ZA200608574B - Use of selective cytokine inhibitory drugs in myelodysplastic syndromes - Google Patents

Description

: METHQCD S OF USING AND COMPOSITIONS COMPRISING

SELECTIVE CYTOKINE INHIBITORY DRUGS FOR THE: :

TREATMENT AND MANAGEMENT OF MYELODYSPLASTIC SYNDROMES

1. FIELD OF THE INVENTION -

This invention relates, in part, to methods of treating, preventing and/or managing myelodysplastic and related syndromes which comprise the administration of a selective cytokine inhibitory drug, ora pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. The use of such drugs alone or in combination with conventional therapy for myelodysplastic syndromes and/or with transplantation therapy is also described. 2. BACKGROUND OF THE INVENTION 2.1 PATHOBIOLOGY OFMDS

Myelodysplastic syndrome (MDS) refers to a diverse group of hematopoietic stem cell disorders. MDS is characterized by a cellular marrow with impaired morphology and maturation (dysmyelopoiesis), peripheral blood cytopenias, and a variable risk of progression to acute leukemia, resulting from ineffective blood cell production. The Merck

Manual 953 am ed. 1999) and List et al., 1990, J. Clin. Oncol. 8:1424.

The initial hematopoietic stem cell injury can be from causes such as, but not limited to, cytotoxic chemotherapy, radiation, virus, chemical exposure, and genetic predisposition.

A clonal mutation predominates over bone marrow, suppressing healthy stem cells. In the early stages of MDS, the main cause of cytopenias is increased programmed cell death (apoptosis). As the disease progresses and converts into leukemia, gene mutation rarely occurs and a proliferation of leukemic cells overwhelms the healthy marrow. The disease course differs, with some cases behaving as an indolent disease and others behaving aggressively with a very short clinical course that converts into an acute form of leukemia.

The actual incidence of MDS in the U.S. is unknown. MDS was first considered a distinct disease in 1976, and occurrence was estimated at 1500 new cases every year. At that time, only patients with less than five percent blasts were considered to have this disorder. Statistics from 1999 estimated 13,000 new cases per year, and about 1000 cases per year are reported in children, surpassing chronic lymphocytic leukemia as the most common form of leukemia in the westem hemisphere. The perception that the incidence is increasing may be due to improvements in recognition and criteria for diagnosis. The disease is found worldwide.

An international group of hematologist, the French-American-British (FAB)

Cooperative Group, classified MDS disorders into five subgroups, differentiating them from acute myeloid leukemia. The Merck Manual 954 (17™ ed. 1999); Bennett JM. et al, Ann.

Intern. Med. 1985 Oct., 103(4): 620-5; and Besa E.C,, Med. Clin. North Am. 1992 May, 76(3): 599-617. An underlying trilineage dysplastic change in the bone marrow cells of the patients is found in all subtypes.

There are two subgroups of refractory anemia characterized by five percent or less myeloblasts in bone marrow: (1) refractory anemia (RA) and; (2) RA with ringed sideroblasts (RARS), defined morphologically as having 15% erythroid cells with abnormal ringed sideroblasts, reflecting an abnormal iron accumulation in the mitochondria. Both have a prolonged clinical course and low incidence of progression to acute leukemia. Besa

E.C., Med. Clin. North Am. 1992 May, 76(3): 599-617.

There are two subgroups of refractory anemias with greater than five percent myeloblasts: (1) RA with excess blasts (RAEB), defined as 6-20% myeloblasts, and (2) RAEB in transformation (RAEB-T), with 21-30% myeloblasts. The higher the percentage of myeloblasts, the shorter the clinical course and the closer the disease is to acute myelogenous leukemia. Patient transition from early to more advanced stages indicates that these subtypes are merely stages of disease rather than distinct entities.

Elderly patients with MDS with trilineage dysplasia and greater than 30% myeloblasts who progress to acute leukemia are often considered to have a poor prognosis because their response rate to chemotherapy is lower than de novo acute myeloid leukemia patients. The recent World Health Organization (WHO) classification (1999) proposes to include all cases of RAEB-T, or patients with greater than 20% myeloblasts, in the category of acute leukemia because these patients have similar prognostic outcomes. However, their response to therapy is worse than the de novo or more typical acute myelogenous leukemia or acute nonlymphocytic leukemia (ANLL) patient. Id.

The fifth type of MDS, the most difficult to classify, is called chronic myelomonocytic leukemia (CMML). This subtype can have any percentage of myeloblasts but presents with a monocytosis of 1000/dL or more. It may be associated with splenomegaly. This subtype overlaps with a myeloproliferative disorder and may have an intermediate clinical course. It is differentiated from the classic chronic myelocytic leukemia (CML) that is characterized by a negative Ph chromosome. The recent WHO classification (1999) proposes that juvenile and proliferative CMML be listed separately from FAB under MDS/myeloproliferative disorder (MPD) with splenomegaly and greater than 13,000 total WBC. CMML is limited to monocytosis, less than 13,000/mm? total leukocytes, and requires trilineage dysplasia. /d. Harris N.L,, et al., J. Clin. Oncol. 1999

Dec., 17(12): 3835-49. Finally, some other international organizations, including WHO, have suggested a sixth class of MDS patients, characterized by a del (5q) abnormality.

MDS is primarily a disease of elderly people, with the median onset in the seventh decade of life. The median age of these patients is 65 years, with ages ranging from the early third decade of life to as old as 80 years or older. The syndrome may occur in any age group, including the pediatric population. Patients who survive malignancy treatment with alkylating agents, with or without radiotherapy, have a high incidence of developing MDS or secondary acute leukemia. About 60-70% of patients do not have an obvious exposure or cause for MDS, and are classified as primary MDS patients.

The most common cases of MDS are primary, or idiopathic. However, a nonspecific history of exposure to indeterminable chemicals or radiation 10-15 years prior to onset of disease may be present in about 50% of patients. This relationship to pathogenesis remains unproved. Compounds such as, but not limited to, benzene, insecticides, weed killers, and fungicides are possible causes of MDS. Goldberg H., et al.,

Cancer Res. 1990 Nov 1; 50(21): 6876-81. Secondary MDS describes development of

MDS or acute leukemia after known exposures to chemotherapy drugs that can cause bone marrow damage. These drugs are associated with a high incidence of chromosomal abnormalities following exposure and at the time of MDS or acute leukemia diagnosis.

Further, MDS is associated with complications associated with severe cytopenias.

Other complications are development of myelofibrosis, which can accelerate decline in blood counts and increase transfusion requirements. Transformation to acute leukemia accelerates the development of complications such as anemia, bleeding, and infections.

Recently, the International MDS Risk Analysis (IMRA) Workshop proposed an

International Prognosis Scoring System (IPSS) to decrease imprecision in predicting survival and AML risk in MDS patients. The IPSS is based on the number of cytopenias, percentage of BM blasts, and type of cytogenetic abnormalities (Table 1). Greenberg P,

Cox C, Le Beau MM, et al., Blood 1997, 89:2079-88. The latter are categorized into good (normal, -Y, del (5q), del (20q)), intermediate, and poor subgroups (complex or chromosome 7 abnormalities).

Table 1. International Prognostic Scoring System for MDS

Score Value

Variable

Bone marrow | <5 5-10 11-20 21-30

El i a a [Gow [meme [ror

CC CC EN

*Good, normal, del (5g), del (20q), -Y; Poor, complex (>3) or chromosome 7 abnormalities;

Intermediate, +8, and other single or double abnormalities. 22 MDS TREATMENT

The current treatment of MDS is based on the stage and the mechanism of the disease that predominates the particular phase of the disease process. Bone marrow transplantation has been used in patients with poor prognosis or late-stage MDS. Epstein and Slease, 1985, Surg. Ann. 17:125. This type of therapy, however, is both painful for donor and recipient, because of the involvement of invasive procedures and can cause severe and even fatal complications to the recipient, particularly with allogeneic transplant and related Graft Versus Host Disease (GVHD) results. Therefore, the risk of GVHD restricts the use of bone marrow transplantation to patients with otherwise fatal diseases.

Further, as most patients are elderly and only a few young MDS patients will have a matched donor, the use of bone marrow transplantation is limited.

An alternative approach to therapy for MDS is the use of hematopoietic growth factors or cytokines to stimulate blood cell development 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 May, 76(3): 599-617. The process of blood cell formation, by which a small number of self-renewing stem cells give rise to lineage specific progenitor cells that subsequently undergo proliferation and differentiation to produce the mature circulating blood cells has been shown to be at least in part regulated by specific hormones. These hormones are collectively known as hematopoietic growth factors. Metcalf, 1985, Science 229:16; Dexter, 1987, J. Cell Sci. 88:1; Golde and Gasson, 1988, Scientific American,

July:62; Tabbara and Robinson, 1991, Anti-Cancer Res. 11:81; Ogawa, 1989, Environ.

Health Presp. 80:199; and Dexter, 1989, Br. Med. Bull. 45:337. The most well characterized growth factors include erythropoietin (EPO), granulocyte macrophage colony stimulating factor (GM-CSF), and granulocyte colony stimulating factor (G-CSF). Apart from inducing proliferation and differentiation of hematopoietic progenitor cells, such cytokines have also been shown to activate a number of functions of mature blood cells, including influencing 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, Vadas et al., 1983, Blood 61:1232; 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 MDS patients treated with recombinant human GM-CSF and G-CSF have shown that while these cytokines can restore granulocytopoiesis in treated patients, their efficacy is restricted to the granulocyte or monocyte lineage with little or no improvement in hemoglobin or platelet counts. Schuster et al., 1990, Blood 76 (Suppl.1):318a. When such patients were treated with recombinant human EPO, a sustained improvement in hemoglobin or decrease in transfusion requirement was achieved . in only less than 25% of patients. Besa et al., 1990, 76 (Suppl.1):133a; Hellstrom et al., 1990, 76 (Suppl.1):279a; Bowen et al., 1991, Br. J. Haematol. 77:419. Therefore, there remains a need for safe and effective methods of treating and managing MDS. 2.3 SELECTIVE CYTOKINE INHIBITORY DRUGS

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

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

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

Further characterization of the selective cytokine inhibitory drugs shows that they are potent PDE4 inhibitors. PDE4 is one of the major phosphodiesterase isoenzymes found in human myeloid and lymphoid lineage cells. The enzyme plays a crucial part in regulating cellular activity by degrading the ubiquitous second messenger cAMP and maintaining it at low intracellular levels. /d. Inhibition of PDE4 activity results in increased cAMP levels leading to the modulation of LPS induced cytokines including inhibition of TNF-a production in monocytes as well as in lymphocytes.

S

3. SUMMARY OF THE INVENTION

This 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, which are described in detail below, are small organic molecules, i.e., they have a molecule weight of

Jess than 1,000 g/mol. The compounds preferably have PDE4 activity and inhibit TNF-a

The invention also encompasses methods of managing MDS (e.g., lengthening the time of remission) which comprise administering to a patient in need of such management a prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. Each of these methods includes specific dosing or dosing regimens including cycling therapy.

The invention further encompasses pharmaceutical compositions, single unit dosage forms, and kits suitable for use in treating, preventing and/or managing 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, a selective cytokine inhibitory drug is used, administered, or formulated with one or more second active ingredients to treat, prevent or manage MDS. Examples of the second active ingredients include but are not limited to cytokines, hematopoietic growth factors, cancer chemotherapeutics, immunosuppressive agents, anti-inflammatories, antibiotics, antifungals, and other standard therapies for MDS. Further, the invention encompasses the use of the compounds of the invention in conjunction 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 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.

As used herein, the term “myelodysplastic syndrome’ or “MDS” means a hematopoietic stem cell disorder characterized by one or more of the following: ineffective blood cell production, progressive cytopenias, risk of progression to acute leukemia or cellular marrow with impaired morphology and maturation (dysmyelopoiesis). The term “myelodysplastic syndrome” or “MDS” unless otherwise noted includes: refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation 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 a pharmaceutical composition comprising a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient wherein the composition is adapted for parenteral, oral or transdermal administration and the amount is sufficient to treat or prevent MDS or to ameliorate the symptoms or progress of the discase.

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

One embodiment of the invention encompasses a method 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 agents conventionally used in MDS patients can act in complementary or synergistic ways in the treatment or management of MDS. It is also believed that the combined use of such agents may reduce or eliminate adverse effects associated with some selective cytokine inhibitory drugs, thereby allowing the administration of larger amounts of selective cytokine inhibitory drugs to patients and/or increasing patient compliance. It is further believed that some selective cytokine inhibitory drugs may reduce or eliminate adverse effects associated with some conventional MDS agents, thereby allowing the administration of larger amounts of the agents to patients and/or increasing patient compliance.

Preferably, the second active agents are capable of affecting or improving blood cell production. Second active agents can be large molecules (e.g., proteins) or small molecules (e.g., synthetic inorganic, organometallic, or organic molecules). The examples of the ,

second active agent include, but are not limited to, cytokines, hematopoietic growth factors, anti-cancer agents such as topoisomerase inhibitors, anti-angiogenic agents, microtubule stabilizing agents, apoptosis inducing agents, alkylating agents and other conventional chemotherapy described in the Physician’s Desk Reference 2002; antivirals; antifungals; antibiotics; anti-inflammatories; immunomodulatory agents; IMiDs™; immunosuppressive agents such as cyclosporins; and other known or conventional agents used in MDS patients.

Specific second active agents include but are not limited to etanercept (Enbrel®), imatinib (Glivec®), anti-TNF-a antibodies, infliximab (Remicade®), G-CSF, GM-CSF, EPO, topotecan, irinotecan, pentoxifylline, doxorubicin, ciprofloxacin, dexamethasone, 11.2, IL8,

IL 18, Ara-C, vinorelbine, isotretinoin, and 13-cis-retinoic acid. This invention also encompasses the use of native, naturally occurring, and recombinant proteins. The invention further encompasses mutants and derivatives (e.g., modified forms) of naturally occurring proteins that exhibit, in vivo, at least some of the pharmacological activity of the proteins upon which they are based. Examples of mutants include, but are not limited to, proteins that have one or more amino acid residues that differ from the corresponding residues in the naturally occurring forms of the proteins. Also encompassed by the term “mutants” are proteins that lack carbohydrate moieties normally present in their naturally occurring forms (e.g., nonglycosylated forms). Examples of derivatives include, but are not limited to, pegylated derivatives and fusion proteins, such as proteins formed by fusing

IgG1 or IgG3 to the protein or active portion of the protein of interest. See, e.g., Penichet,

M.L. and Morrison, S.L., J. Immunol. Methods 248:91-101 (2001). Vaccines that cause the secretion of proteins disclosed herein as well as pharmacologically active mutants, derivatives, and fusion thereof are also encompassed by the invention.

Another embodiment of the invention encompasses a method of reversing, reducing or avoiding an adverse effect associated with the administration of conventional therapy for

MDS to a patient suffering from MDS, which comprises administering to a patient in need of such reversion, reduction or avoidance a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.

Without being limited by theory, it is believed that the combined use of a selective cytokine inhibitory drug, and transplantation therapy of, e.g., stem cells to a patient suffering from MDS provides a unique and unexpected synergism. As inevitable leukemic transformation develops in certain stages of MDS, transplantation of peripheral blood stem cells, processed hematopoietic stem cell preparation, cord blood or bone marrow may be necessary. In particular, without being limited by theory, it is believed that selective cytokine inhibitory drugs exhibit cytokine inhibitory activity that may provide additive or synergistic effects when given concurrently with transplantation therapy. Selective cytokine inhibitory drugs can work in combination with transplantation therapy reducing complications associated with the invasive procedure of transplantation and risk of related

Graft Versus Host Disease (GVHD). Therefore, this invention encompasses a method of treating, preventing and/or managing MDS, which comprises administering to a patient (e.g., a human) a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, i solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, before, during, or after transplantation therapy.

The invention also encompasses pharmaceutical compositions, single unit dosage forms, and kits which comprise 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, the kit may contain one or more compounds of the invention, stem cells for transplantation and an immunosuppressive agent, antibiotic or other drug, each of which is to be used to treat the

MDS patient. 4.1 SELECTIVE CYTOKINE INHIBITORY DRUGS

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

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

As used herein and unless otherwise indicated, the terms “selective cytokine inhibitory drugs” and “SelCIDs™" encompass small molecule drugs, e.g., small organic molecules which are not peptides, proteins, nucleic acids, oligosaccharides or other macromolecules. Preferred compounds inhibit TNF-¢ production, Compounds may also have a modest inhibitory effect on LPS induced IL18 and IL12. More preferably, the compounds of the invention are potent PDE4 inhibitors.

Specific examples of selective cytokine inhibitory drugs include, but are not limited to, the cyclic imides disclosed in U.S. patent nos. 5,605,914 and 5,463,063; the cycloalkyl amides and cycloalkyl nitriles of U.S. patent nos. 5,728,844, 5,728,845, 5,968,945, 6,180,644 and 6,518,281; the aryl amides (for example, an embodiment being N-benzoyl-3- amino-3-(3’,4’-dimethoxyphenyl)-propanamide) of U.S. patent nos. 5,801,195, 5,736,570,

6,046,221 and 6,284,780; the imide/amide ethers and alcohols (for example, 3-phthalimido- 3-(3’,4’-dimethoxyphenyl)propan-1-o!) disclosed in U.S. patent no. 5,703,098; the succinimides and maleimides (for example methyl 3-(3°,4’,5°6’-petrahydrophthalimdo)-3- (3”,4”-dimethoxyphenyl)propionate) disclosed in U.S. patent no. 5,658,940; imido and amido substituted alkanohydroxamic acids disclosed in U.S. patent no. 6,214,857 and WO 99/06041; substituted phenethylsulfones disclosed in U.S. patent nos. 6,011,050 and 6,020,358; substituted imides (for example, 2-phthalimido-3-(3’,4’-dimethoxyphenyl) i propane) disclosed in U.S. patent no. 6,429,221; substituted 1,3,4-oxadiazoles (for example, 2-[1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(1,3,4-oxadiazole-2-yl)ethyl]-5- methylisoindoline-1,3-dione) disclosed in U.S. patent no. 6,326,388; cyano and carboxy derivatives of substituted styrenes (for example, 3,3-bis-(3,4-dimethoxyphenyl) acrylonitrile) disclosed in U.S. patent nos. 5,929,117, 6,130,226, 6,262,101 and 6,479,554; isoindoline-1-one and isoindoline-1,3-dione substituted in the 2-position with an o-(3,4- disubstituted phenyl)alkyl group and in the 4- and/or 5-position with a nitrogen-containing group disclosed in WO 01/34606 and U.S. patent no. 6,667,316; and imido and amido" substituted acylhydroxamic acids (for example, (3-(1,3-dioxoisoindoline-2-yl)-3-(3-ethoxy- 4-methoxyphenyl) propanoylamino) propanoate disclosed in WO 01/45702 and U.S. patent no. 6,699,899. Other selective cytokine inhibitory drugs include diphenylethylene compounds disclosed in U.S. provisional application no. 60/452,460. filed March 5, 2003, the contents of which are incorporated by reference herein in their entirety. The entireties of each of the patents and patent applications identified herein are incorporated herein by reference.

Additional selective cytokine inhibitory drugs belong to a family of synthesized chemical compounds of which typical embodiments include 3-(1,3-dioxobenzo-[f]isoindol- 2-y1)-3-(3-cyclopentyloxy-4-methoxyphenyl)propionamide and 3-(1,3-dioxo-4-azaisoindol- 2-y1)-3-(3 4-dimethoxyphenyl)-propionamide.

Other specific selective cytokine inhibitory drugs belong to a class of non- polypeptide cyclic amides disclosed in U.S. patent nos. 5,698,579, 5,877,200, 6,075,041 and 6,200,987, and WO 95/01348, each of which is incorporated herein by reference.

Representative cyclic amides include compounds of the formula: i

RS” Ne — Bi 12

Lv oH (CoH2n)—C—R nd SH R

I. Expired Amended Sheet: 1 February 2008 wherein n has a value of 1, 2, or 3;

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

R’ is (i) phenyl or phenyl substituted with one or more substituents each selected independently of the other from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, and halo, (ii) benzyl unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of nitro, cyano, trifluoromethyl, carbothoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, and halo, (iii) naphthyl, and (iv) benzyloxy;

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

RS

—N i"

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

R’ is hydrogen, alkyl of 1 to 10 carbon atoms, -COR'" or -SO,R'?, wherein R'is 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-oxisoindolin-yl)propionic acid; 3-(4-methox ypheny!)-3-(1-oxisoindolin-yl)propionamide; 3-(3,4-dimethox yphenyl)-3-(1-oxisoindolin-2-yl)propionic acid; 3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydroisoindol-2-yl)propionamide; 3-(3,4-dimethoxyphenyl)-3-(1-oxisoindolin-2-yl)propionamide; 3-(3,4-diethoxyphenyl)-3-(1-oxoisoindolin-yl)propionic acid; methyl 3-(1-oxoisoindolin-2-yl)-3-(3-cthoxy-4-methoxyphenyl)propionate; 3-(1-oxoisoindolin-2-yl)-3-(3-ethox y-4-methoxyphenyl)propionic acid; 3-(1-oxoisoindolin-2-yl)-3-(3-propoxy-4-methoxypheny!)propionic acid;

3-(1 -oxoisoindolin-2-yl)-3-(3-butoxy-4-methoxyphenyl)propionic acid; 3-(1-oxoisoindolin-2-y1)-3-(3 -propoxy-4-methoxyphenyl)propionamide; 3-(1-oxoisoindolin-2-yl)-3-(3 -butoxy-4-methoxyphenyl)propionamide; methyl 3-(1 -oxoisoindolin-2-yl)-3-(3-butoxy-4-methoxyphenyl)propionate; and methyl 3-(1 -oxoisoindolin-2-yl)-3-(3-propoxy-4-methoxyphenyl)propionate. Other representative cyclic amides include compounds of the formula: 3 0]

N

Da Nin (CnHa2n) in which Z is: 0 7s oN i

RU ON. R3-C—NH— or Ri—

R2 in which:

R! is the divalent residue of (i) 3,4-pyridine, (ii) pyrrolidine, (iii) imidizole, (iv) naphthalene, (v) thiophene, or (vi) a straight or branched alkane of 2 to 6 carbon atoms, unsubstituted or substituted with phenyl or phenyl substituted with nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo, wherein the divalent bonds of said residue are on vicinal ring carbon atoms;

R?is -CO - or -SO; -;

R* is (i) phenyl substituted with 1 to 3 substituents each selected independently from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo, (ii) pyridyl, (iii) pyrrolyl, (iv) imidazolyl, (iv) naphthyl, (vi) thienyl, (vii) } quinotyl, (viii) furyl, or (ix) indolyl,

R* is alanyl, arginyl, glycyl, phenylglycyl, histidyl, leucyl, isoleucyl, lysyl, methionyl, prolyl, sarcosyl, seryl, homoseryl, threonyl, thyronyl, tyrosyl, valyl, benzimidol- 2-yl, benzoxazol-2-yl, phenylsulfonyl, methy!phenylsulfonyl, or phenylcarbamoyl; and n has a value of 1, 2, or 3. Other representative cyclic amides include compounds of the formula:

O

I 0

RE “MN CH—(Coizn)-C—R'2 re 7 in which R® is (i) o-phenylene, unsubstituted or substituted with 1 to 4 substituents each selected independently from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino, ) dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo, or (ii) the divalent residue of pyridine, pyrrolidine, imidizole, naphthalene, or thiophene, wherein the divalent bonds are on vicinal ring carbon atoms;

R® is -CO -, -CH;-, or -SO»-;

R’ is (i) hydrogen if R® is -SO,-, (ii) straight, branched, or cyclic alkyl of 1 to 12 carbon atoms, (iii) pyridyl, (iv) pheny! or phenyl substituted with one or more substituents each selected independently of the other from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo, (v) alkyl of 1 to 10 carbon atoms, (vi) benzyl unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo, (vii) naphthyl, (viii) benzyloxy, or (ix) imidazol-4-yl methyl;

R'? is -OH, alkoxy of 1 to 12 carbon atoms, or

NF

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

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

R” is hydrogen, alkyl of 1 to 10 carbon atoms, -COR', or -SO, R'® in which R'is’ hydrogen, alkyl of | to 10 carbon atoms, or phenyl.

Other representative imides include compounds of the formula: i

HoN—CH—(CHzq)—C—R"?

R7 in which R” is (i) straight, branched, or cyclic alkyl of 1 to 12 carbon atoms, (ii) pyridyl, (iii) phenyl or phenyl substituted with one or more substituents each selected independently of the other from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo, (iv) benzyl unsubstituted or substituted with one to three substituents selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halo, (v) napthyl, (v1) benzyloxy, or (vii) imidazol-4-ylmethyl; .

R'?is -OH, alkoxy of 1 to 12 carbon atoms, -O-CH,-pyridyl, -O-benzyl or 8 —N where n has a value of 0, 1, 2, or 3;

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

R? is hydrogen, alkyl of 1 to 10 carbon atoms, -CHa-pyridyl, benzyl, -COR'", or -

SO,R'? in which R'? is hydrogen, alkyl of 1 to 4 carbon atoms, or phenyl. :

Other specific selective cytokine inhibitory drugs include the imido and amido substituted alkanohydroxamic acids disclosed in WO 99/06041 and U.S. patent no. 6,214,857, each of which is incorporated herein by reference. Examples of such compound include, but are not limited to: oO

R! 4 R3

I “N— oH’ 0 rz” RS (CaHzn—C—N—O—R¢

RY wherein each of R! and R?, when taken independently of each other, is hydrogen, lower alkyl, or R' and R?, when taken together with the depicted carbon atoms to which each is bound, is o-phenylene, o-naphthylene, or cyclohexene-1,2-diyl, unsubstituted or substituted with 1 to 4 substituents each selected independently from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino, dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, and halo;

Ris phenyl substituted with from one to four substituents selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy,

acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, alkylthio of 1 to 10 carbon atoms, benzyloxy, cycloalkoxy of 3 to 6 carbon atoms, Cs-Cs-cycloalkylidenemethyl, C;-Cio-alkylidenemethyl, indanyloxy, and halo;

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

R* is hydrogen or alkyl of 1 to 6 carbon atoms;

RS is -CH;-, -CH,-CO-, -80O,-, -S-, or -NHCO-; and n has a value of 0, 1, or 2; and the acid addition salts of said compounds which contain a nitrogen atom capable of being protonated.

Additional specific selective cytokine inhibitory drugs used in the 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-nitrophthalimido)propionamide;

N-benzyloxy-3-(3-cthoxy-4-methoxyphenyl)-3-(1-oxoisoindolinylpropionamide; 3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-phthalimidopropionamide;

N-hydroxy-3-(3,4-dimethoxyphenyl)-3-phthalimidopropionamide; 3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-(3-nitrophthalimido)propionamide;

N-hydroxy-3-(3,4-dimethoxyphenyl)-3-(1 -oxoisoindolinyl)propionamide; 3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-(4-methyl-phthalimido)propionamide; 3-(3-cyclopentyloxy-4-methoxyphenyl)-N-hydroxy-3-phthalimidopropionamide; 3-(3-ethoxy-4-methoxypheny!)-N-hydroxy-3-(1,3-dioxo-2,3-dihydro-1H- benzo flisoindol-2-yl)propionamide;

N-hydroxy-3- {3-(2-propoxy)-4-methoxyphenyl}-3-phthalimidopropionamide; 3-(3-ethoxy-4-methoxyphenyl)-3-(3,6-difluorophthalimido)-N- hydroxypropionamide; 3-(4-aminophthalimido)-3-(3-ethoxy-4-methoxyphenyl)-N-hydroxypropionamide; 3-(3-aminophthalimido)-3-(3-ethoxy-4-methoxyphenyl)-N-hydroxypropionamide;

N-hydroxy-3-(3,4-dimethoxyphenyl)-3-(1-oxoisoindolinyl)propionamide; 3-(3-cyclopentyloxy-4-methoxyphenyl)-N-hydroxy-3-(1-oxoisoindolinyl) propionamide; and

N-benzyloxy-3-(3-ethoxy-4-methox yphenyl)-3-(3-nitrophthalimido)propionamide.

Additional selective cytokine inhibitory drugs used in the invention include the substituted phenethylsulfones substituted on the phenyl group with a oxoisoindine group.

Examples of such compounds include, but are not limited to, those disclosed in U.S. patent no. 6,020,358, which is incorporated hereln by reference, which include the following:

R

R! fo) Cy RS

R2

N— CH" pee “CH, SO,—R7 .

R4 wherein the carbon atom designated * constitutes a center of chirality;

Y is C=0, CH,, SO, or CH;C=0; each of R', R? R®, and R*, independently of the others, is hydrogen, halo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, nitro, cyano, hydroxy, or -NR®R’; or any two of R', RZ, R?, and R* on adjacent carbon atoms, together with the depicted phenylene ring are naphthylidene; each of R® and R®, independently of the other, is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cyano, or cycloalkoxy of up to 18 carbon atoms;

R’ is hydroxy, alkyl of 1 to 8 carbon atoms, phenyl, benzyl, or NR®R?; each of R® and R® taken independently of the other is hydrogen, alkyl of 1 to 8 carbon atoms, phenyl, or benzyl, or one of R® and R’ is hydrogen and the other is -COR" or -SO,R'®, or R® and R® taken together are tetramethylene, pentamethylene, hexamethylene, or -CH,CH,X'CH,CH,- in which X' is -O-, -S- or -NH-; and each of R® and R® taken independently of the other is hydrogen, alkyl of 1 to 8 carbon atoms, phenyl, or benzyl, or one of R* and R” is hydrogen and the other is -COR'" or -SO,R', or R* and RY taken together are tetramethylene, pentamethylene, hexamethylene, or -CH,CH,X*CH,CH,- in which X? is -O-, -S-, or -NH-.

It will be appreciated that while for convenience the above compounds are identified as phenethylsulfones, they include sulfonamides when R’ is NR¥R?.

Specific groups of such compounds are those in which Y is C=0 or CHa.

A further specific group of such compounds are those in which each of R',R%L, R, and R* independently of the others, is hydrogen, halo, methyl, ethyl, methoxy, ethoxy, nitro, cyano, hydroxy, or -NR®R® in which each of R® and R® taken independently of the other is hydrogen or methyl or one of R® and R’ is hydrogen and the other is -COCHj.

Particular compounds are those in which one of R', R?, R?, and R* is -NH, and the remaining of R', RZ, R®, and R* are hydrogen.

\

Particular compounds aré those in which one of R!, R%, R?, and R* is -NHCOCH, and the remaining of R', R?, R?, and R* are hydrogen.

Particular compounds are those in which one of R', R? R?, and R* is -N(CH3); and the remaining of R', R?, R?, and R* are hydrogen.

A further preferred group of such compounds are those in which one of R', R%, R®, and R* is methyl and the remaining of R', R?, R’, and R* are hydrogen.

Particular compounds are those in which one of R',R% R’ and R* is fluoro and the remaining of R', R%, R?, and R* are hydrogen.

Particular compounds are those in which each of R® and R®, independently of the other, is hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopentoxy, or cyclohexoxy. :

Particular compounds are those in which R” is methoxy and R® is monocycloalkoxy, polycycloalkoxy, and benzocycloalkoxy.: : Co

Particular compounds are those in which R? is methoxy and R® is ethoxy.

Particular compounds are those in which R’ is hydroxy, methyl, ethyl, phenyl, benzyl, or NR®R?" in which each of R® and R? taken independently of the other is hydrogen or methyl.

Particular compounds are those in which R'is methyl, ethyl, phenyl, benzyl or

NR¥R” in which each of R® and R®' taken independently of the other 1s hydrogen or methyl. oo Co :

Particular compounds are those in which R’ ismethy., ~~

Particular compounds are those in which R” is NR*R* in which each of R* and R® taken independently of the other is hydrogen or methyl. .

Additional selective cytokine inhibitory drugs include the enantiomerically pure compounds disclosed in U.S. patent application no. 10/392,195 filed on March 19, 2003; international patent application nos. PCT/US03/08737 and PCT/US03/08738, filed on

March 20, 2003; U.S. provisional patent application nos. 60/438 450°. and 60/438.448 to G.

Muller et al., both of which were filed on January 7, 2003; and U.S. provisional patent application no. 60/452,460 to G. Muller et al. filed on March 5, 2003, all of which are incorporated herein by reference. Preferred compounds include an enantiomer of 2-[1-(3- ethoxy-4-methoxyphenyl)-2-methylsul fonylethyi]-4-acetylaminoisoindoline- 1,3-dione and oo an enantiomer of 3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)- propionamide.

Preferred selective cytokine inhibitory drugs used in the invention are 3-(3,4- dimethoxy-phenyl)-3-(1-0x0-1,3-dihydro-isoindol-2-yl)-propionamide and 17 2. US 2003-0187052A1 3. Expired Amended Sheet: 1 February 2008 4. Expired 5. Expired cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl- ethyl]-3-0x0-2,3-dihydro-1 H-isoindol-4-yl} -amide, which are available from Celgene

Corp., Warren, NJ. 3-(3,4-Dimethoxy-phenyl)-3-(1-oxo-1 ,3-dihydro-isoindol-2-yl)- propionamide has the following chemical structure: 0 ~ 0 0

Other specific selective cytokine inhibitory drugs include, but are not limited to, the cycloalkyl amides and cycloalkyl nitriles of U.S. patent nos. 5,728,844, 5,728,845, 5,968,945, 6,180,644 and 6,518,281, and WO 97/08143 and WO 97/23457, each of which is incorporated herein by reference. Representative compounds are of formula:

R! o-

N= H—(CqHan)—Y “rE wherein: one of R' and R?is R3-X- and the other is hydrogen, nitro, cyano, trifluoromethyl, carbo(lower)alkoxy, acetyl, carbamoyl, acctoxy, carboxy, hydroxy, amino, lower alkyl, lower alkoxy, halo, or R3-X-:

R? is monocycloalkyl, bicycloalkyl, or benzocycloalkyl of up to 18 carbon atoms;

X is a carbon-carbon bond, -CH,-, or -O-;

R3 is (i) o-phenylene, unsubstituted or substituted with 1 to 3 substituents each selected independently from nitro, cyano, halo, trifluoromethyl, carbo(lower)alkoxy, acetyl, or carbamoyl, unsubstituted or substituted with lower alkyl, acetoxy, carboxy, hydroxy, amino, lower alkylamino, lower acylamino, or lower alkoxy; (ii) a vicinally divalent residue of pyridine, pyrrolidine, imidazole, naphthalene, or thiophene, wherein the divalent bonds are on vicinal ring carbon atoms; (iii) a vicinally divalent cycloalkyl or cycloalkenyl of 4-10 carbon atoms, unsubstituted or substituted with 1 to 3 substituents each selected independently from the group consisting of nitro, cyano, halo, trifluoromethyl, carbo(lower)atkoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, lower alkylamino, lower alkyl, lower alkoxy, or phenyl; (iv) vinylene di-substituted with lower alkyl; or (v) ethylene, unsubstituted or monosubstituted or disubstituted with lower alkyl,

RS is -CO-, -CH,-, or -CH,CO-;

Y is -COZ, -C =N, -OR?, lower alkyl, or aryl;

Z is -NH,, -OH, -NHR, -R’, or -OR’

R? is hydrogen or lower alkyl;

R’ is lower alkyl or benzyl; and, n has a value of 0, 1, 2, or 3.

In another embodiment, one of R' and RZis R3-X- and the other is hydrogen, nitro, cyano, trifluoromethyl, carbo(lower)alkoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, lower alkyl, lower alkoxy, halo, or R*-X-;

R’® is monocycloalkyl of up to 10 carbon atoms, polycycloalkyl of up to 10 carbon atoms, or benzocyclic alkyl of up to 10 carbon atoms;

X is -CH;-, or -O-;

R? is (i) the vicinally divalent residue of pyridine, pyrrolidine, imidazole, naphthalene, or thiophene, wherein the two bonds of the divalent residue are on vicinal ring carbon atoms; (ii) a vicinally divalent cycloalkyl of 4-10 carbon atoms, unsubstituted or substituted with 1 to 3 substituents each selected independently from the group consisting of nitro, cyano, halo, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or phenyl; (iii) di-substituted vinylene, substituted with nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, carbamoyl substituted with and alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1 to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halo; (iv) ethylene, unsubstituted or substituted with 1 to 2 substituents each selected independently from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, carbamoyl substituted with and alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1 to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halo;

R® is -CO-, -CH;-, or -CH,CO-;

Y is -COX, -C=N, -OR?, alkyl of 1 to 5 carbon atoms, or aryl;

X is -NH,, -OH, -NHR, -R®, -OR®, or alkyl of 1 to 5 carbon atoms;

R? is hydrogen or lower alkyl;

RY is alkyl or benzyl; and, n has a value of 0, 1, 2, or 3.

In another embodiment, one of R' and R? is R*-X- and the other is hydrogen, nitro, cyano, trifluoromethyl, carbo(lower)alkoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, lower alkyl, lower alkoxy, halo, HF,CO, F3CO, or R3-X-;

R? is monocycloalkyl, bicycloalkyl, benzocyclo alkyl of up to 18 carbon atoms, tetrahydropyran, or tetrahydrofuran;

X is a carbon-carbon bond, -CH»-, -O-, or -N=;

R’ is (i) o-phenylene, unsubstituted or substituted with 1 to 3 substituents each selected independently from nitro, cyano, halo, trifluoromethyl, carbo(lower)alkoxy, acetyl, or carbamoyl, unsubstituted or substituted with lower alkyl, acetoxy, carboxy, hydroxy, amino, lower alkylamino, lower acylamino, or lower alkoxy; (ii) a vicinally divalent residue of pyridine, pyrrolidine, imidazole, naphthalene, or thiophene, wherein the divalent bonds are on vicinal ring carbon atoms; (iii) a vicinally divalent cycloalkyl or cycloalkenyl of 4-10 carbon atoms, unsubstituted or substituted with 1 or more substituents each selected independently from the group consisting of nitro, cyano, halo, trifluoromethyl, carbo(lower)alkoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, lower alkylamino, lower alkyl, lower alkoxy, or phenyl, (iv) vinylene di-substituted with lower alkyl; or (v) ethylene, unsubstituted or monosubstituted or disubstituted with lower alkyl;

R® is -CO-, -CHy-, or -CH,CO-;

Y is -COX, -C=N, -OR®, alkyl of 1 to 5 carbon atoms, or aryl;

X is -NH3, -OH, -NHR, -R®, -OR’, or alkyl of 1 to 5 carbon atoms;

R® is hydrogen or lower alkyl,

R’is alkyl or benzyl; and, n has a value of 0, 1, 2, or 3.

Other representative compounds are of formula: 0] ¢

RY ON—CH—(CH)s=Y

RE 7 wherein:

Y is -C=N or CO(CH;),CH3; mis 0,1, 2, or 3;

R’ is (i) o-phenylene, unsubstituted or substituted with 1 to 3 substituents each selected independently from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, carbamoyl substituted with and alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1 to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halo; (i1) the divalent residue of pyridine, pyrrolidine, imidizole, naphthalene, or thiophene, wherein the divalent bonds are on vicinal ring carbon atoms; (iii) a divalent cycloalkyl of 4-10 carbon atoms, unsubstituted or substituted with one or more substituents each selected independently of the other from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, phenyl or halo; (iv) di-substituted vinylene, substituted with nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, carbamoyl substituted with and alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1 to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halo; or (v) ethylene, unsubstituted or substituted with 1 to 2 substituents each selected independently from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, carbamoyl substituted with and alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1 to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halo;

R® is -CO-, -CHy-, -CH,CO-, or -SO»-;

R’ is (i) straight or branched alkyl of 1 to 12 carbon atoms; (ii) cyclic or bicyclic alkyl of 1 to 12 carbon atoms; (iii) pyridyl; (iv) phenyl! substituted with one or more substituents each selected independently of the other from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, straight, branched, cyclic, or bicyclic alkyl of 1 to 10 carbon atoms, straight, branched, cyclic, or bicyclic alkoxy of 1 to 10 carbon atoms, CH;R where R is a cyclic or bicyclic alkyl of 1 to 10 carbon atoms, or halo; (v) benzyl substituted with one to three substituents each selected independently from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo; (vi) naphthyl; or (vii) benzyloxy; and n has a value of 0, 1, 2, or 3.

In another embodiment, specific selective cytokine inhibitory drugs are of formula:

O

RE N—CH—(CHzIAY

R® ie wherein:

R’ is (i) the divalent residue of pyridine, pyrrolidine, imidizole, naphthalene, or thiophene, wherein the divalent bonds are on vicinal ring carbon atoms; (ii) a divalent cycloalkyl of 4-10 carbon atoms, unsubstituted or substituted with ane or more substituents each selected independently of the other from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1to carbon atoms, phenyl or halo; (iii) di-substituted vinylene, substituted with nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, carbamoyl substituted with and alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1 to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halo; or (iv) ethylene, unsubstituted or substituted with 1 to 2 substituents each selected independently from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, carbamoyl] substituted with and alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1 to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halo;

R® is -CO-, -CHa-, -CH,CO-, or -SO»-; oo

R’ is (i) cyclic or bicyclic alkyl of 4 to 12 carbon atoms; (ii) pyridyl; (iii) phenyl substituted with one or more substituents each selected independently of the other from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, straight, branched, cyclic, or bicyclic alkyl of 1 to 10 carbon atoms, straight, branched, cyclic, or bicyclic alkoxy of 1 to 10 carbon atoms, CH;R where R is a cyclic or bicyclic alkyl of 1 to 10 carbon atoms, or halo; (iv) benzyl substituted with one to three substituents each selected independently from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo; (v) naphthyl; or (vi) benzyloxy; and

Y is COX, -C=N, OR, alkyl of 1 to 5 carbon atoms, or aryl,

X is -NH,, -OH, -NHR, -R’, -OR®, or alkyl of 1 to 5 carbon atoms;

R® is hydrogen or lower alkyl;

R® is 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, the aryl amides (for example, an embodiment being N-benzoyl-3-amino-3-(3’,4’- dimethoxyphenyl)-propanamide) of U.S. patent nos. 5,801,195, 5,736,570, 6,046,221 and 6,284,780, each of which is incorporated herein by reference. Representative compounds are of formula:

Oo Ar

A wherein:

Ar is (i) straight, branched, or cyclic, unsubstituted alkyl of 1 to 12 carbon atoms; (ii) straight, branched, or cyclic, substituted alkyl of 1 to 12 carbon atoms; (iii) phenyl; (iv) phenyl substituted with one or more substituents cach selected independently of the other from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo; (v) heterocycle; or (vi) heterocycle substituted with one or more substituents each selected independently of the other from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to carbon atoms, or halo;

R is -H, alkyl of 1 to 10 carbon atoms, CH;OH, CH,CH;0H, or CH;COZ where Z is alkoxy of 1 to 10 carbon atoms, benzyloxy, or NHR' where R'is H or alkyl of 1 to 10 carbon atoms; and

Y is i) a phenyl or heterocyclic ring, unsubstituted or substituted one or more substituents each selected independently one from the other from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of | to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo or ii) naphthyl. Specific examples of the compounds are of formula:

Ror oR

Y—C—NH—CH—CH;-C—Z wherein:

Ar is 3,4-disubstituted phenyl where each substituent is selected independently of the other from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy,

carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, and halo;

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

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

Other specific selective cytokine inhibitory drugs include, but are not limited to, the imide/amide ethers and alcohols (for example, 3-phthalimido-3-(3’,4’-dimethoxyphenyl) propan-1 -ol) disclosed in U.S. patent no. 5,703,098, which is incorporated herein by reference. Representative compounds have the formula: i

RY SN—CH—(CHy)O—R?

RT RI wherein:

R! is (i) straight, branched, or cyclic, unsubstituted alkyl of 1 to 12 carbon atoms; (ii) straight, branched, or cyclic, substituted alkyl of 1 to 12 carbon atoms; (iii) phenyl; or (iv) phenyl substituted with one or more substituents each selected independently of the other from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, acylamino, alkylamino, di(alkyl) amino, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, bicycloalkyl of 5 to 12 carbon atoms, alkoxy of 1 to 10 carbon atoms, cycloalkoxy of 3 to 10 carbon atoms, bicycloalkoxy of 5 to 12 carbon atoms, and halo;

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

R? is (i) ethylene, (ii) vinylene, (iii) a branched alkylene of 3 to 10 carbon atoms, (iv) a branched alkenylene of 3 to 10 carbon atoms, (v) cycloalkylene of 4 to 9 carbon atoms unsubstituted or substituted with one or more substituents each selected independently from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, amino substituted with alkyl of 1 to 6 carbon atoms, amino substituted with acyl of 1 to 6 carbon atoms, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 12 carbon atoms, and halo, (vi) cycloalkenylene of 4 to 9 carbon atoms unsubstituted or substituted with one or more substituents each selected independently from the group consisting of nitro, cyano, triflucromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, amino substituted with alkyl of 1 to 6 carbon atoms, amino substituted with acyl of 1 to 6 carbon atoms, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 12 carbon atoms, and halo, (vii) o- phenylene unsubstituted or substituted with one or more substituents each selected independently from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, amino substituted with alkyl of 1 to 6 carbon atoms, amino substituted with acyl of 1 to 6 carbon atoms, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 12 carbon atoms, and halo, (viii) naphthyl, or (ix) pyridyl;

R*is -CX-, -CHa- or -CH,CX~;

XisOorS; and : nis0,1,2,0r3.

Other specific selective cytokine inhibitory drugs include, but are not limited to, the succinimides and maleimides (for example methyl 3-(3’,4,5°6’-petrahydrophthalimdo)-3- (3”,4”-dimethoxyphenyl)propionate) disclosed in U.S. patent no. 5,658,940, which is incorporated herein by reference. Representative compounds are of formula: roll yy (< 2h RO wherein:

R'is -CH;-, -CH,CO-, or -CO-;

R? and R? taken together are (i) ethylene unsubstituted or substituted with alkyl of 1- carbon atoms or phenyl, (ii) vinylene substituted with two substituents each selected, independently of the other, from the group consisting of alkyl of 1-10 carbon atoms and phenyl, or (iii) a divalent cycloalkyl of 5-10 carbon atoms, unsubstituted or substituted with one or more substituents each selected independently of the other from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl unsubstituted or substituted with alkyl of 1-3 carbon atoms, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, norbomnyl, phenyl or halo;

R* is (i) straight or branched unsubstituted alkyl of 4 to 8 carbon atoms, (ii) cycloalkyl or bicycloalkyl of 5-10 carbon atoms, unsubstituted or substituted with one or more substituents each selected independently of the other from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, branched, straight or cyclic alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, phenyl or halo, (iii) phenyl substituted with one or more substituents each selected independently of the other from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acctoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, cycloalkyl or bicyctoalkyl of 3 to 10 carbon atoms, cycloalkoxy or bicycloalkoxy of 3 to 10 carbon atoms, phenyl or halo, (iv) pyridine or pyrrolidine, unsubstituted or substituted with one or more substituents each selected independently of the other from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, phenyl or halo; and,

Ris -COX, -CN, -CH,COX, alkyl of 1 to 5 carbon atoms, aryl, -CH,OR, -CH; aryl, or -CH,OH, where X is NH,, OH, NHR, or ORS, where R is lower alkyl; and where R® is alkyl or benzyl.

Other specific selective cytokine inhibitory drugs include, but are not limited to, substituted imides (for example, 2-phthalimido-3-(3’,4’-dimethoxyphenyl) propane) disclosed in U.S. patent no. 6,429,221, which is incorporated herein by reference.

Representative compounds have the formula: 0

I

RY NGHR?

R R! wherein:

R! is (i) straight, branched, or cyclic alkyl of 1 to 12 carbon atoms, (ii) phenyl or phenyl substituted with one or more substituents each selected independently of the other from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, straight or branched alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo, (iii) benzyl or benzyl substituted with one or more substituents each selected independently of the other from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy,

carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo, or (iv) -Y-Ph where Y is a straight, branched, or cyclic alkyl of 1 to 12 carbon atoms and Ph is pheny! or phenyl substituted with one or more substituents each selected independently of the other from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo;

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

R>is i) ethylene, ii) vinylene, iii) a branched alkylene of 3 to 10 carbon atoms, 1v) a branched alkenylene of 3 to 10 carbon atoms, v) cycloalkylene of 4 to 9 carbon atoms unsubstituted or substituted with 1 to 2 substituents each selected independently from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halo, vi) cycloalkenylene of 4 to 9 carbon atoms unsubstituted or substituted with 1 to 2 substituents each selected independently from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halo, or vii) o-phenylene unsubstituted or substituted with 1 to 2 substituents each selected independently from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 4 carbon atoms, alkoxy 1 to 4 carbon atoms, or halo; and,

R%is -CX, or -CH;-;

XisOorS.

Other specific selective cytokine inhibitory drugs include, but are not limited to, substituted 1,3,4-oxadiazoles (for example, 2-[1-(3-cyclopentyloxy-4-methoxyphenyl)-2- (1,3,4-oxadiazole-2-yl)ethyl]-5-methylisoindoline-1,3-dione) disclosed in U.S. patent no. 6,326,388, which is incorporated herein by reference. Representative compounds are of formula:

RS

2

R'" o

RZ Nn

N~" og,

R¢

’ wherein: the carbon atom designated’ constitutes a center of chirality;

Y is C=0, CHz, SO; or CH.C=0;

X is hydrogen, or alkyl of 1 to 4 carbon atoms; each of R', R% R? and R*, independently of the others, 1s hydrogen, halo, trifluoromethyl, acetyl, alkyl of 1 to 8 carbon atoms, alkoxy of 1 to 4 carbon atoms, nitro, cyano, hydroxy, -CH;NR®R®, (CH2);NR®R’, or -NR*R’ or any two of R, R®, RS, and R*on adjacent carbon atoms, together with the depicted benzene ring are naphthylidene, quinoline, quinoxaline, benzimidazole, benzodioxole or 2- hydroxybenzimidazole; each of R® and R®, independently of the other, is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 6 carbon atoms, cyano, benzocycloalkoxy, cycloalkoxy of up to 18 carbon atoms, bicyloalkoxy of up to 18 carbon atoms, tricylcoalkoxy of up to 18 carbon atoms, or cycloalkylalkoxy of up to 18 carbon atoms; each of R®and R’, taken independently of the other is hydrogen, straight or branched alkyl of 1 to 8 carbon atoms, phenyl, benzyl, pyridyl, pyridylmethyl, or one of Rand R’ is hydrogen and the other is -COR'?, or -SO;R', or R* and R’ taken together are tetramethylene, pentamethylene, hexamethylene, -CH=NCH=CH-, or -CH,CH,X'CH,CH;,- in which X' is -O-, -S-, or -NH-

R'%is hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl, cycloalkylmethyl of up to 6 carbon atoms, phenyl, pyridyl, benzyl, imidazolylmethyl, pyridylmethyl, NR''R'2,

CH,RM“R'S, or NR''R 2 wherein R!* and R", independently of each other, are hydrogen, methyl, ethyl, or propyl, and wherein R'' and R'?, independently of each other, are hydrogen, alkyl of 1 to 8 carbon atoms, phenyl, or benzyl; and the acid addition salts of said compounds which contain a nitrogen atom susceptible of protonation.

Specific examples of the compounds are of formula:

R5

R' © ® nes 2h

R*

wherein: the carbon atom designated’ constitutes a center of chirality;

Y is C=0, CHa, SO; or CH2C=0;

X is hydrogen, or alkyl of 1 to 4 carbon atoms, (i) each of R', R%, R?, and R*, independently of the others, is hydrogen, halo, trifluoromethyl, acetyl, alkyl of 1 to 8 carbon atoms, alkoxy of 1 to 4 carbon atoms, mtro, cyano, hydroxy, -CH,NR®*R?, (CH2),NR*R’, or -NR®*R’or (ii) any two of R!, R?, R3, and R* on adjacent carbon atoms, together with the depicted benzene ring to which they are bound are naphthylidene, quinoline, quinoxaline, benzimidazole, benzodioxole or 2-hydroxybenzimidazole; each of R® and RS, independently of the other, is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 6 carbon atoms, cyano, benzocycloalkoxy, cycloalkoxy of up to 18 carbon atoms, bicyloalkoxy of up to 18 carbon atoms, tricylcoalkoxy of up to 18 carbon atoms, or cycloalkylalkoxy of up to 18 carbon atoms, (i) each of R® and R®, independently of the other, is hydrogen, alkyl of 1 to 8 carbon atoms, phenyl, benzyl, pyridyl, pyridylmethyl, or (ii) one of R® and R’ is hydrogen and the other is -COR'®, or -SO,R'Y, in which R'is hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl, cycloalkylmethyl of up to 6 carbon atoms, phenyl, pyridyl, benzyl, imidazolylmethyl, pyridylmethyl, NR''RY, or CH,NR™R", wherein R!'and R'?, independently of each other, are hydrogen, alkyl of 1 to 8 carbon atoms, phenyl, or benzyl and R'* and R", independently of each other, are hydrogen, methyl, ethyl, or propyl; or (iii) R® and R? taken together are tetramethylene, pentamethylene, hexamethylene, -CH=NCH=CH-, or -CH,CH,X'CH,CH,- in which X' is -O-, -S-, or -NH-.

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

R* RS “O45

ROH

R—X wherein:

(2) X is -O- or -(C,Hzp)- in which n has a value of , 1, 2, or 3, and R' is alkyl of one to 10 carbon atoms, monocycloalkyl of up to 10 carbon atoms, polycycloalkyl of up to 10 carbon atoms, or benzocyclic alkyl of up to 10 carbon atoms, or (b) X is -CH= and R! is alkylidene of up to 10 carbon atoms, monocycloalkylidene of up to 10 carbon atoms, or bicycloalkylidene of up to 10 carbon atoms;

R? is hydrogen, nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, lower alkyl, lower alkylidenemethyl, lower alkoxy, or halo;

R? is (i) phenyl, unsubstituted or substituted with 1 or more substituents each selected independently from nitro, cyano, halo, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, carbamoyl substituted with alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1 to 5 carbon atoms, 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, alkylidenemethy! of up to 10 carbon atoms, cycloalkylidenemethyl of up to 10 carbon atoms, phenyl, or methylenedioxy; (ii) pyridine, substituted pyridine, pyrrolidine, imidizole, naphthalene, or thiophene; (iii) cycloalkyl of 4-10 carbon atoms, unsubstituted or substituted with 1 or more substituents each selected independently from the group consisting of nitro, cyano, halo, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, phenyl; cach of R* and R® taken individually is hydrogen or R* and R? taken together are a carbon-carbon bond;

Y is -COZ, -C=N, or lower alkyl of 1 to 5 carbon atoms;

Z is -OH, -NR°R®, -R’, or -OR"; R® is hydrogen or lower alkyl; and R” alkyl or benzyl. Specific examples of the compounds are of formula:

R* RS “O55

R3

RX wherein: (a) X is -O- or -(CyHap)- in which n has a value of 0, 1, 2, or 3, and R' is alkyl of one to 10 carbon atoms, monocycloalkyl of up to 10 carbon atoms, polycycloalkyl of up to 10 carbon atoms, or benzocyclic alkyl of up to 10 carbon atoms, or

(b) X is -CH= and R! is alkylidene of up to 10 carbon atoms, monocycloalkylidene of up to 10 carbon atoms, or bicycloalkylidene of up to 10 carbon atoms;

R? is hydrogen, nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, lower alkyl, lower alkylidenemethyl, lower alkoxy, or halo;

R’ is pyrrolidine, imidazole or thiophene unsubstituted or substituted with 1 or more substituents each selected independently from the group consisting of nitro, cyano, halo, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to carbon atoms, or phenyl; each of R* and R? taken individually is hydrogen or R* and R’ taken together are a carbon-carbon bond;

Y is -COZ, -C =N, or lower alkyl of 1 to 5 carbon atoms;

Z is -OH, -NR°R®, -R’, or -OR’; R® is hydrogen or lower alkyl; and R’ alkyl or benzyl.

Particularly preferred nitriles are compounds of the formula: #H{Ogroesn

RS

RX

#HO)-gronom h3

Rx wherein: (a) X is -O- or (C,Han)- in which n has a value of 0, 1, 2, or 3, and R' is alkyl of up to 10 carbon atoms, monocycloalkyl of up to 10 carbon atoms, polycycloalkyl of up to 10 carbon atoms, or benzocyclic alkyl of up to 10 carbon atoms, or (b) X is -CH=, and R'is alkylidene of up to 10 carbon atoms or monocycloalkylidene of up to 10 carbon atoms;

R? is hydrogen, nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, lower alkyl, lower alkoxy, or halo; and

R? is (i) phenyl or naphthyl, unsubstituted or substituted with 1 or more substituents cach selected independently from nitro, cyano, halo, trifluoromethyl, carbethoxy,

carbomethoxy, carbopropoxy, acetyl, carbamoyl, or carbamoyl substituted with alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1 to 5 carbon atoms, alkoxy or cycloalkoxy of 1 to 10 carbon atoms; or (it) cycloalkyl of 4 to 10 carbon atoms, unsubstituted or substituted with one or more substituents each selected independently from the group consisting of nitro, cyano, halo, tnfluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, ) substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or phenyl.

Particularly preferred nitrile is of formula:

YZ. N

SaeE

So

Oo _O

Other specific selective cytokine inhibitory drugs include, but are not limited to, isoindoline-1-one and isoindoline-1,3-dione substituted in the 2-position with an a-(3,4- disubstituted phenyl)alkyl group and in the 4- and/or S-position with a nitrogen-containing group disclosed in WO 01/34606 and U.S. patent no. 6,667,316, which are incorporated herein by reference. Representative compounds are of formula:

Ri jo ( XL

N

Rs x (CH) Rs

Rs and include pharmaceutically acceptable salts and stereoisomers thereof, wherein: one of X and X’ is =C=0 or =S0;3, and the other of X and X’ is =C=0, =CH;, =80; or =CH,C=0, nisl, 2or3;

R, and R; are each independently (C,-Ca)alkyl, (C;-Cs)alkoxy, cyano, (C;-

Cig)eycloalkyl, (C3-Cig)cycloalkoxy or (Cs-Cig)cycloalkyl-methoxy;

R; is SO,-Y, COZ, CN or (Ci-Ce)hydroxyalkyl, wherein:

Y is (C;-Cg)alkyl, benzyl or phenyl;

Z is -NRgR5, (C,-Ce)alkyl, benzyl or phenyl,

Rg is H, (Ci-Ca)alkyl, (Cs-Cis)cycloalkyl, (C2-Cs)alkanoyl, benzyl or phenyl, each of which can be optionally substituted with halo, amino or (C1-Ce)alkyl-amino;

R7 is H or (C;-Ca)alkyl;

R. and Rs are taken together to provide -NH-CHa-Rs-, NH-CO-Rs-, or -N=CH-Rs-, wherein:

Rg is CH;, O, NH, CH=CH, CH=N, or N=CH,; or one of Rs and Rs is H, and the other of Rs and Rs is imidazoyl, pyrrolyl, oxadiazolyl, triazolyl, or a structure of formula (A),

Re

N—(CHg); —

RY

(A) , wherein: zisQor 1;

Rois: H; (Ci-Ca)alkyl, (C3-Cig)cycloalkyl, (C;-Cs)alkanoyl, or (Cs

Cg)cycloalkanoyl, optionally substituted with halo, amino, (C,-Cs)alkyl-amino, or (C;-

C,)dialkyl-amino; phenyl; benzyl; benzoyl; (C2-Cs)alkoxycarbonyl; (Cs-

Cs)alkoxyalkylcarbonyl; N-morpholinocarbonyl; carbamoyl; N-substituted carbamoyl substituted with (C,-Cs)alkyl; or methylsulfonyl; and

Ryo is H, (C1-Cs)alkyl, methylsulfonyl, or (C3-Cs)alkoxyalkylcarbonyl; or

Ry and R are taken together to provide -CH=CH-CH=CH-, -CH=CH-N=CH-, or (C,-Cy)alkylidene, optionally substituted with amino, (C,-Cs)alkyl-amino, or (C,-

Cg)dialkyl-amino; or

R4 and Rs are both structures of formula (A).

In one embodiment, z is not 0 when (i) R? is -SO;-Y, -COZ, or -CN and (ii) one of

RYorR%is hydrogen. In another embodiment, R® and RC taken together, is -CH=CH-

CH=CH-, -CH=CH-N=CH-, or (C,-C3)alkylidene substituted by amino, (C;-C4)alkyl- amino, or (C,-C4)dialkyl-amino. In another embodiment, R4 and Rs are both structures of formula (A).

Specific compounds are of formula:

Oo o— ow 0 baa le

N O

1 and the enantiomers thereof. ‘Further specific compounds are of formulas: 0—CHs 0) p ); o CHj

N\&y

NOZ S “CH,

NO ’ —CHj; 0 A 0 CHj

N—\ 0s J

HoN “CH

NH, © : 0O—CHj 7 )

NY

0 \

HaCll 'e) CH3

P20 co XK oO H3C , and

O—CHg 0) 0 “CHa

N 0)

Q

Ng 0 CHj

HCP ANF) :

SK

O CH;

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-methylsulfonylethyl] -3- pyrrolino[3,4-h]quinoline-1,3-dione; 2-[1-(3 -Ethoxy-4-methoxyphenyl)-2- methylsulfonylethyl)-3-pyrrolino(3,4-f] quinoxaline-1,3-dione; Cyclopropyl-N-{2-[1-(3- ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-1 ,3-d ioxoisoindolin-4-yi} carboxamide; 2-Chloro-N-{2-[1 -(3-ethoxy-4-methoxyphenyl)-2-methyl sulfonylethyl}-1,3- dioxoisoindolin-4-y!} acetamide; 2-Amino-N- {2-1 -(3-ethoxy-4-methox yphenyl )-2- methylsulfonylethyl]-1 ,3-dioxoisoindolin-4-yl} acetamide; 2-N,N-Dimethylamino-N-{2-[- } (3-ethoxy-4-methoxyphenyl)-2-methylsul fonylethyl }-1,3-dioxoisoindolin-4- yl} acetamide;

N-{2-[1 -(3-ethoxy-4-methoxyphenyl)-2-methylsul fonylethyl]-1,3-dioxoisoindolin-4-y1}- 2,2,2-trifluoroacetamide; N-{2-[1 -(3-Ethoxy-4-methoxyphenyl)-2-methylsulfon ylethyl]- 1,3-dioxoisoindolin-4-yl} methoxycarboxamide; 4-(1 -Aza-2-(dimethylamino)vinyl]-2-[1-(3- ethoxy-4-methox yphenyl)-2-methylsulfonylethyl}isoindoline-1 ,3-dione; 4-[1-Aza-2- (dimethylamino)prop-1-enyl]-2-[1 -(3-ethoxy-4-methoxyphenyl)-2- methylsulfonylethyllisoindoline-1,3-dione; 2-[1 -(3-Ethoxy-4-methoxyphenyl)-2- methylsulfonylethyl]-4-(5-methyl-1,3,4-oxadiazol-2 -yD)isoindoline-1,3-dione; 2-[1-(3-

Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl] -4-pyrrolylisoindoline-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 -cthoxy-4-methoxyphenyt)-3- hydroxybutyi]-1,3-dioxoisoindolin-4-yl} acetamide; N-{2-[1 R-(3-ethoxy-4- methoxyphenyl)-3-oxobutyl]-1,3-dioxoisoindolin-4-yl} acetamide; N-{2-[1 S-(3-Ethoxy-4- methoxyphenyl)-3-hydroxybutyl]-1,3-dioxoisoindolin-4-yl} acetamide; N-{2-[1S-(3-ethoxy- 4-methoxyphenyl)-3-oxobutyl]-1,3-dioxoisoindolin-4-yl} acetamide; 4-Amino-2-[1-(3- ethoxy-4-methox yphenyl)-3-hydroxybutylisoindoline-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-pyrrolylisoindoline-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; 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-cthoxy-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-y1} propanamide; N-{2-[(1R)-1 -(3-cthoxy-4-methoxyphenyl)-2- (methylsulfonyl)ethyl]-1 ,3-dioxoisoindolin-4-yl} -2-(dimethylamino)acetamide; N- {2-[(18)- 1 -(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1 ,3-dioxoisoindolin-4-yl}-2- (dimethylamino)acetamide; 4- {3-[(Dimethylamino)methyl]pyrrolyl} -2-[1-(3-ethoxy-4- methoxyphenyl)-2-(methylsulfonyl)ethyl]isoindoline-1 ,3-dione; Cyclopropyl-N-{2-[(1S)-1- (3-ethoxy-4-methoxyphenyl)-2-(methylsul fonyl)ethyl]-1,3-dioxoisoindolin-4- yl} carboxamide; 2-{1-(3 ,4-dimethoxypheny!)-2-(methylsul fonyl)ethyl]-4- pyrrolylisoindoline-1,3-dione; N-{2-[1 -(3,4-di methoxyphenyl)-2-(methylsuifonyl)ethyl]- 1,3-dioxoisoindolin-4-yl} -2-(dimethylamino)acetamide; Cyclopropyl-N- {2-[1-(3,4- dimethoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3 -dioxoisoindolin-4-yl} carboxamide,

Cyclopropyl-N-{2-[1-(3 -ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-3- oxoisoindolin-4-yl} carboxamide; 2-(Dimethylamino)-N-{2-[1 -(3-ethoxy-4- methoxyphenyl)-2-(methylsulfonyl)ethyl]-3-oxoisoindolin-4-yl acetamide; Cyclopropyl-N- {2-[(18)-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; (3R)-3-[7-(Acetylamino)-1- oxoisoindolin-2-yl]-3-(3-ethoxy-4-methoxypheny!)-N,N-dimethylpropanamide; (3R)-3-[7- (Cyclopropylcarbonylamino)-1-oxcisoindolin-2-y1]-3 -(3-ethoxy-4-methoxyphenyl)-N,N- dimethylpropanamide; 3-{4-[2-(Dimethylamino)acetylamino}-1,3 -dioxoisoindolin-2-y1}-3- (3-ethoxy-4-methoxyphenyl)-N,N-dimethylpropanamide; (3 R)-3-[7-(2-Chloroacetylamino)- 1-oxoisoindolin-2-yl]-3-(3-ethoxy-4-methoxy-phenyl)-N,N-dimethylpropanamide; (3R)-3- {4-[2-(dimethylamino)acetylamino]-1,3-dioxoisoindolin-2-yl}-3-(3 -ethoxy-4- methoxyphenyl)-N,N-dimethylpropanamide; 3-(1 ,3-Dioxo-4-pyrrolylisoindolin-2-y1)-3-(3- ethoxy-4-methoxypheny!)-N,N-dimethylpropanamide; 2-[1 -(3-Ethoxy-4-methoxyphenyl)- 2-(methylsulfonyl)ethyl]-4-(imidazolyl-methyl)isoindoline-1,3-dione; N-({2-[1 -(3-Ethoxy- 4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxoisoindolin-4-yl} methyl)acetamide; 2-

Chloro-N-({2-[1-(3-ethoxy-4-methoxyphenyi)-2-(methylsulfonyl)ethyl]-1,3- dioxoisoindolin-4-yl}methyl)acetamide; 2-(Dimethylamino)-N-( {2-[1-(3-ethoxy-4- methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxoisoindolin-4-yl} methyl)ac etamide; 4- [Bis(methylsulfonyl)amino]-2-[1-(3-ethoxy-4-methoxyphenyl)-2- (methylsulfonyl)ethyllisoindoline-1,3-dione; 2-[1-(3-Ethoxy-4-methoxyphenyl)-2- (methylsulfonyl)ethyl}-4-[(methylsulfonyl Jamino]isoindoline-1,3-dione; N-{2-[1-(3-

Ethoxy-4-methoxyphenyl)-3-hydroxypentyl}-1 3-dioxoisoindolin-4-yl} acetamide; N-{2-[1- (3-Ethoxy-4-methoxyphenyl)-3-oxopentyl]1 ,3-dioxoisoindolin-4-yl} acetamide; 2-[(1R)-1- (3-Ethoxy-4-methoxyphenyl)-3-hydroxybutyl]-4-(pyrrol ylmethyl)isoindoline-1 ,3-dione; 2- [(1R)-1-(3-Ethoxy-4-methoxyphenyl)-3 -oxobutyl]-4-(pyrrolylmethyl)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]isoindoline-1,3-dione; and pharmaceutically acceptable salts, solvates, and stereoisomers thereof.

Still other specific selective cytokine inhibitory drugs include, but are not limited to, imido and amido substituted acylhydroxamic acids (for example, (3-(1,3-dioxoisoindoline- 2-yD)-3-(3-ethoxy-4-methoxyphenyl) propanoylamino) propanoate disclosed in WO 01/45702 and U.S. patent no. 6,699,899, which are incorporated herein by reference.

Representative compounds are of formula:

R7

Fe”

RR o ¢'X

R? — 2-5

R10 RS °

RM N~ R1

R? I wherein: the carbon atom designated * constitutes a center of chirality,

R* is hydrogen or (C=0)-R" each of R! and R'?, independently of each other, is alkyl of 1 to 6 carbon atoms, phenyl, benzyl, pyridyl methyl, pyridyl, imidazoyl, imidazolyl methyl, or

CHR’ (CH,).NR'R’ wherein Rand R®, independently of the other, are hydrogen, alkyl of 1 to 6 carbon atorns, phenyl, benzyl, pyridyl methyl, pyridyl, imidazoyl or imidazolylmethyl, andn=0, 1, or 2;

R’ is C=0, CH,, CH,-CO-, or SO; each of R® and R’, independently of the other, is nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy,

Claims (54)

CLAIMS What is claimed is:

1. Use of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in the preparation of a medicament for treating, managing or preventing a myelodysplastic syndrome, wherein said selective cytokine inhibitory drug is of the formula: 0 ! RE N—GH—(CoHan)-C—R'2 R® 47 in which R’ is (i) o-phenylene, unsubstituted or substituted with 1 to 4 substituents each selected independently from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino, dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo, or (ii) the divalent residue of pyridine, pyrrolidine, imidizole, naphthalene, or thiophene, wherein the divalent bonds are on vicinal ring carbon atoms; R® is -CO -, or -SO,-; R’ is (i) hydrogen if R® is -SO;-, (ii) straight, branched, or cyclic alkyl of 1 to 12 carbon atoms, (iii) pyridyl, (iv) phenyl or phenyl substituted with one or more substituents each selected independently of the other from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo, (v) alkyl of 1 to 10 carbon atoms, (vi) benzyl unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo, (vii) naphthyl, (viii) benzyloxy, or (ix) imidazol-4-yl methyl; R'? is -OH, alkoxy of 1 to 12 carbon atoms, or 64 Amended Sheet: 1 February 2008

_R® “Noe n has a value of 0, 1, 2, or 3; R* is hydrogen or alkyl of 1 to 10 carbon atoms; and R% is hydrogen, alkyl of 1 to 10 carbon atoms, COR" or -SO, R'%in which R'is : hydrogen, alkyl of 1 to 10 carbon atoms, or phenyl.

2. Use of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in the preparation of a medicament for treating, managing or preventing a myelodysplastic syndrome, wherein said selective cytokine inhibitory drug is of the formula: i HoN—CH—(CpHgn)—C—R"2 7 in which R’ is (i) straight, branched, or cyclic alkyl of 1 to 12 carbon atoms, (ii) pyridyl, (ii1) phenyl or phenyl substituted with one or more substituents each selected independently of the other from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo, (iv) benzyl unsubstituted or substituted with one to three substituents selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halo, (v) napthyl, (vi) benzyloxy, or (vii) imidazol-4- ylmethyl; R'? is -OH, alkoxy of 1 to 12 carbon atoms, -O-CH,-pyridyl, -O-benzy! or R® “Nee where n has a value of 0, 1, 2, or 3; R? is hydrogen or alkyl of 1 to 10 carbon atoms; and R”" is hydrogen, alkyl of 1 to 10 carbon atoms, -CH,-pyridyl, benzyl, -COR'?, or -SO,R™® in which R'? is hydrogen, alkyl of 1 to 4 carbon atoms, or phenyl. 65 Amended Sheet: 1 February 2008

3. Use of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in the preparation of a medicament for treating, managing or preventing a myelodysplastic syndrome, wherein said selective cytokine inhibitory drug is of the formula:

R1 9 Or 2S NCH (Coan) —Y “RE wherein:

(1) one of R! and R? is R’-X- and the other is hydrogen, nitro, cyano, trifluoromethyl, carbo(lower)alkoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, lower alkyl, lower alkoxy, halo, or R*-X-;

R? is monocycloalkyl, bicycloalkyl, or benzocycloalkyl of up to 18 carbon atoms;

X is a carbon-carbon bond, -CH;-, or -O-;

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

R® is -CO-, or -CH,CO-;

Y is -COZ, -C=N, -OR¢, lower alkyl, or aryl;

Z is -NH, -OH, -NHR, -R’, or -OR’

R® is hydrogen or lower alkyl;

R® is lower alkyl or benzyl; and,

66 Amended Sheet: 1 February 2008 n has a value of 0, 1, 2, or 3,

(2) one of R! and R%is R*-X- and the other is hydrogen, nitro, cyano, trifluoromethyl, carbo(lower)alkoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, lower alkyl, lower alkoxy, halo, or R3-X-;

R? is monocycloalkyl of up to 10 carbon atoms, polycycloalkyl of up to 10 carbon atoms, or benzocyclic alkyl of up to 10 carbon atoms;

X 1s -CH;-, or -O-;

R® is (i) the vicinally divalent residue of pyridine, pyrrolidine, imidazole, naphthalene, or thiophene, wherein the two bonds of the divalent residue are on vicinal ring carbon atoms;

(ii) a vicinally divalent cycloalkyl of 4-10 carbon atoms, unsubstituted or substituted with 1 to 3 substituents each selected independently from the group consisting of nitro, cyano, halo, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or phenyl;

(ii1) di-substituted vinylene, substituted with nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, carbamoyl substituted with and alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1 to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halo;

(iv) ethylene, unsubstituted or substituted with 1 to 2 substituents each selected independently from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, carbamoyl substituted with and alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1 to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halo;

R°® is -CO-, -CHa-, or -CH,CO-;

Y is -COX, -C=N, -OR?, alkyl of 1 to 5 carbon atoms, or aryl;

X 1s -NH; -OH, -NHR, -R®, -OR’, or alkyl of 1 to 5 carbon atoms;

Ris hydrogen or lower alkyl;

R’ is alkyl or benzyl; and,

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

67 Amended Sheet: 1 February 2008

(3) one of R! and R?is R*-X- and the other is hydrogen, nitro, cyano, trifluoromethyl, carbo(lower)alkoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, lower alkyl, lower alkoxy, halo, HF,CO, F;CO, or R*-X-; R’ is monocycloalkyl, bicycloalkyl, benzocyclo alkyl of up to 18 carbon atoms, tetrahydropyran, or tetrahydrofuran; ) X is a carbon-carbon bond, -CH;-, -O-, or -N=; R’ is (i) o-phenylene, unsubstituted or substituted with 1 to 3 substituents each selected independently from nitro, cyano, halo, trifluoromethyl, carbo(lower)alkoxy, acetyl, or carbamoyl, unsubstituted or substituted with lower alkyl, acetoxy, carboxy, hydroxy, amino, lower alkylamino, lower acylamino, or lower alkoxy; (ii) a vicinally divalent residue of pyridine, pyrrolidine, imidazole, naphthalene, or thiophene, wherein the divalent bonds are on vicinal ring carbon atoms; (iil) a vicinally divalent cycloalkyl or cycloalkenyl of 4-10 carbon atoms, unsubstituted or substituted with 1 or more substituents each selected independently from the group consisting of nitro, cyano, halo, trifluoromethyl, carbo(lower)alkoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, lower alkylamino, lower alkyl, lower alkoxy, or phenyl; (iv) vinylene di-substituted with lower alkyl; or (v) ethylene, unsubstituted or monosubstituted or disubstituted with lower alkyl, R® is -CO-, -CHa-, or -CH,CO-; Y is -COX, -C= N, -OR?, alkyl of 1 to 5 carbon atoms, or aryl; X is -NH;, -OH, -NHR, -R’, -OR’, or alkyl of 1 to 5 carbon atoms; R® is hydrogen or lower alkyl; Ris alkyl or benzyl; and, n has a value of 0, 1, 2, or 3.

4. Use of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in the preparation of a medicament for treating, managing or preventing a myelodysplastic syndrome, wherein said selective cytokine inhibitory drug is of the formula: 68 Amended Sheet: 1 February 2008

0 I AL

RR. NT CH—(CH)rY R RY wherein: - Y is -C= N or CO(CH;)mCH3; mis 0, 1, 2, or 3; R® is (i) o-phenylene, unsubstituted or substituted with 1 to 3 substituents each selected independently from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, carbamoyl substituted with and alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1 to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halo; (ii) the divalent residue of pyridine, pyrrolidine, imidizole, naphthalene, or thiophene, wherein the divalent bonds are on vicinal ring carbon atoms; (iii) a divalent cycloalkyl of 4-10 carbon atoms, unsubstituted or substituted with one or more substituents each selected independently of the other from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, phenyl or halo; (iv) di-substituted vinylene, substituted with nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, carbamoyl substituted with an alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1 to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halo; or (v) ethylene, unsubstituted or substituted with 1 to 2 substituents each selected independently from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, carbamoyl substituted with an alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1 to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halo; R® is -CO-, -CH,-, -CH,CO-, or -SO,-; R’ is (i) straight or branched alkyl of 1 to 12 carbon atoms; (ii) cyclic or bicyclic alkyl of 1 to 12 carbon atoms; (iii) pyridyl; (iv) phenyl substituted with one or more substituents each selected independently of the other from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, straight, 69 Amended Sheet: 1 February 2008 branched, cyclic, or bicyclic alkyl of 1 to 10 carbon atoms, straight, branched, cyclic, or bicyclic alkoxy of 1 to 10 carbon atoms, CH,R where R is a cyclic or bicyclic alkyl of 1 to 10 carbon atoms, or halo; (v) benzyl substituted with one to three substituents each selected independently from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo; (vi) naphthyl; or (vii) benzyloxy; and n has a value of 0, 1, 2, or 3.

5. Use of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in the preparation of a medicament for treating, managing or preventing a myelodysplastic syndrome, wherein said selective cytokine inhibitory drug is of the formula: 0 £ RE ON—CH—(OH)rY RC g7 wherein: R’ is (i) the divalent residue of pyridine, pyrrolidine, imidizole, naphthalene, or thiophene, wherein the divalent bonds are on vicinal ring carbon atoms; (ii) a divalent cycloalkyl of 4-10 carbon atoms, unsubstituted or substituted with one or more substituents each selected independently of the other from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, phenyl or halo; (iii) di- substituted vinylene, substituted with nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy;, carbopropoxy, acetyl, carbamoyl, carbamoyl substituted with an alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1 to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halo; or (iv) ethylene, unsubstituted or substituted with 1 to 2 substituents each selected independently from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, carbamoyl substituted with an alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, amino 70 Amended Sheet: 1 February 2008 substituted with an alkyl of 1 to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halo; R® is -CO-, -CHa-, -CH,CO-, or -SO»-; R’ is (i) cyclic or bicyclic alkyl of 4 to 12 carbon atoms; (ii) pyridyl; (iii) phenyl substituted with one or more substituents each selected independently of the other from nitro, ) cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, straight, branched, cyclic, or bicyclic alkyl of 1 to 10 carbon atoms, straight, branched, cyclic, or bicyclic alkoxy of 1 to 10 carbon atoms, CH,R where R is a cyclic or bicyclic alkyl of 1 to 10 carbon atoms, or halo; (iv) benzyl substituted with one to three substituents each selected independently from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo; (v) naphthyl; or (vi) benzyloxy; and Y is COX, -C=N, OR®, alkyl of 1 to 5 carbon atoms, or aryl; X is -NH,, -OH, -NHR, -R®, -OR’, or alkyl of 1 to S carbon atoms; R® is hydrogen or lower alkyl; R® is alkyl or benzyl; and n has a value of 0, 1, 2, or 3.

6. Use of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in the preparation of a medicament for treating, managing or preventing a myelodysplastic syndrome, wherein said selective cytokine inhibitory drug is of the formula: oO Ar Ae H wherein: Ar is (i) straight, branched, or cyclic, unsubstituted alkyl of 1 to 12 carbon atoms; (i1) straight, branched, or cyclic, substituted alkyl of 1 to 12 carbon atoms; (iii) phenyl; (iv) phenyl substituted with one or more substituents each selected independently of the other from the group 71 Amended Sheet: 1 February 2008 consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo; (v) heterocycle; or (vi) heterocycle substituted with one or more substituents each selected independently of the other from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo; R is -H, alkyl of 1 to 10 carbon atoms, CH,OH, CH,CH,0OH, or CH,COZ where Z is alkoxy of 1 to 10 carbon atoms, benzyloxy, or NHR' where R'is H or alkyl of 1 to 10 carbon atoms; and Y is i) a phenyl or heterocyclic ring, unsubstituted or substituted one or more substituents each selected independently one from the other from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo or ii) naphthyl.

7. The use of claim 6, wherein said selective cytokine inhibitory drug is of the formula: rr 9% Y—C—NH—CH—CH,-C—Z wherein: Ar is 3,4-disubstituted phenyl where each substituent is selected independently of the other from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, and halo; Z is alkoxy of 1 to 10 carbon atoms, benzyloxy, amino, or alkylamino of 1 to 10 carbon atoms; and Y is (i) a phenyl, unsubstituted or substituted with one or more substituents each selected, independently one from the other, from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, and halo, or (ii) naphthyl. 72 Amended Sheet: 1 February 2008

8. Use of claim 6, wherein said selective cytokine inhibitory drug is N-benzoyl-3-amino- 3-(3’,4’-dimethoxyphenyl)-propanamide.

9. Use of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in the preparation of a medicament

. for treating, managing or preventing a myelodysplastic syndrome, wherein said selective cytokine inhibitory drug is of the formula: 0 1 RY N—GH—(CHolr0—R? R4 R! wherein: R'is (i) straight, branched, or cyclic, unsubstituted alkyl of 1 to 12 carbon atoms; (ii) straight, branched, or cyclic, substituted alkyl of 1 to 12 carbon atoms; (iii) phenyl; or (iv) phenyl substituted with one or more substituents each selected independently of the other from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, acylamino, alkylamino, di(alkyl) amino, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, bicycloalkyl of 5 to 12 carbon atoms, alkoxy of 1 to 10 carbon atoms, cycloalkoxy of 3 to 10 carbon atoms, bicycloalkoxy of 5 to 12 carbon atoms, and halo; R? is hydrogen, alkyl of 1 to 8 carbon atoms, benzyl, pyridylmethyl, or alkoxymethyl; R?is (i) ethylene, (ii) vinylene, (iii) a branched alkylene of 3 to 10 carbon atoms, (iv) a branched alkenylene of 3 to 10 carbon atoms, (v) cycloalkylene of 4 to 9 carbon atoms unsubstituted or substituted with one or more substituents each selected independently from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, amino substituted with alkyl of 1 to 6 carbon atoms, amino substituted with acyl of 1 to 6 carbon atoms, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 12 carbon atoms, and halo, (vi) cycloalkenylene of 4 to 9 carbon atoms unsubstituted or substituted with one or more substituents each selected independently from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, amino substituted with alkyl of 1 to 6 3 Amended Sheet: 1 February 2008 carbon atoms, amino substituted with acyl of 1 to 6 carbon atoms, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 12 carbon atoms, and halo, (vii) o-phenylene unsubstituted or substituted with one or more substituents each selected independently from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, amino substituted with alkyl of 1 to 6 carbon atoms, amino substituted with acyl ) of 1 to 6 carbon atoms, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 12 carbon atoms, and halo, (viii) naphthyl, or (ix) pyridyl; R* is -CX-, -CH,- or -CH,CX-; XisOorS; and nis 0, 1, 2, or 3.

10. Use of claim 9, wherein said selective cytokine inhibitory drug is 3-phthalimido-3- (3’,4’-dimethoxyphenyl)propan-1-ol).

11. Use of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in the preparation of a medicament for treating, managing or preventing a myelodysplastic syndrome, wherein said selective cytokine inhibitory drug is of the formula: 0 R4 rel n—< ho ht R® wherein: R' is -CH,-, -CH,CO-, or -CO-; R? and R* taken together are (i) ethylene unsubstituted or substituted with alkyl of 1-10 carbon atoms or phenyl, (ii) vinylene substituted with two substituents each selected, independently of the other, from the group consisting of alkyl of 1-10 carbon atoms and phenyl, or (iii) a divalent cycloalkyl of 5-10 carbon atoms, unsubstituted or substituted with one or more substituents each selected independently of the other from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl unsubstituted or 7 Amended Sheet: 1 February 2008 substituted with alkyl of 1-3 carbon atoms, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, norbornyl, phenyl or halo; R*is (i) straight or branched unsubstituted alkyl of 4 to 8 carbon atoms, (ii) cycloalkyl or bicycloalkyl of 5-10 carbon atoms, unsubstituted or substituted with one or more substituents each selected independently of the other from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, branched, straight or cyclic alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, phenyl or halo, (iii) phenyl substituted with one or more substituents each selected independently of the other from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, 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 carbon atoms, phenyl or halo, (iv) pyridine or pyrrolidine, unsubstituted or substituted with one or more substituents each selected independently of the other from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, phenyl or halo; and, R’is -COX, -CN, -CH,COX, alkyl of 1 to 5 carbon atoms, aryl, -CH,;OR, -CH; aryl, or - CH,OH, where X is NH,, OH, NHR, or OR’, where R is lower alkyl; and where RC is alkyl or benzyl.

12. The use of claim 11, wherein said selective cytokine inhibitory drug is methyl 3- (3’,4°,5°6’-petrahydrophthalimdo)-3-(3”,4”-dimethoxyphenyl)propionate).

13. Use of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in the preparation of a medicament for treating, managing or preventing a myelodysplastic syndrome, wherein said selective cytokine inhibitory drug is of the formula: 3 Amended Sheet: 1 February 2008

Oo I RY ON—GHR? RY R!

wherein:

R'is (i) straight, branched, or cyclic alkyl of 1 to 12 carbon atoms, (ii) phenyl or phenyl substituted with one or more substituents each selected independently of the other from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, straight or branched alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo, (iii) benzyl or benzyl substituted with one or more substituents each selected independently of the other from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo, or (iv) -Y-Ph where Y is a straight, branched, or cyclic alkyl of 1 to 12 carbon atoms and Ph is phenyl or phenyl substituted with one or more substituents each selected independently of the other from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo;

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

R?is i) ethylene, ii) vinylene, iii) a branched alkylene of 3 to 10 carbon atoms, iv) a branched alkenylene of 3 to 10 carbon atoms, v) cycloalkylene of 4 to 9 carbon atoms unsubstituted or substituted with 1 to 2 substituents each selected independently from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halo, vi) cycloalkenylene of 4 to 9 carbon atoms unsubstituted or substituted with 1 to 2 substituents each selected independently from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halo, or vii) o- phenylene unsubstituted or substituted with 1 to 2 substituents each selected independently from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl,

76 Amended Sheet: 1 February 2008 acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 4 carbon atoms, alkoxy 1 to 4 carbon atoms, or halo; and, R*is -CX, or -CHy-; XisOorS. E

14. The use of claim 13, wherein said selective cytokine inhibitory drug is 2-phthalimido- 3-(3’,4’-dimethoxyphenyl) propane).

15. Use of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in the preparation of a medicament for treating, managing or preventing a myelodysplastic syndrome, wherein said selective cytokine inhibitory drug is of the formula: RS RS R' go RZ NN N= R4 wherein: the carbon atom desi gnated” constitutes a center of chirality; Y is C=0, CH,, SO, or CH,C=0; X is hydrogen, or alkyl of 1 to 4 carbon atoms; each of R', R%, R?, and R*, independently of the others, is hydrogen, halo, trifluoromethyl, acetyl, alkyl of 1 to 8 carbon atoms, alkoxy of 1 to 4 carbon atoms, nitro, cyano, hydroxy, -CH,NR*R’, -(CH,),NR®R’, or -NR*R® or any two of R', R?, R?, and R* on adjacent carbon atoms, together with the depicted benzene ring are naphthylidene, quinoline, quinoxaline, benzimidazole, benzodioxole or 2- hydroxybenzimidazole; each of R® and R®, independently of the other, is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 6 carbon atoms, cyano, benzocycloalkoxy, cycloalkoxy of up to 18 carbon atoms, 7 Amended Sheet: 1 February 2008 bicyloalkoxy of up to 18 carbon atoms, tricylcoalkoxy of up to 18 carbon atoms, or cycloalkylalkoxy of up to 18 carbon atoms; each of R® and R’, taken independently of the other is hydrogen, straight or branched alkyl of 1 to 8 carbon atoms, phenyl, benzyl, pyridyl, pyridylmethyl, or one of R¥and Ris hydrogen and the other is -COR'? or -SO,R' or R®and R’ taken together are tetramethylene, ) pentamethylene, hexamethylene, -CH=NCH=CH-, or -CH,CH,X'CH,CHj>- in which X'is-O-, - S-, or -NH- R'%is hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl, cycloalkylmethyl of up to 6 carbon atoms, phenyl, pyridyl, benzyl, imidazolylmethyl, pyridylmethyl, NR''R", CH,R"R", or NR''R"2 wherein R" and R"°, independently of each other, are hydrogen, methyl, ethyl, or propyl, and wherein R'! and R'?, independently of each other, are hydrogen, alkyl of 1 to 8 carbon atoms, phenyl, or benzyl; and the acid addition salts of said compounds which contain a nitrogen atom susceptible of protonation.

16. The use of claim 15, wherein: the carbon atom designated constitutes a center of chirality; Y is C=0, CH;, SO, or CH,C=0; X is hydrogen, or alkyl of 1 to 4 carbon atoms; (1) each of R', R% R?, and RY, independently of the others, is hydrogen, halo, trifluoromethyl, acetyl, alkyl of 1 to 8 carbon atoms, alkoxy of 1 to 4 carbon atoms, nitro, cyano, hydroxy, -CH,NR®R®, -(CH,),NR®R®, or -NR*R’ or (ii) any two of R', R?, R®, and R* on adjacent carbon atoms, together with the depicted benzene ring to which they are bound are naphthylidene, quinoline, quinoxaline, benzimidazole, benzodioxole or 2-hydroxybenzimidazole; each of R® and R®, independently of the other, is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 6 carbon atoms, cyano, benzocycloalkoxy, cycloalkoxy of up to 18 carbon atoms, 78 Amended Sheet: 1 February 2008 bicyloalkoxy of up to 18 carbon atoms, tricylcoalkoxy of up to 18 carbon atoms, or cycloalkylalkoxy of up to 18 carbon atoms; (i) each of R® and R®, independently of the other, is hydrogen, alkyl of 1 to 8 carbon atoms, phenyl, benzyl, pyridyl, pyrnidylmethyl, or (ii) one of R®and R’ is hydrogen and the other is -COR'’, or -SO,R'°, in which R'is ) hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl, cycloalkylmethyl of up to 6 carbon atoms, phenyl, pyridyl, benzyl, imidazolylmethyl, pyridylmethyl, NR' 'R'?, or CH,NR"R"’, wherein R''and R", independently of each other, are hydrogen, alkyl of 1 to 8 carbon atoms, phenyl, or benzyl and R' and R'?, independently of each other, are hydrogen, methyl, ethyl, or propy1; or (iii) R® and R’ taken together are tetramethylene, pentamethylene, hexamethylene, -CH=NCH=CH-, or -CH,CH,X'CH,CH,- in which X' is -O-, -S-, or -NH-.

17. The use of claim 15, wherein said selective cytokine inhibitory drug is 2-[1-(3- cyclopentyloxy-4-methoxyphenyl)-2-(1,3,4-oxadiazole-2-yl)ethyl]-5-methylisoindoline-1,3- dione.

18. Use of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in the preparation of a medicament for treating, managing or preventing a myelodysplastic syndrome, wherein said selective cytokine inhibitory drug is of the formula: R4 RS “OG RX wherein: (a) X is -O- or -(C,Hjy,)- in which n has a value of 0, 1, 2, or 3, and R'is alkyl of one to carbon atoms, monocycloalkyl of up to 10 carbon atoms, polycycloalkyl of up to 10 carbon atoms, or benzocyclic alkyl of up to 10 carbon atoms, or (b) X is -CH= and R' is alkylidene of up to 10 carbon atoms, monocycloalkylidene of up to 10 carbon atoms, or bicycloalkylidene of up to 10 carbon atoms; 9 Amended Sheet: 1 February 2008

R? is hydrogen, nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, lower alkyl, lower alkylidenemethyl, lower alkoxy, or halo; R? is (i) phenyl, unsubstituted or substituted with 1 or more substituents each selected independently from nitro, cyano, halo, trifluoromethyl, carbethoxy, carbomethoxy, ) carbopropoxy, acetyl, carbamoyl, carbamoyl substituted with alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1 to 5 carbon atoms, 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, alkylidenemethyl of up to 10 carbon atoms, cycloalkylidenemethyl of up to 10 carbon atoms, phenyl, or methylenedioxy; (ii) pyridine, substituted pyridine, pyrrolidine, imidizole, naphthalene, or thiophene; (iii) cycloalkyl of 4-10 carbon atoms, unsubstituted or substituted with 1 or more substituents each selected independently from the group consisting of nitro, cyano, halo, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, phenyl; each of R* and R” taken individually is hydrogen or R* and R’ taken together are a carbon-carbon bond; Y is -COZ, -C=N, or lower alkyl of 1 to § carbon atoms; Z is -OH, -NR°R®, -R’, or -OR’; R® is hydrogen or lower alkyl; and R’ is alkyl or benzyl.

19. The use of claim 18, wherein: (a) X is -O- or -(CyHay)- in which n has a value of 0, 1, 2, or 3, and R' is alkyl of one to carbon atoms, monocycloalkyl of up to 10 carbon atoms, polycycloalkyl of up to 10 carbon atoms, or benzocyclic alkyl of up to 10 carbon atoms, or (b) X is -CH= and R' is alkylidene of up to 10 carbon atoms, monocycloalkylidene of up to 10 carbon atoms, or bicycloalkylidene of up to 10 carbon atoms; R? is hydrogen, nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, lower alkyl, lower alkylidenemethyl, lower alkoxy, or halo; R’ is pyrrolidine, imidazole or thiophene unsubstituted or substituted with 1 or more substituents each selected independently from the group consisting of nitro, cyano, halo, 80 Amended Sheet: 1 February 2008 trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or phenyl; each of R* and R’ taken individually is hydrogen or R* and R® taken together are a carbon-carbon bond; Y is -COZ, -C=N, or lower alkyl of 1 to 5 carbon atoms; Z is -OH, -NR®R®, -R’, or -OR’; R® is hydrogen or lower alkyl; and R’ is alkyl or benzyl.

20. The use of claim 18, wherein said selective cytokine inhibitory drug is of the formula: #H{O)gromom 3 RX #H{O)-grovee=n id RX wherein: (a) X is -O- or -(C,Hzp)- in which n has a value of 0, 1, 2, or 3, and R' is alkyl of up to 10 carbon atoms, monocycloalkyl of up to 10 carbon atoms, polycycloalkyl of up to 10 carbon atoms, or benzocyclic alkyl of up to 10 carbon atoms, or (b) X is -CH=, and R'is alkylidene of up to 10 carbon atoms or monocycloalkylidene of up to 10 carbon atoms; R’ is hydrogen, nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, lower alkyl, lower alkoxy, or halo; and R’ is (i) phenyl or naphthyl, unsubstituted or substituted with 1 or more substituents each selected independently from nitro, cyano, halo, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, or carbamoyl substituted with alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1 to 5 carbon atoms, alkoxy or cycloalkoxy of 1 to 10 carbon atoms; or (ii) cycloalkyl of 4 to 10 carbon atoms, unsubstituted or substituted with one or more substituents each selected independently from the group consisting of nitro, cyano, halo, trifluoromethyl, carbethoxy, carbomethoxy, 81 Amended Sheet: 1 February 2008 carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or phenyl.

21. The use of claim 18, wherein said selective cytokine inhibitory drug is of the formula: ~N dd SASH No ONG _O

22. The use of claim 18, wherein said selective cytokine inhibitory drug is 3,3-bis-(3,4- dimethoxyphenyl) acrylonitrile.

23. Use of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in the preparation of a medicament for treating, managing or preventing a myelodysplastic syndrome, wherein said selective cytokine inhibitory drug is of the formula: rR’ a Ro ('X Rr? — N— Oo RS R R11 NR 4 R oO wherein: the carbon atom designated * constitutes a center of chirality, R* is hydrogen or -(C=0)-R", each of R' and R'?, independently of each other, is alkyl of 1 to 6 carbon atoms, phenyl, benzyl, pyridyl methyl, pyridyl, imidazoyl, imidazolyl methyl, or CHR"(CH,),NR'R’, 82 Amended Sheet: 1 February 2008 wherein Rand RO independently of the other, are hydrogen, alkyl of 1 to 6 carbon atoms, phenyl, benzyl, pyridyl methyl, pyridyl, imidazoyl or imidazolylmethyl, and n = 0, 1, or 2; R’ is C=0, CH,, CH,-CO-, or SO; each of R® and R, independently of the other, is nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, cycloalkoxy of 3 to 8 carbon atoms, halo, bicycloalkyl of up to 18 carbon atoms, tricycloalkoxy of up to 18 carbon atoms, 1- indanyloxy, 2-indanyloxy, Cs-Cs-cycloalkylidenemethyl, or C;-C,¢-alkylidenemethyl; each of R®, R’, R' and RR", independently of the others, is (1) hydrogen, nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino, dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, halo, or (ii) one of R®, R%, R'®, and R'! is acylamino comprising a lower alkyl, and the remaining of R®, R%, R! and R!! are hydrogen, or (iii) hydrogen if R® and R’ taken together are benzo, quinoline, quinoxaline, benzimidazole, benzodioxole, 2-hydroxybenzimidazole, methylenedioxy, dialkoxy, or dialkyl, or (iv) hydrogen if R'® and R'!, taken together are benzo, quinoline, quinoxaline, benzimidazole, benzodioxole, 2-hydroxybenzimidazole, methylenedioxy, dialkoxy, or dialkyl, or (v) hydrogen if R® and R'° taken together are benzo.

24. The use of claim 23, wherein said selective cytokine inhibitory drug is (3-(1,3- dioxoisoindoline-2-yl)-3-(3-ethoxy-4-methoxyphenyl) propanoylamino) propanoate.

25. Use of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in the preparation of a medicament for treating, managing or preventing a myelodysplastic syndrome, wherein said selective cytokine inhibitory drug is of formula: 83 Amended Sheet: 1 February 2008

R1 X Ry4 Rs wherein: R, is -CN, lower alkyl, -COOH, -C(O)-N(Ry),, -C(O)-lower alkyl, -C(O)-benzyl, - C(0O)O-lower alkyl, -C(O)O-benzyl; Ry is -H, -NO,, cyano, substituted or unsubstituted lower alkyl, substituted or unsubstituted alkoxy, halogen, -OH, -C(O)(R)2, -COOH, -NH,, -OC(O)-N(R10)2; Rs is substituted or unsubstituted lower alkyl, substituted or unsubstituted alkoxy, or substituted or unsubstituted alkenyl; X is substituted or unsubstituted phenyl, substituted or unsubstituted pyridine, substituted or unsubstituted pyrrolidine, substituted or unsubstituted imidizole, substituted or unsubstituted naphthalene, substituted or unsubstituted thiophene, or substituted or unsubstituted cycloalkyl; each occurrence of Ry is independently -H or substituted or unsubstituted lower alkyl; and each occurrence of Ry is independently -H or substituted or unsubstituted lower alkyl.

26. Use of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in the preparation of a medicament for treating, managing or preventing a myelodysplastic syndrome, wherein said selective cytokine inhibitory drug is of formula: Ri _R2 Ra, Rc poo a Rs Re wherein: 84 Amended Sheet: 1 February 2008

R, and R; are independently -H, -CN, substituted or unsubstituted lower alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -COOH, -C(O)-lower alkyl, - C(0)O-lower alkyl, -C(0)-N(Ry),, substituted or unsubstituted aryl, or substituted or unsubstituted heterocycle;

each occurrence of R,, Ry, R; and Ry is independently -H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, - NO», -OH, -OPO(OH),, -N(Ry)2, -OC(0O)-R¢, -OC(0)-R0-N(R 0), -C(O)N(R 0), -NHC(O)- Rio, -NHS(O),-Ri0, -S(0)2-Ry9, -NHC(O)NH-R 0, -NHC(O)N(R0)2, -NHC(O)NHSO;- Ryo, -NHC(O)-R0-N(R0)2, -NHC(O)CH(R 0)(N(Rg),) or -NHC(O)-Ro-NH,;

Rj is -H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, -NO,, -OH, -OPO(OH),, -N(Ry)a, -OC(0)-R 4, -OC(0)- Ri0-N(Ry0)2, -C(O)N(R19)2, -NHC(O)-R 9, -NHS(O),-R 1g, -S(O)2-R 10, -NHC(O)NH-

Ryo, -NHC(O)N(R10)2, -NHC(O)NHSO2-R10, -NHC(0)-R10-N(R0)2, -NHC(O)CH(R0)(N(Ro)) or -NHC(O)-R0o-NH,, or R; with either R, or with Ry, together form -O-C(R¢R7)-O- or -O- (CR16R17))2-O-;

Ry is -H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, -NO,, -OH, -OPO(OH),, -N(Ry),, -OC(0)-R gy, -OC(O)- Ri0-N(R0)2, -C(O)N(R1p)2, -NHC(O)-R 09, -NHS(O),2-R 0, -S(0)2-R,9, -NHC(O)NH-

Rio, -NHC(O)N(R0)2, -NHC(O)NHSO,-R}9, -NHC(O)-R0-N(R0)2, -NHC(O)CH(R0)(N(Ry),) or -NHC(O)-R;¢-NHj;

Rs is -H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, -NO,, -OH, -OPO(OH),, -N(Ry),, -OC(0)-R 4, -OC(0O)- Ri0-N(R0)2, -C(O)N(R10)2, -NHC(O)-R 0, -NHS(O),-R 1, -S(0)2-Ry0, -NHC(O)NH-

Rig, -NHC(O)N(R 0)2, -NHC(O)NHSO,-R1, -NHC(O)-Ri10-N(R10)2, -NHC(O)CH(R10)(N(Ro),) or -NHC(O)-Rjo-NHz; 85 Amended Sheet: 1 February 2008

Rg is -H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, -NO3, -OH, -OPO(OH);, -N(Ry)3, -OC(O)-R 1, -OC(O)- R10-N(Rj0)2, -C(O)N(R10)2, -NHC(O)-R 0, -NHS(O),-R 10, -S(0)2-R10, -NHC(O)NH- Ryo, -NHC(O)N(R0)2, -NHC(O)NHSO;-R}g, -NHC(O)-R6-N(R0)2, -NHC(O)CH(R 0)(N(Ry)2) : or -NHC(O)-R o-NHy; Ry is -H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, -NO,, -OH, -OPO(OH),, -N(Ro),, -OC(0)-R 9, -OC(O)- Ri0-N(R0)2, -C(O)N(R10)2, -NHC(O)-R 0, -NHS(O)2-R1¢, -S(O)2-R}0, -NHC(O)NH- Rio, -NHC(O)N(R0)2, -NHC(O)NHSO;-Ryo, -NHC(O)-R10-N(Rj0)2, -NHC(O)CH(R 0)(N(Ro)2) or -NHC(O)-R;¢-NH;; Rg is -H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, -NO;, -OH, -OPO(OH),, -N(Ry),, -OC(0)-R¢, -OC(O)- Ri0-N(Ri0)2, -C(O)N(R10)2, -NHC(O)-R 10, -NHS(O),-R10, -S(0)2-R}9, -NHC(O)NH- Rio, -NHC(O)N(R0)2, -NHC(O)NHSO,-R 0, -NHC(O)-R9-N(R¢)2, -NHC(O)CH(R0)(N(Ro),) or -NHC(O)-R;o-NHa, or Rg with either R; or with Ry, together form -O-C(R;¢R;7)-O- or -O- (C(R16R17))2-0-; each occurrence of Ry is independently -H, substituted or unsubstituted lower alkyl, or substituted or unsubstituted cycloalkyl; each occurrence of Rj is independently substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted lower hydroxyalkyl, or Rio and a nitrogen to which it is attached form a substituted or unsubstituted heterocycle, or R)¢ is -H where appropriate; and each occurrence of Rj¢ and R;7 is independently -H or halogen.

27. Use of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in the preparation of a medicament for treating, managing or preventing a myelodysplastic syndrome, wherein said selective 86 Amended Sheet: 1 February 2008 cytokine inhibitory drug is selected from the group consisted of 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 lhydro-3-pyrrolino[3,4 -e]benzimidazole-2,6,8- i trione; 2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-3-pyrrolino[3,4-f]quinoxaline-

1,3-dione; Cyclopropyl-N-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-1,3-d ioxoisoindolin-4-yl} carboxamide; 2-Chloro-N-{2-[1-(3-ethoxy-4-methoxyphenyl)-2- methylsulfonylethyl]-1,3-dioxoisoindolin-4-yl} acetamide; 2-Amino-N-{2-[1-(3-ethoxy-4- methoxyphenyl)-2-methylsulfonylethyl]-1,3-dioxoisoindolin-4-yl} acetamide; 2-N,N- Dimethylamino-N- {2-[-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl ]-1,3- dioxoisoindolin-4-yl} acetamide; N-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]- 1,3-dioxoisoindolin-4-yl}-2,2,2-trifluoroacetamide; N-{2-[1-(3-Ethoxy-4-methoxyphenyl)-2- methylsulfonylethyl]-1,3-dioxoisoindolin-4-yl } methoxycarboxamide; 4-[1-Aza-2- (dimethylamino)vinyl]-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylJisoindoline-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-pyrrolylisoindoline-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-hydroxybutylisoindoline-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-pyrrolylisoindoline-1,3-dione; 2-Chloro-N- {2-[1-(3-ethoxy-4-methoxyphenyl)-3-

87 Amended Sheet: 1 February 2008 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; 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)-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-pyrrolylisoindoline-1,3-dione; N-{2-[1-(3,4- dimethoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxoisoindolin-4-yl}-2- (dimethylamino)acetamide; Cyclopropyl-N-{2-[1-(3,4-dimethoxyphenyl)-2- (methylsulfonyl)ethyl]-1,3-dioxoisoindolin-4-yl } carboxamide; Cyclopropyl-N-{2-[1-(3-ethoxy- 4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-3-oxoisoindolin-4-yl} carboxamide; 2- (Dimethylamino)-N-{2-{1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-3- oxoisoindolin-4-yl} acetamide; Cyclopropyl-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2- (methylsulfonyl)ethyl]-3-oxoisoindolin-4-yl} carboxamide; Cyclopropyl-N-{2-[(1R)-1-(3- ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-3-oxoisoindolin-4-yl } carboxamide; (3R)-3- [7-(Acetylamino)-1-oxoisoindolin-2-yl]-3-(3-ethoxy-4-methox yphenyl)-N,N- dimethylpropanamide; (3R)-3-[7-(Cyclopropylcarbonylamino)-1-oxoisoindolin-2-yl]-3-(3- ethoxy-4-methoxyphenyl)-N,N-dimethylpropanamide; 3-{4-[2-(Dimethylamino)acetylamino]- 1,3-dioxoisoindolin-2-yl }-3-(3-ethoxy-4-methoxyphenyl)-N,N-dimethylpropanamide; (3R)-3-[7- (2-Chloroacetylamino)-1-oxoisoindolin-2-yl]-3-(3-ethoxy-4-methoxy-phenyl)-N,N-

88 Amended Sheet: 1 February 2008 dimethylpropanamide; (3R)-3-{4-[2-(dimethylamino)acetylamino]-1,3-dioxoisoindolin-2-yl}-3- (3-ethoxy-4-methoxyphenyl)-N,N-dimethylpropanamide; 3-(1,3-Dioxo-4-pyrrolylisoindolin-2- yl)-3-(3-ethoxy-4-methoxyphenyl)-N,N-dimethylpropanamide; 2-[1-(3-Ethoxy-4- methoxyphenyl)-2-(methylsulfonyl)ethyl]-4-(imidazolyl-methyl)isoindoline-1,3-dione; N-({2-[1- (3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxoisoindolin-4- ) yl} methyl)acetamide; 2-Chloro-N-({2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]- 1,3-dioxoisoindolin-4-yl} methyl)acetamide; 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; 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- mcthoxyphenyl)-3-hydroxybutyl]-4-(pyrrolylmethyl)isoindoline-1,3-dione; 2-[(1R)-1-(3-Ethoxy- 4-methoxyphenyl)-3-oxobutyl]-4-(pyrrolylmethyl)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]isoindoline-1,3-dione; and pharmaceutically acceptable salts, solvates, and stereoisomers thereof.

28. The use of any one of claims 1-27, wherein said medicament further comprises a therapeutically or prophylactically effective amount of at least one second active agent.

29. The use of claim 28, wherein the second active ingredient is capable of improving blood cell production.

30. The use of claim 28, wherein the second active ingredient is a cytokine, hematopoietic growth factor, anti-cancer agent, antibiotic, proteasome inhibitor, or Immunosuppressive agent. 89 Amended Sheet: 1 February 2008

31. The use of claim 28, wherein the second active ingredient is etanercept, imatinib,anti- TNF-a antibodies, infliximab, G-CSF, GM-CSF, EPO, topotecan, pentoxifylline, ciprofloxacin, irinotecan, vinblastine, dexamethasone, 1L.2, IL8,IL18, Ara- C, vinorelbine, isotretinoin, 13-cis- retinoic acid, or a pharmacologically active mutant or derivative thereof.

32. The use of any one of claims 1-27, wherein the myelodysplastic syndrome is refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, or chronic myelomonocytic leukemia.

33. The use of any one of claims 1-27, wherein the myelodysplastic syndrome is primary or secondary.

34. The use of any one of claims 1-27, wherein the stereoisomer of the selective cytokine inhibitory drug is an enantiomer.

35. The use of any one of claims 1-27, wherein said medicament is in a form suitable for administration before, during or after transplanting umbilical cord blood, placental blood, peripheral blood stem cell, hematopoietic stem cell preparation or bone marrow into the patient.

36. Use of a selective cytokine inhibitory drug mentioned in any one of claims 1-27, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof and a second active ingredient in the preparation of one or more medicaments for reducing or avoiding an adverse effect as associated with the administration of the second active ingredient in a patient suffering from a myelodysplastic syndrome, wherein the patient in need of such reduction or avoidance is administrated an amount of the second active ingredient and said selective cytokine inhibitory drug.

37. The use of claim 36, wherein the second active ingredient is capable of improving 90 Amended Sheet: 1 February 2008 blood cell production.

38. The use of claim 36, wherein the second active ingredient is a cytokine, hematopoietic growth factor, anti-cancer agent, antibiotic, proteasome inhibitor, or immunosuppressive agent.

39. The use of claim 36, wherein the second active ingredient is etanercept, imatinib, anti-TNF-a antibodies, 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 mutant or derivative thereof, or a combination thereof.

40. A pharmaceutical composition comprising the selective cytokine inhibitory drug mentioned in any one of claims 1-27, 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.

41. A pharmaceutical composition comprising the selective cytokine inhibitory drug mentioned in any one of claims 1-27, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and a second active ingredient.

42. The pharmaceutical composition of claim 41, wherein the second active ingredient is capable of improving blood cell production.

43. The pharmaceutical composition of claim 41, wherein the second active ingredient is a cytokine, hematopoietic growth factor, anti-cancer agent, antibiotic, proteasome inhibitor, or immunosuppressive agent.

44. The pharmaceutical composition of claim 41, wherein the second active ingredient is etanercept, imatinib, anti-TNF-a antibodies, infliximab, G-CSF, GM-CSF, EPO, topotecan, 91 Amended Sheet: 1 February 2008 pentoxifylline, ciprofloxacin, irinotecan, vinblastine, dexamethasone, 1L2, IL8, IL18, Ara-C, vinorelbine, isotretinoin, 13-cis-retinoic acid, or a pharmacologically active mutant or derivative thereof, or a combination thereof.

45. A single unit dosage form comprising the selective cytokine inhibitory drug ] mentioned in any one of claims 1-27, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and a second active ingredient capable of improving blood cell production.

46. A single unit dosage form comprising the selective cytokine inhibitory drug mentioned in any one of claims 1-27, 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, proteasome inhibitor, or immunosuppressive agent.

47. A single unit dosage form comprising the selective cytokine inhibitory drug mentioned in any one of claims 1-27, 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, anti-TNF-a antibodies, 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 mutant or derivative thereof, and a combination thereof.

48. The single unit dosage form of claim 45, wherein the dosage form is suitable for intravenous or subcutaneous administration to a patient.

49. The single unit dosage form of claim 46, wherein the dosage form is suitable for intravenous or subcutaneous administration to a patient. 92 Amended Sheet: 1 February 2008

50. The single unit dosage form of claim 47, wherein the dosage form is suitable for intravenous or subcutaneous administration to a patient.

51. A kit comprising: a pharmaceutical composition comprising a selective cytokine inhibitory drug mentioned in any one of claims 1-27, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof; and a pharmaceutical composition comprising a second active ingredient capable of improving blood cell production.

52. A kit comprising: a pharmaceutical composition comprising a selective cytokine inhibitory drug mentioned in any one of claims 1-27, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof; and umbilical cord blood, placental blood, peripheral blood stem cell, hematopoietic stem cell preparation or bone marrow.

53. The kit of claim 51 which further comprises a device for the administration of the pharmaceutical composition or the single unit dosage form.

54. The kit of claim 52 which further comprises a device for the administration of the pharmaceutical composition or the single unit dosage form. 93 Amended Sheet: 1 February 2008