein. The term "variant" also includes proteins that lack the sugar moieties normally found in their native form (e.g., unglycosylated forms). Examples of derivatives include, but are not limited to: pegylated derivatives and fusion proteins, such as those formed by fusing IgG1 or IgG3 to a target protein or to an active portion of a target protein. See, e.g., penechet, m.l. and Morrison, s.l., j.immunol.methods 248: 91-101(2001). The invention also includes vaccines that cause secretion of the proteins disclosed herein and pharmacologically active variants, derivatives, and fusions thereof.

Another embodiment of the invention encompasses methods of reversing, reducing, or avoiding adverse side effects associated with conventional MDS therapy in a subject with MDS, which comprise administering to a subject in need of such reversing, reducing, or avoiding a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.

Without being limited by theory, it is believed that the use of a selective cytokine inhibitory drug in combination with transplantation therapies, such as stem cell transplantation, to patients with MDS provides unique and unexpected synergy. When an inevitable leukemic shift occurs at some stage of MDS, it is necessary to transplant peripheral blood stem cells, hematopoietic stem cell preparations or bone marrow. In particular, without being limited by theory, it is believed that selective cytokine inhibitory drugs have cytokine inhibitory activity that provide additive or synergistic effects when used concurrently with transplantation therapy. Selective cytokine inhibitory drugs can act in combination with transplantation therapies to reduce the complications associated with invasive transplantation procedures and the risk of associated Graft Versus Host Disease (GVHD). Accordingly, the invention encompasses methods of treating, preventing and/or managing MDS, which comprise administering a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, to a patient (e.g., a human) prior to, during, or after transplant therapy.

The invention also encompasses pharmaceutical compositions, single unit dosage forms, and kits that include a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, a second active ingredient, and/or blood or cells for transplantation therapy. For example, a kit may comprise one or more compounds of the invention, stem cells for transplantation, and immunosuppressive agents, antibiotics or other agents, each of which are used to treat a subject with MDS.

4.1 Selective cytokine inhibitory drugs

Compounds useful in the invention include selective cytokine inhibitory drugs that are racemic, stereomerically pure, and enriched in a certain stereoisomer, stereomerically pure, and enantiomerically pure compounds having selective cytokine inhibitory activity, and pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates, and prodrugs thereof. Preferred compounds for use in the present invention are the known selective cytokine suppressors (SeICIDs) of Celgene, N.J^TM)。

As used herein, unless otherwise indicated, the terms "selective cytokine inhibitory drugs" and "SelCIDs" are used^TM"includes small molecule drugs, e.g., small molecules that are not peptides, proteins, amino acids, oligosaccharides, or other macromolecules. Preferred compounds inhibit TNF- α production. The compounds also had moderate inhibitory effects on LPS-induced IL1 β and IL 12. More preferably, the compounds of the present invention are strong PDE4 inhibitors.

Specific examples of selective cytokine inhibitory drugs include, but are not limited to: cyclic imines disclosed in U.S. Pat. nos. 5,605,914 and 5,463,063; cycloalkyl amides and cycloalkyl nitriles disclosed in U.S. Pat. nos. 5,728,844, 5,728,845, 5,968,945, 6,180,644, and 6,518,281; arylamides disclosed in U.S. patents 5,801,195, 5,736,570, 6,046,221, and 6,284,780 (e.g., N-benzoyl-3-amino-3- (3 ', 4' -dimethoxyphenyl) -propionamide); imine/amide ethers and alcohols disclosed in U.S. patent 5,703,098 (e.g., 3-phthalimido-3- (3 ', 4' -dimethoxyphenyl) propan-1-ol); succinimides and maleimides disclosed in U.S. patent 5,658,940 (e.g., methyl 3- (3 ', 4', 5 ', 6' -tetrahydrophthalimido) -3- (3 ", 4" -dimethoxyphenyl) propionate); imino-and amino-substituted alkanohydroxamic acids disclosed in U.S. Pat. No. 6,214,857 and WO 99/06041; substituted phenethylsulfones disclosed in U.S. Pat. nos. 6,011,050 and 6,020,358; substituted imines disclosed in U.S. patent 6,429,221 (e.g., 2-phthalimido-3- (3 ', 4' -dimethoxyphenyl) propane); substituted 1, 3, 4-oxadiazoles (e.g., 2- [1- (3-cyclopentyloxy-4-methoxyphenyl) -2- (1, 3, 4-oxadiazol-2-yl) ethyl ] -5-methylisoindoline-1, 3-dione) disclosed in U.S. patent 6,326,388; cyano and carboxyl derivatives of substituted styrenes disclosed in U.S. Pat. nos. 5,929,117, 6,130,226, 6,262,101, and 6,479,554 (e.g., 3, 3-bis- (3, 4-dimethoxyphenyl) acrylonitrile); isoindoline-1-ones and isoindoline-1, 3-diones substituted at the 2-position with an α - (3, 4-disubstituted phenyl) alkyl group and at the 4-and/or 5-position with a nitrogen-containing group as disclosed in WO01/34606 and U.S. Pat. No. 6,667,316; imino-and amino-substituted acylhydroxamic acids (e.g., (3- (1, 3-dioxoisoindolin-2-yl) -3- (3-ethoxy-4-methoxyphenyl) propanolamino) propanoates) disclosed in WO01/45702 and U.S. Pat. No. 6,699,899. Other selective cytokine inhibitory drugs include the diphenylethylene compounds disclosed in U.S. provisional application 60/452,460, filed 3/5/2003, the contents of which are incorporated herein by reference in their entirety. The contents of each of the patents and patent applications referred to herein are incorporated by reference.

Other selective cytokine inhibitory drugs are synthetic chemical compounds, typical 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 imines disclosed in U.S. Pat. Nos. 5,698,579, 5,877,200, 6,075,041, and 6,200,987, and WO95/01348, each of which is incorporated herein by reference. Representative cyclic imines include compounds having the formula:

wherein n has a value of 1,2 or 3;

R⁵is an ortho-phenylene group unsubstituted or substituted with 1 to 4 substituents each independently selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, alkylamino, dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms and halogen;

R⁷is (i) a phenyl group or a phenyl group substituted with one or more substituents each independently selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms and halogen, (ii) a benzyl group unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms and halogen, (iii) a naphthyl group, and (iv) a benzyloxy group;

R¹²is-OH, alkoxy of 1 to 12 carbon atoms, or

R⁸Is hydrogen or alkyl of 1 to 10 carbon atoms; and

R⁹is hydrogen, alkyl of 1 to 10 carbon atoms, -COR¹⁰or-SO₂R¹⁰Wherein R is¹⁰Is hydrogen, alkyl of 1 to 10 carbon atoms or phenyl.

Specific compounds of this class include, but are not limited to:

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-oxoisoindolin-yl) propionic acid;

3- (4-methoxyphenyl) -3- (1-oxoisoindolin-yl) propionamide;

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

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

3- (3, 4-dimethoxyphenyl) -3- (1-oxoisoindolin-2-yl) propionamide;

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

3- (1-oxoisoindolin-2-yl) -3- (3-ethoxy-4-methoxyphenyl) propionic acid methyl ester;

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;

3- (1-oxoisoindolin-2-yl) -3- (3-butoxy-4-methoxyphenyl) propionic acid methyl ester; and

3- (1-oxoisoindolin-2-yl) -3- (3-propoxy-4-methoxyphenyl) propionic acid methyl ester. Other generations

Representative cyclic imines include compounds having the formula:

wherein Z is:

or

Wherein:

R¹is a divalent residue of: (i)3, 4-pyridine, (ii) pyrrolidine, (iii) imidazole, (iv) naphthalene, (v) thiophene, or (vi) a linear or branched alkane containing 2 to 6 carbon atoms which is unsubstituted or substituted with a phenyl group or a substituted phenyl group, the phenyl substituent being a nitro group, a cyano group, a trifluoromethyl group, an ethyl ester group, a methyl ester group, a propyl ester group, an acetyl group, a carbamoyl group, an acetoxy group, a carboxyl group, a hydroxyl group, an amino group, an alkyl group of 1 to 10 carbon atoms, an alkoxy group of 1 to 10 carbon atoms, or a halogen, wherein the divalent bond of the residue is on the ortho ring of carbon atoms;

R²is-CO-or-SO₂-；

R³Is (i) phenyl substituted with 1 to 3 substituents each independently selected from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms or halogen, (ii) pyridyl, (iii) pyrrolyl, (iv) imidazolyl, (iv) naphthyl, (vi) thienyl, (vii) quinolinyl, (viii) furyl or (ix) indolyl;

R⁴is alanyl, arginyl, glycyl, phenylglycyl, histidinyl, leucyl, isoleucyl, lysyl, methionyl, prolyl, sarcosyl, seryl, homoseryl, threonyl, thyronoyl, tyrosyl, valyl, benzimidazol-2-yl, benzoxazol-2-yl, phenylsulfonyl, methylphenylsulfonyl or phenylaminocarbonyl; and

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

in the formula, R⁵Is (i) an ortho-phenylene group unsubstituted or substituted with 1 to 4 substituents each independently selected from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, alkylamino, dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halogen, or (ii) a divalent residue of pyridine, pyrrolidine, imidazole, naphthalene, or thiophene, wherein the divalent bond is in the ortho ring of carbon atoms;

R⁶is-CO-, -CH₂-or-SO₂-；

R⁷Is (i) hydrogen, if R⁶is-SO₂-, (ii) a linear, branched or cyclic alkyl group having 1 to 12 carbon atoms, (iii) a pyridyl group, (iv) a phenyl group or a phenyl group substituted by one or more substituents, each independently selected from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propinyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halogen, (v) alkyl of 1 to 10 carbon atoms, (vi) a benzyl group unsubstituted or substituted by 1 to 3 substituents selected from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propinyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, carboxyl, amino, alkoxy of 1 to 10 carbon atoms, carboxyl, amino, or a salt thereof, Or halogen, (vii) naphthyl, (viii) benzyloxy, or (ix) imidazol-4-ylmethyl;

R¹²is-OH, alkoxy of 1 to 12 carbon atoms, or

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

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

R^9’is hydrogen, alkyl of 1 to 10 carbon atoms, -COR¹⁰or-SO₂R¹⁰Wherein R is¹⁰Is hydrogen, alkyl of 1 to 10 carbon atoms or phenyl.

Other representative imines include compounds having the formula:

in the formula, R⁷Is (i) a straight chain, branched chain containing 1 to 12 carbon atomsA linear or cyclic alkyl group, (ii) a pyridyl group, (iii) a phenyl group or a phenyl group substituted with one or more substituents, each of which is independently selected from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halogen, (iv) benzyl which is unsubstituted or substituted with 1 to 3 substituents, (vii) the substituent is selected from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halogen, (v) naphthyl, (vi) benzyloxy, or (vii) imidazol-4-ylmethyl;

R¹²is-OH, alkoxy of 1-12 carbon atoms, -O-CH₂-pyridyl, -O-benzyl, or

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

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

R^9’is hydrogen, alkyl of 1 to 10 carbon atoms, -CH₂-pyridyl, benzyl, -COR¹⁰or-SO₂R¹⁰Wherein R is¹⁰Is hydrogen, alkyl of 1 to 4 carbon atoms or phenyl.

Other specific selective cytokine inhibitory drugs include imino-and amino-substituted alkanohydroxamic acids disclosed in WO99/06041 and U.S. Pat. No. 6,214,857, each of which is incorporated herein by reference. Examples of such compounds include, but are not limited to:

in the formula, R¹And R²Each independently is hydrogen, lower alkyl, or R¹And R²Together with the carbon atom to which they are each bound, form an o-phenylene, o-naphthylene or cyclohexene-1, 2-diyl group which is unsubstituted or substituted by 1 to 4 substituents each independently selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propinyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, alkylamino, dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms and halogen;

R³is phenyl substituted by 1 to 4 substituents selected from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, alkylthio of 1 to 10 carbon atoms, benzyloxy, cycloalkoxy of 3 to 6 carbon atoms, C₄-C₆Cycloalkylidenemethyl, C₃-C₁₀-alkylenemethyl, indanyloxy (indanyloxy) and halogen;

R⁴is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl or benzyl;

R^4’is hydrogen or alkyl of 1 to 6 carbon atoms;

R⁵is-CH₂-、-CH₂-CO-、-SO₂-, -S-or-NHCO-; and

n has a value of 0, 1 or 2; and

acid addition salts of said compounds containing a nitrogen atom capable of being protonated.

Other specific selective cytokine inhibitory drugs for use in the present invention include, but are not limited to:

3- (3-ethoxy-4-methoxyphenyl) -N-hydroxy-3- (1-oxoisoindolinyl) propionamide;

3- (3-ethoxy-4-methoxyphenyl) -N-methoxy-3- (1-oxoisoindolinyl) propionamide;

n-benzyloxy-3- (3-ethoxy-4-methoxyphenyl) -3-phthalimidopropionamide;

n-benzyloxy-3- (3-ethoxy-4-methoxyphenyl) -3- (3-nitrophenyldicarboximi) propanamide;

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-nitrobenzodiimido) propanamide;

3- (3, 4-dimethoxyphenyl) -3- (1-oxoisoindolinyl) propionamide;

3- (3-ethoxy-4-methoxyphenyl) -N-hydroxy-3- (4-methyl-phthalimido) propanamide;

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-aminobenzoylimino) -3- (3-ethoxy-4-methoxyphenyl) -N-hydroxypropionamide;

3- (3-aminobenzoylimino) -3- (3-ethoxy-4-methoxyphenyl) -N-hydroxypropionamide;

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-nitrophenyldicarboximido) propanamide.

Other selective cytokine inhibitory drugs useful in the present invention include phenethylsulfone substituted with an oxoisoindoline group on the phenyl group. Examples of such compounds include, but are not limited to, those disclosed in U.S. Pat. No. 6,020,358, which is incorporated herein by reference, including:

in the formula, use^*The carbon atoms represented constitute the chiral center;

y is C-O, CH₂、SO₂Or CH₂C＝O；R¹、R²、R³And R⁴Each independently hydrogen, halogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, nitro, cyano, hydroxy or-NR⁸R⁹(ii) a Or R¹、R²、R³And R⁴Any two of which together with the adjacent carbon atoms and the phenylene ring form a naphthylene group;

R⁵and R⁶Each independently hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cyano or cycloalkoxy of up to 18 carbon atoms;

R⁷is hydroxy, alkyl of 1 to 8 carbon atoms, phenyl, benzyl or NR^8’R^9’；

R⁸And R⁹Each independently hydrogen, alkyl of 1 to 8 carbon atoms, phenyl or benzylOr R is⁸And R⁹One of which is hydrogen and the other is-COR¹⁰or-SO₂R¹⁰Or R is⁸And R⁹Together form a tetramethylene group, pentamethylene group, hexamethylene group or-CH₂CH₂X¹CH₂CH₂-, wherein X¹is-O-, -S-or-NH-; and

R^8’and R^9’Each independently of the other hydrogen, alkyl of 1 to 8 carbon atoms, phenyl or benzyl, or R^8’And R^9’One of which is hydrogen and the other is-COR^10’or-SO₂R^10’Or R is^8’And R^9’Together form a tetramethylene group, pentamethylene group, hexamethylene group or-CH₂CH₂X²CH₂CH₂-, wherein X²is-O-, -S-or-NH-.

It will be appreciated that for convenience, the above compound is defined as phenethylsulfone when R is⁷Is NR^8’R^9’Including sulfonamides.

A particular group of such compounds is that wherein Y is C ═ O or CH₂The compound of (1).

Another particular group of such compounds are those in which R is¹、R²、R³And R⁴Each independently hydrogen, halogen, methyl, ethyl, methoxy, ethoxy, nitro, cyano, hydroxy or-NR⁸R⁹Wherein R is⁸And R⁹Each independently is hydrogen or methyl, or R⁸And R⁹One of which is hydrogen and the other is-COCH₃The compound of (1).

Specific compounds are, wherein R¹、R²、R³And R⁴One is-NH₂And the balance being hydrogen compounds.

Specific compounds are, wherein R¹、R²、R³And R⁴One is-NHCOCH³The remainder being hydrogenThe compound of (1).

Specific compounds are, wherein R¹、R²、R³And R⁴One is-N (CH)₃)₂And the balance being hydrogen compounds.

A further particular group of such compounds are those wherein R is¹、R²、R³And R⁴One is methyl and the others are hydrogen.

Specific compounds are, wherein R¹、R²、R³And R⁴One is fluorine and the remainder are hydrogen compounds.

Specific compounds are, wherein R⁵And R⁶Each independently hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopentyloxy or cyclohexyloxy.

Specific compounds are, wherein R⁵Is methoxy, R⁶Are compounds of monocyclic alkoxy, polycyclic alkoxy and benzocycloalkoxy.

Specific compounds are, wherein R⁵Is methoxy, R⁶Are ethoxy compounds.

Specific compounds are, wherein R⁷Is hydroxy, methyl, ethyl, phenyl, benzyl or NR^8’R^9’Wherein R is^8’And^R9’each independently hydrogen or methyl.

Specific compounds are, wherein R⁷Is methyl, ethyl, phenyl, benzyl or NR^8’R^9’Wherein R is^8’And R^9’Each independently hydrogen or methyl.

Specific compounds are, wherein R⁷A compound that is methyl.

Specific compounds are, wherein R⁷Is NR^8’R^9’Wherein，R^8’And R^9’Each independently hydrogen or methyl.

Other selective cytokine inhibitory drugs include enantiomerically pure compounds disclosed in the following references: U.S. patent application 10/392,195 filed on 3/19/2003; international patent applications PCT/US03/08737 and PCT/US03/08738 filed 3/20/2003; U.S. provisional patent applications 60/438,450 and 60/438,448 by g.muller et al, filed on 7/1/2003; U.S. provisional patent application 60/452,460 to g.muller et al, filed 3/5/2003, all of which are incorporated herein by reference. Preferred compounds include the enantiomer of 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methanesulfonylethyl ] -4-acetylaminoisoindoline-1, 3-dione and the enantiomer of 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide.

Preferred selective cytokine inhibitory drugs for use in the present invention are 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-1H-isoindol-4-yl } -amide, which is commercially available from Celgene corporation (Warren, N.J.). The chemical structure of 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide is as follows:

other specific selective cytokine inhibitory drugs include, but are not limited to: cycloalkyl amides and cycloalkyl nitriles disclosed in U.S. Pat. Nos. 5,728,844, 5,728,845, 5,968,945, 6,180,644 and 6,518,281 and WO97/08143 and WO97/23457, each of which is incorporated herein by reference. Representative compounds have the formula:

in the formula:

R¹and R²One is R³-X-and the other is hydrogen, nitro, cyano, trifluoromethyl, carbo (lower) alkoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, lower alkyl, lower alkoxy, halogen or R³-X-；

R³Is a monocycloalkyl, bicycloalkyl or benzocycloalkyl group of up to 18 carbon atoms;

x is a carbon-carbon bond, -CH₂-or-O-;

R⁵is (i) o-phenylene unsubstituted or substituted with 1 to 3 substituents each independently selected from nitro, cyano, halogen, trifluoromethyl, carbo (lower) alkoxy, acetyl, carbamoyl unsubstituted or substituted by lower alkyl, acetoxy, carboxyl, hydroxy, amino, lower alkylamino, lower acylamino or lower alkoxy; (ii) vicinal divalent residues of pyridine, pyrrolidine, imidazole, naphthalene or thiophene, wherein the divalent bonds are on vicinal ring carbon atoms; (iii) an ortho-divalent cycloalkyl or cycloalkenyl group containing 4 to 10 carbon atoms, unsubstituted or substituted with 1 to 3 substituents, each independently selected from nitro, cyano, halogen, trifluoromethyl, carbon (lower) alkoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, lower alkylamino, lower alkyl, lower alkoxy or phenyl; (iv) vinylidene disubstituted with lower alkyl; or (v) ethylene which is unsubstituted or mono-or di-substituted with lower alkyl;

R⁶is-CO-, -CH₂-or-CH₂CO-；

Y is-COZ, -C ≡ N, -OR⁸Lower alkyl or aryl;

z is-NH₂、-OH、-NHR、-R⁹OR-OR⁹；

R⁸Is hydrogen or lowA lower alkyl group;

R⁹is lower alkyl or benzyl; and

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

In other embodiments, R¹And R²One is R³-X-and the other is hydrogen, nitro, cyano, trifluoromethyl, carbo (lower) alkoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, lower alkyl, lower alkoxy, halogen or R³-X-；

R³Is a monocycloalkyl group of up to 10 carbon atoms, a polycycloalkyl group of up to 10 carbon atoms, or a benzocycloalkyl group of up to 10 carbon atoms;

x is-CH₂-or-O-;

R⁵is (i) an ortho divalent residue of pyridine, pyrrolidine, imidazole, naphthalene, or thiophene, wherein the divalent bonds are on ortho ring carbon atoms;

(ii) an ortho-divalent cycloalkyl group of 4 to 10 carbon atoms which is unsubstituted or substituted with 1 to 3 substituents each independently selected from nitro, cyano, halogen, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms or phenyl;

(iii) vinylidene disubstituted with nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl substituted with alkyl of 1 to 3 carbon atoms, acetoxy, carboxyl, hydroxyl, 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 halogen;

(iv) ethylene which is unsubstituted or substituted by 1 to 2 substituents, each independently selected from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl substituted by alkyl of 1 to 3 carbon atoms, acetoxy, carboxyl, hydroxyl, amino substituted by alkyl of 1 to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halogen;

R⁶is-CO-, -CH₂-or-CH₂CO-；

Y is-COX, -C ≡ N, -OR⁸Alkyl or aryl of 1 to 5 carbon atoms;

x is-NH₂、-OH、-NHR、-R⁹、-OR⁹Or an alkyl group of 1 to 5 carbon atoms;

R⁸is hydrogen or lower alkyl;

R⁹is alkyl or benzyl; and the combination of (a) and (b),

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

In other embodiments, R¹And R²One is R³-X-, another hydrogen, nitro, cyano, trifluoromethyl, carbo (lower) alkoxy, acetyl, carbamoyl, acetoxy, carboxyl, hydroxy, amino, lower alkyl, lower alkoxy, halogen, HF₂CO，F₃CO or R³-X-；

R³Is monocycloalkyl, bicycloalkyl, benzocycloalkyl of up to 18 carbon atoms, tetrahydropyran, or tetrahydrofuran;

x is a carbon-carbon bond, -CH₂-, -O-or-N ═ O;

R⁵is (i) o-phenylene unsubstituted or substituted with 1 to 3 substituents each independently selected from nitro, cyano, halogen, trifluoromethyl, carbo (lower) alkoxy, acetyl, carbamoyl unsubstituted or substituted by lower alkyl, acetoxy, carboxyl, hydroxy, amino, lower alkylamino, lower acylamino or lower alkoxy; (ii) ortho-divalent residues of pyridine, pyrrolidine, imidazole, naphthalene or thiophene, wherein the divalent bonds are to a ring carbon atom at the ortho-positionOn the seed; (iii) an ortho-divalent cycloalkyl or cycloalkenyl group containing 4 to 10 carbon atoms, unsubstituted or substituted by one or more substituents, each independently selected from nitro, cyano, halogen, trifluoromethyl, carbon (lower) alkoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, lower alkylamino, lower alkyl, lower alkoxy or phenyl; (iv) vinylidene disubstituted with lower alkyl; or (v) ethylene which is unsubstituted or mono-or di-substituted with lower alkyl;

R⁶is-CO-, -CH₂-or-CH₂CO-；

Y is-COX, -C ≡ N, -OR⁸Alkyl of 1 to 5 carbon atoms, or aryl;

x is-NH₂、-OH、-NHR、-R⁹、-OR⁹Or an alkyl group of 1 to 5 carbon atoms;

R⁸is hydrogen or lower alkyl;

R⁹is alkyl or benzyl; and the combination of (a) and (b),

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

Other representative compounds have the formula:

in the formula:

y is-C ═ N or CO (CH)₂)_mCH₃，

m is 0, 1,2 or 3;

R⁵is (i) an o-phenylene group which is unsubstituted or substituted by 1 to 3 substituents, each independently selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl substituted by alkyl of 1 to 3 carbon atoms, acetoxy, carboxyA group, hydroxy, amino substituted with alkyl of 1 to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halogen; (ii) divalent residues of pyridine, pyrrolidine, imidazole, naphthalene or thiophene, wherein the divalent bonds are on ortho ring carbon atoms; (iii) a divalent cycloalkyl group of 4 to 10 carbon atoms which is unsubstituted or substituted with one or more substituents each independently selected from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, phenyl or halogen; (iv) vinylidene disubstituted with nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl substituted with alkyl of 1 to 3 carbon atoms, acetoxy, carboxyl, hydroxyl, 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 halogen; or (v) ethylene unsubstituted or substituted with 1 to 2 substituents each independently selected from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl substituted with alkyl of 1 to 3 carbon atoms, acetoxy, carboxyl, hydroxyl, 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 halogen;

R⁶is-CO-, -CH₂-、-CH₂CO-or-SO₂-；

R⁷Is (i) a straight or branched alkyl group containing 1 to 12 carbon atoms; (ii) a cyclic or bicyclic alkyl group containing 1 to 12 carbon atoms; (iii) a pyridyl group; (iv) phenyl substituted with one or more substituents each independently selected from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, straight, branched, cyclic or bicycloalkyl of 1 to 10 carbon atoms, straight, branched, cyclic or bicycloalkoxy of 1 to 10 carbon atoms, CH₂R (wherein R is 1-10 carbons)A cyclic or bicyclic alkyl group of atoms), or halogen; (v) benzyl substituted with 1 to 3 substituents each independently selected from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halogen; (vi) a naphthyl group; or (vii) benzyloxy; and

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

In other embodiments, a particular selective cytokine inhibitory drug has the formula:

in the formula:

R⁵is (i) a divalent residue of pyridine, pyrrolidine, imidazole, naphthalene, or thiophene, wherein the divalent bonds are on ortho ring carbon atoms; (ii) a divalent cycloalkyl group of 4 to 10 carbon atoms which is unsubstituted or substituted with one or more substituents each independently selected from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, phenyl or halogen; (iii) vinylidene disubstituted with nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl substituted with alkyl of 1 to 3 carbon atoms, acetoxy, carboxyl, hydroxyl, 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 halogen; or (iv) an ethylene group which is unsubstituted or substituted by 1 to 2 substituents each independently selected from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl substituted by alkyl of 1 to 3 carbon atoms, acetoxy, carboxyl, hydroxyl, amino substituted by alkyl of 1 to 3 carbon atomsAlkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halogen;

R⁶is-CO-, -CH₂-、-CH₂CO-or-SO₂-；

R⁷Is (i) a cyclic or bicyclic alkyl group containing 4 to 12 carbon atoms; (ii) a pyridyl group; (iii) phenyl substituted with one or more substituents each independently selected from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, straight, branched, cyclic or bicycloalkyl of 1 to 10 carbon atoms, straight, branched, cyclic or bicycloalkoxy of 1 to 10 carbon atoms, CH₂R (wherein R is a cyclic or bicyclic alkyl group of 1 to 10 carbon atoms), or halogen; (iv) benzyl substituted with 1 to 3 substituents each independently selected from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halogen; (v) a naphthyl group; or (vi) benzyloxy; and

y is COX, -C ≡ N, -OR⁸Alkyl of 1 to 5 carbon atoms, or aryl;

x is-NH₂、-OH、-NHR、-R⁹、-OR⁹Or an alkyl group of 1 to 5 carbon atoms;

R⁸is hydrogen or lower alkyl;

R⁹is alkyl or benzyl; and

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

Other specific selective cytokine inhibitory drugs include, but are not limited to: arylamides (e.g., N-benzoyl-3-amino-3- (3 ', 4' -dimethoxyphenyl) -propionamide) disclosed in U.S. patents 5,801,195, 5,736,570, 6,046,221 and 6,284,780, each of which is incorporated herein by reference. Representative compounds have the formula:

in the formula:

ar is (i) a linear, branched or cyclic unsubstituted alkyl group of 1 to 12 carbon atoms; (ii) linear, branched or cyclic substituted alkyl of 1 to 12 carbon atoms; (iii) a phenyl group; (iv) phenyl substituted with one or more substituents each independently selected from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halogen; (v) a heterocycle; or (vi) a heterocycle substituted with one or more substituents each independently selected from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halogen;

r is-H, alkyl of 1-10 carbon atoms, CH₂OH、CH₂CH₂OH or CH₂COZ, wherein Z is alkoxy of 1 to 10 carbon atoms, benzyloxy or NHR¹Wherein R is¹Is H or alkyl of 1 to 10 carbon atoms; and

y is i) a benzene ring or a heterocycle which is unsubstituted or substituted by one or more substituents each independently selected from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halogen, or ii) naphthyl. Specific examples of such compounds have the formula:

in the formula:

ar is 3, 4-disubstituted phenyl wherein each substituent is independently selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms and halogen;

z is alkoxy of 1-10 carbon atoms, benzyloxy, amino or alkylamino of 1-10 carbon atoms; and

y is (i) phenyl unsubstituted or substituted with one or more substituents each independently selected from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, and halogen, or (ii) naphthyl.

Other specific selective cytokine inhibitory drugs include, but are not limited to: imine/amide ethers and alcohols (e.g., 3-phthalimido-3- (3 ', 4' -dimethoxyphenyl) propan-1-ol) disclosed in U.S. patent 5,703,098, which is incorporated herein by reference. Representative compounds have the formula:

in the formula:

R¹is (i) a linear, branched or cyclic unsubstituted alkyl group of 1 to 12 carbon atoms; (ii) linear, branched or cyclic substituted alkyl of 1 to 12 carbon atoms; (iii) a phenyl group; or (iv) phenyl substituted with one or more substituents each independently selected from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, acylamino, alkylamino, di (alkyl) amino, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, di (alkyl) of 5 to 12 carbon atomsCycloalkyl, alkoxy of 1 to 10 carbon atoms, cycloalkoxy of 3 to 10 carbon atoms, bicycloalkoxy of 5 to 12 carbon atoms, and halogen;

R²is hydrogen, alkyl of 1 to 8 carbon atoms, benzyl, pyridylmethyl or alkoxymethyl;

R³is (i) ethylene, (ii) vinylene, (iii) branched alkylene of 3 to 10 carbon atoms, (iv) branched alkenylene of 3 to 10 carbon atoms, (v) cycloalkylene of 4 to 9 carbon atoms, which is unsubstituted or substituted with one or more substituents, each independently selected from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino substituted with alkyl of 1 to 6 carbon atoms, amino substituted with acyl of 1 to 6 carbon atoms, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 12 carbon atoms, and halogen, (vi) cycloalkylene of 4 to 9 carbon atoms, which is unsubstituted or substituted with one or more substituents, each independently selected from nitro, and (iv) cycloalkylene of 3 to 10 carbon atoms, Cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino substituted with alkyl of 1 to 6 carbon atoms, amino substituted with acyl of 1 to 6 carbon atoms, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 12 carbon atoms, and halogen, (vii) o-phenylene unsubstituted or substituted with one or more substituents each independently selected from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino substituted with alkyl of 1 to 6 carbon atoms, amino substituted with acyl of 1 to 6 carbon atoms, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 12 carbon atoms, And halogen, (viii) naphthyl, or (ix) pyridinyl;

R⁴is-CX-, -CH₂-or-CH₂CX-；

X is O is S; and

n is 0, 1,2 or 3.

Other specific selective cytokine inhibitory drugs include, but are not limited to: succinimides and maleimides disclosed in U.S. patent 5,658,940 (e.g., methyl 3- (3 ', 4', 5 ', 6' -tetrahydrophthalimido) -3- (3 ", 4" -dimethoxyphenyl) propionate), which is incorporated herein by reference. Representative compounds have the formula:

in the formula:

R¹is-CH₂-、-CH₂CO-or-CO-;

R²and R³Together form (i) an ethylene group which is unsubstituted or substituted with an alkyl group of 1 to 10 carbon atoms or a phenyl group, (ii) a vinylene group which is substituted with two substituents each independently selected from an alkyl group of 1 to 10 carbon atoms and a phenyl group, or (iii) a divalent cycloalkyl group of 5 to 10 carbon atoms which is unsubstituted or substituted with one or more substituents each independently selected from a nitro group, a cyano group, a trifluoromethyl group, an carbethoxy group, a carbomethoxy group, a propisocarbonyl group, an acetyl group, a carbamoyl group which is unsubstituted or substituted with an alkyl group of 1 to 3 carbon atoms, an acetoxy group, a carboxyl group, a hydroxyl group, an amino group, a substituted amino group, an alkyl group of 1 to 10 carbon atoms, an alkoxy group of 1 to 10 carbon atoms, a norbornenyl group, a phenyl group or a halogen;

R⁴is (i) an unsubstituted straight or branched alkyl group of 4 to 8 carbon atoms; (ii) cycloalkyl or bicycloalkyl of 5 to 10 carbon atoms which is unsubstituted or substituted by one or more substituents each independently selected from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, branched, straight or cyclic alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, phenyl or halogen; (iii) phenyl substituted by one or more substituents, said substituents beingThe substituents are each independently selected from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, cycloalkyl or bicycloalkyl of 3 to 10 carbon atoms, cycloalkoxy or bicycloalkoxy of 3 to 10 carbon atoms, phenyl or halogen; (iv) pyridine or pyrrolidine, unsubstituted or substituted with one or more substituents each independently selected from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, phenyl or halogen; and the combination of (a) and (b),

R⁵is-COX, -CN, -CH₂COX, alkyl of 1-5 carbon atoms, aryl, -CH₂OR、-CH₂Aryl or-CH₂OH，

Wherein X is NH₂OH, NHR OR OR⁶，

Wherein R is lower alkyl; and

wherein R is⁶Is alkyl or benzyl.

Other specific selective cytokine inhibitory drugs include, but are not limited to: substituted imines disclosed in U.S. patent 6,429,221 (e.g., 2-phthalimido-3- (3 ', 4' -dimethoxyphenyl) propane), which is incorporated herein by reference. Representative compounds have the formula:

in the formula:

R¹is (i) a straight, branched or cyclic alkyl group of 1 to 12 carbon atoms; (ii) phenyl or phenyl substituted with one or more substituents each independently selected from nitro, cyano, trifluoroMethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, straight or branched alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halogen; (iii) a benzyl group or a benzyl group substituted with one or more substituents each independently selected from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halogen; or (iv) -Y-Ph, wherein Y is a linear, branched, or cyclic alkyl group of 1 to 12 carbon atoms, Ph is phenyl or phenyl substituted with one or more substituents each independently selected from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propinyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halogen;

R²is-H, branched or straight chain alkyl of 1-10 carbon atoms, phenyl, pyridyl, heterocycle, -CH₂-aryl or-CH₂-a heterocycle;

R³is i) ethylene, ii) vinylene; iii) a branched alkylene group of 3 to 10 carbon atoms; iv) a branched alkenylene group of 3 to 10 carbon atoms; v) cycloalkylene of 4 to 9 carbon atoms which is unsubstituted or substituted by 1 to 2 substituents, each of which is independently selected from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, substituted amino, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halogen, vi) cycloalkylene of 4 to 9 carbon atoms unsubstituted or substituted with 1 to 2 substituents, each of the substituents is independently selected from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, substituted amino, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halogen; or vii) o-phenylene which is unsubstituted or substituted by 1 to 2 substituents, each independently selected fromNitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, substituted amino, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halogen; and the combination of (a) and (b),

R⁴is-CX or-CH₂-；

X is O or S.

Other specific selective cytokine inhibitory drugs include, but are not limited to: substituted 1, 3, 4-oxadiazoles (e.g., 2- [1- (3-cyclopentyloxy-4-methoxyphenyl) -2- (1, 3, 4-oxadiazol-2-yl) ethyl ] -5-methylisoindoline-1, 3-dione) disclosed in U.S. patent 6,326,388, which is incorporated herein by reference. Representative compounds have the formula:

in the formula:

by using^*The carbon atoms represented constitute the chiral center;

y is C-O, CH₂、SO₂Or CH₂C＝O；

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

R¹、R²、R³and R⁴Each independently hydrogen, halogen, trifluoromethyl, acetyl, alkyl of 1 to 8 carbon atoms, alkoxy of 1 to 4 carbon atoms, nitro, cyano, hydroxy, -CH₂NR⁸R⁹、-(CH₂)₂NR⁸R⁹or-NR₈R⁹Or is or

R on adjacent carbon atoms¹、R²、R³And R⁴Any two of which together with the phenyl ring form a naphthylene, quinoline, quinoxaline, benzimidazole, benzodioxole or 2-hydroxybenzeneImidazole;

R⁵and R⁶Each independently hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 6 carbon atoms, cyano, benzocycloalkoxy, cycloalkoxy of up to 18 carbon atoms, bicycloalkoxy of up to 18 carbon atoms, tricycloalkoxy of up to 18 carbon atoms, or cycloalkylalkoxy of up to 18 carbon atoms;

R⁸and R⁹Each independently hydrogen, straight or branched chain alkyl of 1 to 8 carbon atoms, phenyl, benzyl, pyridyl, pyridylmethyl, or R⁸And R⁹One of which is hydrogen and the other is-COR¹⁰or-SO₂R¹⁰Or R is⁸And R⁹Together form tetramethylene, pentamethylene, hexamethylene, -CH-NCH-or-CH₂CH₂X¹CH₂CH_2-Wherein X is¹is-O-, -S-or-NH-;

R¹⁰is hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl, cycloalkylmethyl of up to 6 carbon atoms, phenyl, pyridyl, benzyl, imidazolylmethyl, pyridylmethyl, NR¹¹R¹²、CH₂R¹⁴R¹⁵Or NR¹¹R¹²；

Wherein R is¹⁴And R¹⁵Each independently hydrogen, methyl, ethyl or propyl; and

wherein R is¹¹And R¹²Each independently hydrogen, alkyl of 1 to 8 carbon atoms, phenyl or benzyl; and

acid addition salts of said compounds containing a nitrogen atom capable of being protonated.

Specific examples of such compounds have the formula:

in the formula:

by using^*The carbon atoms represented constitute the chiral center;

y is C-O, CH₂、SO₂Or CH₂C＝O；

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

(i)R¹、R²、R³and R⁴Each independently hydrogen, halogen, trifluoromethyl, acetyl, alkyl of 1 to 8 carbon atoms, alkoxy of 1 to 4 carbon atoms, nitro, cyano, hydroxy, -CH₂NR⁸R⁹、-(CH₂)₂NR⁸R⁹or-NR⁸R⁹Or is or

(ii) R on adjacent carbon atoms¹、R²、R³And R⁴Any two of which together with the phenyl ring form a naphthylene group, a quinoline group, a quinoxaline group, a benzimidazole, a benzodioxole or a 2-hydroxybenzimidazole;

R⁵and R⁶Each independently hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 6 carbon atoms, cyano, benzocycloalkoxy, cycloalkoxy of up to 18 carbon atoms, bicycloalkoxy of up to 18 carbon atoms, tricycloalkoxy of up to 18 carbon atoms, or cycloalkylalkoxy of up to 18 carbon atoms;

(i)R⁸and R⁹Each independently hydrogen, straight or branched chain alkyl of 1 to 8 carbon atoms, phenyl, benzyl, pyridyl, pyridylmethyl, or

(ii)R⁸And R⁹One of which is hydrogen and the other is-COR¹⁰or-SO₂R¹⁰Wherein R is¹⁰Is hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl, cycloalkylmethyl of up to 6 carbon atoms, phenyl, pyridyl, benzyl, imidazolylmethyl, pyridylmethyl, NR¹¹R¹²Or CH₂NR¹⁴R¹⁵Wherein, in the step (A),R¹¹and R¹²Each independently hydrogen, alkyl of 1 to 8 carbon atoms, phenyl or benzyl, R¹⁴And R¹⁵Each independently hydrogen, methyl, ethyl or propyl; or

(iii)R⁸And R⁹Together form tetramethylene, pentamethylene, hexamethylene, -CH-NCH-or-CH₂CH₂X¹CH₂CH_2-Wherein X is¹is-O-, -S-or-NH-.

Other specific selective cytokine inhibitory drugs include, but are not limited to: cyano and carboxyl derivatives of substituted styrenes (e.g., 3, 3-bis- (3, 4-dimethoxyphenyl) acrylonitrile) disclosed in U.S. Pat. Nos. 5,929,117, 6,130,226, 6,262,101, and 6,479,554, each of which is incorporated herein by reference. Representative compounds have the formula:

in the formula:

(a) x is-O-or- (C)_nH_2n) -, where n has the value 0, 1,2 or 3, R¹Is alkyl of 1 to 10 carbon atoms, monocycloalkyl of up to 10 carbon atoms, polycycloalkyl of up to 10 carbon atoms or benzocycloalkyl of up to 10 carbon atoms, or

(b) X is-CH ═ R¹Is alkylene of up to 10 carbon atoms, monocyclic alkylene of up to 10 carbon atoms or bicyclic alkylene of up to 10 carbon atoms;

R²is hydrogen, nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxy, amino, lower alkyl, lower alkylene methyl, lower alkoxy, or halogen;

R³is (i) phenyl which is unsubstituted or substituted by one or more substituentsEach of which is independently selected from nitro, cyano, halogen, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl substituted with alkyl of 1 to 3 carbon atoms, acetoxy, carboxyl, hydroxyl, amino substituted with alkyl of 1 to 5 carbon atoms, alkyl of up to 10 carbon atoms, cycloalkyl of up to 10 carbon atoms, alkoxy of up to 10 carbon atoms, cycloalkoxy of up to 10 carbon atoms, alkylenemethyl of up to 10 carbon atoms, cycloalkylenemethyl of up to 10 carbon atoms, phenyl or methylenedioxy; (ii) pyridine, substituted pyridine, pyrrolidine, imidazole, naphthalene, or thiophene; (iii) cycloalkyl of 4 to 10 carbon atoms which is unsubstituted or substituted with one or more substituents each independently selected from nitro, cyano, halogen, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, phenyl;

R⁴and R⁵Each independently is hydrogen, or R⁴And R⁵Together form a carbon-carbon bond;

y is-COZ, -C ≡ N or lower alkyl of 1-5 carbon atoms;

z is-OH, -NR⁶R⁶、-R⁷OR-OR⁷；R⁶Is hydrogen or lower alkyl; r⁷Is alkyl or benzyl. Specific examples of such compounds have the formula:

in the formula:

(a) x is-O-or- (C)_nH_2n) -, where n has the value 0, 1,2 or 3, R¹Is alkyl of 1 to 10 carbon atoms, monocycloalkyl of up to 10 carbon atoms, polycycloalkyl of up to 10 carbon atoms or benzocycloalkyl of up to 10 carbon atoms, or

(b) X is-CH ═ R¹Is alkylene of up to 10 carbon atoms, monocyclic alkylene of up to 10 carbon atoms or bicyclic alkylene of up to 10 carbon atoms;

R²is hydrogen, nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxy, amino, lower alkyl, lower alkylene methyl, lower alkoxy or halogen;

R³pyrrolidine, imidazole, or thiophene which is unsubstituted or substituted with one or more substituents each independently selected from nitro, cyano, halogen, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or phenyl;

R⁴and R⁵Each independently is hydrogen, or R⁴And R⁵Together form a carbon-carbon bond;

y is-COZ, -C ≡ N or lower alkyl of 1-5 carbon atoms;

z is-OH, -NR⁶R⁶、-R⁷OR-OR⁷；R⁶Is hydrogen or lower alkyl; r⁷Is alkyl or benzyl.

Particularly preferred nitriles are compounds having the formula:

in the formula:

(a) x is-O-or- (C)_nH_2n) -, where n has the value 0, 1,2 or 3, R¹Is alkyl of up to 10 carbon atoms, monocycloalkyl of up to 10 carbon atoms, polycycloalkyl of up to 10 carbon atoms or up to 10 carbon atomsBenzocycloalkyl of, or

(b) X is-CH ═ R¹Is alkylene of up to 10 carbon atoms, monocyclic alkylene of up to 10 carbon atoms;

R²is hydrogen, nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxy, amino, lower alkyl, lower alkoxy or halogen; and

R³is (i) phenyl or naphthyl, unsubstituted or substituted with one or more substituents each independently selected from nitro, cyano, halogen, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl substituted with alkyl of 1 to 3 carbon atoms, acetoxy, carboxyl, hydroxyl, amino substituted with alkyl of 1 to 5 carbon atoms, alkoxy or cycloalkoxy of 1 to 10 carbon atoms; or (ii) cycloalkyl of 4 to 10 carbon atoms which is unsubstituted or substituted by one or more substituents each independently selected from nitro, cyano, halogen, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms or phenyl.

Particularly preferred nitriles have the formula:

other specific selective cytokine inhibitory drugs include, but are not limited to: isoindolin-1-ones and isoindoline-1, 3-diones substituted at the 2-position with an α - (3, 4-disubstituted phenyl) alkyl group and at the 4-and/or 5-position with a nitrogen-containing group are disclosed in WO01/34606 and U.S. Pat. No. 6,667,316, each of which is incorporated herein by reference. Representative compounds have the formula:

and including pharmaceutically acceptable salts and stereoisomers thereof,

in the formula:

one of X and X' is ═ C ═ O or ═ SO₂The other of X and X' is ═ C ═ O, ═ CH₂、＝SO₂Or ═ CH₂C＝O；

n is 1,2 or 3;

R¹and R²Each independently is (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, cyano, (C)₃-C₁₈) Cycloalkyl group, (C)₃-C₁₈) Cycloalkoxy or (C)₃-C₁₈) Cycloalkyl-methoxy;

R³is SO₂-Y, COZ, CN or (C)₁-C₆) Hydroxyalkyl, wherein:

y is (C)₁-C₆) Alkyl, benzyl or phenyl;

z is-NR₆R₇、(C₁-C₆) Alkyl, benzyl or phenyl;

R₆is H, (C)₁-C₄) Alkyl, (C)₃-C₁₈) Cycloalkyl group, (C)₂-C₅) Alkanoyl, benzyl or phenyl, each optionally substituted by halogen, amino or (C)₁-C₄) Alkyl-amino substitution;

R⁷is H or (C)₁-C₄) An alkyl group;

R₄and R₅Together form-NH-CH₂-R₈-、NH-CO-R₈-or-N ═ CH-R₈-, wherein:

R₈is CH_2、O、NH、CH＝CH. CH ═ N or N ═ CH; or

R₄And R₅One of (A) is H, R₄And R₅Is imidazolyl, pyrrolyl, oxadiazolyl, triazolyl or a structure of formula (A),

in the formula:

z is 0 or 1;

R₉is H; (C)₁-C₄) Alkyl, (C)₃-C₁₈) Cycloalkyl group, (C)₂-C₅) Alkanoyl or (C)₄-C₆) Cycloalkanoyl, optionally substituted by halogen, amino, (C)₁-C₄) Alkyl-amino or (C)₁-C₄) Dialkyl-amino substitution; a phenyl group; a benzyl group; a benzoyl group; (C)₂-C₅) An alkoxycarbonyl group; (C)₃-C₅) An alkoxyalkyl carbonyl group; n-morpholinocarbonyl; a carbamoyl group; quilt (C)₁-C₄) An alkyl-substituted N-substituted carbamoyl group; or a methanesulfonyl group; and

R₁₀is H, (C)₁-C₄) Alkyl, methylsulfonyl or (C)₃-C₅) An alkoxyalkyl carbonyl group; or

R₉And R₁₀Together form-CH-, -CH-N-CH-or (C)₁-C₂) Alkylene, optionally substituted by amino, (C)₁-C₄) Alkyl-amino or (C)₁-C₄) Dialkyl-amino substitution; or

R₄And R₅All have the structure of formula (A).

In one embodiment, when (i) R³is-SO₂-Y, -COZ or-CN, and (ii) R⁴Or R⁵When one is hydrogen, Z is not 0. In other embodiments, R⁹And R¹⁰Together form-CH-, -CH-N-CH-, or (C) substituted with an amino group₁-C₂) Alkylene, (C)₁-C₄) Alkyl-amino or (C)₁-C₄) A dialkyl-amino group. In other embodiments, R₄And R₅Are all of the structure of formula (A).

Specific compounds have the formula:

and enantiomers thereof. Other specific compounds have the formula:

and

further examples include, but are not limited to: 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl ] -4, 5-dinitroisoindoline-1, 3-dione, 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl ] -4, 5-diaminoisoindoline-1, 3-dione, 7- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl ] -3-pyrrolino [3, 4-e ] benzimidazole-6, 8-dione, 7- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl ] hydro-3-pyrrolino [3, 4-e ] benzimidazole-2, 6, 8-trione, 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methanesulfonylethyl ] -3-pyrrolo [3, 4-h ] quinoline-1, 3-dione, 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methanesulfonylethyl ] -3-pyrrolo [3, 4-f ] quinoxaline-1, 3-dione, cyclopropyl-N- {2- [1- (3-ethoxy-4-methoxyphenyl) -2-methanesulfonylethyl ] -1, 3-dioxoisoindolin-4-yl } carboxamide, methods of preparation and use thereof, 2-chloro-N- {2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl ] -1, 3-dioxoisoindolin-4-yl } acetamide, 2-amino-N- {2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl ] -1, 3-dioxoisoindolin-4-yl } acetamide, 2-N, N-dimethylamino-N- {2- [ - (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl ] -1, 3-dioxoisoindolin-4-yl } acetamide, and mixtures thereof, N- {2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl ] -1, 3-dioxoisoindolin-4-yl } -2, 2, 2-trifluoroacetamide, N- {2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl ] -1, 3-dioxoisoindolin-4-yl } methoxycarbamoyl, 4- [ 1-aza-2- (dimethylamino) ethenyl ] -2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl ] isoindoline-1, 3-dione, 4- [ 1-aza-2- (dimethylamino) prop-1-enyl ] -2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl ] isoindoline-1, 3-dione, 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl ] -4- (5-methyl-1, 3, 4-oxadiazol-2-yl) isoindoline-1, 3-dione, 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl ] -4-pyrrolyl isoindoline-1, 3-dione, 4- (aminomethyl) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl ] -isoindoline-1, 3-dione, 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl ] -4- (pyrrolylmethyl) isoindoline-1, 3-dione, N- {2- [1- (3-ethoxy-4-methoxyphenyl) -3-hydroxybutyl ] -1, 3-dioxoisoindolin-4-yl } acetamide, N- {2- [1- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl ] -1, 3-dioxoisoindolin-4-yl } acetamide, N- {2- [1R- (3-ethoxy-4-methoxyphenyl) -3-hydroxybutyl ] -1, 3-dioxoisoindolin-4-yl } acetamide, N- {2- [1R- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl ] -1, 3-dioxoisoindolin-4-yl } acetamide, N- {2- [1S- (3-ethoxy-4-methoxyphenyl) -3-hydroxybutyl ] -1, 3-dioxoisoindolin-4-yl } acetamide, N- {2- [1S- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl ] -1, 3-dioxoisoindolin-4-yl } acetamide, 4-amino-2- [1- (3-ethoxy-4-methoxyphenyl) -3-hydroxybutyl isoindoline-1, 3-dione, 4-amino-2- [1- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl ] isoindoline-1, 3-dione, 2- [1- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl ] -4-pyrrolyl isoindoline-1, 3-dione, 2-chloro-N- {2- [1- (3-ethoxy-4-methoxyphenyl) -3 -oxobutyl ] -1, 3-dioxoisoindol-4-yl } acetamide, 2- (dimethylamino) -N- {2- [1- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl ] -1, 3-dioxoisoindolin-4-yl } acetamide, 4-amino-2- [1R- (3-ethoxy-4-methoxyphenyl) -3-hydroxybutyl ] isoindoline-1, 3-dione, 4-amino-2- [1R- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl ] isoindoline-1, 3-dione, a salt thereof, a solvate thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, 2- [1R- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl ] -4-pyrrolylisoindoline-1, 3-dione, 2- (dimethylamino) -N- {2- [1R- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl ] -1, 3-dioxoisoindolin-4-yl } acetamide, cyclopentyl-N- {2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl ] -1, 3-dioxoisoindolin-4-yl } carboxamide, 3- (dimethylamino) -N- {2- [1- (3-ethoxy-4- Methoxyphenyl) -2- (methylsulfonyl) ethyl ] -1, 3-dioxoisoindolin-4-yl } propanamide, 2- (dimethylamino) -N- {2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl ] -1, 3-dioxoisoindolin-4-yl } propanamide, N-2- [ (1R) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl ] -1, 3-dioxoisoindolin-4-yl ] -2- (dimethylamino) acetamide, N- {2- [ (1S) -1- (3-ethoxy-4-methoxyphenyl) -propanamide 2- (methylsulfonyl) ethyl ] -1, 3-dioxoisoindolin-4-yl } -2- (dimethylamino) acetamide, 4- {3- [ (dimethylamino) methyl ] pyrrolyl } -2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl ] isoindoline-1, 3-dione, cyclopropyl-N- {2- [ (1S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl ] -1, 3-dioxoisoindolin-4-yl } carboxamide, 2- [1- (3, 4-dimethoxyphenyl) -2- (methylsulfonyl) ethyl ] -4-pyrrolylisopyrrolidinoisoI Indoline-1, 3-dione, N- {2- [1- (3, 4-dimethoxyphenyl) -2- (methylsulfonyl) ethyl ] -1, 3-dioxoisoindolin-4-yl } -2- (dimethylamino) acetamide, cyclopropyl-N- {2- [1- (3, 4-dimethoxyphenyl) -2- (methylsulfonyl) ethyl ] -1, 3-dioxoisoindolin-4-yl } carboxamide, cyclopropyl-N- {2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl ] -3-oxoisoindolin-4-yl } carboxamide, and pharmaceutically acceptable salts thereof, 2- (dimethylamino) -N- {2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl ] -3-oxoisoindolin-4-yl } acetamide, cyclopropyl-N- {2- [ (1S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl ] -3-oxoisoindolin-4-yl } carboxamide, cyclopropyl-N- {2- [ (1R) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl ] -3-oxoisoindolin-4-yl } carboxamide, and pharmaceutically acceptable salts thereof, (3R) -3- [7- (acetylamino) -1-oxoisoindolin-2-yl ] -3- (3-ethoxy-4-methoxyphenyl) -N, N-dimethylpropionamide, (3R) -3- [7- (cyclopropylcarbonylamino) -1-oxoisoindolin-2-yl ] -3- (3-ethoxy-4-methoxyphenyl) -N, N-dimethylpropionamide, 3- {4- [2- (dimethylamino) acetylamino ] -1, 3-dioxoisoindolin-2-yl } -3- (3-ethoxy-4-methoxyphenyl) -N, n-dimethylpropionamide, (3R) -3- [7- (2-chloroacetamido) -1-oxoisoindolin-2-yl ] -3- (3-ethoxy-4-methoxy-phenyl) -N, N-dimethylpropionamide, (3R) -3- {4- [2- (dimethylamino) acetylamino ] -1, 3-dioxoisoindolin-2-yl } -3- (3-ethoxy-4-methoxyphenyl) -N, N-dimethylpropionamide, 3- (1, 3-dioxo-4-pyrrolylisoindolin-2-yl) -3- (3-ethoxy-4-methoxyphenyl) -N, n-dimethylpropionamide, 2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl ] -4- (imidazolyl-methyl) isoindoline-1, 3-dione, N- ({2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl ] -1, 3-dioxoisoindolin-4-yl } methyl) acetamide, 2-chloro-N- ({2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl ] -1, 3-dioxoisoindolin-4-yl } methyl) acetamide, and mixtures thereof, 2- (dimethylamino) -N- ({2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl ] -1, 3-dioxoisoindolin-4-yl } methyl) acetamide, 4- [ bis (methylsulfonyl) amino ] -2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl ] isoindoline-1, 3-dione, 2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl ] -4- [ (methylsulfonyl) amino ] isoindoline-1, 3-dione, and mixtures thereof, N- {2- [1- (3-ethoxy-4-methoxyphenyl) -3-hydroxypentyl ] -1, 3-dioxoisoindolin-4-yl } acetamide, N- {2- [1- (3-ethoxy-4-methoxyphenyl) -3-oxopentyl ]1, 3-dioxoisoindolin-4-yl } acetamide, 2- [ (1R) -1- (3-ethoxy-4-methoxyphenyl) -3-hydroxybutyl ] -4- (azolylmethyl) isoindoline-1, 3-dione, 2- [ (1R) -1- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl ] -4- (azolylmethyl) Isoindoline-1, 3-dione, N- {2- [1- (3-cyclopentyloxy-4-methoxyphenyl) -3-hydroxybutyl ] -1, 3-dioxoisoindolin-4-yl } acetamide, N- {2- [1- (3-cyclopentyloxy-4-methoxyphenyl) -3-oxobutyl ] -1, 3-dioxoisoindolin-4-yl } acetamide, 2- [1- (3-cyclopentyloxy-4-methoxyphenyl) -3-oxobutyl ] -4-pyrrolylisoindoline-1, 3-dione, 2- [1- (3, 4-dimethoxyphenyl) -3-oxobutyl ] -4- [ bis (methylsulfonyl) amino ] amide Alkyl ] isoindoline-1, 3-dione; and pharmaceutically acceptable salts, solvates and stereoisomers thereof.

Other specific selective cytokine inhibitory drugs include, but are not limited to: imino-and amino-substituted acylhydroxamic acids (e.g., (3- (1, 3-dioxoisoindolin-2-yl) -3- (3-ethoxy-4-methoxyphenyl) propanolamino) propanoate) disclosed in WO01/45702 and U.S. Pat. No. 6,699,899, each of which is incorporated herein by reference. Representative compounds have the formula:

in the formula:

by using^*The carbon atoms represented constitute the chiral center,

R⁴is hydrogen or- (C ═ O) -R¹²，

R¹And R¹²Each independently of the other is alkyl of 1 to 6 carbon atoms, phenyl, benzyl, pyridylmethyl, pyridyl, imidazolyl, imidazolylmethyl, or

CHR^*(CH₂)_nNR^*R⁰，

In the formula, R^*And R⁰Each independently hydrogen, alkyl of 1 to 6 carbon atoms, phenyl, benzyl, pyridylmethyl, pyridyl, imidateOxazolyl or imidazolylmethyl, and n ═ 0, 1, or 2;

R⁵is C-O, CH₂、CH₂-CO-or SO₂；

R⁶And R⁷Each independently of the others is nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, cycloalkoxy of 3 to 8 carbon atoms, halogen, bicycloalkyl of up to 18 carbon atoms, tricycloalkoxy of up to 18 carbon atoms, 1-indanyloxy, 2-indanyloxy, C₄-C₈Cycloalkylidenemethyl or C₃-C₁₀-an alkylene methyl group;

R⁸、R⁹、R¹⁰and R¹¹Each independently is:

(i) hydrogen, nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, alkylamino, dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, halogen, or

(ii)R⁸、R⁹、R¹⁰And R¹¹One of them is an amide group containing a lower alkyl group, R⁸、R⁹、R¹⁰And R¹¹The remainder of (A) is hydrogen, or

(iii) Hydrogen, if R⁸And R⁹Together are benzo, quinoline, quinoxaline, benzimidazole, benzodioxole, 2-hydroxybenzimidazole, methylenedioxy, dialkoxy or dialkyl, or

(iv) Hydrogen, if R¹⁰And R¹¹Together are benzo, quinoline, quinoxaline, benzimidazole, benzodioxole, 2-hydroxybenzimidazole, methylenedioxy, dialkoxy or dialkyl, or

(v) The presence of hydrogen in the presence of hydrogen,if R is⁹And R¹⁰Together are benzo.

Specific selective cytokine inhibitory drugs include, but are not limited to: 7-amino-isoindolyl compounds disclosed in U.S. patent application 10/798,317, filed 3/12/2004, which is incorporated herein by reference. Representative compounds have the formula:

in the formula:

y is-C (O) -, -CH₂、-CH₂C (O) -or SO₂；

X is H;

z is (C)_0-4-alkyl) -C (O) R³、C_1-4Alkyl radicals, (C)_0-4-alkyl) -OH, (C)_1-4-alkyl) -O (C)_1-4Alkyl group), (C)_1-4-alkyl) -SO₂(C_1-4Alkyl group), (C)_0-4-alkyl) -SO (C)_1-4Alkyl group), (C)_0-4-alkyl) -NH₂、(C_0-4-alkyl) -N (C)_1-8-alkyl groups)₂、(C_0-4Alkyl) -N (H), (OH) or CH₂NSO₂(C_1-4-an alkyl group);

R¹and R₂Independently is C_1-8-alkyl, cycloalkyl or (C)_1-4-alkyl) cycloalkyl;

R³is NR⁴R⁵OH or O- (C)_1-8-an alkyl group);

R⁴is H;

R⁵is-OH or-OC (O) R⁶；

R⁶Is C_1-8Alkyl, amino- (C)_1-8Alkyl group), (C)_1-8-alkyl) - (C_3-6-cycloalkyl), C_3-6-cycloalkyl, phenyl, benzylOr an aryl group;

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof;

or the formula:

in the formula:

y is-C (O) -, -CH₂、-CH₂C (O) -or SO₂；

X is halogen, -CN, -NR₇R₈、-NO₂or-CF₃；

Z is (C)_0-4Alkyl) -SO₂(C_1-4-alkyl), -C_0-4-alkyl) -CN, - (C)_0-4-alkyl) -C (O) R³，C_1-4Alkyl radicals, (C)_0-4-alkyl) OH, (C)_0-4Alkyl) O (C)_1-4Alkyl group), (C)_0-4Alkyl) SO (C)_1-4Alkyl group), (C)_0-4-alkyl) NH₂、(C_0-4Alkyl) N (C)_1-8-alkyl groups)₂、(C_0-4Alkyl group N (H), (OH), (C)_0-4-alkyl) -dichloropyridine or (C)_0-4-alkyl) NSO₂(C_1-4-an alkyl group);

w is-C_3-6-cycloalkyl, - (C)_1-8-alkyl) - (C_3-6-cycloalkyl), -C_0-8-alkyl) - (C_3-6-cycloalkyl) -NR₇R₈、(C_0-8-alkyl) -NR₇R₈、(C_0-4Alkyl) -CHR₉-(C_0-4Alkyl) -NR₇R₈；

R₁And R₂Independently is C_1-8-alkyl, cycloalkyl or (C)_1-4-alkyl) cycloalkyl;

R³is C_1-8Alkyl, NR⁴R⁵OH or O- (C)_1-8-an alkyl group);

R⁴and R⁵Independently H, C_1-8Alkyl radicals, (C)_0-8-alkyl) - (C_3-6-cycloalkyl), OH or-OC (O) R⁶；

R⁶Is C_1-8Alkyl radicals, (C)_0-8-alkyl) - (C_3-6-cycloalkyl), amino- (C)_1-8-alkyl), phenyl, benzyl or aryl;

R₇and R₈Each independently is H, C_1-8Alkyl radicals, (C)_0-8-alkyl) - (C_3-6-cycloalkyl), phenyl, benzyl, aryl, or may form together with the carbon atom to which they are attached a 3-7 membered heterocycloalkyl ring or a heteroaromatic ring;

R₉is C_1-4Alkyl, (C)_0-4Alkyl) aryl, (C)_0-4Alkyl group) - (C_3-6-Cycloalkyl group), (C)_0-4Alkyl) -heterocyclyl; or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. In other embodiments, W is

Or

In other embodiments, representative compounds have the formula:

in the formula:

R₁、R₂and R₃Independently is H or C_1-8-alkyl, provided that R₁、R₂And R₃At least one of which is not H;

and pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates or prodrugs thereof.

Specific selective cytokine inhibitory drugs include, but are not limited to: U.S. provisional application 60/454,149 filed 3/12/2003 and the N-alkyl-hydroxamic acid-isoindolyl compounds disclosed in pending U.S. non-provisional application entitled "N-alkyl-hydroxamic acid-isoindolyl compounds and their pharmaceutical uses" filed by Man et al at 3/12/2004, each of which is incorporated herein by reference. Representative compounds have the formula:

in the formula:

y is-C (O) -, -CH₂、-CH₂C (O) -or SO₂；

R₁And R₂Independently is C_1-8-alkyl, CF₂H、CF₃、CH₂CHF₂Cycloalkyl or (C1)_-8-alkyl) cycloalkyl;

Z₁is H, C_1-6-alkyl, -NH₂-NR₃R₄OR OR₅；

Z₂Is H or C (O) R₅；

X₁、X₂、X₃And X₄Independently H, halogen, NO₂、OR₃、CF₃、C_1-6Alkyl radicals, (C)_0-4-alkyl) - (C_3-6-cycloalkanesBase), (C)_0-4-alkyl) -N- (R)₈R₉)、(C_0-4-alkyl) -NHC (O) - (R)₈)、(C_0-4-alkyl) -NHC (O) CH (R)₈)(R₉)、(C_0-4-alkyl) -NHC (O) N (R)₈R₉)、(C_0-4-alkyl) -NHC (O) O (R)₈)、(C_0-4-alkyl) -O-R₈、(C_0-4-alkyl) -imidazolyl, (C)_0-4-alkyl) -pyrrolyl, (C)_0-4-alkyl) oxadiazolyl, (C)_0-4-Alkyl-triazolyl or (C)_0-4-alkyl) -heterocycle;

R₃、R₄and R₅Each independently is H, C_1-6Alkyl, O-C_1-6-alkyl, phenyl, benzyl or aryl;

R₆and R₇Independently is H or C_1-6-an alkyl group;

R₈and R₉Each independently is H, C_1-9Alkyl radical, C_3-6-cycloalkyl, (C)_1-6-alkyl) - (C_3-6-cycloalkyl), (C)_0-6-alkyl) -N (R)₄R₅)、(C_1-6-alkyl) -OR₅Phenyl, benzyl, aryl, piperidinyl, piperazinyl, pyrrolidinyl, morpholino or C_3-7-a heterocycloalkyl group;

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.

Specific selective cytokine inhibitory drugs include, but are not limited to: diphenylethylene compounds disclosed in U.S. patent application 10/794,931 filed 3/5/2004, which application is incorporated herein by reference. Representative compounds have the formula:

and pharmaceutically acceptable salts, solvates or hydrates thereof,

in the formula:

R₁is-CN, lower alkyl, -COOH, -C (O) -N (R)₉)₂-C (O) -lower alkyl, -C (O) -benzyl, -C (O) O-lower alkyl, -C (O) O-benzyl;

R₄is-H, -NO₂Cyano, substituted or unsubstituted lower alkyl, substituted or unsubstituted alkoxy, halogen, -OH, -C (O) (R)₁₀)₂、-COOH、-NH₂、-OC(O)-N(R₁₀)₂；

R₅Is substituted or unsubstituted lower alkyl, substituted or unsubstituted alkoxy or substituted or unsubstituted alkenyl;

x is a substituted or unsubstituted phenyl, substituted or unsubstituted pyridine, substituted or unsubstituted pyrrolidine, substituted or unsubstituted imidazole, substituted or unsubstituted naphthalene, substituted or unsubstituted thiophene, or substituted or unsubstituted cycloalkyl;

R₉independently for each occurrence-H or substituted or unsubstituted lower alkyl; and

R₁₀each occurrence is independently-H or substituted or unsubstituted lower alkyl. In other embodiments, representative compounds have the formula:

and pharmaceutically acceptable salts, solvates or hydrates thereof, wherein:

R₁and R₂Independently is-H, -CN, substituted or unsubstituted lower alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -COOH, -C (O) -lower alkyl, -C (O) O-lower alkyl, -C (O) -N (R)₉)₂Substituted or unsubstituted aryl or substituted or unsubstituted heterocycle;

R_a、R_b、R_cand R_dIndependently for each occurrence-H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, -NO₂、-OH、-OPO(OH)₂、-N(R₉)₂、-OC(O)-R₁₀、-OC(O)-R₁₀-N(R₁₀)₂、-C(O)N(R₁₀)₂、-NHC(O)-R₁₀、-NHS(O)₂-R₁₀、-S(O)₂-R₁₀、-NHC(O)NH-R₁₀、-NHC(O)N(R₁₀)₂、-NHC(O)NHSO₂-R₁₀、-NHC(O)-R₁₀-N(R₁₀)₂、-NHC(O)CH(R₁₀)(N(R₉)₂) or-NHC (O) -R₁₀-NH₂；

R₃is-H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, -NO₂、-OH、-OPO(OH)₂、-N(R⁹)₂、-OC(O)-R₁₀、-OC(O)-R₁₀-N(R₁₀)₂、-C(O)N(R₁₀)₂、-NHC(O)-R₁₀、-NHS(O)₂-R₁₀、-S(O)₂-R₁₀、-NHC(O)NH-R₁₀、-NHC(O)N(R₁₀)₂、-NHC(O)NHSO₂-R₁₀、-NHC(O)-R₁₀-N(R₁₀)₂、-NHC(O)CH(R₁₀₎(N(R₉)₂) or-NHC (O) -R₁₀-NH₂Or R is₃And R_aOr and R₄Together form-O-C (R)₁₆R₁₇) -O-or-O- (C (R)₁₆R₁₇))₂-O-；

R₄is-H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, substituted or unsubstitutedSubstituted alkoxy, halogen, cyano, -NO₂、-OH、-OPO(OH)₂、-N(R⁹)₂、-OC(O)-R₁₀、-OC(O)-R₁₀-N(R₁₀)₂、-C(O)N(R₁₀)₂、-NHC(O)-R₁₀、-NHS(O)₂-R₁₀、-S(O)₂-R₁₀、-NHC(O)NH-R₁₀、-NHC(O)N(R₁₀)₂、-NHC(O)NHSO₂-R₁₀、-NHC(O)-R₁₀-N(R₁₀)₂、-NHC(O)CH(R₁₀)(N(R₉)₂) or-NHC (O) -R₁₀-NH₂；

R⁵is-H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, -NO₂、-OH、-OPO(OH)₂、-N(R⁹)₂、-OC(O)-R₁₀、-OC(O)-R₁₀-N(R₁₀)₂、-C(O)N(R₁₀)₂、-NHC(O)-R₁₀、-NHS(O)₂-R₁₀、-S(O)₂-R₁₀、-NHC(O)NH-R₁₀、-NHC(O)N(R₁₀)₂、-NHC(O)NHSO₂-R₁₀、-NHC(O)-R₁₀-N(R₁₀)₂、-NHC(O)CH(R₁₀)(N(R₉)₂) or-NHC (O) -R₁₀-NH₂；

R₆is-H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, -NO₂、-OH、-OPO(OH)₂、-N(R₉)₂、-OC(O)-R₁₀、-OC(O)-R₁₀-N(R₁₀)₂、-C(O)N(R₁₀)₂、-NHC(O)-R₁₀、-NHS(O)₂-R₁₀、-S(O)₂-R₁₀、-NHC(O)NH-R₁₀、-NHC(O)N(R₁₀)₂、-NHC(O)NHSO₂-R₁₀、-NHC(O)-R₁₀-N(R₁₀)₂、-NHC(O)CH(R₁₀)(N(R₉)₂) or-NHC (O) -R₁₀-NH₂；

R₇is-H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, -NO₂、-OH、-OPO(OH)₂、-N(R₉)₂、-OC(O)-R₁₀、-OC(O)-R₁₀-N(R₁₀)₂、-C(O)N(R₁₀)₂、-NHC(O)-R₁₀、-NHS(O)₂-R₁₀、-S(O)₂-R₁₀、-NHC(O)NH-R₁₀、-NHC(O)N(R₁₀)₂、-NHC(O)NHSO₂-R₁₀、-NHC(O)-R₁₀-N(R₁₀)₂、-NHC(O)CH(R₁₀)(N(R₉)₂) or-NHC (O) -R₁₀-NH₂；

R₈is-H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, -NO₂、-OH、-OPO(OH)₂、-N(R₉)₂、-OC(O)-R₁₀、-OC(O)-R₁₀-N(R₁₀)₂、-C(O)N(R₁₀)₂、-NHC(O)-R₁₀、-NHS(O)₂-R₁₀、-S(O)₂-R₁₀、-NHC(O)NH-R₁₀、-NHC(O)N(R₁₀)₂、-NHC(O)NHSO₂-R₁₀、-NHC(O)-R₁₀-N(R₁₀)₂、-NHC(O)CH(R₁₀)(N(R₉)₂) or-NHC (O) -R₁₀-NH₂Or R is₈And R_cOr and R₇Together form-O-C (R)₁₆R₁₇) -O-or-O- (C (R)₁₆R₁₇))₂-O-；

R₉Each occurrence is independently-H, substituted or unsubstitutedSubstituted lower alkyl or substituted or unsubstituted cycloalkyl;

R₁₀independently for each occurrence, is a substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted lower hydroxyalkyl, or R₁₀Together with the nitrogen to which it is attached form a substituted or unsubstituted heterocyclic ring, or when appropriate R₁₀is-H; and

R₁₆and R₁₇Each occurrence is independently-H or halogen.

The compounds of the present invention may be commercially available or prepared according to the methods described in the patents or patent applications disclosed in this specification. In addition, optically pure compounds can be asymmetrically synthesized or resolved using known resolving agents or chiral columns, as well as other standard organic chemical synthesis techniques.

The term "pharmaceutically acceptable salts" as used herein, unless otherwise indicated, includes non-toxic acid and base addition salts of the compounds to which the term refers. Acceptable non-toxic acid addition salts include those derived from organic and inorganic acids or bases known in the art, including, for example, hydrochloric, hydrobromic, phosphoric, sulfuric, methanesulfonic, acetic, tartaric, lactic, succinic, citric, malic, maleic, sorbic, aconitic, salicylic, phthalic, embolic (embonic acid), heptanoic, and the like.

Naturally occurring acidic compounds are capable of forming salts with various pharmaceutically acceptable bases. The bases that can be used for the preparation of pharmaceutically acceptable base addition salts of such acidic compounds are those that form non-toxic base addition salts, that is, salts containing a pharmaceutically acceptable cation, such as, but not limited to, alkali or alkaline earth metal salts, especially calcium, magnesium, sodium, potassium salts. Suitable organic bases include, but are not limited to, N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), lysine, and procaine.

As used herein, and unless otherwise indicated, the term "prodrug" refers to a derivative of a compound that hydrolyzes, oxidizes, or otherwise reacts under biological conditions (in vitro or in vivo) to provide the compound. Examples of prodrugs include, but are not limited to, derivatives of selective cytokine inhibitory drugs containing biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogs. Other examples of prodrugs include those containing-NO, -NO₂-ONO or-ONO₂Derivatives of a portion of a selective cytokine inhibitory drug. Prodrugs can generally be prepared by well-known methods, such as those described in Burger's Medicinal Chemistry and drug discovery, 172-178, 949-982 (edited E.Wolff, 5 th edition 1995) and Design of Prodrugs (H.Bundgaand, Ed. Elselvier, New York 1985).

As used herein, unless otherwise indicated, the terms "biohydrolyzable amide", "biohydrolyzable ester", "biohydrolyzable carbamate", "biohydrolyzable carbonate", "biohydrolyzable ureide", "biohydrolyzable phosphate" refer to an amide, ester, carbamate, carbonate, ureide, or phosphate, respectively, of a compound having the following properties: 1) does not interfere with the biological activity of the compound, but may confer advantageous properties to the compound in vivo, such as absorption, duration of action or onset of action; or 2) is biologically inactive, but is converted in vivo to a biologically active compound. Examples of biohydrolyzable esters include, but are not limited to, lower alkyl esters, lower acyloxyalkyl esters (e.g., acetoxymethyl, 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 acylaminoalkyl esters (e.g., acetamidomethyl esters). Examples of biohydrolyzable amides include, but are not limited to, lower alkyl amides, alpha-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 of the present invention contain one or more chiral centers and may exist as racemic mixtures of enantiomers or as mixtures of diastereomers. The invention includes the use of stereochemically pure forms of this compound, as well as the use of mixtures of those forms. For example, mixtures containing equal or unequal amounts of enantiomers of a particular selective cytokine inhibitory drug of the present invention may be used in the methods and compositions of the present invention. The pure (R) or (S) enantiomer of a particular compound disclosed herein may be substantially free of other enantiomers at the time of use.

As used herein, unless otherwise indicated, the term "stereomerically pure" refers to a composition that contains one stereoisomer of a compound and is substantially free of other stereoisomers of the compound. For example, a stereomerically pure composition of a compound having one chiral center is substantially free of the opposite enantiomer of the compound. A stereomerically pure composition of a compound having two chiral centers is substantially free of other diastereomers of the compound. Typical stereomerically pure compounds include greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of the other stereoisomers of the compound; more preferably, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound; more preferably, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound; and most preferably comprises greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound.

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

The term "enantiomerically pure" as used herein, unless otherwise specified, refers to a stereochemically pure composition of a compound having one chiral center. Similarly, the term "enantiomerically enriched" refers to a composition that is stereomerically enriched in a compound having one chiral center.

It should be noted that if there is a difference between the structure shown and the name of the structure, the structure shown should be the subject of the difference. Furthermore, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be understood as encompassing all stereoisomers of it.

4.2 second active ingredient

As noted above, a second active ingredient or agent, particularly a conventional agent for use in MDS patients, may be used in the methods and compositions of the invention in combination with a selective cytokine inhibitory drug. Preferably, the second active agent is capable of reversing ineffective hematopoiesis. Specific second active agents are also capable of stimulating the differentiation and differentiation of committed erythroid progenitor cells in the cell in vitro or in vivo.

The second active agent can be a macromolecule (e.g., a protein) or a small molecule (e.g., a synthetic inorganic metal, organometallic, or organic molecule). The second active ingredient comprises cytokine, hematopoietic growth factor, cytotoxic agent, immunomodulator, anticancer agent, antibiotic, antifungal agent, etc. Specific agents include, but are not limited to: etanercept (Enbrel ®), imatinib (Glevec ®), anti-TNF-alpha antibodies, infliximab (Remicade ®), G-CSF, GM-CSF, EPO, dexamethasone, topotecan, irinotecan, thalidomide, IMiDs^TMPentoxifylline, ciprofloxacin, vinorelbine, IL2, IL8, and,IL18, Ara-C, isotretinoin, 13-cis-retinoic acid, 12-O-tetradecanoyl phorbol-13-acetate (TPA), 5-AZA 2' -deoxycytidine, 9-nitrocamptothecin, trans-retinoic acid, amifostine, amphotericin B and amphotericin B liposomes, anti-CD-20 monoclonal antibodies, anti-thymocyte globulin (ATG), arsenic trioxide, azacytidine, bevacizumab, bismuth monoclonal antibodies, bryostatin, busulfan, caspofungin acetate, celecoxib, cladribine, cyclophosphamide, cyclosporine, cytarabine, cytosine, daunorubicin, doxorubicin, depsipeptide, etoposide, farresy transferase inhibitors, flavopiridol, 3 Flt ligand, fludarabine, genetuzumab ozogagin, humanized monoclonal anti-VEGF antibodies, idarubicin, folinic acid, and other anti-retinoic acid, Melphalan, mitoxantrone, monoclonal antibody ABX-CBL, monoclonal antibody CD52, mycophenolate mofetil, omega-3 fatty acid, antisense oligonucleotide, pentostatin, phenyl butyrate, PR1 leukemia peptide vaccine, montanide, sodium phenyl butyrate, sodium salicylate, temozolomide, zizan, troxacitabine, tumor necrosis factor receptor IgG chimera, yttrium Y90 human monoclonal antibody M195. In a particular embodiment of the invention, the compounds of the invention are used in a regimen with pentoxifylline, ciprofloxacin, and/or dexamethasone, respectively.

The invention also includes the use of native, natural and recombinant proteins. The invention also includes variants and derivatives (e.g., modified forms) of the native protein that have at least some of the pharmacological activity of its base protein in vivo. Examples of variants include, but are not limited to, proteins having one or more amino acid residues that differ from the corresponding residues in the native form of the protein. The term "variant" also includes proteins that lack the sugar moieties normally found in their native form (e.g., unglycosylated forms). Examples of derivatives include, but are not limited to: pegylated derivatives and fusion proteins, such as those formed by fusing IgG1 or IgG3 to a target protein or to an active portion of a target protein. See, e.g., penechet, m.l. and Morrison, s.l., j.immunol.methods 248: 91-101(2001).

Recombinant and variant forms of G-CSF may be prepared as described in U.S. patents 4,810,643, 4,999,291, 5,528,823 and 5,580,755, all of which are incorporated herein by reference. Recombinant and variant forms of GM-CSF can be prepared as described in U.S. Pat. Nos. 5,391,485, 5,393,870, and 5,229,496, all of which are incorporated herein by reference. Indeed, in the United states, recombinant forms of G-CSF and GM-CSF are being sold for the treatment of symptoms associated with particular chemotherapy. A recombinant form of GM-CSF, named filgrastim, is sold in the United states under the trade name Neupogen ®. Neupogen ® is known to stimulate the differentiation and maturation of granulocytes, primarily neutrophils, in MDS patients and enhances the erythrocyte response in combination with EPO. Physicians' Desk Reference, 587-. Recombinant forms of GM-CSF, named Saxagrastim, are also sold in the United states under the tradename Leukine ®. Leukine ® is known to stimulate differentiation and maturation of early bone marrow and macrophage precursor cells and has been reported to increase granulocytes. Physicians' Desk Reference, 1755-. Recombinant form of EPO, designated alfa-epoetin, is sold in the united states under the trade name Epogen ®. Epogen ® was used to stimulate erythropoiesis by stimulating differentiation and maturation of committed erythroid precursor cells. It has been reported that Epogen ® is effective in 20-26% of MDS patients when administered alone, and in up to 48% of patients when administered in combination with G-CSF or GM-CSF. The Physicians' Desk Reference, 582-.

Growth factors or cytokines such as G-CSF, GM-CSF, and EPO may also be administered in the form of vaccines. For example, secreted cytokines such as G-CSF and GM-CSF, or vaccines that cause secretion thereof, may be used in the methods, pharmaceutical compositions, and kits of the invention. See, e.g., emers, l.a. et al, curr. opinion mol. ther.3 (1): 77-84(2001).

Other compounds that may be administered or used in combination with the selective cytokine inhibitory drugs of this invention include the compounds disclosed in U.S. provisional patent application 60/380,842 filed 5/17/2002 and U.S. provisional patent application 60/380,843 filed 5/17/2002, both of which are incorporated herein by reference.

4.3 methods of treatment and control

The methods of the invention include methods of preventing, treating and/or managing various types of MDS. The term "preventing", as used herein, unless otherwise indicated, includes but is not limited to inhibiting or avoiding symptoms associated with MDS. Symptoms associated with MDS include, but are not limited to: anemia, thrombotic cytopenia, neutropenia, cytopenia, biperfectic cytopenia (double-deficient cell line) and pancytopenia (triple-deficient cell line). As used herein, unless otherwise indicated, the term "treating" or "treatment" refers to administering a composition after the onset of symptoms of MDS, while "preventing" refers to administering to a subject before the onset of symptoms, particularly to a subject at risk for MDS. As used herein, unless otherwise indicated, the term "managing" includes preventing the recurrence of MDS in a subject who has suffered MDS, extending the time a subject who has suffered MDS is in remission, and/or preventing the development of MDS in a subject at risk of suffering MDS.

The invention includes methods of treating or preventing patients with primary and secondary MDS. The invention also includes methods of treating a subject who has previously been treated for MDS, as well as a subject who has not previously been treated for MDS. Because MDS patients have different clinical indications and different clinical outcomes, it is clear that it is necessary to stratify them according to their prognosis and to schedule treatments according to severity and stage. Indeed, the methods and compositions of the invention can be used for various stages of treatment in patients with one or more types of MDS, including, but not limited to: refractory Anemia (RA), RA with cyclic hyperplastic red blood cells (rars), RA with hypercellular cells (RAEB), transformed RAEB (RAEB-T), or chronic myelomonocytic leukemia (CMML). The invention is particularly suitable for elderly people, for example people over the age of 60.

The methods encompassed by the present invention comprise administering to a subject (e.g., a human) having, or at risk of having, MDS one or more selective cytokine inhibitory drugs, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.

Another method comprises administering: 1) a 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. Examples of selective cytokine inhibitory drugs are disclosed herein (see, e.g., section 4.1); examples of second active agents are also disclosed herein (see, e.g., section 4.2).

Administration of the selective cytokine inhibitory drug and the second active agent to the patient may be simultaneous or sequential, by the same or different routes of administration. The suitability of a particular route of administration for a particular active agent will depend on the active agent itself (e.g., whether it can be administered orally without breaking down before entering the blood stream) and the disease being treated. The preferred route of administration of the selective cytokine inhibitory drug is oral. Preferred routes of administration for the second active agent or component of the invention are known to those of ordinary skill in the art. See, for example, the Physicians' Desk Reference, 1755-.

In one embodiment of the invention, the recommended daily dosage of a selective cytokine inhibitory drug for use in the conditions described herein ranges from about 1 mg/day to about 10,000 mg/day, given in individual daily doses a day or preferably in divided doses. More specifically, the daily dose is administered in equal divided doses in two. Specifically, the daily dose ranges from about 1 mg/day to about 5,000 mg/day, more specifically, from about 10 mg/day to about 2,500 mg/day, from about 100 mg/day to about 800 mg/day, from about 100 mg/day to about 1,200 mg/day, or from about 25 mg/day to about 2,500 mg/day. In controlling the patient, treatment should be initiated at a lower dose, which may be from about 1 mg/day to about 2,500 mg/day, and if necessary, increased to about 200 mg/day to about 5,000 mg/day, as a single dose or as divided doses, depending on the overall response of the patient. In particular embodiments, 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide is preferably administered in amounts of about 400 mg/day, 800 mg/day, 1,200 mg/day, 2,500 mg/day, 5,000 mg/day, or 10,000 mg/day, in two divided portions.

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 from about 1mg to about 1000mg, from about 5mg to about 500mg, from about 10mg to about 350mg, or from about 50mg to about 200 mg. The specific amount of the second active agent will depend upon the specific agent used, the type of MDS being treated or controlled, the severity and stage of MDS, and the amount of selective cytokine inhibitory drug and any optional additional active agent concurrently administered to the subject. In particular embodiments, the second active agent is etanercept (Enbrel ®), imatinib (Glivec ®), anti-TNF- α antibodies, infliximab (Remicade ®), G-CSF, GM-CSF, EPO, trans-retinoic acid, dexamethasone, topotecan, pentoxifylline, ciprofloxacin, dexamethasone, IL2, IL8, IL18, Ara-C, vinorelbine, or a combination thereof. GM-CSF is present at about 60mcg/m²To about 500mcg/m²Is administered intravenously over 2 hours, or at about 5mcg/m²Daily to about 12mcg/m²The amount per day was administered subcutaneously. G-CSF is initially administered subcutaneously in an amount of about 1 mcg/kg/day and can be adjusted according to the increase in total granulocyte count. Maintenance doses were either 300mcg (smaller patients) or 480mcg administered subcutaneously. EPO was administered subcutaneously 3 times per week in an amount of 10,000 units.

In yet another embodiment, the invention encompasses methods of treating, preventing and/or managing DMS, which comprise administering a selective cytokine inhibitory drug of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, in combination with transplantation therapy. As described elsewhere herein, treatment of MDS is based on the stage and mechanism of the disease. Because transformation to leukemia inevitably progresses at some stages of MDS, transplantation of peripheral blood stem cells, hematopoietic stem cell preparations, or bone marrow may be necessary. The use of the selective cytokine inhibitory drugs of the present invention in combination with transplantation therapy provides unique and unexpected synergistic effects. In particular, the selective cytokine inhibitory drugs of the invention have cytokine inhibitory activity, and may provide additive or synergistic effects when used concurrently with transplant therapy in subjects with MDS. The selective cytokine inhibitory drugs of the present invention act in combination with transplantation therapy to reduce complications associated with invasive transplantation procedures and the associated risk of Graft Versus Host Disease (GVHD). The invention encompasses methods of treating, preventing and/or managing MDS, which comprises administering to a patient (e.g., a human) a selective cytokine inhibitory drug of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, before, during, or after transplantation of umbilical cord blood, placental blood, peripheral stem cells, hematopoietic stem cell preparations or bone marrow. Examples of stem cells suitable for use in the methods of the present invention are disclosed in U.S. provisional patent application 60/372,348 filed on 12.4.2002 by r.

In certain embodiments, the prophylactic or therapeutic agents of the invention are administered to the circulation of a patient. Cycling therapy involves administering a first agent for a period of time, then administering the agent and/or a second agent for a period of time, and repeating the sequential administration. Cycling therapy can reduce the development of resistance to one or more therapeutic agents, avoid or reduce the side effects of a therapy, and/or increase the efficacy of a therapy.

In specific embodiments, the prophylactic or therapeutic agent is administered in a cycle of about 24 weeks, about 1 or 2 times per day. One cycle may include administration of a therapeutic or prophylactic agent and at least one (1) or three (3) weeks of rest. The number of cycles administered may be from about 1 to about 12 cycles, more typically from about 2 to about 10 cycles, or more typically from about 2 to about 8 cycles.

4.4 pharmaceutical compositions and Single Unit dosage forms

The pharmaceutical compositions may be used to prepare individual single unit dosage forms. Pharmaceutical compositions and dosage forms of the invention comprise a selective cytokine inhibitory drug of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. The pharmaceutical compositions and dosage forms of the present invention may also comprise one or more excipients.

The pharmaceutical compositions and dosage forms of the present invention may also contain one or more additional active ingredients. Accordingly, the pharmaceutical compositions and dosage forms of the invention comprise an active ingredient as disclosed herein (e.g., a selective cytokine inhibitory drug of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and a second active ingredient). Optional additional active ingredients are disclosed herein (see, e.g., section 4.2).

The single unit dosage forms of the invention are suitable for administration to a patient orally, mucosally (e.g., nasally, sublingually, vaginally, buccally or rectally), or parenterally (e.g., subcutaneously, intravenously, by bolus injection, intramuscularly or intraarterially), transdermally or transdermally. Examples of dosage forms include, but are not limited to: a tablet; a caplet; capsules, such as elastic soft gelatin capsules; a cachet; keeping in mouth; a lozenge; a dispersant; suppositories; a powder agent; aerosols (e.g., nasal sprays or inhalants); gelling agent; liquid dosage forms suitable for oral or transmucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a patient; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.

The composition, shape and type of dosage forms of the present invention generally vary depending on their application. For example, a dosage form for the acute treatment of a disease may contain a greater amount of one or more active ingredients than a dosage form for the chronic treatment of the same disease. Similarly, parenteral dosage forms may contain smaller amounts of one or more active ingredients than oral dosage forms used to treat the same disease. These and other ways of changing a particular dosage form of the present invention from one to another will be apparent to those skilled in the art. See, e.g., Remington's Pharmaceutical Sciences, 18 th edition, Mack Publishing, Easton PA (1990).

Typical pharmaceutical compositions and dosage forms contain one or more excipients. Suitable excipients are well known to those of ordinary skill in the pharmaceutical arts, and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well 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 (e.g., tablets) may contain excipients that are not suitable for use in parenteral dosage forms. The suitability of a particular excipient may depend on the particular active ingredient in the dosage form. For example, some excipients (e.g., lactose), or when exposed to water, may accelerate the decomposition of some active ingredients. Active ingredients containing primary or secondary amines are particularly sensitive to this accelerated decomposition. Thus, the invention includes pharmaceutical compositions and dosage forms that contain little, if any, lactose or other mono-or disaccharides. In the present invention, the term "lactose-free" is used to indicate that the amount of lactose, if any, is insufficient to substantially accelerate the rate of degradation of the active ingredient.

Lactose-free compositions of the invention may contain excipients well known in the art, such as those listed in, for example, the United States Pharmacopeia (USP)25-NF20 (2002). Typically, lactose-free compositions contain pharmaceutically compatible and pharmaceutically acceptable amounts of active ingredient, binder/filler and lubricant. Preferably, the lactose-free dosage form contains the active ingredient, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

The present invention also includes anhydrous pharmaceutical compositions and dosage forms containing the active ingredient, as water may promote the degradation of certain compounds. For example, the addition of water (e.g., 5%) is widely accepted in the pharmaceutical arts as a means of simulating long-term storage in order to determine properties of the formulation over time, such as shelf life or stability. See, e.g., Jens t. carstensen, Drug Stability: principles & Practice, second edition, Marcel Dekker, NY, NY, 1995, pages 379-80. In fact, water and heat will accelerate the decomposition of some compounds. Thus, the effect of water on the formulation is very significant, as moisture and/or humidity is often encountered during manufacture, handling, packaging, storage, shipment, and use of the formulation.

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

Anhydrous pharmaceutical compositions should be prepared and stored in a manner that maintains their anhydrous nature. Accordingly, anhydrous compositions are preferably packaged with materials known to prevent exposure to water, so that they can be packaged in suitable formulation boxes. Examples of suitable packaging include, but are not limited to, sealed films, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

The invention also includes pharmaceutical compositions and dosage forms comprising one or more compounds that reduce the rate of decomposition of the active ingredient. Such compounds are referred to herein as "stabilizers" and include, but are not limited to, antioxidants (such as ascorbic acid), pH buffers, or salt buffers.

As with the amount and type of excipient, the particular type and amount of active ingredient in a dosage form may vary depending on a variety of factors including, but not limited to, the route of administration to the patient. However, a typical dosage form of the invention comprises from about 1mg to about 1,200mg of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. Typical dosage forms comprise about 1,2, 5, 10, 25, 50, 100, 200, 400, 800, 1,200, 2500, 5,000, or 10,000mg of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. In particular embodiments, preferred dosage forms comprise about 400, 800, or 1,200mg of 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide. Typical dosage forms contain from about 1mg to about 1000mg, from about 5mg to about 500mg, from about 10mg to about 350mg, from about 50mg to about 200mg of the second active ingredient. The specific amount of the second active ingredient will, of course, depend upon the particular agent used, the type of MDS being treated or controlled, as well as the amount of the selective cytokine inhibitory drug of the invention and any optional additional active agents concurrently administered to the subject.

4.4.1 oral dosage forms

Pharmaceutical compositions of the invention suitable for oral administration may be formulated in discrete dosage forms such as, but not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups). Such dosage forms contain predetermined amounts of the active ingredient and may be prepared by pharmaceutical methods well known to those of ordinary skill in the art. See generally Remington's Pharmaceutical Sciences, 18 th edition, Mack Publishing, Easton PA (1990).

Typical oral dosage forms are prepared by intimately mixing the active ingredient with at least one excipient according to conventional pharmaceutical compounding techniques. Excipients may take a wide variety of forms depending on the form of preparation desired for administration. For example, excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. Examples of excipients suitable for use in solid oral dosage forms (e.g., powders, tablets, capsules, and caplets) include, but are not limited to, starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.

Because of their ease of administration, tablets and capsules using solid excipients represent the most advantageous oral unit dosage form. If desired, the tablets may be coated by standard aqueous or non-hydrated techniques. Such dosage forms may be prepared by any pharmaceutical method. Pharmaceutical compositions and dosage forms are generally prepared by: the active ingredient is intimately mixed with a liquid carrier, a well-dispersed solid carrier, or both, and the product is then, if necessary, brought into the desired shape.

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

Examples of excipients that may be used in the oral dosage forms of the present invention include, but are not limited to, binders, fillers, disintegrants, and lubricants. Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethylcellulose calcium, carboxymethylcellulose sodium), polyvinylpyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropyl methylcellulose (e.g., nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

Suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. One specific binder is a mixture of microcrystalline cellulose and sodium carboxymethylcellulose sold as AVICELRC-581. Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103^TMAnd Starch 1500 LM.

Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, cellulose powder, dextrates (dextrates), kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. The binder or filler in the pharmaceutical compositions of the present invention is present in an amount of about 50% to about 99% by weight of the pharmaceutical composition or dosage form.

Disintegrants are used in the compositions of the invention to provide tablets that disintegrate upon exposure to an aqueous environment. Tablets containing too much disintegrant may disintegrate in storage, while tablets containing too little may not disintegrate at the desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that does not significantly alter the release of the active ingredient, either too much or too little, should be used to form the solid oral dosage form of the present invention. The amount of disintegrant used varies with the type of formulation and is readily determined by one skilled in the art. Typical pharmaceutical compositions contain from about 0.5% to about 15% by weight of disintegrant, preferably from about 1% to about 5% by weight of disintegrant.

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

Lubricants useful in the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerol, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., 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. Other lubricants include, for example, syloid silica gel (AEROSIL200, manufactured by W.R. Grace Co. of Baltimore, MD), solidified aerosol of synthetic silica (sold by Degussa Co. of Plano, TX), CAB-O-SIL (a sintered silica product sold by Cabot Co. of Boston, MA), and mixtures thereof. Lubricants, if used at all, are generally used in amounts less than about 1% by weight of the pharmaceutical composition or dosage form into which they are incorporated.

Preferred solid oral dosage forms comprise a selective cytokine inhibitory drug, anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous silicon dioxide, and gelatin.

4.4.2 Slow Release dosage forms

The active ingredients of the present invention may be administered by controlled release devices or delivery devices known to those skilled in the art. Examples include, but are not limited to, those described in the following patents: U.S. Pat. nos. 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. Such dosage forms may be used to provide sustained or controlled release of one or more active ingredients by using, for example, hydroxypropylmethyl cellulose, other polymer matrices, gels, permeable membranes, isotonic systems, multilayer coatings, microparticles, liposomes, microspheres or combinations thereof to produce the desired release profile in varying proportions. Suitable controlled release formulations include those described herein, which are well known to those skilled in the art and are readily selected for use with the active ingredients of the present invention. Thus, the present invention encompasses single unit dosage forms suitable for controlled release and for oral administration, including but not limited to tablets, capsules, gelcaps, and caplets.

All controlled release drug products share the following common objectives: improving the therapeutic effect of the drug over that achieved by its uncontrolled products. Ideally, the use of optimally designed controlled release formulations in medical treatment is characterized by: the disease is cured or controlled in the shortest time with the least amount of medicine. Advantages of controlled release formulations include prolonged drug activity, reduced dosing frequency and improved patient compliance. In addition, controlled release formulations may be used to affect the time at which the effect begins or other characteristics, such as blood levels of the drug, and thereby affect the incidence of side effects (e.g., adverse side effects).

Most controlled release formulations are designed to initially release an amount of drug (active ingredient) that immediately produces the desired therapeutic effect, and gradually and continuously release amounts of other drugs to maintain that level of therapeutic or prophylactic effect over an extended period of time. In order to maintain a constant level of drug in the body, the drug must be released from the dosage form at a rate that will compensate for the amount of drug that is metabolized and excreted 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 routes. Since their administration typically bypasses patients' natural defenses against contaminants, parenteral dosage forms are preferably sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, injectable solutions, dry products that can be dissolved or suspended in a pharmaceutically acceptable carrier for injection, injectable suspensions, and emulsions.

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

Compounds that increase the solubility of one or more of the active ingredients disclosed herein may also be incorporated into 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 of the present invention. See, for example, U.S. Pat. No. 5,134,127, which is incorporated herein by reference.

4.4.4 topical and mucosal dosage forms

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

Suitable excipients (e.g., carriers and diluents) and other materials that may be used in the preparation of the topical and transmucosal dosage forms of the present invention are well known to those skilled in the art of pharmacy and depend on the particular tissue to which a given pharmaceutical composition or dosage form is to be administered. In fact, typical excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1, 3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form a non-toxic and pharmaceutically acceptable solution, emulsion, or gel. Moisturizers or humectants can also be added to pharmaceutical compositions and dosage forms, if desired. Examples of such other ingredients are well known in the art. See, e.g., Remington's Pharmaceutical Sciences, 16 th and 18 th edition, Mack Publishing, Easton PA (1980& 1990).

The pH of the pharmaceutical composition or dosage form may also be adjusted to enhance delivery of one or more active ingredients. Similarly, the polarity of the solvent vehicle, its ionic strength, or tonicity can be adjusted to enhance delivery. Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or more active ingredients to enhance delivery. In this regard, stearates can serve as lipid carriers, emulsifiers or surfactants, as well as delivery or penetration enhancers for the formulation. Different salts, hydrates or solvates of the active ingredient may also be used to adjust the properties of the resulting composition.

4.4.5 kits

It is generally preferred that the active ingredients of the invention are not administered at the same time or by the same route of administration. The invention therefore includes kits which, when used by medical personnel, simplify the administration of appropriate amounts of active ingredients to a patient.

A typical kit of the invention comprises a dosage form of a selective cytokine inhibitory drug of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug, or clathrate thereof. The kits of the invention also include other active ingredients, such as G-CSF, GM-CSF, EPO, topotecan, pentoxifylline, ciprofloxacin, dexamethasone, IL2, IL8, IL18, Ara-C, vinorelbine, isotretinoin, 13-cis-retinoic acid, or pharmacologically active variants or derivatives, or combinations thereof. Examples of other active ingredients include, but are not limited to, those disclosed herein (see, e.g., section 4.2).

The kit of the invention may also comprise a device for administering the active ingredient. Examples of such devices include, but are not limited to, syringes, drip bags, patches, and inhalers.

The kits of the invention also include cells or blood for transplantation and a pharmaceutically acceptable carrier that can be used to administer one or more active ingredients. For example, if the active ingredient is in solid form and must be formulated for parenteral administration, the kit may comprise a sealed container containing a suitable carrier in which the active ingredient can be dissolved to form a sterile, particle-free solution suitable for parenteral administration. Examples of pharmaceutically acceptable carriers include, but are not limited to: USP water for injection; aqueous carriers such as, but not limited to, sodium chloride injection, ringer's injection, dextrose and sodium chloride injection, and lactated ringer's injection; water-miscible carriers such as, but not limited to, ethanol, 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. Examples of the embodiments

The overproduction of the growth inhibitory cytokine TNF- α in the plasma of bone marrow of MDS patients has been demonstrated, suggesting that TNF- α is a key negative regulator of erythroid progenitor cell survival in this disease. Therefore, the selective cytokine inhibitory drugs of the present invention have been studied. The following examples are intended to illustrate the invention without limiting its scope in any way.

5.1 pharmacological Studies

A series of non-clinical pharmacological and toxicological studies were conducted to support clinical evaluation of the selective cytokine inhibitory drugs of the present invention in human individuals. Unless otherwise indicated, these studies were conducted in accordance with internationally recognized guidelines for the design of research and meet the requirements of Good Laboratory Practice (GLP).

The pharmacological profile of 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide was characterized in an in vitro study, including activity comparison with thalidomide. The effect of 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide on the production of various cytokines was examined. In addition, a safety pharmacological study of 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide was conducted in dogs and the effect of 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide on ECG parameters was further examined as part of a three-repeat dose toxicity study in primates.

5.2 modulation of cytokine production

The inhibition of TNF-. alpha.production by 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide on human PBMC and human whole blood after LPS stimulation was investigated in vitro (Muller et al, bioorg. Med. chem. Lett.9: 1625-. IC was tested for the inhibition of TNF- α production by 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide on PBMC and human whole blood after LPS stimulation₅₀。

In vitro studies show that the pharmacological activity profile of 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide is similar to that of thalidomide, but 5-50 times stronger than the latter. The pharmacological effect of 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide derives from its action as an inhibitor of the cellular response to receptor-induced nutritional signals (e.g., IGF-1, VEGF, cyclooxygenase-2) and other activities. Thus, 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide inhibits the production of inflammatory cytokines, down-regulates adhesion molecules and apoptosis-inhibiting proteins (e.g., cflp, CLAP), promotes sensitivity to apoptosis initiated by death receptors, and inhibits angiogenic responses. This study shows that 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide abrogates mitotic responses to VEGF in AML cells by quenching ligand-induced Akt-phosphorylation and selectively inhibits MDS over normal myeloid progenitor formation in a preclinical model.

5.3 clinical Studies of MDS patients

Selective cytokine inhibitory drugs, such as 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide, are administered to MDS patients in amounts of about 400 mg/day to about 1,200 mg/day for 24 weeks before the hematological response of the patients is evaluated. The response rates of the classified groups were evaluated according to the risk groups defined by the International Prognostic Scoring System (IPSS) (i.e., IPSS low and intermediate I, as opposed to IPSS intermediate II and high) by classification as to the likelihood of conversion of MDS subclasses to leukemia.

For example, 15 patients are divided into the first group and treated with 1,200 mg/day of 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide. The number of patients who subsequently developed erythroid responses (primary or secondary) by week 24 was assessed. If no response was observed, the study was terminated because there was no effect. But if there are four or more patients responding, the study is terminated because of the desired clinical activity. In intermediate cases (e.g., 1,2, or 3 patients responded), 10 patients from the second group were enrolled. If 4 or more of the 25 treated patients responded after the second group completed treatment, it was concluded that 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide showed promising clinical activity.

5.4 Cyclic treatment of MDS patients

As described above, selective cytokine inhibitory drugs of the invention may be administered cyclically to subjects with MDS. Cycling therapy involves administering a first agent over a period of time, then administering the agent and/or a second agent over a period of time, and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more therapies, avoid or reduce the side effects of a therapy, and/or improve the efficacy of a therapy.

Example 1

In particular embodiments, the prophylactic or therapeutic agent is administered in an amount of 400mg, 800mg, or 1200mg, about once or twice daily, over a cycle of about 24 weeks. One cycle includes administration of a therapeutic or prophylactic agent and an interruption of at least one week (1), two weeks (2), or three weeks (3). The number of cycles administered is from about 1 to about 12 cycles, more typically from about 2 to about 10 cycles, more typically from about 2 to about 8 cycles.

Example 2

The objective of this study was to evaluate the efficacy and safety of oral administration of 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide to subjects with MDS. The compound is administered to the patient on day 21 every 28 days in an amount of 400 mg/day or 800 mg/day for 16 weeks (4 cycles) or 24 weeks (6 cycles) in a 4-week cycle. The test population includes patients with low-or moderate-1-risk MDS (international prognostic scoring system) who have red cell transfusion-dependent anemia who have received at least two units of RBCs at baseline (day one study treatment) for 8 weeks. In addition to hematology laboratory monitoring, bone marrow aspirates/biopsies were obtained for cytogenesis analysis at baseline, after 3 cycles were completed, and after 6 cycles were completed. Bone marrow data, safety data, and efficacy data were summarized to assess risk-benefit ratios throughout the study. This study summarizes red cell transfusion independence and the major erythroid response according to the criteria of the world MDS working group. In addition, this study observed red cell transfusion independence in a subset of patients with 5q deleted cytopoiesis abnormalities, observed platelet, neutrophil, bone marrow and cytopoiesis responses and secondary erythroid responses, i.e., red cell transfusions required a reduction of > 50% but < 100% within 8 weeks. The study also monitored adverse events, hematological tests, serum chemistry, TSH, urinalysis, urine or serum pregnancy tests, vital signs, ECG, and physical examinations.

Example 3

The goal of this study was to compare the efficacy and safety of oral administration of 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide with placebo plus standard of care in MDS patients. Patients received this treatment in 4-week cycles for 16 weeks (4 cycles) or 24 weeks (6 cycles). This population of subjects included patients with low-or moderate-1 risk MDS (international prognostic scoring system) who had red cell transfusion-dependent anemia who had received at least two units of RBCs at baseline (day one study treatment) for 8 weeks. The study evaluated safety and efficacy occurring every 4 weeks with hematology laboratory monitoring every 2 weeks. At baseline, after completion of 3 cycles and completion of 6 cycles, bone marrow aspirate/biopsy was obtained for cytogenetic analysis. Bone marrow findings, safety and efficacy data were summarized to evaluate the risk-benefit ratio throughout the study. Patients who gained clinical benefit from 6 cycles of treatment were given a compound for an extended study of continuous treatment and provided an opportunity for subjects to randomly follow up on the placebo arm until the end of treatment.

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

Claims (37)

1. A method of treating or preventing a myelodysplastic syndrome, which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.

2. A method of managing a myelodysplastic syndrome, which comprises administering to a patient in need of such management a prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.

3. A method of treating or preventing a myelodysplastic syndrome, which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and a therapeutically or prophylactically effective amount of at least one second active ingredient.

4. A method of managing a myelodysplastic syndrome, which comprises administering to a patient in need of such management a prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and a therapeutically or prophylactically effective amount of at least one second active ingredient.

5. The method of claim 3 or 4, wherein the second active ingredient is capable of improving hematopoiesis.

6. The method of claim 3 or 4, wherein the second active ingredient is a cytokine, hematopoietic growth factor, anti-cancer agent, antibiotic, protease inhibitor, or immunosuppressant.

7. The method of claim 3 or 4, wherein the second active ingredient is: etanercept, imatinib, an anti-TNF-alpha antibody, infliximab, G-CSF, GM-CSF, EPO, topotecan, pentoxifylline, ciprofloxacin, irinotecan, vinorelbine, dexamethasone, IL2, IL8, IL18, Ara-C, vinblastine, isotretinoin, 13-cis-retinoic acid, or a pharmacologically active variant or derivative thereof.

8. The method of any one of claims 1 to 4, wherein the myelodysplastic syndrome is refractory anemia, refractory anemia with cricothyroid erythrocytes, refractory anemia with excess blasts in transition, and chronic myelomonocytic leukemia.

9. The method of any one of claims 1 to 4, wherein the myelodysplastic syndrome is primary or secondary.

10. The method of any one of claims 1 to 4, wherein the stereoisomer of the selective cytokine inhibitory drug is an enantiomer.

11. The method of any one of claims 1 to 4, wherein the selective cytokine inhibitory drug is 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide.

12. The method of claim 11, wherein the selective cytokine inhibitory drug is the R enantiomer or the S enantiomer of 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide.

13. The method of any one of claims 1 to 4, wherein the selective cytokine inhibitory drug is cyclopropanecarboxylic acid {2- [1- (3-ethoxy-4-methoxy-phenyl) -2-methanesulfonyl-ethyl ] -3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -amide.

14. The method of claim 13, wherein the selective cytokine inhibitory drug is the R enantiomer or S enantiomer of cyclopropanecarboxylic acid {2- [1- (3-ethoxy-4-methoxy-phenyl) -2-methanesulfonyl-ethyl ] -3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -amide.

15. The method of any one of claims 1 to 4, wherein the selective cytokine inhibitory drug is of formula (I):

wherein n has a value of 1,2 or 3;

R⁵an o-phenylene group which is unsubstituted or substituted with 1 to 3 substituents each independently selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, alkylamino, dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms and halogen;

R⁷is (i) a phenyl group or a phenyl group substituted with one or more substituents each independently selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms and halogen, (ii) a benzyl group unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms and halogen, (iii) a naphthyl group, and (iv) a benzyloxy group;

R¹²is-OH, alkoxy of 1 to 12 carbon atoms, or

R⁸Is hydrogen or alkyl of 1 to 10 carbon atoms; and

R⁹is hydrogen, alkyl of 1 to 10 carbon atoms, -COR¹⁰or-SO₂R¹⁰Wherein R is¹⁰Is hydrogen, alkyl of 1 to 10 carbon atoms or phenyl.

16. The method of claim 15, wherein the selective cytokine inhibitory drug is enantiomerically pure.

17. The method of any one of claims 1 to 4, wherein the selective cytokine inhibitory drug is of formula (II):

in the formula, R¹And R²Each independently is hydrogen, lower alkyl, or R¹And R²Together with the carbon atom to which they are each bound, form an o-phenylene, o-naphthylene or cyclohexene-1, 2-diyl group which is unsubstituted or substituted by 1 to 3 substituents each independently selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propinyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, alkylamino, dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms and halogen;

R³is phenyl substituted by 1 to 4 substituents selected from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, alkylthio of 1 to 10 carbon atoms, benzyloxy, cycloalkoxy of 3 to 6 carbon atoms, C₄-C₆Cycloalkylidenemethyl, C₃-C₁₀-alkylenemethyl, indanyloxy (indanyloxy) and halogen;

R⁴is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl or benzyl;

R⁴' is hydrogen or alkyl of 1 to 6 carbon atoms;

R⁵is-CH₂-、-CH₂-CO-、-SO₂-, -S-or-NHCO-; and

n has a value of 0, 1 or 2.

18. The method of claim 17, wherein the selective cytokine inhibitory drug is enantiomerically pure.

19. The method of any one of claims 1 to 4, wherein the selective cytokine inhibitory drug is of formula (III):

in the formula, use^*The carbon atom represented constitutes the daughter center;

y is C-O, CH₂、SO₂Or CH₂C＝O；

R¹、R²、R³And R⁴Each independently hydrogen, halogen, alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, nitro, cyano, hydroxy or-NR⁸R⁹(ii) a Or R¹、R²、R³And R⁴Any two of which together with the adjacent carbon atoms and the phenylene ring form a naphthylene group;

R⁵and R⁶Each independently hydrogen, alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, cyano or cycloalkoxy of up to 18 carbon atoms;

R⁷is hydroxy, alkyl of 1 to 8 carbon atoms, phenyl, benzyl or NR^8’R^9’；

R⁸And R⁹Each independently of the other hydrogen, alkyl of 1 to 8 carbon atoms, phenyl or benzyl, or R⁸And R⁹One of which is hydrogen and the other is-COR¹⁰or-SO₂R¹⁰Or R is⁸And R⁹Together form a tetramethylene group, pentamethylene group, hexamethylene group or-CH₂CH₂X¹CH₂CH₂-, wherein X¹is-O-, -S-or-NH-; and

R^8’and R^9’Each independently of the other hydrogen, alkyl of 1 to 8 carbon atoms, phenyl or benzyl, or R^8’And R^9’One of which is hydrogen and the other is-COR^10’or-SO₂R^10’Or R is^8’And R^9’Together form a tetramethylene group, pentamethylene group, hexamethylene group or-CH₂CH₂X²CH₂CH₂-, wherein X²is-O-, -S-or-NH-.

20. The method of claim 19, wherein the selective cytokine inhibitory drug is enantiomerically pure.

21. A method of treating, preventing or managing a myelodysplastic syndrome, which comprises administering to a patient in need of such treatment, prevention or management a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, before, during or after transplantation of umbilical cord blood, placental blood, peripheral blood stem cell, hematopoietic stem cell preparation or bone marrow to the patient.

22. A method of reducing or avoiding an adverse side effect associated with the administration of a second active ingredient in a patient with myelodysplastic syndrome, which comprises administering to a patient in need of such reduction or avoidance an amount of the second active ingredient and a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.

23. The method of claim 22, wherein the second active ingredient is capable of improving hematopoiesis.

24. The method of claim 22, wherein the second active ingredient is a cytokine, hematopoietic growth factor, anti-cancer agent, antibiotic, protease inhibitor, or immunosuppressive agent.

25. The method of claim 22, wherein the second active ingredient is: etanercept, imatinib, an anti-TNF-alpha antibody, infliximab, G-CSF, GM-CSF, EPO, topotecan, pentoxifylline, ciprofloxacin, irinotecan, vinblastine, dexamethasone, IL2, IL8, IL18, Ara-C, vinorelbine, isotretinoin, 13-cis-retinoic acid, or a pharmacologically active variant or derivative thereof, or a combination thereof.

26. A pharmaceutical composition comprising a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in an amount effective to treat, prevent or manage a myelodysplastic syndrome, and a carrier.

27. A pharmaceutical composition comprising a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and a second active ingredient.

28. The pharmaceutical composition of claim 27, wherein the second active ingredient is capable of improving hematopoiesis.

29. The pharmaceutical composition of claim 27, wherein the second active ingredient is a cytokine, hematopoietic growth factor, anti-cancer agent, antibiotic, protease inhibitor, or immunosuppressive agent.

30. The pharmaceutical composition of claim 27, wherein the second active ingredient is: etanercept, imatinib, an anti-TNF-alpha antibody, infliximab, G-CSF, GM-CSF, EPO, topotecan, pentoxifylline, ciprofloxacin, irinotecan, vinblastine, dexamethasone, IL2, IL8, IL18, Ara-C, vinorelbine, isotretinoin, 13-cis-retinoic acid, or a pharmacologically active variant or derivative thereof, or a combination thereof.

31. A single unit dosage form comprising a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and a second active ingredient capable of improving hematopoiesis.

32. A single unit dosage form comprising a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and a second active ingredient, wherein the second active ingredient is a cytokine, hematopoietic growth factor, anti-cancer agent, antibiotic, protease inhibitor, or immunosuppressant.

33. A single unit dosage form comprising a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and a second active ingredient selected from the group consisting of: etanercept, imatinib, an anti-TNF-alpha antibody, infliximab, G-CSF, GM-CSF, EPO, topotecan, pentoxifylline, ciprofloxacin, irinotecan, vinblastine, dexamethasone, IL2, IL8, IL18, Ara-C, vinorelbine, isotretinoin, 13-cis-retinoic acid, or a pharmacologically active variant or derivative thereof, and combinations thereof.

34. The single unit dosage form of claim 31, 32 or 33, wherein the dosage form is suitable for intravenous or subcutaneous administration to a patient.

35. A kit, comprising:

a pharmaceutical composition comprising a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof; and

a pharmaceutical composition comprising a second active ingredient capable of improving hematopoiesis.

36. A kit, comprising:

a pharmaceutical composition comprising a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof; and

cord blood, placental blood, peripheral blood stem cells, hematopoietic stem cell preparations, or bone marrow.

37. The kit of claim 35 or 36, further comprising a device for administering the pharmaceutical composition or single unit dosage form.